(ERS Monograph) Fransesco Bonella, Daniel Culver, Dominique Israel - Biet - Sarcoidosis ERS Monograph-European Respiratory Society (2022)

ERS monograph
Sarcoidosis
ERS monograph
Recent reports indicate that the prevalence of sarcoidosis is rising

and mortality
Cyan 0 in chronic sarcoidosis
Pantone 200 CMJN (darker)
Magenta 100
patientsPantone
Pantone 647 CMJN
Cyan 100
Magenta 56
Cyan
Magenta 0
PASTEL 9081 CMJN
is 0increasing. With
Pantone 200 CMJN (darker)
Cyan 0
Magenta 100
Pantone 647 CMJN
Cyan 100
Magenta 56
Pantone PASTEL 9081 CMJN
Cyan 0
Magenta 0
Sarcoidosis
myriad clinical
Yellow 70 manifestations, Yellow and
0 multi-system
Yellow 6 involvement, Yellow 70
Black 14
Yellow 0
Black 24
Yellow 6
Black 8
Black 14 Black 24 Black 8
there is a need for all clinicians to have a working knowledge of the
condition. This Monograph provides a comprehensive overview of Edited by Francesco Bonella,
the most recent advances in sarcoidosis. Opening with chapters
on history, epidemiology and pathobiology, it goes on to provide Daniel A. Culver and
in-depth coverage of: specific organ manifestations and general
diagnostic pathways; traditional as well as innovative treatment Dominique Israël-Biet
strategies; and, importantly, patient quality-of-life assessment.
This book will be useful to clinicians around the world.
ERS monograph 96
ISBN 978-1-84984-145-0
Print ISSN: 2312-508X
Online ISSN: 2312-5098
Print ISBN: 978-1-84984-145-0
Online ISBN: 978-1-84984-146-7
March 2022
€60.00
9 781849 841450
Sarcoidosis
Edited by
Francesco Bonella, Daniel A. Culver
and Dominique Israël-Biet
Editor in Chief
John R. Hurst
This book is one in a series of ERS Monographs. Each individual issue

provides a comprehensive overview of one specific clinical area of
respiratory health, communicating information about the most advanced
techniques and systems required for its investigation. It provides factual and
useful scientific detail, drawing on specific case studies and looking into
the diagnosis and management of individual patients. Previously published
titles in this series are listed at the back of this Monograph.
ERS Monographs are available online at books.ersjournals.com and print

copies are available from www.ersbookshop.com
Editorial Board: Mohammed AlAhmari (Dammam, Saudi Arabia), Sinthia Bosnic-Anticevich (Sydney, Australia),
Sonye Danoff (Baltimore, MD, USA), Randeep Guleria (New Delhi, India), Bruce Kirenga (Kampala, Uganda),
Silke Meiners (Munich, Germany) and Sheila Ramjug (Manchester, UK).
Managing Editor: Rachel Gozzard

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Published by European Respiratory Society ©2022

March 2022
Print ISBN: 978-1-84984-145-0
Online ISBN: 978-1-84984-146-7
Print ISSN: 2312-508X
Online ISSN: 2312-5098
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Printed by Page Bros Group Ltd, Norwich, UK

All material is copyright to European Respiratory Society. It may not be reproduced in any way including
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Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory
Society, editors or publishers.
ERS monograph
Contents
Sarcoidosis Number 96
March 2022
Preface v
Guest Editors vii
Introduction x

List of abbreviations xiv
1. Definition and history 1

Ulrich Costabel and Sonoko Nagai
2. Epidemiology: solving the jigsaw puzzle 8

Yvette C. Cozier, Elizabeth V. Arkema, Juan V. Rodriguez, Jeffrey S. Berman
and Praveen Govender
3. Aetiopathogenesis, molecular determinants and immunological features 25

Paolo Spagnolo and Johan Grunewald
4. Unravelling the genetic basis of sarcoidosis 41

Coline H.M. van Moorsel, Martin Petrek and Natalia V. Rivera
5. Principles of diagnosis 57
Rocco Trisolini, Paolo Spagnolo and Robert P. Baughman
6. Conventional and nuclear imaging techniques 75

Rémy L.M. Mostard and Ruchi Yadav
7. Pathological features and differential diagnosis 91

Giulio Rossi and Carol Farver
8. Serum and imaging biomarkers 107

Ingrid H.E. Korenromp, Lisa A. Maier and Jan C. Grutters
9. Pulmonary sarcoidosis 122

W. Ennis James and Francesco Bonella
10. Cardiac sarcoidosis 142

David H. Birnie and Vasileios Kouranos
11. Granulomatous and nongranulomatous neurological sarcoidosis 160

Jinny Tavee and Mareye Voortman
12. Cutaneous sarcoidosis 174
Christina Murphy, Joaquim Marcoval, Juan Mañá and Misha Rosenbach
13. The calcium–kidney–bone axis 193

Robert P. Baughman and Elyse E. Lower
14. Non-organ-specific manifestations 206

Vivienne Kahlmann, Divya C. Patel, Lucian T. Marts and Marlies S. Wijsenbeek
15. Hepatic and splenic involvement 223

Florence Jeny and Nabeel Hamzeh
16. Sarcoidosis-associated pulmonary hypertension 234

Vikramjit Khangoora, Hilario Nunes and Oksana A. Shlobin
17. Rheumatological manifestations 256

Peter Korsten and Nadera J. Sweiss
18. Ocular sarcoidosis 267

Stéphane Giorgiutti, Yasmine Serrar, Thomas El-Jammal, Laurent Kodjikian
and Pascal Sève
19. Paediatric sarcoidosis 285

Nadia Nathan and Alice Hadchouel
20. The manifestations of rare organ sarcoidosis 295

Marc A. Judson, Jean Pastre and Dominique Israël-Biet
21. When to treat sarcoidosis 316

Daniel A. Culver and Athol U. Wells
22. Treating sarcoidosis and potential new drugs 328

Canay Caliskan and Antje Prasse
23. Quality-of-life assessment 337

Timothy Tully, Marc A. Judson, Amit Suresh Patel and Surinder S. Birring
Preface
John R. Hurst
It’s a pleasure to introduce this latest edition of the ERS

Monograph, which addresses that most enigmatic of conditions:
sarcoidosis. With myriad clinical manifestations, and multi-system
involvement, there is a need for all clinicians – generalists and
specialists alike – to have a working knowledge of the condition.
This collection goes beyond a simple working knowledge,
however, and I’d like to thank Guest Editors Francesco Bonella,
Dominique Israël-Biet and Daniel A. Culver for commissioning
and collating a comprehensive and excellent collection of
state-of-the-art reviews, which provide a critical update on all
aspects of sarcoidosis. The field is moving rapidly with new
developments in both basic science and clinical practice, and
therefore the collection is timely. I would also like to recognise the
work of the individual chapter authors and reviewers for delivering
this collection at a difficult time and, as always, the Monograph
would not be possible without the dedicated support of the
excellent ERS Publications Office. I learnt a lot about sarcoidosis
reading these reviews, and I recommend them to you too.
Disclosures: J.R. Hurst reports receiving grants, personal fees and non-financial
support from pharmaceutical companies that make medicines to treat
respiratory disease. This includes reimbursement for educational activities and
advisory work, and support to attend meetings.
Copyright ©ERS 2022. Print ISBN: 978-1-84984-145-0. Online ISBN: 978-1-84984-146-7. Print ISSN: 2312-508X. Online
ISSN: 2312-5098.
https://doi.org/10.1183/2312508X.10000822 v
Guest Editors
Francesco Bonella
Francesco Bonella is Associate Professor of Medicine and Head of

the Division for Interstitial and Rare Lung Disease, Department of
Pneumology, at the Ruhrlandklinik University Hospital (Essen,
Germany). He received his undergraduate training and his MD
from the University of Verona (Verona, Italy), and completed his
PhD in ILD at the University of Essen under the guidance of
Professor Ulrich Costabel.
His research interests include sarcoidosis, IPF, autoimmune ILD,

and pulmonary alveolar proteinosis, with a special focus on
biomarkers, genetic predisposition and the application of BAL. He
has acted as an investigator for major clinical trials in IPF,
sarcoidosis and pulmonary alveolar proteinosis.
Francesco founded EuPAPNet, the European Network for

pulmonary alveolar proteinosis, and is a member of the Steering
Committee of ERN-LUNG: the European Reference Network on
rare respiratory diseases. He has been actively involved in the
European Respiratory Society (ERS) since 2014 and was Chair of
the Rare DPLD/ILD Group. Francesco is involved in a range of
patient advocacy initiatives and chaired the Scientific Advisory Board
of the European Idiopathic Pulmonary Fibrosis and Related Disorders
Federation (EUIPFF) in 2013–2019. He has been an Executive
Committee member of the World Association for Sarcoidosis and
Other Granulomatous Disorders (WASOG) since 2016.
Francesco is the recipient of several honours and awards, including

the Sarcoidosis Research Prize presented by the German
Sarcoidosis Association. He is a member of the editorial boards of
the European Respiratory Journal and Chest, and is Associate
Editor of Respirology.
Daniel A. Culver
Daniel A. Culver is the Chair of the Department of Pulmonary

Medicine in the Respiratory Institute at Cleveland Clinic
(Cleveland, OH, USA) and the President of WASOG.
ISSN: 2312-5098.
https://doi.org/10.1183/2312508X.10001122 vii
Daniel completed his undergraduate studies at The Ohio State
University (Columbus, OH, USA) and received his medical degree
from the Heritage College of Osteopathic Medicine at Ohio
University (Athens, OH, USA). After completing post-graduate
training in the Cleveland Clinic Health System, he joined the
Departments of Pulmonary and Critical Care in the Respiratory
Institute, as well as Inflammation and Immunity in the Lerner
Research Institute.
Dominique Israël-Biet
Dominique Israël-Biet is Professor Emeritus of pulmonary

medicine of the Université de Paris (Paris, France).
Dominique graduated from the Faculté de Médecine Cochin-Port

Royal, Université Paris V René Descartes (Paris), and obtained a
PhD in Immunology at the Institut Pasteur (Paris).
She was trained in pulmonary medicine under the guidance of

Professor Jacques Chrétien. As Associate Professor of Clinical
Immunology then Professor of Pulmonary Medicine, she worked in
the Department of Lung Diseases at the University hospital
Laënnec (Paris), which Professor Chrétien directed, and was
responsible for both the clinical sector and the BAL laboratory. She
then moved to the University Georges Pompidou hospital (Paris),
and became the Head of the Center for Rare Pulmonary Diseases.
Dominique’s research interests mainly focus on sarcoidosis and

ILDs and she has actively participated as an investigator in clinical
trials in these fields.
Dominique was a member of the ERS Task Force on

Bronchoalveolar Lavage and the ERS Task Force on The Treatment
of Sarcoidosis.
She is actively involved in WASOG. As an elected member of its

Executive Committee since 2011, she co-organised the WASOG
International Conference in Paris in 2013 with Professor
Dominique Valeyre. She is currently the General Secretary of
WASOG.
Dominique is on the Editorial Board of Respiratory Medicine and

is the author of a number of original papers, reviews and textbook
chapters.
viii https://doi.org/10.1183/2312508X.10001122
Introduction
1
Francesco Bonella , Daniel A. Culver2 and Dominique Israël-Biet3
1
Center for Interstitial and Rare Lung Diseases, Pneumology Dept, Ruhrlandklinik University Hospital, University of
Duisburg-Essen, Essen, Germany. 2Dept of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland,
OH, USA. 3Université de Paris and Center of rare pulmonary diseases, Hôpital Européen Georges Pompidou,
Assistance Publique-Hôpitaux de Paris, Paris, France.
Corresponding author: Francesco Bonella (Francesco.Bonella@rlk.uk-essen.de)
@ERSpublications
This book includes the voices of clinicians, basic scientists and patients to better illustrate the most recent
advances in research and care of sarcoidosis, a many-faceted disease with complex pathogenesis and
various clinical manifestations https://bit.ly/32cyVUo
ISSN: 2312-5098.
Sarcoidosis is a systemic, multi-pathway disease and a clinical chameleon. Recent reports

indicate that the prevalence of sarcoidosis is rising and the mortality in patients suffering from
chronic sarcoidosis is increasing [1]. The high variability of manifestations, from asymptomatic
to life-threatening, depends on organ involvement and disease activity, which still lacks a clear
definition. About half of patients experience a chronic course. The consequences on quality of
life and wellbeing can be devastating, especially if patients are not promptly referred to
sarcoidosis specialists. To date, there are few approved treatments for sarcoidosis, mostly based
on expert opinion, and the majority of investigational drugs have failed in clinical development.
Although enormous advances have been made in the understanding of the disease pathogenesis
and in the development of new diagnostic tools and management strategies, the burden of
sarcoidosis, both socially and economically, is still considerable and the unmet needs persist.
It has been 17 years since the first ERS Monograph on Sarcoidosis, edited by Marjolein Drent and
Ulrich Costabel, was published [2]. This Monograph is therefore timely and our main aim is to
provide the reader with a comprehensive overview of the most recent advances in sarcoidosis.
We begin the book by illustrating the newest data on epidemiology [3] and cover the evidence
for pathobiology of granuloma formation, including aetiological agents [4], the link between
genotypes and phenotypes, and the genetic mutations occurring in familiar forms [5].
We then move on to discuss phenotyping, specific organ manifestations [6–9] and general
diagnostic pathways [10], from conventional radiographic features to the use of novel modalities
(e.g. PET scan) for diagnosis and assessment of disease activity [11]. We will also provide an
update on the usefulness of circulating and imaging biomarkers for assessing disease severity
and treatment response [12].
Traditional as well as innovative treatment strategies will be discussed, providing insight into
unique aspects of therapy that differ between various organs. In two chapters focusing on when
x https://doi.org/10.1183/2312508X.10000622
and how to treat sarcoidosis, the principles of treatment and stepwise algorithms will be
critically appraised [13, 14]. The pipeline drugs on the horizon and ongoing clinical trials will
be presented in a dedicated chapter [14].
Another novel and major element is represented by highlighting the patient’s perspective.
Besides a chapter exploring non-organ-related symptoms like fatigue and cognitive impairment
[15], which all belong to the clinical picture of sarcoidosis, a chapter covering the effects of the
disease on quality of life and an overview of tools used to assess quality of life is presented
separately [16].
We have tried to include the voices of clinicians, basic scientists and patients to provide a better
insight into this many-faceted insidious disorder. We believe that readers around the world will
find this book helpful.
References
1 Arkema EV, Cozier YC. Sarcoidosis epidemiology: recent estimates of incidence, prevalence and risk factors.
Curr Opin Pulm Med 2020; 26: 527–534.
2 Drent M, Costabel U, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2005.
3 Cozier YC, Arkema EV, Rodriguez JV, et al. Epidemiology: solving the jigsaw puzzle. In: Bonella F, Culver DA,
Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 8–24.
4 Spagnolo P, Grunewald J. Aetiopathogenesis, molecular determinants and immunological features. In: Bonella F,
Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022;
pp. 25–40.
5 van Moorsel CHM, Petrek M, Rivera NV. Unravelling the genetic basis of sarcoidosis. In: Bonella F, Culver DA,
6 James WE, Bonella F. Pulmonary sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS
Monograph). Sheffield, European Respiratory Society, 2022; pp. 122–141.
7 Birnie DH, Kouranos V. Cardiac sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS
8 Tavee J, Voortman M. Granulomatous and nongranulomatous neurological sarcoidosis. In: Bonella F, Culver DA,
9 Murphy C, Marcoval J, Mañá J, et al. Cutaneous sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds.
Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 174–192.
10 Rossi G, Farver C. Pathological features and differential diagnosis. In: Bonella F, Culver DA, Israël-Biet D, eds.
11 Mostard RLM, Yadav R. Conventional and nuclear imaging techniques. In: Bonella F, Culver DA, Israël-Biet D,
eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 75–90.
12 Korenromp IHE, Maier LA, Grutters JC. Serum and imaging biomarkers. In: Bonella F, Culver DA, Israël-Biet D,
13 Culver DA, Wells AU. When to treat sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS
14 Caliskan C, Prasse A. Treating sarcoidosis and potential new drugs. In: Bonella F, Culver DA, Israël-Biet D, eds.
15 Kahlmann V, Patel DC, Marts LT, et al. Non-organ-specific manifestations. In: Bonella F, Culver DA, Israël-Biet D,
16 Tully T, Judson MA, Patel AS, et al. Quality-of-life assessment. In: Bonella F, Culver DA, Israël-Biet D, eds.
Disclosures: F. Bonella reports receiving the following, outside the submitted work: consulting fees from
Boehringer Ingelheim, Roche and Galapagos; payment or honoraria for lectures, presentations, speakers’ bureaus,
manuscript writing or educational events from Boehringer Ingelheim, Roche and BMS; and support for attending
meetings and/or travel from Boehringer Ingelheim, Savara and Roche. F. Bonella reports participation in data
safety monitoring boards or advisory boards for GSK. D.A. Culver reports receiving the following during the past 36
months: grants/fees to his institution from Boehringer Ingelheim, Genentech, Mallinkrodt, aTyr, the Foundation for
Sarcoidosis Research, the Ann Theodore Foundation and the National Heart, Lung and Blood Institute; consulting
https://doi.org/10.1183/2312508X.10000622 xi
fees from Boehringer Ingelheim and Mallinkrodt; support for attending meetings/travel from Roche; and fees for
participation in a data safety monitoring board or advisory board from Boehringer Ingelheim, Xentria and Roivant.
D.A. Culver is the President of the World Association for Sarcoidosis and Other Granulomatous Disorders. D. Israël-Biet
reports receiving: consulting fees from Boehringer Ingelheim; honoraria for educational events from Boehringer
Ingelheim and Roche; payments from Galapagos as a member of an adjudication committee; and support for
attending meetings and/or travel from Boehringer Ingelheim.
xii https://doi.org/10.1183/2312508X.10000622
List of abbreviations
18F-FDG 18F-fluorodeoxyglucose
ACE angiotensin-converting enzyme
BAL bronchoalveolar lavage
CT computed tomography
DLCO diffusing capacity of the lung for carbon monoxide
EBUS endobronchial ultrasound
EBUS-TBNA EBUS transbronchial needle aspiration
EUS endoscopic ultrasound
EUS-FNA EUS-guided fine-needle aspiration
FEV1 forced expiratory volume in 1 s
FVC forced vital capacity
HLA human leukocyte antigen
HRCT high-resolution CT
IFN interferon
IL interleukin
ILD interstitial lung disease
IPF idiopathic pulmonary fibrosis
MMF mycophenolate mofetil
MRI magnetic resonance imaging
mTOR mechanistic target of rapamycin
MTX methotrexate
PET positron emission tomography
TGF transforming growth factor
Th1 T-helper cell type 1
TNF tumour necrosis factor
Chapter 1
Definition and history

1
Ulrich Costabel and Sonoko Nagai2
1
Dept of Pneumology, Ruhrlandklinik, University Medicine Essen, Essen, Germany. 2Dept of Pneumonology, Central
Clinic, Sanjo-Takakura, Nakagyouku, Kyoto, Japan.
Corresponding author: Ulrich Costabel (ulrich.costabel@ruhrlandklinik.uk-essen.de)
Cite as: Costabel U, Nagai S. Definition and history. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS
Monograph). Sheffield, European Respiratory Society, 2022; pp. 1–7 [https://doi.org/10.1183/2312508X.10031020].
@ERSpublications
Over the last 150 years, our understanding of sarcoidosis has changed drastically, with new diagnostic tools
(e.g. HRCT, BAL) reducing the number of biopsies needed. New treatment options, drugs and patient-centred
outcome measures are being developed. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
The definition of sarcoidosis has changed over time. The histological hallmarks of granuloma,
unknown cause and multisystem involvement emerged as the three essential defining features, and later
the heightened Th1 immune response at sites of disease was added. The history of sarcoidosis started
>150 years ago with early observations made on patients with skin disease. By 1915, the systemic
nature of sarcoidosis became evident. Since the 1940s, our knowledge of the disease including potential
causes, epidemiology, immunology, genetics and clinical presentation has undergone remarkable
changes. The history of the immunology of sarcoidosis is a good example of the change of dogmas in
our understanding of disease concepts. In the 1960s, the dogma was that sarcoidosis is a disease of
decreased immune functions. With the use of BAL as a research tool since the 1970s, the concept
changed to a disease of immunological hyperresponsiveness characterised by an exaggerated Th1
immune response at sites of disease activity.
Introduction
Sarcoidosis is a complex disorder, with diverse presentations, characterised by the histological
hallmarks of noncaseating granulomas in multiple organs and of unknown cause. These three
characteristics are reflected in the definition and in the chronology of the sentinel discoveries in
the history of sarcoidosis.
Definition
The definition of sarcoidosis has changed over time. SCADDING and MITCHELL [1] focused on the
histological characteristics of granuloma formation and wrote: “Sarcoidosis is a disease
characterised by the formation in all of several affected tissues of epithelioid-cell tubercles
without caseation though fibrinoid necrosis may be present at the centres of a few, proceeding
either to resolution or to conversion into hyaline fibrous tissue.”
In addition to the presence of granuloma, most definitions included the unknown aetiology and
the multisystemic nature of the disease with multiple organ involvement, and these emerged as
the three essential defining features, with the heightened Th1 immune response at sites of
disease later added to the definition.
https://doi.org/10.1183/2312508X.10031020 1
ERS MONOGRAPH | SARCOIDOSIS
At the first World Association for Sarcoidosis and Other Granulomatous Disorders (WASOG)
World Congress 1991 in Kyoto, an official working group (M. Yamamoto, O.P. Sharma and
Y. Hosoda) reported an extensive descriptive definition of sarcoidosis, which revised and
expanded the previous definitions of the 2nd International Conference on Sarcoidosis in 1960
(the first official definition) and of the 7th Conference in 1975. The 1991 definition reads as
follows [2]:
Sarcoidosis is a multisystem disorder of unknown cause(s). It commonly affects young

and middle-aged adults and frequently presents with bilateral hilar lymph-adenopathy,
pulmonary infiltration, ocular and skin lesions. Liver, spleen, lymph nodes, salivary
glands, heart, nervous system, muscles, bones and other organs may also be involved.
The diagnosis is established when clinico-radiological findings are supported by

histological evidence of non-caseating epithelioid cell granulomas. Granulomas of known
causes and local sarcoid reactions must be excluded.
Frequently observed immunological features are depression of cutaneous delayed-type

hypersensitivity and increased helper cell (CD4)/suppressor cell (CD8) ratio at the site of
involvement. Circulating immune complexes along with the signs of B-cell hyperactivity
may also be detectable. Other markers of the disease include elevated levels of serum
angiotensin converting enzyme (SACE), increased uptake of radioactive Gallium,
abnormal calcium metabolism and abnormal fluorescein angiography. Kveim–Siltzbach
test, when appropriate cell suspensions available, may be of diagnostic help.
The course and prognosis may correlate with the mode of the onset and the extent of the
disease. An acute onset with erythema nodosum or asymptomatic bilateral hilar
lymphadenopathy usually heralds a self-limiting course, whereas an insidious onset,
especially with multiple extra-pulmonary lesions, may be followed by relentless,
progressive fibrosis of the lungs and other organs.
Corticosteroids relieve symptoms, suppress the formation of granulomas and normalize

the SACE levels and the Gallium uptake.
In the American Thoracic Society (ATS)/European Respiratory Society (ERS)/WASOG

statement on sarcoidosis of 1999 [3], this definition was slightly modified. The last sentence on
corticosteroids was removed, and the immunological part was shortened and reworded to:
“Frequently observed immunological features are depression of cutaneous delayed-type
hypersensitivity and a heightened Th1 immune response at sites of disease. Circulating immune
complexes, along with the signs of B cell hyperactivity, may also be found.”
Since the 1999 statement, no further official updates have been made.
Historical development of sarcoidosis

Sarcoidosis has had an interesting and complicated historical development since the first cases
were described [4]. Its history can be divided into four periods: 1) early observations (1869–
1915), 2) recognition of the systemic disease characteristics (1915–1940), 3) description of the
immunology and the genetic predisposition (since 1940), and 4) the search for potential
aetiological agents (since 1960).
2 https://doi.org/10.1183/2312508X.10031020
DEFINITION AND HISTORY | U. COSTABEL AND S. NAGAI
Early observations were made mainly on patients with skin disease such as Mrs Mortimer, one
of Hutchinson’s patients [5–8]. J. Hutchinson gave the first account on skin sarcoidosis in 1869.
Around 1900, BOECK [8] coined the term “multiple benign sarcoid” because he believed that the
lesions were benign, although they resembled sarcoma. He wrote: “The histology is unique. The
areas of new growth might be described as perivascular sarcomatoid tissue built up by
excessively rapid proliferation of epitheloid connective-tissue cells in perivascular lymph-spaces,
with little addition of other varieties…true giant cells of sarcomatous type were found.” Later,
he considered the histology as identical or closely related to tuberculosis. In 1904, KREIBICH [9]
described sarcoid bone cysts in a patient with lupus pernio. JÜNGLING [10] attributed these
“ostitis multiplex cystica” lesions to tuberculosis.
By 1915, the systemic nature of sarcoidosis had become evident [11–13]. KUZNITSKY and
BITTORF [12] were the first to describe how sarcoidosis affects multiple internal organs including
the lungs and spleen. At the same time, SCHAUMANN [13] recognised that sarcoidosis is
commonly a systemic disease, which is only incidentally causing skin lesions: he termed this
“lupus pernio sine lupo”. He believed, as did many of his contemporaries, that sarcoidosis
probably is a variant of tuberculosis.
Further historical milestones are shown in table 1 [14–20]. Around the time of World War II, mass
health surveys by chest radiography revealed the frequent involvement of hilar lymph nodes and
the lungs, often in asymptomatic cases. Based on these discoveries, WURM et al. [14] developed
the radiographic stages of pulmonary sarcoidosis in 1958. Immunological knowledge was advanced
by the Kveim–Siltzbach skin test, although this is no longer in use [15, 16]. In the 1950s,
corticosteroids were introduced and showed efficacy as a first-line therapy for sarcoidosis [18].
Immunology of sarcoidosis: change of dogmas

The historical development of the immunology of sarcoidosis (table 2) is one of the best
examples of the change of dogmas in our understanding of disease concepts. The change
TABLE 1 Milestones in the history of sarcoidosis

1869 J. Hutchinson: first account of skin lesions
1889 E. Besnier: coined the term “lupus pernio”
1892 M. Tenneson: described the histology
1899 C. Boeck: coined the term “multiple benign sarcoid”
1902 R. Kienbock/K. Kreibich/O. Jüngling: described bone changes
1909–1910 H. Schumacher/C. Heerfordt/F. Bering: recognised uveitis
1915 J. Schaumann: emphasised a multisystemic disorder
1915 E. Kuznitsky/A. Bittorf: described lung lesions and other affected internal organs
1941 A. Kveim: introduced the Kveim skin test
1946 S. Löfgren: described Löfgren syndrome
1951 M. Sones et al.: first use of corticosteroids
1958 K. Wurm: first proposal for radiographic staging
1958 D.G. James: 1st International Conference on Sarcoidosis, London, UK
1961 L. Siltzbach: modified Kveim test using sarcoidosis spleen
1974 H. Reynolds: use of BAL
1975 J. Lieberman: serum ACE levels in sarcoidosis
1978 First sarcoidosis patient group founded in the Netherlands
1984 G. Rizzato: started the journal Sarcoidosis (now called Sarcoidosis, Vasculitis and Diffuse Lung Disease)
1987 G. Rizzato: founded the World Association for Sarcoidosis and Other Granulomatous Disorders
(WASOG), with D.G. James elected as the first president
2002 E. Hoitsma et al.: described small-fibre neuropathy in sarcoidosis
https://doi.org/10.1183/2312508X.10031020 3
TABLE 2 Milestones in the immunology of sarcoidosis

1899 C. Boeck Noncaseating granuloma
1916 C. Boeck Cutaneous anergy to tuberculin
1941 A. Kveim Kveim skin test
1964 K. Hirschhorn Spontaneous lymphoblastic transformation of blood cells
1977 C. Voisin; H. Yeager BAL lymphocytes increased
1980 G.W. Hunninghake Spontaneous lymphokine production by BAL cells
1983 J.S. Adams and O.P. Sharma Hypercalcaemia caused by calcitriol production from
alveolar macrophages
1996 D.R. Moller Th1 immune response
occurred with the introduction of BAL as a research tool by H. Reynolds in 1974, allowing the
recovery of viable cells and solutes locally from the site of disease involvement (i.e. the lungs),
and contrasting the regional changes at active disease sites with those found systemically in the
peripheral blood [21].
The dogma before the BAL era was that sarcoidosis is a disease of decreased immune functions,
as shown by the cutaneous anergy, T-lymphopenia in the peripheral blood, and
hyporesponsiveness of peripheral T-cells and B-cells to in vitro stimulation. Interestingly,
sarcoidosis was classified in some textbooks of the 1960s as an immunodeficiency disorder and
grouped together with agammaglobulinaemia, hypogammaglobulinaemia and Hodgkin disease.
Discrepant data before the BAL era included cutaneous anergy versus granuloma, like an
immunological type IV reaction, T-lymphocytopenia versus an increase in “activated”
T-lymphocytes in peripheral blood, and increased serum Ig levels versus decreased antibody
formation by B-cells after stimulation in vitro. BAL studies helped to clarify these contrasting
issues by showing that lung T-lymphocytes from patients with active pulmonary sarcoidosis are
activated CD4+ T-cells, which spontaneously release IL-2 and IFN-γ. The current dogma is that
the immune response in sarcoidosis is compartmentalised, with an exaggerated Th1 immune
response involving activated T-helper cells and corresponding cytokines such as IL-2, IL-12 and
IL-18 only at sites of disease in involved organs but not systemically [3, 22–24]. In the last two
decades, the concept has been fine-tuned with the recognition that CD4+ T-helper cells can
differentiate into Th17.1 cells, and that these Th17 subsets are the major producers of IFN-γ in
the BAL of sarcoidosis patients. The enhanced Th17.1 response seems to be associated with a
regulatory T-cell deficiency, both probably playing a critical role in perpetuation of the T-cell
proliferation in sarcoidosis [25, 26].
The search for potential aetiological agents

Many environmental agents have been implicated in the past as potential causes of sarcoidosis,
including viruses, bacteria, fungi, and inorganic and organic particles [3]. As sarcoidosis
patients exhibit a generalised increase in serum Ig levels, they frequently demonstrated elevated
antibody titres against viruses and other infectious organisms. Following such discoveries, these
microorganisms were regularly discussed as causative agents. However, enhanced antibody
formation in sarcoidosis is now considered to be an epiphenomenon caused by increased B-cell
activity driven by the exaggerated Th1/Th17 immune response and cannot serve as proof of
causality with infection.
With the application of modern molecular techniques, Mycobacterium tuberculosis and

Propionibacterium acnes remain the only microorganisms with sufficient evidence for an
aetiological role in sarcoidosis, not as active infection but as the cause of hypersensitivity to
microbial antigenic peptides [27, 28]. In Japan, EISHI et al. [28] have been leaders in
4 https://doi.org/10.1183/2312508X.10031020
investigating the role of P. acnes through isolation by culture [29], detection of microbial
components (DNA, proteins) in sarcoid tissue, immunological studies and animal models [28].
They were even able to identify P. acnes in sarcoid granulomas of originally aseptic organs
such as the heart and the eyes [30]. Taken together, current evidence suggests that sarcoidosis is
a polyaetiological syndrome, possibly caused in some patients by P. acnes through endogenous
activation of a dormant form, and in others by poorly degradable mycobacterial antigens.
Changing diagnostic tools in sarcoidosis

The tools for diagnosing sarcoidosis since the first skin biopsies in the 1890s are listed in table 3.
The thoracic biopsy procedures changed from mediastinoscopy to bronchoscopic biopsies and
BAL, and more recently to EBUS-TBNA and transbronchial cryobiopsy. Regarding BAL, a
lymphocytosis with an increased CD4/CD8 ratio may be suggestive of sarcoidosis in an
appropriate clinico-radiological setting, and has been applied in this way for patients without
histology since the 1980s. Regarding imaging techniques, the radiograph stages have been
defined and used clinically since the 1950s, but there is still no generally accepted staging
system based on HRCT findings. MRI has become the preferred technique for the detection of
sarcoidosis in selected organs, such as the brain or heart. In the diagnosis of cardiac sarcoidosis,
MRI and PET have been in use since the 1990s and have now widely replaced gallium and
thallium scintigraphy for this purpose. In other organs, PET scanning can reveal occult organ
involvement and disease activity, but its precise role still needs to be determined (imaging is
discussed in another chapter in this Monograph [31]. More recently, patient-centred outcome
measures including quality-of-life issues and fatigue assessment have entered the platform of
sarcoidosis research. The contribution of genetic markers to diagnosis, prognostication and
treatment decision is the focus of current investigations [3, 32, 33].
The sarcoidosis movement around the world: change in research topics

Since the 1950s, sarcoidosis conferences have been held around the world (table 4), bringing
together clinicians and researchers from various disciplines to exchange scientific information
and create international relationships. The first international conference was organised by D.G.
James in London in 1958 and attended by only 22 participants from eight countries. From the
1970s, the delegates reached 300–400 in number from around 30 different countries, and the
scientific programme was extended to all ILDs. Later, in addition to the WASOG World
Congresses for Sarcoidosis (table 4), international WASOG conferences on diffuse lung diseases
were held in between. The first took place in 2001 in Venice (organiser M.G. Boccieri),
followed by 2003 in Siena (P. Rottoli), 2006 in Catania (N. Crimi), 2007 in Tokyo
(Y. Yoshizawa), 2009 in Charleston (M. Judson), 2012 in Cleveland (D. Culver), 2013 in Paris
(D. Valeyre), 2015 in Sao Paolo (C. Perreira) and 2016 in Gdansk (A. Dubaniewicz).
The change in research topics in the history of sarcoidosis is mirrored in the thematic content of
the congresses. For example, in 1984, the hot topics of the Baltimore conference included basic
mechanisms such as macrophage mediators, activated T-cells, CD4/CD8 ratios of BAL
TABLE 3 The changing tools for diagnosing sarcoidosis

Since 1890s Skin biopsy
Since 1950s Radiograph stages
Since 1950s Mediastinoscopy
Since 1974 Transbronchial biopsy
European groups, 1980s BAL
Since 1990s HRCT, MRI, PET
Since 2007 EBUS-TBNA
https://doi.org/10.1183/2312508X.10031020 5
TABLE 4 International conferences on sarcoidosis#
Year City Organiser(s)
1958 London D. Geraint James

1960 Washington Martin Cummings
1963 Stockholm Sven Löfgren
1966 Paris Jude Turiaf
1969 Prague Ladislav Levinsky
1972 Tokyo Yutaka Hosoda
1975 New York Louis Siltzbach and Al Teirstein
1978 Cardiff William Jones-Williams
1981 Paris Jacques Chretien
1984 Baltimore Carol Johns
1987 Milan Gianfranco Rizzato
1989 Lisbon Manuel Freitas e Costa
1991 Kyoto Takateru Izumi
1993 Los Angeles Om P. Sharma
1995 London Ron du Bois
1997 Essen Ulrich Costabel
1999 Kumamoto Masayuki Ando
2002 Stockholm Anders Eklund and Olof Selroos
2005 Denver Bob Baughman and Lee Newman
2008 Athens Stavros Constantopoulos
2011 Maastricht Marjolein Drent
2014 Izmir Ozdem Ozdemir Kumbasar
2017 Beijing Huaping Dai and Zuojun Xu
2018 Heraklion Katerina Antoniou and Athol Wells
2019 Yokohama Arata Azuma
#
: after 1989, these have been the World Association for Sarcoidosis and Other Granulomatous Disorders
(WASOG) World Congress; the 2008–2014 conferences were combined with BAL conferences.
T-lymphocytes, IL-1 and IL-2 (the only ILs known at that time), the significance of BAL and
gallium scanning as research and clinical tools, the definition of sarcoidosis activity and clinical
trials of corticosteroids. In contrast, the hot topics of the 2011 Maastricht congress moved to
genetics, phenotype–genotype relationships, the usefulness of PET/CT scanning, diagnosis and
treatment of fatigue, the role of biologics as new therapeutic options, pulmonary hypertension,
lung transplantation and the impact of sarcoidosis on patients’ lives. By then, sarcoidosis patient
groups had been founded in many countries and actively participated in the conferences, thereby
also promoting increased public awareness about sarcoidosis [34].
Conclusion
Jonathan Hutchinson recognised the first case of sarcoidosis >150 years ago. Since then, our
understanding of the disease including potential causes, epidemiology, pathomechanisms,
genetics and clinical presentation has undergone remarkable changes. Newer diagnostic tools
such as HRCT and BAL have considerably reduced the number of biopsies. Interestingly, BAL
was first introduced as a research tool in the USA but was clinically studied extensively in
Europe and Japan, where it is now accepted as a standard diagnostic tool for any patient with
ILD. Based on advances in our knowledge on the pathogenesis of sarcoidosis,
anti-TNF-α-directed biologicals have been suggested as treatment options and other newer drugs
are in clinical development (discussed elsewhere in this Monograph [35]). More recently,
patient-centred outcome measures including quality-of-life issues and fatigue assessment have
entered the platform of sarcoidosis research.
6 https://doi.org/10.1183/2312508X.10031020
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11 Heerfordt C. Über eine Febris uveo-parotidea subchronica. Von Graefe’s Arch Opthalmol 1909; 70: 254–273.
12 Kuznitsky E, Bittorf A. Boecksches Sarkoid mit Beteiligung innerer Organe. Münch Med Wochenschr 1915; 62:
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13 Schaumann J. Etude anatomo pathologique et histologique sur les localisations viscerales de la
lymphogranulomatose benigne. Bull Soc Fr Dermatol Syphiligr 1934; 1: 167–322.
14 Wurm K, Reindell H, Heilmeyer L. Der Lungenboeck im Röntgenbild. Stuttgart, Thieme, 1958.
15 Kveim A. En ny og spesifikk kutan-reaksjon ved Boecks sarcoid. Nord Med 1941; 9: 169–172.
16 Siltzbach L. The Kveim test in sarcoidosis: a study of 750 patients. JAMA 1961; 178: 476–482.
17 Löfgren S. Erythema nodosum: studies on etiology and pathogenesis in 185 adult cases. Acta Med Scand 1946;
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18 Sones M, Israel HL, Dratman MB, et al. Effect of cortisone in sarcoidosis. N Engl J Med 1952; 244: 209–213.
19 Liebermann J. Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis. Am J Med 1975; 59:
365–372.
20 Hoitsma E, Marziniak M, Faber CG, et al. Small fibre neuropathy in sarcoidosis. Lancet 2002; 359: 2085–2086.
21 Reynolds HY. Use of bronchoalveolar lavage in humans – past necessity and future imperative. Lung 2000; 178:
271–293.
22 Hunninghake GW, Crystal RG. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte
activity at sites of disease activity. N Engl J Med 1981; 305: 429–434.
23 Crystal RG, Roberts RC, Hunninghake GW, et al. Pulmonary sarcoidosis: a disease characterized and
perpetuated by activated lung T-lymphocytes. Ann Intern Med 1981; 94: 73–94.
24 Moller DR, Forman JD, Lius MC, et al. Enhanced expression of IL-12 associated with Th1 cytokine profiles in
active pulmonary sarcoidosis. J Immunol 1996; 156: 4952–4960.
25 Grunewald J, Grutters JC, Arkema EV, et al. Sarcoidosis. Nature Rev Dis Primers 2019; 15: 45.
26 Zhang H, Costabel U, Dai H. The role of diverse immune cells in sarcoidosis. Front Immunol 2021; 12: 788502.
27 Chen ES, Moller DR. Etiologies of sarcoidosis. Clin Rev Allergy Immunol 2015; 49: 6–18.
28 Eishi Y. Etiologic link between sarcoidosis and Propionibacterium acnes. Respir Investig 2013; 51: 56–68.
29 Homma JY, Abe C, Chosa H, et al. Bacteriological investigation on biopsy specimens from patients with
sarcoidosis. Jpn J Exp Med 1978; 48: 251–255.
30 Yamaguchi T, Costabel U, McDowell A, et al. Immunohistochemical detection of potential microbial antigens in
granulomas in the diagnosis of sarcoidosis. J Clin Med 2021; 10: 983.
31 Korenromp IHE, Maier LA, Grutters JC. Serum and imaging biomarkers. In: Bonella F, Culver DA, Israël-Biet D,
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European Respiratory Society, 2005; pp. 337–339.
Disclosures: U. Costabel has nothing to disclose. S. Nagai has nothing to disclose.
https://doi.org/10.1183/2312508X.10031020 7
Chapter 2
Epidemiology: solving the jigsaw puzzle

Yvette C. Cozier1, Elizabeth V. Arkema 2
, Juan V. Rodriguez3, Jeffrey S. Berman4
and Praveen Govender4
1
Dept of Epidemiology, Slone Epidemiology Center at Boston University School of Medicine, Boston University
School of Public Health, Boston, MA, USA. 2Dept of Medicine Solna, Clinical Epidemiology Division, Karolinska
Institutet, Stockholm, Sweden. 3Dept of Internal Medicine, Boston Medical Center, Boston, MA, USA. 4Dept of
Pulmonary, Allergy, Sleep and Critical Care Medicine, Boston University School of Medicine, The Sarcoidosis Clinic
at Boston Medical Center, Boston, MA, USA.
Corresponding author: Yvette C. Cozier (yvettec@bu.edu)
Cite as: Cozier YC, Arkema EV, Rodriguez JV, et al. Epidemiology: solving the jigsaw puzzle. In: Bonella F, Culver DA,
Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 8–24 [https://
doi.org/10.1183/2312508X.10031120].
@ERSpublications
Epidemiology has informed the study of sarcoidosis, although problems with data collection, case selection
and information bias have hampered advances. Despite the challenges, epidemiological approaches provide
a knowledge base for future discovery. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis is a rare, clinically heterogeneous disease, making the identification of a single aetiological
candidate challenging. Epidemiological research into the aetiology of sarcoidosis has been hampered by
variability of case definition, heterogeneity of organ involvement, and numerous other variables. The
global burden of sarcoidosis is not fully appreciated as there is considerable geographic variability
including numerous countries for which there are no data. While sarcoidosis can strike at any age,
recent data support a later onset of disease, with the average age ranging from 46 to 51 years and an
increasing percentage of cases occurring after age 65 years. Data also suggest that prolonged exposure
to an infectious agent or inorganic antigen may not be required to trigger an immunological cascade,
further complicating efforts to establish associations between sarcoidosis and complex environments.
Taken together, these findings provide a knowledge base for future discovery.
Introduction
Sarcoidosis is a challenging condition to study. Its epidemiology and clinical presentation vary
greatly according to geography, sex, race/ethnicity and age [1], factors which taken together
may reflect different aetiologies [2, 3]. This has led some experts to use the term “the
sarcoidoses” [4], reflecting the possibility that sarcoidosis is an umbrella term, under which
several multisystem granulomatous diseases linked to diverse infectious and non-infectious
antigens have been grouped [5]. Importantly, the geographic variation of sarcoidosis has made it
difficult to assess the global burden of disease [6]. Epidemiological approaches to sarcoidosis
are fraught due to non-uniformity of data collection, and selection and information biases,
among other factors (table 1). Despite these challenges, such approaches promise to provide a
knowledge base for future discovery.
8 https://doi.org/10.1183/2312508X.10031120
EPIDEMIOLOGY | Y.C. COZIER ET AL.
TABLE 1 Epidemiological challenges associated with sarcoidosis

Sarcoidosis around the world
Many countries lack data on sarcoidosis; thus, the global burden of disease is unknown
Inconsistent approaches to diagnosis and data collection, resulting in non-representative samples and
frequency estimates
Age
Sarcoidosis onset after age 65 years reported to be as high as 27% of incident cases
Sex
Differential patterns of screening and healthcare utilisation lead to samples which over-represent men
or women
Race/ethnicity
Race is a socially constructed variable that does not capture the complexity of individual genetic risk or the
social determinants that influence health
Clinicians and researchers must routinely incorporate the social determinants of health into examinations
and analyses, respectively
Phenotypic distribution of sarcoidosis
Cluster analyses have been employed in attempts to identify disease phenotypes with greater accuracy
Intense screening methods (cluster analysis) can identify occult organ involvement (diagnostic/surveillance
bias); thus, validation is needed
Over-association of demographic characteristics with disease phenotypes can lead to under-appreciation of
a disease phenotype in another demographic group
Occupation
Small analytic samples are subject to recall bias
World Trade Center associations may be over-estimated due to increased surveillance of exposed individuals
(surveillance bias)
Seasonality
Inconsistent approaches to diagnosis and data collection, resulting in non-representative samples and
frequency estimates
Misclassification of date of onset
Domestic exposures
Indirect, non-specific measurements (misclassification)
Single time-point exposure measurement
Lifestyle
Bidirectional relationship of sarcoidosis and body mass index (reverse causation)
Nicotine has been found to modulate immune response and suppress granulomatous inflammation,
representing a potential therapy for sarcoidosis
Infections
Bidirectional relationship of sarcoidosis and infection (reverse causation)
Sarcoidosis around the world

The incidence of sarcoidosis in northern Europe ranges from seven to 19 per 100 000 per year
[7, 8], with the highest incidence reported in Scandinavian countries (table 2). Data from the
Swedish National Patient Register estimate an incidence of 11.5 per 100 000 [7], while in the
Danish National Patient Register the incidence varied from 11.3 to 14.8 per 100 000 per year,
from 2001 to 2015 [8]. Conversely, the lowest frequencies of sarcoidosis have been reported in
Asian countries; estimates from South Korea, Malaysia, Taiwan and Japan range from 0.47 to
five per 100 000 [12, 13, 17–20]. Incidence estimates from North America are 6.8 per 100 000
in Canada [9] and 7.6–11 per 100 000 per year in the USA [1, 15, 16]. There remain numerous
countries for which there is no information on sarcoidosis. As such, there is still much we do
not know about the global occurrence of disease [6].
Even within countries, disease distribution has been shown to vary according to geographical
region [1, 11, 16, 21]. For example, within the USA, the lowest rates of disease have been
https://doi.org/10.1183/2312508X.10031120 9
TABLE 2 Studies reporting the prevalence and incidence of sarcoidosis
Country First author Data source Prevalence per Incidence per

[ref.] 100 000 100 000
Canada FIDLER [9] Ontario Health Insurance Plan 143 6.8

Denmark SIKJÆR [8] Danish National Patient Register 77 14.5
France DUCHEMANN [10] Seine-Saint-Denis county, France 30.2 4.9
Italy BEGHÈ [11] University Hospital of Parma 49
South Korea YOON [12] National Health Insurance System 4.69 0.47
Sweden ARKEMA [7] Swedish National Patient Register 160 11.5
Taiwan WU [13] National Health Insurance Research 2.2
Database
USA ERDAL [14] Ohio State University Medical Center, 48
Columbus, OH
USA BAUGHMAN [1] Optum managed healthcare database 60 7.6
USA UNGPRASERT [15] Olmsted County, MN 10
USA DUMAS [16] Nurses’ Health Study II Cohort 100 11
Reproduced and modified from [6] with permission.
consistently reported in the western region of the country [1, 16, 22], while in Europe, as
aforementioned, the highest incidence and prevalence of sarcoidosis has been observed in
Nordic countries [7, 8], and within northern strata of countries [7, 11]. In Sweden, the regional
variation in sarcoidosis frequency is partially attributed to differences in patient demographics as
well as in technologies related to diagnosis and treatment [23]. Studies have also found higher
frequency of sarcoidosis within areas with low population density [4, 7], supporting a role of
rural and agricultural environmental exposures in disease aetiology [24].
As we strive to identify and understand the factors involved in the aetiology of sarcoidosis, it is
useful to make comparisons across and within countries as a means of hypothesis generation.
Such comparisons, however, should be made with caution, as many methodological, analytic
and even practical decisions made by researchers can affect results. For example, sarcoidosis
can be under-estimated in geographic regions with endemic tuberculosis or coccidioidomycosis,
which can mimic and/or obscure symptoms of pulmonary disease [25]. Additionally, the
availability of diagnostic technology (e.g. imaging, biopsy) can also influence whether a
diagnosis and subsequent report of sarcoidosis is made [26]. A study by ERDAL et al. [14]
observed a prevalence of sarcoidosis of 48 per 100 000 in Columbus, Ohio, a mid-western city
in the USA where the population mirrors the race and sex distribution of the USA. The authors
ascribe their findings to improved imaging and biopsy techniques such as CT scanning and
EBUS-guided biopsy. Finally, disease estimates from different countries and regions are often
based on both data sources and clinical settings, which can vary greatly. For example, countries
with universal access to healthcare often maintain comprehensive administrative datasets that
capture clinically significant disease [7–9]. In contrast, countries that lack centralised healthcare
derive estimates from disparate data sources such as hospital systems, insurance databases,
patient registries and observational studies [1, 16, 22, 27–30]. This inconsistent approach to data
collection can result in non-randomly selected population samples that either over-represent
severe disease or capture non-representative samples. Hospital databases may under-count
asymptomatic or mild cases of sarcoidosis likely to be seen in the ambulatory or outpatient
clinic [31]. For example, BAUGHMAN et al. [1] reported frequency estimates within a national
database representing patients actively seeking healthcare, likely under-counting asymptomatic
cases. Alternatively, patient registries may over-represent chronic and high socioeconomic status
10 https://doi.org/10.1183/2312508X.10031120
cases. The Foundation for Sarcoidosis Research – Sarcoidosis Advanced Registry for Cures
(FSR-SARC), a web-based, patient opt-in platform [32], over-represents middle-class, White
women (71%) with more severe disease, a difference likely related to high healthcare and
internet access [33]. Finally, the overall variability in the years of available data can also
contribute to the difficulty of comparing rates of disease across countries. Having many years of
data, as is often the case with administrative databases, can lead to over-estimation of the true
burden of disease if the status of resolved cases is not subsequently updated (length bias) [34].
For example, FIDLER et al. [9], using administrative data from Ontario, Canada, doubled
their prevalence estimate from 66 to 143 per 100 000 by increasing the observation period from
5 to 24 years.
Age
While sarcoidosis can strike at any age, it is rarely diagnosed in people aged <15 years or
>70 years [35]. For decades, the peak onset of disease has been reported to occur between 20
and 45 years of age [36]. Recent data from Europe, Asia and the USA support a later onset of
disease, with the average age ranging from 46 to 51 years [7, 8, 11, 12, 15, 37]. In a
population-based cohort of mostly White Americans of European descent, the peak age at
incidence shifted from 40–59 years to 50–59 years from 1950 to 2010 [15], a shift that may
reflect an increasingly ageing population whose overall health may be more closely monitored.
The onset of disease at age >65 years is frequently defined as “elderly onset”, although this
term is arbitrary and outdated [38]. BAUGHMAN et al. [1] found that 27% of incident cases
reported in a managed healthcare database in the USA were aged >65 years, suggesting that
elderly onset disease may not be infrequent. As the global population continues to age, it will
be important for clinicians to expand their understanding of sarcoidosis. Conversely, paediatric
sarcoidosis, defined as onset before age 15 years, is a rare occurrence with an estimated
incidence of 0.3–0.8 per 100 000 children [39, 40]. Studies in Europe (Denmark and France)
[41, 42] and the USA (Louisiana) [43] report a mean age at diagnosis between 11 and 13 years,
and presentation with multisystem disease similar to adult manifestation. In general, paediatric
disease has a favourable prognosis [42], but in a retrospective follow-up of patients whose
disease onset occurred before age 16 years, nearly half progressed into a chronic adult disease
requiring long-term treatment [41].
Sex
Sarcoidosis occurrence also varies by sex, although the cause of this variation is unknown.
Sarcoidosis is often reported to be more common in women than in men [44]. In the USA,
BAUGHMAN et al. [1] observed a higher prevalence for women than for men in all racial/ethnic
groups, while in data from Minnesota (USA), the annual incidence of sarcoidosis was similar in
men and women: 9.4 versus 10.5 per 100 000, respectively [15]. Of sarcoidosis cases identified
from the Swedish National Patient Register, 55% were male [7]. Similarly, men made up 56%
of the incident cases identified in the Danish Patient Register [8]. In contrast, women made up
57% of sarcoidosis cases in a study based in an outpatient pulmonary clinic in Estonia [45].
Finally, national insurance claims data from South Korea showed a higher incidence of
sarcoidosis in females compared to males (1.55:1 female-to-male ratio) [12]. A recent
multicentre study by ZHOU et al. [37] found the same female-to-male ratio.
Some studies have shown a 10-year difference in age at diagnosis between men and women. In
studies in Europe and Asia, men were, on average, younger at diagnosis compared with women
[37]: 44–47 years versus 51–54.0 years, respectively [7, 11, 12, 46]. The peak incidence in
Swedish males occurred between ages 30 and 50 years, compared to between 50 and 60 years in
females [7]. In Denmark, the peak age-associated incidence of disease occurred between 30 and
https://doi.org/10.1183/2312508X.10031120 11
39 years of age in both men and women; however, among men, incidence decreased with
increasing age, while for women incidence plateaued between 40 and 69 years of age, before
decreasing [8]. In the USA, the sex differential was consistent, but the overall difference in age
at diagnosis was smaller (42.8 years in men versus 48.3 years in women) [47].
Sex differences in incidence and age at onset suggest a hormonal influence on the disease. One
study has explored this association in Black women in the USA. Researchers found a protective
effect of older age at menopause and age at first and last birth (markers of endogenous
oestrogen exposure) on sarcoidosis risk [48]. A recent cross-sectional study of men in the
Netherlands found similar levels of scalp hair testosterone in both sarcoidosis patients and
population-based controls, but higher testosterone levels were inversely correlated with FVC
[49]. Future studies involving both men and women are needed to further examine the
association between sex hormones and sarcoidosis onset and severity.
There are several factors that could contribute to the observed sex differential. Screening chest
radiography associated with military service and occupation [50] may over-represent sarcoidosis
cases among males. Alternatively, decreases in lung function associated with menopause [51]
may result in older women seeking care and pulmonary evaluation. Also, women are 33% more
likely than men to visit a doctor, and older women are more likely to see specialists [52]. Thus,
smaller, clinic-based samples may not represent the larger sarcoidosis population.
Race/ethnicity
The incidence and prevalence of sarcoidosis are strongly associated with self-identified race,
particularly in the USA. Black women experience the highest incidence of sarcoidosis in the
USA, with a lifetime risk of 2.7%, compared to 1.0% for White women [53, 54]. In the Optum
healthcare database in the USA, the incidence among Black men and women was twice the
incidence among White individuals (17.8 versus 8.1 per 100 000, respectively) [1]. Compared to
White sarcoidosis patients, Black patients were also twice as likely to be diagnosed before the
age of 45 years [37]. BAUGHMAN et al. [1] also reported data for Hispanics and Asians, racial/
ethnic groups routinely missing from studies of sarcoidosis in the USA. The incidence in
Hispanics was approximately half that in Whites, but was slightly higher than that in Asians
(4.3 versus 8.1 versus 3.2, respectively); the prevalence rates for the groups were similarly
distributed [1]. Similarly, among White women in the Nurses’ Health Study II (NHSII) cohort,
the average annual incidence of sarcoidosis was 11 per 100 000. As expected, the incidence was
significantly higher in Black women (43 per 100 000), but the incidence was also lower among
Hispanic women (five per 100 000) and women of other races (six per 100 000) [16].
Racial differences have also been observed in other countries. In a study from a racially and
ethnically diverse population in Seine-Saint-Denis, France, patients of Afro-Caribbean and
North African ancestry had the highest incidence of sarcoidosis: 16.9 and 9.7 per 100 000 per
year, respectively. In comparison, the incidence among those of European ancestry was 2.4 per
100 000 per year [10]. Race appears to play a role in paediatric cases of sarcoidosis as well,
with the majority of cases reported in the USA (74%) and France (71%) being of African
descent [41, 43].
Race is commonly viewed as a fixed marker of group membership that is based in biology [55].
Indeed, some racial/ethnic differences, particularly of HLA genotypes, have been observed for
sarcoidosis [56]. It is also the case that biological conceptions of race (i.e. beliefs that racial
groups are fundamentally and biologically different) have been associated with greater
acceptance of racial disparities and biased delivery of healthcare [57, 58]. Race, however, is a
12 https://doi.org/10.1183/2312508X.10031120
socially constructed variable, which captures neither the complexity of individual genetic risk
nor the myriad social determinants that influence health. In the USA, racism (both interpersonal
and structural) is a fundamental cause of health disparities [59]. Furthermore, research has
shown that frequent experiences of interpersonal racism are associated with biological stress and
disruption of the body’s immune, neuroendocrine and autonomic systems [60]. The recent
coronavirus disease 2019 (COVID-19) pandemic has highlighted how systemic and structural
racism in the USA influences Blacks’ social and environmental exposures through housing,
education, employment and timely access to quality healthcare [61–63]. Racial patterning of
sarcoidosis, particularly in the USA, is consistent with this model. To fully understand the role
of race in the diagnosis and prognosis of sarcoidosis, clinicians and researchers must
contextualise disease frequency by routinely incorporating measures of the social determinants
of health into the clinical examination and statistical analyses. This extends to geneticists and
molecular biologists, who can incorporate the “social” by exploring gene–environment
relationships [64] and epigenomic (DNA methylation) studies [65] within sarcoidosis datasets
and population-based cohorts.
Phenotypic distribution of sarcoidosis

The clinical presentation of sarcoidosis is highly variable [66]. Sarcoidosis is often
asymptomatic and diagnosed after a prolonged period of investigation. Early in its clinical
history, distinct phenotypes, such as uveoparotid fever (Heerfordt syndrome (1909)) and
erythema nodosum–bilateral hilar lymphadenopathy (Löfgren syndrome (1952)) were recognised
within Scandinavian populations. In the initial reports, both syndromes were more prevalent in
young females (25–39 years of age) [67, 68]. Over time, it has become apparent that the
inter-relationship of age, sex and race in disease phenotypes is far more complex and even
obsolete. For example, it was long thought that sarcoidosis prevalence in Japan was monophasic
in its distribution in men and biphasic in its distribution in women. A recent nationwide study
in the current ageing Japanese population showed that sarcoidosis is biphasic in its distribution
in men and actually monophasic with a later age of presentation in women [69]. A study
conducted in a Turkish rheumatology centre found that, compared to younger patients, patients
aged >65 years (“elderly onset sarcoidosis”) experienced less Löfgren syndrome, more
comorbid illness, greater delays in diagnosis, and had worse disease prognosis [70]. It is
possible that comorbid disease may complicate diagnostic and therapeutic strategies, resulting in
delayed diagnosis and poorer disease outcomes [71].
Identifying at-risk populations based on sex, age and ethnicity for certain clinical phenotypes
highlights the difficult issue of over-associating these demographic variables with disease
phenotypes. In a geoepidemiological analysis of all large series (>100 cases) of sarcoidosis
published over 20 years [44], including 130 000 cases of sarcoidosis, there was a north–south
gradient in sarcoidosis prevalence in Europe, but this geospatial gradient was less apparent in
other continents. In these other world regions, ethnicity appeared to exert a greater influence on
many phenotypic variables, including frequency, epidemiology, clinical expression and
outcomes of sarcoidosis. For example, in the USA, Black race/ethnicity was associated with
younger age at diagnosis, greater likelihood of stage IV thoracic disease, and higher prevalence
of extrapulmonary disease. Race/ethnicity was also associated with the predominant organ-by-
organ extrathoracic involvements among other racial/ethnic groups. Compared to other groups,
Asian patients were found to have the highest rates of ocular (2–3-fold higher), cardiac (3–
6-fold higher) and renal and muscular (4-fold higher) sarcoidosis, while Black patients have the
highest frequencies of liver (3-fold higher) and bone/joint (2–4-fold higher) sarcoidosis [44].
Data from a multicentre, multiracial international cohort of >1400 sarcoidosis patients showed
https://doi.org/10.1183/2312508X.10031120 13
that patients diagnosed before age 45 years were more likely to have central nervous system
involvement and Löfgren syndrome, and that, overall, 73% experienced multi-organ disease.
Additionally, Black and female patients were more likely to have multi-organ disease compared
to patients who were White or male [37]. In interpreting studies such as these, it is important to
consider that race and ethnicity, and even definitions of “elderly”, are social constructs that have
evolved over time and will continue to evolve [72]. Thus, there is a risk that considering a
particular phenotype solely based on a demographic characteristic will lead to under-diagnosis
or under-appreciation of a disease phenotype in another demographic group.
Newer approaches (i.e. cluster analyses) have been employed in attempts to identify disease
phenotypes with greater accuracy. The Sarcoidosis Genetic Analysis (SAGA) study in
African-Americans (Blacks in the USA) found liver, spleen and bone marrow involvement
segregated into a phenotypic cluster [73]. In Europe (central and western), the multinational
GenPhenReSa consortium of 31 centres identified five phenotypic organ-based clusters:
pulmonary, intra-abdominal organs, musculoskeletal−cutaneous, extrapulmonary and oculo
−cardiac−central nervous system−cutaneous (OCCC) [74]. In a Spanish population, cluster
analysis of 26 phenotypic variables identified six different clinical patterns: three subgroups of
Löfgren syndrome (C1–C3), pulmonary sarcoidosis (C4) and extrapulmonary sarcoidosis (C5
with pulmonary, and C6 with organ involvement other than the lung) [75]. Identifying
phenotypic clusters based on organ involvement raises the important issue of what actually
constitutes organ involvement within a phenotypic cluster (e.g. symptomatic versus asymptomatic
organ involvement). More intense screening methods can identify occult organ involvement
(diagnostic/surveillance bias) [34]. For example, 18F-FDG PET/CT identified bone involvement
that mostly was not detectable (i.e. unknown/occult on CT imaging in 22% of patients with
active chronic sarcoidosis) [76]. More in-depth phenotypic clusters will be revealed as other
determinants of health beyond age, sex and ethnicity become incorporated with newer diagnostic
methods including genetic and molecular signatures. These phenotypic clusters need to be
validated (both internally and externally) to determine whether they can predict clinically
meaningful outcomes in broad groups of patients with sarcoidosis across geographic regions [77].
Environmental factors
Pulmonary and extrapulmonary granulomatous reactions are not exclusive to sarcoidosis.
Granulomas can be the result of exposures to several different organic antigens. Sarcoidosis is
thought to result from an immunological cascade due to exposure to an unknown antigen, or
antigens, in a susceptible individual [4]. This is supported by the fact that the organs most
commonly affected by sarcoidosis (lungs, eyes and skin) are those in direct contact with the
environment and the lymph nodes draining those anatomical regions (intrathoracic and neck)
[4, 6, 78]. Evidence derived from epidemiological studies, case series and disease models
suggests several factors as potential causes of this multisystem granulomatous disease, including
infectious, occupational and environmental exposures [24]. KAJDASZ et al. [79] noted that Blacks
residing along the Atlantic coast of South Carolina experienced a nearly 5-fold increased
prevalence of sarcoidosis-related hospitalisation, suggesting geophysical and differential
environmental exposures likely compounded by residential (segregation) patterns. There are
several challenges to studying associations between environmental exposures and sarcoidosis
(table 3). First, the exposure may precede the disease by many years, or sarcoidosis may already
be present by the time of the suspected trigger. Most of our knowledge comes from
observational studies, where case definitions vary and in which the risks of misclassification
bias and the presence of confounders are limitations. Nevertheless, we know significantly more
about the relationship between sarcoidosis and the environment than we knew one decade ago.
14 https://doi.org/10.1183/2312508X.10031120
TABLE 3 Environmental exposures with a suspected association with sarcoidosis
Exposures Evidence supporting the Limitations References

association
Silica Multiple case–control studies Not all case–control studies have [80–82]
Lymphocyte proliferation test shows found an association with silica
a subset of sarcoid patients have Most are small studies
immunoreactivity to silica Retrospective studies with risk of
Silica has been implicated in other misclassification, recall bias
autoimmune diseases and confounders
Most studies did not quantify
true exposure
Onset of sarcoidosis before index
exposure cannot be excluded
Metal dust Large registry-based Most studies include silica exposure [11, 83–87]
epidemiological studies Retrospective studies with risk of
suggesting an association misclassification, recall bias
Subset of sarcoid patients are and confounders
sensitised to various metals Register-based studies do not quantify
based on lymphocyte true exposure
proliferation test Risk of misclassification of sarcoid-like
Increased presence of metal in BAL reactions or chronic beryllium
in some studies disease as sarcoidosis in
Multiple case–control studies some studies
Organic dust Multiple case–control studies Retrospective studies with risk of [84, 88, 89]
Large epidemiological studies misclassification, recall bias
linking professions with high and confounders
burden of organic dust exposure Risk of misclassification of sarcoid-like
reactions
Correlation with specific organic
antigens lacking
Unable to estimate latency time
between exposure and onset of
disease or duration of the
exposures
Mould Case–control studies reporting Risk of misclassification of sarcoid-like [24, 90, 91]
association reactions and other mimickers
Few studies attempting to quantify Quantification of mould exposure not
exposure and association specific for mould
Most data are self-reported
Small sample size in studies
specifically evaluating this
association
Obesity Associations observed in both Most studies retrospective [92–102]
case–control and prospective Unable to estimate latency time
cohort studies between exposure and onset
Obesity has also been associated of disease in most studies
with other inflammatory (case–control)
conditions Complex bidirectional relationship and
overlapping features
Tobacco Previous early studies showed that Smoking history seems to be a risk [24, 99,
smoking is associated with a factor for severe fibrotic sarcoidosis 103–106]
lower risk of sarcoidosis Smoking status and quantity not
Nicotine replacement seems to be reported systematically
protective against sarcoidosis
Continued
https://doi.org/10.1183/2312508X.10031120 15
TABLE 3 Continued
Exposures Evidence supporting the Limitations References

association
Mycobacteria Presence of mycobacterial RNA or Never cultured from sarcoid [107–115]

DNA in sarcoid granulomas granulomas
Similar immunological profiles in Antimicrobial therapies against
experimental models when mycobacteria were not effective
exposed to mycobacterial in sarcoidosis
antigens Immunosuppression is the mainstay
Similar histopathology and clinical of therapy in sarcoidosis
features in a subset of patients No documentation of contagiousness
or transmissibility
Cutibacterium Cultured from sarcoid granulomas Antimicrobial therapies against [116–119]
acnes Positive association with acne Cutibacterium were not effective
history in sarcoidosis
Immunosuppression is the mainstay
of therapy in sarcoidosis
No documentation of contagiousness
or transmissibility
Occupational exposures
An association between certain work-related exposures and sarcoidosis has been observed in
several epidemiological studies as well as case reports/case series and immunological studies. In
a summary of seven case series, BLANC et al. [120] estimated the contribution of occupation
exposure to the burden of sarcoidosis to be around 30% (95% CI 17–45%), although the studies
were highly heterogeneous. It has also been suggested that occupation is related not only to the
development of disease but also to specific organ involvement and mortality [121, 122].
One of the first large epidemiological studies was the ACCESS study in the USA, a
retrospective, multicentre case–control study of 720 sarcoidosis patients. Study investigators
found associations between the disease and exposure to insecticides, dust, mould and livestock,
among other factors [24]. Since the publication of ACCESS, additional studies have reported a
higher risk in agricultural workers, metal workers, firefighters and construction workers [83]. A
study conducted in the Polish Silesian province attributed the observed geographic variability of
sarcoidosis to environmental exposure to pesticides and wood dust [21, 123]. Silica and metal
dust are important associations of at least a subset of cases of sarcoidosis. Several case–control
studies have reported a higher risk of exposure to silica in patients with sarcoidosis compared to
controls [80, 81]. In a case–control study in the Netherlands, 32% of cases had exposure to
silica versus 25% of controls ( p=0.2). The investigators used the lymphocyte proliferation test
to measure T-cell response to specific antigens and, interestingly, found that only patients with
sarcoidosis showed immunoreactivity to silica, supporting the theory that silica may be
implicated in some cases of the disease [82]. The presence of sensitisation to specific antigens
is an active research field in sarcoidosis [124].
Dust, a heterogeneous conglomerate of organic and inorganic particles, has also been implicated
as a risk factor for the development of sarcoidosis. In the ACCESS study, patients with
sarcoidosis were more likely to have had jobs related to increased dust exposure than controls,
although recall bias could not be excluded [24]. In a cohort study using historical controls,
firefighters at the scene of the World Trade Center (WTC) had a significantly higher incidence
of sarcoidosis (relative risk 2.36, 95% CI 1.17–4.78) [125]. Similarly, in a nested case–control
16 https://doi.org/10.1183/2312508X.10031120
study of biopsy-confirmed cases in the WTC registry, where cases were compared to controls
also present in the WTC disaster, there was a significant association between heavy exposure to
WTC dust and pile, such as performing heavy rescue and digging activities, and sarcoidosis
[88, 89]. This study did not, however, detect an association with the WTC dust cloud
experienced by less involved workers and passers-by. The dust from WTC was rich in inorganic
particular materials such as silica, gypsum and concrete and various other metals [84]. Again, it
is possible that in the case of the WTC, the association is biased (over-estimated) due to more
surveillance of exposed individuals.
Seasonal exposures
There is conflicting evidence on whether sarcoidosis is affected by seasonality, and large
prospective well-conducted studies are lacking. In a retrospective cohort study in Olmsted
County in Minnesota (USA), incident sarcoidosis, noted as the date of histopathological
diagnosis, was less common in the autumn than in winter and summer [126]. In another
retrospective study using the Veterans Affairs Health database in the USA, no seasonal
influence on sarcoidosis incidence was found [127]. In a single-centre retrospective study from
India with approximately 1000 cases, a higher incidence of sarcoidosis was noted in the
summer months, but this finding was not statistically significant [128]. Similar previous studies
have reported higher incidence during the spring, especially of Löfgren syndrome. Seasonal
variation may also be influenced by geography, with higher incidence during the winter months
in countries far from the equator [44].
Each of these studies shares important limitations. Among them are the inherent problems with
retrospective studies, where not all cases are evaluated systematically in the same way with the
same definition of disease. Also, the date of diagnosis was defined as the date of tissue
diagnosis or date of clinical diagnosis, not the start of symptoms, which in sarcoidosis can often
be separated by several months or years. Additionally, access to a specialist and diagnostic
workup may also be subject to seasonal variability (e.g. less availability during the summer or
holidays) and the diagnostic workup can take months.
Domestic exposures
Several studies in the last decade have suggested a relationship between living in areas with high
density of agricultural, metal and hydraulic industries and sarcoidosis [83, 85–87]. A study
conducted in the northern Italian province of Parma correlated residential variation in disease
prevalence to the deposition of metals in lowland compared to mountainous areas of the
region [11]. Similarly, in a retrospective study of 273 cases of sarcoidosis and 618 healthy
subjects, living or working in mouldy or humid environments was associated with higher risk of
the disease [90]. This relationship has also been clearly reported in other granulomatous lung
diseases such as hypersensitivity pneumonitis [129]. In one study, the level of a marker for fungal
biomass was higher in the majority of patients with active sarcoidosis compared to controls [91].
None of the cases had signs of fungal infection. Larger longitudinal studies employing multiple
fungi-specific assessments are needed to assess the potential role of fungi further.
Lifestyle exposures
Among the many possible lifestyle factors associated with sarcoidosis, currently those with most
evidence are obesity and smoking. Obesity is a complex systemic disorder with immunological
and endocrinological implications that lead to chronic inflammation, insulin resistance and
alteration in the immune phenotype [130, 131]. Obesity and metabolic syndrome have been
associated with immunological conditions such as asthma, rheumatoid arthritis and lupus [92–95],
supporting the hypothesis that the proinflammatory milieu of obesity is a risk factor for conditions
https://doi.org/10.1183/2312508X.10031120 17
involving immune dysregulation, including sarcoidosis. It has, however, been difficult to establish
a causal association between these two complex and multisystemic disorders. First, symptoms
common in obese individuals, such as exercise intolerance, poor sleep, fatigue and shortness of
breath, overlap with those common in sarcoidosis [102, 132, 133], and people affected with
sarcoidosis also tend to experience more chronic fatigue, shortness of breath and become less
active, leading to them becoming overweight [134, 135]. Additionally, since sarcoidosis can be
undiagnosed for years, most population studies are limited by their retrospective quality in
assessing the influence of pre-existing exposures such as hormones and obesity [102]. Finally,
patients with sarcoidosis are often treated with steroids, which may contribute to obesity and
metabolic derangement, making it essential that studies measure body mass index (BMI) prior to
disease onset. Prospective data from the Black Women’s Health Study show that incidence of
sarcoidosis increased with increasing BMI and weight gain [96]. This relationship has also been
reported in other large longitudinal studies of mostly White, female participants of European
descent [97–99]. Importantly, the studies by COZIER et al. [96] and DUMAS et al. [97] were able to
evaluate pre-diagnostic BMI, including BMI at age 18 years, a time-point many years (even
decades) prior to symptom onset, in women eventually diagnosed with sarcoidosis. Nevertheless,
observational studies have shown that patients with sarcoidosis are more likely to be overweight
or obese [100, 101]. What happens first is still a matter of active research and debate.
There is also an intriguing relationship between tobacco and sarcoidosis. Several studies, including
the ACCESS study, have suggested a lower risk of developing sarcoidosis in smokers [24, 99,
103]. Nicotine has been found to modulate immune response in animal models and suppress
granulomatous inflammation [104, 105]. A small randomised, double-blinded, placebo-controlled
pilot study in 50 patients with active sarcoidosis investigated the effect of nicotine patches versus
placebo patches for 24 weeks. Nicotine treatment was well tolerated and associated with a small,
statistically significant improvement in FVC [106]. Although the study had several limitations,
including large differences in baseline FVC despite randomisation, and small sample size, these
preliminary results bring to centre-stage nicotine as a potential therapy for sarcoidosis.
Infectious exposures
The multisystemic nature of sarcoidosis, its familial and geographical clustering as well as its
clinical and histological similarity with mycobacterial infections have given rise to the
hypothesis that sarcoidosis is caused by an infectious agent [107]. An aerosolised microbial
agent is a tempting hypothesis that could explain environmental, geographic and seasonal
differences, and systemic manifestations of sarcoidosis. The two infectious agents most
commonly suggested as potential culprits are mycobacterial species and Cutibacterium acnes
(formerly Propionibacterium acnes). Although mycobacteria have never been cultured from or
seen in sarcoid granulomas, several studies using molecular techniques have reported the
presence of mycobacterial RNA or DNA in sarcoid granulomas [108, 109]. Some studies have
demonstrated specific anti-mycobacterial immune responses in sarcoidosis patients, but not in
controls. Additionally, in vitro studies have reproduced a similar immunological profile when
immune cells derived from sarcoidosis patients are exposed to mycobacterial agents [108, 110,
111]. In contrast to mycobacteria, C. acnes, another intracellular pathogen, has been cultured
from sarcoid granulomas [116]. Unfortunately, C. acnes is a common commensal agent also
present in healthy subjects and in other granulomatous diseases [117, 118]. Other studies have
found the presence of antigens from other bacteria and less often from fungi and viruses in
sarcoid tissue [107, 112, 113, 119]. Based on this, DRAKE et al. [114] conducted a randomised,
double-blind, placebo-controlled trial of concomitant levofloxacin, ethambutol, azithromycin
and rifampin (CLEAR) therapy in 97 patients with active pulmonary sarcoidosis. The treatment
group did not show any benefit in pulmonary function, 6-min walk distance and most secondary
18 https://doi.org/10.1183/2312508X.10031120
end-points compared to placebo. The CLEAR regime was a broad-spectrum antimicrobial

therapy based on the effectiveness of some of these agents against mycobacteria and the
immunomodulatory properties of azithromycin and levofloxacin [115]. The authors argue, as do
others, that one possible reason for the failure of antimicrobial therapy is that the persistence of
the infectious agent is not necessary in the pathogenesis of sarcoidosis, and only an initial
exposure triggering an immunological cascade is needed. This could explain why
immunosuppression is effective in most patients whereas antimicrobial therapy is not.
Establishing a relationship between an infectious agent and sarcoidosis is complicated, as most

clinical studies are retrospective and experimental models have several limitations. Retrospective
studies pose the concern that the infection may have happened after the appearance of the
disease, particularly given the long latency between clinically apparent disease and diagnosis
(reverse causation bias) [136]. Using the Swedish National Patient Register, ROSSIDES and
co-workers [137, 138] conducted a nested case–control study to evaluate the risk of sarcoidosis
associated with a history of infectious disease. Notably, they excluded diagnoses of infectious
disease that happened within 3 years of the diagnosis of sarcoidosis to minimise reverse
causation bias. They observed a modest association, potentially explained by a latent immune
disturbance related to undiagnosed sarcoidosis. This is in line with their previous findings that
patients with sarcoidosis, even if not receiving treatment, may be at higher risk of developing
serious infections in the first few years after the diagnosis of sarcoidosis. A limitation of the
study was that they relied on International Classification of Diseases (ICD) codes both for
sarcoidosis and infections and did not have access to imaging, histology or microbiological data.
The complex bidirectional relationship of sarcoidosis with infections is not resolved, but it
seems unlikely that, as in the case with occupational exposures, a single agent (microbial or
inorganic compound) is responsible for all or even most of the cases and it is also unlikely that
a persistent infection is required for sarcoidosis to self-perpetuate.
Conclusion
Sarcoidosis is a rare, clinically heterogeneous and sometimes asymptomatic disease, and
identifying the most likely aetiological candidate(s) is challenging. Epidemiological research
into the aetiology of sarcoidosis has been hampered by variability of case definition,
heterogeneity of organ involvement and severity, and myriad other variables. The possibility
remains that prolonged exposure to any of the aforementioned factors (be that an infectious
agent or an inorganic antigen) may not be required to trigger an immunological cascade, adding
further difficulty to establishing associations between sarcoidosis and complex environments.
Solving the epidemiological jigsaw puzzle may allow identification of the causes of sarcoidosis,
improvement of our understanding of disease pathophysiology, and classification as a spectrum
of multisystem granulomatous diseases rather than as a sole entity with a sole cause and a sole
cure. To accomplish this goal, it is important that research moves from the current silos of
clinical medicine, basic science, genetics and epidemiology towards a truly collaborative,
transdisciplinary model. For example, clinical studies must include population health scientists
and epidemiologists, while large, epidemiological cohorts can be leveraged for gene–
environmental interaction studies. While each approach has its own specific limitations, the
jigsaw puzzle can only be solved through a collection of our scientific strengths.
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Disclosures: None declared.
24 https://doi.org/10.1183/2312508X.10031120
Chapter 3
Aetiopathogenesis, molecular determinants and

immunological features
Paolo Spagnolo1 and Johan Grunewald2,3
1
Respiratory Disease Unit, Dept of Cardiac Thoracic, Vascular Sciences and Public Health, University of Padova,
Padova, Italy. 2Respiratory Medicine Division, Dept of Medicine, Karolinska Institutet, Solna, Sweden. 3Dept of
Respiratory Medicine, Theme Inflammation and Infection, Karolinska University Hospital, Stockholm, Sweden.
Corresponding author: Johan Grunewald ( johan.grunewald@ki.se)
Cite as: Spagnolo P, Grunewald J. Aetiopathogenesis, molecular determinants and immunological features. In:
Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society,
2022; pp. 25–40 [https://doi.org/10.1183/2312508X.10015621].
@ERSpublications
The aetiology of sarcoidosis remains undetermined. However, existing evidence suggests that sarcoidosis
results from a complex interplay between multiple environmental or infectious inciting agents and host
genetic factors. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
In the last decade, our knowledge of sarcoidosis pathobiology has improved substantially, yet its
aetiology remains elusive. Immunological features of sarcoidosis include, among others, enhanced
expression of Th1 (and often Th17) cytokines at disease sites, abnormal regulatory T-cell responses,
oligoclonal expansion of CD4+ T-cells consistent with persistent antigen exposure and granuloma
formation. An emerging body of literature suggests that B-cells and antibody responses may also be
involved in disease pathogenesis. Multiple environmental agents have been associated with sarcoidosis,
including mycobacterial or propionibacterial organisms, but the mechanisms through which microbial
infection may cause sarcoidosis remain speculative. Identification of the inciting agent(s) and insight
into the immunological events that determine granuloma formation and evolution to fibrosis will
inevitably facilitate the development of more efficacious therapies.
Introduction
Sarcoidosis is a chronic systemic disease of unknown aetiology, which is characterized by
the presence of noncaseating epithelioid granulomas at disease sites [1, 2]. Disease
immunopathogenesis involves antigen-driven CD4+ T-cell activation secondary to exposure to
putative inhaled antigen(s) in individuals who are genetically susceptible. Dendritic cells (DCs)
present these antigens to CD4+ T-cells, which leads to their activation and proliferation. Whilst
Th1 CD4+ T-cells make up the majority of the cell population, Th17 and Th17.1 cells are also
present [3]. Sarcoidosis is characterised by an abundance of Th1 inflammatory cytokines
secreted by T-cells and innate cells that propagate the inflammatory environment, including
IL-2, IL-17, IFN-γ, TNF-α and TGF-β [4]. This carefully orchestrated recruitment of
pro-inflammatory cells and cytokines results in granuloma formation. As with many other
inflammatory diseases, it is unlikely that a single trigger causes sarcoidosis pathology. Rather, it
is likely that environmental exposure, genetic background, ethnicity, infections, hormones and
https://doi.org/10.1183/2312508X.10015621 25
epigenetic changes are contributors to disease susceptibility [1]. In this chapter, we focus on
environmental/infectious triggers, and discuss the immune cells and mechanisms contributing to
the enhanced immune response typical of sarcoidosis.
Pathology
Pathologically, sarcoidosis is characterised by the presence of discrete, compact noncaseating
granulomas, which consist of highly differentiated mononuclear phagocytes (epithelioid cells
and giant cells) and lymphocytes, and tend to become confluent, forming nodules in the
millimetre size range (table 1 and figure 1) [5].
The central part of the granuloma is composed of macrophages, epithelioid cells and giant cells
with scattered CD4+ T-lymphocytes between them, whereas CD8+ cells, B-lymphocytes,
TABLE 1 Potential causes of granulomatous lung disease
Infectious Noninfectious
Mycobacteria Inflammation
Mycobacterium tuberculosis Sarcoidosis
Nontuberculous mycobacteria Bronchocentric granulomatosis
Fungi Inflammatory bowel disease
Histoplasma spp. Exposure/toxins
Aspergillus spp. Metals
Protozoa Beryllium
Toxoplasma gondii Aluminium
Leishmania spp. Titanium
Metazoa Zirconium
Schistosoma Inorganic dust
Bacteria Silica
Brucella spp. Talc
Borrelia spp. Mineral fibres
Propionibacteria Drugs
Viruses MTX
Epstein–Barr virus IFN
Herpes viruses bacille Calmette–Guérin
Cytomegalovirus Infliximab
Spirochetes Etanercept
Treponema pallidum Leflunomide
Mesalazine
Sirolimus
Immune checkpoint inhibitors
Hypersensitivity pneumonitis
Foreign body reaction
Cancer
Sarcoid-like reactions
Lymphomatoid granulomatosis
Autoimmune diseases
Rheumatoid arthritis
Primary biliary cirrhosis
Vasculitis
Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
Other
Langerhans cell histiocytosis
Aspiration pneumonia
26 https://doi.org/10.1183/2312508X.10015621
AETIOLOGY | P. SPAGNOLO AND J. GRUNEWALD
FIGURE 1 Sarcoid granulomas. Haemotoxylin and eosin stain, magnification ⨯200.
monocytes, mast cells and fibroblasts are mainly located peripherally [6]. In turn, the granuloma
is surrounded by lamellar rings of hyaline collagen. Focal areas of necrosis may be observed,
but the presence of significant necrosis should raise the suspicion of alternative diagnoses [7].
Typically, sarcoid granulomas are distributed along the pulmonary lymphatics, in the pleura and
septa, and along the pulmonary arteries, veins and bronchi. The perilymphatic distribution of
granulomas, which accounts for the high diagnostic yield of transbronchial biopsies [8], is one
of the most helpful features in distinguishing sarcoidosis from other granulomatous lung
diseases. Over time, granulomatous inflammation may progress to fibrosis, which extends from
the periphery to the centre of the granuloma, leading to its complete fibrosis and/or
hyalinisation.
Immunopathogenesis of granuloma formation

Granuloma formation requires a stepwise series of events – the first being the recruitment of
tissue macrophages to disease sites – triggered by a still-unidentified antigen (or antigens). In
experimental models, granulomatous inflammation is downregulated following clearance of the
antigen [9]; conversely, persistence of the antigen (because of its poor solubility and
degradability, for example) perpetuates the activation of T-cells, leading to further accumulation
of macrophages, which can either fuse to form giant multinucleate cells or give rise to
epithelioid cells (figure 2).
In order to induce a granulomatous response, a presumed sarcoid antigen must be processed by

an antigen-presenting cell (APC), i.e. alveolar or tissue macrophages or DCs, with a peptide
fragment complexed in the groove of major histocompatibility complex (MHC) class II
molecules, usually HLA-DR or HLA-DQ [10]. The MHC peptide-binding groove’s antigen-
binding properties are determined by polymorphic amino acid residues, which form pockets that
interact with the antigenic peptide side chains. This step is critical for T-cell recognition of an
antigen by the T-cell receptor (TCR) [11]. The interaction between CD28, a costimulatory
https://doi.org/10.1183/2312508X.10015621 27
Potential sarcoidosis triggers Presentation of

antigenic peptide Naïve
Infectious agents T-lymphocyte
le TCR
l ecu (Th0)
Inorganic substances mo
HLA
28
Organic substances CD
CD86 Th1
Other substances
Antigen processing
CD4+ T-lymphocyte
APC
Granuloma
3
1 α2.
030 TCR
V
R B1* 0101 V β8
D 3*
-
HLA -DRB CD4+ T-lymphocyte 02 TCR
*06
HLA B1
-DQ CD4+ T-lymphocyte
HLA
APC
Antigen clearance; APC Antigen persistence;
reduced IFN-γ levels and
increased IFN-γ levels, reduced
increased IL-10 and TGF-β levels
TGF-β levels; predominance of
Th2 cytokines
Disease resolution Chronic disease
FIGURE 2 Proposed model of sarcoidosis immunopathogenesis. The putative sarcoid antigen is taken up by the
alveolar macrophages and dendritic cells and transported to the draining lymph nodes. In the lymph nodes,
antigen-specific CD4+ T-cells are stimulated by activated antigen-presenting cells (APCs) expressing certain HLA
molecules. Binding of costimulatory molecules CD28 and CD86 optimises the activation of T-cells. An abundance
of inflammatory mediators is then released. The activated T-cells are highly Th1 polarised. They release IL-2,
which causes clonal proliferation of T-cells. Antigen clearance and increased IL-10 levels facilitate disease
remission (bottom left), whereas antigen persistence and a predominance of Th2 cytokines leads to chronic
disease (bottom right; see text for details). TCR: T-cell receptor.
signalling molecule, on T-cells and CD86 on DCs optimises the activation of the “trimolecular
complex” (MHC/peptide/TCR), with the antigen-specific T-cells now ready to orchestrate the
immune response that culminates with granuloma formation [12, 13].
In sarcoidosis, it is typical to see an oligoclonal TCR response with overexpression of particular

variable regions of the α and β chains (i.e. Vβ5, 8, 15, 16, 18 and Vα2.3) [14–16]. Put another
way, the “sarcoid antigen” induces the accumulation and activation of a limited number of Th1
clones, thereby triggering granulomatous inflammation. These restrictions in TCR expression are
more marked in lung than blood lymphocytes and are accompanied by a background of
polyclonal expansion. In accordance with this, a HLA-restricted response has been noted in the
lungs of a subset of patients. Preferential AV2S3 gene usage by CD4+ T-cells associated with
HLA-DRB1*0301 (i.e. DR17) or HLA-DRB3*0101 (i.e. DR52a) alleles was reported by
GRUNEWALD and co-workers [15, 17]. It is noteworthy that these two HLA variants share
identical amino acid sequences in the regions responsible for antigen binding, which may
facilitate the presentation of similar antigenic peptides and expansion of the same population of
T-cells. CD4+ T-helper lymphocytes then amplify the immune response through the release of
28 https://doi.org/10.1183/2312508X.10015621
IFN-γ, IL-2 and other proinflammatory cytokines with the aid of regulatory T-cells (Tregs),
which can also produce IFN-γ [18]. Increased expression of the transcription factor T-bet and
chemokine receptor CXCR3 contribute to a Th1 orientation.
Despite the exaggerated inflammatory response at disease sites, a peripheral anergy is typical of
sarcoidosis, as demonstrated by a reduced delayed-type hypersensitivity to tuberculin, antigens
from Trichophyton spp. or Candida spp. and chemical haptens [19, 20]. This “immune
paradox” has been attributed to a disequilibrium between effector and Tregs, notably
CD4+CD25brightFoxP3+ cells, which exert anti-proliferative effects on naïve T-cells [21].
Alternative hypotheses for the peripheral anergy have been postulated, and include, among
others, a “compartmentalisation” of activated T-cells at disease sites with consequent peripheral
blood lymphopenia, which is also characteristic of the disease [22].
Cells and mediators involved in sarcoidosis granulomatous inflammation

In sarcoidosis, the immune response leading to granuloma formation involves a plethora of
cytokines and chemokines released by diverse immune cells with an enhanced activation status.
Innate immune response
Macrophages are the predominant cell type in the early phases of granuloma formation. In
comparison with control macrophages they show: an enhanced activation status, as indicated by
an increase in key signalling molecules, such as p38 and IL receptor-associated kinase [23];
enhanced pro-inflammatory cytokine production (i.e. TNF-α); and higher expression of
costimulatory molecules, such as CD80 and CD86 [24].
Alveolar macrophages also function as APCs, interacting with T-cells via HLA molecules and
TCRs. Activation of the metabolic checkpoint kinase mammalian target of rapamycin complex
1 (mTORC1) in macrophages promotes their hypertrophy and proliferation, leading to excessive
granuloma formation in mice [25]. Similarly, in patients with sarcoidosis, mTORC1 activation
has been associated with macrophage proliferation and disease progression [25]. Classical
monocytes (CD14++), or inflammatory monocytes, can infiltrate tissues, release inflammatory
cytokines and differentiate from inflammatory macrophages [26]. Blood monocytes from
sarcoidosis patients have a higher expression of Fc receptors and complement receptors, and
both of these enhance their phagocytic activity [27]. In addition, blood mononuclear cells from
sarcoidosis patients display higher Toll-like receptor (TLR)2 and TLR4 expression, and
combined stimulation of TLR2 and nucleotide-binding oligomerization domain containing 2
induces a four-fold increased secretion in TNF-α and a 13-fold higher secretion of IL-1β
compared with healthy subjects [28]. An abnormal TLR2 response (characterised by increased
production of TNF-α and IL-6) following stimulation with TLR2 ligands has also been
demonstrated in BAL cells from patients with sarcoidosis [29]. Intermediate (CD14+CD16+)
monocytes also display proinflammatory properties, as shown by their ability to produce high
amounts of IL-1β, IL-6, IL-12 and TNF-α upon stimulation [30]. In addition, the gene
expression signature of intermediate monocytes demonstrates their facility for presenting
antigens and inducing T-cell activation [31]. Intermediate monocytes specifically promote
proinflammatory Th17 responses [32], which contribute to granulomatous inflammation in
sarcoidosis [33]. High levels of blood intermediate monocytes at the time of diagnosis are
associated with chronic disease, suggesting they can be used as a predictor of disease outcome
in sarcoidosis [34].
Macrophage activation status and polarisation are critical in determining the formation,
persistence and outcome of granulomatous inflammation. In sarcoidosis, granuloma formation
https://doi.org/10.1183/2312508X.10015621 29
has historically been linked with compartmentalised increased release of Th1 cytokines,
including IL-2, IFN-γ and TNF-α, which is believed to drive classical pro-inflammatory (M1)
macrophage activation [35]. However, enhanced CD163+ staining, indicating a shift towards the
M2 macrophage subset, has recently been reported in granulomas from patients with sarcoidosis
as compared with tuberculous granulomas [36]. Interestingly, M2 macrophages may differentiate
from fibrocyte-like cells and produce collagen [37], but their role in sarcoidosis is unclear (i.e.
definition of a profibrotic mechanism inherent to disease pathogenesis or merely part of a
generalised wound-healing response to lung inflammation and injury).
Alveolar macrophages are a major source of IFN-γ. Indeed, compared with normal individuals,
BAL mononuclear cells from patients with pulmonary sarcoidosis spontaneously release a
considerable amount of IFN-γ [38]. IFN-γ impedes the expression of the macrophage
peroxisome proliferator-activated receptor (PPAR)-γ, a negative regulator of inflammation [39].
In normal physiological conditions, macrophages constitutively express PPAR-γ, which inhibits
TNF-α, IL-12 and matrix metalloproteinase release by inducing macrophage IL-10 production.
It has been noted that BAL specimens from patients with pulmonary sarcoidosis reveal a
striking reduction of PPAR-γ activity in alveolar macrophages compared with healthy controls,
with a concomitant upregulation of nuclear factor-κB, a pivotal mediator of the inflammatory
response, suggesting that insufficient PPAR-γ activity contributes to ongoing dysregulated
inflammation in sarcoidosis [40, 41].
Reduced DC function may contribute to susceptibility and persistence of sarcoidosis

granulomatous inflammation [20]. It has been suggested that while DCs in the end organs are
phenotypically and functionally immature (anergic), DCs in the lymph nodes are mature and
polarise pathogenic Th1 T-cells [42]. In keeping with their immature phenotype, DCs in the
sarcoidosis lung are less able than those in the normal lung to induce T-cell proliferation [43].
However, they are more effective inducers of T-cell proliferation than macrophages, through
TCR and costimulatory molecule engagement, and secretion of potent inflammatory mediators,
which, in turn, polarise Th1 T-cells and amplify T-cell proliferation [42]. Moreover, recent data
show that DCs rather than monocytes from sarcoidosis patients have the ability to activate and
polarise T-cells towards Th1 and Th17.1 cells [44].
Overall, in sarcoidosis, DCs appear to have a paradoxical function; they are able to initiate an
antigen-driven, inflammatory, oligoclonal T-cell response [34, 44, 45] but they have also a
diminished immunostimulatory function [20].
Adaptive immune response

T-cells, particularly activated CD4+ T-cells, play a key role in sarcoidosis granulomatous
inflammation. Different subsets of CD4+ helper T-cells are involved in disease
immunopathogenesis. The main feature of acute disease is a Th1/Th17/Treg-driven inflammatory
process that involves macrophages both as APCs and as key effector cells. When triggered by
(as yet unidentified) antigens, APCs release a plethora of cytokines, resulting in the recruitment
of Th1 CD4+ T-cells and monocytes to the lung. In sarcoidosis, the lung is home to up to 10
times as many CD4+ T-cells as the peripheral blood, thus leading to an elevated BAL CD4/CD8
ratio, which, when interpreted in the context of other diagnostic factors, may assist in the
diagnosis of sarcoidosis [46]. The CD4+ T-cells that trigger granuloma formation display a
strong Th1 polarisation. Following TCR activation, CD4+ T-cells express high levels of IFN-γ,
whereas IL-4 and IL-13, which facilitate the fibroproliferative response, are inhibited. IL-12 and
IL-18 act synergistically to promote granuloma formation. The activation of CD4+ T-cell
increases IL-2 production, thus amplifying Th1 polarisation. Sarcoidosis BAL CD4+ T-cells
30 https://doi.org/10.1183/2312508X.10015621
spontaneously release IL-2; however, they display anergic responses to polyclonal TCR
stimulation, consistent with an anergic/exhausted phenotype, which, at least in some patients,
appears to be due to persistent antigen stimulation [47]. Indeed, Th1 cells from sarcoidosis
patients display a reduced proliferative capacity and higher levels of apoptosis, presumably to
downregulate the immune response and limit chronic T-cell activation [48].
IL-17-expressing Th17 cells are a major source of IFN-γ and play a key role in the formation,
maintenance and progression of sarcoid granuloma [49]. They are detected in both the
peripheral blood and BAL of patients with sarcoidosis alveolitis, and respond to the chemotactic
stimulus CCL20 [33]. In patients with Löfgren syndrome, T-bet+/RORγT+ cells proliferate
actively, and produce IFN-γ and IL-17A, suggesting that a Th1/Th17-permissive environment in
the lung might facilitate disease resolution [50].
Tregs normally exert potent anti-proliferative activity and have a key role in modulating
cell-mediated immune responses. Despite being expanded both peripherally and at disease sites
in patients with sarcoidosis, they do not completely inhibit the production of either TNF-α or
IFN-γ. Conversely, they secrete pro-inflammatory cytokines, including IL-4, which sustain
granuloma formation through fibroblast amplification and mast cell activation [51]. TAFLIN et al.
[52] have shown that Treg depletion accelerates in vitro granuloma growth in the mononuclear
cell cultures of healthy controls, but not in patients with active sarcoidosis, thus arguing for a
more preventative than curative effect of Tregs on granulomatous inflammation.
B-cells
Little is known about the role of B-cells in the pathogenesis of sarcoidosis. B-cell accumulation
at the periphery of granulomatous lesions [53] and polyclonal hypergammaglobulinemia are
common findings in sarcoidosis [22]. In addition, patients with chronic active sarcoidosis have
significantly less circulating memory B-cells and a higher number of IL-10-producing regulatory
B-cells than patients with inactive disease and healthy controls [54]. Perigranuloma localisation
of IgA-producing plasma cells and the presence of abundant B-cells in affected tissues further
support the hypothesis that B-cells might contribute to granuloma formation in sarcoidosis [53].
Moreover, in patients with sarcoidosis, the vimentin-induced immune response is characterised
by localisation of B-cells to granulomas and higher concentrations of anti-vimentin antibodies
[55]. Recently, age-associated B-cells, a subpopulation of B-cells, have been found at increased
levels in peripheral blood and BAL in patients with sarcoidosis (relative to healthy subjects) [56].
Notably, the percentage of age-associated B-cells decreased in the peripheral blood of treated
sarcoidosis patients, suggesting that removal of these cells might be therapeutically useful.
Possible aetiological agents

Sarcoidosis as a transmissible disease: the Kveim–Siltzbach antigen
Despite considerable progress in our understanding of disease pathobiology, the aetiology of
sarcoidosis remains elusive. Multiple studies, some of them discussed below, support a
microbial aetiology but no pathogens have been consistently isolated or cultured so far.
Consequently, there is no consensus on the specific microbial agents implicated in sarcoidosis
aetiology nor on the pathogenesis of the disease following antigen exposure.
Supporting evidence for a role of protein antigens in the development of sarcoid granulomas
was initially provided by the Norwegian pathologist Ansgar Kveim, who reported the results of
an experiment wherein homogenates of lymph nodes or spleen from patients with systemic
sarcoidosis were injected subcutaneously in patients with sarcoidosis or healthy controls [57].
https://doi.org/10.1183/2312508X.10015621 31
After 4–6 weeks, a local granulomatous response pathologically identical to sarcoidosis was
observed in a subgroup of patients with sarcoidosis [57]. This reaction, later referred to as the
Kveim–Siltzbach test, emerged as a diagnostic test for sarcoidosis [58], although the identity of
the responsible antigen/s remains unknown [59, 60].
EBERHARDT et al. [61] used mass spectrometry to identify proteins in the Kveim reagent.
Proteomic analysis of Kveim extracts allowed the identification of 74 sarcoidosis tissue-specific
proteins; of these, vimentin, tubulin and α-actinin-4 were selected for further analysis.
Specifically, peripheral blood mononuclear cells (PBMCs) from sarcoidosis patients and healthy
controls were exposed to the three candidate proteins and the reactions were compared with
those of Kveim reagent. Stimulation with Kveim reagent and vimentin induced similar patterns
of cytokine secretion from sarcoidosis PBMCs, which differed from healthy PBMCs.
Notably, the Kveim reaction is characterised by a limited TCR β-chain repertoire consistent with
an antigen-driven T-cell immune response [62].
Infectious agents
The reported seasonality of sarcoidosis is often cited as evidence for an infectious aetiology of
the disease, although sarcoidosis is neither contagious nor cured by antibiotics. The incidence of
sarcoidosis peaks in spring, and this temporal pattern is observed in ethnically and
geographically distinct patient populations [63–65]. Interestingly, many patients diagnosed
during the spring months present acutely with erythema nodosum, arthralgia and stage I chest
radiograph, carry the HLA-DRB1*0301 allele and have a favourable outcome [65–67],
suggesting a specific infection (or class of infectious agents) may be responsible for this disease
phenotype. Associations with genes involved in host resistance to certain pathogens (e.g. solute
carrier family 11 member 1, formerly natural resistance-associated macrophage protein 1, further
support an infectious aetiology [68–70]. The observation that sarcoidosis can occur following
close interpersonal contact [71] and in space–time clusters [72] suggests that sarcoidosis may
also be transmissible.
Mycobacterial organisms
An infectious (or transmissible) aetiology for sarcoidosis was initially suggested by MITCHELL
and colleagues who demonstrated that passaging of pooled, filtered homogenates or
supernatants of mouse granulomatous tissue into other mice induced a granulomatous response
[73–75]. Notably, acid-fast bacilli were also found in some of these lesions, and mycobacteria
with features of Mycobacterium tuberculosis were grown in some of these homogenates.
Uncertainty remained about the causative role of mycobacteria, mainly due to the difficulty in
repeating the passage experiments. ALMENOFF et al. [76] identified cell wall-deficient pathogens
in patients with sarcoidosis using an antibody against M. tuberculosis whole-cell antigen. Some
studies have reported higher levels of antibodies to mycobacteria in sarcoidosis patients
compared with normal controls [77], further supporting a role for mycobacteria in disease
pathogenesis [78].
DRAKE et al. [79] performed PCR analysis for Mycobacterium species on mediastinal or cervical
lymph nodes and lung biopsies from patients with sarcoidosis (n=25) and controls (n=25).
Mycobacterial rRNA sequences were amplified in 15 sarcoidosis specimens (60%) – including
three whose sequences resembled Mycobacterium species other than M. tuberculosis – but in
none of the control tissue specimens.
32 https://doi.org/10.1183/2312508X.10015621
SONG et al. [80] employed a limited proteomic approach to restrict the search for sarcoidosis
tissue antigens to those with physicochemical properties similar to the antigens of the Kveim
reagent (i.e. relative resistance to neutral detergents, heat, acidity, organic solvents, nucleases
and proteases) [78]. Using matrix-associated laser desorption/ionisation time of flight mass
spectrometry and peptide fingerprint methods, they identified M. tuberculosis catalase-
peroxidase (mKatG) in five (55%) out of nine sarcoidosis tissues but none in the 14 control
tissues [80]. They also confirmed the presence of mycobacterial katG DNA in sarcoidosis
tissues using in situ hybridisation. A subsequent related study found an increased number of
mKatG-reactive, IFN-γ-expressing T-cells in the blood and BAL fluid of patients with
sarcoidosis compared with non-tuberculosis sensitised healthy controls [81]. Notably, circulating
mKatG-reactive T-cells were found in patients with chronic active disease but not in those with
inactive disease.
Propionibacterial organisms
Propionibacterium acnes (currently Cutibacterium acnes) and Propionibacterium granulosum
(currently Cutibacterium granulosum), both known to induce granulomatous inflammation
when injected into sensitised rabbits and rats [82, 83], have been isolated from sarcoidosis
samples. EISHI et al. [84] identified P. acnes DNA in >70% of lymph node specimens
obtained from Japanese and European patients, whereas mycobacterial DNA was not detected
in any of the 35 Japanese sarcoidosis tissues and in only five of the 65 European sarcoidosis
tissues. Moreover, EBE et al. [85] observed that a recombinant protein from a P. acnes DNA
expression library induces a proliferative response in PBMC from some patients with
sarcoidosis but not in healthy controls. More recent studies have shown that P. acnes is
frequently found in the lung and lymph nodes of individuals without sarcoidosis, thus
arguing against a pathogenic role for this organism in sarcoidosis [86]. However, P. acnes
may also reside in the lung as a latent organism that can become active and cause sarcoidosis
in patients with hypersensitivity to it [87].
A general infectious hypothesis is further supported by the apparent transmission of sarcoidosis

from organ donors to recipients. In one case, a 34-year-old man who underwent allogenic bone
marrow transplantation for non-Hodgkin lymphoma developed sarcoidosis within 3 months of
the procedure [88]. The diagnosis was confirmed by lung and liver biopsies. Notably, 2 years
before bone marrow harvest, the donor had been diagnosed with pulmonary sarcoidosis. Other
cases of donor-to-recipient transmission of sarcoidosis [89] as well as recurring disease
following lung [90] or heart [91] transplantation have been described, but the transmissible
agent was not identified in any of these case reports.
Interestingly, while writing the present chapter, a study was published that noted immune
responses against the enzyme NAD-dependent histone deacetylase hst4 (NDPD) derived from
Aspergillus nidulans [92]. Lung CD4+ T-cells of patients with acute sarcoidosis, but not
controls, were found to react against a particular NDPD-derived peptide from A. nidulans, a
reaction that was blocked by adding anti-HLA antibodies. Further, these patients had higher
concentrations of anti-NDPD antibodies. The association between a fungal peptide capable of
stimulating the lung T-cells of a subgroup of sarcoidosis patients suggests the possibility that
sarcoidosis (or a subset of sarcoidosis) could be caused by a fungus, although other
circumstances such as exposure to other candidate antigens, or repeated exposure to the NDPD
peptide, may be necessary for inducing the inflammation, as seen in sarcoidosis.
In patients with cancer, the use of immune checkpoint inhibitors (ICIs), such as anti-cytotoxic T-
lymphocyte-associated protein 4 antibodies, programmed death 1 inhibitors and programmed death
https://doi.org/10.1183/2312508X.10015621 33
ligand 1 inhibitors, has been associated with the development of ICI-induced sarcoid-like reactions
[93]. Unravelling the mechanism(s) through which ICI treatment induces sarcoid-like
granulomatous inflammation may provide insight into the immunopathogenesis of sarcoidosis.
Occupational and environmental exposures

A number of possible causes, including infectious agents and various environmental exposures,
have been entertained, yet with inconclusive results. The worldwide distribution of the disease
supports the notion of multiple causative agents; however, if there are multiple causes, then the
uniform reaction of sarcoidosis patients to a common antigenic challenge (e.g. the Kveim–
Siltzbach reagent – see above) is difficult to reconcile.
A number of agents can cause granulomatous lesions, and they should be considered (and
excluded) before the diagnosis of sarcoidosis is established. Proposed sarcoidosis-inducing
agents include, among others, pine trees, clay soil, zirconium, aluminium and talc [94–97]. With
regard to the latter, the presence of birefringent particles within granulomas of the skin and
other affected organs has been reported in ∼20% of patients with sarcoidosis [96]. In addition, a
cross-sectional study of 718 incident sarcoidosis cases enrolled in ACCESS (A Case Control
Etiologic Study of Sarcoidosis) revealed that several exposures to inhaled organic or inorganic
antigens, including agricultural dusts and wood burning, were associated with a significantly
reduced likelihood of having extrapulmonary disease [97]. Notably, the effects of certain
exposures on disease phenotypes differed significantly based on patient ethnicity.
The importance of environmental exposure to the development of sarcoidosis is further supported

by strong associations between certain occupations and disease risk. For instance, among US
Navy-enlisted men (1965–1993), the risk for sarcoidosis was statistically associated with those
assigned to aircraft carriers, probably because of common environmental exposures [98]. A
dose–response correlation was described between exposures involving the handling or burning of
wood (e.g. use of wood stoves or fireplaces for home heating) and sarcoidosis [99]. Moreover,
clustering of sarcoidosis cases among firefighters in relation to common smoke exposures was
also reported [71], suggesting that inhalation of particles present in smoke may trigger
sarcoidosis. IZBICKI et al. [100] reported that firefighters exposed to “dust” during the collapse of
the World Trade Center were at a significantly increased risk of developing sarcoidosis or
“sarcoid-like” granulomatous pulmonary disease during the 5 years following the disaster.
Vimentin
Vimentin is a type III filament protein that is part of the cytoskeleton of human mesenchymal
cells and bacteria, as well as a component of the Kveim reagent. Vimentin has also been
suggested to serve as a sarcoid antigen causing clonal expansion of CD4+ T-lymphocytes carrying
the TCR Vα2.3+/Vβ22+ in patients with Löfgren syndrome [101]. Indeed, molecular modelling
revealed specific TCR/HLA-DRB1*03-peptide interactions, with a previously identified
vimentin-derived protein [102] perfectly matching both the HLA peptide-binding pocket and the
TCR Vβ22 loop [101]. While reactivity against the self-protein vimentin would suggest that
sarcoidosis has an autoimmune component, the ideal fit of vimentin into the peptide-binding cleft
of HLA-DRB1*03 molecules may be due to molecular mimicry. In other words, vimentin might
merely resemble the molecular structure of the culprit antigen. Other associated antigens/
environmental factors may also trigger granulomatous inflammation through molecular mimicry.
Serum amyloid A
Serum amyloid A (SAA) is a highly conserved, acute-phase protein synthetised predominantly
by the liver. CHEN et al. [103] assessed the role of SAA as an innate regulator of granulomatous
34 https://doi.org/10.1183/2312508X.10015621
inflammation in sarcoidosis. Specifically, they determined SAA expression in sarcoidosis and

control tissues and its effect on nuclear factor-κB induction, cytokine expression and TLR-2
stimulation. SAA localised to macrophages with sarcoidosis granulomas and was able to regulate
experimental Th1-mediated granulomatous inflammation by stimulating TNF-α, IL-10 and IL-18
production. Notably, these effects were inhibited by blocking TLR-2. However, while fairly
specific, SAA staining has a sensitivity of only 44% for a diagnosis of sarcoidosis, suggesting
that SAA production may not be a universal mechanism in the development of the disease [104].
The evolution of granulomatous inflammation: from resolution to fibrosis

Non-resolving granulomatous inflammation may lead to pulmonary fibrosis, which complicates
the course of ⩽20% of patients with sarcoidosis [105]. Recent data support a model of
persistent inflammation – based on several potential abnormalities, including impaired antigen
clearance, hyperresponsive effector T-cells and persistent macrophage activation – followed by
fibrotic transformation [106].
Step 1: persistent granulomatous inflammation

Chronic progressive sarcoidosis is characterised by increased levels of TNF-α and reduced
levels of TGF-β [107]. Indeed, in patients with sarcoidosis, alveolar macrophages releasing
higher levels of TGF-β following ex vivo stimulation are associated with higher rates of
spontaneous remission [108]. These data support the argument for the role of TGF-β as an
anti-inflammatory cytokine, but with opposite effects in disease resolution and fibrosis. Effector
T-cells that are chronically activated often display markers of exhaustion, such as upregulation
of programmed death-1 [109]; this suggests that chronic inflammation results from exhausted
effector T-cell activity with inability to clear the antigen. In contrast with effector T-cells, Tregs
downregulate immune responses. In fact, highly activated circulating Tregs were noted in patients
with Löfgren syndrome, who had a good prognosis and a low risk of chronic disease [110]. In
addition, the ratio of Tregs to effector T-cells in BAL is significantly higher in patients with
inactive or remitting disease compared with those with chronic disease [111]. Furthermore, an
open-label phase II study of 20 patients with histologically proven sarcoidosis showed that
inhalation of vasoactive intestine peptide (VIP) significantly increased the number of BAL
CD4+/CD127−/CD25+ T-cells, which display regulatory activities, and was associated with a
significantly reduced production of TNF-α [111].
Step 2: pulmonary fibrosis

Tissue fibrosis is believed to result from uncontrolled inflammation and persistent immune
activation. However, it is not known whether fibrosis is triggered by an inherent (genetic)
predisposition or by specific profibrotic events, or both. LOCKSTONE et al. [112] showed that genes
involved in leukocyte activation and differentiation, cytokine production, intracellular signalling and
cell life (e.g. apoptosis, cell cycle, cell proliferation and homeostasis) are enriched in transbronchial
biopsy samples from patients with progressive fibrotic sarcoidosis compared with self-limiting
disease. Genetic variations within TGF-β have also been suggested as predisposing factors for the
development of sarcoidosis-associated pulmonary fibrosis, but the results are inconclusive
[113–115]. Other cytokines may also be important. For instance, IL-5 levels were significantly
higher in the sera of sarcoidosis patients with fibrotic versus non-fibrotic disease [116], although
whether this cytokine has a pathogenetic role or is merely a marker of fibrotic disease is unknown.
Conclusion and perspective

Although the aetiology of sarcoidosis remains undetermined, existing evidence supports the
notion of multiple causes of the disease, with its phenotypic heterogeneity being determined by
https://doi.org/10.1183/2312508X.10015621 35
a complex interplay between the trigger/s and host genetic factors. Variables pertaining to the
host genetic background and/or environmental exposures are also likely to account for the
substantial diversity observed across ethnic groups in terms of clinical manifestations and
disease severity. Most of the associations between exposure and sarcoidosis risk and severity are
based solely on epidemiological data. More robust studies combining clinical, microbiological
and immunological data are needed to clarify the link between environmental agents and
sarcoidosis.
Phenotypic heterogeneity within sarcoidosis may result from different triggers but also different
types of immunological response to the inciting factors. Recent data question the traditional
view of sarcoidosis as a purely CD4+ T-cell- and mainly Th-1-driven disease; future studies
should further explore the regulatory features of T-cells, as well as the role of other cells with
potential impact on antigen processing, presentation and downstream effector functions.
A plethora of immune cells and cytokines are involved in the pathogenesis of sarcoidosis;
therefore, potentially successful therapies, either drugs with pleiotropic effects or combinations
of specific treatments, should influence activation, function and survival of multiple immune
cells involved in granuloma formation and maintenance.
Finally, future studies should aim for more rigorous patient classification, not merely according
to Löfgren syndrome and non-Löfgren sarcoidosis, but also according to HLA alleles, sex, the
presence of extrapulmonary manifestations and the type of organ involvement, as this is
essential for proper clinical management and possibly antigen discovery.
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Disclosures: P. Spagnolo reports receiving the following, outside the submitted work: grants, personal fees and
nonfinancial support from Roche, PPM Services and Boehringer-Ingelheim; and personal fees from Red X Pharma,
Galapagos, Chiesi, Santhera, Lupin, Pieris and Novartis. P. Spagnolo’s wife is an employee of
Novartis. J. Grunewald reports receiving support from the Swedish Research Council and the Swedish Heart-Lung
Foundation.
40 https://doi.org/10.1183/2312508X.10015621
Chapter 4
Unravelling the genetic basis of sarcoidosis

Coline H.M. van Moorsel1, Martin Petrek2 and Natalia V. Rivera 3
1
ILD Center of Excellence, St Antonius Hospital, Nieuwegein, The Netherlands. 2Dept of Pathological Physiology,
Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech Republic. 3Respiratory Medicine
Division, Dept of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
Corresponding author: Coline H.M. van Moorsel (c.van.moorsel@antoniusziekenhuis.nl)
Cite as: van Moorsel CHM, Petrek M, Rivera NV. Unravelling the genetic basis of sarcoidosis. In: Bonella F, Culver DA,
Israël-Biet D, eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 41–56
[https://doi.org/10.1183/2312508X.10031320].
@ERSpublications
Genes and genetic variants involved in the risk for sarcoidosis associate with diverse manifestations of
organ involvement, disease severity and clinical course, and commonly vary among different ethnic groups
https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis is a heterogeneous disease with significant heritability and a significant proportion of

familial disease, providing convincing evidence for a role of genetic factors in disease development.
Numerous genes have been shown to be involved in the risk for disease development and its
phenotypic manifestations. So far, strong genetic associations have been detected only for specific
ethnic and phenotypic populations and involve the HLA class II-encoding peptides that are important
for antigen recognition, and may thus be disease trigger related. Many of the genomic regions and
genes that have been shown to associate with sarcoidosis significantly overlap with those identified for
a wide spectrum of immune-mediated diseases, while only a few are specific for sarcoidosis or a
phenotype of the disease. Although recent whole-exome sequencing approaches have not yet provided
easily interpretable results, such unbiased deep-sequencing methods hold promise for further
unravelling of the immunopathogenic pathways underlying the different disease entities in sarcoidosis.
Introduction
For decades, we have presented sarcoidosis as a complex disorder caused by a combination of
genetic and environmental factors [1]. However, only recently have we come to understand that
both discovering and understanding the role of these factors in disease development is even
more complex than anticipated. The influence of genetic factors contributing to disease can be
studied in several ways, from evaluations of familial disease to cracking the genetic code. In this
chapter, we will follow this path and describe the main findings and the search for clinically
translational aspects.
Familial disease
The aggregation of sarcoidosis in families has been reported for over a century and suggests a
shared aetiology among family members. The estimated prevalence of familial disease, defined
by the presence of two or more family members with sarcoidosis, has ranged between 1% in a
Turkish population [2] and 35% in an African-American population [3]. A meta-analysis based
https://doi.org/10.1183/2312508X.10031320 41
on 12 populations reported a pooled prevalence of familial sarcoidosis of 7.3% (95% CI 4.1–

11.4%) [4, 5]. To what extent population differences in the prevalence of familial disease are
caused by methodological confounders or represent true population characteristics is unknown.
Further evidence for familial disease arose from studies comparing the presence of a positive
family history of sarcoidosis between patients and controls. The multicentre ACCESS (A case–
control etiology study of sarcoidosis) study, including 706 case–control pairs, found higher odds
for a positive family history of sarcoidosis in patients than in controls (OR 4.6, 95% CI 2.2–9.6)
[6]. Most importantly, an absence of increased risk for spouses was noted [6], providing further
evidence for a role of heritable factors in disease aetiology. The largest study to date, including
23 880 proband sarcoidosis cases from the Swedish National Patient Register and identification
of relatives through the multigeneration register, found a comparable familial relative risk of 3.7
(95% CI 3.4‒4.1), associated with having at least one first-degree relative with sarcoidosis [7].
A slight increase in risk was observed for two or more relatives with sarcoidosis and for
Löfgren syndrome (OR 4.7 and 4.1, respectively) [7]. Overall, it can be concluded that a
significant proportion of patients have familial sarcoidosis and that having a family member
with sarcoidosis associates with an approximately 4-fold increased risk of developing
the disease.
Familial occurrence of a disease is linked to shared genetic or environmental exposures. The

contribution of heritable genetic factors can be estimated by calculating heritability. Heritability
indicates how much of the variability in a given trait in the population is due to genetic
differences among people. Three studies varying widely in methodology estimated heritability
for sarcoidosis and reported a heritability of 60–70% (SE ±11–18%) in female probands of 80
African-American sarcoidosis patients [3], 66% (95% CI 45–80%) in 210 Danish–Finnish twin
pairs with at least one with sarcoidosis [8], and 39% (95% CI 12‒65%) in the Swedish national
registry study [7]. From these studies, we can infer that there is significant heritability, and that
genetics therefore plays an important role in the development of sarcoidosis. However,
differences among populations, sexes and phenotypes of sarcoidosis exist.
For sarcoidosis as a whole, a clear-cut pattern of inheritance, as is known for monogenic

diseases, is not recognised. Furthermore, limited studies have described clinical phenotypes in
familial disease. So far, it has been found that males and females are equally affected in familial
disease and may express any of the phenotypes of sarcoidosis, including Löfgren syndrome and
Heerfordt syndrome [7, 9, 10]. While pulmonary involvement appears to be the most common,
any organ may be affected [9, 11–13]. Comparisons between familial and sporadic cohorts
found a small difference, hinting towards an increased frequency of specific (combinations of )
organ involvement [13, 14] and more severe disease [12, 14] in familial cases, which deserves
further investigation.
A spectrum of immune-mediated diseases

The family health history of patients is not only informative on risk for disease but can also
identify clusters of diseases, a powerful tool for the detection of shared pathogeneses. A review
of studies up to 2018 showed that significant disease clustering with sarcoidosis was found for
14 immune-mediated diseases with ORs ranging from 1.5 to 12.8 [15]. The evidence is
comprehensive, particularly for autoimmune thyroid disease, coeliac disease and ulcerative
colitis. Not only are these diseases more common in sarcoidosis patients and in families of
sarcoidosis patients, but patients with these diseases also reported an increased prevalence of
sarcoidosis [15]. These studies show that sarcoidosis is a disease phenotype within a spectrum
of immune-mediated disorders. Part of the genetic findings may thus relate to a general
42 https://doi.org/10.1183/2312508X.10031320
GENETICS | C.H.M. VAN MOORSEL ET AL.
susceptibility to immune-mediated disorders, while another part may be specific for sarcoidosis,
phenotypes of sarcoidosis or a particular family with disease (figure 1). Contributing genetic
factors, such as single-nucleotide variants, copy-number variations, epistatic interactions and
modifier effects, act in combination with various environmental factors. Thus, when searching
for heritable factors in sarcoidosis, multiple genes are expected to be found, each contributing to
an increased risk for this polygenic disease under specific environmental circumstances.
Genetic studies
Genetic investigations suggest that the origin of sarcoidosis results from the interplay between
genetic and environmental factors. Moreover, such interplay may vary across ethnicities and
geographical locations. To date, several genetic studies have been conducted to decipher the
ANXA11
Sarcoidosis
NOD2
HLA-DRB1*11 EOS CD
LS BTNL2
HLA-DRB1*03
CS
SLE, T1D FS
HLA-DRB1*15
BACH2
IMD60 XS
MS, SLE
MS, SLE
T1D
HLA-DRB1*04
RA
Immune-mediated diseases
HLA-DRB1*13
Pool of common genetic variants
FIGURE 1 Genetic variation contributes to susceptibility for sarcoidosis and its phenotypic manifestations.
Genetic loci predisposing subjects to sarcoidosis largely overlap with other immune-mediated disorders.
Phenotypes of sarcoidosis include Löfgren syndrome (LS), familial sarcoidosis (FS), chronic sarcoidosis (CS),
extrapulmonary sarcoidosis (XS) and early-onset sarcoidosis (EOS). Examples of specific genes with variants that
predispose to these phenotypes of sarcoidosis or other immune-mediated diseases are provided within the blue
ellipses. Examples of immune-mediated diseases include type I diabetes mellitus (T1D), systemic lupus
erythematosus (SLE), immunodeficiency 60 (IMD60), rheumatoid arthritis (RA), Crohn disease (CD) and multiple
sclerosis (MS). Combinations of genetic variants and environmental factors may influence disease phenotypic
traits such as disease severity, chronicity, organ involvement or treatment response. Red dots indicate rare
mutations that contribute to disease development (shown in red: EOS, IMD60 and FS), particularly in familial
cases. A BACH2 mutation in FS was only observed once. NOD2: nucleotide-binding oligomerisation domain
containing 2 gene; BACH2: BTB domain and CNC homologue 2 gene.
https://doi.org/10.1183/2312508X.10031320 43
genetic architecture of sarcoidosis, including linkage studies, genome-wide association studies

(GWAS), high-density mapping studies (e.g. ImmunoChip) and, more recently, whole-exome
sequencing (WES) and whole-genome sequencing (WGS) studies. Nevertheless, the genetic
architecture of sarcoidosis is far from being fully characterised, and only a few genetic variants
have been identified as genetic risk factors for disease development or disease modification.
The primary reason for this setback has been attributed to the limited number of samples
included in prior studies, the lack of population diversity, and the disease heterogeneity
encountered in the disease definition and its subphenotypes.
Involvement of the HLA region

In the past decades, HLA studies have been a major driving force in the genetics of sarcoidosis.
Immunological features underlying the pathogenesis of the disease, such as an altered immune
response and involvement of different Th subsets and B-cells, as reviewed by LEE et al. [16],
have provided several reasons for investigating genetic variations in the HLA complex [17], also
known as the major histocompatibility complex (MHC). Of note, the MHC spans around 4 Mbp
on the short arm of chromosome 6 (6p21.3). It is the most polymorphic region in the human
genome, with several thousand alleles encoding functional polypeptides [18]. The MHC has
been characterised as the most predominant determinant for complex diseases, including
autoimmune disorders, infectious diseases, cancers and neuropsychiatric diseases [19]. Recent
findings suggest an extended MHC (xMHC) region that comprises 421 loci and spans 7.6 Mbp
[20]. Genetic variations, such as single-nucleotide polymorphisms (SNPs), are abundant in the
MHC and xMHC, and are valuable for constructing HLA haplotypes and mapping
disease-related genes within the HLA region. Concerning sarcoidosis, several SNPs in genes in
the MHC and xMHC have been reported to be associated with disease risk, clinical disease
course and organ manifestations, as highlighted in table 1.
So far, current genetic studies have identified many associations with disease risk and
target-organ phenotypes. HLA class I and II genes appear to be significant drivers in disease
susceptibility, target-organ phenotypes and clinical outcomes of sarcoidosis. Genetic
associations with the MHC class I genes HLA-A, HLA-B and HLA-C have been associated with
disease risk. Among the MHC class II genes, the HLA-DBR1 locus is the predominantly
associated gene, with various alleles demonstrating associations with disease risk, disease course
and extrapulmonary phenotypes. Significant findings between HLA-DRB1 alleles and distinct
sarcoidosis phenotypes are shown in table 2.
Another important finding in the vicinity of the HLA-DRB1 locus is the gene encoding
butyrophilin-like protein 2 (BTLN2), for which it has been shown that the risk variant has an
effect on protein functionality [40]. A recent meta-analysis based on 10 studies showed BTNL2
as a risk factor for sarcoidosis [66].
Phenotypic associations with HLA

Most interestingly, the highly polymorphic nature of the HLA-DRB1 gene causes highly
diverting functional peptides across populations worldwide. The strongest associations in
HLA-DRB1 are population specific, with DRB1*03:01 associations with the mild forms of
sarcoidosis with ORs ranging between 6.71 in Swedish and 12.5 in Dutch populations [50, 61],
and DRB1*03:02 in African-Americans [43]. The HLA-DRB1*03:01 allele is more common in
populations of European ancestry and is largely absent in populations of African and Asian
ancestry. It is noteworthy that variants in the HLA-DRB1 locus represent one of the most
significant risk factors across the spectrum of several autoimmune disorders [67]. However, it is
44 https://doi.org/10.1183/2312508X.10031320
TABLE 1 Major histocompatibility complex (MHC) genes associated with sarcoidosis occurrence and
phenotypes
Extended MHC Established functions Gene First author [ref.]

region [20] for innate or adaptive
immunity [20]#
Extended class I ND ZNF192, PGBD1, ZSCAN12, RIVERA [21]

subregion TRIM27, OR12D3
Antigen processing/ UBD RIVERA [21]
presentation
Classical class I ND ZNRD1, TRIM31, TRIM40, RIVERA [21]
subregion TRIM10, TRIM15, TRIM26,
TRIM39, GNL1, ABCF1,
C6orf134, C6orf136, KIAA1949,
FLOT1, DDR1, GTF2H4, VARS2,
SFTPG, DPCR1, HCG22,
C6orf15, CDSN, PSORS1C1
Antigen processing/ HLA-A MARTINETTI [22]
presentation
Antigen processing/ HLA-C ADRIANTO [23]
presentation
Antigen processing/ HLA-B MÖLLER [24], BREWERTON [25],
presentation SMITH [26], HEDFORS [27], GARDNER [28]
Classical class III ND BAT1 RIVERA [21]
subregion
Inflammation ATP6V1G2 RIVERA [21]
Inflammation TNF-α GRUNEWALD [29], SONG [30],
SHARMA [31], WIJNEN [32], DECOCK [33],
AMBER [34]
ND LTA RIVERA [21], RUDDLE [35]
ND BAT2, CSNK2B, CLIC1, MSH5, RIVERA [21]
C6orf27, VARS, C6orf48,
SLC44A4, CFB, STK19,
TNXB, CREBL1
Stress response HSPA1L FISCHER [36], WOLIN [37]
ND NOTCH4 RIVERA [21], ADRIANTO [23]
Classical class II ND C6orf10 RIVERA [21], FISCHER [38]
subregion
Immunoglobulin BTNL2 RIVERA [21], MORAIS [39], VALENTONYTE [40],
superfamily LI [41], RYBICKI [42]
Antigen processing/ HLA-DRA RIVERA [21], FISCHER [38], LEVIN [43]
presentation
Antigen processing/ HLA-DRB1 RIVERA [21], HEDFORS [27],
presentation GARDNER [28], FISCHER [36], LEVIN [43],
DARLINGTON [44], CLEVEN [45], BERLIN [46],
ROSSMAN [47], GRUNEWALD [48], ZHOU [49],
SATO [50], GARMAN [51]
Antigen processing/ HLA-DRB3 ROSSMAN [47], VOORTER [52],
presentation BOGUNIA-KUBIK [53]
Antigen processing/ HLA-DRB5 ADRIANTO [23]
presentation
Antigen processing/ HLA-DQA1 RIVERA [21], BERLIN [46]
presentation
Antigen processing/ HLA-DQB1 RIVERA [21], VOORTER [52], NARUSE [54],
presentation SCHÜRMANN [55]
Continued
https://doi.org/10.1183/2312508X.10031320 45
TABLE 1 Continued
Extended MHC Established functions Gene First author [ref.]

region [20] for innate or adaptive
immunity [20]#
Antigen processing/ TAP2 FOLEY [56]

presentation
Antigen processing/ TAP1 FOLEY [56]
presentation
ND HLA-DOB RIVERA [21]
ND HLA-DPA1 CLEVEN [45]
ND HLA-DPB1 CLEVEN [45], SCHÜRMANN [55],
MALIARIK [57]
ND: not described in [20]. #: established functions for innate or adaptive immunity described in [20].
not the causal genetic factor for driving autoimmunity, thus stressing the implication of other
genetic factors, along with environmental factors and their gene–environment interactions.
HLA-DRB1 is known for recognising triggers, such as infectious agents, environmental factors
(e.g. smoking and occupational/chemical exposures) and autoantigens (e.g. vimentin). Triggers
associated with HLA-DRB1 alleles may determine risk of disease, disease chronicity and
prognosis across various populations. Together, these HLA-DRB1 associations represent the most
robust genetic findings in sarcoidosis, and some of these are currently the only ones that may be
of clinical utility in specific populations. This illustrates the complexity of unravelling the cause of
disease and the contributions of genetic and environmental factors that may only come together in
particular populations, at a particular locality and under particular circumstances.
Genome-wide findings in sarcoidosis

Next to major genetic findings in the MHC region, robust findings in other parts of the genome
are known, although with lower odds and less replication. Most of these associations have been
identified by GWAS in which the frequencies of up to millions of common variants in the
genome are compared between case and control cohorts. Several findings that represent genetic
associations with sarcoidosis specifically, with sarcoidosis and other immune-mediated disorders
in general, or with specific phenotypes of sarcoidosis are described below.
The best known and most highly replicated genetic association is found in the gene for annexin
A11 (ANXA11) at the locus rs1049550. It was first discovered in a German cohort of 490
patients with sarcoidosis by GWAS [68] and these results were subsequently replicated in
multiple European cohorts [69–72] and in cohorts of European and African-American ancestry
[73]. All studies showed a protective effect for the minor T allele with an OR ranging between
0.59 and 0.84. The polymorphism results in an amino-acid change, substituting arginine with
cysteine at position 230 (R230C) within a highly conserved domain that is responsible for
calcium-binding properties. It is suggested that this change results in dysfunctional ANXA11,
which can influence several cellular processes, including altered cell trafficking and apoptosis,
possibly leading to persistent granuloma formation [74]. The effect of rs1049550 also appeared
to be more pronounced in chronic disease or advanced Scadding stages, but this could not be
confirmed in all studies [39, 69–74]. Additionally, an in-depth study of 209 SNPs covering the
ANXA11 gene showed that rare variants in African-American patients with sarcoidosis were
independently associated with disease susceptibility and radiographic Scadding stage IV [73].
Furthermore, a recent sex-stratified analysis found that the ANXA11 locus was exclusively
46 https://doi.org/10.1183/2312508X.10031320
TABLE 2 Associations between HLA-DRB1 alleles/allelic groups and phenotypes of sarcoidosis
Phenotype HLA-DRB1 First author [ref.]
Risk for sarcoidosis HLA-DRB1*05 SATO [50]

HLA-DRB1*07 YANARDAG [58]
HLA-DRB1*15:01 ROSSMAN [47], SATO [50],
WENNERSTRÖM [59]
HLA-DRB1*12 SATO [50], ISHIHARA [60]
HLA-DRB1*12:01 LEVIN [43], ROSSMAN [47]
HLA-DRB1*11 ZHOU [49], ISHIHARA [60]
HLA-DRB1*11:01 LEVIN [43], ROSSMAN [47]
HLA-DRB1*14 SATO [50], YANARDAG [58]
Löfgren syndrome HLA-DRB1*03 GRUNEWALD [61]
Resolving disease in Europeans/ HLA-DRB1*03:01 LEVIN [43], WENNERSTRÖM [59],
protective in African-Americans GRUNEWALD [61]
Organ involvement in African-Americans HLA-DRB1*03:01 LEVIN [43]
Acute onset/good prognosis HLA-DRB1*03:01 GRUNEWALD [61]
Acute onset/good prognosis in HLA-DRB1*03:01 IDALI [62]
several groups
Decreased risk for persistent HLA-DRB1*03:02 LEVIN [43]
radiographic disease in
African-Americans
Skin sarcoidosis HLA-DRB1*03:02 LEVIN [43]
Risk for non-Löfgren syndrome HLA-DRB1*14, HLA-DRB1*11, GRUNEWALD [61]
HLA-DRB1*15
Protective against non-Löfgren HLA-DRB1*01, HLA-DRB1*03 GRUNEWALD [61]
syndrome and nonresolving disease
Protective against sarcoidosis in several HLA-DRB1*01:01 SATO [50], WENNERSTRÖM [59]
populations
Protective against sarcoidosis in HLA-DRB1*07 ZHOU [49]
Han Chinese
Resistant to disease HLA-DRB1*1302 ISHIHARA [60]
Risk for persistent disease HLA-DRB1*15 LEVIN [43]
Risk for extrapulmonary involvement HLA-DRB1*15 DARLINGTON [44], YANARDAG [58]
Risk for increased lymphocytosis and HLA-DRB1*15 KARAKAYA [63]
cell phenotypes in BAL fluid
Protective against sarcoidosis HLA-DRB1*04:01, ROSSMAN [47]
HLA-DRB1*04:04,
HLA-DRB1*04:07, HLA-DRB1*15:03
Protective against sarcoidosis in several HLA-DRB1*04 DARLINGTON [44]
populations
Risk for Heerfordt syndrome HLA-DRB1*04 DARLINGTON [64]
Risk for uveitis and ocular sarcoidosis HLA-DRB1*04 DARLINGTON [64]
Risk for hypercalcaemia HLA-DRB1*04 WERNER [65]
Risk for extrapulmonary involvement HLA-DRB1*04 DARLINGTON [64]
Risk for stage II/III chest radiograph HLA-DRB1*11:01 ROSSMAN [47]
Risk for severe pulmonary sarcoidosis/ HLA-DRB1*15:01:01 VOORTER [52]
stage II–IV chest radiograph
associated with non-Löfgren syndrome males in European and African-American populations

[75], providing further evidence for the role of ANXA11 in sarcoidosis phenotypes. Most
interestingly, ANXA11 is one of the few genes specifically associated with sarcoidosis and not
with any other immune-mediated diseases in GWAS. Due to this specificity, ANXA11 may
provide the key to understanding sarcoidosis-specific disease processes and should therefore be
the focus of further research.
https://doi.org/10.1183/2312508X.10031320 47
Associations with immune-mediated disease genes

A drawback of GWAS is that they require large patient cohorts that may not always be directly
available in the case of a rare disease or disease phenotype. Targeted candidate gene-association
studies involve single genes chosen on the basis of biological plausibility and have considerable
power in relatively small cohorts but can only be trusted in the case of independent replication
of the results. The CC chemokine receptor 5 (CCR5) plays an important role in T-cell function,
and polymorphisms in the encoding CCR5 gene are known to influence its expression. These
polymorphisms were therefore interesting candidates for a targeted analysis. Subsequent studies
showed that genetic variants in CCR5 did not predispose to sarcoidosis in general but only to
phenotypes of the disease. A CCR5 haplotype was found to be associated with persistent lung
involvement in a study of British and Dutch sarcoidosis patients [76], and a promoter
polymorphism with worsening of pulmonary function over time in chronic beryllium disease [77].
Moreover, promoter polymorphisms in CCR5 were associated with Löfgren syndrome in females
[78]. Löfgren syndrome has sex-specific manifestations, and CCR5 expression may be oestrogen
dependent. Recently, a third CCR5 promoter polymorphism was associated with susceptibility to
Löfgren syndrome and with quantitative and qualitative changes in CCR5, potentially dampening
the inflammatory response [79]. Together, these studies provide evidence for an influence of
CCR5 polymorphisms on the development of certain phenotypes of sarcoidosis.
Multiples other genes outside the HLA region that are involved in immune regulation have been
associated with sarcoidosis and other immune-mediated diseases, such as IL23R and CCDC88B
[80]. The IL-23 receptor gene (IL23R) is one of the most replicated susceptibility genes for
immune-mediated disorders [81]. The receptor is expressed in multiple cell types, including
Th17 cells, natural killer cells and macrophages, promoting signalling and cytokine production
[82, 83], all of which are implicated in sarcoidosis disease development. The IL23R SNP
rs11209026 causes an amino-acid change from arginine to glutamine at position 381 and was
found to be associated with chronic sarcoidosis in a cohort of 1996 German sarcoidosis patients
(OR 0.63) and 342 German trios (OR 0.50) [81]. Further study of the polymorphism in a small
American cohort of predominantly European descent confirmed the finding and described its
association with sarcoidosis with uveitis [84]. Experimental studies on the functional impact of
the polymorphism showed cell-type-specific changes in cellular processes. It was shown that the
IL-23-induced Th17 effector function was impaired in cells derived from healthy controls and
psoriatic patients who were carrying the protective 381 glutamine-encoding allele [83, 85].
Moreover, monocyte-derived macrophages from patients with inflammatory bowel disease who
carried the glutamine-encoding allele showed a reduction in antimicrobial mechanisms and
intracellular bacterial clearance relative to noncarriers [86]. These studies illustrate that, although
the protective effect of the polymorphism is shared among immune-mediated diseases, its role
in pathogenesis may differ between these diseases. This may explain why therapeutic
interference in the associated pathway may be successful in some immune-mediated diseases
but unsuccessful in others, including sarcoidosis [87]. Such differences may be caused by
different subsets of cells that are critically involved in disease pathogenesis but may also depend
on additional genetic variants in IL23R. Several other polymorphisms in IL23R were found to
associate with sarcoidosis in multiple European and Japanese cohorts but not with
African-American patients or other immune-mediated diseases [38, 88]. Furthermore, the most
significant lead locus (rs61780312) for interaction with smoking in sarcoidosis was also
detected in IL23R, supporting a role for environmental factors on the pathogenic effect of
genetic variants in IL23R [89].
So far, GWAS and candidate gene studies on common variants can explain only part of the
heritability in sarcoidosis, and a large proportion of the genetic risk remains to be discovered
48 https://doi.org/10.1183/2312508X.10031320
(also known as the missing heritability [90]). It is therefore thought that not only common
variants, such as those described above, but also rare or unique variants predispose patients to
the development of sarcoidosis.
Exploring the whole exome

Although familial disease is recognised and heritability is considerable, no causal genes have
been identified that carry variants responsible for Mendelian inheritance of sarcoidosis in adults.
However, in early-onset sarcoidosis and particularly in its familial form, called Blau syndrome,
carriage of a mutation in the gene encoding nucleotide-binding oligomerisation domain
containing 2 (NOD2) has been shown to cause monogenic autoinflammatory disease that is
characterised by the triad of skin rash, arthritis and uveitis manifesting before the age of 5 years
[91]. Surprisingly, no significant associations between NOD2 and sarcoidosis have been found,
not even in a subgroup of adult sarcoidosis patients with organ involvement comparable to that
of early-onset sarcoidosis [92, 93], although NOD2-associated signalling pathways are involved
in disease pathogenesis in sarcoidosis.
With WES, all sequence variation in the exonic protein-coding regions (exome) in the genome
is determined at once. Since WES applicability was introduced more than a decade ago [94–96],
its utility has been driven by the idea that 85% of disease-causing variants that have large
effects in Mendelian disorders and disease-related traits are located in coding regions that
account for 1% of the genome [97]. Thus, WES has been suggested to be highly suited for the
discovery of new variants and genes that may be causal to common diseases [96]. However, the
highest yield is achieved in those cases with a very strong family history of disease, where
the presence of rare variants with a very large effect may be expected. The majority of WES
studies in clinical practice and research were therefore performed in families with the aim of
identifying new mutations plausibly linked to the disease arising in the affected child despite
healthy parents. A high yield is achieved with the application of WES in classical monogenic
disease; however, WES may also be valuable in complex diseases, such as sarcoidosis, to
identify rare (minor allele frequency (MAF) <0.01) or low-frequency (0.01<MAF<0.05)
variants in specific genes that can be linked to pathways contributing to disease pathogenesis.
Such studies in monogenic disease require relatively small patient cohorts [98] compared with
GWAS where common polymorphisms are studied, providing a unique opportunity to
investigate the genetics of phenotypes in this heterogeneous disease; this advantage, however,
dissipates in polygenic disease where greater sample sizes are again necessary.
Investigators have started to apply WES to fill in missing parts of our understanding of
sarcoidosis genetics in the hope of discovering rare disease-causing or disease-modifying variants.
The first five studies using WES in sarcoidosis were of relatively modest size and yielded modest
results. WES was applied to small family-based populations, except for one [99], and four out of
the five studies included only subjects of European ancestry. These four sarcoidosis WES studies
[99–102] and one WGS with analysis restricted to the exome [11] are listed in table 3, together
with the bioinformatic approaches applied and primary genes discovered.
Briefly, easily interpretable results were not achieved, but, interestingly, there has been some
overlap in the results. For example, WES studies in French and German families with
sarcoidosis both highlighted pathways related to cell survival and migration, calcium
metabolism and cell adhesion [100–102]. A different approach, searching for variants associated
with disease course, was chosen in a WES study performed in 72 unrelated Finnish sarcoidosis
patients [99]. The results included variants in the genes AADACL3 and C1orf158 that were
https://doi.org/10.1183/2312508X.10031320 49
TABLE 3 Whole-exome and genome studies in sarcoidosis: implicated genes and pathways
First author Type of Probands, including Main genes identified Major suggested
[ref.] study ethnicity (selection) pathways
CALENDER [100] WES, bibliographic Three paediatric Sec16A, AP5B1, RREB1, Autophagy/
function patients+healthy IDO2, IGSF3; total 37 intracellular
analysis parents; French genes trafficking,
(European descent) T-cell
activation
KISHORE [101] WES, linkage and 22 patients from six CX3CL1, ACNT3, FAT3, Immune/
high-penetrance families; German BCO2, SAMD9L, inflammatory
prioritisation (European descent) PRAMEF12, response
approaches PRAMEF19, regulation,
SERPINB11, AADACL3, leukocyte
C1orf158; total 40 proliferation,
genes antibacterial
defence
CALENDER [102] WES, pathogenicity 14 patients from five DPIT4, MLST8, DDIT4L, mTOR signalling/
network analysis families, matched to MTDR, ANXA5, CDH23, autophagy
healthy relatives; DMXL2, TRPV2,
French (European PTPRD, FAT; total 192
descent) genes
LAHTELA [99] WES, clinical 72 unrelated patients; AADACL3, C1orf158, Dendritic cell
course Finnish (European LILRB4 associated activation/
subanalysis descent) with resolving antigen
disease; total >80 presentation
genes
FRITZ [11] WGS, analysis Six patients from one JAK2, BACH2, NCF1; JAK/STAT
restricted to the family of 41 total 34 genes pathway
exome members; Suriname
(African-Caribbean
descent)
WES: whole-exome sequencing; WGS: whole-genome sequencing; JAK: Janus kinase; STAT: signal transducer
and activator of transcription.
over-represented in resolving disease. As these variants were not linked to HLA-DRB1*03:01

and HLA-DRB1*04:01, the known markers for good prognosis, they can be considered
independent markers for resolving disease in Finnish sarcoidosis patients [99]. Most
interestingly, these two genes were also identified in the German family study [101], making
them likely disease genes for patients of European ancestry. Despite the as-yet limited number
of studies and the associated limited number of methodological approaches, we may conclude
that clinical use is not to be expected soon. However, due to the polygenic nature of sarcoidosis
and complex environmental interactions, knowledge on the presence of rare variants in patients
and especially in families may point towards new directions or substantiate evidence for existing
pathways involved in disease pathogenesis and nominate targets for the development of
potential therapies. In this context, autophagy and mTOR pathway(s) are plausible candidates
and in congruence with evidence of mTOR kinase involvement in granuloma formation in an
animal model [103]. The first study assessing its clinical relevance found activated mTOR
complex 1 (mTORC1) signalling in biopsied granulomatous lesions of all 58 patients
investigated [104]. However, mTORC1 activity was not predictive for the clinical course of
sarcoidosis, where no association with disease severity or necessity for treatment was found
[104]. Future investigations with a larger number of samples and better disease characterisation
will show whether additional population-based WES studies, such as the Finnish study by
50 https://doi.org/10.1183/2312508X.10031320
LAHTELA et al. [99], will provide congruent findings. In addition, future studies may use WGS
with the advantage of investigating all variation in the entire genome. However, a huge
disadvantage of WGS includes the high amount of variation in noncoding regions together with
the unknown, and difficult to predict, consequence of each variant. Application of the WGS
technique therefore often results in restricting analyses to exome variants, the approach chosen
by FRITZ et al. [11] for a family with sarcoidosis. In the near future, WGS could pinpoint
unidentified rare risk variants, but in order to reach adequate study power, a very large sample
size, possibly involving multicentre consortia and deep phenotyping, would be required.
Translational challenges
Despite the advancements in our understanding of the genetics of sarcoidosis and ongoing
characterisation of variants contributing to sarcoidosis susceptibility and its disease phenotype,
very little can be translated to the clinic as yet. Due to the extremely variable natural history of
the disease, predictive markers for disease evolution are most needed. It is reasonable to expect
that as more population-based cohorts for sarcoidosis became available with genome-wide data,
there will be the opportunity to conduct polygenic risk score (PRS) analysis, an approach that
has been useful for examining the genetic overlap between two traits or conducting risk
stratification (www.pgscatalog.org/). Notably, PRS-based risk stratification has been suggested
as the most promising approach for patient management [105]. To date, only two PRS studies
on sarcoidosis are available in the literature [106, 107]. Prediction or early detection of an
unfavourable disease course would be most beneficial for an individual patient under a watchful
waiting management strategy. Some centres have considered genotyping for the well-known
combination of HLA class II variants, i.e. HLA-DRB1*14 and HLA-DRB1*15, typically
associated with adverse outcome, versus HLA-DRB1*03 and HLA-DQB1*02:01 conferring a
more favourable outcome [1]. However, genetic testing for HLA types is currently still
expensive due to its complexity, and patient ethnicity highly influences the direction and
strength of the prognostic effect. Moreover, HLA-DRB1*03:01 carriers with good outcome
mostly present with Löfgren syndrome, a relatively easily recognised form of sarcoidosis.
Outside HLA, the effect size of variants with robust genetic associations with sarcoidosis or
phenotypes of sarcoidosis is far below that needed for clinical implementation [108] and has
been insufficiently investigated outside populations of European descent [109].
A potential clinical use of genetic markers is their theranostic application, i.e. using the
information on genetic variation to manage patient treatment ( pharmacogenetics). In this
context, studies investigating genes associated with therapeutic pathways and cohorts based on
treatment response are emerging. In sarcoidosis, the genetic association between TNF-associated
genes and third-line treatment of sarcoidosis with TNF inhibitors has been investigated in Dutch
cohorts. One study reported that TNFA rs1800629 GG homozygous patients had a 3-fold higher
response to TNF inhibitors [32], but this could not be replicated in an second independent study
[110]. Genotyping TNFA polymorphisms was also suggested for predicting the response to
MTX in chronic sarcoidosis [111]; however, for clinical use, these data have to be considered as
rather preliminary, with a need for replication.
For the moment, the genetic studies on sarcoidosis provide an important contribution to
unravelling the disease pathomechanism, thereby dissecting disease-associated pathways and
providing evidence for possible treatment directions.
Integrating omics
As we move forward into the post-GWAS era, integrating various layers of molecular
phenotypes becomes more attractive as high-throughput technologies are reasonably affordable.
https://doi.org/10.1183/2312508X.10031320 51
Adopting a multi-omics study is a statistically robust approach to detect complementary

genomic effects and capture synergistic interactions across molecular phenotypes [112]. It also
offers the opportunity to identify causal genes and functional mechanisms, elucidate disease
aetiology, and potentially provide new disease prevention and treatment targets. Nonetheless,
before generating and integrating multiple molecular data, it is essential to consider that disease
phenotype characterisation is a central element for omics studies to be successful. In many
ways, omics studies are similar to genome-wide studies in that they examine molecular markers
in an unbiased genome-wide screening approach. Notably, with the expansion of sequencing
technologies, the introduction of single-cell techniques and reduced sequencing costs, the omics
field, particularly bulk and single-cell transcriptomics, is slowly growing [113–115]. However,
as we expect the number of omics studies to grow, it is important to keep in mind that such
studies will be most beneficial when conducted under large-scale frameworks, such as consortia,
bringing together multidisciplinary teams working in synergy towards a common goal, and thus
maximising the power of making novel discoveries.
Conclusion
So far, we have learned that multiple genes are involved in disease predisposition for
sarcoidosis, ranging from common variants in mostly immune-mediated genes to unique
variants in diverse disease-associated pathways in families. The strongest associations are
phenotype and population specific, reside in the HLA class II region and are presumably trigger
related. The effect size of other genome-wide risk alleles is small for sarcoidosis in general,
while the effect of thus-far detected rare variants in subjects with sarcoidosis is largely
unknown. Certainly, next-generation sequencing and multilevel omic technologies are promising
approaches for the future. However, their success and clinical applicability will depend on the
development of a deep-phenotyping scheme for capturing disease evolution, and the large-scale
engagement of patients, scientists and practitioners for high-quality clinical data collection and
concomitant biobanking of biological samples from the day of diagnosis until we can improve
the prediction of disease susceptibility, disease severity and treatment response in sarcoidosis.
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Disclosures: C.H.M. van Moorsel has nothing to disclose. M. Petrek reports receiving institutional support for part
of his salary from the Czech Health Ministry (NV18-05-00134). N.V. Rivera reports receiving support from the
Swedish Heart–Lung Foundation (numbers 20200505 and 20200506).
56 https://doi.org/10.1183/2312508X.10031320
Chapter 5
Principles of diagnosis
1,2
Rocco Trisolini , Paolo Spagnolo3 and Robert P. Baughman4
1
Catholic University of the Sacred Heart, Rome, Italy. 2Interventional Pulmonology Unit, Fondazione Policlinico
Universitario A. Gemelli IRCCS, Rome, Italy. 3Respiratory Disease Unit, Dept of Cardiac Thoracic, Vascular Sciences
and Public Health, University of Padova, Padova, Italy. 4Dept of Medicine, University of Cincinnati Medical Center,
Cincinnati, OH, USA.
Corresponding author: Rocco Trisolini (rocco.trisolini@policlinicogemelli.it)
Cite as: Trisolini R, Spagnolo P, Baughman RP. Principles of diagnosis. In: Bonella F, Culver DA, Israël-Biet D, eds.
Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 57–74 [https://doi.org/10.1183/
2312508X.10031420].
@ERSpublications
The diagnosis of sarcoidosis is more likely to be correct if a compatible clinical presentation is corroborated
by evidence of a non-necrotising granulomatous inflammation in at least one organ/tissue, and alternative
causes are reasonably excluded https://bit.ly/3ozzgsF
ISSN: 2312-5098.
The diagnosis of sarcoidosis is tentative and has a higher likelihood of being correct if a compatible
clinical and radiological presentation is supported by evidence of non-necrotising granulomatous
inflammation in at least one organ/tissue. However, some clinical scenarios (Löfgren syndrome,
Heerfordt syndrome, lupus pernio, and asymptomatic bilateral hilar lymphadenopathy) are thought to be
so specific that they allow a presumptive diagnosis of sarcoidosis to be established without a biopsy.
When histological confirmation of the clinical suspicion is needed and an easily accessible superficial
lesion is lacking, bronchoscopy with its ancillary sampling techniques is commonly performed, because
the thorax is involved in the vast majority (>90%) of sarcoidosis patients. The exclusion of alternative
diagnoses is imperative, even when pathological examination of the biopsy sample reveals a
non-necrotising granulomatous inflammation, as several infectious, inflammatory and even malignant
conditions (i.e. lymphomas) may have a granulomatous component.
Introduction
The diagnostic pathway for sarcoidosis is a multistep process through which the clinician
weighs the contribution of clinical, imaging and pathology data and estimates a diagnostic
probability. In this chapter, we discuss the currently accepted diagnostic criteria and general
diagnostic approach to sarcoidosis and focus on invasive sampling strategies and the exclusion
of alternative conditions that may mimic sarcoidosis. A detailed description of the clinical
manifestations specific to different organs (i.e. cardiac, central nervous system sarcoidosis) and
the conventional and novel imaging modalities (i.e. PET), as well as the pathological
characteristics of the disease, will be provided in dedicated chapters of this Monograph.
Diagnostic criteria and general diagnostic approach

Sarcoidosis is a multisystem granulomatous disease of unknown cause for which no definitive
diagnostic tests exist. Expert statements and clinical practice guidelines recommend that the
diagnosis be based on the presence of the following three criteria: 1) a “compatible” clinical–
https://doi.org/10.1183/2312508X.10031420 57
radiological presentation, 2) demonstration of a non-necrotising granulomatous inflammation in at

least one tissue sample, and 3) the reliable exclusion of alternative causes of granulomatous disease
[1, 2]. Unfortunately, clinical and radiological findings in patients with sarcoidosis vary widely,
non-necrotising granulomatous inflammation is nonspecific to sarcoidosis, and ruling out alternative
causes may not be straightforward in many circumstances. As a consequence, the diagnosis of
sarcoidosis is never secure and requires the clinician to carefully weigh up the evidence for and
against it at presentation, and to be open to reconsider its correctness during follow-up.
The algorithm highlighted in figure 1, which will be analysed in more detail in this chapter,
shows an example of a stepwise diagnostic work-up through which a diagnostic likelihood of
sarcoidosis can be established. After the diagnosis of sarcoidosis, some baseline testing to
screen for extrathoracic disease is advised, and its thoroughness depends on the presence or not
of symptoms/signs suggesting a specific organ involvement (table 1) [2].
Contribution of clinical and radiological findings to the diagnostic process

The diagnostic work-up begins with evaluation of the results of clinical and radiological tests
whose chronological order is virtually impossible to standardise, as presentation of the disease
is extremely variable and may range from an asymptomatic state to the presence of several
debilitating symptoms caused by the involvement of multiple organs [2, 3].
Clinical and radiological

presentation
Highly suggestive of sarcoidosis Consistent with sarcoidosis

• Asymptomatic bilateral hilar
adenopathy
• Heerfordt syndrome
• Löfgren syndrome
• Lupus pernio Biopsy
Probable sarcoidosis
Non-necrotising Not consistent Negative and
granulomatous with inadequate#
inflammation sarcoidosis
Alternative Re-evaluate/consider Consider repeating

granulomatous alternative diagnosis biopsy
disease excluded
Probable sarcoidosis
FIGURE 1 A diagnostic algorithm for sarcoidosis. #: negative for granulomas and inadequate indicates a biopsy
whose pathological examination shows neither granulomas nor the presence of material representative of the
target tissues (i.e. lack of prevalence of lymphocytes in a lymph node biopsy or lack of alveolated tissue in a
transbronchial lung biopsy).
58 https://doi.org/10.1183/2312508X.10031420
PRINCIPLES OF DIAGNOSIS | R. TRISOLINI ET AL.
TABLE 1 Assessment for extrathoracic disease at baseline
Organ/tissue of No symptoms/signs of extrathoracic Clinical suspicion of extrathoracic

disease disease disease
Haematological Complete blood cell count

abnormalities
Ocular sarcoidosis Eye examination
Renal sarcoidosis Serum creatinine testing
Hepatic sarcoidosis Serum alkaline phosphatase
Serum transaminase (optional)
Cardiac sarcoidosis ECG MRI
TTE and 24-h ECG (Holter) to be Cardiac PET (if MRI is unavailable)
considered on a case-by-case basis
Calcium metabolism Serum calcium testing
PH TTE
Right-heart catheterisation (when TTE is
suggestive of PH, or on a case-by-
case basis if the suspicion of PH
remains strong after a negative TTE)
Vitamin D metabolism 25- and 1,25-dihydroxyvitamin D levels
in patients being evaluated for
possible vitamin D replacement
PH: pulmonary hypertension; TTE: transthoracic echocardiography.
Although phenotypic expression of the disease is different in different populations, ∼20–50% of

patients are asymptomatic at the time of diagnosis; in such cases, sarcoidosis is suspected based
on evidence of an intrathoracic lymphadenopathy in imaging tests performed for unrelated
reasons [3–5]. Asymptomatic lesions can also be detected by imaging of other areas, including
abdominal lymph nodes or bone lesions [6]. Constitutional and respiratory complaints such as
fatigue, fever, cough and/or exertional dyspnoea are the most common, by far, in symptomatic
patients [3–6]. On occasions, the diagnostic work-up is triggered by extrathoracic symptoms or
signs, such as uveitis, erythema nodosum or arrhythmias. For the diagnosis and management of
specific extrathoracic organ involvement, dedicated diagnostic guidelines have been proposed [7–9].
Imaging findings of the thorax, which is involved in >90% of sarcoidosis patients, can
significantly enhance the diagnostic confidence when they are typical (figure 2), but uncommon
findings are frequently seen in clinical practice (figure 3) [10–13].
Given the lack of rigorous diagnostic criteria, some attempts have been made to help clinicians
interpret the clinical–radiological manifestations possibly associated with sarcoidosis in a less
arbitrary fashion [14–16]. In order to assign the probability to specific clinical findings as
representing organ involvement of sarcoidosis, consensus criteria were established by a panel of
sarcoidosis experts in 1999 [14], and updated in 2014 [15]. The World Association for
Sarcoidosis and Other Granulomatous Disorders (WASOG) sarcoidosis organ assessment
instrument grades as highly probable, probable or possible a number of clinical manifestations
pertaining to each tissue/organ, and is mostly meant to help clinicians standardise the reporting
of clinical disease manifestations [15]. More recently, BICKETT et al. [16] used a slightly
modified version of the WASOG sarcoidosis organ assessment instrument to develop the
so-called “sarcoidosis diagnostic score” (SDS). The authors prospectively enrolled 980 patients
https://doi.org/10.1183/2312508X.10031420 59
a) b)
c) d)
FIGURE 2 Typical CT findings of intrathoracic sarcoidosis. a) Axial HRCT image showing diffuse micronodules
along the bronchovascular bundles and fissures. b) Axial HRCT image showing dense alveolar opacities
surrounded by micronodules (galaxy sign). c) and d) Contrast-enhanced CT images showing symmetrical hilar
and mediastinal (subcarinal) lymph nodes with homogeneous attenuation.
(553 with biopsy-confirmed sarcoidosis and 427 control patients with symptoms compatible with
sarcoidosis but who ultimately received a different diagnosis), divided into an initial and a
validation cohort. By assigning different weight to a biopsy showing granulomas (5 points), as
well as to each of the different clinical criteria of highly probable (3 point), probable (2 points)
and possible (0 points) sarcoidosis involvement, they generated an SDS for patients with clinical
criteria and no biopsy (clinical SDS) and for patients with positive biopsy results (biopsy SDS)
[16]. Overall, the SDS performed well as a diagnostic test, and cut-off values associated with the
best combination of sensitivity and specificity were identified. In particular, the authors focused
on the message that patients with a clinical SDS of ⩾4 have a high likelihood of sarcoidosis and
may not need a biopsy. While this study represented a first step towards making the diagnosis of
sarcoidosis more rigorous and less arbitrary, some key limitations need to be acknowledged to
put the study results into proper context [16, 17]. This was a single-centre study carried out in
the eastern USA, and the organ involvement of patients was graded by two sarcoidosis experts. It
is therefore unclear whether these results would be reproducible in less expert settings, as well as
in other countries where the clinical manifestations of the disease are different [18]. Furthermore,
the control group did not include some conditions, such as active tuberculosis, which are often
challenging to distinguish from sarcoidosis in clinical practice [16, 17]. Finally, the possible
added value of serum biomarkers such as ACE to the performance of the SDS was not
evaluated. While not diagnostic per se, an ACE value elevated 50% above the upper level of
60 https://doi.org/10.1183/2312508X.10031420
a) b) e)
c) d)
FIGURE 3 a–d) Atypical CT and e) PET findings in sarcoidosis patients whose diagnosis was supported by
histology findings and corroborated by a follow-up period of at least 1 year. a) Axial volumetric CT image
showing a single nodule with air bronchogram in the posterior segment of the right upper lobe and mediastinal
lymphadenopathy in a 22-year-old male patient. Non-necrotising granulomas were found both in the
transbronchial lung biopsy specimens of the lung nodule and in the lymph nodes sampled with EBUS-TBNA.
Prednisone treatment led to resolution of the radiological abnormalities. b) Axial HRCT image of a fibrotic ILD
showing irregular septal thickening, traction bronchiectasis and areas of ground-glass opacity, expression of
fine fibrosis. c) Contrast-enhanced CT image showing symmetrical hilar and mediastinal (subcarinal) lymph-
adenopathy. The subcarinal lymph node shows a large central area of reduced attenuation (arrow).
d) Contrast-enhanced CT image showing symmetrical hilar and mediastinal lymphadenopathy. A 1-cm, round
lymph node is evident in the anterior mediastinal station 3A (arrow), rarely involved in sarcoidosis.
e) 18F-FDG PET scan showing unilateral left hilar and mediastinal lymphadenopathy.
normal can strengthen the suspicion of sarcoidosis together with other diagnostic clues [2].
The authors concluded that a multicentre, international study would be needed to confirm the
diagnostic utility and external validity of the SDS.
Tissue biopsy: site selection, sampling strategy and endoscopic procedures

Outside a very limited number of clinical scenarios that are considered specific enough to allow
a presumptive diagnosis of sarcoidosis to be established without a biopsy (Löfgren syndrome,
Heerfordt syndrome, lupus pernio, and asymptomatic bilateral hilar lymphadenopathy),
obtaining a tissue sample that shows a non-necrotising granulomatous inflammation is strongly
advised, as it typically increases the clinician’s confidence in the final diagnosis [1–3].
Whenever possible, sampling of easily accessible superficial lesions suggestive of sarcoidosis

involvement such as some skin lesions, conjunctival nodules or superficial lymph nodes should
be preferred, as this is less invasive and costly than a biopsy of visceral organs (figure 4) [19–21].
However, it should be considered that the finding of noncaseating granulomas in certain tissues
(e.g. liver, skin, peripheral lymph nodes) is of lower diagnostic weight compared with lung or
mediastinal nodes, especially when the clinical manifestations are atypical (e.g. lack of
intrathoracic disease).
When no obvious superficial lesions are detected, sampling of the lung or the hilar/mediastinal
lymph nodes is usually carried out, as the thorax is almost universally involved [4, 5]. Although
https://doi.org/10.1183/2312508X.10031420 61
a) b)
FIGURE 4 Percutaneous ultrasound-guided needle biopsy of a superficial lymphadenopathy in a patient with

sarcoidosis. a) CT slice at the level of the base of the neck showing a few small lymph nodes in the left
supraclavicular area (arrows). b) Ultrasound-guided biopsy with an 18-gauge histology needle of two adjacent
lymph nodes.
surgical options (video-mediastinoscopy, video-assisted thoracic surgery) have the highest

diagnostic success [1–3], endoscopy-based sampling procedures have largely replaced surgery
in the last decades due to their excellent diagnostic yield, lower invasiveness and inherent
flexibility. Depending on the intrathoracic disease pattern, in fact, the operator can decide to
obtain, during a single diagnostic session, tissues samples from the large airways and/or lung
parenchyma and/or intrathoracic lymph nodes [22]. Furthermore, they can perform BAL to
assess the differential cell count and lymphocyte subpopulations, and to rule out infection [22].
Although the combination of different endoscopic techniques clearly improves the diagnostic
success [23–30], the sampling strategy should take into account the pre-test level of confidence
of the clinician for the diagnosis of sarcoidosis, the possible differential diagnoses based on the
imaging findings (involvement of lymph nodes and/or lung parenchyma) and the possible
complications associated with the different techniques. In a patient with isolated intrathoracic
lymphadenopathy, the most common differential diagnoses are sarcoidosis (Scadding stage I),
infection (i.e. tuberculous or fungal lymphadenopathy) and lymphoma [24, 31–35]. In this
specific setting, biopsy of the intrathoracic nodes should be pursued, as it offers a very high
diagnostic yield for the detection of granulomas (∼80%) and may be submitted to extensive
microbiological testing [36]. In fact, when lung disease is absent on CT, the yield of BAL is
disappointing for the diagnosis of infection, and transbronchial lung biopsy (TBLB) does not
add much to the diagnostic yield while increasing the complication rate [29, 37, 38]. In patients
with involvement of both lymph nodes and lung parenchyma on CT (Scadding stage II), the
spectrum of the possible differential diagnoses is much wider [1, 2, 39, 40]. In these cases,
while lymph node biopsy remains useful, TBLB and BAL often reveal unexpected findings
leading to alternative diagnoses and should be performed (figure 5) [24]. TBLB and BAL are
also the mainstay invasive diagnostic tests in patients with isolated lung parenchymal disease
(Scadding stage III/IV) [24].
A more detailed description of the strength and limitation of the different endoscopy-based
sampling techniques available for the detection of granulomas in patients with suspected
sarcoidosis is provided in the following sections.
62 https://doi.org/10.1183/2312508X.10031420
a) b)
c)
d)
FIGURE 5 Lymphangitis carcinomatosis mimicking sarcoidosis. a) Axial HRCT image showing micronodules along
the bronchovascular bundles (red arrows) and fissures (white arrows). An enlarged subcarinal lymph node is
also evident (black arrow). b) Contrast-enhanced CT image at the level of the aortic arch showing a right
paratracheal lymphadenopathy (station 4R, arrow). c) Contrast-enhanced CT image showing lymphadenopathy of
stations 11R, 7 and 10L (arrows). d) ROSE (rapid on-site evaluation) smear of an EBUS-TBNA taken from the
subcarinal lymphadenopathy showing several aggregates of neoplastic cells consistent with adenocarcinoma.
Intrathoracic lymph node biopsy: conventional transbronchial needle aspiration and

endosonography
Not only is lymphadenopathy the most common manifestation of sarcoidosis across all ethnic
groups [1–5], but the number, size and location of lymph nodes seen on CT in most sarcoidosis
patients make lymphadenopathy an attractive target for biopsy [10, 12].
Endoscopic sampling of the mediastinum using conventional transbronchial needle aspiration

(c-TBNA) has revolutionised the diagnostic approach to many conditions involving hilar and
mediastinal lymph nodes, including sarcoidosis. Early studies of c-TBNA in sarcoidosis patients
demonstrated that the detection of granulomas was feasible, although the success rate was quite
variable (46–90%) [25, 31, 41–46]. A systematic review and meta-analysis aimed at
summarising the literature regarding c-TBNA in sarcoidosis attributed a cumulative diagnostic
accuracy of 62% to the procedure [47].
https://doi.org/10.1183/2312508X.10031420 63
More recently, endosonography (EBUS-TBNA, and EUS-FNA or EUS-FNA with an

echobronchoscope (EUS-B-FNA)) has largely replaced c-TBNA owing to its excellent success
rate and safety record [26, 27, 30, 32–35, 37, 48–52]. The main advantages, technical aspects
and drawbacks associated with the use of endosonography in sarcoidosis are listed in table 2 [53].
Endosonography is the nonsurgical procedure associated with the highest diagnostic yield for
the detection of granulomas in sarcoidosis patients featuring intrathoracic lymphadenopathy,
with meta-analyses performed in selected and unselected patient populations showing an overall
diagnostic yield as high as 80% [48, 49]. The clinical utility of endosonography, and of
EBUS-TBNA in particular, is substantial, especially in patients with isolated intrathoracic
lymphadenopathy, for several reasons [53]. First, the diagnostic yield of alternative endoscopic
biopsy procedures, including TBLB, is suboptimal when imaging studies do not show lung
disease [23]. Second, the granuloma detection rate of endosonography has been shown to be
highest (>85%) in patients with Scadding stage I disease [26–35, 49–51]. More importantly,
TABLE 2 Strengths, main technical aspects and drawbacks of endosonography in sarcoidosis
Strengths Technical aspects Drawbacks
Excellent overall diagnostic yield in No difference in diagnostic yield The cytology and histology
patients with intrathoracic for the detection of granulomas findings from samples
lymphadenopathy (suspected of transbronchial (EBUS-TBNA) retrieved with
sarcoidosis stage I/II) versus transoesophageal endosonography are
(EUS-B-FNA) nonspecific to sarcoidosis
Single most useful nonsurgical test in Four needle passes required per The diagnostic yield for the
patients with isolated patient optimise the detection of granulomas was
lymphadenopathy (suspected diagnostic yield lower in large, prospective
sarcoidosis stage I) trials than in small,
retrospective studies
B-mode examination helps identify No difference in diagnostic yield
patterns suggestive of alternative for the detection of granulomas
disease (i.e. infectious of needles of different size
lymphadenopathy) (gauge) and model
B-mode and power-Doppler The number of revolutions of the
examinations help select the best needle into the target lymph
target area for sampling (i.e. node does not influence the
avoidance of hypervascular and/or diagnostic yield
calcified areas)
ROSE of endosonography-derived
samples might help reduce the
overall endoscopy time and
complication rate, and might
enhance triage of specimens
EBUS strain elastography can help
identify fibrotic lymph nodes in
sarcoidosis
Transoesophageal endosonography
(EUS, EUS-B) may also allow safe
sampling of intrathoracic lymph
nodes in patients with poor
performance status, respiratory
failure or severe cough
EUS-B-FNA: EUS-FNA with an echobronchoscope; ROSE: rapid on-site cytological evaluation; EUS-B: EUS with
an echobronchoscope.
64 https://doi.org/10.1183/2312508X.10031420
c-TBNA and endosonography are the only nonsurgical procedures that can strengthen the
clinical suspicion of sarcoidosis or suggest an alternative diagnosis in patients with normal lung
parenchyma on HRCT scan and in whom the pre-test clinical probability of a diagnosis of
sarcoidosis is not exceedingly high [53]. Examples of these conditions include, but are not
limited to: 1) isolated lymphadenopathy in patients with a history of (current/previous, treated/
untreated) malignancy, 2) isolated lymphadenopathy in patients with demographic, clinical or
radiological findings that make tuberculosis or lymphoma a diagnostic possibility, and 3) isolated
lymphadenopathy in patients with suspected extrathoracic sarcoidosis [53].
The possibility of studying lymph-node texture with the B-mode and power-Doppler mode
during endosonography can help select the best site for biopsy by allowing avoidance of lymph
nodes with extensive calcifications or markedly increased vascularity, respectively. Furthermore,
B-mode examination can help differentiate sarcoidosis from alternative diagnoses, especially
infectious lymphadenopathy [53]. Isolated tuberculous lymphadenopathy (TBLA), in particular,
may on occasions display clinical, radiological and pathological findings very much like those
of sarcoidosis, and differentiating the two conditions can be difficult, especially in countries or
ethnic groups with a high prevalence of tuberculosis [36, 54–58]. The most common B-mode
characteristics of sarcoidosis lymph nodes include homogeneous echo texture, tendency to
cluster, distinct margins and increased vascularity (figure 6). In the largest study comparing the
sonographic characteristics of sarcoidosis and TBLA (358 nodes studied, sampled from 165
patients), heterogeneous echotexture (53.4% versus 12.6%; p<0.001) and the coagulation
necrosis sign (26.1% versus 3.3%; p<0.001) were significantly more common in tuberculous
than in sarcoidosis lymph nodes (figure 6) [59]. The combination of a positive tuberculin skin
test and either heterogeneous echotexture or coagulation necrosis had a diagnostic specificity of
98% and a positive predictive value of 91% for tuberculosis [59].
Unlike any other currently available bronchoscopy-based sampling method (BAL,

endobronchial biopsy (EBB) and TBLB), specimens obtained by needle aspiration procedures
(c-TBNA, endosonography) from the lymph nodes can be submitted to rapid on-site cytological
evaluation (ROSE). Theoretically, the identification of non-necrotising granulomas in a ROSE
smear obtained during c-TBNA or EBUS-TBNA might help clinicians reduce the number of
needle passes from the lymph nodes and avoid biopsies from additional targets (i.e. TBLB)
without a loss in diagnostic yield. This, in turn, would reduce the overall bronchoscopy time
and the potential complications associated with the procedure. Furthermore, ROSE might help
effectively triage the EBUS-TBNA material for ancillary studies, especially in cases in which
sarcoidosis is in the differential diagnosis but is not the final diagnosis. Unfortunately, none of
the above potential advantages has been formally assessed from a scientific standpoint, as the
few studies of ROSE in the setting of sarcoidosis have focused mostly on the concordance
between ROSE and the final cytological diagnosis, and on the extra yield obtained with
c-TBNA or endosonography when coupled with ROSE [51, 60, 61]. Finally, the pre-test clinical
probability of sarcoidosis should be considered carefully before assuming that the presence of
granulomas on a ROSE smear equates to sarcoidosis, as several conditions can lead to
mediastinal granulomatous reactions. It is therefore key that an EBUS-TBNA sample (or a
bronchial wash/BAL, especially in patients with parenchymal abnormalities) be analysed to rule
out mycobacterial or fungal infections.
Clinical experience suggests that at least some of the false-negative EBUS-TBNA results in
sarcoidosis patients may be caused by the presence of lymph nodes with extensive fibrosis,
which might have a low density of granulomas [53, 62]. Preliminary evidence suggests that
EBUS strain elastography, a new imaging method that allows measurement of relative tissue
https://doi.org/10.1183/2312508X.10031420 65
a) b)
c) d)
FIGURE 6 Examples of endosonography B-mode findings in patients with a and b) sarcoidosis and c and d)
tuberculous lymphadenopathy (TBLA). a) EBUS B-mode image from a sarcoidosis patient showing two adjacent,
homogeneous lymph nodes separated by a clearly visible hyperechoic line, which corresponds to the lymph
node capsule (arrows) in hilar station 11Rs. b) EUS-B (EUS with an echobronchoscope) B-mode image showing a
cluster of several small, homogeneous lymph nodes (arrows) separated by clearly visible hyperechoic lines
(lymph node capsule) in the subcarinal mediastinal station (station 7). c) EBUS B-mode image from a patient
with isolated intrathoracic TBLA showing a cluster of three lymph nodes with a nonhomogeneous texture in the
mediastinal station 4L. The smallest lymph node shows a central anechoic area (arrow) lacking vascular flow at
Doppler examination (coagulation necrosis sign). d) EBUS B-mode image from a patient with isolated
intrathoracic TBLA showing a small lymph node in station 4R with a nonhomogeneous texture and a peripheral
anechoic area (arrow) lacking vascular flow at Doppler examination (coagulation necrosis sign).
elasticity and that is used mostly to differentiate malignant and benign lymph nodes, can help
identify fibrotic lymph nodes in sarcoidosis [63, 64]. One small pilot study in particular found
that EBUS strain elastography suggesting lymph node stiffness (a likely surrogate of the extent
of fibrosis) was significantly associated with an increased inadequacy rate of EBUS-TBNA
specimens in sarcoidosis [64].
Among the technical aspects that may potentially influence the diagnostic yield of
endosonography in sarcoidosis, a few deserve mention. The intrathoracic lymph nodes can be
sampled both from the airways (EBUS-TBNA) and the oesophagus (EUS-FNA, EUS-B-FNA).
Very recently, the first randomised study performed to compare the value of EBUS-TBNA
versus EUS-B-FNA in patients with suspected sarcoidosis demonstrated a similarly good
diagnostic yield [52]. The endobronchial route is generally preferred in clinical practice as it
allows biopsy of the hilar lymph nodes, inaccessible from the oesophagus, and allows additional
sampling procedures such as BAL, endobronchial and transbronchial biopsies to be carried out,
66 https://doi.org/10.1183/2312508X.10031420
if needed. However, the oesophageal route might be preferred by the operator in patients with
poor performance status, respiratory failure or severe cough, and can be performed in the same
diagnostic session with an echobronchoscope (EUS-B-FNA) if the endobronchial approach fails
for any reason.
Studies that assessed the number of needle passes needed to optimise the diagnostic success
have demonstrated that the yield for the detection of granulomas does not increase significantly
after four passes per patient [65].
A recent systematic review with meta-analysis has suggested that the use of larger 19-gauge
needles increases the diagnostic sensitivity of EBUS-TBNA in sarcoidosis [66]. However, the
only two currently available randomised trials, which compared 22- versus 25-gauge ProCore
needles [52], and 21- versus 22-gauge needles [67] in patients undergoing endosonography for
suspected sarcoidosis, failed to show a significant difference in diagnostic yield for the
detection of granulomas [52, 67].
Finally, the number of revolutions of the EBUS needle (20 versus 10) inside the target lymph
node was not found to influence diagnostic yield, specimen adequacy or complication rate [68].
Despite its indisputable utility, two key drawbacks regarding the use of endosonography in
patients with suspected sarcoidosis need to be taken into account [53]. The main limitation is
certainly the lack of specificity, which makes it crucial that the pathology findings are
interpreted in the individual clinical context. Non-necrotising granulomas indistinguishable from
those seen in sarcoidosis can be found in a variety of conditions. Of these, isolated TBLA is the
most common extrapulmonary manifestation of tuberculosis across all ethnic groups in both the
USA and the UK [34, 69], and represents a perfect example [53]. Studies that assessed the role
of endosonography in the diagnosis of TBLA found that 33–37% of tuberculosis patients had
non-necrotising granulomas at cytological examination [36, 54].
A word of caution is required on the generalisability of the excellent EBUS-TBNA results

described in the literature in the setting of sarcoidosis. Because most trials of EBUS-TBNA in
sarcoidosis have an inherent selection bias represented by the very high prevalence of the
disease (often >90%) in the study population, the results reported cannot be generalised to
populations in which the prevalence of sarcoidosis is lower. Ideally, EBUS-TBNA should be
tested in consecutive patients for whom sarcoidosis is one of the diagnostic possibilities based
on clinical and imaging entry criteria agreed upon beforehand and applied prospectively. This
should allow the selection of a study population more similar to one that the average clinician
deals with in their clinical practice, and most certainly characterised by a lower prevalence of
sarcoidosis. It is not surprising that lower diagnostic success rates (57–74%) have been observed
in large, prospective, rigorous trials [26, 27, 50–52] compared with smaller and often
retrospective studies (85–97%) [30, 32–35, 37].
Lung biopsy: TBLB and transbronchial lung cryobiopsy

TBLB has been the mainstay of the diagnosis of sarcoidosis for decades, at least until c-TBNA
and then endosonography were introduced into clinical practice and gained popularity.
Four or five TBLBs are usually advised to maximise the diagnostic yield for the detection of
granulomas [22, 23, 38, 69, 70], but evidence from the literature suggests that the success rate
of the procedure is significantly higher when lung abnormalities on imaging studies are present
(Scadding stage II/III) [22, 23, 25, 30, 35, 37]. These results find a plausible explanation in
https://doi.org/10.1183/2312508X.10031420 67
studies correlating pathology and imaging findings, which have clearly demonstrated that
non-necrotising granulomas are found in 100% of open-lung biopsies from patients with stage I
sarcoidosis but that the extent of granulomatous disease is significantly less than that seen in
corresponding samples from patients with lung radiographic abnormalities (Scadding stage
II/III) [71]. This, in turn, explains why the diagnostic yield of TBLB in patients with stage I
was significantly and constantly higher in the few studies in which seven to 12 TBLBs were
performed instead of four to five [29, 38, 69, 70]. Of note, TBLB is the endoscopic procedure
associated with the highest complication rate in the setting of sarcoidosis, with pneumothorax
and bleeding being significantly more common than with any other endoscopy-based sampling
modality [37, 61].
Transbronchial lung cryobiopsy (TBLC), a newer method that allows the retrieval of larger
biopsies with preserved lung architecture, is increasingly being used in the diagnosis of ILD,
especially fibrotic ILD [72]. Two studies that focused on sarcoidosis, albeit small and
retrospective, have been published recently [73, 74]. In a series of 36 patients including 18 with
suspected sarcoidosis, ARAGAKI-NAKAHONDO et al. [73] obtained pathological confirmation of
sarcoidosis in 12 (67%) at the cost of four pneumothoraces (11%), all of which required chest
drainage. More recently, JACOB et al. [74] retrospectively analysed 32 patients, of whom 21 had
a high likelihood of sarcoidosis based on clinical and radiological data, six had possible disease
and five had unlikely sarcoidosis. TBLC correctly identified 27 out of 29 patients (93%) who
were finally diagnosed with sarcoidosis. Complications included five pneumothoraces (16%), of
which four required chest drainage, and one case (3%) of moderate bleeding [74]. Larger,
prospective randomised studies are certainly required to determine to what extent and in which
clinical settings TBLC can be useful in patients with suspected sarcoidosis, considering the high
diagnostic success and low complications rate of conventional endoscopy-based methods.
EBB
Large-airway involvement by sarcoidosis has long been known, with studies mentioning the
detection of granulomas in EBBs dating back to 1941 [75, 76]. Ever since, EBBs taken during
flexible bronchoscopy have been added to the armamentarium of sampling methods used to
diagnose sarcoidosis and have been demonstrated to increase the diagnostic success of
bronchoscopy when coupled with other sampling methods [77–84]. However, their value has
only been assessed in small studies, mostly retrospective [77–84], and the diagnostic yield has
been shown to be widely variable across studies conducted in different populations (5–71%)
[43, 77–84]. These studies have clearly demonstrated that patients of African–American descent
and those who have bronchoscopically visible abnormalities of the mucosa (figure 7) have a
significantly higher likelihood of having endobronchial sarcoidosis demonstrated by EBB
[22, 23, 43, 77–84]. The “cobblestone” endobronchial involvement pattern (figure 7a), in
particular, is associated with the presence of granulomas at histological examination of the
bronchial biopsy in the vast majority of cases [22, 23, 43, 77–84]. However, even in patients
with normal-appearing bronchial mucosa, EBB has been shown to feature noncaseating
granulomas in up to 37% of cases, which suggests that microscopic involvement of the mucosa,
not visible or not plainly visible at standard bronchoscopy, is present in a non-negligible, yet
difficult-to-establish percentage of sarcoidosis patients [22, 23, 43, 77–85]. The recent
introduction on the market of high-definition videobronchoscopes, which provide substantially
higher-resolution images compared with conventional white-light bronchoscopes, might
theoretically result in improved detection of subtle airway abnormalities in the setting of several
diseases, including sarcoidosis. The first large, prospective, multicentric, international study of
high-definition videobronchoscopy for the diagnosis of endobronchial sarcoidosis is currently
ongoing (ClinicalTrials.gov identifier NCT04743596).
68 https://doi.org/10.1183/2312508X.10031420
a) b)
c) d)
e)
FIGURE 7 Patterns of abnormalities seen most frequently at bronchoscopy in endobronchial sarcoidosis.

a) Multiple coalescing tiny nodules in the right upper lobe bronchus (“cobblestone” pattern). b) Scattered tiny
nodules are evident in a limited area (circle) of the medial aspect of the left main stem bronchus. c) Small
whitish plaque (arrows) in the medial aspect of the bronchus intermedius. d) Marked, irregular thickening of the
left interlobar carina. e) Increased vascularity in the medial aspect of the left main stem bronchus.
BAL
Unlike needle aspiration or forceps biopsy procedures, pathological examination of BAL fluid
cannot demonstrate the presence of granulomas, with a handful of lucky exceptions [86, 87].
However, performing BAL can be useful, especially in patients with suspected sarcoidosis who
feature lung involvement on imaging studies to exclude an infectious aetiology [22].
https://doi.org/10.1183/2312508X.10031420 69
Furthermore, the presence of a lymphocyte count >15%, especially if accompanied by a

CD4/CD8 ratio >3.5 in the BAL fluid, can significantly strengthen suspicion of the disease in
the appropriate clinical and radiological setting [88–91]. Unfortunately, the differential cell
count is normal in ∼15% of patients with confirmed sarcoidosis and the sensitivity of a
CD4/CD8 lymphocyte ratio >3.5 is <60% [88–91].
Sarcoidosis mimics
Given the lack of clinical, imaging and pathology findings specific to sarcoidosis, careful
exclusion of alternative diagnoses is a pillar of the diagnostic process. Unfortunately, an
impressive number of infectious, inflammatory and even neoplastic conditions can mimic
sarcoidosis [2, 19, 39]. Therefore, knowledge of the medical history, demographics, exposures,
imaging, pathology and laboratory findings associated with these alternative disorders is critical.
Some conditions that may involve the lung and/or the intrathoracic lymph nodes represent, de
facto, the most common and/or insidious differential diagnoses of pulmonary sarcoidosis
worldwide (table 3) [2, 19, 39].
A key step in identifying a possible sarcoidosis mimic is obtaining a comprehensive medical

history aimed at identifying occupational (i.e. beryllium), environmental (i.e. bioaerosols known
to cause hypersensitivity pneumonitis), drug (i.e. immune check-point inhibitors) or infectious
exposures that may cause granulomatous disease [2, 19, 39].
TABLE 3 A partial list of either common or insidious sarcoidosis mimics characterised by possible
thoracic involvement
Condition Lung involvement Lymph node

involvement
Infection
Tuberculosis ✓ ✓
Nontuberculous mycobacteria ✓ ✓
Fungi
Aspergillus spp. ✓ ✓
Histoplasma spp. ✓
Blastomyces spp. ✓
Coccidioides spp. ✓
Autoimmune/immune dysfunction
Aspiration pneumonia ✓
GLILD associated with CVID ✓ ✓
Exposures
Hypersensitivity pneumonitis ✓ ✓
Hot-tub lung syndrome ✓ ✓
Chronic beryllium disease ✓ ✓
Drug-induced granulomatous disease ✓ ✓
Foreign body reaction to injected or aspirated ✓ ✓
substances
Malignancy
Lymphoma ✓ ✓
Lymphangitis carcinomatosis ✓ ✓
Sarcoid-like reaction to tumour ✓ ✓
Idiopathic
Necrotising sarcoid granulomatosis ✓ ✓
GLILD: granulomatous–lymphocytic ILD; CVID: common variable immune deficiency.
70 https://doi.org/10.1183/2312508X.10031420
When lung and/or intrathoracic lymph nodes are involved, imaging features possibly orienting
towards a specific disease should be scrupulously assessed. Furthermore, the imaging findings
should be used to select the site for biopsy and the type of sampling procedures in order to
increase the chances of establishing the correct diagnosis (figure 5) [53]. As an infectious
aetiology is almost always a concern in patients with thoracic involvement, a sample from the
lymph nodes (needle aspirate) and/or the lung (bronchial wash, BAL or TBLB), depending on
the disease pattern, should undergo microbiological tests for mycobacteria and fungi.
Finally, a careful histological examination of the biopsy specimen is extremely important, as

some distinctive feature of the granuloma may help direct the search for a sarcoidosis mimic
[92, 93]. Anatomic distribution (airway centred, perilymphatic, angiocentric or random),
qualitative features ( poorly formed, well formed, necrotising) and the presence of accompanying
findings ( perigranulomatous extensive fibrosis, birefringent material, mononuclear cell infiltrate)
can all point to specific aetiologies and suggest further investigations [92, 93]. However,
distinctive pathological features are not always present and are significantly more difficult to
recognise in small TBLBs and in cytology samples obtained with endosonography [53]. It is
well known, for instance, that non-necrotising granulomas totally indistinguishable from those
seen in sarcoidosis are identified in EBUS-TBNA samples of up to 37% of patients with
culture-positive tuberculous intrathoracic lymphadenopathy [36].
Conclusion
Despite considerable research efforts, nothing substantial has changed in the diagnostic criteria
and general diagnostic approach to sarcoidosis in the last two decades. Clinical acumen and a
thorough evaluation of the patient’s history, exposures, imaging and pathology data remain key
to establishing a probability estimate of the likelihood of the disease. Endoscopy-based
sampling methods, in particular endosonography, offer an effective, safe and minimally invasive
way to obtaining a biopsy sample from lung and lymph nodes of patients with suspected
sarcoidosis, but knowledge of the strengths and limitations of these procedures is important to
interpret their results correctly.
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89 Costabel U, Guzman J, Albera C, et al. Bronchoalveolar lavage in sarcoidosis. In: Baughman RP, ed. Lung
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Disclosures: R. Trisolini reports receiving the following, outside the submitted work: personal fees for
presentations at conferences from Pentax Medical; and personal fees for participation on advisory boards from
AstraZeneca. P. Spagnolo reports receiving the following, outside the submitted work: grants, personal fees and
nonfinancial support from Roche, PPM Services and Boehringer-Ingelheim; and personal fees from Red X Pharma,
Galapagos, Chiesi, Santhera, Lupin, Pieris and Novartis. P. Spagnolo’s wife is an employee of Novartis.
R.P. Baughman reports receiving the following, outside the submitted work: grants from Bayer, Genentech, aTyr,
Novartis, Gilead, the Foundation for Sarcoidosis Research and the National Institutes of Health; grants and
personal fees from Bellephron, Actelion and Mallinckrodt; and personal fees from United Therapeutics and
Boehringer Ingelheim.
74 https://doi.org/10.1183/2312508X.10031420
Chapter 6
Conventional and nuclear imaging techniques

Rémy L.M. Mostard1 and Ruchi Yadav2
1
Dept of Respiratory Medicine, Zuyderland Medical Centre, Heerlen, The Netherlands. 2Section of Thoracic Imaging,
Cleveland Clinic, Cleveland, OH, USA.
Corresponding author: Rémy L.M. Mostard (r.mostard@zuyderland.nl)
Cite as: Mostard RLM, Yadav R. Conventional and nuclear imaging techniques. In: Bonella F, Culver DA, Israël-Biet D,
eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 75–90 [https://doi.org/10.1183/
2312508X.10031520].
@ERSpublications
Imaging contributes to the diagnosis of sarcoidosis and the exclusion of other causes of granulomatous
disorders. It is useful in detecting disease complications, provides prognostic information and is an
important factor in treatment decisions. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Imaging contributes to the diagnosis of sarcoidosis and the exclusion of other causes of granulomatous
disorders, is useful in detecting disease complications, provides prognostic information, and is an
important factor in treatment decisions. In clinical practice, conventional imaging techniques, such as
chest radiography and HRCT, are part of the routine work-up in sarcoidosis. Certain HRCT patterns are
highly specific for the diagnosis of sarcoidosis, whereas other features are typical for potentially
reversible or, on the contrary, fibrotic disease. Although not indicated in the routine work-up, imaging
techniques such as MRI and PET can be of major added value in the evaluation of the extent of
disease. PET can also help establish the presence of inflammatory activity in specific patient
populations, including those with suspected sarcoidosis, those with unexplained persistent disabling
symptoms, and those with (suspected) cardiac sarcoidosis. Furthermore, PET can provide prognostic
information and can be useful in monitoring treatment effect.
Introduction
Imaging techniques have a major role in the diagnosis and management of sarcoidosis. Even
though the presence of some typical radiographic abnormalities and HRCT patterns is highly
suggestive of sarcoidosis, definitive diagnosis of sarcoidosis cannot be made purely based on
imaging and requires compatible clinical and pathological findings. Furthermore, imaging
contributes to the exclusion of other causes of granulomatous disorders, is useful in detecting
disease complications, provides prognostic information and is an important factor in
treatment decisions.
Evaluation of extrapulmonary localisations of sarcoidosis requires additional imaging techniques

such as MRI and PET. Nuclear imaging techniques like PET also enable assessment of
disease activity.
This chapter discusses the value and limitations of conventional and nuclear imaging techniques
in sarcoidosis.
https://doi.org/10.1183/2312508X.10031520 75
Chest radiography
Due to its high availability, low cost and low radiation exposure, together with its ability to
provide valuable information, chest radiography (CXR) continues to have a crucial role in the
diagnosis, prognosis and follow-up of sarcoidosis.
85–95% of sarcoidosis patients have abnormalities on CXR and these findings are often the initial
reason for further analysis and the diagnosis (R.L.M. Mostard, personal communication and [1, 2]).
Up to 60% of sarcoidosis patients present with asymptomatic abnormalities on CXR. The most
common abnormalities are bilateral hilar lymphadenopathy (BHL), which is present in 50–80%
of cases, often in combination with right paratracheal lymph nodes [3, 4]. Bihilar
lymphadenopathy is typically symmetric in sarcoidosis. Unilateral hilar predominance,
lymphadenopathy in a single lymphatic station or mediastinal lymphadenopathy in the absence
of bihilar lymphadenopathy should raise suspicion of alternative diagnoses, such as infections
(mycobacterial, fungal), lymphoma or other malignancies. In chronic disease, calcifications can
be present in the mediastinal or hilar lymphadenopathy [5].
Parenchymal involvement is present in 25–50% of sarcoidosis patients and usually bilateral,

predominantly in the mid and upper lung areas. The most common pattern is micronodular or
reticulonodular. Symmetric perihilar confluent consolidations are also seen with architectural
distortion in patients with fibrotic changes [3].
Half a century ago, well before the introduction of the CT scan, the Scadding radiographic staging
system was published. This was modified by DeRemee in 1983 and consists of five stages of
radiographic abnormality: stage 0, normal CXR; stage I, BHL; stage II, BHL and parenchymal
abnormalities; stage III, parenchymal abnormalities without BHL; and stage IV, advanced lung
fibrosis with evidence of hilar retraction, bullae, cysts and/or emphysema (figure 1) [6, 7].
Patients initially present with CXR stage 0 in 5–15%, stage I in 40–50%, stage II in 30–40%, stage
III in 7–15% and stage IV in 4–10% (R.L.M. Mostard, personal communication and [1]). It should
be stressed that the Scadding system is a descriptive staging system and does not necessarily reflect
either severity of disease or inflammatory activity. There is no obvious correlation between the
results of lung function tests and the findings of CXR, although prominent lung restriction is
particularly seen in patients with chest radiographic stages III–IV [8, 9] Moreover, CXR findings
usually correlate poorly with symptoms related to pulmonary involvement. In a prospective study
involving 36 patients, JUDSON et al. [10] compared clinical status and spirometry during pulmonary
sarcoidosis flares, with CXR findings as described by the CXR International Labour Organization
profusion score. They noted that there was too much variation to be able to identify a cut-off that
would reliably diagnose exacerbations. In approximately one-half of the radiographic readings, either
an improvement or no change was seen during a significant exacerbation. In line with this, no clear
relation between CXR stages and PET findings has been found, further demonstrating the
shortcomings of CXR in predicting inflammatory activity [11, 12].
However, the staging system has prognostic importance as, in general, patients with a lower
radiographic stage have a higher chance of resolution of their symptoms and CXR abnormalities [9].
In stage I disease, CXR findings usually improve spontaneously or stabilise. Spontaneous
remissions occur in: 55–90% of patients with stage I disease; 40–70% of patients with stage II
disease; 10–20% of patients with stage III disease; and 0% of patients with stage IV disease [2, 13]
NARDI et al. [14] noted that survival significantly decreased in CXR stage IV patients, and that
75% of fatalities could be directly attributed to respiratory causes.
76 https://doi.org/10.1183/2312508X.10031520
IMAGING TECHNIQUES | R.L.M. MOSTARD AND R. YADAV
a)
b)
c)
d)
FIGURE 1 Legend overleaf.
https://doi.org/10.1183/2312508X.10031520 77
FIGURE 1 Chest radiographic staging system in sarcoidosis. a) Stage I: chest radiography (CXR) (left) and coronal
HRCT image (right) showing bilateral hilar lymphadenopathy, without parenchymal abnormalities. b) Stage II:
CXR (left) and coronal HRCT image (right) showing both hilar and mediastinal lymphadenopathy and
parenchymal abnormalities (nodular and reticulonodular opacities). c) Stage III: CXR (left) and coronal HRCT
image (right) showing parenchymal abnormalities without hilar lymphadenopathy. d) Stage IV: CXR (left) and
coronal HRCT image (right) showing signs of lung fibrosis with hilar retraction and architectural distortion of the
pulmonary parenchyma.
Other limitations of the radiographic staging system are interobserver variability and a lack of
proper definitions of changes in time, as a result of which it has limited applicability in
individual patient assessments, including treatment decisions [15, 16].
CT features of pulmonary sarcoidosis

CT plays a pivotal role in the diagnostic assessment, monitoring and prognostic evaluation of
pulmonary sarcoidosis. It is more sensitive than CXR in its ability to detect lymphadenopathy,
subtle micronodular and reticular abnormalities, and faint ground-glass opacities, as well as in
its ability to distinguish between active inflammation and irreversible fibrosis. The diagnostic
contribution of CT in difficult cases is significant and it is important in the investigation of
pulmonary complications, including aspergilloma and pulmonary hypertension. Moreover, a
typical CT pattern in a consistent clinical context may potentially obviate the need for
histological confirmation of pulmonary sarcoidosis, especially in patients with an increased risk
of biopsy-related complications.
CT scanning protocol
Multidetector CT using helical volumetric acquisition, thin-slice thickness (1–1.5 mm) and no
intravenous contrast is now the widely used imaging technique in the initial assessment of
patients with pulmonary sarcoidosis. In the presence of airflow obstruction, expiratory images
can be useful to identify air trapping in patients with small-airway involvement. It should be
noted, however, that multidetector CT acquisitions will increase the radiation burden.
Pattern of lymphadenopathy in pulmonary sarcoidosis

Well-defined, discreet and symmetric hilar and right paratracheal lymphadenopathy is the most
common pattern of nodal involvement on CT, occurring in 47–95% of patients with pulmonary
sarcoidosis (figure 2a) [17–19]. In an asymptomatic patient with no known malignancy, the
most common cause of symmetric bilateral lymphadenopathy is sarcoidosis. Involvement of
additional mediastinal lymph node stations (left paratracheal, subcarinal, subaortic and
interlobar) is seen in 50% of patients [20]. Lymphadenopathy in sarcoidosis is typically
non-compressive and non-necrotic. Asymmetric or isolated unilateral hilar or isolated
mediastinal lymphadenopathy is uncommon in sarcoidosis, seen in <5% of cases [21–24].
Involvement of the paravertebral, retrocrural and internal mammary regions is less frequent in
sarcoidosis. These atypical patterns of nodal involvement lead to the inclusion of fungal
infection, tuberculosis, metastatic disease and lymphoma in the differential diagnosis; these
patients may benefit from a contrast-enhanced CT scan in addition to correlation with patient
risk factor and clinical presentation. The presence of intrapulmonary lymph nodes with typical
CT features (noncalcified solid nodule with sharp margins; a round, oval or polygonal shape;
distanced ⩽15 mm from the pleura; generally located below the level of the carina) should not
be confused with isolated subpleural nodules from sarcoidosis in patients with classical
sarcoid-related lymphadenopathy, upstaging the patient from stage I to stage III.
Lymph node calcification is frequent in sarcoidosis and, as in other chronic granulomatous

disease, the occurrence of lymph node calcification is closely related to the duration of the
78 https://doi.org/10.1183/2312508X.10031520
a) b)
c)
FIGURE 2 Pattern of lymphadenopathy in sarcoidosis. a) Axial contrast-enhanced CT showing typical bilateral

and symmetric hilar lymphadenopathy with multistation mediastinal lymphadenopathy. b) Axial unenhanced CT
in a patient with sarcoidosis showing eggshell-like calcification of mediastinal and hilar lymph nodes. c) Axial
unenhanced CT in a patient with sarcoidosis showing soft calcification of mediastinal and hilar lymph nodes.
disease, increasing from 3% to 20% at 5 years and 10 years after disease, respectively [21].
Lymph node calcification in sarcoidosis is typically bilateral and symmetric and tends to be
more focal than complete. Various patterns of calcification that can be seen in pulmonary
sarcoidosis including punctate, amorphous, popcorn or eggshell-like in appearance (figure 2b).
These patterns of calcification are not pathognomonic for sarcoidosis and are indistinguishable
from those seen in fungal infection or occupational lung disease. Soft (faint/cloudy)
calcification of the thoracic lymph nodes occurs in sarcoidosis (figure 2c). This finding, in
addition to the absence of calcified granulomata in the liver and spleen, is an important clue that
favours sarcoidosis over histoplasmosis in patients residing in endemic regions.
Nonfibrotic and fibrotic patterns

The parenchymal abnormalities in pulmonary sarcoidosis are characteristically seen in a
perilymphatic distribution transaxially, involving the bilateral perihilar peribronchovascular
interstitium, subpleural interstitium (including fissures) and interlobular septa. Additionally,
these parenchymal findings demonstrate a mid and upper lung zone predilection in a
craniocaudal distribution. There are distinct CT patterns in pulmonary sarcoidosis that can be
characterised as fibrotic and nonfibrotic.
https://doi.org/10.1183/2312508X.10031520 79
Nonfibrotic parenchymal findings

Nodules, peribronchovascular thickening and consolidative opacities on CT are almost always
suggestive of a nonfibrotic pattern in sarcoidosis, representing granulomatous inflammation that
may demonstrate spontaneous or under treatment resolution [25, 26].
Micronodular pattern
The most characteristic feature of pulmonary sarcoidosis is bilateral, symmetric, micronodules
(2–5 mm) with irregular borders in a peribronchovascular and subpleural distribution as well as
predilection for the upper and mid lung zones (figure 3a) [27]. These are seen in 80–100% of
all patients but are observed less frequently in stage IV disease [28]. The perilymphatic nodules
in sarcoidosis characteristically produce a fissural and bronchovascular nodularity/“beaded”
appearance, a sign that is considered virtually pathognomonic of sarcoidosis (figure 3a).
Nodular thickening of the interlobular septa is a frequently associated finding. Asymmetric
involvement of the lung parenchyma and a lower lung zone-predominant distribution pattern are
less common presentations [20]. A miliary/random distribution of micronodules is occasionally
seen in sarcoidosis (figure 3b).
Macronodular and confluent masses

As these micronodules become more profuse, they coalesce together to form larger
macronodules or confluent masses that demonstrate characteristic peribronchovascular and
a) b)
c) d)
FIGURE 3 Nonfibrotic patterns in pulmonary sarcoidosis. a) Axial HRCT of the chest showing the typical
perilymphatic distribution of micronodules, producing a fissural and bronchovascular nodularity/“beaded”
appearance. b) Axial HRCT of the chest showing a miliary pattern in a patient with sarcoidosis. c) Axial HRCT of
the chest in a patient with sarcoidosis showing symmetric bilateral perihilar consolidative opacities
demonstrating air bronchogram and surrounding micronodules. d) Axial HRCT of the chest depicting the “galaxy
sign” in sarcoidosis – a central dominant nodule with satellite micronodules.
80 https://doi.org/10.1183/2312508X.10031520
subpleural distribution with a predilection for upper and mid lung zones. The occasional air
bronchogram may be seen [29]. These macronodular and consolidative opacities demonstrate
ill-defined contours as they fade to a micronodular pattern toward the surrounding lung (figure 3c).
A pattern with a central dominant nodule with surrounding innumerable satellite micronodules
is termed as the “galaxy sign” in sarcoidosis, pathologically characterised by innumerable
coalescent granulomas (figure 3d) [30]. These are typically bilateral and multifocal. In contrast,
the “sarcoid cluster” corresponds to clusters of numerous small nodules that are close to each
other but not confluent. Granulomas without coalescence are seen on pathology [31].
Bilateral confluent large bronchocentric masses, mimicking progressive massive fibrosis, are a
distinct pattern seen in sarcoidosis (figure 4a) [23]. A history of occupational exposure is
valuable to exclude silicosis and coal workers’ pneumoconiosis.
Cavitary lesions are rare in sarcoidosis (3.4–6.8% of cases), usually indicating severe and active
sarcoidosis, resulting from either ischaemic necrosis or vasculitis [20, 32]. These cavitary
lesions are frequently multiple and bilateral but can occasionally be an isolated finding. In most
cases they manifest as thin-walled cysts or thick-walled cavities [32]. The presence of a cavitary
lesion on imaging in a patient with sarcoidosis warrants exclusion of superimposed infection
and granulomatosis with polyangiitis as primary cavitary sarcoidosis is rare.
Linear opacities
Sarcoid granuloma can cause thickening of the peribronchovascular interstitium with resultant
nodular or irregular septal thickening on CT. There is a tendency for septal thickening from
intense granulomatous infiltration to reverse; in contrast, irregular distorted lines are more likely
to be fibrotic [22, 33]. Functional impairment is relatively minor with a linear pattern.
Ground-glass opacities
Ground-glass opacities in patients with sarcoidosis are typically multifocal with incidence
ranging 18–83% [33]. These findings are typically upper lobe-predominant, overlaid on a
a) b)
FIGURE 4 Nonfibrotic patterns in pulmonary sarcoidosis. a) Axial HRCT of the chest depicting bilateral large
perihilar masses mimicking progressive massive fibrosis, a distinct pattern seen in sarcoidosis. b) Axial HRCT of
the chest showing a diffuse ground-glass pattern produced by coalescent micronodules.
https://doi.org/10.1183/2312508X.10031520 81
background of small perilymphatic nodules (figure 4b) [34]. Ground-glass opacity is more
commonly seen at presentation rather than later in disease course. Over time, ground-glass
opacities may improve (representing granulomas), remain steady or worsen (representing fine
fibrosis, especially if they are coarse in texture or associated with traction bronchiectasis [35].
Fibrotic parenchymal findings

Pulmonary fibrosis may develop in 20–25% of patients with sarcoidosis. Typical features of
interstitial fibrosis, such as reticulation, traction bronchiectasis, architectural distortion, fissural
and bronchial displacement and distortion, and volume loss located predominantly in the mid
and upper lung zones, are findings seen in patients with fibrotic sarcoidosis and indicate
irreversible disease. A typical feature of fibrotic sarcoidosis is the posterior displacement of the
main or upper lobe bronchus with associated volume loss, particularly in the posterior segment
of the upper lobes (figure 5a) [28]. The perihilar lymphadenopathy and confluent masses cause
encasement of the central bronchovasculature, frequently resulting in central bronchi becoming
deformed, angulated or stenosed, a common feature of stage IV disease [36]. The stenoses can
be solitary or multiple, lobar or segmental and may cause or contribute to pulmonary symptoms.
a) b)
c)
FIGURE 5 Fibrotic patterns in pulmonary sarcoidosis. a) Axial HRCT of the chest depicting posterior
displacement with associated volume loss in the posterior segment of the upper lobes – a typical feature of
fibrotic sarcoidosis. b) Coronal HRCT of the chest in a patient with sarcoidosis showing the upper lobe and
peribronchial with subpleural predominant fibrotic ILD and macrocystic honeycomb changes. An intra-cavitary
mycetoma is visible in the upper left lobe. c) Axial HRCT of the chest with stage IV fibrocystic sarcoidosis;
bilateral cystic spaces and cavities, some with intra-cavitary mycetomas.
82 https://doi.org/10.1183/2312508X.10031520
The fibrotic changes are frequently associated with paracicatrial emphysematous and bullae
noted in the periphery of the upper and mid lung zones [20]. Honeycombing (typically
macrocytic) is rarely seen in advanced fibrocystic sarcoidosis, classically along bilateral perihilar
peribronchovascular and subpleural distribution in the mid to upper lung zones with sparing of
the lung bases (figure 5b). This is associated with restriction and lower DLCO.
Three distinct patterns of distribution have been recognised in stage IV disease: the central
bronchial distortion or bronchiectasis pattern (47% of patients, predominantly obstructive
physiology), with or without coexistent masses; the peripheral honeycombing pattern (29%,
restrictive physiology and low DLCO); and the diffuse linear fibrotic pattern (24%, more mild
effect on respiratory function) [28, 37].
Aspergilloma
A solid mass developing within pre-existing cysts or bullae, representing mycetoma, is typically
seen in advanced fibrocystic sarcoidosis, with a reported incidence of 2% (figure 5c) [38].
These are frequently bilateral and multiple, and they demonstrate adjacent pleural thickening.
Aspergillomas may be associated with haemoptysis, which can occasionally be massive and
life-threatening.
Pleural involvement
Pleural involvement, effusion (bland, chylous, haemorrhagic) or thickening are rare in
sarcoidosis, seen in about 1–4% of patients [39]. Rarely, in patients with advanced fibrocystic
sarcoidosis, pneumothorax may be seen as a result of rupture of a cavitary lesion [32].
Airway involvement
Airway disease is common in sarcoidosis and frequently involves the central (detailed above) as
well as distal bronchi. Air trapping with or without pulmonary fibrosis can be seen in
pulmonary sarcoidosis, a frequent finding related to distal airway involvement. It is caused by
peribronchial or intraluminal granulomas or fibrosis obstructing the small airways [40, 41]. CT
findings of predominant bronchial distortion, peribronchovascular thickening, air trapping and
bronchial compression by lymphadenopathy are various mechanisms of airflow obstruction,
which are associated with obstruction on pulmonary function tests [37].
Low-dose CT
CT demonstrates high sensitivity in characterisation of lung abnormalities. Hence, it is
recommended that surveillance CT is performed in patients demonstrating unexplained symptom
or lung function deterioration, as well as in those with clinical or radiographical warning signs
of complications, such as pulmonary hypertension or aspergilloma [42]. A patient undergoing
an annual chest CT can accumulate >100 mSv of exposure in their lifetime [43].
Increasing ionising radiation, especially in young patients, is frequently an area of concern.
Current scanner generation with recent advances in CT technology, including implementation of

iterative reconstruction algorithms and active dose modulation using inbuilt scanner software,
have led to a significant reduction of the ionising radiation dose associated with this imaging
modality. Low-dose CT (radiation dose ranging 1–2 mSv) and ultralow-dose CT (radiation dose
<1 mSv) are newer, promising radiation-saving techniques that have utility in the assessment of
parenchymal lesions but limited value in the assessment of thoracic lymphadenopathy [44].
These techniques need data to validate their widespread clinical use.
https://doi.org/10.1183/2312508X.10031520 83
PET
18
F-FDG PET is used to detect high glucose metabolism in malignancies, to identify infectious
foci and to explain fever of unknown origin [45–48]. Combined PET/CT is preferred as it
provides more accurate morphological information and attenuation correction. It also allows
morphological and physiological changes to be studied together.
The glycolysis of inflammatory cells is enhanced when these cells are stimulated. This can
largely be attributed to the high number of glucose transporters that are present in these cells, as
well as to the enhanced affinity of these transporters for glucose [49]. 18F-FDG uptake follows
the same path as glucose, but once it has entered the cell, it is phosphorylated by hexokinase
enzyme to 18F-2′-FDG-6 phosphate. This cannot be further degraded via the glycolysis pathway
nor can it easily undergo dephosphorylation by glucose-6-phosphatase [50]. Inflammatory cells
such as activated macrophages and lymphocytes at the site of inflammation are responsible for
the accumulation of 18F-FDG [45].
Assessment of inflammatory activity using PET

PET has been shown to be very sensitive in the assessment of inflammatory activity in sarcoidosis
by detecting and quantifying the degree of inflammatory and granulomatous reactions that occur in
the lungs and elsewhere in the body [11, 51, 52]. It has limitations for assessment of: the urinary
tract, due to 18F-FDG excretion into the urine; the brain, due to high accumulation of 18F-FDG; and,
potentially, the gastrointestinal tract, due to diffuse or focal uptake as a result of peristalsis [45].
The indications for cardiac PET/CT and its clinical relevance are discussed in chapter 10 of this
Monograph [53].
Assessment of the extent of disease using PET

The assessment of organ involvement using PET has been shown to establish a higher rate of
involvement of the various organs compared with using findings from history, physical
examination, laboratory testing, CXR and pulmonary function tests [1, 54]. When compared
with more conventional imaging techniques, including CT, PET is superior in demonstrating
extrapulmonary involvement, such as bone/bone marrow involvement [52, 55]. This indicates that
physiological changes precede morphological changes, a concept recognised in oncology PET [56].
In patients with proven sarcoidosis, the extent of involvement and quantification of

inflammatory activity can be more accurately assessed with 18F-FDG PET than with 67Gallium
scintigraphy [57–59]. In addition, PET has several practical advantages: it is less
time-consuming, interobserver agreement is higher and radiation exposure is lower [57].
In studies using PET in active sarcoidosis, the prevalence of extrathoracic involvement was
found to be ⩽80%; in almost two-thirds of patients with extrathoracic PET-positive lesions,
these lesions had not been previously suspected [11, 52, 54, 60].
Nevertheless, due to radiation exposure, cost and its limited availability, PET/CT should
certainly not be included in routine work-up in sarcoidosis.
Indications for PET scanning

The merit of PET particularly lies in the evaluation of the extent of disease and the presence of
inflammatory activity. Patient populations in which PET can be of major added value include
those with suspected sarcoidosis, those with unexplained persistent disabling symptoms and
those with (suspected) cardiac sarcoidosis.
84 https://doi.org/10.1183/2312508X.10031520
If routine diagnostic procedures like bronchoscopy with transbronchial biopsy and BAL do not
provide sufficient evidence for diagnosis, performing a PET scan can provide a suitable location
for biopsy to obtain histological evidence for the diagnosis through detection of previously
unknown sites of active disease [52, 61]. Besides, detecting extrathoracic lesions, and thus a
more accurate evaluation of the extent of disease, can be of value in certain patients, providing
an explanation for (mainly extrathoracic) symptoms.
Performing a PET scan for the assessment of inflammatory activity is of added value in patients
with persistent disabling symptoms that cannot be explained by the results of routine diagnostic
procedures, including the absence of lung functional or chest radiographic deterioration [11].
Several studies have demonstrated an excellent positive predictive value of elevated serological
inflammatory markers (ACE, soluble IL-2 receptor and neopterin) for the presence of
inflammatory activity on PET. The negative predictive value, however, was moderate [11, 51, 60].
Based on these findings, PET appears to offer added value in assessing inflammatory activity in
patients with unexplained persistent disabling symptoms in the absence of signs of serological
inflammatory activity (figure 6).
a) b)
FIGURE 6 18F-FDG PET findings in a sarcoidosis patient with disabling symptoms in the absence of signs of
serological inflammatory activity. a) Coronal PET image at baseline showing pathologically increased 18F-FDG
uptake in the pulmonary parenchyma and para-oesophageal lymph nodes. b) Coronal PET image after 6 months
of therapy with infliximab showing resolution of the pathologically increased 18F-FDG uptake in the pulmonary
parenchyma and para-oesophageal lymph nodes.
https://doi.org/10.1183/2312508X.10031520 85
It has been demonstrated that the severity of pulmonary involvement as assessed by HRCT
features and lung function parameters correlates with PET activity in sarcoidosis [12]. In this as
well as in other studies, positive pulmonary PET findings were noted in a proportion of the
patients with normal chest radiographic findings (stage 0) and in the majority of patients with signs
of fibrosis on chest radiograph (stage IV) or HRCT (figure 7) [12, 52, 60]. As most of the patients
also had extrathoracic PET-positive findings and increased serological inflammatory markers, these
results strongly suggest the presence of inflammatory activity. This contributes to the differentiation
between the presence of potential partial reversible granulomatous disease among the fibrotic areas
versus exclusively irreversible fibrosis and thus may have therapeutic consequences.
The use of a semiquantitative HRCT scoring system appeared to offer better identification of
patients with PET-positive pulmonary findings than the Scadding radiographic staging system
[12]. In a retrospective study involving 95 patients in whom 18F-FDG PET results were
obtained, a clinical prediction rule, based on soluble IL-2 receptor levels and HRCT scoring
results, was derived and internally validated [62]. This prediction rule was shown to be useful in
identifying patients for whom there was a high probability that PET would show the presence of
inflammatory activity. If this approach is validated in future prospective studies, it has the
potential to substantially reduce the number of referrals for PET scanning.
Prognostic and therapeutic implications of PET findings

Aside from prognostic value through assessment of inflammatory activity, PET can provide
prognostic information by establishing organ involvement known to be associated with chronic
disease, like bone involvement [55].
18
F-FDG PET maximal standard uptake value (SUVmax) was found to be a predictor of future
deterioration of transfer factor of the lung for carbon monoxide (TLCO) when treatment was
withheld [63]. A significant reduction of 18F-FDG uptake after initiating or modifying treatment
was found in various studies and this related to clinical improvement [52, 55, 59, 64–66].
Furthermore, high baseline SUVmax values have been shown to predict the response to
immunosuppressive therapy, particularly in pulmonary disease, [64, 65].
Although measurement of total lung glycolysis provides information regarding the cumulative
metabolic activity in the lung and SUVmax only reflects focal activity, total lung glycolysis was
not found to be superior when evaluating sarcoidosis activity in the lung parenchyma in a
retrospective cohort study consisting of 27 patients with refractory pulmonary sarcoidosis [67].
a) b)
FIGURE 7 18F-FDG PET/CT findings in sarcoidosis with signs of pulmonary fibrosis. a) Axial CT of the chest
showing perihilar parenchymal consolidations, reticulonodular opacities and architectural distortion of the
parenchyma. b) Corresponding PET/CT fusion images showing increased 18F-FDG uptake in the parenchymal
consolidations as well as in the areas with reticulonodular opacities.
86 https://doi.org/10.1183/2312508X.10031520
PET can also help guide the duration of treatment. VORSELAARS et al. [68] demonstrated that
high SUVmax on 18F-FDG PET at initiation of therapy was a significant predictor of relapse. In
two studies with a limited sample size, one retrospective and the other of prospective, which
included sarcoidosis patients assigned to receive systemic glucocorticoids, no relapse was found
during the follow-up periods of 1 and 5 years, respectively, in patients with a decrease in
SUVmax of >75% from baseline on follow-up 18F-FDG PET [64, 69].
Further prospective and larger studies are required to standardise response criteria for PET and
to validate PET-guided therapy in sarcoidosis.
Novelties and potential research fields

MRI has been explored in pulmonary sarcoidosis. CHUNG et al. [43] showed good agreement on
comparison of MRI and HRCT, with the highest correlation for parenchymal opacification and a
weaker correlation for smaller nodules. Late-enhanced MRI using a specific turboFLASH pulse
sequence with an inversion time individually chosen to null the pulmonary arterial blood pool
signal following contrast material administration is able to identify all patients with fibrotic
pulmonary sarcoidosis, with good correlation with HRCT for its extent (Spearman correlation
coefficient 0.84) [43]. The “dark lymph node sign” (internal hypointense region with peripheral
hyperintensity) is a characteristic MRI sign seen on T2-FSE (BLADE) and post-gadolium
3D-GRE (VIBE) images within the mediastinal and hilar lymph nodes in up to 49% of patients
with sarcoidosis [70].
Proton MRI methods such as ultrashort echo time offer the possibility to image ILD and
structural changes at greater resolution; contrast enhancement offers a means of pulmonary
perfusion assessment [43].
MRI of inhaled hyperpolarised gases offers the ability to assess changes in lung ventilation,
microstructure and gas exchange assessment. Hyperpolarised helium (3He) and xenon (129Xe) have
the properties of atoms with half spin; this means they can be imaged with conventional MRI
methods using dedicated frequency coils [71]. The gas is inhaled in its pure state or mixed with
oxygen or nitrogen; the patient is asked to hold their breath for a few seconds during acquisition.
Diffusion limitation can be probed using magnetic resonance spectroscopic techniques, which can
evaluate the unique chemical shift of the hyperpolarised gas in gaseous, aqueous (tissue plasma)
and red blood cell environments. Regional information in the form of red blood cell/tissue plasma
ratios potentially forms the basis of regional gas exchange mapping of the lungs [72, 73]. Patients
with IPF shows a reduced red blood cell peak compared with tissue plasma peak. This technique
has not been studied in sarcoidosis but could in theory provide support in the assessment and
quantification of interstitial thickening and fibrotic changes in this disease [44].
In PET/CT, the use of alternative, more specific tracers like Gallium 68-DOTA-NaI-octreotide
and 3′-deoxy-3′-(18F)fluoro-thymidine may provide additional benefits compared with the
nonspecific 18F-FDG for the assessment of specific organ involvement (e.g. cardiac or central
nervous system) in sarcoidosis [74, 75]. Studies in larger patient cohorts are needed to confirm
the added value of such tracers.
Conclusion
Imaging plays a central role in the management of sarcoidosis. CXR is suitable for initial
evaluation and routine follow-up, whereas CT offers more detailed information that is indicative
of the reversible versus fibrotic nature of the abnormalities.
https://doi.org/10.1183/2312508X.10031520 87
Surveillance CT is recommended in patients with unexplained deterioration of symptoms or

lung function, and in those with clinical or radiographical warning signs of complications such
as pulmonary hypertension or aspergilloma.
In selected patients, PET can provide a suitable location for biopsy, contribute to the assessment
of inflammatory activity and prognosis, and aid treatment decisions.
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72 Kaushik SS, Robertson SH, Freeman MS, et al. Single-breath clinical imaging of hyperpolarized (129)Xe in the
airspaces, barrier, and red blood cells using an interleaved 3D radial 1-point Dixon acquisition. Magn Reson
Med 2016; 75: 1434–1443.
73 Weatherley ND, Eaden JA, Stewart NJ, et al. Experimental and quantitative imaging techniques in interstitial
lung disease. Thorax 2019; 74: 611–619.
74 Gormsen LC, Haralsen A, Kramer S, et al. A dual tracer (68)Ga-DOTANOC PET/CT and (18)F-FDG PET/CT pilot
study for detection of cardiac sarcoidosis. EJNMMI Res 2016; 6: 52.
75 Martineau P, Pelletier-Galarneau M, Juneau D, et al. FLT-PET for the assessment of systemic sarcoidosis
including cardiac and CNS involvement: a prospective study with comparison to FDG-PET. EJNMMI Res 2020;
10: 154.
Disclosures: R.L.M. Mostard has nothing to disclose. R. Yadav reports receiving consulting fees from Bioclinica,
outside the submitted work.
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Chapter 7
Pathological features and differential diagnosis

Giulio Rossi1 and Carol Farver2
1
Pathology Unit, Fondazione Poliambulanza, Brescia, Italy. 2Dept of Pathology, University of Michigan, Ann Arbor,
MI, USA.
Corresponding author: Giulio Rossi (giurossi68@gmail.com)
Cite as: Rossi G, Farver C. Pathological features and differential diagnosis. In: Bonella F, Culver DA, Israël-Biet D,
eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 91–106 [https://doi.org/10.
1183/2312508X.10031620].
@ERSpublications
Identification of sarcoid granulomas is a key point in the diagnosis of sarcoidosis. Typical/atypical histology,
differential diagnosis with other granulomatous processes involving the lungs and the diagnostic yield of
sampling techniques are illustrated. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Pathologists are frequently involved in the diagnosis of sarcoidosis when tissue specimens are required to
confirm the presence of sarcoid granulomas. In general, this occurs when the clinical and imaging features
are atypical for sarcoidosis. In this setting, evaluation of granulomas in the lung is related to their
qualitative characteristics (well-formed aggregate of epithelioid histiocytes lacking necrosis and surrounded
by few lymphocytes and fibrotic tissue) and anatomic involvement (lymphatic distribution along the
subpleural space, the interlobular septa and around the bronchovascular bundles). The pathological
differential diagnoses mainly include infections, hypersensitivity pneumonitis, autoimmune diseases and a
drug reaction, particularly with novel immunotherapeutic agents. Transbronchial biopsy/fine-needle
aspiration of the lung parenchyma and/or mediastinal lymph nodes usually results in an accurate final
diagnosis when interpreted within the appropriate clinical, laboratory and radiological findings.
Introduction
The American Thoracic Society/European Respiratory Society/World Association for Sarcoidosis
and Other Granulomatous Disorders Statement on Sarcoidosis [1] states that the diagnosis of
sarcoidosis relies on clinical and radiological findings, evidence of typical noncaseating
granulomas and excluding alternative causes sustaining a granulomatous process. Thus, the
diagnosis of sarcoidosis in the great majority of cases requires a histological biopsy or a cytological
sample showing sarcoid granulomas in the correct clinico-radiological context [2–5]. As
sarcoidosis is one of the numerous granulomatous diseases encountered in the lungs, pathologists
should rule out alternative differential diagnoses mimicking sarcoidosis through the correct
management of available specimens and close collaboration with clinicians and radiologists [6–14].
The major diagnostic procedures to procure tissue for diagnosis are bronchoscopy-guided methods,
particularly transbronchial needle aspiration (TBNA), transbronchial biopsy with/without EBUS
and use of a cryoprobe [15–18]. Imaging methods are covered elsewhere in this Monograph [19].
In a correct clinico-radiological setting, recognition of sarcoid granulomas in limited cytological
material is sufficient for a diagnosis of sarcoidosis [20, 21]. In this chapter on the pathologist’s role
in the diagnosis of sarcoidosis, we focus on the classic features and differential diagnosis of
sarcoidosis in the lung, and the diagnostic yield of different available samples.
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Expected pathological features

The granuloma is the histological hallmark of sarcoidosis, and its morphology does not change
in the numerous organs that may be involved. Lung involvement is almost always present, and
although patients may be asymptomatic or present with nonspecific symptoms, extrapulmonary
manifestations are quite common, occurring mainly in the lymph nodes, skin, eyes, liver, central
nervous system and heart, although any organ can be affected [1–5, 18, 22]. The typical sarcoid
granuloma consists of well-formed, non-necrotising aggregates of histiocytes surrounded by
hyaline collagen leading to their compact appearance (figure 1). In the early phases, granulomas
may be surrounded by a more oedematous myofibroblastic tissue [13, 22]. The other key feature
in discriminating sarcoid granulomas is their anatomic distribution. Sarcoid granulomas in lung
parenchyma tend to coalesce along lymphatics characteristically present on the pleural surface,
in the interlobular septa and around the bronchovascular bundles. The number of granulomas in
each of these locations may vary, but generally they are more abundant around the
bronchovascular bundles (figure 2). This airway-centred involvement helps explain the clinical
symptoms of obstructive function alterations and wheezing that can be present in some of these
patients. In addition, this lymphatic/lymphangitic involvement, which spares the alveolar
airspaces, closely correlates with the anatomic distribution observed on HRCT of the chest, and
may explain the asymptomatic patients with normal respiratory function tests in the presence of
a significantly altered imaging appearance.
The lymphatic distribution along the bronchoalveolar bundles also gives rise to the high
diagnostic yield of bronchoscopic procedures and the frequent observation of vascular
involvement of sarcoidosis (53% in transbronchial biopsy, 69% in surgical lung biopsy and
100% of autopsies) [23–26]. This vascular involvement usually takes the form of sarcoid
granulomas and/or giant cells located around and possibly invading all three layers (adventitia,
FIGURE 1 Cell-block preparation obtained during EBUS-TBNA demonstrating numerous fragments of lymph
node tissue with several sarcoid granulomas. Haematoxylin and eosin stain; magnification ×100.
92 https://doi.org/10.1183/2312508X.10031620
PATHOLOGICAL FEATURES AND DIFFERENTIAL DIAGNOSIS | G. ROSSI AND C. FARVER
a) b)
FIGURE 2 a) Surgical lung biopsy and b) transbronchial cryobiopsy showing lymphangitic distribution of sarcoid
granulomas along the alveolar septa and bronchovascular bundles. Haematoxylin and eosin stain; magnification ×40.
media and intima) of pulmonary arteries or veins with a weak to absent inflammatory infiltrate
and without necrosis of the vessel (figure 3). Of note, vascular involvement in sarcoidosis rarely
leads to pulmonary hypertension or veno-occlusive disease [27].
Coalescence of sarcoid granulomas tends to form large nodules/masses of fibrogranulomatous

tissue leading to the so-called nodular sarcoid, which often radiologically mimics neoplastic
conditions (figure 4). The finding of granulomas along the lymphatics at the periphery of this
nodule is generally recognisable and represents a diagnostic clue. Nevertheless, acellular hyaline
fibrosis in old nodules may become very prominent, obscuring and replacing granulomas
(burned-out granulomas), also assuming an “onion-skin” appearance, and comprising
birefringent coniotic deposits, resembling silicotic nodules.
Intracytoplasmic inclusions, including calcium oxalate crystals, and asteroid and Schaumann
bodies seen in giant cells represent the products of endogenous macrophage metabolism and are
frequently noted in sarcoid granulomas (figure 5) [2, 3, 6–10, 22, 28]. Pathologists should be
aware that these inclusions are not specific to sarcoidosis and may confound the pathologist,
suggesting a diagnosis of foreign-body granulomas as observed in chronic aspiration pneumonia.
Finally, necrotic foci are present in about one-fifth of transbronchial biopsies and more
frequently in surgical biopsies [22]. Necrosis in sarcoid granulomas generally presents as foci of
“rheumatoid-like”, central fibrinoid necrotic debris. More extensive areas of fibrinoid, infarct or
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a) b)
FIGURE 3 a) Example of a transbronchial cryobiopsy showing the distribution of sarcoid granulomas along the
bronchovascular bundles comprising the bronchiole and arteriole (haematoxylin and eosin stain, magnification
×100). b) Obliteration of a vascular vessel by sarcoid granulomas in the same biopsy. Haematoxylin and eosin
stain; magnification ×200.
suppurative (“granulomatosis with polyangiitis-like”) necrosis are quite uncommon. When

significant necrosis is present, the diagnosis of necrotising sarcoid granulomatosis should be
considered [29, 30]. Although the existence of this entity is controversial, most believe it is an
unusual variant of sarcoidosis with larger areas of necrosis.
The inflammatory infiltrate in sarcoidosis is generally restricted to a limited number of

lymphocytes around granulomas (so-called “naked granulomas”). When the unusual finding of
a larger amount of inflammatory, interstitial infiltrate together with foci of organising
pneumonia is present, the possibility of alternative diagnoses should be raised, including
hypersensitivity pneumonitis, infections, some collagen vascular diseases (e.g. Sjögren
syndrome), pulmonary involvement of inflammatory bowel disease, chronic aspiration or
toxicity from various drugs associated with a sarcoid-like reaction, as well as common variable
immunodeficiency [31–43].
In more chronic phases of sarcoidosis, hyaline fibrosis penetrates and fragments the sarcoid
granulomas (figure 6), finally leading to barely recognisable granulomas/giant cells [31, 32]. Of
note, in the late phase of sarcoidosis, a very few isolated giant cells and/or calcifications
entrapped in dense fibrosis may be the only pathological evidence of the disease. Pathologists
should carefully examine the lung tissue for these remnants of giant cells with dense hyaline
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FIGURE 4 Surgical lung biopsy showing a large nodule consisting of numerous coalescent aggregates of sarcoid
granulomas leading to a tumour-like mass (so-called nodular sarcoidosis). Haematoxylin and eosin stain;
magnification ×40.
FIGURE 5 A sarcoid granuloma containing a multinucleated giant cell with a couple of intracytoplasmic asteroid
bodies, a nonspecific stellate inclusion frequently observed in inflammatory granulomatous processes including
sarcoidosis. Haematoxylin and eosin stain; magnification ×200.
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FIGURE 6 Chronic sarcoidosis characterised by abundant collagen-rich fibrosis replacing and disrupting
granulomas. Haematoxylin and eosin stain; magnification ×200.
fibrosis along the lymphatics, as they are a helpful diagnostic clue to achieve a correct diagnosis
[13, 22, 31, 32]. With time, sarcoidosis generally leaves a normal or slightly scarred lung, but in
the progressive phase, it leads to significant fibrosis with traction bronchiectasis and
honeycombing. In these rare cases, infections ( particularly fungi) may complicate these chronic
cystic cavities. Finally, pathologists should be conscious that sarcoidosis is frequently
asymptomatic and can be seen as a background incidental finding in association with other
clinically significant diseases.
The role and efficacy of various diagnostic procedures

The diagnosis of sarcoidosis requires cytological or histological demonstration of granulomas
along with the appropriate clinical and radiological scenario.
BAL fluid analysis is a minimally invasive diagnostic tool in patients with suspected
sarcoidosis, particularly in excluding infections with employment of histological special stains
(i.e. Ziehl–Neelsen, periodic acid–Schiff, Gram, Warthin–Starry and methenamine silver stains)
or immunocytochemistry (i.e. primary antibodies against Pneumocystis spp., specific fungi and
mycobacteria) [44–48]. The finding of CD4+ Th1 lymphocytic alveolitis and the increased ratio
(>3.5/1) of CD4+/CD8+ lymphocytes are immunological features of sarcoidosis, although a
subset of cases shows a normal inflammatory cell count, and other mimicking granulomatous
diseases (e.g. hypersensitivity pneumonitis and connective tissue diseases) have significant
lymphocytosis (>30%) at BAL examination [44, 46–48].
Several biopsy procedures may be employed to demonstrate sarcoid granulomas, including

endobronchial and conventional transbronchial biopsy, TBNA with/without EBUS, EUS-FNA
with/without the use of an echobronchoscope, transbronchial biopsy with a cryoprobe, and
surgical lung biopsy by video-assisted thoracoscopy with or without a nonintubated “awake”
approach (table 1) [2–5, 9, 22, 32, 45–59]. The choice of the best invasive approach is based on
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TABLE 1 Diagnostic yield and invasiveness of different procedures in the diagnosis of sarcoidosis
Method Diagnostic yield Invasiveness Granuloma Lymphatic Comments

pattern

BAL Low/intermediate None/low No No Useful when CD4+/CD8+ lymphocytic ratio is high (>3.5); no
possibility of showing granuloma
TBNA Very high (up to Intermediate Yes No Possibility of obtaining cell block for special stains; rapid-on
100% when site evaluation increases sensitivity and reduces unnecessary
combined with passes
transbronchial
biopsy)
Bronchial biopsy Low/intermediate Low/intermediate Yes No Sarcoid granulomas are present in ∼20% in submucosal tissue;
several serial sections of paraffin-embedded blocks may
highlight granulomas not present in the first slides
Conventional High (up to Intermediate/high Yes Yes Sarcoid granulomas and lymphatic pattern may be
transbronchial 70–80%) appreciated; serial sections may be very helpful in highlighting
biopsy granulomas when absent in the first slides
Transbronchial Very high (up to High (10–15% pneumothorax; Yes Yes Very helpful in case of negative results with more conventional
cryobiopsy 100%) occasionally haemorrhagic events) procedures and to avoid open-lung biopsy
Surgical lung Very high (100%) Very high (patients should be Yes Yes Limited to very challenging cases when transbronchial
biopsy carefully selected); nonintubated procedures failed to demonstrate granulomas (i.e. chronic
“awake” biopsy reduces form with hyaline sclerosis replacing granulomas and
complications mimicking other ILDs)
TBNA: transbronchial needle aspiration.
97
clinical judgement, weighing up the diagnostic yield and the risk of complications for the
patient [3, 15, 22, 51]. Alternatively, clinicians should first consider the most accessible
extrathoracic site, including biopsy of superficial involved sites such as the skin or lymph nodes
[3, 15, 22].
TBNA is a reliable, safe and widely adopted procedure to obtain diagnostic tissue from
pathological mediastinal lymph nodes, leading to a very high (>90%) diagnostic yield in the
hands of experienced bronchoscopists and pathologists, with or without the assistance of
rapid-on site evaluation (ROSE) [21, 54]. To optimise the yield of a positive/diagnostic result,
smeared slides are prepared for ROSE after the first pass, accompanied by preparation of a cell
block that can be used for special stains (i.e. histochemical and immunohistochemical stains).
When different (cytology plus biopsy) bronchoscopy-based procedures are combined, the
diagnostic rate is close to 100% [18]. To achieve a high diagnostic yield, bronchial and
transbronchial biopsies should consist of multiple samples, possibly from different areas (at least
four good pieces of bronchial wall and lung parenchyma) [13, 22, 50]. At histological
examination, it may be helpful to obtain serial sections from the paraffin-embedded blocks,
which increases the probability of detecting granulomas [50, 60].
A generous transbronchial biopsy ( particularly when using a cryoprobe) may demonstrate

several compact, coalescent, non-necrotising sarcoid granulomas surrounded by hyaline fibrosis
along lymphatic routes, features highly suggestive of sarcoidosis. Frequently, both bronchial and
transbronchial biopsies may show small granulomas, a single giant cell or a Schaumann body,
which may be enough for a diagnosis of sarcoidosis when appropriate clinical and imaging
features are present [13, 15, 17, 22, 51].
In a recent review on the role of different techniques using bronchoscopy, PEDRO et al. [17]
argued that endosonographic techniques, such as EBUS-TBNA alone or in combination with
EUS-FNA, were superior to conventional bronchoscopic modalities in diagnosing sarcoidosis at
stages I and II (figure 7). In addition, the authors supported the usefulness and safety of
transbronchial lung cryobiopsy (TBLC) as a diagnostic tool overcoming some limitations of
conventional transbronchial lung biopsy and avoiding surgical approaches. DZIEDZIC et al. [56]
retrospectively analysed 653 patients with suspected stage I and II sarcoidosis and demonstrated
a positive result in 101 (30%) endobronchial biopsies, with the sensitivity of transbronchial
biopsy alone as 44%, figures significantly lower than those observed in EBUS-TBNA (84%;
p<0.001). Of note, the combination of EBUS-TBNA with endobronchial biopsy or
transbronchial lung biopsy had a diagnostic accuracy of 89% with a safe and feasible profile,
possibly representing the upfront procedure in patients with suspected sarcoidosis and enlarged
intrathoracic lymphadenopathy. JACOB et al. [57] showed a diagnostic yield of 92.6% in
suspected sarcoidosis investigated by TBLC, also evidencing alternative diagnoses (fungal
infection, hypersensitivity pneumonitis, silicosis), with an acceptable complication rate
including pneumothorax in 15.6% and moderate bleeding in one patient. In their cohort of 32
patients, TBLC appeared a useful tool in cases where a definitive diagnosis was not achieved
with less invasive diagnostic procedures. In a retrospective study of 36 patients aimed at
describing the yield of both EBUS-FNA and TBLC in the diagnosis of suspected sarcoidosis,
ARAGAKI-NAKAHODO et al. [58] noted an overall diagnostic rate of 80.6% (definite pathological
diagnosis in 29 patients). For patients with a possible diagnosis of sarcoidosis, the diagnostic
yield with EBUS-FNA and TBLC was 66.7% (12 out of 18 patients), but the combined use of
EBUS-FNA and TBLC permitted a diagnosis in all cases (the overall pneumothorax rate was
11%). Finally, surgical lung biopsy or surgical sampling of mediastinal lymph nodes should be
restricted to patients in whom the diagnosis of sarcoidosis is still uncertain after the failure of
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FIGURE 7 Smear cytology of mediastinal lymph nodes by transbronchial needle aspiration of the mediastinum
showing a granulomatous process surrounded by numerous lymphocytes on a clean background without
necrotic debris. As at histology, granulomas are relatively rounded and well defined with tightly packed
epithelioid histiocytes. Haematoxylin and eosin stain; magnification ×200.
bronchoscopy-based procedures. Of note, recent studies have shown that “awake” nonintubated
open-lung biopsy may offer a safe and feasible technique with high diagnostic yield even for
ILDs, including challenging cases of sarcoidosis [59].
The pathological differential diagnosis of sarcoidosis

The differential diagnosis of sarcoidosis includes several pathological entities (table 2) [2–13, 22, 61].
Granulomatous pathological patterns of injury in the lung comprise the main differential diagnosis for
sarcoidosis. Interestingly, in a recent review on challenging cases mimicking sarcoidosis, EL JAMMAL
TABLE 2 Main granulomatous diseases in differential diagnosis with sarcoidosis

Infections: mycobacteria (tuberculosis and atypical), fungi, Pneumocystis jirovecii
Hypersensitivity pneumonitis
Pneumoconiosis: beryllium (chronic beryllium disease), aluminium, titanium
Chronic aspiration
Drug reactions including drug-induced sarcoidosis-like reactions
Collagen vascular diseases (Sjögren syndrome)
Primary biliary cirrhosis and inflammatory bowel diseases
Common variable immunodeficiency
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et al. [61] identified seven different subsets of granulomatous disorders simulating sarcoidosis,
comprising infections, neoplasms (e.g. Hodgkin disease), iatrogenic sarcoid-like reactions (e.g. drug
toxicities), device- or microparticle-induced granulomatous reactions (e.g. beryllium, silicosis),
primary immunodeficiencies with granulomas, systemic disorders with granulomas and organ-specific
entities (e.g. hypersensitivity pneumonitis). As frequently stated here, a definitive diagnosis of
sarcoidosis relies on a meticulous integration of histology/cytology with clinical presentation, imaging
studies and laboratory data. The consistency and confidence level of histology varies from case to
case, and pathologists should always clearly discuss this point with the clinician.
The most common and difficult differential diagnosis is with infectious processes showing
granulomatous inflammation (table 3) [2–13, 22, 61]. While sarcoidosis consists of well-formed
and compact, rigid granulomas surrounded by lamellar dense fibrosis, granulomatous infections
tend to have more discohesive granulomas with necrosis (minimal/absent in atypical
mycobacteria) and a more pronounced inflammatory infiltrate with the presence of neutrophils.
In general, the amount of necrosis is directly related to infectious processes and a careful search
for microorganisms is mandatory, possibly performing more special stains on serial sections. In
addition, the quality of necrosis in sarcoidosis is often fibrinoid, whereas in infection necrosis it
is often eosinophilic and granular (“caseous”) or suppurative.
The anatomic distribution of granulomas is another clue: granulomas in infectious lesions have
a random distribution in the lung parenchyma (into the alveolar spaces and/or peribronchiolar
region) and do not involve lymphatics as observed in sarcoidosis. The finding of well-formed
granulomas along the lymphatic routes (visceral pleura and interlobular septa) in cases with
prominent granulomas localised around the bronchioles is most consistent with sarcoidosis. In
contrast, the finding of granulomas in the parietal pleura is more indicative of granulomatous
infection, and compact granulomas involving the vessel wall is a subtle hallmark favouring
sarcoidosis over infections [13, 22]. Again, the presence of a moderate-to-marked cellular
inflammatory infiltrate with lymphocytes and plasma cells associated with foci of organising
pneumonia is generally absent in sarcoidosis but very common in infections, particularly when
the patient presents with fever and the tissue demonstrates necrosis. Most importantly, when
pathologists encounter areas of granulomas with necrosis and/or airspace prevalence, infections,
mainly from mycobacteria and fungi, should be considered [2–4, 6–13]. In this setting,
pathologists should perform microbiological or cultural investigations and special tissue stains
(e.g. methenamine silver for fungi, stains for Nocardia, Actinomyces and Pneumocystis spp.,
and Ziehl–Neelsen) or other stains to detect mycobacteria such as immunohistochemistry with
specific antibodies [13, 22, 51].
The histology of subacute hypersensitivity pneumonitis (extrinsic allergic alveolitis) is

characterised by a triad of chronic interstitial inflammation with lymphocytes and plasma cells,
an increase in chronic inflammatory infiltrate in the peribronchiolar area (cellular bronchiolitis),
and small, dispersed and discohesive interstitial granulomas, sometimes appearing as single,
scattered giant cells (figure 8) [38]. Hypersensitivity pneumonitis is also characterised by the
presence of obstructive features in the form of organising pneumonia and foamy histiocytes,
particularly evident in the peribronchiolar alveoli. The morphology of the granulomas in
hypersensitivity pneumonitis is much less compact, and they are localised in the peribronchiolar
zone and associated with a moderate-to-marked chronic inflammatory infiltrate [2, 3, 6–13, 15, 22].
Of note, after exposure to some specific antigens, such as Mycobacterium avium in so-called
“hot-tub lung” or in farmer’s lung hypersensitivity pneumonitis, the qualitative features of
interstitial granulomas consist of larger granulomas but still surrounded by prominent
inflammation and lacking the rigidity and compactness of sarcoid granulomas [13, 22, 33].
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TABLE 3 Histological and cytological features of sarcoidosis: comparison with differential diagnoses

Morphology of granulomas Location Chronic Necrosis Fibrosis
inflammation
with
organising
pneumonia
Sarcoidosis Non-necrotising or with minimal fibrinoid necrosis; Lymphatic Uncommon Tiny foci, never as Very common
compact; coalescent; embedded within hyaline fibrosis involvement large areas
and vascular involvement
Infections with Necrotising (but necrosis can be absent); well formed but Random, or Common Frequent Uncommon
granulomas not very compact; tend to be solitary; not much broncho- or
perigranuloma fibrosis bronchiolocentric
Hypersensitivity Loose/inconspicuous (frequently just giant cells isolated Bronchiolocentric Typical with Never Uncommon (present in
pneumonitis or in small groups); no necrosis centrilobular chronic form)
accentuation
Aspiration Giant cells and granulomas often with granulocytes and Bronchiolocentric Common Uncommon Uncommon (present in
foreign particles recurrent, chronic
form)
101
FIGURE 8 An open-lung biopsy of hypersensitivity pneumonitis showing an interstitial ill-defined and tiny
granuloma in a prominent chronic inflammatory infiltrate. Haematoxylin and eosin stain; magnification ×100.
The pathological features observed in berylliosis are quite similar if not morphologically
indistinguishable from sarcoidosis [3, 13, 22, 43]. The disease is secondary to chronic exposure
to inhaled particles of beryllium, a metal generally used in ceramics, rocket and aerospace
manufacturing, production of food boxes, the computer industry, dental laboratories and mining
activities [3, 4]. The histology of chronic berylliosis may show entirely overlapping features
with sarcoidosis, varying from a cellular nonspecific interstitial pneumonia with granulomas to a
prominent granulomatous pathology. Diagnosis is based on demonstration of a history of
beryllium exposure, a positive serological lymphocytic proliferation test and demonstration of
the presence of beryllium in lung tissue by mass spectrometry [4].
In chronic sarcoidosis, the exuberant fibrous tissue can replace lung parenchyma with a significant
amount of environmental pigment and roughly mimicking some histological features of silicotic
nodules or granulomatous silicosis. Nevertheless, a helpful clue for pathologists is the observation
that silicotic nodules do not contain granulomas [3, 13, 22]. Sarcoid-like granulomatous reactions
may also be observed in response to aluminium and titanium, and demonstration of a clinical
history of chronic exposure may be the most helpful finding in this differential diagnosis.
Various autoimmune diseases, including collagen vascular diseases ( particularly Sjögren

syndrome), inflammatory bowel diseases (especially Crohn disease), primary biliary cirrhosis
and common variable immunodeficiency may produce a granulomatous lung disease simulating
sarcoidosis [13, 22, 61]. Nevertheless, granulomas are generally less compact, do not show a
lymphatic distribution, and have more inflammation around bronchioles (cellular bronchiolitis)
and organising pneumonia.
Several drugs may induce a sarcoid-like reaction that is indistinguishable from sarcoidosis and
occurs in a temporal relationship with drug initiation. It is important to underline that this
phenomenon has recently been described with various biological drugs, such as
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immunotherapeutic agents (i.e. nivolumab, ipilimumab, atezolizumab), tocilizumab, pirfenidone

and lorlatinib, used mainly in the treatment of melanoma and carcinomas (lung, bladder) or
autoimmune diseases (e.g. giant-cell arteritis) [61–66].
The chronic form of sarcoidosis can mimic other diffusely fibrosing diseases, particularly usual
interstitial pneumonia/IPF [13, 15, 18, 22, 31, 32]. A correct diagnosis of chronic fibrosing
sarcoidosis relies on finding the following: 1) small granulomas, often isolated and sparse or
obscured by large areas of hyaline fibrosis, 2) the uniform and homogeneous characteristics of
dense fibrosis with absence of active fibroblastic foci, and 3) the characteristic radiographic
findings of sarcoidosis with upper-lobe-predominant fibrosis. Isolated granulomas may be
observed in IPF for several reasons, namely chronic aspiration due to the concurrent presence of
gastro-oesophageal reflux, mycobacterial infections or an incidental coexistence of an
underlying sarcoidosis.
The finding of sarcoid-like granulomas embedded in or around malignancies or in draining

lymphatics/lymph nodes is a controversial and unresolved issue. In our view, the pertinent
literature is still limited and inconclusive, while the great majority of this occurrence merely
represents an incidental finding without any clinical impact or subclinical, asymptomatic cases
of sarcoidosis [3, 13, 15, 22]. Finally, as stated previously, necrotising sarcoidosis is a rare
occurrence characterised by mass-like areas of granulomas with necrosis and necrotising
vasculitis. The lesion probably represents just an unusual variant of sarcoidosis with prominent
areas of necrosis [13, 22, 29, 30, 61].
Chronic aspiration pneumonia generally occurs in patients with underlying diseases (e.g.
gastro-oesophageal reflux disease, neurological diseases, diabetes mellitus) favouring aspiration
of foreign material (e.g. vegetables or skeletal muscle from food, pill fragments) and leading to
a bronchiolocentric non-necrotising granulomatous reaction consisting of loose giant-cell
granulomas or dispersed giant cells [22, 35, 36, 67]. Organising pneumonia and abscess
formation may accompany the granulomatous reaction, but the finding of foreign bodies is the
only diagnostic hallmark. Nevertheless, foreign material may be absent or showing degenerative
changes. In the clinical suspicion of a granulomatous process secondary to chronic aspiration,
pathologists should meticulously search for foreign material in several serial and deeper sections
or additional tissue.
A careful evaluation of the pathological differential diagnosis of sarcoidosis relies on a

meticulous integration of histology/cytology with clinical presentation, imaging studies and
laboratory data. A careful analysis of qualitative features, anatomic distribution and
accompanying findings considerably narrows the differential diagnosis [2–4, 6–13, 15, 22].
Although these characteristics are most easily evaluated on open-lung biopsy, they can be
appreciated on transbronchial biopsy, particularly in larger samples obtained with cryobiopsy.
Key messages
• Sarcoidosis represents the most common cause of non-necrotising granulomas in the lungs.
• The diagnostic histological features of sarcoid granuloma are tightly packed, non-necrotising
granulomas surrounded by lamellar hyaline fibrosis and displaying a lymphangitic
distribution.
• BAL fluid examination is a less invasive diagnostic procedure and, in a robust

clinico-radiological scenario, supports a diagnosis of sarcoidosis with alveolar lymphocytosis
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(with predominance of a CD4+/CD8+ T-lymphocyte ratio >3.5). BAL fluid may also help to
rule out opportunistic infections in immunosuppressed patients with sarcoidosis on steroids,
who have been chronically immunosuppressed.
• Sarcoid granulomas may be reliably identified on cytology obtained from TBNA of

mediastinal lymph nodes (with or without EBUS) and cell-block preparation allows special
stains to be performed to rule out an infectious aetiology.
• Among biopsy procedures, transbronchial biopsy with a cryoprobe represents the diagnostic
tool with the highest yield, permitting larger samples to be obtained without unnecessary
surgery and with an acceptable complication rate.
• Atypical forms of sarcoidosis may occur, and knowledge of unusual histological features is
mandatory to prevent misdiagnoses.
• The main differential diagnoses include infections (mycobacteria and fungi), hypersensitivity
pneumonitis, pneumoconiosis, drug toxicity leading to sarcoid-like reactions and autoimmune
diseases.
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106 https://doi.org/10.1183/2312508X.10031620
Chapter 8
Serum and imaging biomarkers

Ingrid H.E. Korenromp1, Lisa A. Maier2,3 and Jan C. Grutters1,4
1
Dept of Pulmonology, ILD Center of Excellence, St Antonius Hospital, Nieuwegein, The Netherlands. 2Division of
Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO, USA. 3Dept of Medicine,
School of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, CO,
USA. 4Division of Hearth and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
Corresponding author: Jan C. Grutters ( j.grutters@antoniusziekenhuis.nl)
Cite as: Korenromp IHE, Maier LA, Grutters JC. Serum and imaging biomarkers. In: Bonella F, Culver DA,
[https://doi.org/10.1183/2312508X.10031720].
@ERSpublications
No single biomarker in serum is a gold standard in sarcoidosis, but in imaging 18F-FDG PET shows promise
for diagnosis and monitoring. Novel biomarker approaches are needed to determine the sensitivity and
specificity of biomarkers used in combination. https://bit.ly/3ozzgsF
This chapter has supplementary material available from books.ersjournals.com
ISSN: 2312-5098.
Over the last 10 years, a range of biomarkers have been evaluated in sarcoidosis. Based on extensive
literature reviews over this period, the single serum analytes serum ACE, soluble IL-2 receptor and
chitotriosidase stand out as potential diagnostic and monitoring tools with significant sensitivity and
specificity, although none functions alone as a gold standard biomarker. Other proteins, such as
YKL-40, Krebs von den Lungen-6, cathepsin S and IFN-γ-induced protein 10, show potential as
biomarkers. Unfortunately, data on serum biomarkers for use as a prognostic tool (to predict
disease outcome, irrespective of treatment) or as a predictive tool (to predict the effect of therapy) are
scarce. With respect to imaging modalities as biomarkers, 18F-FDG PET seems to have potential
as a prognostic tool. This nuclear biomarker may also help in determining treatable inflammatory
lesions in symptomatic patients with indecisive conventional tests. Future research on biomarkers,
including those emerging from novel technologies, as well as the utility of combined biomarkers,
should rely on carefully designed prospective trials to allow translation and implementation in routine
clinical care.
Introduction
Over the last decade, numerous biomarkers have been studied in patients with sarcoidosis.
Studies have also evaluated conventional and novel blood and other fluid analytes, alone and in
combination, including proteins, mRNA/microRNA, exosomes, and/or other blood or imaging
biomarkers [1–4]. However, so far, no single biomarker has been found with the characteristics
of a gold standard to allow strong recommendation in guidelines or for application in routine
clinical care. This chapter will provide an overview of the serum biomarkers that have been
studied over the last 10 years and the use of imaging as a biomarker of sarcoidosis prognosis,
with a focus on nuclear imaging. To lay the groundwork for this overview and prevent
confusion about the terms and concepts, a definition will be given of the concept of a
biomarker, as well as the different types of biomarkers and their characteristics.
https://doi.org/10.1183/2312508X.10031720 107
Biomarkers
Definition of a biomarker
The term biomarker (short for biological marker) refers to a broad subcategory of medical signs
that can be measured accurately and reproducibly. In contrast to medical symptoms as perceived
by the patients themselves (also referred to as patient-reported outcomes), biomarkers are
objective measures of the patient’s medical status [5]. It is important to distinguish biomarkers
from direct measures of how a person feels, functions or survives. The latter category, also
known as clinical outcome assessment, is often used as an end-point in clinical studies [6].
The National Institutes of Health Biomarkers Definitions Working Group has defined a
biomarker as “a characteristic that is objectively measured and evaluated as an indicator of
normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic
intervention” [7]. Here, we will focus primarily on serum biomarkers that can be objectively,
accurately and reproducibly measured in a laboratory, and we will describe the usefulness of
imaging as a biomarker, focusing on nuclear imaging.
Types of biomarker
A single biomarker may be used for one or multiple purposes: as a diagnostic, monitoring,
prognostic and/or predictive tool. These different types of biomarkers are explained below.
Diagnostic biomarkers
A diagnostic biomarker detects or confirms the presence of a certain disease or condition of
interest, or identifies an individual with a subtype of the disease ( phenotype) [6]. Such
biomarkers may be used not only to identify people with a specific disease but also to redefine
the classification of the disease [6]. For example, in sarcoidosis, a diagnostic biomarker would
ideally discriminate between cardiac and noncardiac sarcoidosis.
Monitoring biomarkers
In order to detect an effect of a medical intervention (e.g. anti-inflammatory therapy), a
biomarker can be measured serially, providing information on the change in status of a disease
or medical condition. A biomarker used in this way is a monitoring biomarker. Monitoring
biomarkers have important applications in clinical care [6].
Prognostic biomarkers
A prognostic biomarker is used to identify the likelihood of a clinical event, disease recurrence
or disease progression in patients with a disease or medical condition of interest. For instance,
in sarcoidosis, a particular serum level of a biomarker at diagnosis might be correlated with
spontaneous recovery, a chronic course and/or progression of the disease. Although a genetic
test rather than a serum biomarker, HLA-DRB1*0301 has been used as a prognostic biomarker
in Sweden for Löfgren syndrome [8, 9]. It is important to discriminate prognostic biomarkers
from predictive biomarkers: prognostic biomarkers are associated with different disease
outcomes, irrespective of therapy [6].
Predictive biomarkers
Predictive biomarkers indicate whether patients will or will not respond to therapy. The
presence of or change in a predictive biomarker indicates whether an individual or a group of
individuals is more likely to experience a favourable or unfavourable effect from the medical
intervention or therapy [6]. The term theragnostic biomarker may also be used to describe a
predictive biomarker.
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SERUM AND IMAGING BIOMARKERS | I.H.E. KORENROMP ET AL.
TABLE 1 Sensitivity and specificity of biomarkers
Test Condition or illness

Present Not present
Positive True positive (A) False positive (B)

Negative False negative (C) True negative (D)
Sensitivity=(A/(A+C)); specificity=(D/(B+D)).
Quality of biomarkers
The two most important qualities of a biomarker are sensitivity and specificity, as they reflect
the performance of the biomarker. Sensitivity refers to the proportion of positive/abnormal tests
that are correctly identified (table 1). If the biomarker is positive, the individual is correctly
identified as having the condition (in this case, sarcoidosis), a specific organ manifestation or
course of disease. Sensitivity is also known as a true positive [10]. In contrast, specificity refers
to true negatives. Specificity measures the proportion of negative tests that are correctly
identified as negative, or the proportion of those who do not have the condition (unaffected) that
are correctly identified as such (table 1) [10].
In daily medical practice, however, the term specificity is often used to indicate the extent to
which a positive result from a sensitive test also confirms a particular condition. For instance, in
the case of diagnosis, to what extent do elevated levels of a biomarker (e.g. serum ACE
(sACE)) specifically point to the diagnosis of sarcoidosis and not to another disease or
condition? In this respect, the word specifically is used interchangeably with exclusively when
the latter is more appropriate. As the diagnostic power of any test is determined by its
sensitivity and specificity, we will focus on these characteristics of serum biomarkers for
sarcoidosis in this chapter.
Other important qualities of an ideal biomarker include reliability, precision, repeatability and
cost ( preferably a low cost) [6]. Moreover a biomarker should be relatively easy to obtain in a
noninvasive manner, provide clinical value and be easily integrated into clinical practice, and
should exclude and not be related to other diseases [11].
Why use biomarkers in sarcoidosis?

As sarcoidosis is a heterogeneous disease with regard to presentation, severity and chronicity, it
may be of clinical value to be able to discriminate among the different phenotypes and disease
states or activity, or to predict remission or progression in sarcoidosis patients. Apart from this
prognostic point of view, it would also be useful to predict which patients would profit from
specific treatment. This knowledge may improve care and outcomes, as well as allowing
personalised approaches (or personalised medicine) and cost savings [11].
The literature search for this chapter was performed according to the steps described in
Appendix A of the online supplementary material. All studies evaluating serum biomarkers over
the last 10 years were retrieved and evaluated as diagnostic, monitoring, prognostic and
predictive biomarkers.
Serum biomarkers for sarcoidosis

Over the last decade, many serum biomarkers have been studied in sarcoidosis.
https://doi.org/10.1183/2312508X.10031720 109
sACE
As levels of sACE were first reported to be elevated in active sarcoidosis patients in 1975 [12],
this has been the most used and studied biomarker. sACE is thought to be produced by
granuloma epithelioid cells and macrophages and to be regulated by genetic variants variably
associated with sarcoidosis [13]. Over the last 10 years, 14 studies have reported on sACE.
sACE as a diagnostic tool

The sensitivity and specificity of sACE in the diagnosis of sarcoidosis are still debated, ranging
from 29% to 90.5% for sensitivity [14–17] and from 47% to 89.9% for specificity (table 2)
[15, 16, 18, 19]. The low percentages on both qualities suggest a limited role for sACE as a
diagnostic tool [31].
sACE as a monitoring tool

While early on LIEBERMAN [12] recommended use of sACE as a monitoring tool to detect
disease activity, LOPES et al. [18] confirmed that sACE levels were higher in patients with active
disease than in controls or patients in remission, with a sensitivity of 88% and a specificity of
47%. Moreover, the highest ACE levels were found in patients at radiological stages 0, 1 and 2,
although the study did not correct for genotype.
A study by POPEVIĆ et al. [24] corrected for genotype and found significantly higher sACE
levels in patients with active compared with those with inactive sarcoidosis, although the
authors found no difference between acute and chronic sarcoidosis patients. Even with these
associations, the sensitivity (66%) and specificity (54%) of sACE were low. While VORSELAARS
et al. [20] demonstrated that serial sACE and serum soluble IL-2 receptor (sIL-2R) levels
correlated well with lung function improvement, especially DLCO, during MTX treatment, the
sensitivity and specificity of these two biomarkers were not described.
sACE as a prognostic tool

Over the last 10 years, no publications have reported on sACE as a prognostic tool.
sACE as a predictive tool

High levels of sACE before treatment were found to correlate significantly with lung function
improvement after 6 months of MTX treatment, although no estimates of sensitivity or
specificity were supplied [20]. These early data suggest that sACE might be considered as a tool
to predict treatment outcome.
Reported limitations of sACE

A common error in misinterpretation of sACE levels is the use of ACE inhibitors (as
antihypertensive therapies), which impact the levels, estimates of sensitivity and specificity, and
the ability to use ACE as any kind of biomarker in sarcoidosis [32–34]. In a study by EURELINGS
et al. [15], patients using an ACE inhibitor prior to sACE measurement were therefore excluded
from analysis.
Furthermore, there is a genetic insertion/deletion (I/D) polymorphism that impacts sACE levels,
so it has been recommended that levels be corrected for genotype [13]; nevertheless, studies
evaluating sensitivity and specificity have not reported on this correction, probably impacting
these estimates as well as study findings. As those with the I/I genotype have the lowest sACE
levels, D/D the highest and I/D intermediate, finding I/I individuals with levels in the normal
110 https://doi.org/10.1183/2312508X.10031720
https://doi.org/10.1183/2312508X.10031720
TABLE 2 Sensitivity and specificity rates of different serum biomarkers in sarcoidosis as found in the literature over the last 10 years
Biomarker Diagnostic First author Monitoring First author Prognostic tool First author
tool [ref.] tool [ref.] [ref.]
Sensitivity, Specificity, Sensitivity, Specificity, Sensitivity, Specificity,
% % % % % %
sACE# 29–90.5 47–89.9 NGUYEN [14], EURELINGS [15], 66–88 47–54 LOPES [18],
UYSAL [16], CSONGRÁDI [17], VORSELAARS
LOPES [18], UNGPRASERT [19] [20]

sIL-2R 47–94.4 90.4 NGUYEN [14], EURELINGS [15], 50–75 62–94.4 VORSELAARS
KEIJSERS [21], SCHIMMELPENNINK [22], [20]
MIYATA [23]
CTO 82.5–88.6 70–92.8 POPEVIĆ [24], ENYEDI [25], 55 100 LOPES [18]
BARGAGLI [26]
YKL-40 83.1 92 UYSAL [16]
KL-6 78 73 BERGANTINI [27]
Albumin 90.5 98.2 ISMA [28]
Cathepsin S 70 78 TANAKA [29]
IP-10 78 87 GEYER [30]
No calculations on sensitivity and specificity were found in the literature over the last 10 years with respect to biomarkers as a predictive tool (indicating whether patients
will respond to therapy or not). sACE: serum ACE; sIL-2R: soluble IL-2 receptor; CTO: chitotriosidase; KL-6: Krebs von den Lungen-6; IP-10: IFN-γ-induced protein 10. #: as
noted in the text, these results are impacted by the use of ACE inhibitors as antihypertensive therapy.
111
range could in fact reflect those with relatively higher levels. Using the genotype correction for
the I/D polymorphism might have improved the interpretation of sACE levels in these studies
by 8.5% [13].
Although no genotype correction was used by ENYEDI et al. [25], their study evaluated sACE
levels combined with chitotriosidase (CTO), another potential diagnostic biomarker for
diagnosing sarcoidosis. The combination of biomarkers yielded a sensitivity of 90.5% and a
specificity of 79.3%.
Lastly, elevated sACE is not found exclusively in sarcoidosis, as it can also be increased in
many other ILDs.
sIL-2R
The second most used and studied biomarker in sarcoidosis is sIL-2R. Since HUNNINGHAKE et al.
[35] detected elevated levels of IL-2 released by T-cells of active pulmonary sarcoidosis
patients, the circulating form of the membrane receptor for this marker has been the focus of
many studies. Over the last 10 years, there have been eight publications on this subject.
sIL-2R as a diagnostic tool

A few studies have demonstrated higher and superior sensitivity and specificity of serum sIL-2R
compared with ACE for diagnosing sarcoidosis [14, 15, 21]. Regardless, the sensitivity of
serum sIL-2R levels to detect sarcoidosis varied between 47% and 94.4%, whereas the
specificity was high at 90.4% (table 2) [14, 15, 21–23].
Additionally, sIL-2R levels were significantly higher in patients with multiple organ
involvement and parenchymal infiltration, suggesting that sIL-2R may potentially discriminate
between the phenotypes of sarcoidosis [14].
sIL-2R as a monitoring tool

As mentioned, VORSELAARS et al. [20] also showed that serial sIL-2R levels correlated well with
lung function improvement during MTX treatment. No other publication was found using
sIL-2R as a monitoring tool.
sIL-2R as a prognostic tool

SCHIMMELPENNINK et al. [22] revealed that sIL-2R at diagnosis is a significant predictor of the
development of chronic sarcoidosis, with a sensitivity of 75% and a specificity of 62%.
Furthermore, this study showed that high sIL-2R levels indicated the need for systemic
treatment, with a sensitivity of 58% and a specificity of 78%.
ZHOU et al. [36] used sIL-2R as a prognostic tool, as only sIL-2R was a significant independent
predictor of spontaneous remission in a multivariate logistic regression model, with a sensitivity
ranging from 50% to 66.7%, and a specificity from 68.7% to 94.4%, depending on the stage
of disease.
sIL-2R as a predictive tool

Two studies have indicated sIL-2R as a possible predictor of treatment outcome. VORSELAARS
et al. [20] found that baseline levels of sIL-2R correlated significantly with a change in DLCO
during treatment with MTX. In another study, high serum sIL-2R at initiation of infliximab
therapy was a significant predictor of relapse after discontinuation of treatment [37]. However,
no calculation of sensitivity or specificity was supplied in either study.
112 https://doi.org/10.1183/2312508X.10031720
Reported limitations of sIL-2R

Elevated sIL-2R is not found exclusively in sarcoidosis, as it is also increased in patients with
other ILDs such as IPF and chronic hypersensitivity pneumonitis [38].
CTO
The enzyme CTO, which derives from activated macrophages, has been studied extensively, as
a direct correlation between this biomarker and sACE levels was reported in sarcoidosis [39].
Over the last 10 years, there have been 12 publications using CTO foremost as a diagnostic as
well as a monitoring tool.
CTO as a diagnostic tool

As a diagnostic tool, the sensitivity of CTO varies between 82.5% and 88.6%, while specificity
ranges from 70% to 92.8% (table 2) [24, 26]. HARLANDER et al. [40] showed that significantly
lower initial levels of CTO were found in patients with Löfgren syndrome compared with other
sarcoidosis patients, potentially discriminating between subgroups. However, no data on
sensitivity or specificity were supplied.
ENYEDI et al. [25] showed that CTO levels alone could discriminate between sarcoidosis patients
and controls, but that, in combination, the parameters of ACE and CTO showed improved
diagnostic accuracy with a sensitivity of 90.5%, and a specificity of 79.3%.
One study also showed that higher CTO concentrations were correlated with elevated levels of
sIL-2R, although sensitivity and specificity rates of the combination of these two parameters
were not presented [41].
CTO as a monitoring tool

With respect to CTO as a biomarker of change in disease status, LOPES et al. [18] reported that
levels of CTO differentiated between patients with active versus remitting sarcoidosis with a
sensitivity of 55% and a specificity of 100%.
A number of studies have evaluated CTO as a monitoring tool, but none supplied estimates of
the sensitivity or specificity. BARGAGLI et al. [26] reported the lowest CTO concentrations in
untreated remitting patients and the highest concentrations in symptomatic patients with
persistent disease treated with steroids and with functional deterioration over the prior year. In
this same subgroup, CTO decreased significantly after an increased steroid dose or introduction
of a new immunosuppressant therapy.
Other studies have found that low CTO levels correlated with remitting or minimal disease, while
high values corresponded with increased clinical symptoms, deterioration of the chest radiograph
and FVC/DLCO ratio, persistent disease and extrapulmonary involvement [40, 42, 43]. In these
same studies, increased CTO levels correlated with relapse and increased treatment requirement
(e.g. steroid dose) [40–42, 44]. Additionally, CTO was used as a monitoring tool to establish the
effect of therapy. Both BOOT et al. [42] and TERČELJ et al. [43] found that after regular treatment
with corticosteroids over 6 months, CTO activity decreased in the majority of patients.
CTO as a prognostic tool

BERGANTINI et al. [45] showed that high levels of CTO (and Krebs von den Lungen-6 (KL-6)) were
observed in chronic sarcoidosis patients, regardless of therapy. CTO activity was significantly
higher in patients with multiple organ involvement, suggesting potential in the prognosis of
multisystemic sarcoidosis, although no sensitivity or specificity estimates were available.
https://doi.org/10.1183/2312508X.10031720 113
CTO as a predictive tool

No publications were found on the use of CTO as a tool to predict therapy outcome.
Reported limitations of CTO

Of note, elevated levels of CTO are not exclusive to sarcoidosis. High serum levels have also
been found in Gaucher disease, malaria, multiple sclerosis, atherosclerosis, Alzheimer disease
and tuberculosis [18].
Another major limitation for CTO as a biomarker relates to the genetic duplication of 24 bp in
the CTO gene, which results in an inactive protein in 5–6% of the general population. The
impact of this duplication polymorphism on CTO concentration has not been clarified in
sarcoidosis patients, or in terms of its use as a biomarker. This is important to consider, as
sarcoidosis patients with the 24-bp duplication polymorphism may have low or false-negative
CTO levels. Therefore, CTO genotyping would be necessary for interpretation of CTO levels
and its use as a biomarker [17]. It remains unclear to what extent the studies reported here have
addressed this issue; only HARLANDER et al. [40] excluded subjects with no CTO activity as it
was presumably due to the duplication polymorphism.
YKL-40
One of the first studies to find elevated levels of YKL-40 (named based on its three N-terminal
amino acids, tyrosine (Y), lysine (K) and leucine (L), and its molecular mass of 40 kDa) in
sarcoidosis patients was that of KRUIT et al. [46] in 2007. YKL-40 is a growth factor for
fibroblasts and vascular endothelial cells, secreted by macrophages and neutrophils. KRUIT et al.
[46] found serum YKL-40 to be elevated in 79% of sarcoidosis patients, and levels were
inversely correlated with DLCO at presentation but not after 2–4 years of follow-up. They
concluded that YKL-40 may be used as a sarcoidosis disease marker but that it was unsuitable
as a marker to predict disease course. Over the last 10 years, two studies have been published
on YKL-40.
YKL-40 as a diagnostic tool

In a meta-analysis, TONG et al. [47] compared serum YKL-40 levels in patients with different
types of ILD and found that those with sarcoidosis had the highest levels of serum YKL-40.
The other types of ILD included connective tissue-related ILD, asbestosis ILD, IPF, cryptogenic
pneumonia, pulmonary alveolar proteinosis and idiopathic nonspecific interstitial pneumonia.
YKL-40 as a monitoring tool

UYSAL et al. [16] reported significantly higher YKL-40 levels in active sarcoidosis patients
compared with those with inactive disease, with a sensitivity of 83.1% and a specificity of
92% (table 2).
YKL-40 as a prognostic tool and a predictive tool

No studies were retrieved from the literature search for YKL-40 as either type of biomarker.
B-cell activating factor

B-cell activating factor (BAFF) is a cytokine of the TNF family that affects the development
and function of B-cells. It is also expressed by granuloma epithelioid cells in sarcoidosis. Our
literature search retrieved four publications on BAFF as a biomarker [48–51].
114 https://doi.org/10.1183/2312508X.10031720
BAFF as a diagnostic tool

All studies showed elevated BAFF levels in sarcoidosis patients compared with healthy
controls. However, HASHEMZADE et al. [48] reported that the mean BAFF concentration in active
chronic sarcoidosis did not significantly differ from concentrations in acute sarcoidosis. No
estimates of sensitivity or specificity were provided, indicating that BAFF needs more
evaluation as a diagnostic biomarker.
BAFF as a monitoring, prognostic or predictive tool

There was no evidence in the literature from the last 10 years for the use of BAFF as any of
these three types of biomarker.
Other serum biomarkers

In addition to the proteins described, the literature search revealed a single study for each of the
following serum biomarkers over the last 10 years. We will only give a summary of the
biomarkers in which estimates for sensitivity and/or specificity has been reported.
KL-6
KL-6 was evaluated as a diagnostic biomarker to discriminate between sarcoidosis patients and
healthy controls with 78% sensitivity and 73% specificity (table 2) [27]. KL-6 concentrations
were significantly elevated in pulmonary sarcoidosis patients, especially those with
fibrotic disease.
Albumin
Albumin appeared to be a prognostic biomarker and able to predict sarcoidosis disease duration
of >10 years with 90.5% sensitivity and 98.2% specificity [28]. Hypoalbuminaemia can result
in increased systemic inflammation, and as it is associated with those with longer sarcoidosis
duration, this simple biomarker could help predict the duration of disease in patients upon initial
presentation.
Cathepsin S
Cathepsin S concentrations were significantly increased in sarcoidosis compared with not only
controls but also other lung diseases, with 70% sensitivity and 78% specificity as a diagnostic
tool (table 2) [29].
IFN-γ-induced protein 10
IFN-γ-induced protein 10 (IP-10) has potential as a diagnostic biomarker, as elevated levels of
IP-10 in sarcoidosis patients discriminate them from healthy controls with a sensitivity of 78%
and a specificity of 87% (table 2) [30].
Potential future biomarkers

Finally, a number of studies have shown biomarkers elevated in sarcoidosis patients but did not
estimate sensitivity and/or specificity [52–60]. With information on these characteristics in
future studies, some of these biomarkers may have promising roles in diagnosing and/or
monitoring sarcoidosis. As an example, IFN-γ-inducible chemotactic cytokines (CXCL) are
probably worth future study, as serum CXCL9 levels correlated with systemic organ
involvement [61], high serum CXCL10 levels were strongly associated with deteriorating lung
function outcomes [61], and elevated levels in serum of CXCL11 appeared to correlate with
organ involvement and negatively with lung function [30]. In contrast, CC chemokine ligand 18
(CCL18) was found to be elevated in sarcoidosis as well as in various other ILDs, probably
reflecting an inflammatory immune response and thus with limited diagnostic potential [62].
https://doi.org/10.1183/2312508X.10031720 115
Nonspecific inflammation, as reflected by elevated baseline C-reactive protein (CRP) in sarcoidosis,

has been associated with a good prognosis and was a negative predictive indicator of radiological
progression [54]. Thus, a routine marker like CRP reflecting foremost the inflammatory status of
the patient may also show promise as a prognostic biomarker in sarcoidosis.
Elevated serum levels of neopterin [63], as well as of serum amyloid A [64], were associated
with disease severity, although without determination of sensitivity or specificity, the clinical
implications of these markers are unclear.
In contrast, the two biomarkers visfatin and fibroblastic growth factor were not significantly
different between patients and healthy controls, and thus are unlikely to be useful as diagnostic
biomarkers [65, 66].
Nuclear imaging modalities as a biomarker for sarcoidosis

Our literature search on serum biomarkers retrieved two studies, showing correlations between
CT patterns and lung function [67], and typical versus atypical sarcoidosis patterns on HRCT
and sACE (the atypical pattern correlated with lower ACE levels, and also with chronicity of
disease) [68], although estimates of the sensitivity and/or specificity of HRCT were unclear. In
addition, over the last decade, numerous studies on nuclear imaging as a potential biomarker, in
particular for diagnosing treatable inflammatory lesions in symptomatic patients with indecisive
conventional tests, and for monitoring disease evolution with therapy, have been performed
[69]. Here we will discuss 18F-FDG PET. An additional literature search (see Appendix B of the
online supplementary material) retrieved eight publications evaluating 18F-FDG PET.
Nuclear imaging modalities as a diagnostic tool

18
F-FDG PET has been proposed as a reliable diagnostic biomarker, with a sensitivity ranging
from 80% to 97% and a specificity of 100% [70–74]. At diagnosis, an abnormal 18F-FDG PET
correlates with increased levels of sACE and sIL-2R [21]. Nevertheless, from clinical experience
it is known that in chronic sarcoidosis patients increased 18F-FDG uptake reveals disease
activity despite ACE and serum sIL-2R being within normal ranges. Figure 1 illustrates the
potential of PET as a monitoring tool showing the effects of infliximab therapy. However, to
what extent nuclear imaging can serve as a monitoring or as a prognostic biomarker that may
predict differential disease outcomes irrespective of therapy is unclear.
Nuclear imaging modalities as a prognostic tool

Some support for 18F-FDG PET as a potential prognostic biomarker was found by VORSELAARS
et al. [37] with high serum sIL-2R levels and mediastinal maximal standard uptake value
(SUVmax) on 18F-FDG PET at the start of therapy predicting relapse after discontinuation.
Moreover, especially in pulmonary disease, high 18F-FDG PET SUVmax values at treatment
initiation predicted clinically relevant lung function improvement [75]. No sensitivity or
specificity estimates were presented in either study.
Of note, a prospective study of 11 untreated patients with active lung parenchymal disease
compared 18F-FDG PET results with pulmonary function tests [71]. Diffuse active lung
parenchymal disease at baseline correlated with a significant decrease in DLCO after 6 months
when untreated. These findings suggest that inflamed lung parenchyma noted on 18F-FDG PET
may predict pulmonary function outcomes, albeit in a limited number of patients. Furthermore,
the untreated patients without inflammatory changes in lung parenchyma demonstrated no
change in DLCO, FVC or FEV1.
116 https://doi.org/10.1183/2312508X.10031720
a) b)
FIGURE 1 Illustration of the value of PET as a biomarker. a) CT (top) and PET (bottom) scan of a chronic
pulmonary sarcoidosis patient showing marked areas of increased 18F-FDG uptake despite serum ACE and serum
soluble IL-2 receptor being within normal ranges. b) CT (top) and PET (bottom) images of same patient after
6 months of infliximab therapy. Lung function tests showed a clinically relevant improvement: FEV1, 2.3 L (51%
predicted) to 2.7 L (62% pred); DLCO (corrected for haemoglobin), 63% pred to 71% pred.
Additionally, our literature search revealed the clinical value of 18F-FDG PET in evaluation of
the location/organ involvement and activity of sarcoidosis [76], in particular for cardiac
sarcoidosis [77]. The sensitivity of 18F-FDG PET/CT for detection of cardiac sarcoidosis ranged
from 68.8% to 85% and the specificity from 93.3% to 100% [74, 78]. In addition, 18F-FDG
PET showed potential as a monitoring biomarker in a serial evaluation of cardiac sarcoidosis
patients and their response to treatment [79–83]. Lastly, in cardiac sarcoidosis, 18F-FDG uptake
has been shown to predict adverse events. Uptake in the right ventricle appears to be associated
with death or ventricular tachycardia. Unfortunately, estimates of the sensitivity/specificity of
18
F-FDG PET as a monitoring biomarker are not available [84].
Conclusion and future perspectives and recommendations

The literature over the past 10 years has revealed several potential biomarkers in serum with
estimates of sensitivity and specificity. In particular, sACE, sIL-2R and CTO have been studied
extensively as potential diagnostic and monitoring tools, albeit with limitations as noted in this
chapter. Some studies of YKL-40, KL-6, cathepsin S and IP-10 suggest that they may have
potential as biomarkers. Moreover, in addition to its diagnostic value, the use of 18F-FDG PET
https://doi.org/10.1183/2312508X.10031720 117
as a prognostic tool is starting to be realised. However, sensitivity and specificity estimates are
lacking in the literature. From a clinical standpoint, both sACE and CTO would be more
complicated biomarkers to use, as adjustment by genotyping is needed. The studies presented in
this chapter suggest that a single serum biomarker may not be as useful as combinations of
biomarkers. Certainly in other diseases, combinations of biomarkers are proving more sensitive
and specific [85]. The use of markers other than proteins needs to be considered in future
studies of biomarkers, including genetic markers, mRNA/microRNA, panels of proteins and
other omic targets, alone or in combination [1–4, 86]. Additionally, other imaging modalities
and analytical approaches to current imaging techniques may also provide opportunities for
future biomarkers. As an example, computer-based methods for quantifying disease on CT in
sarcoidosis and other ILDs are beginning to be evaluated as biomarkers of disease. Furthermore,
with respect to PET, tracers other than 18F-FDG that are specific for sarcoid granulomas would
expand the possibilities for diagnosing and monitoring treatment response and/or organ
involvement. For instance, somatostatin receptors such as 68Ga-DOTA-NaI-octreotide [87] and
68
GA-DOTA-D-Phe-Tyr-octreotide [88] show potential as alternatives, with the latter potentially
finding application in cardiac sarcoidosis [89].
Although some serum biomarkers may be already used in clinical practice in some centres for
sarcoidosis, none is uniformly applied around the world. Additional research is still needed to
address the gap between scientific evidence and recommendations for application in clinical
practice. The highest priority for sarcoidosis clinical care is diagnosing and monitoring patients.
Prospective longitudinal studies that would supply scientific proof are further complicated and
difficult to conduct, as sarcoidosis is a rare disease with relatively small numbers of patients.
The heterogeneity of clinical presentations and variety in disease behaviour and/or response to
therapy all challenge clinical and biomarker trial design to move the field forward. Recently, the
PREDMETH (Effectiveness of methotrexate versus prednisolone as first-line therapy for
pulmonary sarcoidosis) study was launched, which will be the first randomised controlled trial
comparing first-line treatment of prednisone and MTX, and will provide valuable data on
efficacy, safety, quality of life and various biomarkers (both conventional and those emerging
from novel technologies) for their utility in sarcoidosis [90]. Hopefully, this study as well as
others evaluating novel biomarker targets and combinations of different biomarkers will allow
some new conclusions in a fascinating field with a high level of unmet clinical need.
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84 Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic
assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014; 63: 329–336.
85 Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer.
N Engl J Med 2015; 373: 2005–2014.
86 Guerrero CR, Maier LA, Griffin TJ, et al. Application of proteomics in sarcoidosis. Am J Respir Cell Mol Biol 2020;
63: 727–738.
87 Sharma S, Singh AD, Sharma SK, et al. Gallium-68 DOTA-NOC PET/CT as an alternate predictor of disease
activity in sarcoidosis. Nucl Med Commun 2018; 39: 768–778.
88 Nobashi T, Nakamoto Y, Kubo T, et al. The utility of PET/CT with 68Ga-DOTATOC in sarcoidosis: comparison with
67
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89 Gormsen LC, Haraldsen A, Kramer S, et al. A dual tracer 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT pilot study
for detection of cardiac sarcoidosis. EJNMMI Res 2016; 6: 52.
90 Kahlmann V, Janssen Bonás M, Moor CC, et al. Design of a randomized controlled trial to evaluate effectiveness
of methotrexate versus prednisone as first-line treatment for pulmonary sarcoidosis: the PREDMETH study. BMC
Pulm Med 2020; 20: 271.
Disclosures: J.C. Grutters has nothing to disclose. L.A. Maier reports receiving NIH grants, Foundation for
Sarcoidosis grants, MNK14344100 and ATYR1923-C-002, outside the submitted work. L.A. Maier is a member of the
Foundation for Sarcoidosis Research Scientific Advisory Board, which is an unpaid position. I.H.E. Korenromp has
nothing to disclose.
https://doi.org/10.1183/2312508X.10031720 121
Chapter 9
Pulmonary sarcoidosis
1 2
W. Ennis James and Francesco Bonella
1
Division of Pulmonary and Critical Care Medicine, Susan Pearlstine Sarcoidosis Center of Excellence, Medical
University of South Carolina, Charleston, SC, USA. 2Center for Interstitial and Rare Lung Diseases, Pneumology
Dept, Ruhrlandklinik University Hospital, University of Duisburg-Essen, Essen, Germany.
Corresponding author: Francesco Bonella (francesco.bonella@rlk.uk-essen.de)
Cite as: James WE, Bonella F. Pulmonary sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS
Monograph). Sheffield, European Respiratory Society, 2022; pp. 122–141 [https://doi.org/10.1183/2312508X.
10031820].
@ERSpublications
Understanding and management of common clinical presentations, high-risk features, and complications of
advanced disease in pulmonary sarcoidosis is instrumental in making informed treatment decisions and
improving patient outcome https://bit.ly/3ozzgsF
ISSN: 2312-5098.
The lung is the most common organ affected by sarcoidosis. Multiple tools are available to assist
clinicians in assessing lung disease activity and in excluding alternative causes of respiratory symptoms.
Improving outcomes in pulmonary sarcoidosis should focus on preventing disease progression and
disability, and preserving quality of life, in addition to timely identification and management of
complications like fibrotic pulmonary sarcoidosis. While steroids continue to be first-line therapy, other
therapies with fewer long-term side-effects are available and should be considered in certain
circumstances. Knowledge of common clinical features of pulmonary sarcoidosis and specific
pulmonary sarcoidosis phenotypes is important for identifying patients who are more likely to benefit
from treatment.
Introduction
Pulmonary sarcoidosis is observed in 90% of patients and the lung is the most common organ
affected by sarcoidosis. The clinical findings and outcomes of pulmonary sarcoidosis are highly
variable. Most patients will have spontaneous remission, but up to 30% of patients will have
chronic disease and about 20% will develop fibrotic pulmonary sarcoidosis [1–5]. Mortality
rates from sarcoidosis range from 2.8 to 4.3 per million aged over 12 and 20 years,
respectively [6, 7]. Mortality rates in sarcoidosis patients are higher than for the population
at large and death often results from complications of fibrotic pulmonary sarcoidosis [7–10].
Recent evidence suggests mortality rates are increasing in certain subgroups such as
African-American women, and those with advanced disease may have mortality rates as
high as 25% [11]. A thoughtful approach to diagnosis and evaluation is necessary to
determine the best management strategy for each individual patient. This chapter will review
typical and atypical clinical features of pulmonary sarcoidosis, strategies for determining
prognosis and need for treatment, as well as the management of complications of advanced
pulmonary sarcoidosis.
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PULMONARY SARCOIDOSIS | W.E. JAMES AND F. BONELLA
Clinical presentation
Between 30% and 60% of pulmonary sarcoidosis patients are asymptomatic, especially those
with stage I disease, and may be diagnosed after an abnormal incidental finding found on chest
imaging. Nonspecific pulmonary symptoms such as nonproductive cough, dyspnoea and chest
pain are observed in 30–50% of patients. Wheezing is present in over 50% of patients during
acute exacerbations, which are rare, and is typically attributed to the impact of sarcoidosis on
airways, including proximal airway narrowing or endobronchial disease and more peripherally
along bronchovascular bundles [12–14]. Dyspnoea in sarcoidosis patients can certainly be
affected by the presence of fatigue, which is the most reported symptom in sarcoidosis patients
and is a better predictor of quality of life than lung function testing [15–17]. Other generalised
symptoms may include fevers, night sweats and weight loss. The physical examination is often
normal even when chest imaging is not. Crackles are present on lung examination in <20% of
patients. Digital clubbing and peripheral cyanosis are rare [13, 18–20]. Rare and ultra-rare
manifestations of thoracic sarcoidosis include pleural effusion, chylothorax and spontaneous
pneumothorax; the latter is in general attributed to rupture of subpleural blebs, especially when
advanced fibrocystic disease is present [21].
Imaging
Chest radiographs
The prevalence of radiographic abnormalities in pulmonary sarcoidosis varies depending on the
population studied but can range anywhere from 67% to 93% [2, 22]. Bilateral hilar
lymphadenopathy (BHL) is the most characteristic finding, often with enlarged right paratracheal
lymph nodes. Evidence of parenchymal abnormalities is present in 35–50% of patients, and
typically involves the mid and upper lung zones bilaterally [2, 23]. Unilateral parenchymal
abnormalities or adenopathy is atypical, and pleural effusions are seen in only 0.7–10% of
patients on routine imaging [24]. Pleural effusions are observed in only 2.8% on ultrasound
screening, and the prevalence of effusions that could be attributed to sarcoidosis was even lower at
1.1% [25]. Because sarcoidosis-related pleural effusions are often exudative and lymphocytic, they
can mimic malignant effusions and clinicians should be wary and thoughtful before jumping to
sarcoidosis as the underlying cause. The presence of unilateral radiographic abnormalities or
pleural effusions should prompt additional examinations to exclude alternative diagnoses.
The Scadding stages for pulmonary sarcoidosis were first published in 1961 based on review of
imaging from 136 patients [26]. Stages 0–4 were defined as follows: 0=normal, I=BHL without
pulmonary abnormalities, II=BHL and pulmonary disease, III=pulmonary disease without BHL,
and IV=fibrosis regardless of adenopathy (figure 1). The stages were remarkable for their ability
to predict resolution of radiographic abnormalities over the subsequent 5 years (table 1) [26, 27].
Multiple studies have replicated the original data, but it is important to note that Scadding
stages have several limitations, including poor interobserver reliability and poor sensitivity for
parenchymal disease on CT scans [28, 29]. More importantly, multiple studies have shown poor
correlation between Scadding stages and lung function testing, symptoms and disease severity
[30, 31]. While obstruction on pulmonary function tests (PFTs) is more common with advanced
stages, there is significant overlap [32]. Higher stages (III, IV) are associated with a higher risk
of chronic disease, and scarring (i.e. stage IV) is an obvious prerequisite for developing
complications of fibrotic sarcoidosis [33]. In our experience, however, Scadding stages are not
useful for making treatment decisions and can cause unwarranted stress and anxiety for some
patients due to the assumption that they are akin to cancer stages in their ability to predict
outcomes. We do not routinely discuss stages with patients, and typically only do so as just one
of the many considerations in a discussion on prognosis in pulmonary sarcoidosis.
https://doi.org/10.1183/2312508X.10031820 123
124

a) b) c)
d) e)
https://doi.org/10.1183/2312508X.10031820
FIGURE 1 Example of Scadding stages on chest radiography. a) Stage I, b) stage II, c) stage III, and d and e) stage IV.
TABLE 1 Radiographic stages at presentation and clinical outcomes [26, 27]
Radiographic stage Radiographic description Frequency % Resolution# %
0 Normal 5–15
I BHL 25–65 60–90
II BHL and pulmonary infiltrates 20–40 40–70
III Pulmonary infiltrates without BHL 10–15 10–20
IV Pulmonary fibrosis 5 0
BHL: bilateral hilar lymphadenopathy. #: over the subsequent 5 years.
CT scans
CT imaging is superior to conventional chest radiographs in delineating parenchymal
abnormalities and mediastinal/hilar structures and has a stronger correlation with PFT trends
than plain radiographs [34–37]. Typical features of sarcoidosis on CT include mediastinal and/
or hilar adenopathy, which are typically symmetrical and homogeneous. Approximately 50% of
patients may have calcified adenopathy, which tends to be bilateral and in a focal/punctate,
eggshell, or popcorn-like pattern [38, 39]. Adenopathy in tuberculosis patients, by comparison,
is more commonly unilateral and completely calcified [38]. Parenchymal abnormalities in
sarcoidosis primarily involve the upper and mid-lung zones. Typical parenchymal findings
include bilateral/symmetric nodular opacities and micronodules in a perilymphatic distribution
that is usually best appreciated along the bronchovascular bundles, fissures and subpleural
locations. Confluent nodules may result in larger nodules or masses and may appear as a
“galaxy sign” with a central mass surrounded by numerous smaller nodules (figure 2). Patchy
ground-glass opacities may also be seen, typically in the upper and mid-lung zones, and usually
coexist with perilymphatic nodules [3]. Correlation of the galaxy sign with clinical
characteristics of sarcoidosis patients, and its diagnostic relevance, have been poorly
investigated; however, it is a much more common finding in sarcoidosis (23%) than in those
with pulmonary tuberculosis (2%) [40].
Using the calculated scores based on the degree of findings and number of zones involved,
BENAMORE et al. [41] found that inclusion of nodularity, interlobular septal thickening,
consolidation, and ground-glass opacities in the CT Activity Score (CTAS) correlated to FVC.
DUAN et al. [3] found that the CTAS also correlated to changes in FVC, FEV1 and ACE levels
over 6 months without treatment. While these scoring systems may have a role in clinical
practice, additional studies are needed prior to widespread dissemination.
Atypical CT findings include alveolar sarcoidosis, which is typically described when nodules
coalesce to form a dense consolidation. Linear reticular opacities may be present and can appear
similar to lymphangitic carcinomatosis. Nodular pulmonary sarcoidosis and necrotising sarcoid
granulomatosis (NSG) are rare presentations of pulmonary sarcoidosis where patients can
present with one or multiple masses (nodules >3 cm) (figure 3) [42]. These typically involve
the upper lobes and mediastinal adenopathy is commonly present. In the case of NSG,
cavitation within the nodules may be seen, which results in granulomatous vasculitis causing
infarct-like necrosis and is the primary distinguishing characteristic between nodular pulmonary
sarcoidosis and NSG [43]. It should be noted that the vasculitis seen in NSG is granulomatous
and distinct from the invasive or granulocytic type of vasculitis seen in granulomatosis with
polyangiitis. Because of the atypical findings in these forms of sarcoidosis, careful consideration
is required to exclude alternative causes of these CT findings (e.g. infection, malignancy,
vasculitis, etc.); hence, the diagnosis of NSG almost always requires a lung biopsy.
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FIGURE 2 Axial HRCT scan of a 48-year-old man with sarcoidosis, illustrating the “galaxy sign” (arrows).
Despite its superior resolution, the exact role of CT imaging in pulmonary sarcoidosis is
unclear. Some have advocated for increasing its utility in clinical practice as a routine part of
the evaluation, while others have found that the use of CT scans provided no additional
clinically relevant information [44–46]. A diagnosis of pulmonary sarcoidosis should never be
based solely on CT findings in the absence of additional supporting clinical findings and/or
histological confirmation of granulomatous inflammation. In the presence of biopsy-confirmed
extrapulmonary sarcoidosis, expert consensus identified the presence of perilymphatic nodules,
symmetrical hilar or mediastinal adenopathy, and/or peribronchial thickening as sufficient
findings on CT to make a clinical diagnosis of pulmonary sarcoidosis [47]. When patients with
long-standing diagnosis of pulmonary sarcoidosis have new or progressive symptoms, CT can
help exclude interval development of other ILDs, pneumonia, or complications of pulmonary
FIGURE 3 Nodular pulmonary sarcoidosis.
126 https://doi.org/10.1183/2312508X.10031820
sarcoidosis such as mycetomas that may not respond to typical anti-sarcoidosis therapy. CT also
has prognostic value. Perilymphatic nodules are more likely to resolve with treatment, while
resolution of ground-glass opacities and interlobular septal thickening is less common. Patients
with >20% fibrosis in the lungs have a higher mortality.
While there are currently inadequate data to support their use in the baseline evaluation of all
patients, it is the opinion of the authors that in clinical practice a thorax CT scan should be
considered to further define parenchymal abnormalities or to clarify the presence and degree of
fibrotic lung disease. On a case-by-case basis, thorax CT could be considered to help identify
lymph nodes suitable for biopsy and evaluate for evidence of alternative/concomitant diagnoses.
Preliminary studies in the field of radiomics in which CT patterns are quantified and analysed
have shown promise in distinguishing sarcoidosis from controls and may better explain
variability in FVC than Scadding stages [48, 49]. Additional studies are needed to validate this
emerging technology as a biomarker in pulmonary sarcoidosis, and its widespread use may be
limited by the need for specific CT and analytic technology.
Pulmonary function testing

There is poor correlation between symptoms and lung function testing, and most sarcoidosis
patients will have normal PFTs [50, 51]. Abnormal PFTs are observed in 40–80% of patients
with parenchymal lung disease on chest imaging and in 20% of patients with hilar adenopathy
only. A reduction in diffusing capacity is the most common abnormality observed [51–53]. The
prevalence of airflow obstruction on PFTs ranges from 4% to 75% and is more commonly seen
in African-American sarcoidosis patients and those with advanced pulmonary fibrosis or
proximal airway involvement [1, 32, 54, 55]. Up to 50% of patients with stage I or II disease
may have abnormal methacholine challenge testing consistent with airway hyperreactivity,
although this may be an over-estimation from false positives resulting from airway narrowing in
endobronchial sarcoidosis [19]. Consequently, a concomitant diagnosis of asthma is common in
patients with sarcoidosis and can be problematic in terms of management [56]. Since from the
functional and clinical point of view the two conditions are indistinguishable, serum IgE,
sputum eosinophilia and exhaled nitric oxide measurements can be performed as additional tests
to exclude pre-existing extrinsic asthma [56].
Just over 30% of patients in the ACCESS study had an FVC <80%, and restriction has been
reported as the most common abnormality on spirometry, but obstruction is most associated
with fibrotic pulmonary sarcoidosis with bronchial distortion [57]. Restriction and reduced
diffusing capacity are more common when the predominant fibrotic pattern on CT is
honeycombing [4]. A recent study found that mixed ventilatory defects, defined as a reduced
FEV1/FVC and a reduced total lung capacity, occur in 10.4% of patients and have a stronger
association with fibrotic sarcoidosis compared to obstructive and restrictive patterns. Mixed
ventilatory defects were also associated with a higher mortality compared to obstructive but not
restrictive patterns [58].
Muscle weakness and exercise testing abnormalities may provide better insight into symptoms
of dyspnoea in sarcoidosis [59]. Impaired inspiratory muscle endurance is present in sarcoidosis
patients with normal lung function and correlates to impairments in quality of life [60, 61].
Cardiopulmonary exercise tests (CPETs) are abnormal in up to 47% of patients, and can be
abnormal even when PFTs are normal, suggesting muscle weakness and fatigue may be the
primary cause of exercise limitations in many patients [62–64]. A recent study following daily
physical activity found that steps per day correlated with maximal oxygen uptake on CPET in
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multivariate analysis [65]. CPETs may be more accurate than PFTs for predicting exercise
capacity, but availability of this test is generally limited. Daily activity is strongly associated
with 6-min walk distance, which is more practical for use in routine evaluation of sarcoidosis
patients, but correlations between 6-min walk testing and dyspnoea are inconsistent and can be
affected by other conditions and comorbidities [66, 67]. The presence of fibrosis on CT imaging
is associated with reduced distance-saturation product on 6-min walk testing but not walk
distance [68].
Peculiar intrathoracic sarcoidosis presentations

Sarcoidosis associated with malignancy and its treatment
Real sarcoidosis or sarcoid-like manifestations have been described in the setting of malignancy,
especially skin cancer, lymphoma and testis cancer, and can occur 7 months to 10 years after
the malignancy [69–72]. Most patients are asymptomatic and are diagnosed incidentally on
surveillance imaging, with 90% having lung involvement that is usually Scadding stage I or II.
TNF antagonists, immune checkpoint inhibitors, and IFN or pegylated IFN therapeutics are the
most common medications associated with drug-induced sarcoidosis-like reactions (DISR) [73–76].
It remains unclear in many cases whether the sarcoidosis is related to the underlying
malignancy or its treatment. Biopsies are generally required for confirmation as there are no
reliable radiological or serological markers that can differentiate reliably between cancer
progression and DISR [76]. DISR usually resolves if the inciting drug can be stopped. In the
case of patients in whom the risk of stopping the medication is unacceptable (i.e. immune
checkpoint inhibitor for metastatic cancer), the patients’ sarcoidosis manifestations can be
successfully managed with typical anti-granulomatous medications. Development of sarcoidosis
or DISR seems to have no impact on malignancy treatment or outcomes, and 79–91% of
patients will have complete remission of their sarcoidosis [69, 77–79].
Proximal airway stenosis

Airflow obstruction from proximal airway stenosis is rare, with reported prevalence rates of
<1% to as high as 8% of pulmonary sarcoidosis patients (figure 4) [52, 80]. Patients may
present with wheezing, inspiratory “squeaks,” and nonreversible obstruction on spirometry.
Management options depend on the underlying aetiology of airway narrowing, which can result
from endoluminal (endobronchial accumulation of granulomas in the airway) or extraluminal
disease activity (extrinsic compression from enlarged lymph nodes). Patients who are started on
anti-sarcoidosis therapy within 3 months of symptom onset are more likely to have resolution of
stenosis [52]. Ballooning of refractory airway stenosis may be effective in reducing
post-procedure symptoms, but often provides only temporary relief [81].
SARS-CoV-2 infection in patients with sarcoidosis

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in January 2020
as the aetiological agent of a cluster of cases of pneumonia detected in Wuhan City (China).
Worldwide, more than 220 million cases were confirmed by 10 September 2021 [82]. Studies
that have analysed the impact of SARS-CoV-2 infection in large cohorts of patients with
sarcoidosis are limited. The prevalence of SARS-CoV-2 infection in patients with sarcoidosis
has been estimated at between 2% and 5% [83, 84]. Sarcoidosis has some specific features that
could favour an increased risk for developing severe coronavirus disease 2019 (COVID-19),
including ILD and involvement of kidney and liver [83]. As in the general population,
cardiovascular comorbidities, diabetes mellitus and treatment with immunosuppressive drugs are
associated with higher hospitalisation rate during SARS-CoV-2 infection in patients with
sarcoidosis [84]. African-American ethnicity and severity of pulmonary impairment prior to
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FIGURE 4 Airway stenosis in pulmonary sarcoidosis.
SARS-CoV-2 infection have been described as independent risk factors of poor outcome but
confirmation of these findings is needed [85].
The management of sarcoidosis patients with mild SARS-CoV-2 infection does not differ from
the general population and depends essentially on comorbidities and concomitant treatment. A
slight reduction of the corticosteroid dose or a de-escalation (by reducing the dose or prolonging
the dosing interval) of disease-modifying anti-sarcoid drugs have been proposed to reduce the
risk of SARS-CoV-2 pneumonia. In patients with organ- or life-threatening sarcoidosis, a
significant dose reduction or discontinuation of therapy may be contraindicated because of the
risk of severe unfavourable outcomes [86]. If immunosuppression is reduced, closer monitoring
and prompt treatment of exacerbations of sarcoidosis is warranted.
The sporadic description of sarcoidosis onset during or soon after SARS-CoV-2 infection has
led to speculation on a possible role of SARS-CoV-2 as a trigger of sarcoidosis [83, 87].
Diagnosis
As with other organ involvement, a diagnosis of pulmonary sarcoidosis requires a compatible
clinical presentation, histological evidence of granulomatous inflammation, and exclusion of
other causes. Patients with certain characteristic presentations of pulmonary sarcoidosis may not
need to undergo biopsy, including Löfgren syndrome and asymptomatic BHL. One
meta-analysis found that those with asymptomatic BHL had a 99.95% chance of having
sarcoidosis; however, more recent analyses identified alternative diagnoses in 1.9% [88, 89]. Since
these alternative diagnoses can be life threatening (e.g. malignancy, tuberculosis), recent guidelines
made no recommendation for or against obtaining lymph node sampling in patients with
asymptomatic BHL [89]. The guidelines did support forgoing biopsy in patients with clinical
presentations that are highly specific for sarcoidosis (Löfgren syndrome, lupus pernio, Heerfordt
syndrome), with close clinical follow-up. In the authors’ opinion, shared decision-making is the
best approach to the patient with asymptomatic BHL. Our practice is generally not to pursue a
https://doi.org/10.1183/2312508X.10031820 129
biopsy procedure in these patients if a clear plan for close follow-up is in place. Patients should
be informed of the low likelihood of alternative diagnoses and the plan for clinical monitoring.
We generally will perform a biopsy if the patient accepts the risks of the procedure, and they
feel strongly that the peace of mind provided by ruling out alternative diagnoses outweighs
those risks. Any other patient with symptoms, especially weight loss and fevers or night sweats,
and imaging findings concerning for pulmonary sarcoidosis should undergo biopsy if possible.
For those patients with enlarged mediastinal or hilar nodes on imaging, EBUS-guided lymph
node sampling is recommended over mediastinoscopy [89]. This almost complication-free
examination has a diagnostic yield of 87% (95% CI 94–91%) [89, 90]. If EBUS is not
available, other bronchoscopic biopsy methods can be considered. Transbronchial lung biopsy
has an overall yield of 61–90% for sarcoidosis, when endobronchial abnormalities are present
[13, 90–95]. Although the new guidelines on diagnosis of sarcoidosis assign a marginal role
to BAL, it is common practice in many centres to include this tool in the diagnostic flow. Up
to 85% of patients show a lymphocytic alveolitis in the differential cell count, with an
elevated CD4/CD8 ratio [96]. BAL can be useful for excluding infections or malignancy or to
identify cellular patterns suggestive of differential diagnoses like eosinophilic or hypersensitivity
pneumonitis [89].
Management
Immunosuppressive drugs
Treatment indications for pulmonary sarcoidosis are not standardised. Most pulmonary
sarcoidosis patients will not need treatment and avoiding unnecessary or harmful medications
should be a primary goal for clinicians. Treatment of patients with asymptomatic stage I
sarcoidosis has not been shown to improve outcomes, and <15% of patients without evidence of
progressive disease will decline in the absence of treatment [97–99]. Treatment should be
considered in patients reporting symptoms that impair quality of life and in whom there is
evidence that those symptoms can be attributed to active inflammation from sarcoidosis. Other
considerations that should be taken into account in treatment decisions are shown in table 2.
As a general rule, treatment may be considered for sarcoidosis resulting in impaired quality of
life or lung function impairment, or if increased risks for permanent disability or mortality are
present. Clinical features associated with progressive disease may help inform treatment
decisions and are described in table 3. Treatment decisions based on imaging only (chest
radiography/Scadding stage or CT scans) should be avoided, especially in early disease stages.
In the case of fibrotic sarcoidosis, the use of PET scans has shown that, in patients with
TABLE 2 Relative value of patient and provider input into potential treatment in pulmonary sarcoidosis
Considerations Patient Provider
Impaired quality of life from pulmonary sarcoidosis +++ +

Risk of future impairment in quality of life/morbidity/mortality + +++
Presence of chronic disease predictors (see table 3)
Worsening spirometry
Elevated/rising serum biomarkers (ACE, serum IL-2R)
Chest imaging consistent with worsening sarcoidosis
Concomitant high-risk extrapulmonary organ involvement
Risk of adverse events from therapy ++ ++
Treatment outcome priorities/values +++ ++
IL-2R: IL-2 receptor.
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TABLE 3 Predictors of progressive or chronic disease in sarcoidosis
Chronic disease risk factor Reference
Low income [100]

Female sex [2]
African-American race [2]
>3 organs affected [101]
Dyspnoea at presentation [30]
Parenchymal disease on chest imaging [102]
Absence of adenopathy on chest imaging [103]
Requiring anti-sarcoidosis medications at initial visit [30]
Obstructive pattern on spirometry [104]
Peribronchial conglomeration on chest imaging [103]
Parenchymal PET activity [105]
persistent symptoms, 73% overall and 93% of those with stage IV disease have active
inflammation present [106]. Higher standardised uptake values on PET predict improvement in
FVC on treatment, while patients with PET activity are more likely to have a decline in lung
function if treatment is withheld [105, 107]. Because of the significant cost and radiation of
PET scans, we do not use them routinely in practice. However, they should be considered in
patients with parenchymal disease in whom it is unclear whether there is ongoing active
inflammation and there is little other evidence to inform the decision to treat.
Surveys have shown that the outcomes of improving quality of life, functionality and survival
are the highest priority for patients [108]. As such, when the treatment goal is to improve
quality of life, educating and involving patients in the decision to start treatment is of utmost
importance. It should be noted that treatment can have a negative impact on outcomes.
Clinicians and patients should be aware that treatment may increase the risk of relapse and
chronic disease compared to observation without treatment, and patients who receive higher
(>500 mg) cumulative annual prednisone have worse fatigue and quality of life, and increased
healthcare utilisation [109–111]. In the presence of progressive or advanced/fibrotic disease,
treatment may be considered to avoid additional loss of lung function, decrease in quality of
life, and complications of fibrotic pulmonary sarcoidosis.
When the decision to treat is made, both the clinician and the patient should establish a plan for
toxicity monitoring and how treatment response will be assessed. Detailed recommendations on
treatment were recently published by the European Respiratory Society (ERS) [112] and are
also reviewed in another chapter in this Monograph [113]. For the purposes of this chapter, we
will provide a brief overview.
Prednisone is considered first-line therapy for sarcoidosis, and 20 mg is considered the optimal
starting dose, since no additional benefit has been shown with higher doses [14, 112]. Whereas
no additional benefit for treating pulmonary disease with >20 mg of prednisone a day has been
reported [112], in clinical practice, 20–40 mg daily are commonly administered as induction
doses in many centres worldwide [114]. The goal of prednisone treatment is to start on a
moderate dose and then taper to the lowest effective dose (ideally <10 mg daily). How quickly
prednisone should be tapered is an area of some debate. Some have recommended slower
tapers, but recent data suggest that tapering the dose to 10 mg over 3.5 months was equally
effective and associated with fewer steroid side-effects compared to tapering over
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6.9 months [97]. In patients who are intolerant of prednisone side-effects or have
therapeutic failure (i.e. inability to taper prednisone to ⩽10 mg without worsening), recent ERS
guidelines and Delphi consensus recommendations suggest that second-line therapy such as
MTX or other immunosuppressants like azathioprine should be added [112, 114]. Similarly, if
the addition of a second-line agent is not tolerated or fails to improve the disease, addition of a
third-line agent such as infliximab should be considered [114]. Inhaled steroids may improve
cough but have no role as disease-modifying therapy in sarcoidosis.
Sarcoidosis patients who are on immune-suppressing medications are at increased risk of

infection, with higher rates of severe infections observed in those on multiple immune-
suppressing medications [115, 116]. There is little data on the prevalence of opportunistic
infections in sarcoidosis patients on immune suppressants to guide the use of antibiotic or
antifungal prophylaxis [117]. Some have encouraged the use of prophylaxis in patients on
prednisone ⩾20 mg or double immunosuppression for an extended period of time; however,
practice patterns vary widely [118, 119]. Additional studies are needed to advise best practices
in this area.
Nonpharmacological therapy
Nonpharmacological therapy is an important tool for improving sarcoidosis patients’ quality of
life and can have a significant impact on their respiratory symptoms. Providing patients with
resources for education and self-management is a strategy that can improve outcomes in chronic
disease and is an important part of the comprehensive care model [120]. Inpatient and
outpatient pulmonary rehabilitation programmes have been shown to improve functional status,
perceived dyspnoea, fatigue, and quality of life [121]. Inpatient rehabilitation in stage IV
sarcoidosis patients has been shown to result in longstanding improvements in exercise capacity,
dyspnoea and fatigue [122]. High-intensity resistance training in newly diagnosed sarcoidosis
patients led to improvements in fatigue, dyspnoea and quality of life without requiring systemic
medications [123]. Wearing activity trackers can result in improvements in exercise performance
and decreased fatigue compared to controls, with the largest improvements occurring in patients
who wore the activity tracker and had coaching [124]. There is a strong link between stress,
anxiety, depression and quality of life in sarcoidosis [50, 125–127]. Patients who are struggling
with these issues should be connected with resources for assistance, which can range from
patient support groups to referrals for counselling.
Fibrotic pulmonary sarcoidosis: management and related complications

The underlying mechanism that drives the transition from inflammation to fibrosis [128] is
poorly understood compared to other fibrotic lung diseases, and the amount of fibrosis that
develops is unpredictable in individual pulmonary sarcoidosis patients [129]. Mortality rates in
patients with fibrotic sarcoidosis are higher than the general population (84% survival at
10 years); the most common causes of death are pulmonary hypertension and chronic
respiratory insufficiency [130]. When present, fibrosis typically involves the upper and mid-lung
zones and manifests as reticulonodular opacities, traction bronchiectasis and architectural
distortion (figure 5). Fibrocystic pulmonary sarcoidosis is classically described as fibrosis with
associated cysts or cavity formation in the upper lung zones. Evidence of mycetomas within
cavities are found in 2.7% of patients [2]. Careful consideration should be given to determining
the presence and amount of active inflammation from sarcoidosis when determining the best
treatment for patients with fibrotic pulmonary sarcoidosis. Evidence supporting the use of
systemic corticosteroids for preventing or halting the development of fibrosis is low, and data on
second- and third-line medications are lacking [131, 132]. There is no evidence that use of
132 https://doi.org/10.1183/2312508X.10031820
FIGURE 5 CT findings consistent with fibrocystic sarcoidosis.
immune suppressants affects fibrosis directly, but it may lead to clinical improvements by
decreasing adjacent inflammation. Patients treated with TNF inhibitors were shown to have
improvement in % predicted FVC after 24 weeks and improvement in reticulonodular opacities
on chest radiograph was observed, but the potential risk and benefit to patients with fibrotic
pulmonary sarcoidosis should be assessed on a case-by-case basis [133].
Antifibrotic treatment
Data on the use of antifibrotics in fibrotic pulmonary sarcoidosis are limited and addition of
these drugs alone or on top of immunosuppressants should be carefully evaluated. Nintedanib, a
tyrosine kinase inhibitor, was recently found to be effective in non-IPF ILDs, which included
sarcoidosis patients, but the effect on outcomes specifically for sarcoidosis warrants further
investigation before it should be considered routinely in fibrotic sarcoidosis [134, 135]. A trial
with pirfenidone, to date approved only for IPF, is ongoing (ClinicalTrials.gov identifier
NCT03260556).
Lung transplantation for fibrotic pulmonary sarcoidosis

Lung transplantation may be the only intervention that can improve survival and quality of life
in end-stage sarcoidosis with severe fibrocystic lung disease and/or the presence of World
Health Organization Group 5 pulmonary hypertension [136–138]. To date, sarcoidosis is an
uncommon indication for lung transplantation, accounting for 2–4% of all lung transplantations
worldwide [139].
The same indications and contraindications as for other ILDs also apply to sarcoidosis [140].
The presence of active cardiac and neurosarcoidosis is also considered a relative contra-
indication to transplant. Post-transplant survival is also similar to other ILDs; however,
transplant outcomes are worse in patients with mycetomas [141, 142]. The main predictors of
poorer survival have been identified as older age, pulmonary hypertension and more extensive
pre-operative lung fibrosis on CT. Furthermore, extensive fibrosis seems to be associated with
significantly higher rates of primary graft dysfunction and haemothorax [138].
https://doi.org/10.1183/2312508X.10031820 133
Whereas previous studies did not show any difference in post-transplant survival of sarcoidosis
patients versus other ILDs, a recent report involving 16 European transplantation centres shows
a favourable post-transplant outcome in patients with sarcoidosis, with a median survival of
9.7 years and a 5-year survival of 69% [138]. Post-transplant recurrence of sarcoidosis in lung
allografts, originating from the recipient, have been reported in up to 35% of patients [138,
143]. The decreased occurrence of sarcoidosis relapses from 2013 onwards have been imputed
to the widespread use of mTOR inhibitors like tacrolimus to prevent rejection, which may also
inhibit granuloma formation [144].
Bronchiectasis
Bronchiectasis in patients with radiographic stage IV disease has been reported to range from
18% to 40% on HRCT scanning, and bronchiectasis is present in nearly 100% of patients listed
for lung transplantation [137]. They typically involve the mid and upper lung zones [145].
Bronchiectasis may cause recurrent infections or colonisation with multidrug-resistant bacteria
or nontuberculous mycobacterial species, obstruction on PFTs, mycetoma formation or
haemoptysis. Suppurative bronchiectasis with recurrent infectious exacerbations can be seen in
some patients, and active infection should be excluded in any patient with bronchiectasis
presenting with worsening respiratory symptoms before considering immune suppression to treat
a sarcoidosis flare [145, 146]. While the goal is to prevent this complication, once it has developed
management primarily involves ensuring patients have optimal airway clearance measures.
Aspergillomas
Chronic pulmonary aspergillosis can occur in patients with pulmonary sarcoidosis, and while
invasive aspergillosis is possible, chronic cavitary pulmonary aspergillosis and simple
aspergillomas are most common. Aspergilloma/mycetoma formation, mostly in pre-existing
cysts in the upper lobes, can occur in radiographic stage III or IV sarcoidosis and are observed
in 1–10% of patients with chronic pulmonary sarcoidosis (figure 6) [137, 147]. Aspergillus
serology is positive in 90% of patients. Aspergillomas are more common in African-American
patients who are more likely to develop fibrocystic sarcoidosis [148–151]. Death usually results
from progressive respiratory failure and rarely from massive haemoptysis; 5-year survival is
FIGURE 6 Aspergilloma in fibrotic pulmonary sarcoidosis.
134 https://doi.org/10.1183/2312508X.10031820
only 73% [150]. No specific consensus recommendations currently exist for management of
aspergillomas in patients with sarcoidosis. The benefit of treating asymptomatic patients is
unclear, but those with haemoptysis should receive either itraconazole or voriconazole. Only
those treated for at least 6 months had improvement in symptoms and decreased pleural/cavity
wall thickness [152, 153]. Interventional therapy is reserved for patients with radiographic
progression or refractory haemoptysis despite antifungals and includes intracavitary/
intrabronchial antifungals, bronchial artery embolism and surgical resection. In non-surgical
candidates, intracavitary amphotericin B given through a small-bore chest tube for 10 days led
to resolution of haemoptysis in 90% by the time of discharge, although complication rates are
high (26%) and severe haemoptysis recurred in 30% [154]. Bronchial artery embolisation for
haemoptysis in non-sarcoidosis aspergillomas is successful in alleviating haemoptysis in 67%,
with recurrence rates around 33%, although sarcoidosis patients were more likely to rebleed
after a shorter time period and 36% had severe complications [150, 155]. Mortality rates for
surgical resection range from 25% to 4.1% in more recent studies, and seem to be higher in
those with complex aspergillomas, thickened cavity walls and pleural involvement [156–158].
Pre-operative FEV1 >75% is associated with favourable outcomes [159]. Post-operative
antifungal pharmacological therapy in sarcoidosis patients with mycetoma undergoing lung
transplantation has been associated with better survival [160].
Pulmonary hypertension
Sarcoidosis-associated pulmonary hypertension (SAPH) can occur in sarcoidosis patients
without severe parenchymal disease, but it is most commonly seen as a complication of fibrotic
sarcoidosis. One case series reported that 60% of patients with SAPH lacked evidence of
significant fibrosis on chest radiography [161]. Studies have reported prevalence rates from
5.7% to 20.8% in sarcoidosis [162–164]. Up to 29% of patients with stage IV sarcoidosis may
develop pulmonary hypertension, and the prevalence increases to 45% in those with persistent
dyspnoea. However, a predominantly Caucasian cohort found a prevalence of only 3%, which is
much lower than the reported rates for other ethnic groups [165]. The 5-year transplant-free
survival in SAPH ranges from 55% to 62%, with worse survival seen in those with a diffusing
capacity <35% and a 6-min walk distance <300 m [166, 167]. Clinicians should have a low
threshold to getting a screening echocardiogram in patients with dyspnoea that seems out of
proportion to parenchymal abnormalities, heart failure symptoms, reduced walk distance with
oxygen desaturation, or a diffusing capacity reduced out of proportion to FVC [168, 169].
Consideration of clinical findings and potential therapeutic options should be taken into account
on a case-by-case basis when deciding on whether a right heart catheterisation is warranted.
However, when possible, a right heart catheterisation should be used to confirm the diagnosis in
patients with clinical findings highly suspicious for and a transthoracic echocardiogram
suggestive of pulmonary hypertension [89].
Management of SAPH is beyond the scope of this chapter and is covered in detail in another
chapter in this Monograph [170].
Conclusion
Recognition of typical and atypical presentations of pulmonary sarcoidosis enables clinicians to
make better diagnostic and management decisions. It is important to reconsider the diagnosis or
consider alternative causes of symptoms in patients with known sarcoidosis when unusual clinical
findings are present, especially when deciding whether treatment is warranted. The primary goal
of treating pulmonary sarcoidosis is to improve quality of life and prevent disability. Patients
should be heavily involved in the treatment decision and informed of the reason(s) treatment may
https://doi.org/10.1183/2312508X.10031820 135
be indicated and how treatment response will be assessed. Improving patient outcomes in fibrotic
pulmonary sarcoidosis depends on preventing progressive loss of lung function in addition to
evaluation and management of complications of fibrotic pulmonary sarcoidosis.
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Disclosures: W.E. James reports receiving grants or contracts from the NIH and the Foundation for Sarcoidosis
Research, outside the submitted work. W.E. James has leadership or fiduciary roles in other boards, societies,
committees or advocacy groups, paid or unpaid, for the Foundation for Sarcoidosis Research. F. Bonella reports
receiving the following, outside the submitted work: consulting fees from Boehringer Ingelheim, Roche and
Galapagos; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational
events from Boehringer Ingelheim, Roche and BMS; and support for attending meetings and/or travel from
Boehringer Ingelheim, Savara and Roche. F. Bonella reports participation in data safety monitoring boards or
advisory boards for GSK.
https://doi.org/10.1183/2312508X.10031820 141
Chapter 10
Cardiac sarcoidosis
David H. Birnie1 and Vasileios Kouranos2
1
Division of Cardiology, University of Ottawa Heart Institute, University of Ottawa, Ottawa, ON, Canada. 2Interstitial
Lung Disease/Sarcoidosis Unit, Royal Brompton Hospital, London, UK.
Corresponding author: David H. Birnie (DBirnie@ottawaheart.ca)
Cite as: Birnie DH, Kouranos V. Cardiac sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS
Monograph). Sheffield, European Respiratory Society, 2022; pp. 142–159 [https://doi.org/10.1183/2312508X.10031920].
@ERSpublications
In ∼5–10% of sarcoidosis patients, clinically manifest cardiac involvement will present with conduction
abnormalities, heart failure, or one or more ventricular arrhythmias. The prognosis from cardiac sarcoidosis
is much improved in the current era. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
It is estimated that 20–25% of systemic sarcoidosis patients have clinically silent cardiac involvement.
Approximately 5–10% will have clinically overt cardiac involvement presenting with major arrhythmias
(conduction abnormalities, ventricular arrhythmias) and/or new-onset unexplained heart failure. Such
cardiac presentations (and even sudden cardiac death) can be the first manifestation of cardiac
sarcoidosis (CS). While cardiac MRI is the gold standard for identifying myocardial fibrosis, 18F-FDG
PET is used to detect active myocardial inflammation and guide immunosuppression. Treatment in CS
is multidisciplinary and includes immunosuppression and heart-failure and anti-arrhythmic medications
and/or devices, typically implantable cardioverter defibrillators (ICDs). Immunosuppression focuses on
the elimination of myocardial inflammation with conflicting evidence about the impact on disease
evolution. The extent of left ventricular dysfunction is the most important predictor of outcome among
patients with CS. The prognosis for CS is much improved in the current era of earlier diagnosis,
modern heart-failure treatment and use of ICD therapy.
Introduction
Clinically manifest cardiac involvement occurs in ∼5–10% of sarcoidosis patients. Cardiac
symptoms in these patients predominate, as most patients with clinically manifest cardiac
sarcoidosis (CS) have low levels of extracardiac disease [1–5]. Autopsy studies also estimate
that the true prevalence of cardiac involvement is 20–25%, with most patients having clinically
silent disease [6]. Data employing late gadolinium enhancement (LGE) cardiac MRI (CMR)
technology corroborate these numbers [7].
Studies indicate that CS is increasing. However, such increases are most likely the outcome of:
1) increased clinical awareness and, as a consequence, more thorough investigation, and/or
2) advances in imaging technology. This chapter will review cardiac sarcoidosis clinical
manifestations, screening and diagnosis, management, prognosis and ongoing research.
Clinical manifestations
CS may develop prior to, concomitant with or after the diagnosis of pulmonary disease. In
addition, there is increasing evidence that CS can be the first manifestation of sarcoidosis in any
142 https://doi.org/10.1183/2312508X.10031920
CARDIAC SARCOIDOSIS | D.H. BIRNIE AND V. KOURANOS
organ [2, 3, 8, 9]. The clinical features of CS are dependent on the location, extent and
activity of the disease. Different modes of initial presentation have been described. Patients
with known systemic sarcoidosis can develop ECG or echocardiographic abnormalities with
or without accompanying clinical symptoms. Cardiac symptoms are usually dominant over
extracardiac symptoms, with most patients with clinically manifest disease having modest
extracardiac disease. This has been shown to be consistent in the phenotype of mainly
Caucasian patients of northern European descent [1, 5, 10]. The principal manifestations
are conduction abnormalities, ventricular arrhythmias including sudden death and heart
failure. Patients can present with palpitations (due to atrial or ventricular arrhythmias),
presyncope, syncope, heart-failure symptom events and, more rarely, atypical or angina-type
chest pain.
Screening for CS
Screening for cardiac involvement in patients with biopsy-proven, extracardiac sarcoidosis
There are few data comparing the specificity and sensitivity of screening tests for cardiac
involvement in patients with extracardiac sarcoidosis. A review by MEHTA et al. [11] of 62
extracardiac sarcoidosis patients with echocardiography, who had detailed cardiac histories,
Holter monitoring and ECGs, found specificity and sensitivity values of 87% and 100%,
respectively, for a diagnosis of CS. KOURANOS et al. [12] studied 321 patients with
biopsy-proven sarcoidosis who had conventional cardiac testing and CMR with LGE. The
results of these two studies are summarised in figure 1.
The 2014 Heart Rhythm Society (HRS) consensus suggested doing a cardiac history, ECG and
echocardiogram on all patients, and further investigations with CMR and/or 18F-FDG PET, if
defined abnormalities were found on initial history/tests [14]. In 2020, the American Thoracic
Society (ATS) recommended the following in their Clinical Practice Guideline for Diagnosis
and Detection of Sarcoidosis [15]:
1) Performing baseline ECG and avoiding routine baseline echocardiography or 24-h

ambulatory ECG (Holter) monitoring to screen for possible cardiac involvement in patients
with extracardiac sarcoidosis who do not have cardiac symptoms or signs. (Conditional
recommendation, very low-quality evidence.)
2) Echocardiography and/or Holter should be considered on a case-by-case basis. (Conditional

recommendation, very low-quality evidence.)
3) Performing MRI, rather than 18F-FDG PET or echocardiography, to obtain both diagnostic
and prognostic information in patients with extracardiac sarcoidosis and suspected cardiac
involvement based on baseline assessment. (Conditional recommendation, very low-quality
evidence.)
Further studies are required to define the sensitivity and specificity of screening tests and
strategies that aim to uncover asymptomatic cardiac involvement. Studies are required that apply
to possible screening with CMR. Studies are also needed to find data on whether or not interval
rescreening is required [14]. A number of studies are underway including CHASM-CS (Cardiac
sarcoidosis multi-center prospective cohort; ClinicalTrials.gov identifier NCT01477359),
PAPLAND (Routine cardiac screening in sarcoidosis patients; ClinicalTrials.gov identifier
NCT03902223) and CASPA (Cardiac sarcoidosis in Papworth; ClinicalTrials.gov identifier
NCT03599414) [15]. For now, given the easy reproducibility of ECG, we suggest obtaining a
cardiac history and an ECG on an annual basis.
https://doi.org/10.1183/2312508X.10031920 143
Sensitivity Specificity
100
90
80
70
60
95% CI
50
40
30
20
10
0
Cardiac Sx
ECG
Holter
TTE
Any
variable
Cardiac Sx
ECG
Holter
TTE
Sx±ECG
Sx±Holter
Sx±TTE
Sx±ECG
±Holter
Sx±ECG
±TTE
Sx±Holter
±TTE
CMR
Mehta Kouranos
FIGURE 1 The sensitivity and specificity of various tests for the diagnosis of cardiac sarcoidosis in two
sarcoidosis cohorts. The results from MEHTA et al. [11] are shown on the left and those of KOURANOS et al. [12] on
the right. Red and black lines indicate 95% CI values for the specificity and sensitivity, respectively, of various
tests with the means identified. Sx: symptoms; Holter: 24-h ambulatory electrocardiographic monitoring; TTE:
transthoracic echocardiogram; any variable: combination of all previous tests; CMR: cardiac MRI. Reproduced
and modified from [13] with permission.
CS screening in patients with specific cardiac presentations

In many cases, cardiac presentations may be the initial manifestation of sarcoidosis. CS should
be considered in the differential of such presentations.
Unexplained Mobitz II or third-degree atrioventricular block in middle-aged patients

A study from Finland of 72 individuals <55 years old with new-onset, unexplained, significant
conduction-system disease found biopsy-verified CS in 14 out of 72 patients (19%), while
“probable” CS was found in four out of 72 patients (6%) and giant cell myocarditis was found
in four out of 72 patients (6%) [8]. Compared with those who had idiopathic complete
atrioventricular (AV) block, the prognosis for CS patients was poorer. An analogous study at a
Canadian institution found that 11 out of 32 patients (34%) aged <60 years had CS [3]. As a
result, the HRS consensus recommended the performance of a HRCT chest scan and CMR or
18
F-FDG PET in patients aged <60 years presenting with unexplained advanced AV block [14].
Sustained monomorphic ventricular tachycardia of unknown aetiology

A prospective study examined patients with ventricular tachycardia (VT) of unknown aetiology
for sarcoidosis and found that four out of 14 patients (29%) had CS [2]. In another study, where
144 https://doi.org/10.1183/2312508X.10031920
participants were 85% Caucasian, 7% African-American and 8% Asian, 17 out of 103 patients
(16.5%) with VT and nonischaemic cardiomyopathy at presentation had previously undiagnosed
CS [9].
Arrhythmogenic right ventricular cardiomyopathy

CS may present similarly to arrhythmogenic right ventricular cardiomyopathy (ARVC). The CS
diagnosis may have an epsilon wave and may even fulfil the diagnostic criteria as defined by
the ARVC Task Force. Based on Task Force criteria, VASAIWALA et al. [16] investigated 15
patients diagnosed with ARVC. They found that three out of 15 patients (20%) had sarcoidosis
on endomyocardial biopsy. PHILIPS et al. [17] reported 15 patients who were positive for the
ARVC Task Force criteria and, as a result, found to have CS. This group was compared with 42
patients with genuine ARVC. AV block may be a distinct feature in this scenario, as it was found
in 10 out of 15 of the CS patients (67%) but in none of the ARVC patients ( p<0.001) [17].
Apparent “pacing-induced” cardiomyopathy

Left ventricular (LV) systolic dysfunction is known to occur after permanent pacemaker
implantation in a subset of patients. Two recent reports have highlighted that some of these
patients may have undiagnosed CS [18, 19].
Idiopathic heart failure

CS is frequently overlooked as the underlying cause of heart failure. In a study evaluating the
actual diagnosis of explanted hearts among 130 heart-transplant patients with a clinical
diagnosis of nonischaemic cardiomyopathy, eight (6.2%) were found to have undiagnosed CS
[20]. There were similar findings in a French nationwide study [21]. Core LV biopsies during
LV assist device implantation identified previously undiagnosed CS in six out of 177 mixed
cardiomyopathy patients (3.4%) [22].
Isolated CS
The prevalence and clinical importance of isolated CS is debated [23, 24]. Isolated CS varies
widely, with prevalence rates of between 3% and 54% [1, 5, 25, 26]. Such rate variability can
be explained in three ways: 1) many of the cohorts were heterogeneous, 2) isolated CS lacks an
agreed-upon definition, and 3) different methods are used for diagnosing and assessing
extracardiac involvement. Some experts believe that the optimal way to assess extracardiac
disease is by applying “whole-body” 18F-FDG PET imaging and clinical skin and
ophthalmological examination [27]. Based on this and using a precise definition of isolated CS
as “active or inactive disease on 18F-FDG PET-CT only in the myocardium and absence of
sarcoidosis anywhere else including in hilar and/or mediastinal lymph nodes and no clinical
evidence of skin or eye sarcoidosis”, the rate of isolated CS has been described as 3.2% [10]
and 9.2% [28]. Recent Japanese guidelines suggest a similar means to diagnose isolated CS
(table 1) [29]. However, one aspect is different and controversial, as they propose that it is
possible to diagnose isolated CS without a positive cardiac biopsy and we do not agree with this.
Key diagnostic tools

ECG
Patients with clinically manifest CS usually have an abnormal ECG. Varying levels of
conduction block including isolated bundle branch block and fascicular block are the most
frequent abnormalities. Consistently, right-bundle branch block is far more common than left in
all CS cohorts [11, 30–34]. In comparison, only 3.2–8.6% of patients with clinically silent CS
have an abnormal ECG [11, 30, 32, 33].
https://doi.org/10.1183/2312508X.10031920 145
TABLE 1 Japanese guidelines for diagnosis of isolated cardiac sarcoidosis (CS)

Definition
1) No clinical findings characteristics of sarcoidosis are observed in any organs other than the heart. (The
patient should be examined for respiratory, ophthalmic and skin involvement. When the patient is
symptomatic, other aetiologies that can affect the corresponding organs must be ruled out.)
2) 67Ga scintigraphy or 18F-FDG PET reveals no abnormal tracer accumulation in any organs other than the
heart.
3) A chest CT scan reveals no shadow along the lymphatic tracts in the lungs or no hilar and mediastinal
lymphadenopathy (minor axis >10 mm).
Histological diagnosis group
Isolated CS is diagnosed histologically when endomyocardial biopsy or surgical specimens demonstrate
noncaseating epithelioid granulomas.
Clinical diagnosis group
Isolated CS is diagnosed clinically when 67Ga scintigraphy or 18F-FDG PET reveals abnormally high
tracer accumulation in the heart and at least three of the following criteria are met:
High-grade atrioventricular block (including complete atrioventricular block) or ventricular arrhythmia
(e.g. sustained ventricular tachycardia and ventricular fibrillation).
Basal thinning of the ventricular septum or abnormal ventricular wall anatomy (ventricular aneurysm,
thinning of the middle or upper ventricular septum, regional ventricular wall thickening).
Left ventricular contractile dysfunction (left ventricular ejection fraction <50%).
Gadolinium-enhanced MRI reveals delayed contrast enhancement of the myocardium.
Ga: gallium. Reproduced and modified from [29] with permission.
Echocardiography
The most common feature of CS is interventricular thinning ( particularly basal), a feature that
has been found to be highly specific to a CS diagnosis [12]. A less common feature of CS is an
increase in thickness of the myocardial wall that can resemble hypertrophic cardiomyopathy
[35]. Other abnormalities, such as aneurysms, LV and/or right ventricular (RV) diastolic and
systolic dysfunction, and isolated wall motion abnormalities, may also be present [36].
CMR
CMR offers an accurate review of the cardiac morphology but most importantly provides tissue
characterisation with T2-weighted imaging and a gadolinium study. Detection of oedema in
T2-weighted imaging is associated with the presence of active myocardial inflammation, while
LGE is considered to represent areas of myocardial damage/fibrosis. Multiple LGE patterns
have been described in CS but none is pathognomonic. Typically, LGE is multifocal and
patchy, with sparing of the endocardial border [37], favouring the intraventricular septum and
the basal segments (lateral wall) [38, 39]. Ischaemic LGE patterns such as subendocardial and
transmural involvement have also been reported [32]. VITA et al. [40] noted that subepicardial
LGE in the septum extending into the RV wall (“hook sign”) is highly indicative of CS.
18
F-FDG PET imaging
FDG, a glucose analogue, is useful for assessing inflammatory lesions (in which activated
pro-inflammatory macrophages display a relatively high metabolic rate) [41]. No single clinical
finding is pathognomonic for a CS diagnosis, but focal or focal-on-diffuse 18F-FDG uptake
patterns denote active CS [42, 43]. Notably, only medical institutions that have people
experienced in CS imaging protocols should undertake 18F-FDG PET testing; inadequate
preparation may lead to a false positive and, consequently, to nondiagnostic 18F-FDG PET scans
[44]. The suppression of physiological 18F-FDG uptake in the cardiac muscle is a key factor in
optimising diagnostic accuracy [45]. Preparation protocols vary, but patients are all usually
required to fast for ⩾12 h and to eat fat-rich and low-carbohydrate meals the day before [45].
146 https://doi.org/10.1183/2312508X.10031920
a) b)
FIGURE 2 Cardiac uptake with a) 18F-fluorothymidine and b) 18

F-FDG in the same subject. Reproduced and
modified from [47] with permission.
Nonspecific myocardial uptake is present in as many as 20% of patients, which can pose a
challenge for diagnosing CS with 18F-FDG PET [46]. Acquiring whole-body 18F-FDG PET
images is recommended along with the cardiac study. 18F-FDG PET images help evaluate
extracardiac involvement and achieve biopsy targets in cases where CS seems likely [45] A few
non-18F-FDG PET radiotracers have shown potential for enabling CS evaluation without
needing as much patient preparation. A particularly promising candidate is 3′-deoxy-3′-18F-
fluorothymidine (FLT) (figure 2) [47].
Tissue biopsy
Lung or lymph-node biopsy is used first on suspected sarcoidosis patients due to low procedural
risk. Endomyocardial biopsy can be necessary in selected cases, but due to the disease’s focal
nature, unguided endomyocardial biopsy has low sensitivity [48]. Both PET and CMR [1] and
electrophysiologically guided biopsy procedures [49, 50] were found to increase the diagnostic
yield to 40–50% [1, 4, 14, 50, 51].
Consensus guidelines for diagnosing CS

In 2014, in collaboration with several other medical societies, experts from the HRS published
the first international CS diagnosis consensus statement (table 2) [14]. The only published
diagnostic guidelines until 2014 were those produced by the World Association for Sarcoidosis
and Other Granulomatous Disorders (WASOG) [52] and the Japanese Ministry of Health and
Welfare’s criteria [53]. The HRS document was closely aligned with the WASOG document
[14, 52]. The Japanese Circulation Society published new guidelines for the diagnosis of CS in
2019 [29].
Many similarities exist among the HRS, WASOG and most recent Japanese guidelines. When
the three main diagnostic criteria available were compared, researchers found good concordance
between WASOG and HRS criteria, while concordance was poor between the WASOG/HRS
and Japanese criteria [54]. Such discrepancy emphasises the important issue of whether CS can
be diagnosed without a positive biopsy. Our opinion is that there are some cases where the
clinical features and imaging findings are so clear cut that we do not always seek biopsy
confirmation (after careful discussion with the patient), for example a patient in their early 50s
with new-onset advanced conduction-system disease and classic findings on cardiac and
whole-body 18F-FDG PET scans. This is consistent with the recent ATS document, and an
update of the 2014 HRS guidelines is planned [14, 55].
https://doi.org/10.1183/2312508X.10031920 147
TABLE 2 Expert consensus recommendations on criteria for the diagnosis of cardiac sarcoidosis (CS)
There are two pathways to a diagnosis of CS:
1) Histological diagnosis from myocardial tissue
CS is diagnosed in the presence of noncaseating granuloma on histological examination of myocardial tissue
with no alternative cause identified (including negative organismal stains if applicable)
2) Clinical diagnosis from invasive and noninvasive studies
It is probable# that there is CS if:
a) There is a histological diagnosis of extracardiac sarcoidosis
AND
b) One or more of following is present
Steroid±immunosuppressant-responsive cardiomyopathy or heart block
Unexplained left ventricular ejection fraction <40%
Unexplained sustained (spontaneous or induced) ventricular tachycardia
Mobitz type II second-degree heart block or third-degree heart block
Patchy uptake on dedicated cardiac FDG PET (in a pattern consistent with CS)
Late gadolinium enhancement on CMR (in a pattern consistent with CS)
Positive gallium uptake (in a pattern consistent with CS)
AND
c) Other causes for the cardiac manifestation(s) have been reasonably excluded
CMR: cardiac MRI. #: in general, “probable involvement” is considered adequate to establish a clinical diagnosis
of CS. Reproduced and modified from [14] with permission.
Clinical management
Role of immunosuppression
FAZELPOUR et al. [56] recently published an updated systematic review of corticosteroids and
immunosuppressant therapy (IST) for the treatment of CS. 34 publications met the inclusion
criteria. Only two studies were rated good in quality; no randomised trials were identified for
inclusion. The 34 reports had a total of 1297 patients; 1125 received corticosteroids, 235
received additional or other IST, and 97 received no therapy at all. Out of the 178 patients
treated for AV conduction disease, 76 (42.7%) improved. In comparison, of the 21 patients not
treated with corticosteroids and/or IST, none improved. Prevention of LV function deterioration
was associated with therapy. Of the eight publications on ventricular arrhythmia burden and 19
on mortality that were included in the systematic review, the researchers deemed that the data
quality was too limited to draw conclusions for these two outcomes.
The guidelines have been proponents of treating CS, despite this scarcity of data [29, 57]. The
2021 European Respiratory Society clinical practice guidelines on treatment of sarcoidosis
recommended the use of glucocorticoids (with or without other IST) in patients with CS and
evidence of functional cardiac abnormalities, including heart block, dysrhythmias or
cardiomyopathy (noted as “strong recommendation, very low quality of evidence”) [57].
Additional suggestions from this guideline are shown in figure 3.
Increasing data suggest that PET may be a useful marker for disease activity to help guide CS
therapy (figure 4). Figure 5 illustrates the current PET-guided immunosuppression protocol at
one of our institutions. However, it should be noted that currently there is no evidence that
tailoring treatment according to serial PET studies improves clinical outcomes. Other centres
favour a more clinically based strategy that relies on repeat assessments of symptoms,
ventricular function, AV conduction and ventricular arrhythmias, etc., to guide immuno-
suppression adjustment, and PET scans are repeated only when considered clinically necessary.
Also, whether it is best to treat all CS patients or only to treat those with clinically manifest
148 https://doi.org/10.1183/2312508X.10031920
Pacemaker Clinically relevant

ICD cardiac sarcoidosis
As indicated by cardiology consult
MTX
Azathioprine Good clinical response
Glucocorticoids ±
Leflunomide Successful GC taper
MMF
Switch to different
second-line agent if
significant GC side-effects OR
continued disease OR relapse
MTX
Azathioprine Good clinical response
Leflunomide Successful GC taper
MMF
Quality of evidence codes:
Strong recommendation Continued disease
Very low quality of evidence OR relapse
Current practice
Infliximab
Therapeutic decision codes: Adalimumab
Continuation of therapy
recommended Cyclophosphamide
FIGURE 3 European Respiratory Society clinical practice guidelines’ suggested approach to clinically relevant
cardiac sarcoidosis (defined as rhythm disturbances, heart failure or high risk for sudden cardiac death). Note that
the information depicted as current practice (in white) is not intended as a recommendation for clinical practice.
ICD: implantable cardioverter defibrillator; GC: glucocorticoid. Reproduced and modified from [57] with permission.
disease with ongoing myocardial inflammation is currently unclear. Other unknowns exist such
as the best techniques for assessing the response to treatment and the optimal doses of
corticosteroids. Most experts recommend a starting dose of 30–40 mg prednisone daily [60]. If
significant steroid side-effects develop, or in refractory cases, MTX is often used as a
second-line treatment [61]. Infliximab, azathioprine and MMF are also sometimes used to
treat CS [62].
The current randomised treatment trial specific to CS, CHASM-CS (ClinicalTrials.gov identifier
NCT03593759), is a good step in the right direction for producing better-quality data [63].
Clinically manifest CS patients are randomised in a ratio of 1/1 to prednisone
0.5 mg·kg−1·day−1 for 6 months (maximum dose 30 mg·day−1), or to prednisone 20 mg daily
for 1 month and then 10 mg daily for 1 month, 5 mg daily for 1 month and MTX 15–20 mg
once a week for 6 months [63].
Two other trials are ongoing. MAGiC-ART (Interleukin-1 blockade for treatment of cardiac
sarcoidosis; ClinicalTrials.gov identifier NCT04017936) is a single-centre, 28-patient,
placebo-controlled, 4-week treatment trial with a primary outcome of change in C-reactive
protein. J-ACNES ( Japanese antibacterial drug management for cardiac sarcoidosis) is a
multicentre, open-label, randomised, controlled study [64]. The patients are randomised to
receive either standard corticosteroid therapy plus antibiotics or standard corticosteroid therapy.
The primary end-point is a change in the total cardiac 18F-FDG uptake at 6 months versus
baseline using 18F-FDG PET. The investigators plan to enrol a minimum of 80 patients and then
perform a sample size calculation [64].
https://doi.org/10.1183/2312508X.10031920 149
Presentation Follow-up
FIGURE 4 18F-FDG PET imaging before and after treatment. Top: whole-body image; bottom: axial slice.
LV dysfunction management
According to current guidelines, patients with CS and LV dysfunction should be treated with
standard medical and device therapies for heart failure. Heart transplantation should be considered
in patients with advanced heart failure despite optimal medical therapy, as well as those with
persistent arrhythmias despite medical treatment and interventional therapies. Recurrence of CS in
the transplanted heart has been reported, but long-term patient outcomes are similar or better than
outcomes for control groups [65–67]. In a pooled analysis of 14 studies, post-transplant survival
was statistically significantly higher in CS than in non-CS patients after 5 years [68].
Management of conduction abnormalities

Those patients presenting with normal or near-normal ventricular function and complete AV
block have a high risk of developing subsequent ventricular arrhythmias. In one study of
Japanese CS patients with high-grade AV block, with a median follow-up of 45 months, two
out of 22 patients experienced aborted sudden cardiac death (SCD) and nine had sustained VT
[68]. In 2018, NORDENSWAN et al. [69] reported on CS patients presenting with third-degree AV
block or Mobitz type II. Among their cohort of 143 participants, 107 (74.8%) received
pacemakers, 35 (24.5%) received implantable cardioverter defibrillators (ICDs) and one refused
a device implant. During the follow-up period (median of 4.1 years), 23 out of 143 patients
150 https://doi.org/10.1183/2312508X.10031920
Prednisone 0.5 mg·kg–1·day–1 for 2–3 months (maximum dose 30 mg)
Repeat PET scan after 3 months of treatment
No abnormal cardiac 18F-FDG uptake on PET Abnormal cardiac 18F-FDG uptake on PET
Steroid taper over 3 months to 0.2 mg·kg–1·day–1 Add second-line agent (usually MTX)
to continue for 9 months, then taper and stop
(total of 12 months of treatment)
PET scan 3 months after stopping treatment
Disease relapse No relapse
Restart immunosuppression Follow patient with echocardiogram

with second-line agent, usually MTX, and ECG at 6, 12, 24 and 36 months
sometimes with brief prednisone course after stopping treatment
depending on clinical features
Repeat PET scan after 6 months of Consider repeat PET if LVEF

treatment falls significantly and/or if there is
development of a new significant
conduction-system disease and/or if
the patient develops significant
ventricular arrhythmias
FIGURE 5 Treatment algorithm at the University of Ottawa Heart Institute (Ottawa, ON, Canada) for patients with
clinically manifest cardiac sarcoidosis. It should be noted that there are no data to suggest that a PET-guided
approach to the titration of immunosuppression improves clinical outcomes. LVEF: left ventricular ejection
fraction. Reproduced and modified from [59] with permission.
(16.1%) suffered either fatal or aborted SCD (13 and 10 patients, respectively). In addition, 21
patients experienced sustained VT, with a combined end-point of SCD/VT occurring in 44 out
of 143 (30.8%) patients. The combined end-point in the patients with normal left ventricular
ejection fraction (LVEF) occurred at an annual rate of 5% [69]. These two studies support the
recommendation of the HRS CS consensus that an ICD “can be useful” for CS patients with
indications for pacing (table 3) [14]. Cardiac resynchronisation therapy should also be used
based on generic device guideline recommendations, although results have been shown to be
variable [70, 71].
Management of ventricular arrhythmias

The most common mechanism of ventricular arrhythmia is macro re-entrant arrhythmias near
areas of granulomatous scarring [72, 73]. Probably by triggering it with ventricular ectopy or
slowing conduction in diseased tissue within granulomatous scarring, active inflammation can
https://doi.org/10.1183/2312508X.10031920 151
TABLE 3 Expert consensus recommendations on management of arrhythmias associated with cardiac

sarcoidosis (CS)
Recommendations Class
Diagnosis and screening

It is recommended that patients with biopsy-proven extracardiac sarcoidosis should be asked about I
unexplained syncope/presyncope/significant palpitations
It is recommended that patients with biopsy-proven extracardiac sarcoidosis should be screened for I
cardiac involvement with a 12-lead ECG
Screening for cardiac involvement with an echocardiogram can be useful in patients with IIa
biopsy-proven extracardiac sarcoidosis
Advanced cardiac imaging, CMR or 18F-FDG PET, at a centre with experience in CS imaging protocols, IIa
can be useful in patients with one or more abnormalities detected on initial screening by
symptoms/ECG/echocardiogram
Screening for CS in patients <60 years of age with unexplained second-degree (Mobitz II) IIa
or third-degree atrioventricular block can be useful
Advanced cardiac imaging (CMR or 18F-FDG PET) is not recommended for patients without III
abnormalities on initial screening by symptoms/ECG/echocardiogram
Management of conduction abnormalities
Device implantation can be useful in CS patients with an indication for pacing, even if the IIa
atrioventricular block reverses transiently
Immunosuppression can be useful in CS patients with second-degree (Mobitz II) or third-degree IIa
atrioventricular block
ICD implantation can be useful in patients with CS and an indication for permanent pacemaker IIa
implantation
Management of ventricular arrhythmias
Assessment of myocardial inflammation with 18F-FDG PET can be useful in CS patients with IIa
ventricular arrhythmias
Immunosuppression can be useful in CS patients with ventricular arrhythmias and evidence of IIa
myocardial inflammation
Anti-arrhythmic drug therapy can be useful in patients with ventricular arrhythmias refractory to IIa
immunosuppressive therapy
Catheter ablation can be useful in patients with CS and ventricular arrhythmias refractory to IIa
immunosuppressive AND anti-arrhythmic therapy
CMR: cardiac MRI; ICD: implantable cardioverter defibrillator. Reproduced and modified from [14] with permission.
contribute to monomorphic VT resulting from re-entry. Recently, a systematic review of catheter

ablation for CS reported on 83 patients from five studies [74]. The median number of VTs was
three (range 2.6–4.9) per patient; 15 out of 83 (18.1%) required epicardial ablation. During a
follow-up period (average 2 years), 38 out of 83 patients (45.8%) experienced no recurrent VT
and 61 out of 83 patients (73.5%) improved following ablation (i.e. were free from arrhythmia
or experienced a reduction of burden) [74]. A stepwise approach is generally recommended
(table 3) [14]. It should be noted that an electrical storm has been reported after initiation of
steroid therapy [75].
When to consider implanting an ICD and risk stratification for SCD

CS carries the risk of sudden death, but data to support risk stratification are scarce. The 2014
HSR consensus document illustrates the suggested approach to risk stratification and when to
consider implanting an ICD (figure 6) [14]. Perhaps due to the variable involvement of the RV
and/or LV, or possibly as a result of active granulomatous inflammation, CS may not act the
same as other types of nonischaemic cardiomyopathy. As an example, CS patient cohorts seem
to have higher rates of ICD therapies than other patients [76–78].
152 https://doi.org/10.1183/2312508X.10031920
1) Spontaneous sustained ventricular arrhythymias, including

prior cardiac arrest
AND/OR
2) LVEF ≤35% despite optimal medical therapy and a period of Yes ICD recommended
immunosuppression (if there is active inflammation)
No
1) Indication for permanent pacemaker implantation
AND/OR Yes ICD may be useful
2) Unexplained syncope or near-syncope, felt to be arrhythmic in
aetiology
AND/OR
3) Inducible ventricular arrhythmias (>30 s of monomorphic VT,
or clinically relevant polymorphic VT/VF)
No
LVEF 36–49% and/or RVEF <40%, despite optimal Yes ICD may be considered
medical therapy and a period of immunosuppression, if
appropriate (CMR with/without an electrophysiological study may
be considered to help with risk stratification of these patients)
No
Class I
CMR may be considered
Class IIa
Class IIb
No late gadolinium Late gadolinium
Class III
enhancement enhancement
An electrophysiological
ICD not recommended study may be considered
Patient should be followed
for deterioration in
ventricular function Negative Positive ICD may be useful
FIGURE 6 The 2014 Heart Rhythm Society consensus’ suggested risk stratification approach, as well as when to
consider implantable cardioverter defibrillator (ICD) implantation. LVEF: left ventricular ejection fraction;
VT: ventricular tachycardia; VF: ventricular fibrillation; RVEF: right ventricular ejection fraction; CMR: cardiac MRI.
A recent meta-analysis of outcomes following ICD implantation found 10 studies with 585
patients [78]. Appropriate and inappropriate ICD treatments were reported in 39% and 15% of
patients, respectively, over a mean follow-up period of 25 months. A high-degree AV block was
the only independent predictor of appropriate therapy.
In 2017, a report by the American College of Cardiology/American Heart Association Task

Force on Clinical Practice Guidelines and HRS produced a similar set of guidelines for using
ICDs in CS patients [79]. The main difference between the two sets of guidelines is pertinent to
patients without substantial LV systolic dysfunction (i.e. LVEF >35%) (table 4). The difference
may partly be understood by considering new CMR data published since 2014. In a
meta-analysis of seven studies incorporating 694 suspected CS patients where 199 patients had
LGE on CMR, the authors reported that cardiovascular-related mortality occurred in 10
LGE-positive and two LGE-negative patients [81]. Moreover, ventricular arrhythmias resulted in
41 LGE-positive patients and, as long as the CMR was negative for LGE, no patients incurred
VT/ventricular fibrillation (VF). While such emerging CMR data are important, they have
significant limitations: 1) almost all of the studies were retrospective and/or were conducted in a
single centre; 2) the confidence intervals of the odds ratios were extremely wide, and 3) data on
how many of the cardiovascular deaths were SCD were scanty.
https://doi.org/10.1183/2312508X.10031920 153
154

TABLE 4 Comparison of recommendations for primary prevention ICDs in CS patients with near normal or normal ventricular function
2014 HRS Expert Consensus Statement Expert Consensus Statement on the Diagnosis and 2017 AHA/ACC/HRS Guideline for Management of Patients With
Management of Arrhythmias Associated With CS [14] Ventricular Arrhythmias and the Prevention of Sudden Cardiac
Death [79]
For patients with one or ICD implantation (class IIb recommendation) LVEF >35% ICD implantation (class IIa recommendation) in
both (i) LVEF 36% to patients with evidence of extensive# myocardial scar
49% (ii) RVEF <40% by cardiac MRI or PET scan
LVEF normal Consider CMR and if LGE + then do EPS. If EPS is positive, then ICD
implantation (class IIa recommendation). ICD implantation is not
recommended in patients with normal LVEF/RVEF and a negative
electrophysiology study (regardless if LGE on CMR)
https://doi.org/10.1183/2312508X.10031920
ICD: implantable cardioverter defibrillator; CS: cardiac sarcoidosis; HRS: Heart Rhythm Society; AHA: American Heart Association; ACC: American College of Cardiology; LVEF:
left ventricular ejection fraction; RVEF: right ventricular ejection fraction; CMR: cardiac MRI; LGE: late gadolinium enhancement; EPS: electrophysiology study. #: extensive not
defined. Reproduced from [80] with permission.
TABLE 5 Recent studies reporting on mortality in cardiac sarcoidosis
First author [ref.] Year Follow-up, months # Patients, n Mortality, n (%)
KANDOLIN [8] 2010 48 (1–123) 17 2 (11.8)

YODOGAWA [89] 2013 7.3±5.9 31 0 (0)
YODOGAWA [90] 2013 85.2±63.6 15 1 (6.7)
ISE [83] 2014 39±19 43 6 (14)
KANDOLIN [5] 2015 79.2 102 14 (13.7)
ZHOU [91] 2017 104 73 7 (9.6)
CHAPELON-ABRIC [92] 2017 60 59 5 (8.5)
MUSER [93] 2018 35 (20–66) 20 1 (5)
FUSSNER [94] 2018 44 (20–77) 70 5 (6.8)
BALLUL [95] 2019 43 (12–182.4) 36 3 (8.3)
CHIBA [96] 2019 84 91 4 (4.4)
KOYANAGAWA [97] 2019 34.6 (5.0–51.8) 38 3 (7.9)
GILOTRA [98] 2020 40.4 38 0 (0)
ROSENBAUM [99] 2021 21 361 36 (10)¶
#
: results shown as median (range) or mean±SD; ¶: no difference between subsets of definite, presumed and
probable. Reproduced and modified from [56] with permission.
Some recent studies have started to show that the extent of LGE is important, with the great
majority of events occurring in patients with a greater extent of LGE (LGE expressed as % LV
mass), such as LGE >21.4% [82], >20% [83] or >8% [84]. Location may also be important. In
51 CS patients with LVEF >35%, RV-delayed enhancement, if present, was associated with
mortality or an increased risk of VT/VF [85–87]. Furthermore, recent findings suggest that RV
involvement on CMR or PET might also have predictive value [85, 88].
Prognosis
In the contemporary period of heart-failure therapy, which includes active transplant surgery,
fatality from heart failure is rare, with most deaths resulting from ventricular arrhythmias. A
recent nationwide Finnish study found that 10-year cardiac survival was 92.5% in 102 patients
with clinically manifest CS [5]. Other recent studies have also found that prognosis is greatly
improved among contemporary study populations. Table 5 provides a summary of recent
studies. It should be noted that in the studies where cause of death was reported, many patients
had noncardiovascular mortality. For example, ROSENBAUM et al. [99] reported seven deaths
from unknown causes, five due to sepsis and eight from cardiovascular causes (three heart
failure, three stroke, one myocardial infarction, one SCD). LV dysfunction extent is often
regarded as the single most important predictor of survival [5]. RV dysfunction is also
important prognostically [100, 101].
Conclusion and future directions

Around 5% of sarcoidosis patients will have clinically manifest cardiac involvement in one or
more of the following ways: ventricular arrhythmias, conduction abnormalities and/or heart
failure. Another 20–25% will have clinically silent disease (asymptomatic cardiac involvement).
That CS can be the first manifestation of sarcoidosis in any organ is being increasingly realised.
Physicians should think about the possibility of CS in patients aged <60 years presenting with
idiopathic advanced conductions and/or those with VT of unknown aetiology. While the data
are modest, IST (usually with corticosteroids) is suggested to treat clinically manifest CS. The
most important predictor of prognosis is the degree of LV dysfunction. Clinically manifest
disease frequently requires device therapy, most commonly with ICDs. Importantly, our current
https://doi.org/10.1183/2312508X.10031920 155
knowledge is limited in that most data arise from white (largely northern European) or Japanese
populations; few data exist on CS among other ethnic groups. Many unknowns still exist,
especially in terms of best practices for diagnosing and managing CS patients. Fortunately,
multicentre research is also underway. This research will allow for comparative studies among
larger and more diverse populations.
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69 Nordenswan HK, Lehtonen J, Ekström K, et al. Outcome of cardiac sarcoidosis presenting with high-grade
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70 Patel D, Trulock KM, Toro S, et al. Effect of cardiac resynchronization therapy on left ventricular remodeling in
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71 Yufu K, Kondo H, Shinohara T, et al. Outcome of patients with cardiac sarcoidosis who received cardiac
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72 Jefic D, Joel B, Good E, et al. Role of radiofrequency catheter ablation of ventricular tachycardia in cardiac
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82 Agoston-Coldea L, Kouaho S, Sacre K, et al. High mass (>18g) of late gadolinium enhancement on CMR
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87 Ahmed AI, Abebe AT, Han Y, et al. The prognostic role of cardiac positron emission tomography imaging in
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89 Yodogawa K, Seino Y, Ohara T, et al. Effect of corticosteroid therapy on ventricular arrhythmias in patients
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90 Yodogawa K, Seino Y, Shiomura R, et al. Recovery of atrioventricular block following steroid therapy in
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91 Zhou Y, Lower EE, Li HP, et al. Cardiac sarcoidosis: the impact of age and implanted devices on survival.
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18
F-fluorodeoxyglucose uptake by PET/CT in patients with cardiac sarcoidosis presenting with ventricular
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94 Fussner LA, Karlstedt E, Hodge DO, et al. Management and outcomes of cardiac sarcoidosis: a 20-year
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95 Ballul T, Borie R, Crestani B, et al. Treatment of cardiac sarcoidosis: a comparative study of steroids and
steroids plus immunosuppressive drugs. Int J Cardiol 2019; 276: 208–211.
96 Chiba T, Nakano M, Hasebe Y, et al. Prognosis and risk stratification in cardiac sarcoidosis patients with
preserved left ventricular ejection fraction. J Cardiol 2020; 75: 34–41.
97 Koyanagawa K, Naya M, Aikawa T, et al. The rate of myocardial perfusion recovery after steroid therapy and
its implication for cardiac events in cardiac sarcoidosis and primarily preserved left ventricular ejection
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98 Gilotra NA, Wand AL, Pillarisetty A, et al. Clinical and imaging response to tumor necrosis factor alpha
inhibitors in treatment of cardiac sarcoidosis: a multicenter experience. J Card Fail 2020; 27: 83–91.
99 Rosenbaum AN, Kolluri N, Elwazir MY, et al. Identification of a novel presumed cardiac sarcoidosis category for
patients at high risk of disease. Int J Cardiol 2021; 335: 66–72.
100 Kagioka Y, Yasuda M, Okune M, et al. Right ventricular involvement is an important prognostic factor and risk
stratification tool in suspected cardiac sarcoidosis: analysis by cardiac magnetic resonance imaging. Clin Res
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Disclosures: D.H. Birnie reports participation on a data safety monitoring board/advisory board for Star
Therapeutics in 2021 and Kinevant/Roivant Sciences Inc. outside the submitted work. V. Kouranos reports
receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational
events from Novartis and Roche, outside the submitted work.
https://doi.org/10.1183/2312508X.10031920 159
Chapter 11
Granulomatous and nongranulomatous

neurological sarcoidosis
Jinny Tavee1 and Mareye Voortman2
1
National Jewish Health, Division of Neurology, Denver, CO, USA. 2Dept of Pulmonology, University Medical Centre,
Utrecht, The Netherlands.
Corresponding author: Jinny Tavee (taveej@njhealth.org)
Cite as: Tavee J, Voortman M. Granulomatous and nongranulomatous neurological sarcoidosis. In: Bonella F,
pp. 160–173 [https://doi.org/10.1183/2312508X.10032020].
@ERSpublications
Neurosarcoidosis can be challenging to diagnose and treat. Recognition of the various clinical manifestations
along with newer diagnostic testing and treatment options can help improve quality of life in affected
patients. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Neurological complications of sarcoidosis include not only granulomatous disease but also
nongranulomatous disorders such as small-fibre neuropathy (SFN) and headache. This chapter reviews
the clinical manifestations of both types of disorder as well as updated diagnostic criteria, and
describes newer diagnostic studies including SFN testing and details regarding current treatment
options. In the last few years, there have been several reports demonstrating the beneficial effects of
infliximab in treating neurosarcoidosis. Similarly, intravenous immunoglobulins may be helpful with
sarcoidosis-associated SFN.
Introduction
While neurosarcoidosis has traditionally been defined as an immune-mediated granulomatous
disorder that may affect any portion of the neural axis, the spectrum of neurological
complications of sarcoidosis has expanded to include nongranulomatous manifestations such as
small-fibre neuropathy (SFN) and headache. These latter neurological disorders are not
associated with the pathological hallmark of noncaseating granulomas but are commonly seen
among patients with systemic disease. In recent years, specialised testing has allowed increased
diagnosis of SFN, while studies centred on patient-reported symptoms have helped bring
neuropathic pain, autonomic disorders and headache to the attention of treating clinicians. Both
granulomatous and nongranulomatous forms of neurological sarcoidosis markedly affect quality
of life and require prompt recognition and management.
Granulomatous manifestations
Granulomatous involvement of the nervous system is clinically apparent in 5–10% of patients
with sarcoidosis and can be divided into central nervous system (CNS; brain, spinal cord,
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GRANULOMATOUS AND NONGRANULOMATOUS | J. TAVEE AND M. VOORTMAN
cranial nerves) and peripheral nervous system (PNS; neuromuscular) manifestations [1, 2].
In >50% of cases, it can be the presenting symptom of sarcoidosis, and in some instances may
remain the only manifestation [2, 3]. Although previously thought to be rare, more recent
studies have demonstrated that isolated neurological involvement is seen in 10–20% of cases [4, 5].
In addition, autopsy studies have shown higher rates of sarcoidosis involvement of the nervous
system, with one series demonstrating subclinical neuropathology in up to 50% of cases post
mortem [6, 7]. Neurosarcoidosis is more common among African-Americans compared with
Caucasians, and affects women more than men [1].
CNS neurosarcoidosis
Invasion of the CNS arises from spread of leptomeningeal inflammation along perivascular
spaces, which are largest and most abundant at the base of the brain and allow communication
between the lymphatic fluid and parenchyma.
Cranial neuropathy
The most common presentation of neurosarcoidosis is cranial neuropathy, which accounts for
50% of cases and most frequently involves the facial nerve followed by the optic nerve [2, 3, 8].
While facial palsy usually resolves within a few months even without treatment, optic
neuropathy, especially when present bilaterally, may have a worse prognosis, leaving the patient
with residual visual impairment [3, 9]. Hearing loss (involving cranial nerve VIII) and facial
pain/sensory changes (cranial nerve V) are also commonly reported.
Meningitis
Aseptic meningitis manifesting as leptomeningeal and less frequently pachymeningeal
inflammation typically presents with headache and cranial neuropathies, although seizures,
cognitive impairment and gait disturbance may also be seen [10–12]. In severe cases that are
complicated by hydrocephalus, patients may present with obtundation, which requires urgent
evaluation and possibly shunt placement if the patient fails to respond to medical management.
Intracranial parenchymal lesions

Intraparenchymal lesions may occur with or without meningeal involvement and can present as
headache, seizures, cognitive changes, gait imbalance and focal sensorimotor deficits,
depending on lesion location. Involvement of the basal neuroendocrine structures can lead to
hypothalamic–pituitary dysfunction, which can often be permanent. Stroke is uncommon and
may be due to perivascular inflammation with penetration into vessel walls, vasculitis (rarely) or
direct granulomatous compression of an intracranial artery [13–15].
Myelopathy
Spinal-cord involvement is one of the most severe clinical manifestations of neurosarcoidosis, as
it can often result in residual paraparesis, sensory dysesthesias and bowel/bladder dysfunction,
despite aggressive treatment and resolution/improvement of MRI abnormalities. Patients
typically present with subacute sensory changes, difficulty walking and subjective weakness,
although muscle strength is often mildly reduced or normal on examination, which may reflect
the patchy, noncontiguous pattern of cord involvement often seen on MRI [15].
PNS neurosarcoidosis
PNS neurosarcoidosis affecting the muscle or large (myelinated) peripheral nerve fibres is
uncommon (although subclinical granulomatous inflammation of muscles has been reported
post mortem) and accounts for <2% of all neurological complications. Sarcoidosis myopathy
typically presents with gradually progressive weakness in a proximal-to-distal distribution with
https://doi.org/10.1183/2312508X.10032020 161
occasional involvement of the neck, facial, bulbar and respiratory muscles. Less common
muscle manifestations include a nodular myopathy, acute myositis and a distal predominant
presentation similar to inclusion-body myositis.
The pattern of large-fibre nerve involvement in sarcoidosis varies widely but most commonly
presents as either a distal sensorimotor polyneuropathy with glove–stocking pain and
paresthesias or an asymmetric polyradiculoneuropathy in which proximal and distal nerve
segments are equally affected in a nonlength-dependent distribution [16–18]. Other
manifestations include mononeuritis multiplex, pure sensory or pure motor neuropathy, and
entrapment syndromes [18]. Isolated cases of a demyelinating polyneuropathy similar to chronic
inflammatory demyelinating polyneuropathy and Guillain–Barré syndrome have also been
reported [15, 19].
Nongranulomatous manifestations
Apart from neurological granulomatous manifestations (i.e. neurosarcoidosis), as discussed,
sarcoidosis patients also suffer from SFN and headache, which are neurological conditions that
are nongranulomatous in nature. The aetiology of these nongranulomatous manifestations is
poorly understood and may potentially be due to a number of factors including active
inflammation, cytokine release and medication side-effects.
SFN
SFN is a disorder of thinly myelinated Aδ and unmyelinated C fibres that has been objectively
confirmed in one-third of patients with systemic sarcoidosis, although the frequency of reported
symptoms is 40–90% [20–24]. Sarcoidosis-associated SFN (SSFN) often results in disabling
symptoms of pain and/or autonomic dysfunction that interfere with daily living [25, 26].
Pathophysiology
Small nerve fibres mediate thermal and nociceptive sensations and autonomic function [23, 25–27].
The exact pathophysiological mechanism of SFN degeneration in sarcoidosis is unknown but is
thought to be due to inflammatory mediators, which include IL-1β, IL-16, IL-18 and TNF-α.
[28–31]. Of these, IL-1β and TNF-α are known to reduce mechanical nociceptive thresholds
and have been found in higher concentrations in skin biopsies in patients with SFN [28, 32, 33].
Intravenous immunoglobulin (IVIG) and TNF-α inhibitors have also been reported to reduce
SFN-associated symptoms in sarcoidosis patients, further supporting an immune-mediated
mechanism [34–36].
The clinical presentation of SSFN is heterogeneous and often nonlength dependent, leading to a
patchy distribution of symptoms. Symptoms are mainly sensory (e.g. pain, numbness, burning
paresthesias), although autonomic dysfunction may also be seen either concomitantly or in
isolation (table 1) [35, 37–39]. In addition, SSFN is seen more commonly in Caucasians, in
contrast to systemic disease. In one series of 115 subjects with SSFN, 87% were Caucasian,
while 10% were African-American [35].
Headache
Although headache is common with granulomatous CNS involvement of the brain parenchyma
and meninges, it may also be the only neurological symptom in patients with systemic
sarcoidosis. In these cases, the clinical presentation is that of a tension-type headache that is not
steroid responsive and is described as a severe global headache occurring daily or near-daily [40].
Migraines have also been associated with sarcoidosis, and in one series were seen in 29% of
162 https://doi.org/10.1183/2312508X.10032020
TABLE 1 Sarcoidosis-associated small-fibre neuropathy symptoms
Sensory disturbances Dysautonomia
Numbness Hypo- or hyperhidrosis

Tingling Diarrhoea or constipation
Pins/needles sensations Urinary incontinence or retention
Burning pain Bloating/gastroparesis
Electric shock-like pain Dry eyes/mouth
Itching Blurred vision
Bedsheet intolerance Facial flushing
Abnormal warm and cold sensations Orthostatic intolerance/syncope
Cramps Cardiac palpitations
Sexual dysfunction
patients with sarcoidosis compared with 13% of healthy controls [5]. For those presenting with
morning headaches, the diagnosis of obstructive sleep apnoea should be considered, as a higher
prevalence of obstructive sleep apnoea has been reported among sarcoidosis patients [41].
Diagnostic evaluation
According to a joint statement by the American Thoracic Society, European Respiratory Society
and the World Association for Sarcoidosis and Other Granulomatous Disorders, the diagnosis of
sarcoidosis is based on typical clinical and radiographic manifestations in the presence of
noncaseating granulomas with exclusion of other disorders [42]. While this is applicable to
most organ systems, the approach to diagnosing neurosarcoidosis is often more challenging for
a number of reasons, which include the inherent difficulty in obtaining CNS tissue for biopsy,
the lack of a reliable diagnostic biomarker (e.g. low sensitivity of serum and cerebrospinal fluid
(CSF) ACE in detecting neurological involvement), and the various imaging and clinical
manifestations of neurosarcoidosis that can mimic other disorders such as lymphoma and
neuromyelitis optica (table 2) [2, 15].
For patients presenting with suspected neurosarcoidosis, a variety of diagnostic studies including
MRI and CSF can be helpful in demonstrating inflammation, as noted later. In those with no
prior history of sarcoidosis, which accounts for 50% of cases, histological confirmation from the
affected portion of the nervous system or extraneural source that may also be involved should be
obtained (figure 1) [3]. This necessitates a careful systemic evaluation to assess for extent of
disease and a potential extraneural tissue source for biopsy, especially when the lesion is in the
brain or spinal cord (table 3). For those with known systemic sarcoidosis, histological
confirmation of the affected neural tissue is not as critical, but every effort should be made to
exclude disorders that present with similar clinical and imaging findings. In particular,
evaluation for infections such as fungal meningitis or tuberculosis should be performed, given
the immunocompromised state of many of these patients.
In 2018, the Neurosarcoidosis Consortium Consensus Group, which consists of neurologists and
pulmonologists, developed a new consensus diagnostic criteria for neurosarcoidosis that built
upon the criteria originally published by ZAJICEK et al. [44] and STERN et al. [45]. As with the
original criteria, the diagnosis of neurosarcoidosis was classified as “definite” when there was
histological confirmation of the affected neural tissue in the appropriate clinical setting (based
on presentation, MRI and CSF findings), “probable” with evidence of systemic/extraneural
involvement and “possible” when there was no histological confirmation or other supportive
evidence (table 4). Updates in the new consensus criteria include the specification of
https://doi.org/10.1183/2312508X.10032020 163
TABLE 2 Differential diagnoses of neurosarcoidosis

Infection
Progressive multifocal leukoencephalopathy (JC virus)
Cryptococcus
Histoplasmosis
Tuberculosis
HIV
Varicella-zoster virus
Neurosyphilis
Listeria
Borrelia (Lyme disease)
Cytomegalovirus
Toxoplasmosis
Whipple disease
Immune mediated
IgG4-related meningeal disease
CNS vasculitis
Granulomatosis with polyangiitis
Common variable immunodeficiency syndrome
Behçet disease
Systemic lupus erythematosus
Vogt–Koyanagi–Harada disease
Lymphocytic hypophysitis
Rosai–Dorfman disease
Malignancy
CNS lymphoma
Carcinomatous meningitis
Leptomeningeal or dural metastases
Meningioma
Glioma
Germ-cell tumours
Demyelinating
Multiple sclerosis
Neuromyelitis optica (Devic disease)
Acute demyelinating encephalomyelitis
Transverse myelitis
CNS: central nervous system. Reproduced and modified from [43] with permission.
granulomatous-type inflammation, addition of electromyography (EMG)/nerve conduction studies

(NCS) to account for PNS involvement and a new subcategory of isolated neurosarcoidosis under
the “definite” classification. This aims to investigate whether isolated disease represents a distinct
clinical entity based on the overall course, response to treatment and prognosis.
Imaging studies
Gadolinium-enhanced MRI is the most important diagnostic study for the evaluation of CNS
sarcoidosis. A wide range of imaging manifestations may be seen intracranially that include
nonspecific periventricular white-matter lesions (most common but typically have no clinical
correlate), enhancement/thickening of cranial nerves or basal neuroendocrine structures, and a
gadolinium-enhancing intraparenchymal mass lesion [46–48]. The most characteristic finding is
leptomeningeal enhancement with a basilar predominance that often has a patchy, nodular
appearance on MRI (figure 2) [46, 47]. Dural enhancement may accompany the leptomeningeal
findings but can occur in isolation, in which case it may have a smooth, thickened appearance.
Patchy and nodular meningeal enhancement may also be seen in patients with spinal-cord
164 https://doi.org/10.1183/2312508X.10032020
Neurological manifestations
suggestive of neurosarcoidosis
• Neurological examination
• MRI CNS axis PNS involvement confirmed
• EMG for PNS involvement
• CSF analysis
Nerve or muscle biopsy

CNS involvement confirmed
Systemic Negative Positive

sarcoidosis Look for alternative Definite
present? diagnoses neurosarcoidosis
Yes No
Alternative Systemic evaluation
diagnoses excluded (see table 3)
No Yes Positive Negative

Probable Neural biopsy
neurosarcoidosis
(consider neural
biopsy if low risk and
lesion accessible)
Negative Positive
Look for Definite
alternative neurosarcoidosis
diagnoses (isolated)
FIGURE 1 Diagnostic algorithm for neurosarcoidosis. CNS: central nervous system; EMG: electromyography; PNS:
peripheral nervous system; CSF: cerebrospinal fluid. Reproduced and modified from [43] with permission.
TABLE 3 Systemic evaluation for sarcoidosis

First tier
Serological studies
Comprehensive metabolic profile
Complete blood count
ACE
Soluble IL-2 receptor level
Chest imaging: HRCT
Pulmonary function testing
Ophthalmological evaluation
Skin survey
Tuberculin skin test or IFN-γ assay for Mycobacterium tuberculosis
ECG
Second tier
CT of the body with biopsy of abnormal tissue suggestive of sarcoidosis
Bronchoscopy or EBUS-TBNA
18
F-FDG PET of the body
https://doi.org/10.1183/2312508X.10032020 165
TABLE 4 Consensus diagnostic criteria for central nervous system (CNS) and peripheral nervous system (PNS)
neurosarcoidosis
Possible 1) The clinical presentation and diagnostic evaluation suggest neurosarcoidosis, as defined by the
clinical manifestations and MRI, CSF and/or EMG/NCS findings typical of granulomatous
inflammation of the nervous system and after rigorous exclusion of other causes.
2) There is no pathological confirmation of granulomatous disease.
Probable 1) The clinical presentation and diagnostic evaluation suggest neurosarcoidosis, as defined by the
inflammation of the nervous system after rigorous exclusion of other causes.
2) There is pathological confirmation of systemic granulomatous disease consistent
with sarcoidosis.
Definite 1) The clinical presentation and diagnostic evaluation suggest neurosarcoidosis, as defined by the
inflammation of the nervous system after rigorous exclusion of other causes.
2) The nervous system pathology is consistent with neurosarcoidosis:
Type a: extraneural sarcoidosis is evident.
Type b: no extraneural sarcoidosis is evident (isolated CNS sarcoidosis).
CSF: cerebrospinal fluid; EMG: electromyography; NCS: nerve conduction studies. Reproduced and modified
from [45] with permission.
sarcoidosis, which helps to distinguish it from multiple sclerosis. Another characteristic of

spinal-cord sarcoidosis is extension of the lesion over three or more vertebral levels, similar to
neuromyelitis optica [49]. The presence of gadolinium enhancement typically indicates active or
ongoing inflammation and is an important finding that can help guide management of the
patient with neurological involvement.
FIGURE 2 Nodular gadolinium enhancement of the meninges seen on brain MRI (coronal view; arrows) of a
patient with neurosarcoidosis.
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Imaging studies may also be helpful in the evaluation of sarcoidosis myopathy. 18F-FDG PET
may show increased uptake in affected muscles, indicating active inflammation. MRI may
demonstrate findings of inflammation characterised by increased signal intensity on T2 and
short TI inversion recovery images, muscle atrophy and fatty degeneration [50]. While imaging
studies are not routinely part of the neuropathy evaluation, MRI may demonstrate gadolinium
enhancement and/or enlargement of the affected nerve roots or plexus.
CSF
Although CSF analysis may help to establish the presence of inflammation and exclude other
potential disorders, there are no CSF abnormalities specific for neurosarcoidosis. Elevated CSF
protein is the most common finding, followed by pleocytosis. Oligoclonal bands and elevated
IgG indices may also be seen. Hypoglycorrhachia (defined as a CSF glucose level of 40 mg·dL–1
or <40% of serum glucose) occurs in 25–31% of patients and is also nonspecific, but this
finding is rarely seen outside infectious and carcinomatous meningitis, and in the proper clinical
context may point toward neurosarcoidosis [51]. In up to one-third of cases, however, the CSF
can be normal [52, 53].
A number of CSF biomarkers have recently been described as potential diagnostic tools that
may correlate with disease activity and/or help to distinguish neurosarcoidosis from mimickers
such as multiple sclerosis, CNS vasculitis and other inflammatory neurological disorders. These
include S100 calcium-binding protein B, CD4/CD8 ratio, serum amyloid A protein, IL-6 and
soluble IL-2 receptor levels. CSF ACE is an insensitive marker that is elevated in 25–35% of
patients, and in one series (n=27) was not observed in any of the patients [4].
Serological studies
Serological studies are used to evaluate for evidence of systemic disease or other possible
diagnoses, but there are currently no serum diagnostic markers for neurosarcoidosis. Elevated
serum ACE is seen in 30–40% of cases, can be affected by genetic polymorphisms and does
not correlate with disease activity [2, 54]. In patients with sarcoidosis myopathy, creatinine kinase
levels may be normal or elevated, and can fluctuate throughout the course of the disease [55].
EMG and muscle/nerve biopsy

EMG is used to diagnosis muscle and large nerve fibre involvement in sarcoidosis patients. The
pattern of abnormalities, however, is nonspecific for sarcoidosis and may be seen with
myopathy or neuropathy due to other causes. Thus, histological confirmation of the affected
tissue or evidence of systemic disease is still required for a definite or probable diagnosis of
peripheral neurosarcoidosis, respectively. Fortunately, in most cases, the affected muscle and
nerve are readily accessible for biopsy. The underlying pathophysiology, as with CNS
neurosarcoidosis, is granulomatous inflammation, with some cases demonstrating perivasculitic
inflammation on biopsy.
In cases of sarcoidosis neuropathy, biopsy of both muscle and nerve tissue increases the
diagnostic yield as granulomas between muscle fibres tend to be larger and more developed
than those found within the epineurium or endoneurium [16, 17, 56]. For those with distal
involvement, the superficial peroneal nerve and peroneus brevis may be obtained via a single
incision.
SFN testing
Various diagnostic modalities have been described, none of which is sensitive enough to
definitively diagnose or exclude SFN. Although a number of patient questionnaires may be used
https://doi.org/10.1183/2312508X.10032020 167
to characterise neuropathy, the SFN screening list was specifically developed and validated for
SSFN [57, 58]. The minimal important difference was determined to interpret a clinically relevant
change in score, making it useful for follow-up in clinical practice and research studies [59].
Diagnostic modalities can be divided into nerve-fibre quantification (e.g. skin biopsy with
intraepidermal nerve-fibre density (IENFD) evaluation), sensory testing and autonomic function
tests (table 5). The most commonly used tests for SSFN are described in this section. In
addition, NCS may be performed to exclude large-fibre involvement [37].
Although there is currently no gold standard, skin biopsy with evaluation for IENFD, axonal
swelling or nerve-fibre branching is one of the most widely used tests for diagnosing SFN [60].
The reported sensitivity and specificity of skin biopsy are high but seem to be lower in
sarcoidosis patients due to the patchy, nonlength-dependent distribution, which results in limited
sampling. Therefore, a normal skin biopsy in sarcoidosis does not exclude SFN [37].
Furthermore, skin biopsy results inconsistently correlate with clinical manifestations [61, 62].
Corneal confocal microscopy is a promising noninvasive technique that quantifies corneal
nerve-fibre density, which in early reports has been found to correlate with neuropathy severity
and IEFND, although further studies are needed [63–65].
Quantitative sensory testing is a simple but time-consuming technique that consists of various
modalities. The most common is the temperature threshold test, which has a sensitivity of 69%
in sarcoidosis patients [22, 66, 67].
Quantitative sudomotor axon reflex testing is a sudomotor function test that measures evoked
local sweat production and may complement the skin biopsy findings in SSFN but can be
technically difficult to perform [35, 68]. Cardiovascular autonomic function tests with tilt-table
testing display low sensitivity and specificity but may be considered in patients with prominent
TABLE 5 Diagnostic testing for small-fibre neuropathy
Diagnostic test Measurement
Sensory testing
Quantitative sensory testing (multiple Detection threshold of vibratory, thermal, pain and other
modalities) sensory stimuli
Pain-related evoked potentials Latency of pain-evoked cerebral potentials (Aδ-fibre stimulation)
Laser-evoked potentials Latency of laser heat-evoked cerebral potentials (Aδ-/C-fibre
stimulation)
Contact-heat-evoked potentials Latency of heat-evoked cerebral potentials (Aδ-/C-fibre stimulation)
Nerve-fibre density quantification
Skin biopsy Intraepidermal nerve-fibre density
Corneal confocal microscopy Corneal nerve-fibre density
Autonomic function
Cardiac scintigraphy with 123I-MIBG Myocardial sympathetic nerve function
Quantitative sudomotor axon reflex Sweat output and latency
test
Sudoscan Electrochemical skin conductance
Tilt-table testing with cardiovagal Heart rate, blood pressure
manoeuvres
Thermoregulatory sweat test Pattern of sweating
MIBG: metaiodobenzylguanidine.
168 https://doi.org/10.1183/2312508X.10032020
cardiac symptoms [69]. Cardiac scintigraphy with 123I-metaiodobenzylguanidine (MIBG) also

assesses cardiac autonomic function. Reduced 123I-MIBG uptake in the myocardium, regional
defects or a higher washout of 123I-MIBG correlate with myocardial sympathetic dysfunction [21].
Treatment
Granulomatous neurological disease
As there are no randomised clinical trials for the treatment of neurosarcoidosis,
immunosuppressive management is based largely on anecdotal reports, small case series and
studies of treatments used for systemic disease. Choice of medication is also dependent on the
location and extent of neurological involvement, although corticosteroids remain the first-line
therapy. For most patients with isolated facial palsy, monotherapy with oral corticosteroids (0.5–
1 mg·kg–1·day–1) is adequate. An i.v. pulse dose of methylprednisolone of 500–1000 mg·day–1
for 5 days followed by maintenance therapy with oral corticosteroids may also be considered for
those with acute CNS or PNS disease. Second-line therapeutic agents include MTX,
azathioprine, hydroxychloroquine and MMF. However, MMF has been shown to be inferior to
MTX in two series [51, 70] and was found to have less efficacy in CNS disease compared with
other medications [51, 71]. The use of leflunomide, which may be helpful in pulmonary
sarcoidosis, is limited in neurosarcoidosis by the potential for peripheral nerve toxicity.
Third-line agents include cyclophosphamide, which may be helpful in refractory cases, and
rituximab, an anti-CD20 B-cell monoclonal antibody. Rituximab has also been shown in a few
small case series and case reports to be beneficial in neurosarcoidosis [15, 51].
In recent years, TNF-α antagonists, specifically infliximab (IFX), have emerged as one of the most
promising therapeutic agents in neurosarcoidosis and are supported by a growing amount of data
demonstrating their efficacy and rapidity of action. In six retrospective studies involving nearly 200
patients with neurosarcoidosis, clinical improvement was reported in 71–89% within the first
6 months of initiating IFX. [2, 4, 51, 72–74]. Furthermore, in 14 out of 24 series and case reports,
improvement was seen in the first three treatments [2, 51, 73–75]. While doses vary, treatment
every 4 weeks (compared with every 6–8 weeks) is increasingly being used based on the half-life
of IFX and higher relapse rates seen with longer intervals between doses [51, 73]. Complication
rates of 10–39% have been reported and were mainly related to infection [2, 73, 74].
The use of IFX biosimilars has been reported in two retrospective series, both of which
demonstrated relapses or progression of disease in <6 months of switching from the IFX
originator in two out of eight [76] and four out of four [72] patients. The reason for this is
unclear but may be related to less CNS bioavailability of the biosimilar [72]. Side-effect profiles
were similar. Further studies are needed to support the use of biosimilars in neurosarcoidosis.
Other promising therapies for neurosarcoidosis include tocilizumab, an anti-IL-6 receptor

monoclonal antibody, which was reported to be beneficial in a case report [77]. Tofacitinib, a
Janus kinase inhibitor typically used for rheumatoid arthritis, has shown efficacy in cutaneous
and multiorgan sarcoidosis, but its use in neurosarcoidosis has not yet been reported [78, 79].
The overall prognosis of neurosarcoidosis is dependent on the treatments used and the extent of
neurological involvement. While clinical remission has been described in 70–89% of patients
[2, 73, 80], more recent studies have demonstrated relapse rates of 31–56% on discontinuation
of therapy, with CNS lesions commonly recurring in the same area [72–74]. Optimal duration
of treatment is currently unknown, but for those with CNS involvement, the use of
immunosuppressants such as IFX for ⩾2 years may be considered, given the high relapse rates
https://doi.org/10.1183/2312508X.10032020 169
reported during this time period. Finally, mortality rates in neurosarcoidosis obtained from two
recent retrospective studies were 11% and 18%, with a median follow-up of 8 years and
32 months, respectively [71, 81]. The most common causes of death included sepsis and
neurosarcoidosis [71, 81].
SFN
Treating SSFN is challenging, as no specific treatment has yet been approved. In selected cases,
IVIG, TNF-α inhibitors or ARA-290 (Cibinetide) may be an option, but further clinical trials
are needed before these drugs can be indicated for use in SSFN.
In a retrospective case series involving 115 patients with SSFN, IVIG was found to be effective
in up to 75% of patients [35]. However, these results are limited by the absence of a defined
standard for assessing treatment response, patient selection bias, differences in concomitant
treatment regimens and lack of a placebo group.
TNF-α has been found in high concentrations in skin biopsies of patients with length-dependent
SFN and is known to reduce mechanical nociceptive thresholds [28, 32]. In SSFN, TNF-α
inhibitors can be effective in reducing symptoms [34, 36]. In a retrospective cohort study, the
use of IFX reduced symptoms in ∼70% of SSFN patients (n=26), although the magnitude of the
effect is difficult to ascertain from the available data [35].
Another potential treatment for SSFN is ARA-290 (Cibinetide), an erythropoietin derivative that
activates the innate repair receptor, which is involved in anti-inflammatory pathways and tissue
repair [82–84]. Three randomised, double-blind controlled trials have shown beneficial effects
after 28 days of ARA-290 in reducing SFN-associated symptoms and increasing IENFD and
corneal nerve-fibre area in SSFN, although a reduction in corneal nerve-fibre area was seen after
discontinuation [85–87].
Supportive therapies
Treatment of chronic pain due to SSFN, headache and other affected areas is essential to
improving quality-of-life issues for patients with sarcoidosis. As no specific treatment for SSFN
has yet been approved, treatment is generally symptomatic, consisting of medications such as
antidepressants (tricyclic: amitriptyline and nortriptyline; serotonin–norepinephrine reuptake
inhibitors: duloxetine and venlafaxine), anti-epileptics (gabapentin and pregabalin) and topical
analgesics [88–90]. Unfortunately, these drugs only provide partial pain relief, have little to no
effect on autonomic dysfunction and are often associated with side-effects. Headache treatment is
focused on avoidance of medication overuse, proper sleep hygiene and abortive medications, such
as triptans or calcitonin gene-related peptide antagonists for headaches with migrainous features.
Nonsteroidal anti-inflammatory drugs or hot/cold compresses may be used for tension headaches.
Conclusion
The neurological complications of sarcoidosis are challenging to diagnose and treat.
Granulomatous manifestations of neurosarcoidosis can result in significant deficits that are
apparent on imaging studies and neurological examination, but tissue diagnosis is sometimes
not feasible. Similarly, nongranulomatous manifestations that greatly affect quality-of-life issues
are often reported by patients but are not readily evident on routine diagnostic testing.
Fortunately, increased recognition of these clinical presentations along with specific patterns on
MRI, the emergence of CSF biomarkers, updated diagnostic criteria and new tests for SFN can
help clinicians better identify these neurological complications in sarcoidosis patients and
provide optimal management options.
170 https://doi.org/10.1183/2312508X.10032020
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Disclosures: J. Tavee reports that in 2014–2015 she was part of a pharmaceutical research trial for Araim
Pharmaceuticals evaluating the use of cibenitide in sarcoidosis small-fibre neuropathy and received travel funds
for presentation from the pharmaceutical company. M. Voortman has nothing to disclose.
https://doi.org/10.1183/2312508X.10032020 173
Chapter 12
Cutaneous sarcoidosis
Christina Murphy1,5, Joaquim Marcoval2,5, Juan Mañá3,6 and Misha Rosenbach4,6
1
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 2Dept of Dermatology, Hospital
Universitari de Bellvitge, Barcelona, Spain. 3Dept of Internal Medicine, Clínica Corachan and Clínica Sagrada
Familia, Barcelona, Spain. 4Dept of Dermatology and Internal Medicine, University of Pennsylvania, Philadelphia,
PA, USA. 5These authors contributed equally. 6These authors contributed equally.
Corresponding author: Misha Rosenbach (Misha.Rosenbach@pennmedicine.upenn.edu)
Cite as: Murphy C, Marcoval J, Mañá J, et al. Cutaneous sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds.
2312508X.10032120].
@ERSpublications
Cutaneous involvement is present in one-quarter of patients with sarcoidosis. It may be the initial
manifestation, the most impacted organ or a site amenable for diagnostic biopsy. Recognition and
management of skin sarcoidosis is essential. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Cutaneous involvement is present in one-quarter of sarcoidosis patients. In some patients the skin may
be minimally affected; in others it may serve as a sign of systemic disease activity; and in a subset of
patients, cutaneous sarcoidosis may be the primary manifestation of the disease. Skin disease can be
uncomfortable, disfiguring and have a profound impact on patients and quality of life. Cutaneous
lesions may also serve as readily accessible, low-risk sites for tissue biopsy and histological evidence of
granulomatous disease, and the ability to recognise and diagnose sarcoidosis in the skin is essential for
all clinicians caring for patients with the disease.
The skin is affected in up to 30% of patients with systemic sarcoidosis, making it the most
commonly affected organ after the lungs [1, 2]. Cutaneous lesions are often the initial
presenting symptom, and therefore it is critical to identify them: a study of 41 individuals with
systemic sarcoidosis involving the skin found that 87.5% initially presented with cutaneous
lesions [3]. Cutaneous sarcoidosis can arise at any point relative to internal organ involvement
and may remain the primary impact of the disease.
Historical background
The first description of cutaneous sarcoidosis was reported in 1869 by the British dermatologist
Jonathan Hutchinson, who described a patient with chronic purplish skin lesions. He used the
eponym “Mortimer’s malady” to describe the disease of his most famous patient: a woman in
her sixties who presented with raised, dusky red lesions of her forearms and face [4]. In 1889,
the French dermatologist Ernest Besnier introduced the term lupus pernio. By 1900, Norwegian
dermatologist Caesar Boeck had first described the histopathology of these cutaneous lesions,
characterised by the presence of noncaseating granulomas and the absence of micro-organisms.
He coined the term “sarkoid” to describe the benign, sarcoma-like appearance of the lesions.
Boeck was the first to establish the multiorgan nature of the disease in a case series reporting
involvement of lung, conjunctiva, bone, lymph node and spleen [4]. At the beginning of the
174 https://doi.org/10.1183/2312508X.10032120
CUTANEOUS SARCOIDOSIS | C. MURPHY ET AL.
20th century, Jorgen Schaumann, a Swedish dermatologist, drew further attention to the
systemic nature of the disease [4]. Over the years, it became apparent that sarcoidosis could
affect other organs without involving the skin, and that granulomatous skin lesions appeared
only in some patients. In the 1950s, Sven Löfgren reported an additional manifestation of acute
sarcoidosis, namely erythema nodosum: a nongranulomatous skin lesion characterised
histopathologically by panniculitis, which, combined with bilateral hilar adenopathy, is now
known as Löfgren syndrome [5]. Both specific granulomatous lesions and erythema nodosum
may coexist in the same patient [6].
Epidemiology
Incidence and prevalence
Sarcoidosis affects people of all ages, sexes, racial identities, ethnicities and regions of the world,
although the incidence varies widely [7, 8]. Sarcoidosis seems to be most prevalent in developed
countries, ranging from 10 to 40 per 100 000 in the United States and Europe [9, 10]. Disease
prevalence varies by region, from 1–5 per 100 000 in Japan [11], South Korea [12] and Taiwan
[13] to between 120 and 160 per 100 000 in Canada [14], Sweden [15] and Switzerland [16].
These observed geographical differences in disease burden can be informative, and potentially
lend insight into risk factors for disease, although they should be examined carefully as
information is missing for certain regions of the world and varied data collection methods may
preclude direct comparison [17]. Sarcoidosis occurs at all ages, but it is more frequent in young
and middle-aged adults with a peak age at diagnosis in men at 30–50 years and at 50–60 years in
women. It is less common in elderly people and is rare in children [17]. Sarcoidosis is slightly
more common in women than in men [17]. In the subpopulation with Löfgren syndrome there is
a clear predominance in white women [18, 19]. In the United States, sarcoidosis has been shown
to be particularly common in African Americans, with an annual incidence of 35.5 per 100 000,
while for white Americans the annual incidence is 10.9 per 100 000 [1].
In addition, there is significant heterogeneity in disease presentation and course. African

Americans and Asian Indians usually have more severe disease at diagnosis [1, 20], while
asymptomatic cases and Löfgren syndrome are more common in Caucasians [21, 22]. Black
Americans are more likely to have chronic cutaneous sarcoidosis [1], and experience poorer
overall outcomes as indicated by age-adjusted, disease-specific mortality [1, 23, 24]. Reported
prevalence is lower in other populations of African descent, such as those studied in the West
Indies and West Africa [25, 26], suggesting that the relatively high disease incidence in Black
Americans cannot be attributed to genetics or ancestry alone.
The frequency of specific (granulomatous) skin lesions in sarcoidosis ranges from 9% to 37%,
depending on the series [2, 6]. Specific cutaneous lesions are usually an early disease
manifestation. In a Spanish study, granulomatous cutaneous lesions were present in 86 (17%) of
a series of 507 patients with sarcoidosis [27]. There was cutaneous involvement prior or
simultaneous to the diagnosis of systemic sarcoidosis in 80% of the patients, while it appeared
during follow-up in 20% [27]. The presence of granulomatous cutaneous involvement prompts
the need to assess for the potential presence of systemic sarcoidosis. While sarcoidosis is
typically a multiorgan disease, the evolving concept of isolated organ-specific sarcoidosis
suggests that there may be a subset of patients with cutaneous-only sarcoidosis [28].
Risk factors
It is hypothesised that sarcoidosis develops due to a combination of environmental antigens,
genetic susceptibility and a dysregulated immune system [8]. Genetic susceptibility is an
https://doi.org/10.1183/2312508X.10032120 175
important risk factor for disease, as evidenced by genome-wide association studies of HLA
class II alleles, disease-associated genetic polymorphisms and familial aggregation studies [29].
The association of HLA-DQB1 and HLA-DRB1 with the risk of developing sarcoidosis has
been confirmed by various studies [29, 30]. Some HLA allele variants have even been linked to
specific disease phenotypes, such as HLA-DRB1 with the development of diastolic dysfunction
[31] and Löfgren syndrome [21]. Non-HLA genes associated with sarcoidosis include ANXA11,
BTNL2, CCR5, COX2 and NOTCH4, and some are enriched within certain ethnic groups [29].
Because of the tendency for sarcoidosis to involve organs exposed to the environment, such as
the lung, eyes and skin, an environmental cause for sarcoidosis has been suspected. Seasonal
outbreaks also support this possibility [32]. Multiple environmental agents have been reported
to confer increased risk of sarcoidosis, including exposure to tree pollen, inorganic particles,
insecticides and moulds [33]. Occupational studies have shown associations with US Navy
personnel, metalworking, firefighters and the handling of building supplies [31, 34].
In the case of the skin, it is known that sarcoidosis can develop within previous scars resulting
from surgery or trauma [35], in injection sites of insulin [36], silicone [37], hyaluronic acid [38]
desensitising injections and cosmetic fillers [39], venipuncture points for blood sample
collection [40], tattoos [41] or as a foreign body reaction [42–44]. Interestingly, polarisable
material may be seen in ∼25% of skin biopsies of sarcoidosis, which suggests that foreign
material may act as a nidus for granuloma formation [41–44], although this finding neither
confirms nor excludes sarcoidosis when observed histologically.
Comorbidity
Patients with sarcoidosis suffer from many comorbidities in addition to a high burden of
disease. Sarcoidosis is associated with increased risk of infection [45], congestive heart failure
[45, 46], thromboembolic events [46] and autoimmune disease [14]. A systematic review and
meta-analysis of malignancy risk in sarcoidosis revealed an association with increased risk of
cancers of the blood, skin, upper digestive tract, kidney, liver and colon [47], and the concept of
an increased risk of lymphoma in patients with sarcoidosis (the “sarcoidosis–lymphoma
syndrome”) has existed for decades [48]. The ability to attribute excess risk to sarcoidosis is
confounded by the prolonged use of steroids and other systemic treatments and increased
healthcare utilisation.
Furthermore, sarcoidosis has been reported coexisting with other skin diseases such as
cutaneous lymphoma, vitiligo and alopecia areata [49]. There are numerous small studies
indicating a potential increased risk of both melanoma and nonmelanoma skin cancers in
patients with sarcoidosis [50, 51].
Aetiopathogenesis
Granulomas form when macrophages and T-lymphocytes aggregate to defend against a
particulate antigen presented to the immune system that cannot be eliminated by individual
immune cells. It is hypothesised that sarcoidosis represents a group of diseases [52], with a
variety of environmental or infectious agents that may induce the antigen-presenting cells to
produce high levels of TNF-α and to present these antigens to CD4+ T-cells. Cutibacterium
acnes (formerly Propionibacterium acnes), mycobacterial infections, misfolded self-protein,
accumulation of serum amyloid A and organic or inorganic ambient molecules all may serve as
potential antigens in pathogenesis, although a disease-specific aetiology has yet to be identified
[8, 53–55].
176 https://doi.org/10.1183/2312508X.10032120
Presentation of such antigens to CD4+ Th cells sets off a Th1-predominant immune response
through secretion of IFN-γ and IL-2, including Th cells differentiating into Th1 and Th17.1
effector cells that produce IFN-γ and IL-17. As a result, macrophages aggregate and evolve into
epithelioid cells, which secrete mediators important to granuloma maintenance, including
pro-inflammatory cytokines such as TNF-α, IL-12, IL-18 and IL-6, and regulatory cytokines,
such as TGF-β and IL-10, which are upregulated in affected tissues. IFN-γ activates
macrophages and induces transformation into giant cells, while TNF-α induces differentiation
into epithelioid cells. It is postulated that IFN-γ inhibits apoptosis in macrophages through the
expression of high levels of P21, which leads to granuloma perpetuation [56]. TNF-α is
considered the main cytokine in the development and maintenance of the granuloma, and the
cause of pulmonary fibrosis by stimulating fibroblast proliferation and collagen synthesis [57].
Clinical presentations
Cutaneous findings are varied, and the clinical appearance of cutaneous findings may differ
based on chronicity and patient skin colour. “Specific” sarcoidosis findings are defined by the
presence of noncaseating epithelioid cell granulomas on histology, while “nonspecific” lesions
lack granuloma formation; the most common nonspecific manifestation is erythema nodosum.
Sarcoidosis can present with many different clinical morphologies and mimic numerous disease
processes, so clinicians should maintain a high index of suspicion when evaluating patients with
possible sarcoidosis. The skin is a readily accessible site for biopsy to obtain histological
confirmation of granulomas.
Specific cutaneous sarcoidosis findings, common and uncommon

Specific cutaneous lesions present with both common and uncommon morphologies. Common
morphologies of specific findings include papules (figure 1), plaques (figure 2), subcutaneous
nodules (figure 3) and lupus pernio (figure 4), along with scar- (figure 5) or tattoo-associated
disease (figure 6). Uncommon morphologies include ichthyosiform sarcoidosis (figure 7),
hypopigmented (figure 8), verrucous and sometimes psoriasiform or lichenoid disease. Rare
manifestations include erythroderma, or involvement of other sites such as mucosal, alopecic
and nail sarcoidosis.
FIGURE 1 Papular sarcoidosis: flesh-coloured papules on the forehead.
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FIGURE 2 Plaque sarcoidosis: pink to violaceous indurated dermal plaque on the deltoid arm.
Phenotypes of prognostic significance

Distinct clinical presentations may predict prognosis, pattern of disease or response to treatment.
Therefore, certain disease phenotypes carry clinical implications for evaluation and
management.
Lupus pernio is a clinical variant of plaque sarcoidosis that presents with brown to violaceous or
erythematous smooth, shiny plaques, some with associated scale. Lesions are distributed on the
head and neck, particularly the nose and central face. Lupus pernio portends a more chronic,
recalcitrant course that may require a specific treatment strategy with systemic drugs such as
TNF inhibitors [27, 58].
Lesions of the nose can be incredibly disfiguring, and even infiltrate the nasal mucosa and
septum, causing collapse of the nasal bridge, as seen in granulomatosis with polyangiitis.
Sarcoid involvement of the sinuses and upper airway is common in patients with lupus pernio
and patients may require referral to otorhinolaryngology.
Löfgren syndrome or acute sarcoidosis is the clinical tetrad of erythema nodosum, hilar
adenopathy, migratory polyarthralgia and fever with acute onset. Löfgren syndrome is associated
with favourable long-term prognosis, although patients can experience severe symptoms initially
[59]. Management is typically with nonsteroidal anti-inflammatory drugs or steroids when
necessary, and disease often resolves within 2 years. Chronic sarcoidosis is less common
following an initial presentation with Löfgren syndrome phenotype.
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FIGURE 3 Subcutaneous sarcoidosis develops in the deep dermis and subcutaneous fat, and can be hard to
appreciate in photographs. Here, the deltoid and upper abdomen have flesh-coloured subcutaneous nodules.
Nonspecific cutaneous sarcoidosis findings

Nonspecific cutaneous findings related to sarcoidosis include erythema nodosum, calcinosis
cutis, clubbing, erythema multiforme and prurigo. Sweet syndrome has been reported rarely
with sarcoidosis [60]. Other cutaneous findings may result from therapy, such as corticosteroids
inducing acne and TNF inhibitors causing psoriasis.
Erythema nodosum is a reactive inflammatory panniculitis that presents as tender, red

subcutaneous nodules of the anterior legs. It is the most common nonspecific manifestation of
cutaneous sarcoidosis, developing in >20% of patients [2]. Erythema nodosum is associated
with Löfgren syndrome, and has a good prognosis [61]. It is relatively more common in people
with Scandinavian ancestry and is rare in Black Americans [1].
Histopathology
The histopathologic finding of noncaseating granulomas in the appropriate clinical setting is key to
diagnosing sarcoidosis and excluding mimics. Punch or incisional biopsy has better diagnostic yield
than shave biopsy. When noncaseating granulomas are reported on histopathological examination,
it is important to exclude diseases with similar histology and clinical presentation [62].
Noncaseating epithelioid granulomas of sarcoidosis are termed “naked granulomas”, as they

typically lack surrounding lymphocytic inflammation. Multinucleated giant cells are seen within
https://doi.org/10.1183/2312508X.10032120 179
FIGURE 4 Lupus pernio: extensive papules and plaques infiltrating the nose.
the granuloma and can contain cytoplasmic inclusions such as eosinophilic asteroid bodies or
calcified Schaumann bodies [63]. Although naked granulomas classically lack lymphoid and
fibrinoid necrosis, these features do not exclude the diagnosis of sarcoidosis if present [59, 63].
Noncaseating granulomas are not specific to sarcoidosis. The histological differential diagnosis
includes tuberculoid leprosy, cutaneous Crohn disease, Melkersson–Rosenthal syndrome,
FIGURE 5 Scar-associated sarcoidosis: sarcoidosis papules and plaques developing at sites of repeated
phlebotomy and peripheral intravenous access sites.
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FIGURE 6 Tattoo involvement is common in sarcoidosis, but can range from subtle to severe. Tattoo sarcoidosis
can involve any pigment, and usually shows up as papules, which may have some scaling.
granulomatous rosacea, specific immunodeficiency disorders and silica, beryllium and

zirconium granulomas [64]. Foreign body reactions and fungal infections can also reveal
noncaseating granulomas on histopathology. Specimens should be stained for micro-organisms,
and tissue culture may be considered. Examining slides under polarised light can identify a
foreign body, although their presence does not exclude sarcoidosis [42–44].
Evaluation
Differential diagnosis
Sarcoidosis is one of the great imitators and is a diagnosis of exclusion by histology, radiology,
laboratory evaluation and clinical examination. The differential diagnosis for cutaneous
sarcoidosis is broad. Entities to consider along with sarcoidosis include granulomatous
secondary syphilis, granulomatous mycosis fungoides, Blau syndrome, as well as granulomatous
diseases such as granuloma annulare, necrobiosis lipoidica and necrobiotic xanthogranuloma.
Workup
A workup for systemic sarcoidosis should be undertaken in all patients with cutaneous disease
[6, 65–68]. The major organs routinely assessed are the lungs, eyes, liver and heart, with assays
for hypercalcaemia. Basic assessment should include a general history, physical examination, chest
radiograph, pulmonary function tests, electrocardiogram, assay for tuberculosis (QuantiFERON-TB
Gold In-Tube assay or tuberculin skin test), ophthalmologic examination and routine laboratory
tests, including calcium levels.
In some cases, additional investigations may be helpful to establish the diagnosis and extent of
sarcoidosis. Thoracic CT is useful to confirm the presence of suspected parenchymal or
mediastinal involvement or atypical radiological findings on the chest radiograph [69]. Cardiac
https://doi.org/10.1183/2312508X.10032120 181
FIGURE 7 Ichthyosis: sarcoidosis can occasionally present with an acquired ichthyosis, resembling dry
fish-scales, usually on the lower leg. Biopsy will demonstrate sarcoidal granulomas, differentiating this from the
acquired ichthyosis of lymphoma or HIV.
involvement is better assessed by cardiac MRI and cardiac PET [70], and some cases may
require electrophysiological evaluation. MRI of the central nervous system is the best tool for
the suspicion of neurosarcoidosis [71]. Apart from the assessment of cardiac sarcoidosis, 18F-FDG
PET may be useful for assessing disease activity, extent and response to treatment [72]. However,
a positive 18F-FDG PET/CT finding alone is not an indication for treatment [73].
The diagnosis of sarcoidosis is based on a compatible clinical and radiological picture,

demonstration of noncaseating granulomas with negative cultures for mycobacteria and fungus,
and exclusion of other granulomatous diseases [74]. When sarcoidosis is suspected, cutaneous
examination is important, as a skin biopsy showing granulomas may avoid more invasive
sampling. In the A Case Control Etiologic Study of Sarcoidosis (ACCESS) study, the skin was
the second most commonly biopsied organ after the lung [75]. In addition, in ACCESS, the
presence of skin sarcoidosis often allowed a more rapid diagnosis than in patients with
pulmonary or other organ involvement [75]. Conversely, some clinical and radiological pictures,
such as Löfgren syndrome, are so typical of sarcoidosis that histological confirmation is not
necessary [18].
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FIGURE 8 Hypopigmented sarcoidosis: sarcoidosis can present with pink, red, violaceous, flesh-toned or
occasionally hypopigmented lesions, as shown here.
If systemic sarcoidosis cannot be demonstrated, a long-term follow-up should be undertaken, as

some cases will progress to develop systemic involvement [6, 76]. Other cases will continue to
show no clinical or radiological evidence of the disease elsewhere. By definition, the diagnosis
of sarcoidosis requires involvement of at least two organ systems [59], and so some authors
classify these lesions as local sarcoid-like cutaneous granulomatous disease [77]. However,
since skin lesions in sarcoid-like reactions and in true multiorgan sarcoidosis are clinically and
histologically indistinguishable, other authors suggest that these cases are best considered to be
sarcoidosis limited to the skin [78].
Medication-induced sarcoidosis
Sarcoidosis has been described in association with IFN-α treatment of hepatitis C and
melanoma. It has been suggested that IFN-α increases IFN-γ and IL-2, promoting granuloma
formation [79–84]. The development of cutaneous sarcoidosis as a paradoxical adverse effect of
TNF-α and IL-17 blockers has also been reported [85–90].
More recently, multiple cases of sarcoidosis induced by inhibitors of CTLA-4, PD1–PDL-1 and
BRAF/MEK have been observed. Downregulating peripheral tolerance using anti-CTLA4 or
anti-PD1–PDL-1 antibodies may propagate sarcoidosis inflammation. The association with
BRAF inhibitors could be explained by the increase of TNF-α and IFN-γ during BRAF
inhibition treatment [6, 91]. In a recent study, 22% of patients receiving nivolumab alone or in
combination with ipilimumab developed a sarcoid-like reaction [92]. Additionally, sarcoidosis
has been reported during treatment with vemurafenib for melanoma [93]. It is not mandatory to
stop these drugs, since sarcoidosis may remain stable even when therapy is maintained [91, 92,
94, 95]. Sarcoidosis has been reported to be induced by dendritic cell vaccination
https://doi.org/10.1183/2312508X.10032120 183
immunotherapy in melanoma patients [96] and has been observed in patients treated with
pembrolizumab [97], natalizumab [98] and rituximab [99–101]. It is generally advisable to
consider medication-induced disease when rendering a diagnosis of sarcoidosis, but
management requires balancing the original disease, necessity of the culprit medication,
availability of alternative treatments and severity of the sarcoidosis.
Measuring disease impact

There are no adequate serum markers for disease activity in sarcoidosis; levels of ACE, vitamin
D3, chitotriosidase, adenosine deaminase and others have been studied without clear evidence
of clinical utility [74, 102]. However, clinical assessment tools can be useful to quantify disease
activity and track treatment response. The Cutaneous Sarcoidosis Activity and Morphology
Instrument and the Sarcoidosis Activity and Severity Index have both been studied for this
purpose and can be used in the clinical or research setting [103–106]. Patient-centred and
health-related quality-of-life assessments provide tools for clinicians to assess holistic patient
wellbeing in a standardised way and direct therapy accordingly [107].
Management
Initial therapy should be directed toward the most severely affected organ system; improvement
of cutaneous disease will often follow. If the cutaneous disease is the primary impact,
skin-directed treatments may be considered. Cutaneous sarcoidosis should be treated if severe,
symptomatic, disfiguring or distressing. Therapeutic options include both local and systemic
drugs (table 1). Combination therapy is often utilised. Therapeutic recommendations are based
largely on case series data, limited prospective studies and expert opinion.
A stepwise approach should guide the management of cutaneous sarcoidosis, allowing at least a
3-month trial of therapy before proceeding to another treatment or escalating therapy. The goal
of therapy is to achieve stable, improved disease for a period of ∼6 months before beginning a
taper off medication.
Local therapies
First-line therapy for cutaneous sarcoidosis includes topical and intralesional steroids as well as
steroid-sparing topical agents. Superpotent topical steroids, such as clobetasol and halobetasol,
may be sufficient for mild cutaneous disease [59]. They should be applied twice daily until
lesions resolve. While systemic absorption is minimal, patients should be counselled to avoid
excessive or prolonged use, which can lead to skin atrophy and breakdown.
Intralesional injections of triamcinolone acetonide are also effective and enhance drug delivery
to the dermis where granulomas form, which is especially useful for thicker lesions. Injections
of 2.5–20 mg·mL−1 (or more) at 3–4-week intervals demonstrate efficacy [59]. The
concentration of steroid delivered should be adjusted for the density and size of a lesion,
although it should not exceed a total dose of 40 mg per month due to increased risk of
iatrogenic Cushing disease [108].
Alternative topicals include tacrolimus applied twice daily, or topical retinoids [109, 110].
Recent reports have highlighted potential benefits with compounded off-label topical Janus
kinase ( JAK)-inhibitors [111, 112]. Local procedures may also provide benefit, including
phototherapy and laser therapy [110], although lesions may recur when treatment is stopped.
Notably, lasers can also worsen disease, and should be used cautiously [113].
184 https://doi.org/10.1183/2312508X.10032120
TABLE 1 Treatments for cutaneous sarcoidosis
Typical dosing Indication(s) Comments
Local therapies
Topical corticosteroids Superpotent (class I) First-line May cause skin atrophy,
twice daily hypopigmentation
Use less potent steroids
(class II–VII) depending
on site
Intralesional 2.5–20 mg·mL−1 (or First-line, thick lesions May cause skin atrophy,
corticosteroids more) triamcinolone hypopigmentation
acetonide Dose <40 mg per month due
monthly to risk of iatrogenic
Cushing disease
Topical calcineurin 0.1% tacrolimus Alternative first-line, May be effective even if
inhibitors ointment site-specific steroids are not; less risk
twice daily of atrophy
Less evidence in literature
than topical
corticosteroids
Systemic immunomodulatory therapies
Antimalarials 200–400 mg First-line systemic for Hydroxychloroquine
(hydroxychloroquine, hydroxychloroquine recalcitrant or preferred over chloroquine
chloroquine) 250–500 mg extensive disease (lower risk of ocular
chloroquine daily toxicity)
Requires baseline and
routine ophthalmic exam
Tetracycline antibiotics 100 mg minocycline or First-line systemic for Minocycline supported by
(minocycline, doxycycline recalcitrant or more clinical data, but has
doxycycline) twice daily extensive disease risk of hyperpigmentation
Doxcycyline has frequent
side-effects of nausea,
photosensitivity
Tetracycline-class antibiotics
contraindicated in
pregnancy
Phosphodiesterase-4 20 mg apremilast Chronic cutaneous Pentoxifylline studied mainly
inhibitors twice daily sarcoidosis in the context of
(apremilast, 400 mg pentoxifylline pulmonary sarcoidosis,
pentoxifylline) three times daily but is well tolerated;
exhibits some benefit for
skin disease
Systemic immunosuppressive therapies
Oral corticosteroids 40–80 mg prednisone Internal involvement Higher dose necessary for
daily for 4–6 weeks, internal involvement
followed by slow taper Cutaneous disease may
respond to lower doses
Antimetabolites 7.5–25 mg MTX weekly First-line Folate supplementation,
(MTX) immunosuppressive avoid other hepatotoxic
agents (including alcohol);
requires regular
blood work
Biologics (TNF 40 mg adalimumab Severe, ulcerative, Best evidence to support
inhibitors: weekly refractory disease; adalimumab and
adalimumab, 5 mg·kg−1 infliximab at lupus pernio infliximab
infliximab) weeks 0, 2, 6; then Higher dosing than for
every 4–6 weeks typical dermatological
indications
https://doi.org/10.1183/2312508X.10032120 185
Systemic immunomodulatory therapies

The antimalarial drugs hydroxychloroquine and chloroquine are used as first-line systemic
agents in the treatment of extensive cutaneous disease or recalcitrant local disease. Evidence
supporting the efficacy of antimalarials in sarcoidosis is drawn from small, uncontrolled studies.
A systematic review of study data prior to 2004 found that 82% of patients treated had a
favourable response [114]. Time to response may be slow, and clinicians must be mindful of
dosing and duration of therapy, given the risk of ocular toxicity. Patients should be monitored
with baseline and routine eye examinations.
Tetracycline antibiotics such as minocycline and doxycycline are also used as first-line systemic
treatment for cutaneous sarcoidosis [115, 116]. Minocycline has been shown to be effective in
larger studies, but frequently leads to hyperpigmentation, including within lesions, and most
experts start with doxycycline. A combination antimicrobial regimen of concomitant
levofloxacin, ethambutol, azithromycin and rifampin has been reported to treat chronic
cutaneous sarcoidosis in one study [117].
Pentoxifylline and apremilast are phosphodiesterase-4 inhibitors useful in the treatment of

sarcoidosis. Pentoxifylline has been studied mainly in the context of pulmonary sarcoidosis,
with reported efficacy for concomitant skin involvement [118]. A study of apremilast in 12
patients showed benefit in cutaneous sarcoidosis [119].
Other agents supported by data from case series and reports include isotretinoin, leflunomide
and thalidomide [120–122]. A recent negative double-blind, placebo-controlled study with
thalidomide failed to show benefit, and the advent of newer agents has led to reduced
utilisation [123]. In general, these treatments are not first-line, but may be considered in
recalcitrant disease.
Systemic immunosuppressive therapies

Systemic corticosteroids are often used in the management of pulmonary sarcoidosis and may
be used to treat cutaneous disease. Significant associated morbidity complicates chronic use, so
patients should be maintained on the lowest effective dose [124]. Effective doses range from 40
to 80 mg·day−1 and should be tapered slowly. Steroids may also be administered via repository
corticotropin injection for patients with recalcitrant disease [125].
a) b)
FIGURE 9 a) Extensive lupus pernio with scarring and hyperpigmentation. b) Post-treatment with infliximab
(5 mg·kg−1 dose, week 0, 2 and 6 loading, and maintenance infusions every 6 weeks), with resolution of active
inflammation and improvement in post-inflammatory hyperpigmentation, but residual scarring remains.
186 https://doi.org/10.1183/2312508X.10032120
MTX is used as a first-line immunosuppressive agent for patients who have failed trials of
topical and immunomodulatory treatment. Weekly MTX, from 7.5 to 25 mg weekly, has been
shown to benefit up to 80% of patients [126, 127]. A randomised controlled trial of MTX in
sarcoidosis demonstrated efficacy, although response time was generally ⩾6 months [128].
MMF and azathioprine are alternative steroid-sparing agent in the treatment of sarcoidosis.
However, for patients that did not respond to a trial of MTX, switching to MMF is unlikely to
provide benefit [129, 130]. In general, both agents seem to be less efficacious for skin disease
than for other organ-specific manifestations of sarcoidosis.
TNF inhibitors are beneficial in the treatment of severe, refractory sarcoidosis, including lupus
pernio. Adalimumab and infliximab have the most clinical data to support their use, with
efficacy reported in numerous small studies, including randomised controlled trials [58, 131–
136] (figure 9). Etanercept is generally avoided in the treatment of cutaneous sarcoidosis
because it has been more frequently associated with the development of cutaneous
granulomatous disease [137, 138], and due to a small negative study in lung disease [139].
Golimumab demonstrated a nonsignificant trend towards improvement in skin disease in a study
underpowered to capture cutaneous disease; ustekinumab was ineffective in the same trial [140].
Rituximab has been reported in single cases to be helpful, but is not widely used [141].
Emerging therapies
New therapies are currently under investigation, including evaluation of benefits of nicotine in
the treatment of sarcoidosis [142]. JAK inhibitors have been reported to treat cutaneous
sarcoidosis [112, 143–145] and have been beneficial for other granulomatous diseases [146,
147]. In general, the rapidly emerging data from the use of these agents offers real excitement
about future impacts in sarcoidosis [148].
Conclusion
Sarcoidosis is a multisystem disease, and a significant number of cases involve the skin. It is
valuable to recognise the varied cutaneous manifestations of sarcoidosis as the skin provides
easily accessible tissue for biopsy to help reach a diagnosis. Evaluation for sarcoidosis should
involve a thorough workup that screens for multiorgan involvement. Treatment should be
directed toward the most impacted organ and cutaneous disease may be monitored or treated
specifically. The pathogenesis of cutaneous sarcoidosis is incompletely understood and remains
an active area of investigation. Discoveries in the field will elucidate risk factors for disease,
prognostic indicators and potential drug targets for next-generation therapies.
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Conflict of interest: C. Murphy has nothing to disclose. J. Marcoval has nothing to disclose. J. Mañá has nothing to
disclose. M. Rosenbach reports receiving consulting fees from aTyr Pharma, outside the submitted
work. M. Rosenbach reports having leadership or fiduciary roles in other boards, societies, committees or
advocacy groups, some paid, some unpaid, for the Foundation for Sarcoidosis Research and the Medical
Dermatology Society.
192 https://doi.org/10.1183/2312508X.10032120
Chapter 13
The calcium–kidney–bone axis

Robert P. Baughman and Elyse E. Lower
Dept of Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA.

Corresponding author: Robert P. Baughman (BAUGHMRP@ucmail.uc.edu)
Cite as: Baughman RP, Lower EE. The calcium–kidney–bone axis. In: Bonella F, Culver DA, Israël-Biet D, eds.
2312508X.10032220].
@ERSpublications
Calcium plays a key role in bone health, and abnormalities in calcium metabolism in sarcoidosis can lead to
renal dysfunction and disturbed bone health https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis can lead to abnormal calcium metabolism in up to one-quarter of patients. This can lead to
hypercalcaemia and nephrocalcinosis. Both of these may lead to renal dysfunction. Direct renal
involvement from sarcoidosis occurs in a smaller proportion of patients. Granulomatous interstitial
nephritis has been associated with hypercalcaemia. The interaction between calcium and renal
dysfunction should be evaluated in all sarcoidosis patients as part of their initial evaluation and on a
regular basis as clinically indicated. Bone health in sarcoidosis patients can be impacted by abnormal
calcium metabolism and anti-inflammatory therapy, especially glucocorticoids. Evaluation of the
calcium–kidney–bone axis is an important aspect of the management of sarcoidosis.
Introduction
Several abnormalities of calcium metabolism have been reported in sarcoidosis patients. These
include hypercalcaemia and hypercalciuria [1]. The latter can lead to nephrolithiasis. Renal
disease can be the direct result of hypercalcaemia [2] or granulomatous inflammation in the
kidneys. This chapter will review the mechanism of action, risk factors, treatment and clinical
implications of calcium abnormalities on bone health in sarcoidosis patients. In addition, we
will discuss renal disease occurring independently of abnormalities of calcium metabolism.
Epidemiology of calcium abnormalities

Abnormalities of calcium metabolism have been observed in sarcoidosis centres around the
world. Figure 1 shows the reported prevalence of hypercalcaemia from various centres across
the world [2–8]. In patients with known sarcoidosis, the World Association for Sarcoidosis and
Other Granulomatous Disorders (WASOG) has defined abnormalities of calcium metabolism
as highly probably due to sarcoidosis if hypercalcaemia has occurred plus all of the following:
1) a normal serum parathyroid hormone (PTH) level, 2) a normal or increased 1,25-
dihydroxyvitamin D (calcitriol) level, and 3) a low 25-hydroxyvitamin D level. Sarcoidosis as a
probable cause was defined as hypercalciuria plus all of the following: 1) a normal serum PTH
level, 2) a normal or increased 1,25-dihydroxyvitamin D level, and 3) a low 25-hydroxyvitamin
D level. Sarcoidosis as a possible cause was defined as nephrolithiasis plus all of the following:
1) a normal serum PTH level, 2) a normal or increased 1,25-dihydroxyvitamin D level, and 3) a
https://doi.org/10.1183/2312508X.10032220 193
Charleston black subjects

Charleston white subjects
Cincinnati
Spain
Latvia
Paris
London
Oman
India
0 5 10 15 20 25 30 35
Hypercalcaemia, %
FIGURE 1 Reported prevalence of hypercalcaemia from various centres across the world [2–8].
low 25-hydroxyvitamin D level, OR hypercalciuria without serum PTH and 25-hydroxyvitamin

D and 1,25-dihydroxyvitamin D levels, OR nephrolithiasis with calcium stones, without serum
PTH and 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels. [9]. Around the world, the
prevalence of abnormal calcium metabolism has been reported as >20% of sarcoidosis patients
in India [3], Brazil [10], Latvia [7], Spain [11] and China [12], while in the USA, the reported
prevalence was over three times higher for white versus black patients [12, 13] and the rate of
cases increased over time of observation (figure 2) [14].
The aetiology of hypercalcaemia in sarcoidosis can be multifactorial (discussed later). However,

the major factor leading to hypercalcaemia is increased vitamin D, specifically calcitriol. Early
studies found that seasonal variations of calcium metabolism occur with higher serum calcium
and calcitriol measured during the summer months [15, 16]. Figures 1 and 2 reveal the higher
prevalence of abnormalities of calcium observed in countries with subtropical climates such as
India, Brazil and the Middle East [3, 6, 10] versus countries further from the equator. This was
confirmed in a multinational study that utilised a standardised definition of abnormal calcium
Cincinnati black subjects

Cincinnati white subjects
Shanghai Han
US black subjects at 2 years
US black subjects initial
US white subjects at 2 years
US white subjects initial
Spain
Latvia
India
Brazil
0 5 10 15 20 25 30 35
Abnormal calcium metabolism, %
FIGURE 2 Prevalence of abnormal calcium metabolism from various parts of the world [3, 7, 8, 10, 12–14].
194 https://doi.org/10.1183/2312508X.10032220
CALCIUM–KIDNEY–BONE AXIS | R.P. BAUGHMAN AND E.E. LOWER
metabolism at all sites [17]. In addition, skin pigmentation may impact the risk for increased
calcium as an explanation for increased rates observed for white subjects compared with black
subjects [12, 13]. Increased calcium metabolism was also observed more frequently in men
[7, 8] and in those >40 years of age [13].
Causes of abnormal calcium metabolism in sarcoidosis

The most common reason for abnormal calcium metabolism in sarcoidosis is increased levels of
calcitriol. The source of vitamin D can be from exogenous vitamins or local production in the
skin with exposure to sunlight (cholecalciferol (vitamin D3)) or food (ergocalciferol (vitamin
D2)) (figure 3). These proteins are then hydroxylated in the liver to 25-hydroxyvitamin D. This
precursor form of vitamin D is normally converted in the kidney by 1-α-hydroxylase to
calcitriol. PTH regulates the activity of 1-α-hydroxylase in the kidney [18] and PTH secretion is
regulated by serum calcium levels. In patients with renal failure, 1-α-hydroxylase activity can be
suppressed leading to poor calcium absorption. As a consequence, these patients will develop
secondary hyperparathyroidism to compensate for the low levels of calcitriol.
In sarcoidosis, the macrophages within the granuloma are another source of calcitriol [19, 20].
Increased levels of 1-α-hydroxylase activity in the macrophage can be induced by IFN-γ
[21, 22]. This increased activity of 1-α-hydroxylase is independent of the serum calcium level.
Exogenous 7-dehydrocholesterol Food,

vitamins in the skin e.g. milk
Sun exposure
Ergocalciferol (D2)
Cholecalciferol (D3)
25-hydroxylase in liver
25-hydroxyvitamin D
In non-sarcoidosis conditions:
In sarcoidosis:
1-α-hydroxylase in the kidneys
1-α-hydroxylase in macrophages
Regulated by serum PTH and serum
Regulated by local secretion of IFN-γ calcium
1,25-dihydroxyvitamin D
(calcitriol)
Binds to vitamin D receptors
Biological actions
FIGURE 3 Vitamin D metabolism in health and disease. The source of vitamin D includes diet (e.g. milk), sun
exposure and supplements. Regardless of source, it is converted to 25-hydroxyvitamin D in the liver. Normally,
the enzyme 1-α-hydroxylase metabolises 25-hydroxyvitamin D to calcitriol in the kidney. The activity of
1-α-hydroxylase is regulated by parathyroid hormone (PTH), which responds to serum calcium. In sarcoidosis,
1-α-hydroxylase activity in the granuloma is regulated by IFN. This can lead to excessive serum levels of
calcitriol. Reproduced and modified from [1] with permission.
https://doi.org/10.1183/2312508X.10032220 195
The result of this increased activity may be increased serum levels of calcitriol. In
cross-sectional studies, elevated calcitriol levels were measured in >10% of patients [2, 23],
with subnormal levels of 25-hydroxyvitamin D reported in over half of patients in both studies.
Table 1 displays the clinical course of a hypercalcaemic sarcoidosis patient. This 58-year-old
white male presented in 2019 with asymptomatic hypercalcaemia. At the time, he was taking
25-hydroxyvitamin D supplementation of 50 000 units once a week. One month after stopping
this supplementation, his calcium normalised, and he did not receive anti-inflammatory therapy.
In June of that year, his calcium increased again and he developed worsening renal function.
Other markers of disease activity were noted, including leukopenia and an elevation of his
alkaline phosphatase. He was prescribed daily prednisone and hydroxychloroquine. Within
1 month of systemic therapy, his calcium again normalised but his creatinine remained elevated.
After an additional 2 months of anti-inflammatory therapy, his serum creatinine decreased to
within the normal range. During the winter, he remained healthy, and his prednisone and
hydroxychloroquine doses were tapered. The next summer, his calcium and alkaline
phosphatase again increased, while his white blood count decreased. The patient remained
asymptomatic and the dosage of systemic therapies was unchanged, and so far progression of
his disease has not been noted.
In one study, primary hyperparathyroidism was the cause of abnormal calcium metabolism in
10% of sarcoidosis cases [2]. Hyperparathyroidism can occur before, after or concurrently with
the diagnosis of sarcoidosis [24]. As definitive treatment of hyperparathyroidism is surgical, it is
important to recognise this as a potential cause of hypercalcaemia. Elevated calcitriol can
suppress PTH levels, so serum measurements of calcitriol and PTH can help distinguish
between these two conditions. However, overlap can occur, with some hypercalcaemic patients
exhibiting increased PTH and calcitriol serum levels. Continued follow-up of both potential
markers may uncover a secondary problem [24]. In some hypercalcaemic patients, the serum
calcitriol level may be within the normal range, but anti-inflammatory treatment may improve
renal function. In one report, it was postulated that active granulomas may release calcitriol
locally [25].
TABLE 1 Clinical course of a patient with hypercalcaemic renal failure due to sarcoidosis
Normal 7 2 18 16 17 22
range November December June July September July
2019 2019 2020 2020 2020 2021
Calcium, mg·dL−1 8.6–10.3 11 10.3 12.2 10.1 9.6 10.3

Creatinine, mg·dL−1 0.60–1.30 1.24 1.05 1.54 1.42 1.05 1.13
1,25-dihydroxyvitamin D, 19.9–79.3 77 73
pg·mL−1
25-hydroxyvitamin D, 30.0– 19.4 20.3
ng·mL−1 100.0
PTH, pg·mL−1 12.0–88.0 6 2
Alkaline phosphatase, 36–125 200 159 414 183 161 217
U·L −1
WBC, cells·mm–3 3800– 3800 2600 2000 3500 3900 2700
10 800
Prednisone, mg 20 10 5
Hydroxychloroquine, mg 400 400 200
Vitamin D supplement Yes No No No No No
PTH: parathyroid hormone; WBC: white blood count.
196 https://doi.org/10.1183/2312508X.10032220
The presence of hypercalcaemia with elevated calcitriol can be a diagnostic clue for sarcoidosis.
Figure 4 reveals imaging of a 65-year-old African-American female who presented to the
emergency room with decreased mental status, renal insufficiency and hypercalcaemia. After
admission to hospital and treatment with fluids, she underwent a PET scan for presumed
malignancy. Subsequent blood work found an elevated calcitriol level and reduced
25-hydroxyvitamin D and PTH. A review of her PET scan showed an area of intense activity on
the skull, confirmed by her merged CT/PET scan. Examination of the scalp revealed a lesion
originally thought to be skin cancer. Pathological examination of the biopsied lesion revealed
only non-necrotising granulomas, and she was referred for treatment of sarcoidosis.
Treatment of abnormal calcium metabolism in sarcoidosis

Treatment of abnormal calcium metabolism in sarcoidosis depends on the cause. As noted
earlier, most cases are due to increased 1-α-hydroxylase activity in the granuloma leading to
increased calcitriol levels. As the increased enzyme activity is related to local IFN-γ secretion,
anti-inflammatory drugs are the usual first line of therapy. Figure 5 shows the various
anti-inflammatory agents used to treat hypercalcaemia at a US clinic [2]. Of the 86 patients with
adequate follow-up in this series, 48 (56%) responded to a single change in therapy. This
a) b)
c)
FIGURE 4 Patient who presented with hypercalcaemia and acute renal failure. a) Whole-body PET scan,
b) merged PET/CT of the lesion on the skull (orange area) and c) skin lesion. Biopsy of the skin lesion identified
granulomas consistent with sarcoidosis.
https://doi.org/10.1183/2312508X.10032220 197
Vitamin D discontinuation
lnfliximab
Sole treatment Treatment
Cyclophosphamide
Leflunomide
Azathioprine
MTX
Hydroxychloroquine
Prednisone
0 10 20 30 40 50
Patients, n
FIGURE 5 Summary of the treatment of 86 sarcoidosis patients with hypercalcaemia due to sarcoidosis. Half of
patients responded to a single change in treatment (sole treatment). In the remaining cases, more than one
treatment intervention was required. Data from [2].
included eight patients in whom withdrawal of vitamin D supplementation alone was the only
necessary treatment intervention. The remaining patients underwent two or more interventions to
minimise drug toxicity.
Prednisone is frequently the first drug used to treat symptomatic hypercalcaemia [26, 27].
Antimalarial agents such as chloroquine and hydroxychloroquine may be effective alternatives
with less toxicity [28]. In general, this intervention leads to a modest improvement in serum
calcium. However, given the relative low toxicity of antimalarials, they are often employed in
mild hypercalcaemia or in those with hypercalcuria alone [27].
Antimetabolites have become a standard steroid-sparing alternative for chronic sarcoidosis [29].
MTX is the preferred drug for most manifestations of chronic disease [30]. This is in part due
to more published experience compared with other antimetabolites [31–33]. However,
MTX is cleared by the kidney, and the drug may be contraindicated in those with renal
impairment [34]. In the setting of renal insufficiency, azathioprine or mycophenolate are
acceptable alternatives [35].
For refractory sarcoidosis, the monoclonal anti-TNF antibody infliximab (IFX) has been used
[2, 36, 37]. In general, IFX has been reported as superior to other monoclonal anti-TNF
therapies for the treatment of sarcoidosis [38]. However, in patients who develop intolerance to
IFX, adalimumab may be an effective alternative [39].
In addition to these sarcoidosis-specific anti-inflammatory treatments, other treatments have

been reported for sarcoidosis-associated hypercalcaemia. Ketoconazole inhibits vitamin D
metabolism and has been used to treat sarcoidosis-associated hypercalcaemia [40]. The
bisphosphonates zoledronic acid and pamidronate have also been prescribed as treatment for
symptomatic hypercalcaemia [41, 42]. Due to their rapid onset of action, these drugs can more
quickly correct hypercalcaemia due to sarcoidosis than other agents [43–45]. Repository
corticotropin injection (RCI) has also been reported as useful in hypercalcaemia [46]. A report
198 https://doi.org/10.1183/2312508X.10032220
of three patients with hypercalcuria from sarcoidosis treated with RCI showed improvement
in vitamin D metabolism but no reduction in urinary calcium during the 12 weeks of treatment
[47]. This study used a higher dose but shorter treatment schedule of RCI than used by others
[35]. The use of RCI for abnormal calcium metabolism should be considered on a case-by-
case basis.
For the sarcoidosis patient who presents with hypercalcaemia or nephrolithiasis, serum levels of
calcitriol and PTH should be obtained. Figure 6 outlines an approach to patients with a low
PTH and normal-to-elevated calcitriol. Discontinuation of calcium and vitamin D supplements
should be recommended in all patients. For those with nephrolithiasis, mild renal dysfunction or
no symptoms, blood work should be repeated and 24-h urine calcium measured ⩾1 month after
the withdrawal of supplements. If serum and urine values are normal, no further intervention is
required. For those with persistent calcium abnormalities, hydroxychloroquine can be a safe first
step. Patients who do not respond to hydroxychloroquine should be started on glucocorticoids
with or without other anti-inflammatory drugs.
A more aggressive approach to therapy should be considered for those patients presenting with
moderate-to-severe renal disease or mental status changes. In some cases, intravenous fluid with
or without diuretics (e.g. furosemide) should be administered. Bisphosphonates can rapidly
reduce calcium but are not a long-term treatment. Glucocorticoids should be initiated to treat
Low PTH, normal or elevated calcitriol
No symptoms Nephrolithiasis Moderate-to-severe renal dysfunction

and/or and/or
Discontinue calcium and Mild renal dysfunction Altered mental status
vitamin D supplements
Check serum and Discontinue calcium

24-h urine after and vitamin D supplements
supplement Consider:
withdrawal Intravenous fluids
Diuretics
No response: Bisphosphonates
Initiate hydroxychloroquine
Response: No response: Begin glucocorticoid therapy

Observe Begin glucocorticoid
therapy Taper prednisone/prednisolone
to <10 mg·day–1
Yes: No:
Observe Add MTX, azathioprine
or mycophenolate
No response:
Consider infliximab,
adalimumab, rituximab or
RCI on a case-by-case basis
FIGURE 6 Approach towards patients with a low parathyroid hormone (PTH) level and normal-to-elevated
calcitriol. RCI: repository corticotropin injection.
https://doi.org/10.1183/2312508X.10032220 199
sarcoidosis. Once the patient has improved, glucocorticoid reduction should be initiated. For
patients able to reduce prednisone to <10 mg·day–1 or its equivalent, glucocorticoids alone may
be appropriate. For those with glucocorticoid toxicity or unable to dose reduce, an
antimetabolite such as MTX, azathioprine or mycophenolate should be considered. MTX should
be avoided in patients with residual renal dysfunction. In some cases, third-line therapy with
IFX, adalimumab, rituximab or RCI may be appropriate, as these agents have been useful in
other manifestations of sarcoidosis [29, 30].
Renal disease
Direct granulomatous infiltration of the kidney can be seen with sarcoidosis [17]. In one study
from France, 1.5% of sarcoidosis patients had documented renal disease [48]. All but one
patient presented with acute renal failure, and this one case had documented infiltration of the
kidney seen on CT. Table 2 summarises the experience reported from five centres across the
world [48–52]. While two European centres reported a higher ratio of men/women, the other
centres found renal disease more frequently in women. Although renal disease can occur,
screening for renal disease should be limited to serum creatinine and calcium. A prospective
study evaluating proteinuria in sarcoidosis patients using a spot urine protein/creatine ratio in
190 consecutive sarcoidosis identified proteinuria in 14 patients. However, nine patients had
other risk factors for proteinuria such as diabetes. The authors concluded that routine screening
of urine for proteinuria was not necessary [53].
The results of renal biopsy from the five centres in table 2 are shown. Granulomatous interstitial
nephritis can be due to multiple causes, the most frequent being drug toxicity [54]. If other factors
are excluded, the presence of granulomatous interstitial nephritis in a sarcoidosis patient makes
renal involvement highly probable [9]. In a pathological review of all renal biopsies at one centre,
18 cases of granulomatous interstitial nephritis were identified and evaluated. Five of these cases
were attributed to sarcoidosis with only one patient having known sarcoidosis prior to the biopsy
[55]. Interstitial nephritis without granulomas can also be seen in renal sarcoidosis. As seen in table 2,
TABLE 2 Features of renal sarcoidosis
First author [ref.]

MAHÉVAS [48] LOFFLER [49] KAMATA [50] ZAMMOURI [51] BAGNASCO [52]
Country France Germany Japan Tunisia USA

Patients, n 47 27 16 24 52
Male/female ratio 1.8 1.7 0.8 0.1 0.4
Age, years 47 (21–76)# 55 (25–86)# 65 (18–78)# 46 (18–69)# 50¶
Patients with biopsy, n+ 47 27 16 14 51
Granulomatous interstitial nephritis 37 (79) 8 (30) 13 (81) 6 (43) 19 (37)
Nongranulomatous interstitial nephritis 10 (21) 12 (44) 3 (13) 8 (57) 8 (16)
IgA glomerulonephritis 2 (4) 7 (26) 2 (12)§ NR 3 (6)
Nephrocalcinosis 8 (17) 3 (11) 2 (13) NR NR
Hypercalcaemia 15 (32) 5 (19) 5 (31) 9 (38) 7/19 (37)f
Proteinuria 31 (66) NR 10 (63) 20 (83) 12/19 (63)f
Response to therapy 34/41 (83)f 8/16 (50) 10 (67) 10 (71) 9/10 (90)
Complete responsef 27/41 (66) 5/16 (31) NR NR 5/10 (50)
Results are given as n (%), unless otherwise indicated. NR: not reported. #: median (range); ¶: mean; +: patients
could have more than a pathological pattern observed; §: described glomerular lesions concurrent with
interstitial nephritis, IgA glomerulonephritis not specific; f: number positive/number studied (%).
200 https://doi.org/10.1183/2312508X.10032220
glomerulonephritis, including immune complex-associated disease, was reported by most of the

series. Three reports documented nephrocalcinosis in >10% of cases. In a study evaluating renal
biopsies from 52 sarcoidosis patients, causes other than sarcoidosis were documented including
diabetic nephropathy and advanced sclerosing changes from hypertensive nephrosclerosis [52].
Normal serum renal function is reported in up to one-third of renal sarcoidosis patients [49, 51].
As shown in table 2, proteinuria was seen in two-thirds of the cases, and hypercalcaemia was
reported in one-third of patients. In a study of nine sarcoidosis patients with renal disease
confirmed by biopsy, the serum calcitriol levels were significantly higher compared with serum
levels from non-sarcoidosis patients with renal dysfunction. In these sarcoidosis patients, the
serum calcitriol level and renal function improved with therapy [56].
The five studies in table 2 reported a response to therapy in patients treated for renal sarcoidosis.
Most patients witnessed improvement in renal function, with up to two-thirds of patients felt to
have had a complete response. Glucocorticoids of varying doses were the initial therapy for all
centres. In some cases, steroid-sparing agents were added for renal and nonrenal indications. As
noted, MTX is contraindicated in patients with moderate-to-severe renal dysfunction.
Azathioprine and mycophenolate are acceptable alternatives in this situation [48].
As seen in table 2, only half of patients experienced a complete response to anti-inflammatory

therapy and >10% had no response at all. Patients with more advanced renal disease at the time of
treatment initiation were less responsive to anti-inflammatory therapy [48, 50]. Also, patients with
more extensive fibrosis on biopsy were less likely to respond to anti-inflammatory therapy [48,
51]. Most of the improvement in the estimated glomerular filtration rate (eGFR) occurred in the
first month of therapy [49, 50], and the greater the improvement in eGFR in the first months of
treatment, the better the renal outcome. In a multiregression analysis, the presence of multiple
organ involvement (more than three organs), advanced renal fibrosis and extensive interstitial
granulomas were independent risk factors for progression to end-stage renal disease [51].
Bone health
The impact of sarcoidosis and its treatment on bone health is complicated [1, 57]. It has been
reported that patients with sarcoidosis have an increased odds ratio for developing osteoporosis
[58]. MONTEMURRO et al. [59] using quantitative CT found that untreated sarcoidosis patients had
a lower bone density compared with sex- and age-matched controls. However, a meta-analysis
of over 6000 sarcoidosis patients compared with 77 000 controls failed to demonstrate an
increased risk for osteoporosis. Several risk factors for osteoporosis may be encountered in
sarcoidosis patients. These include female sex, older age, sedentary life style and prolonged use
of corticosteroids [1]. The presence of one or more of these factors is an indication for more
aggressive monitoring for bone thinning. In one study, a single year of glucocorticoid therapy
was associated with significant bone loss, which may improve after glucocorticoid withdrawal [60].
Figure 7 was adapted from a suggested approach to the management of bone health in
sarcoidosis patients [1]. Patients not on prolonged glucocorticoid therapy who are either male or
pre-menopausal females should undergo yearly screening for the possible development of risk
factors for osteoporosis. Post-menopausal females or patients on prolonged glucocorticoid
therapy should have a bone-density study and determination of serum 25-hydroxyvitamin D,
calcitriol and PTH levels to assess risk and guide management of bone thinning. Patients at risk
for osteoporosis who have a normal bone density and no evidence of abnormal calcium
metabolism and low 25-hydroxyvitamin D and low normal calcitriol should be considered for
https://doi.org/10.1183/2312508X.10032220 201
202

Risk of osteoporosis:
Post-menopausal or >3 months glucocorticoids
No Yes
25-hydroxyvitamin D, 1,25-dihydroxyvitamin D (calcitriol)

Repeat screening yearly Bone density study
Parathyroid hormone
Normal bone-density study Osteopenia/osteoporosis History of hypercalcaemia, hypercalciuria

and and or nephrolithiasis
No evidence for abnormal calcium No evidence for abnormal calcium and/or
metabolism metabolism Normal to elevated calcitriol
and
Low serum 25-hydroxyvitamin D and low
https://doi.org/10.1183/2312508X.10032220
normal calcitriol
Treat with bisphosphonate, Abnormal bone density Normal bone density
zoledronic acid, or denosumab
and
Vitamin D and calcium
Treat with bisphosphonate or
supplementation with follow-up
Vitamin D supplementation with follow-up zoledronic acid Repeat bone density in 1 year
labs in 3–6 months
labs in 3–6 months If risk for osteonecrosis: denosumab
FIGURE 7 Approach to evaluating and treating bone thinning in sarcoidosis patients. Reproduced and modified from [1] with permission.
vitamin D supplementation with repeat laboratory testing of calcium and 25-hydroxyvitamin D

and calcitriol levels after 3–6 months of treatment. For those with abnormal calcium metabolism
by history or current blood work and a normal bone-density scan, bone density should be
reassessed every 1–2 years. If radiographic evidence for osteopenia or osteoporosis occurs,
patients should be considered for bisphosphonate or denosumab therapy. For those with normal
calcium metabolism, calcium and vitamin D supplementation with repeat laboratory testing of
calcium and vitamin D-25 and calcitriol levels after 3–6 months of treatment should be
considered. Those with abnormal calcium metabolism should be considered for bisphosphonate
or denosumab therapy alone.
Conclusion
The interaction between calcium and renal disease can lead to significant morbidity in
sarcoidosis. Routine screening includes determining serum calcium and creatinine levels. In
patients with hypercalcaemia or hypercalciuria, 25-hydroxyvitamin D, calcitriol and PTH serum
levels should be determined. Abnormal calcium metabolism often responds to anti-inflammatory
therapy. Because sarcoidosis patients are also at risk for bone health issues, all patients should
receive periodic evaluation to determine the harm versus benefit of calcium and vitamin D
supplements.
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59 Montemurro L, Fraioli P, Rizzato G. Bone loss in untreated longstanding sarcoidosis. Sarcoidosis 1991; 8: 29–34.
60 Rizzato G, Montemurro L. Reversibility of exogenous corticosteroid-induced bone loss. Eur Respir J 1993; 6:
116–119.
Disclosures: R.P. Baughman reports receiving the following during the conduct of the study: grants from Bayer,
Actelion, Genentech, aTyr, Novartis and Gilead; grants and personal fees from Bellephron and Mallinckrodt; and
personal feels from United Therapeutics and Boehringer Ingleheim. R.P. Baughman reports receiving the following,
outside the submitted work: grants from the Foundation for Sarcoidosis Research and the National Institutes of
Health. E.E. Lower reports receiving the following during the conduct of the study: grants from Bayer, Genentech
and aTyr. E.E. Lower reports receiving the following, outside the submitted work: grants from the Foundation for
Sarcoidosis Research.
https://doi.org/10.1183/2312508X.10032220 205
Chapter 14
Non-organ-specific manifestations
Vivienne Kahlmann 1,4, Divya C. Patel 2,4
, Lucian T. Marts 3
and
Marlies S. Wijsenbeek 1
1
Centre of Excellence for Interstitial Lung Diseases and Sarcoidosis, Dept of Respiratory Medicine, Erasmus MC,
University Medical Center, Rotterdam, The Netherlands. 2Division of Pulmonary, Critical Care and Sleep Medicine,
University of Florida, Gainesville, FL, USA. 3Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Dept
of Medicine, Emory University School of Medicine, Atlanta, GA, USA. 4These authors share first authorship.
Corresponding author: Marlies S. Wijsenbeek (m.wijsenbeek-lourens@erasmusmc.nl)
Cite as: Kahlmann V, Patel DC, Marts LT, et al. Non-organ-specific manifestations. In: Bonella F, Culver DA,
[https://doi.org/10.1183/2312508X.10032320].
@ERSpublications
Non-organ manifestations of sarcoidosis are common, but under-recognised, and can have significant impact
on HRQoL. Management includes (non)-pharmacological treatment, physical activity-based treatments,
psychological counselling and support groups. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Non-organ-specific manifestations such as fatigue, anxiety, depression, pain, cognitive dysfunction and
small-fibre neuropathy are common in patients with sarcoidosis. These symptoms do not usually require
immunosuppressive therapy and often persist, even while there are no signs of organ-specific
sarcoidosis activity. These invisible manifestations of sarcoidosis often have significant impact on
health-related quality of life, and therefore should be adequately addressed and not be overlooked. In
this chapter, we summarise the current literature about non-organ manifestations, including their
prevalence, impact, assessment and treatment. Subsequently, we advocate a multidisciplinary and
overarching approach for management and discuss future directions.
Introduction
The frequent invisible burden of sarcoidosis is predominantly caused by non-organ-specific
manifestations of sarcoidosis such as fatigue, pain, cognitive dysfunction, anxiety, depression
and small-fibre neuropathy (SFN) (figure 1). The reported prevalence of these symptoms varies
in the literature, but fatigue and pain in particular are reported in up to 60–90% of patients with
sarcoidosis, although it should be realised that these numbers can be biased by the method and
the population sampled (figure 2) [1–14]. These invisible and under-recognised manifestations
of sarcoidosis have a major impact on the patient’s and their family’s wellbeing and directly
impact health-related quality of life (HRQoL) [15] and can negatively impact social
participation [16, 17]. In the past decade, more value has been placed on patient-centred
outcomes, which has led to increasing awareness and treatment trials for these manifestations.
In this chapter we summarise the most recent insights on assessment and treatment of fatigue,
pain, cognitive dysfunction, anxiety and depression in sarcoidosis, and propose a multi-
disciplinary and overarching management approach. We only briefly touch on SFN and HRQoL
206 https://doi.org/10.1183/2312508X.10032320
NON-ORGAN-SPECIFIC MANIFESTATIONS | V. KAHLMANN ET AL.
Pain
Fatigue Small-fibre neuropathy
Stress and anxiety

Cognitive impairment
Depression
FIGURE 1 Non-organ manifestations of sarcoidosis include fatigue, pain, anxiety, depression, cognitive
impairment and small-fibre neuropathy.
measurement, as these are discussed in detail elsewhere in this Monograph [18, 19]. As the lack
of good treatments for these invisible manifestations is unfortunately still a major frustration for
patients and clinicians, we conclude with future directions and research needs.
Sarcoidosis-associated fatigue
Fatigue is a common and challenging symptom in patients with sarcoidosis, and often has a
large impact on the lives of patients [1]. There is no unambiguous definition of fatigue. It is
usually described as a subjective symptom of lack of energy, tiredness, malaise and/or aversion
to activity. Patients can experience limitations in physical and social functioning as well as work
participation, and can be confronted with financial losses [20–22]. Even when there are no signs
of disease activity, fatigue is often present [23, 24]. The challenge for patients and providers is
that those suffering from fatigue often look completely healthy and therefore the consequences
of fatigue can be easily underestimated [25]. Remarkably, in a recent multinational patient
survey, fatigue was reported in 90% of cases and extreme fatigue in 48% [1]. In contrast, in the
British Thoracic Society (BTS) sarcoidosis registry, a physician-reported registry, fatigue was
only reported as a significant complaint in 30% of patients [26]. This discrepancy between
patient- and provider-reported outcomes emphasises the need for more awareness of fatigue.
Management of fatigue is complicated due to incomplete understanding of the aetiology as well
as multiple potential contributors to fatigue [27]. Nevertheless, recognising patients with fatigue
as well as identifying and treating underlying causes are necessary to improve care and quality
of life for patients with sarcoidosis.
https://doi.org/10.1183/2312508X.10032320 207
Lowest and highest prevalence reported in the literature
Headache ? 29
Cognitive impairment 34 35
Anxiety 31 50
Small-fibre neuropathy 40 60
Depression 29 60
Chest pain ?
Fatigue 30 90
0 10 20 30 40 50 60 70 80 90 100
Prevalence %
FIGURE 2 Prevalence of various non-organ manifestations of sarcoidosis represented as lowest and highest
ranges reported in the medical literature. Note that prevalences vary and are influenced by many factors,
including the population sampled.
Assessment of fatigue
Patients should be asked regularly about the presence and impact of fatigue, as it can occur
during all stages of sarcoidosis and often persists even while there are no signs of disease
activity. Several patient-reported outcome measures (PROMs) have been developed to measure
fatigue in sarcoidosis, such as the Fatigue Assessment Scale (FAS) and the Sarcoidosis
Assessment Tool (SAT) fatigue subscale (table 1) [30, 31, 45]. If fatigue is present, an extensive
patient history should be obtained. Multiple physical, psychological and behavioural factors may
play a role in the development and persistence of fatigue, and each should be independently
assessed, as management may differ depending on the underlying cause (figure 3).
Physical factors
A structured approach is useful to assess causes of fatigue, starting with evaluation of the
potentially opposing roles that immunosuppressive therapy may have in both the management
and development of fatigue (figure 4). Granulomatous inflammation can cause fatigue; in this
case patients might benefit from immunosuppressive therapy [46]. Conversely, fatigue may be a
side-effect of medication [47, 48]. This is particularly true in the case of corticosteroid treatment
[49, 50]. Importantly, comorbidities that can trigger or aggravate fatigue must be excluded:
additional blood tests might be required to exclude anaemia, hyperglycaemia, iron deficiency or
a thyroid disorder.
Several studies have found that sleep disturbance was associated with higher levels of fatigue,
cognitive dysfunction, depression and overall poorer HRQoL [51–53]. Sleep disorders such as
sleep disordered breathing or obstructive sleep apnoea (OSA), periodic limb movement disorder
and restless legs syndrome are more prevalent in patients with sarcoidosis compared to healthy
controls [54–56]. Moreover, the use of corticosteroids can lead to weight gain, which increases
the risk of developing OSA, and may worsen it [57]. Patients can be screened for sleepiness
using a validated questionnaire, for example the Epworth Sleepiness Scale, or OSA using the
STOP-BANG (snoring, tiredness, observed apnoea, high blood pressure, body mass index, age,
neck circumference and male gender) questionnaire (table 1) [58]. Since the diagnostic accuracy
of these questionnaires is debatable, polysomnography could still be considered in patients with
208 https://doi.org/10.1183/2312508X.10032320
TABLE 1 Patient-reported outcome measures often used to evaluate non-organ manifestations of sarcoidosis
Development and main Short Cut-off values/

characteristics description MCID
General assessment of symptoms

Visual analogue Not validated in Psychometric response
scales [28, 29] sarcoidosis scale: left side of the line
Validated in other chronic represents lowest scores
disorders (also in (lesser symptoms), the right
interstitial pulmonary side of the line represents
fibrosis) the highest score (worse
symptoms)
Fatigue
SAT-fatigue [30] Developed to assess Five items on fatigue, Estimated MCID 3.1
manifestations of answered on a 5-point Validation of cut-off
sarcoidosis Likert scale values: work in progress
Eight domains, including Maximum score 25
fatigue
Fatigue Assessment Developed to measure Self-report questionnaire Fatigue: score ⩾22
Scale [31, 32] fatigue in patients with 10 questions (five on Extreme fatigue:
sarcoidosis physical fatigue and five on score ⩾35
mental fatigue) answered MCID 4
on a 5-point Likert scale
Maximum score 50
OSA
Epworth Sleepiness Originally developed to Self-report questionnaire Score >10 signifies
Scale [33, 34] assess daytime sleepiness Eight questions answered daytime sleepiness
Also used as a tool for on a 3-point Likert scale
comprehensive assessment Maximum score 24
of OSA
STOP-BANG Originally developed to Four dichotomous Score 0–2: low risk
Questionnaire assess the risk of OSA in questions on OSA-related of OSA
[35, 36] pre-operative patients symptoms and four clinical Score 3–4: intermediate
characteristics risk of OSA
Maximum score 8 Score 5–8: high risk
of OSA
Pain
Numeric pain rating Developed to measure Unidimensional Higher scores indicate
scale [37, 38] pain intensity in adults measurement of pain greater pain intensity
High reliability and validity 11-point scale ranging from
in patients with 0 (no pain) to 10 (worst
rheumatic pain pain imaginable)
SAT-pain interference Developed to assess Pain module consists of five Estimated MCID 3.2
[30] manifestations of questions answered on a Validation of cut-off
sarcoidosis 5-point Likert scale values: work in progress
“Pain interference” is one Maximum score 25
of eight modules
SFN
Small Fiber Developed to assess SFN Self-report questionnaire Score <11: few or no
Neuropathy in patients with sarcoidosis 21 questions answered on a SFN-related symptoms
Screening List Two parts: experience of 5-point Likert scale Score 11–48: probable
[39, 40] specific complaints and Score range 0–84 or highly likely SFN
severity of complaints Score <48: indicative
of SFN
MCID 3.5
Continued
https://doi.org/10.1183/2312508X.10032320 209
TABLE 1 Continued
Development and main Short Cut-off values/

characteristics description MCID
Depression/anxiety
Abbreviated Centers Developed to assess the 11-item self-reporting tool Score >9 indicates
for Epidemiologic presence and severity of modified from the original depression
Studies Depression depressive symptoms; has 20-item self-reporting tool
Scale [6, 41] high validity and reliability Questions are answered on
a 3-point Likert scale
Score range 0–33
Hospital Anxiety and Developed to assess 14-item self-reporting tool Score 0–7: no anxiety
Depression Scale anxiety and depression in the domains of anxiety or depression
[7, 8, 11, 42, 43] among non-psychiatric and depression Score 8–10: possible
patients Questions are answered on anxiety or depression
a 3-point Likert scale Score 11–21: probable
Score range for separate anxiety or depression
domains 0–21
Anxiety Sensitivity Designed to assess anxiety 18-item self-reporting tool Higher scores signify
Index-3 [7, 42, 44] sensitivity in the domains: Questions are answered on more anxiety
physical concerns, a 5-point Likert scale
cognitive concerns, social Score range 0–90
concerns
Cognitive Failure Developed to assess 25-question assessment Higher scores signify
Questionnaire impairments in perception, tool more cognitive failure
[12, 13] memory and motor Questions are answered on
function a 5-point Likert scale
Score range 0–100
Specific quality-of-life measurement strategies and results of studies from sarcoidosis-specific patient-reported
outcome measures are reviewed in detail in chapter 23 [19]. MCID: minimal clinically importance difference;
SAT: Sarcoidosis Assessment Tool; OSA: obstructive sleep apnoea; STOP-BANG: snoring, tiredness, observed
apnoea, high blood pressure, body mass index, age, neck circumference and male gender questionnaire; SFN:
small-fibre neuropathy.
high clinical suspicion of OSA or in cases of severe unexplained fatigue. In a prospective

cohort study, continuous positive airway pressure (CPAP) treatment had a positive impact on
fatigue in patients with good CPAP compliance. As this was a single-arm study, these results
need to be validated in future studies [33]. Interestingly, adequate OSA treatment does not
always seem to improve fatigue in patients with sarcoidosis [47]. If fatigue persists despite
adequate treatment of OSA, additional interventions could be considered and are addressed later
in this section.
Fatigue is also associated with physical inactivity, dyspnoea and muscle weakness [42, 59–61].
In addition to contributing to OSA, obesity in itself appears to have a negative effect on fatigue
[62]. Providers should regularly address the importance of physical activity and a healthy
lifestyle (e.g. referral to a dietician and activity training) [63].
Psychological factors
Symptoms of anxiety and depression are common in sarcoidosis and have a bidirectional
association with severe fatigue [23, 25, 60, 64, 65]. Routine screening for anxiety and
depressive symptoms should take place in the management of fatigue.
210 https://doi.org/10.1183/2312508X.10032320
Physical factors:
• Inflammation
• Medication (prednisone)
• Comorbidities (e.g. anaemia,
thyroid dysfunction)
• Dyspnoea
• Sleep disordered breathing
Sarcoidosis as a trigger: Psychological factors:

• Inflammation • Anxiety
• Physical deterioration • Depression
• Psychological stress • Cognitive decline
• Social stress
Behavioural factors:
• Nocturnal awakening
• Excessive caffeine or alcohol
intake
• Poor coping
• Physical inactivity
• Low social support
FIGURE 3 The various factors that play a role in the onset and persistence of fatigue in sarcoidosis including
physical, psychological and behavioural factors.
Behavioural factors
Patients with sarcoidosis have various coping mechanisms for their disease, and those can play
a role in fatigue. Patients who find it difficult to cope are more likely to have disabling
symptoms [23, 42]. With this in mind, some patients might benefit from cognitive behavioural
therapy (CBT) to help improve coping and management skills [25]. Moreover, general
behavioural factors such as excessive alcohol and caffeine intake, low social support, and
inactivity can also play a role in the persistence of fatigue, and should be assessed regularly and
managed if present.
Treatment of fatigue
Once secondary causes of fatigue are excluded, there are several non-pharmacological and
pharmacological interventions proposed as treatment for sarcoidosis-associated fatigue. Physical
activity programmes including physiotherapy and pulmonary rehabilitation were found to be
effective in reducing fatigue in sarcoidosis [66–68]. Therapy-based treatments, such as
mindfulness training and CBT, seemed to have a positive effect on fatigue in two small studies.
These non-pharmacological treatment options are discussed in more detail at the end of
this chapter.
Two small randomised controlled trials (RCTs) investigated the effect of neurostimulants on
fatigue (methylphenidate and armodafinil) [69, 70]. The European Respiratory Society (ERS)
guidelines suggest neurostimulants in cases of exercise-based treatment strategy failure [71].
Neurostimulants increase dopamine and noradrenaline within the brain and could potentially
have a positive effect on fatigue. Several contraindications must be considered before
prescribing these agents: among others, the presence of cardiovascular disease, cerebrovascular
disease and a history of psychotic symptoms or severe depression. While the results of these
studies are promising, more research on the efficacy of neurostimulants is needed. A larger RCT
for methylphenidate has been deemed feasible [72].
https://doi.org/10.1183/2312508X.10032320 211
Fatigue
Extensive history taking

Assess the impact of fatigue
Evaluate whether comorbidities

Evaluate if disease control
are present:
is adequate:
anaemia, iron deficiency,
optimise treatment and assess
thyroid disorder,
for drug side-effects
hyperglycaemia, hypertension
Screen for sleep disorders, psychological symptoms and

behavioural factors and treat accordingly
Treatment options after exclusion of underlying cause
Psychological Physical Pharmacological

interventions interventions interventions
FIGURE 4 Algorithm for the assessment and management of fatigue in sarcoidosis patients.
The discrepant impact of corticosteroids on fatigue may be due in part to the presence or
absence of inflammation during use. Some studies showed that corticosteroids use seem to have
a negative impact on fatigue [49, 50]. Controversially, dexamethasone 1 mg daily has been
shown to improve fatigue based on PROMs from 3 months to 12 months of follow-up [73].
Notably, in the BTS guidelines, a non-unanimous consensus was reached to treat fatigue with
steroids (no consensus dosage), but the authors did acknowledge that only a minority of
patients with fatigue would improve with this strategy [74]. Several studies have suggested a
positive effect of anti-TNF-α treatment on fatigue, but this was only assessed as a secondary
end-point [75, 76].
Pain
Pain is a frequent symptom in individuals with sarcoidosis and is associated with high
morbidity related to impact on HRQoL, sleep and functional status [77]. This symptom can
manifest in multiple ways, including headaches, chest pain, abdominal pain, back pain,
musculoskeletal complaints and SFN [5, 14, 77–81]. Sarcoidosis providers should assess for
pain regularly and treat accordingly, although chronic pain can be difficult to manage, as
anecdotally it is often refractory to opioid and non-opioid analgesics [82]. A primary reason for
treatment challenge lies in the fact that pain may be secondary to disparate causes including
sarcoidosis granulomatous aetiologies (e.g. chest pain due to thoracic lymphadenopathy, skeletal
pain due to bone involvement), sarcoidosis non-granulomatous aetiologies (e.g. chest pain due
to chronic cough, SFN) and a broad range of non-sarcoidosis aetiologies (e.g. migraine, spinal
pathology) [77, 79, 83, 84]. To optimise treatment decisions, clinicians need to examine for and
212 https://doi.org/10.1183/2312508X.10032320
differentiate between the various aetiologies of pain. Note that pain related to granulomatous
inflammation including chronic arthralgias/myalgias, as well as SFN, are discussed in detail
elsewhere in this Monograph [18].
Chest pain
Chest pain in sarcoidosis is frequently substernal and/or intrascapular [4, 5]. In a single-centre
study, chest pain occurred in 64% of individuals with sarcoidosis, and was the most
burdensome symptom in close to a third of cases [4, 5]. However, the true prevalence of chest
pain in sarcoidosis is unknown, since it has never been studied systematically in large clinical
trials and no registry studies have published such data. As chest pain can also be driven by
non-sarcoidosis organic aetiologies including angina, pericarditis, pulmonary embolism,
gastro-oesophageal reflux and other oesophageal pathology, a thorough history and evaluation
should be performed to exclude these aetiologies. Sarcoidosis-related chest pain is likely to be
multifactorial; early studies suggested that pain is related to granulomatous inflammation with
resultant anatomic distortion of intrathoracic lymph nodes, breasts, chest wall or the oesophagus,
which may be radiographically apparent in a minority of patients [5]. In contrast, one
prospective study suggests that this pain is independent of anatomic abnormalities and may be
secondary to chronic cough based on the lack of associated CT abnormalities and pleuritic
nature in the majority of cases [4]. In a cohort of patients with sarcoidosis presenting with
typical and atypical anginal chest pain, symptoms were suspected to be due to microvascular
vasospasms triggered by myocardial sarcoidosis, as suggested by abnormal thallium myocardial
scintigraphy and normal coronary angiography in the majority of patients [84].
Headaches
Headaches appear to be common in sarcoidosis. A single-centre cohort study reported migraine
affecting nearly 30% of 96 patients with sarcoidosis, versus 13% of healthy controls [14].
Notably, the presence of neurosarcoidosis or immunosuppression was not significantly
associated with migraine development, suggesting that this symptom may be independent of
granulomatous inflammation [14]. These results should be interpreted with caution, as the study
sample size was small and it remains uncertain if there is truly a greater risk of headaches in
patients with sarcoidosis.
Assessment of pain
There is no standardised sarcoidosis-specific metric with a primary emphasis on pain, though
the SAT “pain interference” module has a moderate correlation with other validated pain scales
and is a potential tool for future studies evaluating pain in sarcoidosis [30]. Pain related to SFN
can be assessed using the Small Fiber Neuropathy Screening List [39, 40]. Additionally, the
numeric pain rating scale or visual analogue scale (VAS) can be rapidly employed to assess
pain (table 1).
Pain management
The first step in pain management is a thorough assessment to identify whether pain is of a
sarcoidosis or a non-sarcoidosis organic aetiology. Dependent on the site of pain, a
multidisciplinary approach is useful to guide and narrow this assessment. There are no
data-driven guidelines regarding pain management, and treatment is based on underlying
aetiology. Pain attributed to granulomatous inflammation may respond to corticosteroids,
although there are data to suggest that this response can be limited [49]. Anti TNF-α therapies
such as infliximab and intravenous immunoglobulin have been studied in SFN [85–87].
However, the recent ERS clinical practice guideline did not provide a recommendation on these
therapies due to the lack of evidence [71]. Additionally, pain attributed to sarcoidosis
https://doi.org/10.1183/2312508X.10032320 213
non-granulomatous changes may respond to over-the-counter and topical analgesics such as

non-steroidal anti-inflammatories, acetaminophen, lidocaine cream/gel and capsaicin patches.
Anticonvulsants such as gabapentin, pregabalin and topiramate, as well as tricyclic
antidepressants are also frequently used in the management of sarcoid SFN, but strong evidence
to support this practice is lacking [88]. Finally, in an early-phase safety study, ARA-290
(cibinetide), a small peptide activating anti-inflammatory and tissue repair pathways, has been
shown to reduce pain and neuropathic symptoms in patients with sarcoidosis [89, 90].
Psychological stress and cognitive dysfunction

Sarcoidosis is associated with a high burden of depression, anxiety, memory impairment and
poor concentration [6–8, 11, 12, 91]. There is a complex interplay between these psychological
and cognitive impairments with fatigue, HRQoL and additional organ-specific and non-organ
manifestations of disease including dyspnoea, skin changes and pain [20, 42, 44, 64, 92–96].
Depression and anxiety

Assessment of depression and anxiety
While true prevalence is challenging to define, depression is estimated to occur in 30–60% of
patients with sarcoidosis; this is substantially greater than the general population, and slightly
higher than in individuals with other chronic ILDs [6–8, 97, 98]. Given the high estimated
prevalence, screening for depression could be considered in all sarcoidosis patients, and special
attention should be given to those with risk factors for depression including female sex and
those with poor access to care, multiorgan involvement and the presence of dyspnoea and other
comorbidities [6, 8]. While there are no sarcoidosis-specific metrics that screen for depression in
isolation, the Sarcoidosis Health Questionnaire is designed to assess HRQoL including
emotional wellbeing [99]. An abbreviated Centers for Epidemiologic Studies Depression Scale
was used to identify depression in a heterogeneous population of sarcoidosis patients in the
United States [6, 100]. The Hospital Anxiety and Depression Scale (HADS) is another
well-validated self-report tool that has been used to identify anxiety and depression in
sarcoidosis (table 1) [7, 8].
Anxiety presents as frequently as depression, with an estimated prevalence of 30–50% [7, 8, 11].
Anxiety sensitivity, or fear of anxiety-provoking symptoms, is a related but distinct entity that is
also common in sarcoidosis and can be evaluated with the Anxiety Sensitivity Index-3 (table 1)
[7, 44, 101]. As noted previously, there is an interdependent relationship between anxiety,
anxiety sensitivity and other psychological and non-psychological manifestations of sarcoidosis.
Specifically, high levels of anxiety and anxiety sensitivity are strongly associated with clinical
symptoms, and, conversely, fatigue and clinical symptoms, including dyspnoea, predict anxiety
[7, 8, 42]. Strikingly, anxiety sensitivity was found to be a stronger predictor for dyspnoea
severity in sarcoidosis than other traditional metrics, including FVC [44]. With these details in
mind, it is important to evaluate for and treat anxiety and anxiety sensitivity in all patients, even
when primarily presenting with physical, organ-specific symptoms.
Management of depression and anxiety

Studies have failed to show a clear improvement in depressive symptoms following treatment
with corticosteroids, and in fact their use may lead to worsening psychiatric symptoms, as mood
swings and depression are well-known side-effects of these medications [50, 73, 96]. Treatment
with corticosteroids should be re-evaluated when depressive symptoms are present, and use of
immunosuppressive medications for treatment of depression in isolation should be avoided.
There are no studies to date evaluating depression as a primary outcome of any specific
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intervention in patients with sarcoidosis. Reduced depressive symptoms was a secondary

outcome noted in a multicentre study evaluating a 3-week inpatient pulmonary rehabilitation
programme for patients with sarcoidosis. Since the study was not powered to detect
improvement in depression specifically, these results warrant further study [102]. With all this in
mind, for patients with sarcoidosis with depression, the current approach is to offer traditional
management strategies including counselling and psychotherapy with or without antidepressive
medications.
Treatment of anxiety with mind–body medical techniques including meditation, yoga, tai chi
and biofeedback could be considered along with more traditional treatments for anxiety
including counselling, antidepressants and anxiolytics [88].
Assessment of cognitive impairment
Cognitive impairments, specifically memory difficulties and poor concentration, are estimated to
occur in one-third of general sarcoidosis patients and 50% of the neurosarcoidosis population
[12, 13]. Cognitive failure in sarcoidosis may be measured by the Cognitive Failures
Questionnaire (CFQ) (table 1) [12, 20, 103]. Given the associations between cognitive failure,
fatigue, symptoms of SFN and depression, it is useful to assess and manage psychological and
non-psychological contributors to cognitive failure. Furthermore, patients should be screened for
neurosarcoidosis when cognitive failure is present [12, 20].
Treatment of cognitive impairment

Regarding specific therapy, the use of corticosteroids and MTX have not been shown to be
clearly beneficial, although there is one small study suggesting that anti-TNF-α medications
including infliximab and adalimumab are associated with decreased cognitive failure following
6 months of treatment, as measured by the CFQ [12]. It should be noted that this was not a
RCT and the control group included normal healthy patients from a separate study on ageing.
Multidisciplinary and overarching approach for management

Non-organ-specific manifestations significantly impair HRQoL in patients with sarcoidosis
(figure 5). One study showed that reduced HRQoL in sarcoidosis patients compared to the general
population was particularly related to fatigue [104]. Compared to the general population, patients
with sarcoidosis experience a reduction in work ability as measured by earnings and lost work
days for up to 5 years after diagnosis [105]. Indeed, fatigue has been shown to be the single most
important predictor of HRQoL in patients with sarcoidosis [106]. Many patients express feelings
of disregard from healthcare providers regarding symptoms of fatigue and pain [107]. All these
factors underline the burden that non-organ related manifestations place on patients as well as the
healthcare system and the urgent need for adequate management strategies.
Multidisciplinary approach to management

An overall strategy to assess and manage these conditions starts with asking the patient simple
questions to elicit whether fatigue, pain, depression, anxiety and cognitive impairment are
present. Ideally, to structurally assess these symptoms, PROMs are used, but we acknowledge
that these are not always feasible in a busy daily practice and there is a need for quick screening
tools. VAS enable quick assessment and evaluation of symptoms. VAS have not been studied in
sarcoidosis, but have been validated in other chronic diseases, including ILDs [29, 108].
https://doi.org/10.1183/2312508X.10032320 215
Non-organ manifestations of sarcoidosis Negative impact of sarcoidosis
Tiredness Reduced quality of life
Small-fibre neuropathy Psychological distress
Pain Physical deconditioning
Stress and anxiety $ Financial loss
Depression Reduced work participation
Cognitive impairment Negative impact on social participation and family life
FIGURE 5 Non-organ manifestations of sarcoidosis and the impact on quality of life, as reported in the medical
literature.
Several studies have shown that anti-granuloma therapy targeting specific organ involvement
does not necessarily improve HRQoL [60, 96, 109]. A multidisciplinary approach that includes
non-pharmacological and pharmacological intervention is needed (figure 6). Physical
activity-based modalities such as pulmonary rehabilitation programmes have been shown to
impact HRQoL [110, 111]. In one study of patients with pulmonary sarcoidosis, a 12-week
pulmonary rehabilitation training programme which met for 90 min twice a week led to an
overall improvement in perceived wellbeing and HRQoL as measured using the St George’s
Respiratory Questionnaire (SGRQ), which was durable for 3 months post-training [111]. Along
with HRQoL, several studies also show improvement in fatigue as measured by the FAS when a
12- or 13-week supervised physical training programme is provided [67, 68]. An individualised,
multimodal combination of treatments including pulmonary rehabilitation is recommended for
sarcoidosis-associated fatigue in the BTS clinical statement on pulmonary sarcoidosis and in the
ERS guidelines [71, 74].
Several studies have evaluated the impact of pulmonary rehabilitation programmes on anxiety
and depression using the HADS questionnaire, but the results have been mixed [111]. One
study of pulmonary sarcoidosis patients with Scadding stage 3 and 4 disease who received
12 weeks of structured and supervised exercise training showed improvement in anxiety [110].
Another study with 300 patients using only a 3-week duration of pulmonary rehabilitation
showed improvements in the HADS score, SGRQ score and FAS, suggesting that anxiety,
depression and fatigue decreased [102]. A RCT on the effect of an online 12-week
tele-rehabilitation in sarcoidosis is ongoing (NCT03914027).
The effect of psychotherapy or counselling in patients with sarcoidosis has not been studied
systematically. However, it is likely that these treatment modalities improve HRQoL and it is
plausible that these therapies impact outcomes, since depression and anxiety are associated with
worse clinical outcomes [95]. Mindfulness training was studied in a small cohort of sarcoidosis
patients, and showed decreased physical and psychological symptom burden [112]. CBT has
216 https://doi.org/10.1183/2312508X.10032320
Non-pharmacological treatments Pharmacological treatments
Physical activity-based treatments: Neurostimulants: methylphenidate,

Fatigue/ armodafinil
cognitive Pulmonary rehabilitation
programme; TNF-α inhibitors: infliximab
dysfunction Corticosteroids: dexamethasone
Physical therapy, physiotherapy;
Aquatic-based exercise
programmes Intravenous immunoglobulin
Non-steroidal anti-inflammatory drugs
Pain/small-fibre Therapy-based treatments: TNF-α inhibitors: infliximab
neuropathy Psychological counselling;
Anti-epileptics: gabapentin, pregabalin,
Mindfulness;
topiramate
CBT;
Support group participation Tricyclic antidepressants
Nerve blocks
Multidisciplinary programmes:
Depression/ Comprehensive pain Selective serotonin reuptake inhibitors
anxiety management; Serotonin and norepinephrine
Comprehensive sleep medicine reuptake inhibitors
Long-acting benzodiazepines
(avoid if possible)
FIGURE 6 Non-pharmacological and pharmacological treatment options for non-organ-specific manifestations of

sarcoidosis. If non-pharmacological treatments are unsuccessful, consider pharmacological treatments. In cases
of disease activity, immunosuppressive therapy might be preferred before or simultaneously with
non-pharmacological treatments. Please note that most of these pharmacological treatments are only studied in
small cohort studies and evidence of efficacy is limited, therefore no recommendation could be made for these
therapies in the recent European Respiratory Society clinical practice guideline. A careful consideration must be
made before prescribing these agents. CBT: cognitive behavioural therapy.
been shown to improve fatigue after 1 year of practice in a small pilot study [113]. CBT has a
positive effect on fatigue in other chronic diseases, and an ongoing RCT is investigating the
efficacy of online CBT (Netherlands Trial Register number NL7816) [114]. Related treatment
strategies including tai chi have been shown to be effective in other chronic conditions, and may
also be beneficial in patients with sarcoidosis [115]. Counselling and psychotherapy can be
employed concomitantly or alone, depending on the specific issues a patient is facing. If none
of these strategies are effective, pharmacological therapies could be added, as alluded to earlier
in this chapter.
Referrals to patient associations such as the Foundation for Sarcoidosis Research and
Sarcoidosis UK can be helpful. These organisations provide education, access to support
groups, nurse helplines and seminars incorporating physical activity, mindfulness, journalling
and various other educational opportunities.
Socioeconomic status and other social determinants

When discussing HRQoL and non-organ related manifestations, we should keep in mind that
socioeconomic status, implicit racism in the medical system and social determinants of care are
intertwined with sarcoidosis and its outcomes [116]. HARPER et al. [117] showed that
low-income sarcoidosis patients had worse HRQoL and outcomes. The landmark study, A
Case-Control Etiologic Study of Sarcoidosis, was the first to demonstrate that low-income
patients were more likely to be black and female and to encounter barriers to getting care [118].
Access to multidisciplinary care may be even more limited for those with a low income, and the
non-insured and under-insured. As a sarcoidosis community we need to be aware of these
mechanisms and invest in ways to ensure equal access to care for all patients.
https://doi.org/10.1183/2312508X.10032320 217
Future directions
Many physicians are unaware of non-organ-specific manifestations of sarcoidosis, so additional
education and dissemination of these complications is imperative. Clinical trials for new
therapies should also include fatigue and pain as end-points and research into the pathogenesis
and management of fatigue, depression and pain should be encouraged. Studies that evaluate
direct aetiology and those that investigate the interdependence with behavioural characteristics
and clinical phenotypes are needed. In addition, objective tests/measures to determine the
presence and severity of these manifestations is important. Collaborating with investigators in
other areas such as neuroscience, muscle physiology and other conditions such as fibromyalgia
and chronic fatigue syndromes could help advance the field. Finally, in order to make progress
in our understanding and management of these manifestations, patient participation in the
design of clinical trials of therapy and other studies is imperative.
Conclusion
Non-organ manifestations of sarcoidosis are common, but under-recognised. Management of
these conditions is complicated by the lack of good insights in the pathogenesis and the
multifactorial interactions. More research in this field is needed, as these conditions have a
significant impact on quality of life, but are challenging to diagnose and treat. PROMs can help
to screen for these conditions. Treatment should start with non-pharmacological measures since
limited data are available to support pharmacological efficacy. Physical activity-based treatments
can help improve fatigue, anxiety and depression. Other modalities such as psychological
counselling and support groups can help. The impact of race and socioeconomics on patients
with sarcoidosis and their outcomes should be considered. Patient participation in clinical trials
and research in these conditions could help us gain greater understanding of the conditions.
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222 https://doi.org/10.1183/2312508X.10032320
Chapter 15
Hepatic and splenic involvement

Florence Jeny1,2 and Nabeel Hamzeh 3
1
AP-HP, Pulmonology Dept, Avicenne Hospital, Bobigny, France. 2INSERM UMR 1272, Sorbonne Paris-Nord
University, Bobigny, France. 3Dept of Medicine, University of Iowa, Iowa City, IA, USA.
Corresponding author: Nabeel Hamzeh (nabeel-hamzeh@uiowa.edu)
Cite as: Jeny F, Hamzeh N. Hepatic and splenic involvement. In: Bonella F, Culver DA, Israël-Biet D, eds.
2312508X.10032820].
@ERSpublications
Hepatic and splenic sarcoidosis have variable presentations. They also mimic a wide range of differential
diagnoses. Careful assessment and management are essential to avoid misdiagnosis and potential
complications. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Hepatic and splenic sarcoidosis are detected clinically in about 10% of sarcoidosis patients but are
asymptomatic in up to 79% of cases. Splenic involvement is usually asymptomatic, and hepatic
involvement can vary from asymptomatic to showing nonspecific symptoms to presenting with signs
and symptoms of cirrhosis and portal hypertension. Diagnostic criteria mainly rely on compatible
clinical variables in the setting of established sarcoidosis, and occasionally on pathological findings.
The differential diagnosis for both hepatic and splenic involvement is wide, and careful assessment is
needed to avoid misdiagnosis, as sarcoidosis is a diagnosis of exclusion. Various imaging modalities
reveal organ enlargement and nodularity, but the findings are not pathognomonic for sarcoidosis.
Treatment is indicated in symptomatic cases and when there is evidence of significant organ
dysfunction. Ursodeoxycholic acid is a therapeutic option in predominantly hepatic sarcoidosis, and
splenic and hepatic involvement tend to respond to standard anti-sarcoidosis regimens. Careful
monitoring for potential complications is imperative. Liver transplantation has been successful in cases
of end-stage liver disease due to sarcoidosis.
Introduction
Sarcoidosis is a multisystemic inflammatory disorder characterised by formation of granulomas
in the affected organs [1]. It predominantly affects the lungs but any organ can be affected,
including the liver and spleen [1]. The presentation of both liver and spleen sarcoidosis is
variable and can range from asymptomatic involvement to significant symptomatic involvement
with organ dysfunction and subsequent complications. In this chapter, we discuss the
epidemiology, presentation, imaging, diagnosis and differential diagnosis, pathological findings,
and therapeutic approaches for both liver and spleen sarcoidosis.
Hepatic sarcoidosis
Epidemiology
The liver is the most common gastrointestinal organ to be involved in sarcoidosis. Its
involvement can range from asymptomatic disease to cirrhosis. The estimated prevalence of
https://doi.org/10.1183/2312508X.10032820 223
liver involvement in sarcoidosis varies depending on the definition used. Liver biopsy and
autopsy specimens from sarcoidosis patients estimate that up to 50–79% of patients have
evidence of granulomas on biopsy [2, 3], whereas the clinical definitions of liver sarcoidosis
based on liver function testing show a much lower prevalence of liver sarcoidosis [4]. The
ACCESS study (A Case Control Etiologic Study of Sarcoidosis), which enrolled newly
diagnosed sarcoidosis cases, estimated the prevalence of clinically diagnosed liver sarcoidosis at
11.5%, with Blacks having liver involvement twice as frequently as Whites [5]. In a European
multicentre study recruiting mainly White sarcoidosis patients, the prevalence of liver
sarcoidosis based on the ACCESS criteria was 4.9% [6], whereas a retrospective study from
Florida identified hepatic involvement in sarcoidosis in 9.4% of their cohort [7]. A recent report
from 14 centres that recruited 100 consecutive sarcoidosis patients per centre reported a
prevalence of hepatic sarcoidosis of 9% based on the World Association for Sarcoidosis and
Other Granulomatous Disorders (WASOG) criteria [8, 9]. Table 1 gives some examples of the
prevalence seen in different studies [5, 6, 8, 10–15].
Presentation
Hepatic sarcoidosis is usually asymptomatic but can be detected by biopsy in up to 79% of
cases [2, 3]. It can be discovered on routine lab testing, which can be abnormal in about a third
of patients [2, 16], or by detecting abnormalities incidentally on unrelated imaging [2–4]. About
5–30% of patients present with nonspecific systemic symptoms, abdominal discomfort or
pruritus, or manifest with signs and symptoms of cirrhosis and portal hypertension [4, 17, 18].
Physical examination can reveal hepatomegaly with or without splenomegaly [4, 17]. The most
common liver function test abnormalities are elevated alkaline phosphatase (ALP) and gamma-
glutamyl transferase, whereas elevated transaminases are not common but can be seen [2, 3, 7].
Imaging
The most common imaging finding of hepatic sarcoidosis is hepatomegaly [19]. On ultrasound,
nodules appear hyperechoic [19]. The appearance of the liver on abdominal CT can vary from a
homogeneous pattern to hypodense nodular lesions [2, 3]. On MRI, the liver appears
hypointense and hypoenhancing relative to the background liver [19]. 18F-FDG PET scanning
can show diffuse or multinodular uptake but is nonspecific and cannot differentiate between
sarcoidosis and other 18F-FDG PET hepatic lesions [20].
Diagnosis
Diagnostic criteria for liver sarcoidosis have been proposed by WASOG [9]. The criteria rely on
imaging evidence of hepatomegaly and/or hepatic nodules and serum ALP three times over the
upper limit of normal in an individual with known sarcoidosis [9]. Liver biopsies, when
performed, show evidence of granulomatous reaction. In general, about 3.8% of all liver
biopsies performed for various indications show evidence of granulomatous reaction [21, 22].
The differential diagnosis for granulomas on liver biopsy includes both infectious and
non-infectious aetiologies, including immune disorders such as primary biliary cirrhosis,
autoimmune hepatitis, hypersensitivity reactions, neoplasms, drug reactions and various
infectious aetiologies [22, 23]. The most common diagnosis in the cases showing
granulomatous reaction is primary biliary cirrhosis (23.8–48.7%), whereas sarcoidosis accounts
for 8.4–11.1% of cases, infectious causes account for 3.4% of cases, drug reactions account for
2.5–9.5% of cases and in 36% of cases the cause is undetermined [21, 22]. The differential
diagnosis should take into account the geographic location of the patient and exposure risk factors.
224 https://doi.org/10.1183/2312508X.10032820
https://doi.org/10.1183/2312508X.10032820
TABLE 1 Prevalence of liver and splenic sarcoidosis across studies
First author, Location Patients Prevalence of liver Prevalence of Criteria of diagnosis Details of the study
year [ref.] n sarcoidosis splenic sarcoidosis
JAMES, 1976 [10] Multicentric, 3676 Not reported 6% Splenomegaly

worldwide
BAUGHMAN, 2001 Multicentric, USA 736 11.5% 6.7% ACCESS proposed At diagnosis
[5] instrument
JUDSON, 2012 Monocentric, USA 1774 White 15.9%; White 9.6%; ACCESS proposed
[11] Black 22.2% Black 6.4% instrument
UNGPRASERT, 2016 Monocentric, USA 345 6% 4% Not specified for liver; At diagnosis
[12] splenomegaly for spleen
SCHUPP, 2018 [6] Multicentric, Europe 2163 4.9% 3.9% ACCESS proposed Study in Caucasian patients
(Caucasian) instrument
HEPATIC AND SPLENIC | F. JENY AND N. HAMZEH

MAÑÁ, 2017 [13] Monocentric, Spain 640 17.7% 7.5% WASOG organ assessment At diagnosis
instrument
LHOTE, 2021 [14] Multicentric, France 1237 24% 16% WASOG organ assessment Patients with involvement of at least
instrument one extrapulmonary organ
TE, 2020 [15] Monocentric, USA 187 17.6% 20.9% WASOG organ assessment
instrument
ZHOU, 2021 [8] Multicentric, 1445 9% 10% WASOG organ assessment More frequent in Black patients
worldwide instrument
ACCESS: A Case Control Etiologic Study of Sarcoidosis; WASOG: World Association for Sarcoidosis and Other Granulomatous Disorders.
225
a) b)
FIGURE 1 Core biopsy from a patient with sarcoidosis and liver involvement. a) Low-power image showing
compact granulomas in the hepatic parenchyma. b) High-power image of one of the granulomas.
Pathological findings
Granulomatous involvement of the liver in cases of sarcoidosis is typically in the portal and
periportal region (figure 1) [24]. Stains and cultures, by definition, should be negative. In a
study that examined 100 patients with sarcoidosis and evidence of liver injury, the authors
noted three categories of histological changes: cholestatic (58%), necroinflammatory (41%) and
vascular (20%) [24]. The cholestatic pattern showed bile duct lesions, periductal fibrosis or
reduced number of bile ducts (ductopenia) [24]. The necroinflammatory lesions were
characterised by spotty necrosis and chronic portal inflammation [24]. The vascular changes
were characterised by sinusoidal dilatation and nodular regenerative hyperplasia. Frank cirrhosis
was seen in 6% of the cases [24]. The primary differential diagnosis for granulomas in the liver
includes primary biliary cirrhosis [25]. The differentiation on biopsy can sometimes be
challenging; thus, consultation with a liver pathologist is essential to clarify the diagnosis. Portal
hypertension can arise due to pre-sinusoidal blockage of venous flow but can also occur due to
hepatic venous outflow obstruction, as cases of Budd–Chiari syndrome with venous outflow
obstruction have been reported [26–28]. In addition, rare cases of portal hypertension can also
develop secondary to portal and hepatic vein thrombosis due to granulomatous phlebitis [16, 29].
Indication for therapy

Indication for treatment of liver sarcoidosis follows the same principles as for other organ
involvement in sarcoidosis: treat when the patient is symptomatic or there is evidence of
elevated liver enzymes three times above upper limits of normal, organ dysfunction or
progressive disease [30]. In subjects with suspected isolated or predominantly liver involvement
in sarcoidosis, histological confirmation and exclusion of other mimickers is important prior to
initiating therapy. Long-term therapy with corticosteroids is discouraged due to the numerous
side-effects of corticosteroids [31]. Ursodeoxycholic acid (UDCA) has gained some favour in
treating hepatic sarcoidosis, especially in cases of isolated hepatic sarcoidosis [32]. Studies have
shown that treatment of hepatic sarcoidosis with UDCA is associated with improvement in liver
function tests, pruritus and fatigue [32]. The reported dose of UDCA is 10–15 mg·kg−1·day−1 [32].
UDCA is actually a bile acid that is present in low concentrations (3%) in the human bile [33].
It is the first-line therapy for various cholestatic diseases. Its exact mechanism of action is
unclear but does include improving bile acid transport, detoxification, and cytoprotective and
anti-apoptotic mechanisms [33]. Other agents such as anti-metabolites and anti-TNF-α agents have
226 https://doi.org/10.1183/2312508X.10032820
been used successfully in managing resistant hepatic sarcoidosis or when other organ involvement
co-exists [18]. In patients who develop cirrhosis and portal hypertension, management follows
the standard guidelines for management of cirrhosis and portal hypertension [34].
Prognosis
Hepatic sarcoidosis overall has a good prognosis, although it can progress to end-stage liver
disease with subsequent cirrhosis- and portal hypertension-related complications [26]. In a small
single-centre study that included 19 patients with liver sarcoidosis, liver involvement was a
significant prognostic factor for death with hazard ratio of 5.79, after adjustment for age, sex
and calendar year of sarcoidosis diagnosis [3]. In cases that require liver transplantation, the
success rates for transplants secondary to hepatic sarcoidosis are comparable to transplants for
other cholestatic diseases [35, 36]. The reported 1-, 3-, 5- and 10-year survival rates are 84.6%,
76.9%, 61.1% and 51.3% [35].
Splenic sarcoidosis
Introduction
The spleen acts primarily as a blood filter and is a secondary lymphoid organ where
lymphocytes transit and are activated. Unlike the lymph nodes it possesses only efferent and not
afferent lymphatic vessels [37]. Sarcoidosis granulomas typically occur in the white pulp that is
associated with the arterial vascularisation [38]. Although the granulomas are most often of
small size, they can coalesce to produce macroscopically visible nodules [38]. In sarcoidosis,
the spleen, although rarely enlarged, is the second most common site involved on autopsy series
[39] and splenic biopsy showed evidence of granuloma in more than half of sarcoidosis patients
[40]. Splenic involvement in sarcoidosis is often related to granulomatous localisation and much
more rarely to portal hypertension secondary to severe liver damage or comorbidity such as
lymphoma [41, 42]. However, unexplained recurrent peripheral lymphadenopathy and
worsening splenomegaly in a patient with sarcoidosis must raise suspicion of concurrent
lymphoproliferative disease [43]. Interestingly, spleen tissue extracts from sarcoidosis patients
were historically used for diagnosis [44]. Kveim reagent skin testing, consisting in injection of
sarcoidosis spleen tissue extracts, resulted in a granuloma response at the injection site by
4–6 weeks. Recent proteomic analysis on Kveim reagent identified 74 sarcoidosis tissue-specific
proteins. Among these is vimentin, which specifically induced IFN-γ and TNF-α secretion from
sarcoidosis peripheral blood mononuclear cells [45].
Epidemiology
The frequency of splenic sarcoidosis is difficult to assess and depends on the diagnostic
methods (clinical, radiological or by biopsy). In different large cohorts/series of sarcoidosis, the
frequency of splenic sarcoidosis, detected mostly on physical examination and/or imaging, was
between 3.9% and 20.9% of patients, with the differences possibly related to the cohort under
study and the diagnostic criteria used [5, 6, 8, 10–15] (table 1).
The age and sex of patients with splenic sarcoidosis are similar to other sarcoidosis patients
[46, 47], but in the rare cases of isolated splenic sarcoidosis, a female predominance has been
observed [48, 49]. Contradictory results were found regarding differences in ethnicity. Black
patients had more splenic involvement than White or Asian in one multicentric study and
meta-analysis [8, 50] and the opposite result was found in a monocentric study from the USA
[11]. In a phenotyping cluster analysis of 1237 sarcoidosis patients with involvement of at least
one extrapulmonary organ, a phenotypic cluster including among other organs the spleen was
associated with a low proportion of labour workers and mostly being non-Europeans [14].
https://doi.org/10.1183/2312508X.10032820 227
Clinical and biological presentation

Splenic sarcoidosis is more frequent in patients with a subacute than an acute onset of
sarcoidosis disease [6]. In 83.3% of cases, splenic involvement is detected during the 6 months
following the sarcoidosis diagnosis [13]. Splenic sarcoidosis is associated with an extensive
extrathoracic sarcoidosis disease that almost always includes the lung and often the liver
[47, 51]; however, rare cases of isolated splenic sarcoidosis or exceptionally accessory splenic
sarcoidosis have been described [48, 49]. In a recent cluster analysis in 2163 patients, the most
common organs involved in patients with splenic involvement in addition to lung were liver
(45.2% versus 3.0% without liver involvement) and kidney (11.0% versus 2.7% without) [6].
Another cluster analysis revealed an association between hepatosplenic, bone and peripheral
lymph nodes [14].
Splenic sarcoidosis is usually asymptomatic [46, 52]. Symptoms such as night sweats, fever,
malaise [51] or weight loss [6] are more common than in sarcoidosis patients without splenic
involvement. Splenomegaly is identified in 5% of sarcoidosis patients [13]. In a review
including 6074 cases with sarcoidosis, massive splenomegaly was rare and was described in 20
patients (0.3%) [53]. The definition of massive splenomegaly was when it extended into the left
lower quadrant or pelvis, or when it crossed the midline of the abdomen [53], but others
consider that it is characterised by a weight over 1000–1500 g or a largest dimension >20 cm
[54]. It may be associated with attendant discomfort from capsular distention or mass effect
within the abdomen, with symptoms like early satiety or left upper quadrant fullness [51, 55].
Symptoms related to hypersplenism with anaemia, thrombocytopenia and leukopenia, and

pancytopenia [56] are rare, observed in <1% of cases [13], but could occur in 20% of patients
with large splenomegaly [51]. A reduction in blood cell lines can also be observed in
sarcoidosis because of bone marrow involvement, an immune thrombocytopenia or from drug
toxicities [57, 58].
Serum ACE level was found to be higher in patients with diffuse splenic involvement than in
those without [47]. A linear relationship was noted between serum ACE level and splenic size,
or with the presence of nodules [59]. Another association was identified between the level of
serum IL-2 receptor (sIL-2R; a marker of Th1 cell activation) and spleen 18F-FDG uptake [60].
Both ACE and sIL-2R levels are neither sensitive nor specific for sarcoidosis or a specific organ
involvement. Hypercalcaemia may be related to splenic granulomas: 1,25-dihydroxyvitamin
D-mediated hypercalcaemia has been observed in isolated splenic sarcoidosis [61].
Exceptionally, cases have been reported with splenic rupture [62], infarction [63] or functional
asplenia [64]. Ectopic secretion of insulin-like growth factor-1 by the splenic sarcoidosis,
inducing hypoglycaemia, has also been described [65].
Imaging
On imaging, the spleen may show splenomegaly defined by a greatest dimension of ⩾14 cm or
the presence of multiple nodules.
Ultrasound
Ultrasound is a safe technique to detect splenomegaly and splenic nodules. The latter are
described as hypoechoic relative to background splenic parenchyma [66]. However, these
lesions cannot be differentiated easily from other disorders such as splenic lymphoma.
Contrast-enhanced ultrasound could be an interesting tool in splenic sarcoidosis [66].
228 https://doi.org/10.1183/2312508X.10032820
FIGURE 2 Hepatosplenic sarcoidosis on intravenous contrast-enhanced CT, with small hypodense nodules
throughout the spleen and liver, associated with abdominal adenopathy.
CT
The frequency of radiographic abnormalities of the spleen is unknown in sarcoidosis because all
series reported have involved significant selection biases [67]. Splenomegaly is the most
frequent manifestation in CT [68] and is associated with abdominal adenopathy in 69% of cases
[59]. Splenic nodules on CT, in the Spanish monocentric cohort of 640 patients with
sarcoidosis, were seen in 2.7% of cases [13]. Splenic nodules are usually discrete and multiple.
They appear hypodense and on intravenous contrast-enhanced CT the hypodensity is contrasted
relatively to background spleen [38, 69] (figure 2). They range in size from 1–2 mm to 2 cm,
are larger than hepatic nodules and are diffusely distributed. Nodules can be confluent with
increasing size [38, 69]. Approximately 50% of patients with splenic nodules will also show
hepatic nodules on CT and nodules occur most commonly in enlarged spleens [38, 69].
MRI
On MRI, splenic nodules associated with sarcoidosis are hypointense relative to background
spleen on T1-weighted and T2-weighted imaging (figure 3a). Following intravenous gadolinium,
nodules show no substantial enhancement (figure 3b). Lesions are most conspicuous on
T2-weighted fat-suppressed images or on early post-contrast images [38, 70]. Nodules on MRI
also show a contour irregularity [71]. The association of multiple hepatic and splenic nodules
with low signal intensity on T2-weighted images is highly suggestive of sarcoidosis and may aid
in the differential diagnosis of conditions such as metastasis or lymphoma [72].
18
F-FDG PET
18
F-FDG PET can identify lesions that are undetectable by CT and MRI. Splenic involvement
shows an increased 18F-FDG uptake that can be diffuse or multinodular, and less frequently
unifocal [60, 73]. Diffuse and moderate 18F-FDG uptake in the spleen is not specific and can be
related to nonspecific inflammatory conditions [60]. In a cluster analysis, a phenotype with
18
F-FDG uptake in muscle, bone, spleen and skin was evidenced [73].
Diagnosis
The diagnosis of splenic involvement in sarcoidosis is usually made without performing a
biopsy when granuloma has been evidenced in an extrasplenic organ in a compatible context.
https://doi.org/10.1183/2312508X.10032820 229
a) b)
FIGURE 3 MRI from a patient with splenic sarcoidosis. a) T2-weighted fat-suppressed MRI shows hypointense
splenic nodules. b) Early-phase gadolinium-enhanced MRI shows hypoenhancing splenic nodules.
Major differential diagnoses for splenic nodules include tuberculosis, lymphoma, metastasis and
abscess [74]. An extensive discussion on differential diagnosis was recently published [75].
Lymphoma should be strongly considered in instances where splenic lesions increase in size in
a sarcoidosis patient while other clinical manifestations of sarcoidosis are improving [57]. An
association of sarcoidosis and lymphoproliferative disease has previously been reported as the
sarcoidosis–lymphoma syndrome, defined as a condition in which sarcoidosis occurred several
years before the diagnosis of lymphoma. Several studies found an increased risk of lymphoma
in sarcoidosis patients. A few cases of sarcoidosis following lymphoma have also been reported
[42, 76, 77]. Splenic involvement is considered probable, according to the WASOG organ
assessment instrument, if there is evidence of low-attenuation nodules on CT and/or PET/
gallium-67 uptake in splenic nodules and splenomegaly on imaging or physical examination [9].
Because of the potential complications (haemoperitoneum, haematoma, pneumothorax), splenic
biopsy is rarely performed. In cases of isolated splenic involvement in sarcoidosis or in cases of
atypical presentation, percutaneous fine-needle splenic aspiration is usually successful in
recovering adequate tissue to allow a diagnosis of noncaseating granulomatous inflammation,
without major complications [40]. More recently, EUS-FNA has also been considered useful
and safe [78].
Prognosis
Outcome studies on spleen sarcoidosis are limited. In most cases, the disease remains benign, and
splenomegaly may resolve spontaneously, especially with a spleen that extended <4 cm below the
costal margin [51]. However, a severe evolution may occur at any time, sometimes after a long
period. Spleen enlargement can lead to hypersplenism and, when very voluminous, to risk of rupture.
Patients with splenic involvement also present significantly more often with impaired lung
function [6], and pulmonary fibrosis is more common with splenomegaly from sarcoidosis [55].
Spleen involvement and splenomegaly are associated with a chronic disease [13, 47, 79] and
this association has been evaluated in one study with an odds ratio of 3.2 [12]. In a recent
study, splenic sarcoidosis was also identified as an independent factor for mortality [12].
Treatment
Splenic sarcoidosis usually does not require treatment as patients are asymptomatic.
Corticosteroids have been effective in decreasing splenic size and in treatment of haematological
230 https://doi.org/10.1183/2312508X.10032820
abnormalities due to hypersplenism, but only in small series [51, 80]. Thus, the dose and
duration of corticosteroid is not standardised. A case report also found that adalimumab was an
effective alternative [81]. Treatment is indicated for symptomatic abdominal pain from
splenomegaly, hypersplenism, functional asplenia, or splenic rupture [46]. Thrombocytopenia
associated with hypersplenism is usually mild (50 000–100 000 platelets per μL) and requires no
specific treatment.
Splenectomy is rarely performed for splenic sarcoidosis, and should be considered after
corticosteroid trial [46]. Indications include massive splenomegaly with signs of discomfort,
infarction, precaution against splenic rupture, need for excluding lymphoma or malignancy, and
severe hypersplenism with reduction in one or several blood cell lines [56, 80]. In a small
cohort of 13 sarcoidosis patients who had splenectomy and a strict prophylactic protocol, in the
long-term follow-up none of the 13 patients developed serious infections or sepsis [56].
Conclusion
In summary, hepatic and splenic involvement in sarcoidosis have various presentations and
manifestations. One should consider the broad differential diagnoses that sarcoidosis can mimic,
as the diagnosis is a diagnosis of exclusion. Indications for therapy follow the general
sarcoidosis treatment guidelines: treat when symptomatic or progressive.
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76 El Jammal T, Pavic M, Gerfaud-Valentin M, et al. Sarcoidosis and cancer: a complex relationship. Front Med
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https://doi.org/10.1183/2312508X.10032820 233
Chapter 16
Sarcoidosis-associated pulmonary hypertension

Vikramjit Khangoora1, Hilario Nunes2 and Oksana A. Shlobin1
1
Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA. 2Service de
Pneumologie, Centre de Référence Des Maladies Pulmonaires Rares, Hôpital Avicenne, Assistance Publique
Hôpitaux de Paris, Université Sorbonne Paris Nord, Bobigny, France.
Corresponding author: Oksana A. Shlobin (oksana.shlobin@inova.org)
Cite as: Khangoora V, Nunes H, Shlobin OA. Sarcoidosis-associated pulmonary hypertension. In: Bonella F,
pp. 234–255 [https://doi.org/10.1183/2312508X.10032920].
@ERSpublications
Patients with sarcoidosis-associated pulmonary hypertension have increased morbidity and mortality.
Studies suggest that pulmonary vasodilators may benefit some patients but more data are needed to
determine the ideal medications and treatment candidates. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis-associated pulmonary hypertension (SAPH) is a common complication of pulmonary

sarcoidosis that contributes to increased symptoms of dyspnoea and morbidity and decreased survival.
The mechanisms by which SAPH develops are complex, multifactorial and often overlapping. There
remain many unknowns regarding the pathogenesis, natural history and effective treatment of this
disease. Over the past decade, a growing body of literature has provided additional insights that have
helped the medical community to better characterise and treat this disease. This chapter aims to
summarise both the previous literature and the most recent developments in SAPH.
Introduction
Sarcoidosis-associated pulmonary hypertension (SAPH) is a common complication of
pulmonary sarcoidosis with prevalence varying from 3% to 73% depending on the severity of
pulmonary disease, the population studied and the method of diagnosis [1, 2]. SAPH not only
contributes to increased symptoms of dyspnoea and overall morbidity but is also associated with
decreased survival [3–6]. The mechanisms by which SAPH develops are complex,
multifactorial and often overlapping. There remain many unknowns regarding the pathogenesis,
natural history and effective treatment of this disease.
Classification of pulmonary hypertension

According to the 6th World Symposium on Pulmonary Hypertension held in 2019, pulmonary
hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) of >20 mmHg on
right heart catheterisation (RHC) [7], differing from the most recent 2015 European Society of
Cardiology (ESC)/European Respiratory Society (ERS) guidelines, which maintain an mPAP
threshold of 25 mmHg [8]. Further delineation of pre-capillary, post-capillary and combined
pre-/post-capillary PH is determined by evaluation of the pulmonary vascular resistance (PVR)
and pulmonary artery (PA) occlusion pressure, as outlined in table 1 [7, 8].
234 https://doi.org/10.1183/2312508X.10032920
SARCOIDOSIS-ASSOCIATED PH | V. KHANGOORA ET AL.
TABLE 1 Haemodynamic definition of pulmonary hypertension (PH)
Haemodynamic PH definition Haemodynamic characteristics Clinical groups #
Pre-capillary PH mPAP >20 mmHg, PAWP ⩽15 mmHg, PVR ⩾3 WU 1, 3, 4 and 5

Post-capillary PH mPAP >20 mmHg, PAWP >15 mmHg, PVR <3 WU 2 and 5
Combined pre- and post-capillary PH mPAP >20 mmHg, PAWP >15 mmHg, PVR ⩾3 WU 2 and 5
mPAP: mean pulmonary artery pressure; PAWP: pulmonary artery wedge pressure; PVR: pulmonary vascular
resistance; WU: Wood units. #: as defined in table 2. Reproduced and modified from [8] with permission.
According to the ESC/ERS Task Force and 6th World Symposium on Pulmonary Hypertension,
five PH groups are defines, with SAPH placed in group 5 along with other forms of PH deemed
to be multifactorial and/or with unclear pathophysiological mechanisms (table 2) [7]. Although
the predominant aetiology of SAPH is the underlying fibrotic lung disease (figure 1), there are a
multitude of other pathophysiological mechanisms of SAPH that resemble the pathophysiology
of PH in groups 1, 2, 3 and/or 4 (figure 2) [10, 11]. It is of the utmost importance to determine
the dominant aetiology (or combinations thereof ) of SAPH in each patient, as this information
subsequently drives the approach to treatment.
Epidemiology
The exact prevalence of SAPH remains uncertain due to significant variability in the diagnostic
methods and criteria used, as well as the populations studied. The overall prevalence of PH in
sarcoidosis is ∼2–6%, although a greater prevalence has been observed in particular ethnic
groups and in more advanced parenchymal disease (table 3). A recent report of data from the
PULSAR (Pulmonary hypertension in pulmonary sarcoidosis) study, a prospective Dutch SAPH
registry of largely Caucasians, found a prevalence of haemodynamically diagnosed SAPH of
2.9% [16]. Similarly, a combined analysis with previously reported prospective PULSAR data
from a German cohort demonstrated a combined prevalence of 2.9% [1, 17]. A higher
prevalence has been reported using a transthoracic echocardiography (TTE)-derived right
ventricular systolic pressure (RVSP) cut-off value of ⩾40 mmHg: 5.7% in Japanese patients,
14% in a cohort of predominantly African-Americans and 20.8% in an Arab cohort [18–20].
Patients with advanced (radiographic stages III and IV) parenchymal disease appear to have a
higher prevalence of SAPH [20], ranging from 38.5% in patients with persistent dyspnoea
despite adequate systemic sarcoidosis treatment [13] to 73.8% in those listed for transplant
[2, 14, 16, 21]. Prevalence using a new lower mPAP definition of PH (⩾20 rather than
⩾25 mmHg) is not known [7] and further prospective studies are needed.
Pathophysiology
Due to multifactorial and often overlapping pathophysiological mechanisms, SAPH can fall into
all five phenotypic groups of PH, or a combination of several processes (figures 1 and 2).
Patients with more advanced parenchymal disease are more likely to present with PH with
“out-of-proportion” elevation of mPAP and PVR [4, 11, 13, 16–20, 22–24]. This subtype of
SAPH is attributed to capillary-bed destruction and hypoxic pulmonary vasoconstriction [9].
Interestingly, the degree of parenchymal disease and spirometric restriction do not correlate
with the degree of PH, suggesting the presence of other pathophysiological mechanisms
[10, 13, 20, 22, 25].
https://doi.org/10.1183/2312508X.10032920 235
TABLE 2 Clinical classification of pulmonary hypertension (PH) groups
PH group Associated disease
Group 1: PAH PAH

Idiopathic
Heritable (BMPR2 and other mutations)
Drug and toxin induced
Associated with:
Connective tissue diseases
HIV infection
Portal hypertension
Congenital heart diseases
Schistosomiasis
Pulmonary veno-occlusive disease and/or pulmonary capillary
haemangiomatosis:
Idiopathic
Heritable (EIF2AK4 mutation)
Drug, toxin and radiation induced
Associated with connective tissue diseases and HIV infection
Group 2: PH due to left heart disease Left ventricular systolic dysfunction
Left ventricular diastolic dysfunction
Valvular disease
Congenital/acquired left heart inflow/outflow tract obstruction and
congenital cardiomyopathies
Congenital/acquired pulmonary vein stenosis
Group 3: PH due to lung diseases Chronic obstructive pulmonary disease
and/or hypoxia ILD
Other pulmonary diseases with mixed restrictive and obstructive pattern
Sleep disordered breathing
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental lung diseases
Group 4: CTEPH and other pulmonary CTEPH
artery obstructions Other pulmonary artery obstructions:
Angiosarcoma
Other intravascular tumours
Arteritis
Congenital pulmonary arteries stenoses
Parasites (hydatidosis)
Group 5: PH with unclear and/or Haematological disorders:
multifactorial mechanisms Chronic haemolytic anaemia
Myeloproliferative disorders
Splenectomy
Systemic disorders:
Sarcoidosis
Pulmonary histiocytosis
Lymphangioleiomyomatosis
Neurofibromatosis
Metabolic disorders:
Glycogen storage disease
Gaucher disease
Thyroid disorders
Others:
Pulmonary tumoural thrombotic
Microangiopathy
Fibrosing mediastinitis
Chronic renal failure
Segmental PH
PAH: pulmonary arterial hypertension; CTEPH: chronic thromboembolic PH. Reproduced and modified from [8]
with permission.
236 https://doi.org/10.1183/2312508X.10032920
Vasculocentric Parenchymal
Granulomatous vascular involvement Granulomas
Occlusive vasculopathy Vessel distortion Fibrosis

from fibrosis
PVOD
IPAH-Iike lesions Capillary bed destruction and
vascular ablation
Hypoxic vasoconstriction
Thrombotic angiopathy
Acute and chronic Ventilation/perfusion
pulmonary embolism mismatch
Sarcoidosis-associated
pulmonary hypertension
Myocardial systolic and
Fibrosing mediastinitis
diastolic dysfunction
Adenopathy
Portopulmonary hypertension
Sleep apnoea Vascular compression
Anaemia
Extrapulmonary involvement and Hilar/mediastinal

comorbidities
FIGURE 1 Pathophysiology of sarcoidosis-associated pulmonary hypertension. IPAH: idiopathic pulmonary arterial

hypertension; PVOD: pulmonary veno-occlusive disease. Reproduced and modified from [9] with permission.
Granulomatous infiltration in and around the pulmonary arterial, venous and lymphatic
circulations may contribute to the development of SAPH [11, 26–29]. Noncaseating granuloma
infiltration occurs in all layers of pulmonary vessel walls, thus resulting in higher PVR [26].
Furthermore, it may lead to endothelial proliferation, media, adventitial and basal laminar
disruption and destruction, necrosis and inflammation. A rare subset of SAPH patients has
small-vessel arteriopathy with plexiform lesions, mirroring the pathological changes seen in
idiopathic pulmonary arterial hypertension (PAH), with genetic mutations in BMPR2 and
KCNA5 [26, 30–33]. Increased expression of endothelin-1 and TNF-α, implicated in the
pathogenesis of idiopathic PAH, has been noted in sarcoidosis [34, 35].
Approximately 5% of sarcoidosis patients have clinical myocardial involvement, manifesting as

left ventricle (LV) systolic or diastolic dysfunction, with clinically silent cardiac sarcoidosis
(CS) reported in 25% of patients [36]. CS usually presents with conduction disease and
ventricular arrhythmias due to myocardial granulomatous infiltration; however, diastolic
dysfunction is increasingly recognised [15, 36–42]. Thus, cardiac SAPH may present with both
post-capillary and combined pre-/post-capillary PH [13]. Isolated right ventricle (RV) failure in
the absence of pulmonary or hepatic disease involvement has also been reported [43, 44].
Large population-based studies report a 2–3-fold increased risk of pulmonary embolism in

patients with sarcoidosis compared with the general population [45–48]. In addition, in situ
thrombotic angiopathy, attributable to ongoing chronic systemic inflammation, may contribute
https://doi.org/10.1183/2312508X.10032920 237
Group 1 physiology
Granulomatous
inflammation of
Group 5 physiology arterioles
PVOD lesions
Liver disease Group 2 physiology
Phenotype overlap
Cardiac sarcoidosis
Systolic dysfunction
Diastolic dysfunction
SAPH
Group 4 physiology Group 3 physiology
Sarcoidosis parenchymal
In situ thrombi disease
CTEPH Sleep apnoea
FIGURE 2 Phenotypes of sarcoidosis-associated pulmonary hypertension (SAPH). PVOD: pulmonary veno-

occlusive disease; CTEPH: chronic thromboembolic pulmonary hypertension.
to the pathogenesis of SAPH [49]. Fibrosing mediastinitis and bulky mediastinal adenopathy
can cause direct central and segmental pulmonary vascular compression with resultant
pulmonary arterial and venous stenosis (figure 3) [10, 50, 51]. Anaemia of chronic disease
occurs in 20% of patients with sarcoidosis and, if severe, may lead to high-output heart failure [52].
Obstructive sleep apnoea is very common and, if untreated, may contribute to the development
of SAPH [9, 34, 53]. Although liver involvement is common in sarcoidosis, it only rarely
results in cirrhosis and portal hypertension [54, 55].
Like sarcoidosis, SAPH occasionally presents with clinical features that mirror entirely another
disease. Given granulomatous infiltration of post-capillary venules and interlobular veins, a
pulmonary veno-occlusive disease (PVOD)-like phenotype may develop [45, 56, 57]. Small
arteriolar occlusions as well as sarcoid-associated fibrosing mediastinitis can mimic chronic
thromboembolic PH [58, 59]. Finally, diffuse alveolar capillary multiplication, a similar
pathological process to pulmonary capillary haemangiomatosis, has presented rarely as SAPH [60].
Diagnosis
The multifactorial mechanisms of SAPH, in addition to disease progression, often obscure the
predominant pathway(s) responsible for a patient’s symptomatology. It is imperative to conduct
a thorough diagnostic evaluation, as individual disease mechanisms and their corresponding
severity will ultimately affect the approach to therapy in each individual patient. Persistent or
worsening dyspnoea in the absence of worsening parenchymal disease should prompt
consideration of SAPH. Evaluation for SAPH should include pulmonary function testing, a
6-min walk test (6MWT), chest imaging, an ECG, laboratory tests and TTE.
238 https://doi.org/10.1183/2312508X.10032920
TABLE 3 Studies on the prevalence of pulmonary hypertension in patients with sarcoidosis
First author Study design Cohort Population Diagnostic Diagnostic Prevalence,

[ref.] size, n method criteria %
GLUSKOWSKI [12] Not specified 50 Various disease states RHC mPAP 6

⩾25 mmHg
BAUGHMAN [13] Retrospective 130 Persistent dyspnoea RHC mPAP 38.5
despite systemic ⩾25 mmHg
therapy
SULICA [14] Retrospective 106 Various TTE RVSP 51
cardiorespiratory ⩾40 mmHg
symptoms
RAPTI [15] Cross-sectional 313 Various disease states TTE±RHC mPAP 2.9
⩾25 mmHg
HUITEMA [16] Prospective 399 Various disease states TTE±RHC mPAP 2.9
(Dutch) ⩾25 mmHg
PABST [17] Prospective 111 Various disease states TTE±RHC mPAP 3.6
(German) ⩾25 mmHg
ALHAMAD [18] Retrospective 96 Various disease states TTE RVSP 20.8
(Saudi Arabian) ⩾40 mmHg
BOURBONNAIS [19] Prospective 141 Various disease states TTE±RHC mPAP 14
with 6MWT data ⩾25 mmHg
(African-American)
HANDA [20] Prospective 212 Various disease states TTE RVSP 5.7
(Japanese) ⩾40 mmHg
SHORR [2] Retrospective 363 Listed for lung RHC mPAP 73.8
transplant ⩾25 mmHg
(African-American)
RHC: right heart catherisation; mPAP: mean pulmonary artery pressure; TTE: transthoracic echocardiogram;
RVSP: right ventricular systolic pressure; 6MWT: 6-min walk test.
Dyspnoea is the most common presenting symptom in SAPH; however, diagnosis may be
delayed by the presence of confounding symptoms such as chest pain, palpitations, cough and
the misattribution of dyspnoea to underlying parenchymal lung disease (PLD) [13, 14]. Only
8% of SAPH patients are asymptomatic, and the classic clinical signs of right heart failure
develop late in the disease [14]. Analysis of the French Pulmonary Hypertension Registry found
a mean time from the diagnosis of sarcoidosis to SAPH of 17 years [22]. The Registry for
Sarcoidosis Associated Pulmonary Hypertension (ReSAPH) of 159 patients showed a shorter
time of 12.6 years [21].
Pulmonary function tests

Patients with SAPH have a lower FVC and DLCO than other sarcoidosis patients, although
one-quarter have near-normal pulmonary function tests [11, 14, 15, 19, 20]. A diffusion
capacity <60% predicted is associated with a 7-fold increase in underlying PH [34, 53, 61], and
severely reduced DLCO <30% pred is associated with worse transplant-free survival [21]. In
scleroderma patients, an FVC/DLCO ratio >1.6 is associated with an increased risk of PAH,
although data in sarcoidosis remain less robust [55, 62].
6MWT
6MWT data have both a diagnostic and a prognostic role in SAPH. The 6-min walk distance
(6MWD) is generally reduced in SAPH patients, although factors such as PLD, muscle
https://doi.org/10.1183/2312508X.10032920 239
a) b)
FIGURE 3 Right upper lobe pulmonary artery compressed by adenopathy causing sarcoidosis-associated
pulmonary hypertension. a) CT with biopsy-proven sarcoidosis and pulmonary hypertension demonstrating
calcified hilar lymphadenopathy with compression of the right upper lobe pulmonary artery. b) Right upper lobe
pulmonary artery compression demonstrating absent blood flow on pulmonary angiography. Images provided by
and reproduced with the kind permission of R.P. Baughman (University of Cincinnati, OH, USA).
weakness, CS and arthritis may affect test performance. Decreased distance and/or new or
worsening desaturation on the 6MWT should prompt further evaluation for SAPH, especially in
those with minimal or stable PLD [9]. In the ReSAPH dataset, the average 6MWD was 305 m
and most patients desaturated by ∼5% on exertion [4]. A reduced 6MWD with oxygenation
desaturation <90% is associated with an OR of 12.1 (95% CI 3.7–19.7) of having SAPH
[19, 63]. The absence of desaturation on exertion, conversely, makes the diagnosis of SAPH
less likely [34]. The composite product of 6MWD and oxygen saturation, known as the
distance–saturation product, is correlated with a greater number of factors associated with
reduced 6MWT performance, including CT fibrosis and the presence of PH [18, 64]. In
ReSAPH, patients with a 6MWD <300 m had a significantly higher chance of adverse clinical
outcomes ( p=0.0120) and worse pre-transplant survival ( p<0.001) [21, 65]. The 6MWD also
has a significant correlation with mPAP (r=0.167; p=0.0272), systolic PA pressure (r= − 0.245;
p=0.0011), FEV1 (r=0.289; p=0.0001), and FVC (r=0.295; p=0.0001) [65].
Laboratory evaluation
Plasma biomarkers such as brain natriuretic peptide (BNP) or N-terminal proBNP are often
elevated in patients with SAPH, but their sensitivity and specificity for discriminating PH are
lower than that for isolated group I PAH [66, 67].
ECG
ECG abnormalities including right axis deviation, right ventricular hypertrophy or strain, right
bundle branch block and corrected QT interval prolongation are typically only seen in the
presence of significant right heart dysfunction and rarely in early disease [11, 68].
Imaging
In sarcoidosis, chest radiography may show hilar fullness, which may be from either hilar
adenopathy or PA enlargement [34], and can be further assessed by CT angiography, which can
assess the degree of parenchymal disease, PA enlargement and vascular compression by bulky
adenopathy [29, 34]. A ratio of PA/ascending aorta (PA/A) diameter >1.0, an RV/LV ratio >1.0
and a PA diameter ⩾29 mm all predict PH in ILD [11, 61, 68–71]. PA diameter indexed to
body surface area may be able to discriminate between the presence and absence of PH
( p<0.006) with greater diagnostic accuracy (area under the curve (AUC) 0.91) than the PA/A
ratio (AUC 0.71) [72]. A recent study utilising combined PET and cardiac MRI (CMR) in
240 https://doi.org/10.1183/2312508X.10032920
suspected CS patients evaluated the correlation of 18F-FDG uptake in the PA wall and
mPAP [73]. mPAP was significantly higher in the group with PA 18F-FDG uptake (34.4±7.2
versus 25.6±9.3 mmHg; p=0.003). In the subgroup that underwent TTE, signs of PH were more
common in patients with PA 18F-FDG uptake (51.9% versus 29.8%; p<0.05) and the intensity
of 18F-FDG uptake correlated with the PA pressure as measured on RHC [73]. Given the
increased risk for venous thromboembolism, an investigation for concurrent chronic
thromboembolic pulmonary hypertension (CTEPH) should be done [45, 46]. A ventilation/
perfusion scan usually used to screen for CTEPH does not allow assessment of underlying PLD
and vascular compression by bulky adenopathy. Dual-energy CT is an emerging technology that
allows a detailed and simultaneous assessment of vascular anatomy and parenchymal
morphology [74–76].
Echocardiography
TTE is the most frequently used screening tool for diagnosing PH. It also assesses left
ventricular systolic and diastolic function, valvular abnormalities, the presence of shunts and
pericardial effusions [34]. Conventionally, TTE-derived RVSP is calculated using a modified
Bernoulli equation (RVSP=4(TRVmax)2+right atrial pressure) via measurement of the maximum
tricuspid regurgitant jet velocity (TRV). Clinically significant SAPH is more likely to be present
with a higher estimated RVSP. A recent prospective study in patients screened for the presence
of SAPH with TTE showed that a TRV >3.4 m·s−1 confirmed whereas a TRV <2.9 m·s−1 ruled
out PH in all patients [16].
The concurrent presence of lung disease may impair the ability to obtain adequate
echocardiographic images and subsequently result in an inaccurate estimation of PAP in 30–46%
of patients as demonstrated by prior studies [9, 11, 77–79]. TTE can both overestimate and
underestimate PAP in as many as 48% of patients [9, 11, 34, 61]. The presence of RV dilation,
hypertrophy and dysfunction, PA dilation, right atrial dilation, and interventricular septal
flattening have been shown to improve the sensitivity of TTE for detection of SAPH; however,
in a recent study, secondary TTE signs of PH in patients with a TRV between 2.9 and 3.4 m·s−1
did help discriminate the presence or absence of PH [8, 9, 34, 80].
Recent studies have suggested that using alternative TTE measures such as RV outflow tract
diameter, fractional area of change, and tricuspid annular plane systolic excursion and
three-dimensional (3D) imaging may be more accurate in detecting PH and RV dysfunction in
patients with PLD [81]. In contrast to two-dimensional TTE, 3D TTE allows the assessment of
RV volume and a more complete assessment of RV structural and regional abnormalities. 3D
echo-derived RV ejection fraction closely correlates with gold-standard CMR-derived RV ejection
fraction and is independently associated with outcomes [82]. In a study of patients with group 3
PH, a 3D echo-derived fractional area of change of above and below 28% discriminated risks of
both mortality and heart-failure hospitalisation [83]. The use of RV strain analysis allows
improved prognostication in group 1 PAH [84] and most strongly correlates with CMR-derived
RV ejection fraction (r=0.83; p<0.005) [85–88], but has not been studied in SAPH.
Right heart catheterisation

Given the potential for underdiagnosis of PH with TTE alone, in patients with high clinical
suspicion of PH despite normal TTE, RHC should be performed to evaluate the presence of
SAPH [9, 11, 34, 61]. Although no guideline recommendations exist on testing in group 5 PH,
RHC should be performed in patients with symptoms and/or testing considered to be “out of
proportion” to the underlying PLD, and/or signs of right heart dysfunction with a high index of
suspicion for PH (figure 4) [8]. Given the multifactorial nature of SAPH and the increased risk
https://doi.org/10.1183/2312508X.10032920 241
242

Concern for SAPH
• Persistent/worsening dyspnoea on immunosuppression • Signs of right heart failure

• 6MWD <300 m and/or >5% desaturation • Drop in 6MWD >20% without change in spirometry Other echo signs of PH
• Worsening FC with stable spirometry • Drop in DLCO >15% with stable spirometry and/or DLCO <60% RV/LV >1
• Elevated BNP/NT-proBNP • Concern for PH or RV dysfunction on CMR IVS flattening
• Dilated PA on CT • Fibrosis >20% of parenchyma on CT PA diameter >25 mm
RVOT acceleration <105 m·s–1
Diastolic pulmonary regurgitation velocity
≥1 above criteria or undergoing transplant evaluation >2.2 m·s–1
IVC diameter >21 mm and <50%
decrease with sniff
TTE RAA >18 cm2
High risk Intermediate risk Low risk
TRV 2.9–3.4 m·s–1 TRV >3.4 m·s–1 TRV ≤2.8 m·s–1 TRV 2.9–3.4 m·s–1 or TRV ≤2.8 m·s–1 TRV ≤2.8 m·s–1
with other with/without other or unmeasurable with unmeasurable without with other echo without other
echo signs of PH echo signs of PH other echo signs of PH other echo signs of PH signs of PH echo signs of PH
Is FVC <50% Follow-up in

RHC No
https://doi.org/10.1183/2312508X.10032920
predicted? 6–12 months
Yes
Proceed with RHC if plan for Consider RHC on

transplant evaluation case-by-case basis
FIGURE 4 Proposed algorithm for diagnosis of sarcoidosis-associated pulmonary hypertension (SAPH). 6MWD: 6-min walk distance; FC: functional class; BNP: brain natriuretic
peptide; NT-proBNP: N-terminal proBNP; PA: pulmonary artery; PH: pulmonary hypertension; RV: right ventricle; CMR: cardiac MRI; LV: left ventricle; IVS: interventricular
septum; RVOT: right ventricular outflow tract; IVC: inferior vena cava; RAA: right atrial area; TTE: transthoracic echocardiography; TRV: tricuspid regurgitant jet velocity;
RHC: right heart catheterisation. Reproduced and modified from [89] with permission.
TABLE 4 Definition of pulmonary hypertension (PH) in the setting of chronic lung disease (CLD)
CLD without PH mPAP <21 mmHg, or mPAP 21–24 mmHg with PVR <3 WU
CLD with PH mPAP 21–24 mmHg with PVR ⩾3 WU, or mPAP 25–34 mmHg
CLD with severe PH mPAP >35 mmHg, or mPAP >25 mmHg with CI <2.0 L·min−1·m−2
mPAP: mean pulmonary artery pressure; WU: Wood units; PVR: pulmonary vascular resistance; CI: cardiac
index. Data from [7].
for left heart dysfunction, provocative manoeuvres during RHC such as fluid challenge and
exercise should be strongly considered. Furthermore, RHC is compulsory for any patient with
lung disease undergoing a transplant evaluation.
The 6th World Symposium on Pulmonary Hypertension definition of PH in chronic lung

disease appears appropriate for parenchymal sarcoidosis without other aetiologies for PH
(table 4) [90]. Given the multifactorial nature of SAPH, however, it may present as either pre-,
post- or combined PH. A comprehensive workup is required to identify the presence of all
phenotypes (figures 1 and 2) to guide the most appropriate treatment approach.
Treatment
The optimal treatment of SAPH is not well defined, as available studies are small and lack
long-term efficacy and safety data. The approach to therapy depends on the dominant
pathophysiological phenotype. Identification and treatment of comorbidities and modifiable risk
factors is crucial. Referral to a specialised PH centre should be strongly considered to identify
both the aetiology of PH and potential treatment options. Resting and exertional hypoxaemia
(oxygen saturation measured by pulse oximetry <88%) is common in SAPH and should be
treated with supplemental oxygen to address possible hypoxic pulmonary vasoconstriction.
Patients with obstructive sleep apnoea, left heart dysfunction, acute or chronic thromboembolic
disease and anaemia should be treated appropriately. In addition, patients with SAPH should be
referred to pulmonary rehabilitation to address deconditioning.
PLD treatment considerations

In patients with active parenchymal disease as evidenced by 18F-FDG PET, it makes intuitive
sense to control inflammation either before or in parallel with treatment of PH. This concept has
not been rigorously studied but appears to be supported by limited data. In a small study of
patients with Scadding stage II and III sarcoidosis and predominantly exercise-induced PH
treated with corticosteroids for 12 months, 92% of patients had improvement in chest
radiography and pulmonary function tests, and 50% in pulmonary haemodynamics [91]. In
another small study, 3–6 months of treatment with high-dose prednisone (0.5–1 mg·kg−1·day−1)
resulted in improvement in haemodynamics in 60% of patients with no pulmonary fibrosis but
no change in those with stage IV disease [10]. Patients with extrinsic compression of the PAs
may potentially benefit from immunosuppressive therapy in the presence of active nodal
inflammation via 18F-FDG PET [22, 92]. The majority of the patients with SAPH, however,
present with stage 4 fibrocystic disease, and immunosuppressive therapy is unlikely to be
beneficial, thus making treatment of SAPH a priority.
Vascular considerations
When proximal PA stenosis is identified in the absence of metabolically active extrinsic
compression, stenting may be beneficial [92, 93]. Eight SAPH patients with extrinsic PA
https://doi.org/10.1183/2312508X.10032920 243
compression were treated with balloon angioplasty with a significant improvement in mPAP
from 42.5±4.6 to 20.5±3.2 mmHg (mean±SD), PVR from 12.3±1.2 to 3.81±0.275 Wood units
(WU) and 6MWD from 236.8±36.7 to 456.4±48.2 m ( p<0.05) [92]. Stenting can also be
considered for pulmonary venous stenosis but is associated with higher mortality and is more
likely to recur [94].
Use of pulmonary vasodilators in the treatment of SAPH

According to the Pulmonary Hypertension Registry and ReSAPH data, 72–77% of patients with
SAPH are treated with pulmonary vasodilators worldwide, despite the scarcity of long-term
safety and efficacy data [21, 22]. Available studies are limited by retrospective design, small
trial size and short duration. In addition, there is variability in patient selection, with
inconsistently described PH phenotypes. Despite these limitations, many studies have
demonstrated improvements in pulmonary haemodynamics, although this benefit has not been
consistently observed in 6MWT, BNP and functional status (table 5) [5, 95–109].
Treatment with pulmonary vasodilators may be considered for select patients with
moderate-to-severe SAPH under close monitoring for worsening hypoxaemia (figure 5). Patients
with pulmonary venous disease due to left heart dysfunction or PVOD phenotype may develop
pulmonary oedema if treated with pulmonary vasodilator therapy [10, 16]. Worsening
hypoxaemia due to ventilation/perfusion mismatch and shunting has not been demonstrated, but
it is prudent to monitor patients, especially those with pre-existing hypoxaemia.
Phosphodiesterase type 5 inhibitors

Phosphodiesterase type 5 inhibitors (PDE5is) (sildenafil and tadalafil) work via the nitric oxide
pathway, inhibiting intracellular cyclic guanosine monophosphate degradation, resulting in
smooth-muscle relaxation. There is limited evidence on the use of PDE5i monotherapy from
retrospective and open-label studies [95–97]. Most studies demonstrate haemodynamic
improvement without worsening in oxygenation.
Several studies also showed improvements in 6MWD, World Health Organization (WHO)
functional class (FC) and serum BNP (table 5).
Guanylate cyclase stimulators

Riociguat is the only drug in this class and works via the nitric oxide pathway by increasing
intracellular guanosine monophosphate, resulting in vascular smooth-muscle relaxation. The
recent prospective, double-blind, placebo-controlled RioSAPH (Riociguat for Sarcoidosis
Associated Pulmonary Hypertension) trial of riociguat in eight patients with FVC >50% over
the course of 12 months demonstrated a significantly delayed time to clinical worsening, with
clinical worsening in 62.5% of patients receiving placebo (n=8). Patients in the riociguat group
had a significant improvement in 6MWD of 42.7 m (median; range −7.5 to 91.4 m), whereas
the placebo group had a decline of 55.9 m (−176.8 to 60 m) [98]. In addition, no worsening in
oxygenation was noted in the riociguat-treated patients.
Endothelin receptor antagonists

Several endothelin receptor antagonists (ERAs) have been evaluated for use in SAPH, with
bosentan being the only ERA studied in a double-blind, placebo-controlled trial in SAPH, in
addition to retrospective reports (table 5) [99, 101, 102]. The study showed that in 23 patients
with moderate-to-severe PH (mean±SD: 36±6.9 mmHg, PVR 5.9±2.9 WU), patients treated with
bosentan for 16 weeks had an 11% (4±6.6 mmHg) improvement in mPAP and a 25% decrease
in PVR (5.9±2.9 to 4.4±2.0 WU) without improvement in 6MWD or FC [102].
244 https://doi.org/10.1183/2312508X.10032920
https://doi.org/10.1183/2312508X.10032920
TABLE 5 Studies on the treatment of sarcoidosis-associated pulmonary hypertension (PH)
First Drug Study design Cohort size Measurements Results Comments

author
[ref.]
Phosphodiesterase type 5 inhibitors

MILMAN Sildenafil Retrospective 12 6MWT Decrease in mPAP from 48 to Improvement in baseline SpO2
[95] RHC 39 mmHg (p=0.03) and PVR from
5.9±2.93 to 4.4±2.0 WU (p<0.01)
No change in 6MWD
KEIR [96] Sildenafil (n=29) Retrospective 33 6MWT Increase in 6MWT by 13 m (p=0.04) Similar improvements in BNP,
Sildenafil+bosentan TTE Decrease in BNP and TAPSE TAPSE and 6MWD in both
(n=4) BNP WHO FC improved in 14, stable in 12, groups
WHO FC worse in eight
FORD [97] Tadalafil Placebo-controlled 12 (seven 6MWT No change in 6MWD, BNP, dyspnoea Well tolerated
open label completed BNP or QoL Cohort with mild PH (mPAP

trial) WHO FC 34.8±7 mmHg, PVR 6±4 WU)
Borg scale
QoL: SF-36, SGRQ,
FAS
Soluble guanylate cyclase stimulators
BAUGHMAN Riociguat Double-blind 8 (riociguat) TCW Improved 6MWD by 42.7 m in Well tolerated
[98] randomised 8 (placebo) 6MWT riociguat group compared with Longer TCW with riociguat
control trial Spirometry decrease of 55.9 m in placebo (p=0.0124)
WHO FC (p=0.0149)
Endothelin receptor antagonists
PALERMO Bosentan Retrospective 40 6MWT Decrease in mPAP of 4.9±2.4 Well tolerated
[99] RHC (p=0.005) and PVR of 4.2±6 (p=0.017)
6MWD improved by 74.6 m
Continued
245
246

TABLE 5 Continued

author
[ref.]
JUDSON Ambrisentan Prospective open label 21 6MWT No improvement in 6MWT or High dropout rate (52%)
[100] WHO FC dyspnoea, BNP or QoL Worsened dyspnoea in 38%
Borg scale WHO FC improved in 10 out of 21
QoL: SF-36 who completed the study
QUA [101] Bosentan Retrospective 45 6MWT Decrease in mPAP by 7.8±2 mmHg Five patients with treatment
RHC (p=0.005) and PVR by 2.3±0.9 WU cessation due to hepatic
(p=0.01) at 36 months (29 patients) toxicity
BAUGHMAN Bosentan Double-blind 25 (23 6MWT Decrease in mPAP by 4±6.6 mmHg Cohort with mild PH
[102] randomised control completed RHC (p=0.0105) and PVR by 1.7±2.75 WU Two patients required
trial trial) Borg scale (p=0.0104) increased oxygen
QoL: SF-36, SGRQ, supplementation
FAS
MATHIJSSEN Macitentan (n=3) Retrospective 6 6MWT 6MWD improved in all three patients Well tolerated
[103] Macitentan BNP with follow-up data at 12 months
+sildenafil (n=3) WHO FC WHO FC improved in four patients
Sildenafil (n=1)
Prostanoid-based therapy
https://doi.org/10.1183/2312508X.10032920
FISHER Epoprostenol (n=6) Retrospective 7 WHO FC Six out of seven patients had an One patient died after starting
[104] Treprostinil (n=1) improvement in WHO FC epoprostenol
One patient developed
cardiogenic pulmonary
oedema
BAUGHMAN Iloprost Prospective open label 15 6MWT Eight out of 15 had increase in 6MWD Two patients required an
[105] RHC ⩾30 m or decrease in PVR ⩾20% increase in
WHO FC Significant improvement in dyspnoea supplemental oxygen
QoL: SF-36, SGRQ, (SGRQ) Cough was the most common
FAS, SHQ Improved WHO FC in four, worsened adverse event
in one
Continued
https://doi.org/10.1183/2312508X.10032920
TABLE 5 Continued

author
[ref.]
BONHAM Treprostinil (n=6) Retrospective 13 RHC Well tolerated

[5] Epoprostenol (n=7) NT-proBNP 62% also on PDE5i and 38%
WHO FC also on ERA
ABSTON Epoprostenol (n=6) Retrospective 12 RHC Decrease in mPAP from 59±10 to 36 Well tolerated
[106] Epoprostenol ±11 mmHg (p=0.002)
+tadalafil (n=4) CO/CI and PVR improved significantly

Epoprostenol
+sildenafil (n=1)
Epoprostenol
+ambrisentan (n=1)
6MWT: 6-min walk test; RHC: right heart catherisation; mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; WU: Wood units; 6MWD: 6-min walk
distance; SpO2: oxygen saturation measured by pulse oximetry; TTE: transthoracic echocardiography; BNP: brain natriuretic peptide; WHO FC: World Health Organization
functional class; TAPSE: tricuspid annular plane systolic excursion; QoL: quality of life; SF-36: 36-Item Short Form Health Survey; SGRQ: St George’s Respiratory
Questionnaire; FAS: Fatigue Assessment Scale; TCW: time to clinical worsening; SHQ: Sarcoidosis Health Questionnaire; PDE5i: phosphodiesterase type 5 inhibitor; ERA:
endothelin receptor antagonist; CO: cardiac output; CI: cardiac index.
247
248

Confirmed PH
Combined
Normal haemodynamics Pre-capillary PH Post-capillary PH
pre-/post-capillary PH
Follow-up as Management of left heart dysfunction

Identify phenotype of
clinically indicated as indicated. Consider cardiac
SAPH. Exclude and treat
other causes of PH. sarcoidosis evaluation.
Pulmonary angiography
Anticoagulation V'/Q' and pulmonary CTA
MDT review and (consider DECT if available)
Evidence of Hepatic ultrasonography
evaluation
CTEPH Polysomnography
Treatment as indicated
CBC
Extrinsic Stable Advanced Stable

pulmonary parenchymal disease parenchymal disease parenchymal disease
vascular with active (Scadding stage IV, without
compression inflammation FVC <50%) active inflammation
Mediastinal Trial of Parenchymal

18F-FDG PET Yes immunosuppressive Yes 18F-FDG PET Stratify PH
No
uptake? therapy uptake? severity
https://doi.org/10.1183/2312508X.10032920
No
Consider BPA Mild-to-moderate PH Severe PH

and/or stenting No haemodynamic improvement
Consider Initiate
PAH-targeted PAH-targeted
therapy on therapy
individual basis Referral for
transplant
evaluation
FIGURE 5 Legend overleaf.

FIGURE 5 Proposed algorithm for treatment of sarcoidosis-associated pulmonary hypertension (SAPH). PH:
pulmonary hypertension; MDT: multidisciplinary team; CTEPH: chronic thromboembolic PH; V′/Q′: ventilation/
perfusion; CTA: CT angiogram; DECT: dual-energy CT; CBC: complete blood count; BPA: balloon pulmonary
angioplasty; PAH: pulmonary arterial hypertension.
Ambrisentan was evaluated in 21 patients with SAPH, but 11 patients dropped out due to
increasing oedema or dyspnoea. In the remaining 10 patients, there was a nonsignificant trend
towards improvement in WHO FC and quality of life after 24 weeks of therapy [100]. In a
small retrospective study of macitentan mono- or combination therapy with sildenafil, the drug
was tolerated, and 50% of patients had improved BNP and 6MWD and 90% experienced an
improved WHO FC [103].
Prostanoid therapy
Prostacyclins are potent pulmonary vasodilators available in oral, inhaled, intravenous and s.c.
formulations, and are generally reserved for patients with severe PAH. As with other classes of
pulmonary vasodilator therapy, available studies on SAPH are small and retrospective [5, 104,
106]. Significant improvements in haemodynamics and FC were observed with i.v. epoprostenol
therapy in two studies of severe SAPH; however, most patients were on combination therapy
with a PDE5i or ERA [5, 106].
In patients with less severe SAPH, inhaled iloprost significantly improved quality of life, and
40% of patients had an improvement in PVR by ⩾20% [105], but it was associated with
worsening cough and increased oxygen requirements in several patients. The recent INCREASE
(Safety and efficacy of inhaled treprostinil in adult PH with ILD including CPFE) trial
demonstrated the safety and efficacy of inhaled treprostinil in patients with ILD/PH and is
currently the only pulmonary vasodilator approved for this indication, although it excluded
SAPH patients [107]. Inhaled treprostinil appears to be an attractive drug to study in SAPH
patients with the parenchyma phenotype and is currently being studied in the SAPPHIRE
(Inhaled treprostinil in sarcoidosis patients with pulmonary hypertension) trial (ClinicalTrials.gov
identifier NCT03814317).
The oral selective prostacyclin receptor antagonist selexipag has demonstrated significant benefit in
patients with group 1 PAH, with reduced hospitalisation and slowing of disease progression [108].
The efficacy and safety of selexipag in SAPH are currently being evaluated in the SPHINX
(A study in participants with SAPH to assess the efficacy and safety of oral selexipag)
randomised controlled trial (ClinicalTrials.gov identifier NCT03942211).
In contrast to group 1 PAH, in which upfront combination therapy has been shown to be more
effective than monotherapy, there remains a lack of robust prospective data on the optimal approach
in SAPH [109]. Analysis of ReSAPH found that out of 176 patients, 76.7% were on
sarcoidosis-specific and 72.3% on pulmonary vasodilator treatment (53.4% on PDE5i alone, 34.8%
on ERA alone, 17.6% on a PDE5i and ERA combination, and 6.3% on a combination of PDE5i,
ERA and prostanoid) [21]. Similarly, 77% of patients in the French Pulmonary Hypertension
Registry were on pulmonary vasodilators, with 62% on ERA monotherapy and 15% on combination
ERA with either PDE5i or prostacyclin therapy [22]. Additionally, the French Pulmonary
Hypertension Registry only included patients with severe SAPH patients (defined as mPAP
⩾35 mmHg), whereas ReSAPH captured patients with mPAP ⩾25 mmHg [21, 22]. Analysis of the
French Pulmonary Hypertension Registry cohort showed that treatment with pulmonary vasodilators
resulted in improved pulmonary haemodynamics and FC but not 6MWD [22].
https://doi.org/10.1183/2312508X.10032920 249
Lung transplantation
Patients with advanced sarcoidosis refractory to therapy should be considered for lung
transplantation (LTx). More specifically, those with poor FC (New York Heart Association FC
III/IV), rapidly progressive disease, resting hypoxaemia and PH should be referred for LTx
evaluation [34, 110]. According to analysis of the International Society for Heart and Lung
Transplantation Registry, sarcoid patients only account for ∼2.5% of all LTx recipients [111].
Surgically, patients with sarcoidosis may be more challenging due to an increased likelihood of
pleural adhesions and thickening, perihilar fibrosis and bulky hilar adenopathy [34]. Although
short-term post-LTx survival is poorer, long-term survival of sarcoidosis patients is similar to
that of patients with other indications for LTx, with 1-, 3- and 5-year survival rates of 86%,
76% and 69%, respectively, and a median survival of 8.5 years in those who survive to 1 year
[111, 112]. Furthermore, the presence of SAPH does not appear to affect long-term post-LTx
survival [112].
Prognosis and risk factors for mortality

Patients with SAPH, particularly those with an isolated pre-capillary phenotype, have up to a
7–10-fold increase in mortality compared with those without PH [13, 53, 113, 114]. Median
survival in patients with SAPH is between 4.2 and 6.8 years, with an estimated 3-year survival
of 68–75% and a 5-year survival of only 58% [3, 13, 22, 115]. In patients with severe SAPH
(mPAP >35 mmHg or mPAP 25–35 mmHg and cardiac index <2.5 L·min−1·m−2), survival at
1, 3 and 4 years is 93%, 74% and 55%, respectively [22]. In a cohort of 159 pre-capillary
SAPH patients using a lower mPAP cut-off (⩾25 mmHg), SHLOBIN et al. [21] found an adjusted
transplant-free survival at 1, 3 and 5 years of 89.2%, 71.7% and 62.0%, respectively. In a
single-centre study of 95 patients with severe PH (median mPAP 49 mmHg, median PVR
8.5 WU) and advanced sarcoidosis (stage IV in 77%), 3-year mortality was 32% [3].
BAUGHMAN et al. [13] stratified sarcoidosis patients into three cohorts: those without PH (mPAP
<25 mmHg,), isolated pre-capillary PH (mPAP ⩾25 mmHg, pulmonary capillary wedge
pressure <15 mmHg) and PH with left heart disease (mPAP ⩾25 mmHg, pulmonary capillary
wedge pressure ⩾15 mmHg). Patients with PH and left heart disease had a hazard ratio (HR) for
death of 3, whereas those with isolated pre-capillary PH had a HR of 10. According to analysis
of the European SAPH registry data, HUITEMA et al. [16] found that systolic PA pressure of
>50 mmHg was associated with increased mortality. In contrast, in another severe SAPH cohort,
6MWD, but not haemodynamics, was associated with poor survival (HR 0.995, 95% CI 0.991–
0.999) [13]. In the multinational ReSAPH, patients with isolated pre-capillary SAPH with a
reduced 6MWD of <300 m or DLCO of <35% pred had significantly worse transplant-free
survival [21]. A preserved FEV1/FVC ratio and a reduced 6MWD were both independent risk
factors for reduced transplant-free survival [21]. PARIKH et al. [3] found that in a cohort with
severe SAPH, NT-proBNP levels were higher in patients who were hospitalised and/or died
(1258.0 versus 262.0 pg·mL−1; p=0.007), suggesting that elevated NT-proBNP may reflect right
heart dysfunction and be a useful prognostic marker in SAPH.
Various available risk stratification tools have been developed for group 1 PAH and have
demonstrated efficacy in predicting mortality in patients with pre-capillary PH. The most
commonly used models in clinical practice are the ESC/ERS risk score and the REVEAL 2.0
score [109, 116–119]. There are few to no data validating the use of these tools in SAPH. One
study that evaluated the prediction of mortality of the REVEAL score in patients with PH
groups 2–5 demonstrated comparable discerning power as for group 1 PH patients but did not
delineate its efficacy in SAPH patients specifically [120].
250 https://doi.org/10.1183/2312508X.10032920
Conclusion
In a minority of patients with sarcoidosis who develop PH, this is associated with increased
morbidity and mortality. Clinicians should maintain a high index of suspicion for PH in patients
with symptoms that appear out of proportion to the degree of PLD. Given the complex,
multifactorial pathophysiology at play, it is vitally important to complete a thorough diagnostic
evaluation to clarify the predominant phenotype of SAPH to help guide therapy. There remains
a need for high-quality prospective studies for the treatment of SAPH. Available studies suggest
that pulmonary vasodilators may benefit select patients; however, more data are needed to
determine who the ideal treatment candidates are and which agents should be used. Select
patients with advanced, refractory disease should be referred early for consideration and workup
for lung transplantation.
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hypertension: a case-series. Sarcoidosis Vasc Diffuse Lung Dis 2020; 37: 74–78.
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long-term epoprostenol treatment. Chest 2006; 130: 1481–1488.
105 Baughman RP, Judson MA, Lower EE, et al. Inhaled iloprost for sarcoidosis associated pulmonary
hypertension. Sarcoidosis Vasc Diffuse Lung Dis 2009; 26: 110–120.
106 Abston E, Hon S, Lawrence R, et al. Treatment of newly diagnosed sarcoid associated pulmonary hypertension
with ambrisentan and tadalafil combination therapy. Sarcoidosis Vasc Diffuse Lung Dis 2020; 37: 234–238.
107 Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to
interstitial lung disease. N Engl J Med 2021; 384: 325–334.
108 Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J
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110 Meyer KC. Lung transplantation for pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2019; 36: 92–107.
111 Yusen RD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung
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113 Nardi A, Brillet PY, Letoumelin P, et al. Stage IV sarcoidosis: comparison of survival with the general
population and causes of death. Eur Respir J 2011; 38: 1368–1373.
114 Tiosano S, Versini M, Dar Antaki L, et al. The long-term prognostic significance of sarcoidosis-associated
pulmonary hypertension – a cohort study. Clin Immunol 2019; 199: 57–61.
115 Dobarro D, Schreiber BE, Handler C, et al. Clinical characteristics, haemodynamics and treatment of
pulmonary hypertension in sarcoidosis in a single centre, and meta-analysis of the published data. Am J
Cardiol 2013; 111: 278–285.
116 Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015
European pulmonary hypertension guidelines risk stratification model. Eur Respir J 2017; 50: 1700740.
117 Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension:
insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease
Management (REVEAL). Circulation 2010; 122: 164–172.
118 Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly
diagnosed with pulmonary arterial hypertension. Chest 2012; 141: 354–362.
119 Benza RL, Gomberg-Maitland M, Elliott CG, et al. Predicting survival in patients with pulmonary arterial
hypertension. The REVEAL risk score calculator 2/0 and comparison with ESC/ERS-based risk assessment
strategies. Chest 2019; 156: 323–337.
120 Cogswell R, McGlothlin D, Kobashigawa E, et al. Performance of the REVEAL model in WHO group 2 to 5
pulmonary hypertension: application beyond pulmonary arterial hypertension. J Heart Lung Transplant 2013;
32: 293–298.
Disclosures: V. Khangoora has nothing to disclose. H. Nunes reports receiving the following during the current
work: personal fees from Actelion Pharmaceuticals for acting as a board expert for a clinical trial. H. Nunes reports
receiving the following, outside the current work: consultant and research support fees from Roche/Genentech
and Boehringer Ingelheim; personal fees from Galapagos for work on an expert clinical end-point committee; and
other support for acting as an investigator of a clinical trial for Sanofi, Gilead, Novartis, Galecto Biotech AB and
BMS. O.A. Shlobin reports receiving the following, outside the submitted work: personal fees for consultancy from
Bayer, United Therapeutics and Janssen & Janssen.
https://doi.org/10.1183/2312508X.10032920 255
Chapter 17
Rheumatological manifestations
1 2
Peter Korsten and Nadera J. Sweiss
1
Dept of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany. 2Division of
Rheumatology, Dept of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Corresponding author: Peter Korsten ( peter.korsten@med.uni-goettingen.de)
Cite as: Korsten P, Sweiss NJ. Rheumatological manifestations. In: Bonella F, Culver DA, Israël-Biet D, eds.
2312508X.10033020].
@ERSpublications
Musculoskeletal complaints are frequent in sarcoidosis and range from nonspecific findings to overt arthritis,
sacroiliitis, dactylitis, bone disease or myositis. Treatment typically includes glucocorticoids, immuno-
suppressives or biologics. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Musculoskeletal complaints are commonly present in sarcoidosis and can range from nonspecific
arthralgias and myalgias to well-defined findings, such as overt arthritis, sacroiliitis, bone sarcoidosis or
myositis. Further adding to the complexity of the disease, sarcoidosis may mimic other rheumatic diseases
that need to be ruled out before a diagnosis of sarcoidosis can be made. A frequent presentation is Löfgren
syndrome (erythema nodosum, bilateral ankle periarthritis and bilateral hilar lymphadenopathy). To control
Löfgren syndrome, anti-inflammatory drugs are often required, but the prognosis is usually good. Chronic
sarcoidosis can involve the joints with arthritis, dactylitis, bone sarcoidosis or sacroiliitis. Therefore,
treatment decisions need to take into consideration which organ systems are affected and require treatment.
While no therapies are approved explicitly for sarcoid arthritis, glucocorticoids and disease-modifying
anti-sarcoid drugs (conventional or biological) are used sequentially as needed to control symptoms.
Introduction
Sarcoidosis is a systemic and heterogeneous disease that can mimic many other rheumatic
diseases, depending on the chief complaints and organs affected, or co-exist with distinct
autoimmune diseases [1]. Physicians caring for sarcoidosis patients may be consulted in
complex or atypical cases where sarcoidosis is a possible differential diagnosis or when
immunosuppressive drugs must be administered. In addition, musculoskeletal complaints are
frequent in sarcoidosis patients. They can range from relatively nonspecific symptoms, such as
arthralgias, myalgias, bone pain or disabling fatigue, to well-defined findings of arthritis,
dactylitis, sacroiliitis, bone disease or myositis. Therefore, a basic understanding of
musculoskeletal rheumatic conditions that may mimic or be overlapping with sarcoidosis is
essential for sarcoidosis healthcare providers. This chapter aims to give an overview of possible
acute and chronic presentations, the suggested workup and the treatment approach.
Clinical features
Acute sarcoidosis (Löfgren syndrome)
The most commonly encountered acute presentation of sarcoidosis is Löfgren syndrome [2]. The
typical manifestations are summarised in table 1. Löfgren syndrome was first described in
256 https://doi.org/10.1183/2312508X.10033020
RHEUMATOLOGICAL MANIFESTATIONS | P. KORSTEN AND N.J. SWEISS
TABLE 1 Clinical manifestations of Löfgren syndrome

Fever
Bilateral hilar lymphadenopathy
Erythema nodosum
Bilateral ankle periarthritis
Data from [2].
1952 by Löfgren and Lundbäck in a study involving 212 patients with bilateral hilar
lymphadenopathy [3]. It has a seasonal association, occurring more commonly in spring [4, 5].
A clear association with the HLA has been identified in recent years, influencing the disease
course [6, 7]. The HLA allele DRB1*03, which is more commonly present in patients with
Löfgren syndrome, is associated with resolving disease, whereas about half of
HLA-DRB1*03-negative patients take a non-resolving disease course [6]. As a consequence,
Löfgren syndrome usually resolves with treatment [6]. The occurrence of Löfgren syndrome in
association with various vaccines, including vaccination against the novel severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), has been described [8]. Typical findings of
erythema nodosum and periarthritis are shown in figure 1. Bilateral ankle periarthritis is highly
suggestive of acute sarcoid arthritis and has high sensitivity (93%) and specificity (99%),
corresponding to a positive predictive value of 75% and a negative predictive value of 99.7%
when additional disease features are present [5]. These include a short symptom duration
(<2 months), age <40 years and erythema nodosum (table 2). Besides ankle periarthritis,
erythema nodosum and bilateral hilar lymphadenopathy, fever is also a common feature of
Löfgren syndrome [2, 9].
It has to be noted that not all classic features of Löfgren syndrome may be present at the time of
presentation (so-called “forme fruste”). Because incomplete forms exist, a histopathological
confirmation may be warranted to exclude differential diagnoses in these cases. When Löfgren
syndrome presents typically, histological confirmation is usually not required to reach the
FIGURE 1 Löfgren syndrome with typical findings of erythema nodosum and bilateral ankle periarthritis.
https://doi.org/10.1183/2312508X.10033020 257
TABLE 2 Criteria for acute sarcoid arthritis

Bilateral ankle arthritis
Symptom duration <2 months
Age <40 years
Erythema nodosum
⩾3 out of 4 criteria have a sensitivity of 93%, specificity of 99%, positive predictive value of 75% and negative
predictive value of 99.7%. Data from [5].
diagnosis. However, in incomplete forms, histological confirmation of the presence of

granulomas may be very helpful to support or refute the diagnosis, and to rule out other
conditions [10].
Chronic rheumatological manifestations

Chronic musculoskeletal manifestations in sarcoidosis are usually encountered with multisystem
involvement and are rarely an isolated finding. These can include arthritis, dactylitis, bone
disease or myositis.
The arthritis of chronic sarcoidosis usually presents as oligoarthritis involving ⩽4 joints, rarely
as a mono- or polyarthritis (figure 2) [11]. Therefore, it can mimic seronegative
spondyloarthropathies, such as psoriatic arthritis, especially when dactylitis is present [12–15].
In the presence of dactylitis, patients must be carefully assessed for skin manifestations because
the dermatological findings of skin sarcoidosis are usually different from psoriasis [16].
However, both conditions may co-exist [17], and certain types of skin sarcoidosis can resemble
psoriasis [18, 19], making a distinction challenging. In addition, severe granulomatous
inflammation may lead to acro-osteolysis with mutilating arthritis (figure 3a and b). Jaccoud
arthropathy, which can mimic typical findings also seen in rheumatoid arthritis or systemic
lupus erythematosus, such as ulnar deviation and swan neck deformity, is, in contrast to arthritis
seen in rheumatoid arthritis, not characterised by bone erosions. An exception is the
FIGURE 2 Clinical findings in sarcoid arthritis/dactylitis. Note the diffuse swelling of the fourth digit of the left
hand and the third digit of the right hand.
258 https://doi.org/10.1183/2312508X.10033020
a) b)
FIGURE 3 Chronic sarcoid arthritis with osseous involvement. a) Clinical findings with (granulomatous)
inflammation of the left and right middle fingers and mutilating arthritis with acro-osteolysis of the right fifth
finger. b) Corresponding radiograph of the right hand with multiple bone cysts, ulnar deviation of the middle
finger, and osteolysis of the distal phalanx of the fifth finger leading to mutilation.
concomitant occurrence of Jaccoud arthropathy with granulomatous erosions. In these cases, a

distinction between sarcoidosis and rheumatoid arthritis can be difficult, especially when
specific antibodies of rheumatoid arthritis (rheumatoid factor or anti-cyclic citrullinated peptide
antibodies) are absent [20, 21].
Axial manifestations (sacroiliitis) of sarcoidosis can mimic spondyloarthropathies, and the

clinical differentiation between the two entities can be challenging. In addition, both diseases’
characteristic findings can be present concomitantly, varying between studies and ranging from
about 12% to approximately half of the patients with inflammatory back pain [22]. A recent
study has demonstrated an association of sarcoidosis and the appearance of spondy-
loarthropathies with an odds ratio of 1.42 for axial spondyloarthropathy and 1.81 for psoriatic
arthritis, respectively [23].
Bone disease, classically described as osteitis cystoides multiplex Jüngling, was described in
sarcoidosis as early as 1920 [24]. Later, it was found in 5% of sarcoidosis patients and 8% of a
control group, thus questioning the usefulness of bone cysts as a characteristic feature of
sarcoidosis (figure 3b) [24]. In a more recent study, bone sarcoidosis was associated with
multisystemic disease involving the spleen, liver and extrapulmonary lymph nodes [25].
Furthermore, the spine was identified as the most frequently affected bone, followed by the
pelvis [25]. Bone sarcoidosis may be asymptomatic and detected on imaging studies during
routine workup for pulmonary or extrapulmonary manifestations, or can be symptomatic with
bone pain [11, 25]. In unclear cases, a bone biopsy may be required because there are no specific
imaging findings, and lesions may mimic a metastatic malignant disease (figure 4) [11, 12].
However, in the setting of known multisystemic sarcoidosis with lesions on imaging that are
consistent with sarcoidosis, a bone biopsy is not required.
Table 3 summarises clinical features, imaging findings and possible differential diagnoses,
depending on the primary type of musculoskeletal involvement.
https://doi.org/10.1183/2312508X.10033020 259
FIGURE 4 Bone sarcoidosis on MRI (T2 weighting) with hyperintense lesions in the pelvic bones (white circles).
The patient was asymptomatic. Of note, imaging findings are nonspecific and may mimic metastatic
malignant diseases.
Granulomatous myositis
Clinically relevant muscle involvement is rare in sarcoidosis (about 1–2% of patients), whereas
histological evidence of granulomas in muscle biopsies is relatively frequent (found in up to
75% of patients) [11, 26]. In a recent French nationwide multicentre study, four different types
of muscle involvement could be identified: a nodular type; a smouldering type; an acute,
subacute or progressive myopathy type; and a mixed myopathic and neurogenic pattern type
[27]. In this study, muscle involvement was associated with the involvement of multiple organs,
and the cases differed in their presentation with respect to myalgia, nodules or weakness [27].
In addition, there have been case reports of sarcoidosis mimicking classical myopathies, such as
polymyositis [28], dermatomyositis or inclusion body myositis [29–32], which also may
co-exist. In rare cases, muscle involvement may be life-threatening when the diaphragm is
involved [33, 34]. A diagnosis of granulomatous myositis secondary to sarcoidosis usually
requires a muscle biopsy, since electromyography, ultrasound and other imaging modalities may
be unremarkable or show only nonspecific findings [12, 35].
Laboratory findings
There are no specific laboratory findings for musculoskeletal manifestations of sarcoidosis.
Nevertheless, a comprehensive workup is usually required to assess the patient with
musculoskeletal complaints secondary to sarcoidosis for other disease manifestations and
distinguish sarcoidosis from other inflammatory diseases associated with specific laboratory
abnormalities. The recently published clinical practice guideline for diagnosing and detecting
sarcoidosis suggests a diagnostic workup for many manifestations of sarcoidosis [10]. However,
no recommendations are provided for musculoskeletal manifestations. Nonspecific inflammatory
markers, such as leukocytosis, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)
or soluble IL-2 receptor (sIL-2R), may be elevated [36, 37]. The role of the latter for diagnostic
and monitoring purposes has not been clearly established. However, it shows promise as a
monitoring tool as correlations with PET scans have been described [38]. Creatine kinase levels
may or may not be elevated in granulomatous muscle disease and are, therefore, of limited value.
The minimum required workup in the patient with rheumatic symptoms includes a whole blood
count, basic metabolic panel, inflammatory markers (CRP, ESR, sIL-2R), electrolytes
(especially calcium), 25-OH- and 1,25-OH-vitamin D3, and a urinalysis. In addition, an
advanced immunological investigation, including autoantibodies, should be requested depending
on the clinical presentation. Table 4 shows our suggested workup.
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https://doi.org/10.1183/2312508X.10033020
TABLE 3 Clinical features, imaging findings and differential diagnoses of the main musculoskeletal symptoms in chronic sarcoidosis
Arthritis Dactylitis Sacroiliitis Bone sarcoidosis
Clinical manifestations Oligoarthritis; less frequently Swelling of entire fingers or toes Inflammatory back pain Asymptomatic, numbness,
mono- or polyarthritis (“sausage digit”) or bone pain

Imaging findings Phalangeal cysts, granulomatous Soft tissue swelling of an entire Bone marrow oedema, usually Multiple contrast-enhancing
erosions, trabecular pattern, finger or toe, with or without asymmetrical in sarcoidosis; lesions
Jaccoud arthropathy granulomatous erosions erosions
Recommended imaging Diagnosis: MSUS, conventional Diagnosis: MSUS, conventional Diagnosis: MRI, CT Diagnosis: conventional
modality radiographs radiographs, MRI, PET (rarely Monitoring: MRI radiographs, CT, MRI, PET
Monitoring: MSUS, MRI required) Monitoring: MRI, PET
Monitoring: MSUS, MRI, PET (rarely
required)
Differential diagnoses Seronegative spondyloarthropathy Psoriatic arthritis; gout Axial spondyloarthropathy; Metastatic disease;
in oligoarthritis; systemic lupus psoriatic arthritis infections
erythematosus or rheumatoid
arthritis in Jaccoud arthropathy
MSUS: musculoskeletal ultrasound.
261
TABLE 4 Recommended laboratory investigations in patients with musculoskeletal presentations
Parameter Consideration Possible associated

diagnosis
Basic investigations
Blood count Screening for inflammation, anaemia, bone
marrow involvement
Liver enzymes Screening for hepatic involvement
Uric acid Screening for hyperuricaemia (especially in Gout
the presence of dactylitis)
Creatinine Screening for renal involvement
Calcium (with albumin) Screening for hypercalcaemia Primary or secondary
hyperparathyroidism
Urinalysis Screening for renal involvement (proteinuria,
hypercalciuria)
Inflammatory markers
CRP Nonspecific elevations in active disease
ACE Classically described biomarker but with low
sensitivity and specificity (not universally
recommended)
Soluble IL-2 receptor Promising biomarker with superior sensitivity
and specificity compared to ACE;
correlations with PET activity described;
may not be universally available
Endocrinological investigations
25-OH-vitamin D3 May be low in active disease
1,25-OH-vitamin D3 May be high-normal or (rarely) elevated in
active disease
PTH Usually suppressed in vitamin D Primary or secondary
dysregulation associated with sarcoidosis hyperparathyroidism
Immunological investigations
RF or ACPA In Jaccoud arthropathy or polyarthritis Rheumatoid arthritis
Anti-nuclear antibodies Screening for connective tissue disease
(indirect or mimickers
immunofluorescence)
Anti-dsDNA antibodies, If renal abnormalities and systemic Systemic lupus
complement factor C3, C4 symptoms are present erythematosus
In Jaccoud arthropathy or polyarthritis
Anti-SSA/SSB antibodies or If parotid or salivary glands are affected Sjögren syndrome,
IgG4 IgG4-related disease
ANCA In lung disease or renal disease with systemic GPA, MPA
symptoms
CRP: C-reactive protein; OH: hydroxy; PTH: parathyroid hormone; RF: rheumatoid factor; ACPA: anti-citrullinated
peptide antibodies; dsDNA: double-stranded DNA; SSA/SSB: Sjögren syndrome type A/B; ANCA: anti-neutrophil
cytoplasmic antibodies; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis.
Imaging studies
Imaging studies are frequently performed and required in the workup of sarcoidosis patients,
since systemic involvement is common and may be missed on clinical examination alone. In
many rheumatology practices and clinics, musculoskeletal ultrasound is readily available and
will be the first imaging modality in patients presenting with signs of arthritis. In Löfgren
syndrome, there is usually a diffuse and extensive subcutaneous oedema with or without the
involvement of the tendon sheaths (tenosynovitis). True joint inflammation (synovitis) is rare [39].
262 https://doi.org/10.1183/2312508X.10033020
Musculoskeletal ultrasound may also be used in dactylitis to differentiate sarcoidosis from gouty
arthritis. In the latter, the double-contour sign, a hyperechogenic line on top of the anechoic
cartilage, is a characteristic finding and may also be found in asymptomatic joints [40, 41].
Conventional radiographs are often performed as a baseline examination and screening tool for
joint erosions, phalangeal cysts, a trabecular pattern, or Jaccoud arthropathy [12, 42].
Advanced imaging studies include CT, MRI and PET. For diagnostic purposes, CT is often
used as the first-line imaging technique to assess lung involvement, and it may also be helpful
for the detection of bone sarcoidosis and, rarely, for the evaluation of suspected sacroiliitis. MRI
is, in most cases, not required to monitor sarcoidosis arthritis but is useful to detect sacroiliitis
or bone sarcoidosis. PET is sometimes necessary in patients with unclear and systemic
symptoms; in these cases, PET may reveal potential sites of active inflammation that may be
accessible for a diagnostic tissue biopsy [11, 12, 26, 42]. Also, it has been shown that PET can
be used as an imaging modality to monitor treatment responses [43–45]. In bone sarcoidosis,
osseous lesions may also be monitored with MRI scans. Recommended imaging modalities
depending on the type of involvement are shown in table 3.
Approach to treatment
There are no drugs approved explicitly for or systematically investigated in sarcoid arthritis, and
treatment practices among physicians vary considerably [46]. Treatment decisions depend on
the presence of additional symptoms and organ manifestations. Drugs commonly used in
other rheumatic conditions, such as glucocorticoids (GCs), hydroxychloroquine (HCQ),
disease-modifying anti-sarcoidosis drugs and biologics, are frequently required to treat chronic
disease [42]. Recently, the European Respiratory Society’s clinical practice guidelines have been
published but, in the absence of firm evidence, do not make a statement on sarcoid arthritis
treatment [47].
Treatment of acute sarcoidosis (Löfgren syndrome)

In Löfgren syndrome, the optimal treatment approach is not established. Milder cases may
resolve with nonsteroidal anti-inflammatory drugs alone. Nevertheless, at least one-third of
patients, if not more, require GC treatment when the presentation is highly inflammatory and
symptomatic, which is often the case [12, 48]. Up to one-third of patients eventually requires
treatment with GCs [48], and many patients experience an immediate symptom relief with GCs
as first-line treatment. Relapses are infrequent, and additional GC-sparing drugs are usually
not needed.
Treatment of chronic musculoskeletal manifestations

In the absence of firm evidence, treatment decisions must be individualised and be weighed
against the potential risks of treatment. In patients with symptomatic disease impairing quality
of life, benefits usually outweigh the possible side-effects of treatment.
Limited manifestations of chronic articular sarcoidosis, such as monoarthritis or oligoarthritis,

may be managed with intra-articular GC injections alone [42].
Treatment usually follows a stepwise approach, with GC therapy as the first-line treatment with
a starting dose of 20 mg of prednisolone for most disease manifestations, including arthritis [11,
42, 47]. In patients with a high risk for GC-associated complications, such as osteoporosis,
diabetes mellitus, arterial hypertension or obesity, the simultaneous initiation of a GC-sparing
https://doi.org/10.1183/2312508X.10033020 263
Rheumatological
manifestations
Chronic sarcoidosis
Löfgren syndrome (arthritis, dactylitis, sacroiliitis,
bone sarcoidosis)
More
Localised
extensive
disease
disease
First-line
Intra- GC#
NSAID or GC# 10–20 mg·day−1
articular 10–20 mg·day−1
tapering
GC tapering
Second-line
MTX 10–15 (max 25) mg·week−1 p.o./s.c.

AZA 1–2 mg·kgBW−1·day−1 p.o.
LEF 20 mg·day−1 p.o.
HCQ 5 mg·kgBW−1·day−1 p.o.
Additional therapies
Third-line
IFX 3–5 (max 7.5) mg·kgBW−1 i.v./s.c.

ADA 40–80 mg q2w s.c.
Consider ATC, JAKi, RCI, RTX
FIGURE 5 Therapeutic algorithm for rheumatological presentations of sarcoidosis. ADA: adalimumab; ATC:
abatacept; AZA: azathioprine; BW: body weight; GC: glucocorticoids; HCQ: hydroxychloroquine; IFX: infliximab;
JAKi: Janus kinase inhibitor; LEF: leflunomide; NSAID: nonsteroidal anti-inflammatory drugs; q2w: once every
2 weeks; RCI: repository corticotropin injection; RTX: rituximab. #: prednisolone or equivalent dose of other GC.
agent, such as MTX, may be considered [1, 49]. Other agents commonly used include HCQ,
azathioprine, leflunomide, or biological agents such as infliximab or adalimumab [47]. There is
little evidence for B-cell-depleting agents, such as rituximab for pulmonary sarcoidosis [50] or
abatacept, repository corticotropin and Janus kinase inhibitors [51] for cutaneous or other
sarcoidosis manifestations. Nevertheless, these may also be considered for refractory rheumatic
manifestations because they are approved for other rheumatic conditions. For details on doses
and potential side-effects, the reader is referred elsewhere in this Monograph [52]. It must be
noted that none of the mentioned therapies has been approved to treat sarcoidosis and sarcoid
arthritis. Based on the available evidence and our personal experience, our treatment approach
to musculoskeletal manifestations is summarised in figure 5.
Conclusion
Musculoskeletal complaints and manifestations of sarcoidosis are relatively frequent. Acute
presentations usually follow a benign course. However, chronic manifestations, such as arthritis,
dactylitis, sacroiliitis and bone disease, may require more aggressive therapy, including
disease-modifying anti-sarcoidosis drugs or biological agents. Unfortunately, firm evidence for
treatment of rheumatological manifestations is not available, and treatment decisions must take
other disease manifestations into account.
264 https://doi.org/10.1183/2312508X.10033020
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42 Korsten P, Sweiss NJ, Baughman RP. Chapter 124. Sarcoidosis. In: Firestein GS, Budd RC, Gabriel SE, et al., eds.
Firestein and Kelley’s Textbook of Rheumatology. 11th Edn. Philadelphia, Elsevier, 2021; pp. 2088–2104.
43 Vorselaars ADM, Crommelin HA, Deneer VHM, et al. Effectiveness of infliximab in refractory FDG PET-positive
44 Cremers JP, Van Kroonenburgh MJ, Mostard RL, et al. Extent of disease activity assessed by 18F-FDG PET/CT in
45 Gajate AS, Incerti E, Cremona G, et al. 18F-FDG PET/CT for the clinical management of patients with
sarcoidosis. Eur J Nucl Med Mol Imaging 2014; 41: Suppl. 2, S596.
46 Hammam N, Evans M, Morgan E, et al. Treatment of sarcoidosis in U.S. rheumatology practices: data from
the American College of Rheumatology’s rheumatology informatics system for effectiveness (RISE) registry.
Arthritis Care Res 2020; in press [https://doi.org/10.1002/acr.24496].
47 Baughman RP, Valeyre D, Korsten P, et al. ERS clinical practice guidelines on treatment of sarcoidosis.
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study of 80 cases]. Med Clin 2014; 143: 166–169.
49 Korsten P, Mirsaeidi M, Sweiss NJ. Nonsteroidal therapy of sarcoidosis. Curr Opin Pulm Med 2013; 19: 516–523.
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Eur Respir J 2014; 43: 1525–1528.
Disclosures: P. Korsten reports receiving the following, outside the submitted work: personal fees from Abbvie,
Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Gilead/Galapagos, Janssen-Cilag, Lilly, Pfizer and
Sanofi-Aventis; grants and personal fees from GlaxoSmithKline. N.J. Sweiss has nothing to disclose.
266 https://doi.org/10.1183/2312508X.10033020
Chapter 18
Ocular sarcoidosis
Stéphane Giorgiutti1, Yasmine Serrar2, Thomas El-Jammal 1
, Laurent Kodjikian2
and Pascal Sève1
1
Dept of Internal Medicine, Hôpital de la Croix-Rousse, Université Claude Bernard Lyon I, Lyon, France. 2Dept of
Ophthalmology, Hôpital de la Croix-Rousse, Université Claude Bernard Lyon I, Lyon, France.
Corresponding author: Pascal Sève ( pascal.seve@chu-lyon.fr)
Cite as: Giorgiutti S, Serrar Y, El-Jammal T, et al. Ocular sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds.
2312508X.10033120].
@ERSpublications
Uveitis and optic neuropathy are sight-threatening manifestations in sarcoidosis. Systemic treatment is
indicated when uveitis does not respond to topical corticosteroids and in patients with intermediate and
posterior uveitis and bilateral involvement. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis is one of the leading causes of inflammatory eye disease. All ocular structures can be affected
but uveitis and optic neuropathy are the two main manifestations responsible for vision loss in ocular
sarcoidosis. Typical sarcoid anterior uveitis presents with mutton-fat keratic precipitates, iris nodules and
posterior synechiae. Posterior involvement includes vitritis, vasculitis and choroidal lesions. Cystoid
macular oedema is the most important and sight-threatening consequence of sarcoid uveitis. Patients with
clinically isolated uveitis at diagnosis rarely develop other organ involvement. Even though ocular
sarcoidosis can have a severe impact on visual prognosis, early diagnosis and a wider range of available
therapies (including intravitreal implants) have lessened the functional impact of the disease, particularly in
the last decade. Corticosteroids are the cornerstone of treatment for sarcoidosis but up to 30% of patients
achieve remission requiring high dosages of systemic steroids. In these cases, the use of steroid-sparing
immunosuppressive therapy (such as MTX) is unavoidable. Among these immunosuppressive treatments,
anti-TNF-α drugs have been a revolution in the management of noninfectious uveitis.
The eye is the second most frequently affected extrathoracic organ in patients with sarcoidosis, with
30–60% developing ophthalmologic involvement during the course of the disease [1–3]. Ocular
sarcoidosis can be clinically isolated in 7.7–32.9% of cases depending on the case series.
Sarcoidosis can affect all segments of the eye as well as its adnexa (table 1) [4–9] but uveitis,
which is a sight-threatening condition, remains the most common ocular manifestation, affecting up
to 20–30% of patients with sarcoidosis [10]. This chapter will focus on uveitis using the most
recent data, including the classification criteria for sarcoidosis-associated uveitis established by the
Standardization of Uveitis Nomenclature (SUN) working group and the recommendations for the
management of ocular sarcoidosis from the International Workshop on Ocular Sarcoidosis (IWOS).
Epidemiology
Ocular sarcoidosis
The prevalence of ocular involvement (including adnexal involvement and sicca syndrome)
during sarcoidosis ranges from 10% to 50% in predominantly Caucasian population series [4, 11].
https://doi.org/10.1183/2312508X.10033120 267
TABLE 1 Involvement of ocular structures and adnexa in sarcoidosis (except uveitis) [4–9]
Location Description
Lacrimal glands and lacrimal Often asymptomatic

drainage system (10–69%) Keratoconjunctivitis sicca (15–31%)
Enlargement of the glands is less frequent; the diagnosis can be
made by biopsy of the lacrimal gland
Orbit Women aged >50 years
Diffuse orbital inflammation, usually unilateral, can result in ptosis,
limitations in movement and diplopia
Ocular nerve palsy can occur from sarcoid involvement of the 3rd,
4th and 6th cranial nerves
Lid Granuloma
Conjunctiva (6–40%) Paucisymptomatic; granuloma, conjunctivitis
Sclera (<3%) Scleritis, episcleritis: diffuse inflammation, plaque or nodule; the
diagnosis may be made by biopsy of a scleral nodule
Cornea Interstitial keratitis (extremely rare)
Optic nerve (1–5%) Optic neuropathy mainly, granuloma, retrobulbar optic neuropathy
Predominantly Caucasian females
Frequently accompanied by uveitis and other findings of
neurosarcoidosis
Patients often have chronic disease and corticosteroid-sparing
alternatives are commonly used
Other neuro-ophthalmic Rare: Horner syndrome, tonic pupil and optic-tract involvement
manifestations
Japanese studies on sarcoidosis found ocular disease in 64–89% of patients but these studies were
mostly reported by ophthalmologists and only mention eye involvement. In the USA, ocular
involvement is more common in African Americans than in Caucasians [12]. Compared to
Caucasians, African American patients tend to be younger at first contact with the ophthalmologist
and present more frequently with uveitis and/or adnexal granulomas. There is a predominance of
chronic forms of uveitis in Caucasian women over the age of 50 years. Although good overall, the
visual prognosis seems to be better in Afro-Caribbean patients [13].
Uveitis
The proportion of uveitis of sarcoidosis origin in a population depends on the intrinsic (age, sex
and ethnic origin) and extrinsic (geographical location) characteristics of the patients, the
diagnostic modalities of sarcoidosis, and the population from which the group is extracted
(tertiary centre or not, inaugural uveitis or not) [14]. Sarcoidosis is by far the main cause of
uveitis in elderly patients [15]. Sarcoidosis uveitis accounts for 2–17% of uveitis referred to a
tertiary centre, depending on the series [16–20]. The recently observed increase in the rate of
sarcoid uveitis may be explained by more sensitive paraclinical investigations, such as chest CT
and/or nuclear imaging [1]. In 60–80% of cases, uveitis was the revealing symptom of
sarcoidosis at the time of ophthalmologic consultation [21–23].
Ocular sarcoidosis has two peaks of incidence with two distinct evolutions: a peak in young
patients (20–30 years old), with a more acute evolution, and a second peak after 50 years old,
with a more chronic evolution [24, 25]. In ocular involvement, as in other organ involvement,
there is a predominance of females, with a sex ratio of up to 6.5 depending on the series [1].
Clinically isolated uveitis that revealed sarcoidosis remained a strictly ocular condition in most
268 https://doi.org/10.1183/2312508X.10033120
OCULAR SARCOIDOSIS | S. GIORGIUTTI ET AL.
cases [22, 26]. However, SCHUPP et al. [2], in a clustering analysis, showed an association
between eye, cardiac, cutaneous and central nervous system involvement. In contrast, we
recently showed in a retrospective cohort of sarcoid uveitis that only 2.4% patients developed
cardiac sarcoidosis [26].
Clinical features
Clinical course and type of uveitis
Uveitis is the most common ocular manifestation of sarcoidosis [12, 27]. It is usually bilateral
(75–90%) with the same findings and clinical course in both eyes [4, 13]. Anterior uveitis is by
far the most frequent subtype (41–81% of sarcoid uveitis) [3, 4, 27], followed by posterior
uveitis, intermediate uveitis and panuveitis. However, in recent publications, panuveitis has been
identified as the most common anatomic form of uveitis in tertiary centre patients [13, 21, 22].
Recently, the SUN working group published classification criteria for sarcoid uveitis (table 2)
[28]. Uveitic pictures consistent with ocular sarcoidosis include anterior uveitis, intermediate
uveitis, and posterior uveitis with choroiditis or vasculitis (figure 1) [28]. The IWOS also
defined seven intraocular signs suggestive of ocular sarcoidosis [30].
Anterior uveitis
Anterior uveitis can be acute (abrupt onset and duration <3 months) or chronic (relapse within
3 months after treatment discontinuation), the latter being more common [31]. In anterior
uveitis, the primary site of inflammation is the anterior chamber, and is defined as iritis,
iridocyclitis or anterior cyclitis [31]. The classic anterior uveitis in ocular sarcoidosis is bilateral
and granulomatous, with anterior and posterior synechiae (adhesions between the iris and
cornea, and between the iris and lens, respectively). Intraocular hypertension may also be found
[28]. The term “granulomatous” refers to a subset of uveitis with specific clinical features: 1)
large mutton-fat keratic precipitates (figure 2a); or 2) iridial nodules located either at the pupil
margin (Koeppe nodules) (figure 2b) or in the iridial stroma (Busacca nodules). Granulomatous
anterior uveitis is not pathognomonic of sarcoidosis (table 3). Its chronic counterpart can lead to
the development of band keratopathy, glaucoma and cataract formation. Moreover,
nongranulomatous uveitis is a more likely presentation, particularly in the course of Löfgren
syndrome [28, 32] and represents two thirds of anterior uveitis in some series [12].
TABLE 2 Classification criteria for sarcoid uveitis according to the Standardization of Uveitis Nomenclature
Classification criteria
Compatible uveitic syndrome (one of the following)
Anterior uveitis
Intermediate or anterior/intermediate uveitis
Posterior uveitis with choroiditis (paucifocal choroidal nodule(s) or multifocal choroiditis)
Panuveitis with choroiditis or retinal vascular sheathing or retinal vascular occlusion
AND
Evidence of sarcoidosis (one of the following)
Tissue biopsy demonstrating noncaseating granulomas
Bilateral hilar adenopathy on chest imaging
Exclusion criteria
Positive serology for syphilis using a treponemal test
Evidence of infection with Mycobacterium tuberculosis (IGRA, tuberculin test, or histologically or
microbiologically confirmed infection)
IGRA: IFN-γ release assay. Reproduced and modified from [28] with permission from the publisher.
https://doi.org/10.1183/2312508X.10033120 269
Cornea
Sclera
Choroid
Iris
Anterior
chamber Vitreous
Aqueous humour
humour
Lens
Ciliary body Retina

Anterior uveitis and eye anatomy Intermediate uveitis
Posterior uveitis Panuveitis
FIGURE 1 Anatomic patterns of uveitis. Anterior uveitis: iritis, iridocyclitis, anterior cyclitis; intermediate uveitis:
pars planitis, posterior cyclitis, hyalitis; posterior uveitis: focal or diffuse choroiditis, chorioretinitis,
retinochoroiditis, retinitis, neuroretinitis; panuveitis: involvement of all three segments of the eye. Reproduced
from [29] with the permission of the publisher and the kind permission of the original illustrator, L. Adélaïde
(Centre Hospitalier de Vienne Lucien Hussel, Vienne, France).
Intermediate uveitis
In intermediate uveitis, the primary site of inflammation is the vitreous humour ( pars planitis,
posterior cyclitis or hyalitis) [31]. It is usually idiopathic but sarcoidosis is responsible for 7–18%
of cases, being one of the most frequent causes along with multiple sclerosis [19, 33, 34].
a) b)
FIGURE 2 Biomicroscopic findings in sarcoidosis-associated anterior uveitis. a) Large mutton-fat keratic

precipitates (arrow). b) Iris Koeppe nodules (arrow). Reproduced and modified from [1] with permission.
270 https://doi.org/10.1183/2312508X.10033120
TABLE 3 Main differential diagnoses of ocular sarcoidosis
Presentation Differential diagnosis
Anterior uveitis Tuberculosis, syphilis, herpes virus, leptospirosis, toxoplasmosis, Behçet disease, Fuch
heterochromic iridocyclitis
Intermediate uveitis Idiopathic (pars planitis), multiple sclerosis, lymphoma, Lyme disease
Posterior uveitis Birdshot chorioretinopathy, Vogt–Koyanagi–Harada syndrome, sympathetic ophthalmia,
toxoplasmosis, Behçet disease, histoplasmosis, acute multifocal choroiditis, multiple
sclerosis, tuberculosis, syphilis, Whipple disease, acute posterior multifocal placoid
pigment epitheliopathy, neoplasms
Panuveitis Tuberculosis, syphilis, toxoplasmosis, Vogt–Koyanagi–Harada syndrome, Behçet disease
Intermediate uveitis is not common among patients with sarcoid uveitis (6–19%) [12, 13, 35].
According to the SUN working group, the most common features of intermediate uveitis
in sarcoidosis are vitreous “snowballs” [28] that may be organised into a “string of pearls” (figure
3). The leading cause of vision loss in patients with intermediate uveitis is cystoid macular
oedema, followed by vitreous opacity, epiretinal membrane, optic neuritis and glaucoma [33].
Posterior uveitis
In posterior uveitis, the primary site of inflammation is retina or choroid. It includes choroiditis,
chorioretinitis, retinochoroiditis, retinitis and neuroretinitis [31]. Posterior uveitis is seen in
5–28% of patients with ocular sarcoidosis [4, 12, 13, 27, 35]. According to the SUN working
group, peripheral and central multifocal choroiditis (figure 4) are the most classic findings in
sarcoidosis [28]. Choroidal granulomas are less common [36] but are highly suggestive of
sarcoidosis or tuberculosis. They are larger than multifocal choroiditis and can be located
around the optic disc or in the peripheral retina. They can induce vision loss in cases of optic
nerve or macular involvement. Choroiditis and granulomas may evolve into atrophic scars of the
pigmentary epithelium after uveitis resolution. Macular oedema is the main cause of vision loss
in posterior uveitis during sarcoidosis [12, 37].
FIGURE 3 Vitreous opacities (snowballs and string of pearls) (arrows). Reproduced and modified from [1] with
permission.
https://doi.org/10.1183/2312508X.10033120 271
a) b)
FIGURE 4 Ultrawide-field retinal imaging in ocular sarcoidosis. a) Multifocal choroiditis. b) Inferior occlusive
venous vasculitis treated by retinal photocoagulation (blue arrow) with retinal perivenous sheathing and
infiltrates referred to as “candle wax drippings” or “tâches de bougies” (red arrows).
Panuveitis
Panuveitis, defined as the combination of inflammation in the anterior chamber, vitreous and
retina/choroid [31] affects 9–48% of cases of sarcoid uveitis. Sarcoidosis accounts for up to
one-third of the causes of panuveitis [4, 11, 13] and is also the systemic disease most frequently
associated with this clinical presentation, along with Behçet disease and tuberculosis [19, 38, 39].
Retinal vasculitis
Retinal vasculitis (figure 4) is a very common feature of sarcoidosis and is found in 18% of
cases according to the SUN working group [28]. It can occur in intermediate or posterior
uveitis, or in panuveitis. It is most often a segmental periphlebitis that can involve capillaries
[40, 41]. The most classical finding is the “candle-wax dripping” aspect of retinal perivenous
sheathing and infiltrates [6]. The picture can be misleading to an untrained operator because the
involvement may be subclinical and visible only with fluorescein angiography [6]. Candle-wax
drippings are typically seen in acute ocular sarcoidosis and are usually associated with a poor
long-term prognosis with more frequent relapses [42]. Occlusive vasculitis (mostly venous) and
ischaemia are uncommon but classical, and may result in retinal neovascularisation in 1–5% of
cases [43, 44].
Differential diagnosis
Because of its many clinical features, ocular sarcoidosis can mimic almost any other uveitis or
even a Masquerade syndrome [45, 46]. Many conditions can mimic ocular sarcoidosis (table 3).
Infectious causes like tuberculosis and syphilis must be ruled out. Apart from infectious causes,
multiple sclerosis, Birdshot retinochoroidopathy and Vogt–Koyanagi–Harada syndrome are the
main differential diagnoses to rule out in cases of panuveitis.
Visual prognosis
Ocular sarcoidosis usually has a favourable visual prognosis. However, up to 10% of patients
with sarcoid uveitis have severe visual impairment [21, 22, 47, 48]. As noted above, the main
cause of vision loss by far is cystoid macular oedema (as a consequence of uveitis) [21]. Other
causes of visual impairment are cataract and glaucoma, epimacular membranes, and vitreous
haemorrhage due to retinal neovascularisation or tractional retinal detachment [49]. Several risk
272 https://doi.org/10.1183/2312508X.10033120
factors have been associated with poor functional prognosis such as a late-age onset, African
American origin, female sex, underlying chronic systemic sarcoidosis, posterior segment
involvement, chronic cystoid macular oedema, multifocal choroiditis, persistent ocular
inflammation and glaucoma [6, 12, 22, 24, 50].
A baseline ophthalmologic screening is recommended when extraocular sarcoidosis is

diagnosed to prevent vision loss, as some patients may have asymptomatic uveitis [51].
Optic neuropathy
A severe but rare manifestation of ocular sarcoidosis is optic neuritis (1–7%) [41, 52, 53]. It
typically presents with optic disc oedema. Red flags such as severe vision loss to no perception
of light and bilateral visual loss are common in sarcoidosis-associated optic neuritis. Patients
with optic neuropathy secondary to sarcoidosis often have a chronic course [7]. A recent
multicentre case series of sarcoid optic neuropathy by WEBB et al. [54] showed that the majority
of patients with optic neuritis had radiological evidence of other nervous system involvement.
Optic neuritis can be the first ocular manifestation of sarcoidosis [7, 54]. Visual impairment is
much more common after optic neuritis than after uveitis [54].
Ancillary ocular images of sarcoidosis

In ocular sarcoidosis, multimodal imaging is necessary for the diagnosis of important clinical
features (figure 5). Spectral domain optical coherence tomography may show the presence of
macular oedema and choroidal granulomas. Fluorescein angiography is important for the
diagnosis of retinal vasculitis (vascular leakage on retinal vessels or capillaries) and optic disc
oedema (optic disc leakage). In cases of retinal vasculitis, fluorescein angiography is mandatory
to detect occlusive vasculitis and retinal ischaemia, and decide whether retinal photocoagulation
is indicated. Finally, indocyanine green angiography is helpful to explore choroidal lesions such
as choroidal granulomas or choroiditis.
a) b)
c) d) e) f)
FIGURE 5 Multimodal imaging findings in ocular sarcoidosis. a) Cystoid macular oedema on Spectral domain
optical coherence tomography (SD-OCT): hyporeflective cysts in retina (orange arrow) and subretinal fluid under
retina (green arrow). b) Granuloma (red arrow) on SD-OCT (hyporeflective mass in the choroid) complicated with
subretinal fluid (green arrowhead). c) Optic disc leakage and vascular leakage on proximal branches of the
central retinal vein on fluorescein angiography. d) Optic disc leakage and vascular leakage on capillaries of the
macula. e) Macular choroidal granuloma (arrow) on early-phase indocyanine green angiography. f ) Multifocal
choroiditis (arrows) on late-phase indocyanine green angiography.
https://doi.org/10.1183/2312508X.10033120 273
Screening for ocular sarcoidosis

From histological proof to the IWOS criteria and the SUN for disease classification criteria
A definite diagnosis of ocular sarcoidosis requires histological evidence of the presence of
noncaseating epithelioid granulomas [55]. However, biopsy of intraocular tissue carries a high
risk of tissue damage. Furthermore, the diagnostic value of untargeted biopsies of
normal-appearing conjunctival tissue is still debated. Indeed, SPAIDE and WARD [56] reported
that among 47 patients with suspected sarcoidosis, conjunctival biopsies were positive in 31.4%
of patients with normal conjunctiva, while CHUNG et al. [57] reported a yield of 37.9% in a
similar population. These series included a low number of patients and other groups found these
biopsies to be unsuccessful [58, 59]. Therefore, the diagnosis of ocular sarcoidosis is often
based on clinicoradiological features. The evaluation of patients with uveitis and suspected
sarcoidosis should be performed in a stepwise fashion, starting with noninvasive laboratory and
radiological tests, and progressing to invasive tests if necessary [46]. International criteria for
the diagnosis of ocular sarcoidosis were first available in 2009 after the first IWOS [60].
Unfortunately, the initial IWOS clinical criteria had a low sensitivity, except for bilateral hilar
lymphadenopathy [61], so revised criteria were proposed in 2017 [30]. A validation study in
Japan demonstrated the utility of this revision [62]. If definitive diagnosis of ocular sarcoidosis
still requires histological evidence, two other categories of diagnosis were defined: presumed
ocular sarcoidosis ( presence of bilateral hilar lymphadenopathy) and probable ocular sarcoidosis
(absence of bilateral hilar lymphadenopathy) [30]. More recently, the SUN working group
published key criteria for sarcoidosis-associated uveitis that include a compatible uveitic
syndrome associated with evidence of sarcoidosis (histological evidence or hilar adenopathy)
(table 2) [28, 63].
In 2020, the American Thoracic Society published recommendations for diagnosis and detection
of sarcoidosis in which a baseline eye examination to screen for ocular sarcoidosis was advised
for each new patient, including those who do not have ocular symptoms. However, the quality
of evidence is very low and a recent prospective study including 49 patients showed no benefit
of screening for asymptomatic patients [51].
Exclude differential diagnosis

A critical point is to exclude other causes of granulomatous uveitis, especially tuberculosis,
which remains the major differential diagnosis of granulomatous uveitis. IFN-γ release assays
are often used for this purpose but should be interpreted with caution because data are lacking
and because this type of assay suffers from a low positive predictive value for tuberculosis
diagnosis [64]. Empiric antituberculosis treatment may be required in questionable cases [65].
Systemic investigations
Increased ACE and serum lysozyme levels may be useful diagnostic tools for the presumptive
diagnosis of sarcoid uveitis. The sensitivity varies among series from 58–84% for ACE levels
and 60–78% for lysozyme levels, and the specificity from 83–95% for ACE and 76–95% for
lysozyme [45, 66, 67]. Moreover, the combination of such markers (e.g. ACE and lysozyme
levels with chest radiography or CT) was found to increase both sensitivity and specificity of
diagnostic tests for sarcoidosis [25, 68]. Compared with ACE, increased serum levels of soluble
IL-2 receptor seem to be more sensitive for the diagnosis of ocular sarcoidosis but the assay
cannot be routinely performed in many countries [30, 69].
Lymphopenia appears in the 2017 IWOS criteria [70], as JONES et al. [71] reported that
lymphopenia below 1000 cells per μL was higher in sarcoidosis-associated uveitis than in other
forms of uveitis and predicted the presence of the disease. GROEN-HAKAN et al. [72] reported
274 https://doi.org/10.1183/2312508X.10033120
that sensitivity and specificity of lymphopenia for the diagnosis of sarcoidosis were 75% and
77%, respectively. In this study, lymphopenia <1500 cells per µL was associated with a 12-fold
increased risk of having sarcoidosis in patients with a first uveitis attack. In a recent study,
COTTE et al. [73] evaluated the diagnostic value of elevated serum ACE and lymphopenia, alone
or in combination, in diagnosing sarcoid uveitis in a cohort of 996 adult patients referred to our
department. The combination of elevated serum ACE and lymphopenia more convincingly
suggests sarcoid uveitis than these investigational tests alone, especially in patients with
granulomatous uveitis ( positive predictive value 73.3%), whereas the absence of these markers
corresponds to a high negative predictive value (89.5%).
Several studies have suggested that BAL fluid analysis evidencing an elevated CD4/CD8 ratio
(>3.5) may be an efficient diagnostic tool for sarcoidosis, even with normal chest imaging
[74, 75]. Two studies reported that CD4/CD8 ratios in other biological liquids (e.g. vitreous
fluid) were significantly higher in sarcoidosis patients compared with other causes of uveitis but
this sample is considered too invasive by many experts [30, 76, 77].
Parenchymal lung changes consistent with sarcoidosis appeared for the first time in the 2017
IWOS criteria, with the condition “as determined by pulmonologists or radiologists” [30].
18
F-FDG PET has become the preferred nuclear imaging technique in sarcoidosis guidelines
[30]. It is a useful investigation to increase the diagnostic efficiency of biopsies [78] especially
in situations where these are difficult or impossible and an alternative site must be chosen (i.e.
cardiac or neurosarcoidosis) [71]. We recently showed that older age at diagnosis, presence of
posterior synechiae and increased ACE levels were significantly associated with an abnormal
18
F-FDG PET-CT. In this study, 30% of patients with suspected sarcoid uveitis and a normal
chest CT had hypermetabolic foci on their 18F-FDG PET consistent with sarcoidosis [80].
Minor salivary gland biopsy (MSGB) is not mentioned in the revised IWOS criteria. The
positivity rates for MSGB were 5.2% and 3% in two previous studies [81, 82]. Granulomas
were only found in the MSGBs of patients with increased ACE levels and/or compatible chest
CT (i.e. mediastinohilar lymph nodes and perilymphatic pulmonary nodules for the most).
However, there was no association between positive MSGB and the characteristics of uveitis.
These results suggested that MSGB, due to its low sensitivity, should be performed in
patient from a population where the prevalence of sarcoidosis is high (i.e. patients with
compatible chest CT and/or raised ACE) [82]. Furthermore, MSGB positivity does not
exclude tuberculosis [78].
Algorithm
Based on these data, our team proposed an algorithm to evaluate sarcoidosis probability in
patients with uveitis (figure 6) [1]. The value of fine-needle mediastinal aspiration in patients
with lymph node labelling on 18F-FDG PET needs to be demonstrated.
Management of ocular sarcoidosis

The literature regarding medical treatments of sarcoid uveitis essentially relies on small series
and case reports [1, 46]. Recently, a committee was developed by the European Respiratory
Society to develop new guidelines for treating sarcoidosis using a standardised methodology
[83]. The committee did not find sufficient information to make recommendations on ocular
involvement because of the paucity of studies specifically regarding this topic. The management
of ocular sarcoidosis was also discussed in the seventh IWOS and recommendations were
published in 2020 [70]. These are based on expert opinion. The majority of the patients required
https://doi.org/10.1183/2312508X.10033120 275
Compatible ocular signs
Physical examination
Blood count, ACE, intradermal skin tests, IGRA, chest radiography
Rash, conjunctival nodule, adenopathy
+ –
Biopsy – Chest CT
+
MSGB (if chest CT + + –
+ and/or ACE is high
– 18F-FDG PET
Transbronchial lung biopsy

+ BAL +
EBUS
If severe uveitis:
+ EBUS± –
mediastinoscopy
Definite ocular Presumed
sarcoidosis ocular sarcoidosis
FIGURE 6 Algorithm for the assessment of uveitis in patients with suspected sarcoidosis. IGRA: IFN-γ release assay;
MSGB: minor salivary gland biopsy. Reproduced and modified from [1] with permission from the publisher.
local treatment (i.e. topical or injected steroids) while 45–70% required systemic therapy, either
for ocular inflammation alone or for active systemic disease [1]. Medical treatment differs
depending on the anatomical site of uveitis (figure 7) [70]. Surgical management may be
required in various complications such as cataract, glaucoma and epiretinal membrane.
Argon-laser photocoagulation is mandatory in patients with retinal ischaemia while choroidal
neovascularisation requires intravitreal administration of anti-vascular endothelial growth factor
agents in combination with anti-inflammatory drugs [10].
Local treatment
Anterior uveitis
Active anterior uveitis is treated with a combination of topical corticosteroids and mydriatic/
cycloplegic agents [4]. When anterior uveitis is severe, second-line therapy can be used, such as
subconjunctival injections of dexamethasone or triamcinolone acetonide [70, 84, 85]. IWOS
experts recommend their use in cases of active inflammation in the anterior chamber such as
cells, new nodules or new synechiae [70].
Intermediate and posterior uveitis

The decision to treat intermediate and posterior uveitis depends not only on symptoms but also
on visual acuity and clinical features such as macular oedema, severity of vasculitis or active
choroiditis [70]. IWOS experts recommend that first-line therapy in intermediate or posterior
276 https://doi.org/10.1183/2312508X.10033120
Sarcoid uveitis
Anterior uveitis Intermediate Posterior

uveitis uveitis
Topical CS + mydriatic agents Presence of complication#?
If failure
No resistance or CI Yes
Intraocular CS Consider local CS (periocular,

Systemic CS
(subconjunctival, periocular) intravitreal, implant)
If failure If CS
and severe dependence
anterior uveitis or side-effects
Consider Consider biologics If failure Steroid-sparing IS

systemic CS (TNFi: ADA) (MTX, AZA, MMF)
FIGURE 7 Algorithm for management of sarcoid uveitis. CS: corticosteroids; CI: contraindication; IS:
immunosuppression; AZA: azathioprine; TNFi: TNF inhibitor; ADA: adalimumab. #: macular oedema, optic disc
nodules/granulomas, nodular and/or segmental periphlebitis, active chorioretinal peripheral lesions and
choroidal nodules.
uveitis should be either local or systemic corticosteroids depending on multiple factors [70].
Topical corticosteroids are not efficient in treating the posterior segment [84, 86].
Subconjunctival or intravitreal steroids are used as a corticosteroid-sparing agent, particularly in
unilateral uveitis in pseudophakic patients, although bilateral uveitis and phakic status are not
contraindications, especially in cases of unilateral asymmetric recurrence. General treatment may
be preferred in case of severe bilateral uveitis, severe glaucoma or in young phakic patients.
Subconjunctival injections of triamcinolone have been shown to be effective in the treatment of

macular oedema [86, 87] but this drug remains in the subconjunctival space for only 3 weeks
[86]. Longer-lasting molecules that can help reduce the burden of patients suffering from
chronic ocular sarcoidosis are currently available. Ozurdex (Allergan Inc., Irvine, CA, USA) is a
0.7 mg dexamethasone biodegradable polymer implant with a duration of 4–6 months, and is
indicated as first-line therapy for noninfectious uveitis in the USA and in Europe. Several
studies have shown interesting results in noninfectious uveitis of various causes [88–93] and
specifically in ocular sarcoidosis [94].
Systemic corticosteroids
Systemic corticosteroids are considered as a second-line therapy in severe anterior uveitis and as a
first-line therapy in bilateral intermediate active uveitis along with local corticosteroids (periocular,
intravitreal or implant). The IWOS recommendations consider the first-line therapy of unilateral
active intermediate uveitis to be exactly the same as that of bilateral active intermediate uveitis.
In posterior uveitis, macular oedema, optic disc nodules/granulomas, nodular and/or segmental
periphlebitis, active chorioretinal peripheral lesions, and choroidal nodules are considered as a
definite indication for treatment with systemic corticosteroids, alone or in combination with a
corticosteroid-sparing drug and/or with local treatment [70].
https://doi.org/10.1183/2312508X.10033120 277
First-line therapy for active bilateral posterior uveitis includes systemic corticosteroids, alone or
combined with nonbiologic corticosteroid-sparing drugs and local corticosteroids ( periocular,
intravitreal or implant). The first-line therapy for active unilateral posterior uveitis is exactly the
same as above. Systemic corticosteroids are used in refractory patients or patients with systemic
disease, or in cases of intolerance to local treatment [95].
The expert panel recommends an average initial dosage of prednisone of 0.5–

1.0 mg·kg−1·day−1 up to a maximum dosage of 80 mg·day−1. The initial dosage should be
maintained for 2–4 weeks and the total average duration of prednisone therapy should remain
between 3 and 6 months [70]. In cases of severe disease, intravenous corticosteroid pulses might
be used but evidence-based data are scarce [96].
Immunosuppressive agents
In 5–27% of cases, the use of corticosteroid-sparing agents is mandatory because corticosteroids
do not have a favourable outcome (requiring >10 mg·day−1 prednisone to control the disease) or
because disabling side-effects occur [4, 13, 21, 97]. The choice of the corticosteroid-sparing
agent should be based on the patient’s history and comorbidities. In the IWOS
recommendations, the initial corticosteroid-sparing drugs could be MTX, azathioprine (AZA),
MMF or cyclosporine. Biologics are then used if necessary [70].
MTX is considered by several authors to be the preferred second-line treatment but this remains
an off-label use. DEV et al. [98] reported the efficacy of MTX in 10 out of 11 cases. In a
retrospective monocentric analysis of 50 sarcoidosis patients, two-thirds of patients responded
after >6 months MTX therapy [99]. BAUGHMAN et al. [100] reported a large series of 465
sarcoidosis patients with ocular disease, including 365 patients treated with MTX, which was
both effective and well tolerated.
In the same series, AZA was quite effective but not as well tolerated as MTX. Out of 68
patients, 46 (67.7%) remained on AZA and 13 (19.1%) discontinued AZA because of drug
toxicity. The main limitation to the use of AZA appears to be the high toxicity rate, whic can
be anticipated by testing for polymorphism of the thiopurine S-methyltransferase gene.
Data regarding the use of MMF in sarcoidosis uveitis are scarce. BHAT et al. [101] described the
use of MMF as monotherapy in a retrospective case series of seven patients (14 eyes). The
best-corrected mean logMAR (logarithm of the minimum angle of resolution) visual acuity
revealed improvement in all 14 eyes, with a manageable side-effect profile. For cyclosporine,
the data are even more lacking. However, cyclosporine is the only immunosuppressive drug
available to treat uveitis in Japan [102].
Leflunomide has been shown to be effective in refractory sarcoid uveitis, either alone or in
combination with MTX. In a series of 32 patients treated with leflunomide, 16 out of
32 patients had complete response (50%) and nine had a partial response (28%). In 15 patients
with progressive sarcoidosis despite 6 months of MTX therapy, add-on therapy with
leflunomide resulted in a complete response in nine cases and a partial response in three
cases [103].
Anti-TNF-α treatment
In the IWOS recommendation, 74% of the panel use biologics as a third-line treatment,
especially adalimumab, which is the only biologic cited.
278 https://doi.org/10.1183/2312508X.10033120
Adalimumab has been approved by the US Food and Drug Administration to treat noninfectious
uveitis in adults and children aged ⩾2 years [97]. This approval is based on three international
prospective trials in which ocular sarcoidosis was one of the main diseases, although subgroup
analysis could not be performed [104–106]. The results of these studies demonstrated a
statistically significant reduction in the risk of treatment failure in patients treated with
adalimumab compared with patients receiving placebo. However, adalimumab was not more
effective than placebo in the subgroup of patients treated concurrently with other
immunosuppressants [104].
In a retrospective analysis of 160 refractory uveitis, VALLET et al. [107] found no significant
difference between adalimumab and infliximab in terms of safety and efficacy. A randomised
clinical trial of etanercept did not report any improvement in refractory ocular sarcoidosis and
therefore, this molecule should not be preferred. Data on golimumab and certolizumab pegol are
sparse in uveitis but could represent an effective and safe treatment option for patients with
uveitis even when unsuccessfully treated with other anti-TNF-α drugs [108, 109].
Our team reported an efficacy of anti-TNF-α drugs in 67% of patients among 17 patients
with refractory sarcoid uveitis [110]. Similarly, ERCKENS et al. [111] reported an
improvement in 85% of patients with sarcoid uveitis who did not respond to prednisone and
MTX. After 12 months, no relapses were reported in patients initially treated successfully.
Severe adverse events were frequent, requiring anti-TNF-α drug interruption in 33% of
patients. Their efficacy was transient and relapses occurred in most patients within 3 months
after treatment discontinuation.
In our single-centre experience, refractory uveitis, defined as the absence of response after
1 month prednisone at a dosage of 1 mg·kg−1·day−1, is unusual in sarcoidosis (six (2.6%) out
of 234 patients; data not published) and clinicians must first rule out poor compliance,
infectious uveitis or lymphoma before starting anti-TNF-α [112]. Secondary failures occurring
in the course of TNF antagonist therapy should alert to patient compliance or immunisation
against the monoclonal antibody [113].
Other biologics
Other biologic treatments could be used in refractory ocular sarcoidosis after failure of
anti-TNF-α treatment [114, 115].
The use of rituximab, a monoclonal chimaeric antibody targeting CD20+ cells, is based only on
case reports showing clinical response in two patients [116, 117].
Tocilizumab (TCZ), an IL-6 receptor (IL-6R) inhibitor, improved visual acuity and reduced
central foveal thickness in nonanterior uveitis in the randomised, open-label STOP-uveitis trial
[118]. This drug shows interesting efficacy on macular oedema [119]. In 2016, SILPA-ARCHA
et al. [120] reported the effect of TCZ in inflammatory ocular diseases in a case series of 17
patients. Among them, one had multidrug-resistant ocular sarcoidosis and improved with TCZ
therapy, without major side-effects. No case reports are available concerning the use of IL-1
blockade therapy.
FRIEDMAN et al. [121] lead a proof-of-concept study using tofacitinib, a Janus kinase ( JAK)
inhibitor, as a corticosteroid-sparing therapy in pulmonary sarcoidosis. We recently reported the
case of a patient with rheumatoid arthritis who developed paradoxical sarcoid panuveitis under
https://doi.org/10.1183/2312508X.10033120 279
adalimumab. While arthritis and uveitis remained active after adalimumab discontinuation,
uveitis and adenopathies resolved upon tofacitinib treatment [122]. Tofacitinib is currently tested
in a phase 2 open label trial in noninfectious uveitis (www.clinicaltrials.gov identifier number
NCT03580343).
Conclusion
The eye is the second most affected extrathoracic organ in sarcoidosis. The manifestations of
ocular sarcoidosis are heterogenous, but uveitis remains the most common of them. Clinicians
should be aware of the clinical features of ocular sarcoidosis, and work in collaboration with
ophthalmologists in the diagnosis strategy and management of ocular sarcoidosis. Recent IWOS
guidelines, which are detailed in this chapter, have attempted to achieve consensus in practice.
Corticosteroids (topical or systemic) are the mainstay treatment for sarcoid uveitis but >30% of
patients will require second-line immunosuppressants. Biologics, especially anti-TNF-α, are
increasingly used after failure of conventional corticosteroid-sparing therapies. New-line
(anti-IL-6R and JAK inhibitor) are being tested to expand the treatment panel for ocular
sarcoidosis.
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Disclosures: S. Giorgiutti has nothing to disclose. Y. Serrar has nothing to disclose. T. El-Jammal has nothing to
disclose. L. Kodjikian reports receiving consulting fees from Abbvie, Allergan, Novartis, Roche, Bayer and Théa,
outside the submitted work. P. Sève has nothing to disclose.
284 https://doi.org/10.1183/2312508X.10033120
Chapter 19
Paediatric sarcoidosis
1,2 3,4
Nadia Nathan and Alice Hadchouel
1
Paediatric Pulmonology Dept and Reference Center for Rare Lung Diseases (RespiRare), AP-HP Sorbonne
Université, Armand Trousseau Hospital, Paris, France. 2Sorbonne Université, Inserm Childhood Genetic Disorders,
Armand Trousseau Hospital, Paris, France. 3AP-HP, Hôpital Universitaire Necker-Enfants Malades, Service de
Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l’Enfant, Paris, France.
4
Faculté de Médecine, Université de Paris, Paris, France.
Corresponding author: Nadia Nathan (nadia.nathan@aphp.fr)
Cite as: Nathan N, Hadchouel A. Paediatric sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS
10033220].
@ERSpublications
Paediatric-onset sarcoidosis is very rare and severe with multiorgan involvement at diagnosis.
Corticosteroids are the first-line treatment. The course of paediatric sarcoidosis is unpredictable and
relapses of the disease are frequent in adulthood. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis is very rare in children, with an estimated prevalence of 0.40–0.80 per 100 000 children.
Teenagers are more affected, but the disease can be observed in children of all ages. The
pathophysiology of paediatric sarcoidosis is likely to be similar to that of adults, including an aberrant
inflammatory and granulomatous response to an antigenic trigger (organic or mineral, especially dusts)
in genetically predisposed patients (genes involved in autophagy and mitophagy). The disease is often
severe at presentation, with general signs (fever, weight loss, asthenia) and multiorgan involvement,
with the lungs, liver and eyes predominantly affected. Diagnosis requires an exhaustive workup to
exclude other causes of granulomatous disorders. Corticosteroids are the first-line treatment, either
orally or intravenously (high-dose pulses) for months to years, with immunosuppressive drugs as a
second-line treatment. The course of sarcoidosis is unpredictable, and relapses are frequent in
adulthood. This argues for long-term follow-up of patients and an optimal transition of care from
paediatric to adult departments.
Introduction
Sarcoidosis affects mainly adults and is a rare disease in children. The management and
treatment of paediatric-onset sarcoidosis remain challenging owing to the rarity of the disease in
this population.
It is important that paediatric sarcoidosis is distinguished from Blau syndrome, also called
early-onset sarcoidosis, a close granulomatous disease occurring mostly in children aged
<5 years. Blau syndrome is characterised by a clinical triad of uveitis, arthritis and dermatitis
with no or exceptional lung involvement. Blau syndrome is known to be due to a
NOD2/CARD15 heterozygous mutation involved in the immune response to bacterial and viral
antigens. Although similar to sarcoidosis from a pathological point of view, Blau syndrome, as
with other causes of granulomatous disease, has to be excluded before a diagnosis of paediatric
sarcoidosis is made [1].
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Epidemiology
Sarcoidosis occurs probably 10 times less frequently in children than in adults and only a few
case series have been reported so far in just four countries within the last 15 years. The disease
incidence is not yet known because of the absence of systematic reports; however, the
prevalence, as evaluated by these reports, is estimated to range between 0.40 and 0.80 per
100 000 children compared with >50 per 100 000 (>0.05%) in adults [2–5]. The incidence is
rarely reported but seems to increase with age. An incidence of 0.06 per 100 000 child-years
was reported in a Danish cohort at 4 years old and up to 1.02 per 100 000 child-years at
14–15 years of age [6]. There may also be geographical variations in the incidence of paediatric
sarcoidosis, as reported in adults. The disease affects predominantly young teenagers, with a
mean age at diagnosis of 11 years, but children of all ages can be affected, with extreme
presentations in infants, when Blau syndrome is excluded (table 1). In adults, the epidemiology
of sarcoidosis is characterised by wide variations according to age, sex and geographical
origin [11]. Younger patients <45 years and black patients are more likely to present with
multiple-organ involvement, to have severe localisation of the disease and to require treatment
[12]. In children, the sex ratio is roughly equal and, interestingly, as in adults, a predominance
of black patients of Afro-Caribbean and sub-Saharan origin has been reported, except in the
oldest Danish cohort, which was exclusively a white-patient cohort (table 1).
Pathophysiology: knowledge and assumptions

The causes and pathophysiology of sarcoidosis are not fully understood, nor the reasons why
the disease can manifest in childhood or in adulthood. The current hypothesis suggests a
combination of genetic predisposition triggered by repeated or prolonged exposure to an organic
or mineral antigen, which results in the activation of an aberrant granulomatous, immunological
and inflammatory reaction [13]. Thus, some authors consider sarcoidosis to be an
autoinflammatory disease [14, 15].
From immune theory to observed histological changes

Sarcoidosis pathophysiology is believed to be similar in adults and children. Sarcoidosis
granulomas have a typical pathology of a central follicle comprising activated macrophages,
TABLE 1 Epidemiology of the reported series of patients with paediatric-onset sarcoidosis
Country Year of Patients, Sex ratio Population Median age at

publication n (M/F) diagnosis
(range), years
Denmark [6, 7] 2004 48 26/22 Caucasian (100%) 13 (0.7–15)

(1.18)
France [2, 8] 2015–2020 41–52 19/22 Afro-Caribbean and 11 (1.1–15.8)
(0.86) sub-Saharan (88%),
Caucasian (10%), other (2%)
USA [9] 2016 27 14/13 Afro-Caribbean and 11 (2–23)
(1.08) sub-Saharan (74%),
Caucasian (22%)
India [10] 2019 18 10/8 (1.25) NR 9 (NR)
Total 2004–2020 145 69/65 (1.1) Afro-Caribbean and 11 (0.7–23)
sub-Saharan (48%),
Caucasian (48%), other (3%)
M: male; F: female; NR: not reported.
286 https://doi.org/10.1183/2312508X.10033220
PAEDIATRIC SARCOIDOSIS | N. NATHAN AND A. HADCHOUEL
named epithelioid cells, and CD4+ T-lymphocytes, mainly Th1. A lymphocytic ring of CD8+
T- and B-cells surrounds the central follicle. The granuloma contains no necrotic features [16, 17].
The mechanism of granuloma formation remains uncertain but probably involves an aberrant
immune response to environmental triggers. In most cases, the granulomas resolve
spontaneously, but in some cases, depending on the nature of the offending antigen and the
genetic background of the patient, they persist and evolve towards fibrosis [18]. There is
growing evidence on role of autophagy dysfunction in granuloma formation and disease
pathophysiology. Autophagy is an innate defence mechanism of the cell for elimination of
intracellular pathogens and foreign bodies. It involves both the host defence and regulation of
inflammation. A key player in autophagy regulation is the autophagy suppressor mTOR
complex 1 (mTORC1), which limits autophagy activity. Interestingly, in a mouse model in
which the tuberous sclerosis 2 (TSC2) gene involved in mTORC1 pathway activation was
deleted, M2 polarisation of the macrophages, similarly to what is observed in sarcoidosis, and
development of excessive granuloma formation were observed [19]. Moreover, inhibition of
mTORC1 completely resolved the granulomas by inducing apoptosis in these TSC2-deficient
mice. Although incompletely understood, it is likely that autophagy and perhaps genetic defects
of autophagy play a crucial role in the aberrant response to antigens and triggers, or that they
perpetuate sarcoidosis granuloma formation.
A polygenic disease?
Observations of a familial form of the disease, including in children, favour a genetic
background for sarcoidosis [2, 20–22]. It has been suggested that a first-degree relative with
sarcoidosis increases the risk of developing sarcoidosis by a factor 3.7 [23]. Recent
whole-genome sequencing studies suggest that sarcoidosis could be promoted by gene
variations in multiple gene clusters including those involved in autophagy and mitophagy [15].
Rather than a causal factor, these variants are considered predisposing factors [16, 24]. Among
the large spectrum of pathogenic variants, germline mutations in genes encoding various
regulators of mTOR and autophagy-related proteins have been implicated. This was first evidenced
by whole-exome sequencing in five families presenting multigenerational sarcoidosis [25].
Following this report, activation of the mTORC1 pathway was confirmed in sarcoidosis,
supporting the hypothesis that mTOR is a significant driver in granuloma formation [26].
Interestingly, inhibition of mTOR by sirolimus has been reported to be a successful alternative
treatment in sarcoidosis [27, 28].
In children, genetic studies are very limited due to the low number of patients. However, a
French study of three families (each comprising one child with sarcoidosis and two healthy
parents) was consistent with other studies and indicated 37 candidate genes clustering with
pathways involved in autophagy, intracellular trafficking, G-protein regulation, T-cell activation,
mitosis and/or immune synapse [29]. However, further studies are required to decipher whether
a specific molecular signature is associated with early-onset forms of sarcoidosis.
An environmental disease?
In sarcoidosis, granuloma formation could be an exaggerated response to an environmental/
infectious antigen [16, 30, 31]. The role of organic antigens (especially bacterial, mycobacterial
and fungal elements) has been suggested in the development of sarcoidosis [32, 33]. In parallel,
several studies have demonstrated a link between inorganic particles and sarcoidosis. For
instance, beryllium or crystalline silica has been associated with “sarcoidosis-like”
granulomatous diseases [34–37]. As discussed earlier, this environmental hypothesis is
sustained by molecular studies involving foreign-body reaction pathways such as autophagy in
sarcoidosis [25, 29]. In adults, the ACCESS (A case control etiologic study of sarcoidosis)
https://doi.org/10.1183/2312508X.10033220 287
study and the French pilot MINASARC (Mineralo-nano-sarcoidosis) study using BAL analysis
of mineral dusts were also in favour of a mineral trigger in sarcoidosis pathogenesis [32, 38].
More recently, a Dutch study highlighted increased exposure but also increased
immunoreactivity to metal and silica in 256 adult patients with sarcoidosis compared with a
control population of 73 individuals with obstructive sleep apnoea [36, 37]. Most of these
studies, as well as older studies in the USA [39], showed that this mineral exposure could be
due to occupational exposures. Agricultural and construction occupations where there is
exposure to a lot of dust appeared to be associated with sarcoidosis, and a higher steel load was
found in the BAL fluid of the patients [38].
In children, an ongoing study highlighted that occupational exposure (especially crystalline silica,
metal and talcum) of the adult coresidents of the child was associated with paediatric-onset
sarcoidosis, whereas direct mineral exposure of the children did not seem to be correlated [40].
Clinical presentation in children

The clinical presentation of paediatric sarcoidosis is highly polymorphic, and demonstration of
granulomatous lesions is usually necessary to confirm the diagnosis, after exclusion of other
causes of granulomatosis. A few paediatric cohorts have been published that identify the most
common clinical presentations. However, due to the rarity of this condition in children, the sizes
of these cohorts remain limited, ranging from 27 children [9] to 52 children [8]. Depending on
whether they are single-centre or multicentre studies, and the specialty of the departments
investigating these children, these series may therefore have recruitment biases, with, for
example, a predominant recruitment of ocular involvement [9]. Many case reports also show the
possibility of very atypical presentations.
The age of onset of symptoms is most often in adolescence. In a number of different series,
mean or median ages at diagnosis were 11, 11.8, 12.0 and 13 years [2, 6, 8, 9]. Both girls and
boys were equally affected, although girls were slightly more prevalent in some publications.
Paediatric-onset sarcoidosis is usually characterised by a combination of general signs and organ

involvement, the most common being the lungs, liver and eyes. General signs are predominant in
paediatric forms of sarcoidosis. As in adults, fatigue is very frequent and is seen in 36–56% of
children with sarcoidosis. Fever is seen in 26–50% of children but is very rare in adults [2, 6, 8, 9].
Fever is increasingly common, the younger the age of the child. It was reported in 71% children
<10 years of age but in only 29% of children aged 10–15 years [2]. Weight loss is also frequently
observed (26–48%) [2, 6, 9].
Lung involvement is an essential part of the diagnosis, as it is present in the majority of patients.
It is observed in 56–90% of paediatric-onset sarcoidosis [2, 6, 8]. Cough, chest pain and
exertional dyspnoea are the most frequent symptoms. Ocular involvement is also very common,
observed in 29–50% of children [2, 6, 8]. Chronic granulomatous anterior uveitis is the most
frequent presentation of ocular sarcoidosis, with mutton-fat keratic precipitates and iris nodules [41].
Although uveitis is frequently seen in paediatric sarcoidosis, it should be noted that sarcoidosis
accounts for <10% of uveitis in children [42]. Iridocyclitis and conjunctivitis may also be
observed. Liver involvement with hepatomegaly is observed in 31–56% of children [2, 6, 8, 9].
Some other extrarespiratory manifestations are less frequently observed but are nevertheless
present in 10–50% of children: skin manifestations including erythema nodosum, erythema, and
sarcoid skin lesions, peripheral lymphadenopathy, splenomegaly, joint involvement with pain in
288 https://doi.org/10.1183/2312508X.10033220
extremities and arthritis, and neurological symptoms. The most common manifestations of
neurosarcoidosis include cranial neuropathy, papilloedema or optic neuritis, seizures (24.5%)
and hypothalamic dysfunction, with the latter two being more likely in younger children [43].
Many other manifestations have been described in some cases of childhood sarcoidosis,
sometimes as the main symptoms. It is important in these situations to carefully investigate
other organ involvement, as multisystemic presentation is by far the most common in paediatric
sarcoidosis. These rare conditions include: parotitis, pericarditis, renal involvement with
granulomatous nephritis and renal failure, rapidly progressive bilateral sensorineural hearing loss
with labyrinthitis, granulomatous myositis, and bone marrow involvement with bleeding
manifestations [9, 44–47].
To date, due to the small size of the reported cohorts, apart from Blau syndrome, no definitive
conclusion can be made on the clinical differences in sarcoidosis presentation and severity
related to age at presentation. In our experience, lung function (DLCO only) seems lower in
teenagers than in younger children [2]. This has not yet been confirmed by larger studies and
needs to be further studied.
Sarcoidosis workup in children

Sarcoidosis in children is a diagnosis of exclusion. Thus, other causes of granulomatous
disorders must first be excluded (mainly Blau syndrome, Crohn disease, infectious
granulomatous diseases and primary immune deficiency). A negative tuberculosis skin test in a
vaccinated child is a classical finding [48].
Although thoracic CT is essential for the investigation of sarcoidosis in children, the Scadding
classification based on chest radiography findings is still currently used in children and adults.
However, chest radiography seems to lack sensitivity in paediatric sarcoidosis and is reported as
normal in more than one-third of children, whereas the CT scan is abnormal in 95% of
cases [2]. Hilar and/or mediastinal lymphadenopathy are nearly constant. Other lesions
frequently observed include nodules >3 mm, ground-glass opacity and thickening of the
pleura/fissure [49, 50]. Interlobular septal thickening is less frequently observed, as well as
atelectasis, consolidation, bronchiectasis, intraparenchymal and subpleural cysts, fibrotic bands
and an enlarged pulmonary artery [49, 50].
A flexible bronchoscopy with BAL is usually performed to document lymphocytic alveolitis.

However, this finding is inconsistent and was reported to be absent in 5% of proven paediatric
cases [2]. When present, it is usually moderate, with an increase in the proportion of lymphocytes
of 40–50% and a predominance of CD4+ lymphocytes [2, 50]. Bronchoscopy is also an
opportunity to perform bronchial and/or transbronchial biopsies, depending on the imaging. The
lungs are the most informative site to document the presence of typical granulomas [2]. However,
if lung histological confirmation is required, lung biopsy is usually performed by open lung
biopsy in young children. Although preferred for its minimal invasiveness, EBUS-TBNA is rarely
performed in children because of the small size of the respiratory airways and the absence of
adapted devices in most centres. However, in some centres, this expertise has been developed and
paediatricians trained to carry out this procedure. In these centres, its efficacy and safety have
been reported for evaluation of mediastinal lymphadenopathy [51]. Its use will certainly be
developed in paediatric centres in the coming years.
Respiratory function tests are essential, including DLCO. These measurements will also be very
useful for follow-up. A restrictive syndrome is frequently measured, including in children
https://doi.org/10.1183/2312508X.10033220 289
<10 years of age [2]. DLCO is frequently lowered, with a decrease that appears to be greater after
the age of 10 years [2, 6]. The 6-min walk test and other exercise tests are important in
managing adult patients with sarcoidosis, but their usefulness has not been evaluated
in children.
The biological signs are not specific, but their combination may be suggestive, such as elevated
erythrocyte sedimentation rate, anaemia, hypergammaglobulinaemia, lymphocytosis or
lymphopenia, thrombocytosis, increased levels of transaminases and serum ACE, and
hypercalcaemia [6, 52]. Elevated serum ACE levels are measured in less than two-thirds of
paediatric cases [2, 6].
Pathological examination of the biopsied organs that reveal noncaseating granulomas remains
critical to assess sarcoidosis diagnosis. More than one organ biopsy is often needed to
demonstrate a typical granuloma. The most minimally invasive sites should, of course, be
preferred in children. The most informative sites are the lungs, salivary glands, liver and
peripheral glands [2].
Treatment and evolution in adulthood

Treatment
In children, spontaneous regression of the disease has been reported rarely without any
treatment. However, due to a usually severe clinical expression of the disease, therapeutic
abstention is rarely recommended, and the majority of the children receive treatment at
diagnosis [53]. As in adults, corticosteroids are the first-line treatment (up to 94% of patients)
[54]. However, in children, high doses of corticosteroids are often delivered orally
(1–2 mg·kg−1·day−1) and/or with monthly intravenous pulses (300 mg·m−2·day−1,
3 days·month−1; up to 51% of patients) [8]. The total duration of corticosteroid therapy was
prolonged in this series with a median of 5 (range 1.38–10.3) years [8]. In contrast, for
sarcoidosis beginning in adulthood, it is reported that only 40% of patients required prolonged
corticosteroid therapy [55, 56]. As well as corticosteroids, various immunosuppressive therapies
are reported to be used in paediatric sarcoidosis, occasionally as a first-line treatment but more
often as a second-line treatment in case of corticosteroid resistance or dependence (up to 100%
of the patients in the Indian cohort and 48% of the patients in the French cohort), with a mean
duration of 3 years (range 1.1–5 years) in the latter [8, 10].
Evolution in adulthood
The evolution in young adults of paediatric-onset sarcoidosis was studied recently in a cohort of
52 French patients followed since diagnosis at a median age of 11 years to adulthood with a
median follow-up of 11.5 years in adulthood (figure 1) [8]. Overall, 40% of the patients
recovered during childhood. Thirty patients (57%) presented relapses or a continuation of the
disease expression in adulthood (total of 84 relapses), with a median of two relapses per patient
(but up to 12 relapses in a patient). Figure 2 provides an example of the evolution in adulthood
of a paediatric patient with a severe lung disease associated with liver and ocular involvement
in childhood.
While the paediatric patients were characterised by a large number of involved organs (median
4) and general signs (fever), the clinical picture of adults remaining symptomatic joined that of
classical sarcoidosis in adults: absence of fever and low number of involved organs (1.9 per
patient) [8]. Thus, it appeared that clinical presentation in adulthood relied more on the actual
age of the patients than on the age at disease onset.
290 https://doi.org/10.1183/2312508X.10033220
20 37%
35%
18
16
14
Patients, n
12
19%
10
8
6
8%
4
2 2%
0
Stable for Stable for Controlled Uncontrolled Pulmonary
>1 year >3 years transplantation
FIGURE 1 Adulthood evolution of 52 French patients with paediatric-onset sarcoidosis. At the end of paediatric
follow-up, 51.9% of the patients were stable at last paediatric evaluation with no treatment, whereas 48.1% still
required treatment. The graph shows the clinical status of the patients after a median follow-up of 11.5 (range
3–44.5) years in adulthood. Two distinct groups can be described: 53.8% (n=28) of the patients were stable for
>1 year (n=10, 19%) or >3 years (n=18, 35%), whereas 46.2% (n=24) were still under treatment, with 19 (37%)
having controlled disease, four (8%) having an active disease and one (2%) needing a lung transplant.
Relapses in adulthood most often occurred while decreasing the treatment, but were also
observed after a long period of clinical stability (>3 years). They manifested preferentially in an
organ previously affected, although new localisation of the disease was also reported, such as
neurosarcoidosis [8].
Based on this study, it seems that the last evaluation at paediatric age is therefore insufficient to
predict the outcome in adulthood and justifies a prolonged follow-up in adulthood. One-fifth of
the patients considered as stable at the end of paediatric follow-up, with no treatment, finally
relapsed in adulthood. Conversely, one-fifth of patients still requiring treatment at the
child-to-adult transition had resolved the disease in adulthood [8].
This unpredictable course often results in a long duration of the disease (median 7 (range
1.5–44) years) and prolonged treatment [8]. These results contrast with an earlier follow-up
study by MILMAN et al. [7] on a Danish cohort of 46 children, who reported, after 23 years of
evolution, that 38 patients (83%) were cured, whereas five (11%) still presented with active
disease and three died. The quality of life of 34 of these Danish patients was also evaluated in
adulthood and showed similar scores to those of the control population [57]. As well as the
12 years between these two studies [7, 8], the reported populations were highly different, as all
of the Danish patients were of European origin, whereas most of the French patients were of
sub-Saharan or Caribbean origin. Whether these differences played a role in the sarcoidosis
evolution remains to be discovered.
Long-term impacts of treatments

The cumulative doses of corticosteroids administered during childhood are sometimes
impressive (median 17 800 mg and maximum 35 200 mg in the French cohort [8]), sometimes
with additional immunosuppressive therapy. Interestingly, only a few severe side-effects (3.8%)
were observed in childhood [8], in contrast to what would have been expected in adults [58].
In children, i.v. methylprednisolone pulses appear to be well tolerated, as reported in other
https://doi.org/10.1183/2312508X.10033220 291
a) b)
c) d)
FIGURE 2 Evolution of lung involvement of sarcoidosis in a patient from childhood to adulthood. a and b) CT
scans at 12 years old with multiple perihilar and mediastinal lymphadenopathies (a) and diffuse ground-glass
opacities and micronodules (b). The patient benefited from corticosteroid pulses and hydroxychloroquine, with a
poor adherence to the treatment. c) At age 16, she presented with disease progression with persistence of
ground-glass opacities, localised micronodules, traction bronchiectasis and scissural distortion in favour of a
fibrotic evolution of the disease. d) Despite corticosteroids and MTX, her lung disease continued to evolve, and
at 21 years, she presented with late-stage lung fibrosis with traction cysts and honeycombing.
paediatric indications [59]. However, in adulthood, more than one-third of the patients finally
present adverse effects of the treatments, the most frequent being obesity and overweight. Thus,
the minimum required dose of corticosteroids is recommended for as long as possible, and
corticosteroid-sparing agents should be used in case of corticodependence or corticoresistance.
Lifestyle adaptations
As for all chronic respiratory diseases, prevention of environmental exposure is a crucial issue.
Paediatricians may have little experience in smoking prevention and often find it difficult to
discuss these issues with teenagers and young adults. Based on recent knowledge on the link
between mineral exposure and sarcoidosis, occupational issues should be discussed early with
teenagers, and professions that avoid this risk should be encouraged.
Conclusion
Sarcoidosis in children remains an intriguing disease. Its clinical expression is more severe than
in adults and its evolution is hazardous in adulthood, with eventual persistence or long-term
relapse justifying a long-term follow-up. Exploring this restricted population of patients could
be a unique opportunity to better understand the pathophysiological basis of the disease,
especially regarding genetic and environmental aspects.
292 https://doi.org/10.1183/2312508X.10033220
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treatment. Cureus 2021; 13: e14507.
47 Meshram RM, Gajimwar VS, Gholap S, et al. Bone marrow involvement: atypical presentation of early-onset
childhood sarcoidosis. Eur J Rheumatol 2020; 7: 190–194.
48 Rappl G, Pabst S, Riemann D, et al. Regulatory T cells with reduced repressor capacities are extensively
amplified in pulmonary sarcoid lesions and sustain granuloma formation. Clin Immunol 2011; 140: 71–83.
49 Gorkem SB, Köse S, Lee EY, et al. Thoracic MRI evaluation of sarcoidosis in children. Pediatr Pulmonol 2017; 52:
494–499.
50 Sileo C, Epaud R, Mahloul M, et al. Sarcoidosis in children: HRCT findings and correlation with pulmonary
function tests. Pediatr Pulmonol 2014; 49: 1223–1233.
51 Madan K, Iyer H, Madan NK, et al. Efficacy and safety of EBUS-TBNA and EUS-B-FNA in children: a systematic
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52 Mărginean CO, Meliţ LE, Grigorescu G, et al. Hypercalcemia, an important puzzle piece in uncommon onset
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53 Sergi CM. Pediatric sarcoidosis with diagnostic and therapeutical insights. Curr Opin Pulm Med 2021; 27: 472–477.
54 Nathan N, Sileo C, Calender A, et al. Paediatric sarcoidosis. Paediatr Respir Rev 2019; 29: 53–59.
56 Baughman RP, Nagai S, Balter M, et al. Defining the clinical outcome status (COS) in sarcoidosis: results of
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294 https://doi.org/10.1183/2312508X.10033220
Chapter 20
The manifestations of rare organ sarcoidosis
Marc A. Judson1, Jean Pastre2 and Dominique Israël-Biet3
1
Division of Pulmonary and Critical Care Medicine, Albany Medical College, Albany, NY, USA. 2Service de
Pneumologie et Soins Intensifs, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris,
Paris, France. 3Université de Paris and Center of rare pulmonary diseases, Hôpital Européen Georges Pompidou,
Assistance Publique-Hôpitaux de Paris, Paris, France.
Corresponding author: Marc A. Judson ( judsonm@mail.amc.edu)
Cite as: Judson MA, Pastre J, Israël-Biet D. The manifestations of rare organ sarcoidosis. In: Bonella F, Culver DA,
[https://doi.org/10.1183/2312508X.10033320].
@ERSpublications
Several organs are only rarely involved with sarcoidosis and often have no symptoms, but if treatment is
required, standard therapy is usually sufficient. Knowledge of the differential diagnoses is required for
exclusion of alternative potential diseases. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis is a multisystem granulomatous disease that can affect any organ. However, several organs
are rarely involved with the disease, and are reviewed in this chapter. The specific manifestations of
sarcoidosis in these organs are discussed in detail. Although organs that are rarely involved with
sarcoidosis often cause no symptoms and usually do not require treatment, there is often the possibility
that an alternative condition is present such as an infection or malignancy that mandates that a
diagnostic biopsy be performed. Therefore, adequate management of rare organ involvement with
sarcoidosis requires knowledge of alternative potential diagnoses that need to be excluded. When
treatment is required for rare organ involvement with sarcoidosis, typical sarcoidosis therapy is usually
sufficient.
Introduction
Several organs are rarely involved in sarcoidosis: cardiac sarcoidosis (discussed in another
chapter in this Monograph [1]), for example, is the 10th to 13th most common organ
involved with sarcoidosis [2, 3]. However, involvement of such organs can be of major
importance because they can be life-threatening [4, 5]. Other rarely involved organs,
although they contain granulomas, lead to few clinically important consequences.
Nonetheless, it is important for the clinician to be aware of the manifestations of rare organ
sarcoidosis (ROS) for several reasons. First, ROS can sometimes result in clinically
significant disease that warrants therapy. Second, ROS may be confused with more common
diseases that occur in that organ, which may result in inappropriate and harmful treatment.
Third, the natural history of ROS is not well described, and this knowledge gap places the
sarcoidosis patient at risk of being overtreated or undertreated for ROS. In this chapter, we
review the manifestations of ROS, including their clinical presentations, the diagnostic
approach, treatment and outcomes.
https://doi.org/10.1183/2312508X.10033320 295
Gastrointestinal tract sarcoidosis

The exact frequency of gastrointestinal tract (GIT) sarcoidosis is unknown for several reasons.
First, GIT sarcoidosis may be underdetected because it often causes no symptoms and is usually
diagnosed by endoscopy that is performed for another GIT abnormality. Second, symptomatic
GIT sarcoidosis may be over-reported because GIT symptoms may be attributed to sarcoidosis
when they have an alternative cause. Third, GIT sarcoidosis may be misdiagnosed as a more
common alternative granulomatous GIT disease. GIT symptoms in sarcoidosis patients are
rarely attributable to sarcoidosis, as one report confirmed the presence of sarcoidosis in only one
out of 224 endoscopic GIT biopsies [6]. Therefore, it should not be assumed that GIT
symptoms in a sarcoidosis patient reflect GIT sarcoidosis without a thorough evaluation,
including assessment of other potential causes.
GIT sarcoidosis is more common in individuals of African descent [7]. Any portion of the GIT
may be involved with sarcoidosis. The stomach and colon seem to be most frequently involved
[6, 7], although this may be because most portions of the small intestine cannot be easily
visualised or biopsied. GIT sarcoidosis is persistent in only one-quarter of patients [7], which
supports the contention that many of these cases cause no symptoms and are found
unexpectedly on GIT endoscopy. Sarcoidosis may involve multiple portions of the GIT [8],
including a diffuse granulomatous enterocolitis resembling Crohn disease [9, 10].
Symptomatic oesophageal sarcoidosis most often presents with dysphagia [11]. Other common
symptoms include weight loss, odynophagia and a hoarse voice/dysphonia [11]. Oesophageal
sarcoidosis may cause oesophageal dysmotility from involvement of the muscles of peristalsis,
involvement of the oesophageal lumen or oesophageal compression from para-oesophageal
lymphadenopathy [11–13]. Additional manifestations of oesophageal sarcoidosis include
Barrett-like oesophagitis [14], an achalasia-related syndrome from granulomatous infiltration
of nerve fibres innervating the oesophagus [15], oesophageal stricture from previous
granulomatous inflammation [16] and a pseudodiverticulum related to granulomatous
infiltration [17]. Oesophageal sarcoidosis almost always responds to corticosteroid therapy [11].
Surgery may be required in selective cases when there is muscular infiltration (cricopharyngeal
myotomy) [18], suspected achalasia (oesophageal myotomy) [17] or oesophageal strictures/
perforation/fistulisation [11, 19, 20]. Portal hypertension, which occurs in <3% of patients with
hepatic sarcoidosis [21], may lead to the development of oesophageal varices that require
intervention [22].
Gastric sarcoidosis is the most common site of GIT involvement in many series [7, 11]. As
with all forms of GIT sarcoidosis, such involvement usually causes no symptoms. One study
found that 10% of male African-American sarcoidosis patients had gastric granulomas when
biopsy of normal gastric mucosa was performed [23]. This suggests that asymptomatic
microscopic gastric sarcoidosis may be fairly common. Clinically significant gastric sarcoidosis
is much rarer. The most common presenting symptoms of gastric sarcoidosis are epigastric
pain, weight loss, nausea, vomiting and melena [11, 24]. Irritable bowel syndrome and
pernicious anaemia are unusual presentations [25, 26]. Symptomatic gastric sarcoidosis most
commonly causes diffuse gastric infiltration or ulcerative lesions [11, 26]. Specific pyloric
involvement and gastric polyps are less common manifestations [11]. Occasionally, a linitis
plastica-type presentation occurs that is usually irreversible [27, 28]. A diagnostic stomach
biopsy should be performed when symptomatic gastric sarcoidosis is suspected [8]. When a
biopsy reveals granulomatous inflammation, alternative causes should be excluded including
Helicobacter pylori, Crohn disease, tuberculosis, lymphoma and a sarcoidosis-like reaction to
malignancy (gastric cancer) [8, 29, 30]. Symptomatic gastric sarcoidosis is usually successfully
296 https://doi.org/10.1183/2312508X.10033320
RARE ORGAN SARCOIDOSIS | M.A. JUDSON ET AL.
treated with corticosteroids and proton pump inhibitors [11, 31, 32]. Gastric resection is
reserved for those with refractory disease, obstruction, life-threatening haemorrhage or a linitis
plastica-type presentation.
The small bowel is the rarest location for GIT sarcoidosis, although this may be because the
small bowel is rarely well visualised on clinical studies. The clinical manifestations of small
bowel sarcoidosis include dyspepsia, malabsorption, diarrhoea, abdominal pain, constitutional
symptoms (fever, weight loss), bowel obstruction, and intestinal haemorrhage [8, 11, 33, 34].
Small intestine sarcoidosis may rarely cause a protein-losing enteropathy [35] or megaloblastic
anaemia from terminal ileum involvement [36]. Corticosteroids are usually effective for small
bowel sarcoidosis [11], and infliximab has also been used successfully [35, 37].
Colonic sarcoidosis may occur in any location, including rarely in the appendix and the rectum.
Common symptoms of colonic sarcoidosis include abdominal pain, diarrhoea, weight loss,
haematochezia and constipation [11]. The endoscopic findings may range from a colonic mass
[38] to polyposis [39] to colitis [11, 40]. Sarcoidosis of the appendix may cause appendicitis or
perforation [41, 42]. Glucocorticoids have been successfully used for colonic sarcoidosis [43],
although the disease is often asymptomatic and does not require treatment. Often, the disease is
treated by colonic resection, as a colonic malignancy can rarely be definitely excluded by
endoscopic biopsy [11].
Sarcoidosis and Crohn disease are granulomatous diseases of unknown cause with several
overlapping features including impairment of cell-mediated immunity, anergy and extra-GIT
findings such as uveitis, erythema nodosum and arthritis [36, 44, 45]. Distinguishing these two
entities can be problematic and, at times, impossible [8]. As GIT symptoms are unusual in GIT
sarcoidosis, Crohn disease is more likely to cause significant diarrhoea, bloody diarrhoea or
intestinal obstruction [8]. Upper GIT Crohn disease is uncommon in the absence of disease
beyond the ligament of Treitz, and alternative granulomatous diseases of the GIT should be
considered in these cases. One study comparing GIT sarcoidosis with Crohn disease found that
sarcoidosis much more commonly involved the upper GIT, whereas Crohn disease more
commonly involved the ileum and colon [7]. Estimates of the prevalence of granulomas in
Crohn disease range from 15% to as high as 70% [46]. Although the granulomas of Crohn
disease tend to be less well formed than those of sarcoidosis, there is too much overlap to
distinguish these diseases on the basis of histology alone [8]. Table 1 displays clinical features
that may favour one of these two diagnoses or that are found commonly in both conditions.
Genital tract sarcoidosis

Sarcoidosis involves the reproductive tract of both men and women in <1% of sarcoidosis
patients [47–49]. In the male reproductive tract, the epididymis is most commonly involved,
followed by the testes [49, 50]. Involvement may be unilateral or bilateral [50]. Most cases have
been reported in African-Americans [49, 51]. Male genital tract sarcoidosis usually presents as
painless masses, although they may be tender [51]. Rare presentations include infertility and
azoospermia from vasal obstruction [52, 53]. Painless intrascrotal masses are concerning for
malignancy, especially as the majority of testicular sarcoidosis patients are in their 20s and 30s
[54], which is the peak age of presentation of testicular carcinoma. Scrotal sonographic findings
of sarcoidosis usually demonstrate hypoechoic masses in the testis or epididymis (figure 1).
However, these sonographic findings are problematic to differentiate from malignant lesions
[55]. In patients with previously diagnosed sarcoidosis and negative tumour markers, testicular
carcinoma is less likely but still possible. The diagnosis of testicular sarcoidosis often requires a
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TABLE 1 Clinical data supporting the possibility of sarcoidosis versus Crohn disease
Supports Supports Does not favour

sarcoidosis Crohn disease either diagnosis
Isolated GIT disease ++
History of extra-GIT sarcoidosis ++
Gastrointestinal symptoms ++
Rectal/perianal lesions +
Disease isolated above the ligament of Trietz +
Histology
Granulomas ✓
Crypt inflammation ++
Aphthae ++
Ulceration ++
Extra-GIT manifestations
Erythema nodosum ✓
Pyoderma gangrenosum ++
Aphthous ulcers ++
Cheilitis ++
Uveitis ✓
Arthritis ✓
Pulmonary nodules and/or thoracic ++
adenopathy
Spondylitis ++
Uric acid nephrolithiasis +
Calcium oxalate nephrolithiasis ✓
Elevated 24-h urine calcium or elevated ++
serum 1,25-dihydroxyvitamin D
GIT: gastrointestinal tract; +: supports diagnosis; ++: strongly supports diagnosis; ✓: condition common in both
disorders. Reproduced and modified from [8] with permission.
tissue biopsy to exclude malignancy. The surgical approach is problematic because a

testis-sparing approach has the potential risk of leaving behind malignant tissue in the case of
testicular carcinoma, whereas a radical orchiectomy in a patient with testicular sarcoidosis may
be excessive, especially in the case of bilateral disease where infertility and hypogonadism will
result [49, 51]. A biopsy should be considered over orchiectomy in patients with pre-existing
sarcoidosis or who present with extratesticular manifestations of sarcoidosis. It should be noted
that granulomatous lesions can be found concomitantly with seminomas [56]. Corticosteroids
are usually effective for testicular sarcoidosis [49]. Sarcoidosis involvement of the prostate is
extremely rare, and often presents as a prostatic mass [49]. Penile sarcoidosis is exceedingly
rare, and can present as ulcerative lesions [57].
Sarcoidosis may affect the female reproductive tract. Most reported cases involve the uterus.
However, it is important to note that the presence of uterine granulomas is usually related to a
cause other than sarcoidosis. Two series examining 41 cases of uterine granulomas found that
only one was clearly related to sarcoidosis, and the vast majority were in women with a
previous history of uterine instrumentation that was thought to be responsible for the
granulomatous reaction [58, 59]. Uterine sarcoidosis may present as a polypoid lesion [60, 61].
Sarcoid granulomas have also been identified within uterine leiomyomas (figure 2) [62].
Vaginal wall and vulvar involvement with sarcoidosis are extremely rare [63–66] but should be
considered in a sarcoidosis patient with a vulvar mass or vaginal irritation. Although vaginal
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FIGURE 1 Scrotal ultrasound of a man with biopsy-confirmed pulmonary sarcoidosis and a testicular mass.
In the right upper mid-testis, there is a 5-mm average-dimension, rounded, hypoechoic lesion with a few
low-level internal echoes. This lesion was biopsied, and histology revealed noncaseating granulomas consistent
with sarcoidosis.
sarcoidosis responds to standard anti-sarcoidosis therapy [63, 66], corticosteroid vaginal creams
may also be helpful [63]. Fallopian-tube sarcoidosis is also exceedingly rare [67, 68].
Sarcoidosis has also rarely been reported in multiple portions of the female reproductive tract [69].
Female reproductive tract sarcoidosis may occur synchronously or after the development of a
reproductive tract malignancy [70, 71]. The development of sarcoidosis in these cases may be
related to chemotherapy or a sarcoidosis-like reaction to malignancy [70–73].
Sarcoidosis of serosal surfaces ( peritoneum, pericardium and pleura)

Peritoneal sarcoidosis may mimic ovarian cancer by presenting as diffuse nodular omental
thickening and often as ascites [74–77]. Biopsy of the omental thickening reveals noncaseating
granulomatous inflammation. These patients may have elevated levels of tumour markers such
as CA 125 and CA 15.3 [74, 75]. Such peritoneal presentations have been found exclusively
in females.
Although the pulmonary sarcoidosis lesions are commonly located in subpleural locations [78],
pleural effusions are a rare manifestation of sarcoidosis. Sarcoidosis-associated pleural effusions
(SAPE) were found in 1% of 181 consecutive sarcoidosis patients who underwent
ultrasonography [79]. The mechanism of pleural fluid formation in sarcoidosis is probably
similar to other infiltrative diseases [79]. Other causes of pleural effusions in sarcoidosis include
superior vena cava obstruction [80], trapped lung [81], endobronchial sarcoidosis causing
atelectasis [82], and lymphatic disruption with the development of a chylothorax [83]. Because
pleural effusions in sarcoidosis patients are often unrelated to sarcoidosis, the diagnosis of
SAPE requires exclusion of other causes by obtaining an adequate history and often a
thoracentesis with pleural fluid analysis. A definitive diagnosis of SAPE requires a pleural
biopsy demonstrating noncaseating granuloma and the exclusion of alternative causes of this
histology [79]. SAPE are more commonly right sided than left sided [84]. These effusions may
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a)
b)
FIGURE 2 Endometrial sarcoidosis. a) Low-power image (haematoxylin and eosin stain, magnification ×40) of
endometrial curettings demonstrating a small fragment of endometrium with proliferative epithelial changes and
foci of syncytial cellular change (black arrow) consistent with nonmenstrual breakdown and a fragment of
endometrial stroma with two well-formed granulomas (yellow arrows). b) Higher-power image (haematoxylin
and eosin stain, magnification ×400) showing that the two discrete granulomas lack necrosis and comprised
epithelioid histiocytes with a few intermixed multinucleated giant histiocytes and sparse admixed lymphocytes.
be transudates or exudates, although the latter are more common [79]. The appearance of the
fluid is typically serous [79]. The pleural fluid glucose is usually normal but is low in 20% of
cases [79]. SAPE are typically lymphocyte predominant, with >80% lymphocytes in half of
the cases [79]. These effusions typically respond to corticosteroids [85].
Pericardial sarcoidosis may cause pericardial effusion, chest pain and abnormal electro-
cardiographic changes [86]. Occasionally, sarcoidosis pericardial effusions may cause cardiac
tamponade [87, 88] or constrictive pericarditis that may be either fibrous or effusive constrictive
[89, 90]. The diagnosis of pericardial sarcoidosis is firmly established by pericardial biopsy
[90]. The diagnosis may also be established on clinical grounds on the basis of a history of
sarcoidosis and either compatible 18F-FDG uptake in the pericardium on PET [89, 91] or
delayed gadolinium enhancement of the pericardium on nuclear MRI. Pericardial sarcoidosis
has developed in patients both with [90] and without [88] evidence of myocardial sarcoidosis.
Pericardial sarcoidosis usually responds to corticosteroids and other anti-sarcoidosis therapies.
Sarcoidosis of the breast

Sarcoidosis may develop in the breast. Breast sarcoidosis may present as a solitary lesion or
multiple lesions, and may be unilateral or bilateral [92]. These lesions may be palpable or
detected on mammography (figure 3), ultrasound (figure 4), or MRI and PET scan [92–95].
The mammographic appearance of breast sarcoidosis is usually an irregular or poorly defined
mass that may be spiculated [92]. However, well-defined small masses have also been described
that are thought to reflect intramammary lymph-node involvement [92].
A breast mass in a sarcoidosis patient should not be assumed to be sarcoidosis, as breast cancer
is always a concern. Histology of breast sarcoidosis reveals granulomatous lesions that usually
have typical features of sarcoidosis including minimal to no caseation and tight borders [92].
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FIGURE 3 Mammogram showing the left breast cranio-caudal view of a biopsy-proven breast sarcoidosis lesion.
A 0.4-cm oval, noncalcified lesion with indistinct margins is seen (circle).
The differential diagnosis of granulomatous breast lesions includes various infections, foreign
body reactions, fat necrosis, a localised reaction to silicone, connective tissue diseases,
vasculitides, idiopathic granulomatous mastitis or a sarcoidosis-like reaction of malignancy from
breast cancer [92, 96]. In addition, silicone breast implants can induce an autoimmune/
inflammatory syndrome induced by adjuvants that can induce a systemic syndrome
indistinguishable from sarcoidosis in multiple organs beyond the breast [97–99].
In addition, there appears to be a relationship between sarcoidosis and breast cancer. Sarcoidosis
appears to frequently develop before, concomitant with and after the presentation of breast
cancer [100, 101]. The clinical features and clinical course of sarcoidosis and breast cancer are
similar to those with stand-alone sarcoidosis [100].
Treatment of breast sarcoidosis is rarely required as it has essentially no significant health

consequences. It is usually only treated when there is a sarcoidosis treatment indication present
outside of the breast.
Musculoskeletal manifestations of sarcoidosis

Musculoskeletal sarcoidosis (MSKS) refers to sarcoidosis involvement of joints, bones and/or
muscles. The four major types of MSKS are: 1) acute sarcoid arthritis, as seen with Löfgren
syndrome, 2) chronic arthritis, 3) osseous sarcoidosis, and 4) sarcoid myopathy. Muscle and
bone sarcoidosis coexist in up to half of affected patients [102]. The reported prevalence of
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FIGURE 4 Breast ultrasound of the biopsy-proven breast sarcoidosis lesion shown in figure 3. An oval hypoechoic
mass with indistinct margins and a hyperechoic halo is visible (within the “x” and “+” markers).
MSKS has ranged from “rare” [103] to between 6% and 25% [102, 104–106]. These disparate
estimates are related to several factors. First, MSKS is frequently asymptomatic and is often
detected on imaging performed for other purposes. Second, the prevalence largely varies with
patient ethnicity. Third, there are no standardised diagnostic criteria for MSKS. The frequency
of MSKS has been found to be 6% and 15% in two large cohorts [102, 107]. Finally, series that
used more sensitive imaging techniques such as PET/CT have reported higher prevalence rates
[102]. Although 18F-FDG PET/CT is particularly useful in detecting bone sarcoidosis, positive
studies are not specific for sarcoidosis and may be seen in other inflammatory conditions and
metastatic lesions [107–109]. 18F-FDG PET/CT is also a useful tool to assess disease activity
[110] and to detect asymptomatic involvement.
The outcome of MSKS is generally favourable [111], but can range from an asymptomatic
condition to simple arthralgias to widespread destructive bone lesions. Therefore, eliciting
symptoms of musculoskeletal complaints should be a routine part of the initial sarcoidosis
evaluation.
Joint involvement (sarcoid arthropathy) is observed in 6–35% of sarcoidosis patients [112–114].

In a retrospective study [112], 31 out of 39 (82%) sarcoidosis patients with clinical arthritis had
ultrasound-confirmed synovitis. The arthritis was usually bilateral and symmetrical,
predominantly affecting the ankles (85%), wrists (46%) and metacarpophalangeal joints (31%).
Acute arthritis was observed in 19 patients (49%) and 89% of those had Löfgren syndrome. The
remaining 51% had chronic sarcoid arthropathy.
Löfgren syndrome is characterised by the triad of symmetrical hilar adenopathy, erythema

nodosum and joint pain [115]. It affects predominantly Caucasians and women [116]. The
ankles are the most frequently involved joint, but other joints may be affected including the
wrists, elbows and metacarpophalangeal joints. Ultrasonography shows that the joint swelling is
usually attributable to periarticular soft-tissue swelling and tenosynovitis. Therefore, Löfgren
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syndrome usually manifests as a periarthritis rather than a true joint synovitis; joint effusions are
rare. The natural course of Löfgren syndrome is usually characterised by spontaneous resolution
within a few months [116]. Relapses are rare. The condition is associated with specific genetic
polymorphisms: HLA-DRB1 and the HLA-DRB1*03-positive genotype portend an excellent
prognosis [117].
Chronic sarcoid arthritis is much less frequent than Löfgren syndrome. It commonly affects the
ankles [105, 118] and is characterised by persistent (>3 months), symmetrical, oligo- or
polyarthritis of moderately sized to large joints [113, 119]. It can mimic other forms of
inflammatory arthritis. True synovitis must be distinguished from tenosynovitis, which is much
more frequent and less severe. Rarely, chronic sarcoid arthritis presents as a monoarthritis,
requiring the exclusion of gout, calcium pyrophosphate and septic arthritis. It is noteworthy that
sarcoidosis and gout may be associated [120]. Polyarthritis affecting the hand joints is a very
rare manifestation of sarcoidosis, and rheumatoid arthritis should be considered an alternative
diagnosis. In addition, a sarcoid polyarthritis may develop concurrently with rheumatoid
arthritis, and usually such patients demonstrate a systemic sarcoid presentation with skin and
lung parenchymal lesions [105, 118, 121].
A Jaccoud-type arthropathy is characterised by a deforming but not erosive arthropathy. It is

more frequent in connective tissue disease and is rare in sarcoidosis [122].
Bone involvement
Osseous sarcoidosis may manifest at disease onset but more frequently develops with chronic
and multisystemic sarcoidosis [123]. The hands and feet are most commonly involved, but any
bone can be affected.
The prevalence of bone sarcoidosis is dependent on the sensitivity of the imaging procedure
used, as this condition causes no symptoms in more than half of cases [118, 124]. Sarcoidosis
bone involvement has been reported in between 0.5% and 30% of patients, with an estimate of
1.5% in a large sarcoidosis cohort [125]. Studies with MRI and 18F-FDG PET/CT have
reported much higher frequencies [107, 108]. Multiple bones are usually involved, typically in
the axial skeleton (spine, pelvis, and then sternum) and the long bones [126, 127]. Sarcoidosis
bone lesions are 1.5 times more common in women than men and three times more common in
white than in black people [128]. Bone sarcoidosis is associated with multiorgan disease, as
well as liver, spleen and/or extrathoracic lymph-node involvement [128]. Bone lesions are
usually bilateral and may have a varied radiographic appearance: sclerotic (mostly in the spine),
lytic, cystic and punched out. In particular, the radiographic appearance of phalangeal
sarcoidosis often demonstrates cystic lesions that are very similar to those seen with Jüngling
disease [129]. Lytic sarcoidosis bone lesions are often mistaken for metastatic disease [130].
Bone sarcoidosis and bone metastasis cannot reliably be distinguished by radiographic studies
and a biopsy may be required for diagnosis. Dactylitis is frequently observed with chronic,
multiorgan sarcoidosis, particularly affecting the skin, and presents as swelling and erythema of
the second and third digits of both hands and feet. This form of bone sarcoidosis is most
common in black people. Imaging typically shows cystic bone lesions with a characteristic
lattice-like aspect [131]. Skull lesions are probably among the rarest of the bone sarcoid lesions
[132], with most having been diagnosed in patients with a known sarcoidosis diagnosis.
Sarcoid vertebral involvement may be asymptomatic and is most frequently detected when
patients undergo radioisotope imaging for other reasons. It can involve the vertebral bodies or
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the sacroiliac joints. Sarcoidosis causes sacroiliitis in ∼10% of patients, and it can be
problematic to distinguish this condition from seronegative spondyloarthopathies [133, 134].
Furthermore, these two entities may be truly associated.
Muscle involvement
Sarcoidosis muscle involvement is usually asymptomatic [135], with symptoms present in
<3% [136, 137]. 18F-FDG PET/CT is a sensitive technique to identify muscle sarcoidosis that
has increased the prevalence estimate of this manifestation [110]. Sarcoidosis patients report
myalgias, generalised weakness, fatigue and reduced exercise capacity more often than
healthy controls [118]. It should be noted that these symptoms may be caused by conditions
unrelated to sarcoidosis muscle involvement such as small-fibre neuropathy and
sarcoidosis-associated fatigue. Myalgias are more specific for true sarcoidosis muscle
involvement. The three major patterns of sarcoidosis muscle involvement are chronic, nodular
and acute myopathy.
Chronic sarcoid myopathy is the most common expression of sarcoid muscle involvement and
usually occurs in women >50 years of age. Neurophysiological studies show myopathic changes
similar to other inflammatory muscle disorders, while muscle biopsy typically shows
granulomas. MRI may reveal muscle atrophy with fatty degeneration [138]. The diagnosis is
often problematic to differentiate from a corticosteroid-induced myopathy in chronically treated
patients, and often requires imaging studies (MRI, PET/CT) or even muscle biopsy, as well as a
holistic view of the entire clinical presentation.
Nodular sarcoidosis myopathy is characterised by one or several palpable intramuscular nodules

that typically involve the extremities and are usually painful. Serum levels of muscular enzymes
and neurophysiological studies are often normal. MRI is particularly sensitive and demonstrates
lesions between muscles bundles leaving muscle fibres untouched [139]; this probably explains
why serum muscle enzymes are often not elevated. The “three stripes sign” on MRI might be
specific for nodular sarcoid myopathy [140].
Acute myopathy is the least common form of sarcoid myopathy. It presents with rapid onset of
proximal weakness and myalgia in patients typically <40 years of age. Muscle enzyme levels
are usually elevated, and muscle biopsy reveals granulomas [139]. Most patients with acute
sarcoid myopathy improve with anti-granulomatous treatment, whereas chronic forms are often
resistant to treatment and are typically associated with severe disability.
Patients with sarcoid muscle involvement have a worse prognosis and more severe
extrapulmonary organ involvement than those without muscle disease [141]. A recent
retrospective analysis found that almost half of patients with sarcoidosis muscle involvement
met the criteria for a sporadic inclusion-body myositis, and this factor was associated with
resistance to treatment [142]. In terms of prognosis, a study evaluating the outcome of the
different myopathy presentations classified them into four distinct patterns: 1) nodular (27%),
2) smouldering (29%), 3) acute, subacute or progressive type (35%), and 4) combined
myopathic and neurogenic form (10%) [143]. The latter two were the most severe. Muscle
sarcoidosis is usually associated with multisystem disease with a median of three extramuscular
organs affected [143].
The respiratory muscles are rarely involved with sarcoidosis [144]. Diaphragmatic involvement
can cause a restrictive functional pattern with diaphragm elevation [144].
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Bone-marrow and haematological sarcoidosis

Bone-marrow sarcoidosis (BMS) is infrequent, although its precise prevalence is unknown, as
bone-marrow biopsy, the definitive test, is not performed routinely. In a study of 50 consecutive
sarcoidosis patients who underwent a bone-marrow biopsy, noncaseating granulomas were
found in 10% [145], which is higher than in clinical series. BMS appears to be more common
in black than in white people, as no cases were identified at the time of diagnosis and 0.3%
developed BMS during follow-up in a large white cohort [146], whereas BMS was found in 4%
of a sarcoidosis cohort with a large percentage of black patients, and BMS was found to be
statistically more common in black patients than in white ones [1]. In the latter study, most
BMS patients exhibited multisystemic disease as well as haematological abnormalities: leukopenia,
lymphopenia, anaemia and/or pancytopenia. Therefore, haematological abnormalities, although
nonspecific, may be an important clue to the presence of BMS.
Haematological abnormalities are common in sarcoidosis, and the 2020 sarcoidosis diagnostic
guidelines suggest that sarcoidosis patients undergo a baseline complete blood cell count for
screening of haematological abnormalities [147]. Anaemia, leukopenia and lymphopenia have
each been reported in ⩾20% of sarcoidosis patients [147]. However, BMS may not be the most
common cause of haematological abnormalities, as they may occur from splenomegaly with
sequestration, compartmentalisation of leukocytes to the site of organ involvement,
haematological side-effects from sarcoidosis treatment such as MTX, and haematological
abnormalities unrelated to sarcoidosis. Indeed, the frequency of bone-marrow granulomas was
only 38% (95% CI 13–64%) in sarcoidosis patients with known anaemia [147]. Consequently,
bone-marrow biopsy is not mandated in a sarcoidosis patient with haematological abnormalities
[147]. However, the cause of haematological abnormalities should be determined, considering
that leukopenia has been associated with more severe disease [148] and anaemia can contribute
to sarcoidosis symptoms including fatigue or shortness of breath. In the absence of
haematological abnormalities, 18F-FDG PET/CT is potentially useful to detect asymptomatic
BMS [107]. BMS is rarely an isolated form of sarcoidosis [149, 150].
Given the rare occurrence of BMS, there are few data regarding therapeutic management. Case
reports describe a beneficial response to corticosteroid treatment [150, 151]. Although MTX is
widely used as a corticosteroid-sparing agent in sarcoidosis, it has restricted use in BMS due to
cytotoxicity.
Sarcoidosis of the upper respiratory tract

Sarcoidosis of the upper respiratory tract (SURT) includes nasopharyngeal, laryngeal and
tracheal involvement. It should be suspected in patients with systemic sarcoidosis and upper
respiratory tract symptoms. SURT occurs in ∼2–7% of sarcoidosis patients [1, 152]. The
clinical presentation of SURT varies from asymptomatic to severe. The main symptoms of
sinonasal disease include nasal obstruction, crusting, epistaxis and anosmia [153, 154]. The
coexistence of facial lupus pernio and rhinosinusitis due to sarcoidosis is frequently reported
[154, 155]. Laryngeal disease symptoms include hoarseness, inspiratory dyspnoea, dysphagia,
stridor, chronic cough and airway obstruction, which could progress to life-threatening
upper-airway obstruction. Obstructive sleep apnoea is also frequent and may necessitate
diagnostic evaluation. Fibreoptic nasolaryngoscopy of patients with sinonasal sarcoidosis
typically reveals pale, yellow, nodular lesions and inflammation with mucus crusting [156]. CT
imaging in sinonasal sarcoidosis reveals turbinate or septal nodularity/thickening,
osteoneogenesis and often bony erosions (figure 5) [157, 158]. Such clinical or radiological
findings, even in the context of a known sarcoidosis, should raise the possibility of other
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FIGURE 5 CT coronal sinus image of a patient with biopsy-proven sinus sarcoidosis. Marked mucosal
inflammatory change/thickening in the left maxillary sinus is demonstrated (arrows).
granulomatous diseases, such as fungal infections or granulomatosis with polyangiitis. In

laryngeal disease, the supraglottic region, particularly the epiglottis, is typically involved [159],
followed by the subglottis, whereas the glottis itself is rarely affected [160]. Flexible fibreoptic
laryngoscopy often shows pale pink, oedematous and nodular thickening of the mucosa.
SURT rarely undergoes spontaneous remission and often requires systemic treatment [159, 161].
Corticosteroids represent the main treatment in symptomatic SURT. High doses are often required,
especially in cases of laryngeal or tracheal involvement [152], and many patients require long-term
systemic therapy. While corticosteroids are typically the initial drug of choice, cytotoxic agents are
often effective. TNF antagonists may be beneficial for refractory SURT and should be considered
when prolonged or high dosages of corticosteroids are required [162]. Surgical indications are
usually limited to patients who fail to respond to medical therapy, or in cases where the airway or
another vital structure is threatened. Minimally invasive endoscopic procedures with intralesional
corticosteroid injection, especially in patients with severe nasal obstruction, may also improve
symptoms and reduce the need for systemic corticosteroids [163]. However, in our experience, the
extent of SURT often exceeds the practical limits of localised injection. Surgical options may also
be considered for laryngeal involvement as an adjunct to systemic treatment, such as carbon
dioxide laser excision of tissue that removes the involved mucosa and allows suturing to promote
primary healing of mucosal surfaces [164]. The above discussion implies that SURT requires
interdisciplinary management and collaboration with otolaryngologists.
Submandibular gland sarcoidosis

Submandibular gland sarcoidosis (SGS) is more common in females [165] and has a higher
prevalence in those between 30 and 40 years of age [166]. Parotid involvement has been
reported in 6% of sarcoidosis patients [167–169]. The most common presentation is uni- or
bilateral painless enlargement of the gland. Other symptoms include xerostomia, swollen glands
and, rarely, facial pain or paralysis. SGS is usually a disseminated form, and isolated SGS
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should not be assumed without investigating alternative conditions including Sjögren syndrome,
acute lithiasis, lymphoma and malignant tumours. Salivary gland biopsy is usually the most
expeditious method to determine the correct diagnosis [170]. Heerfordt syndrome, or
uveoparotid fever, is a specific sarcoidosis condition characterised by mild fever and painless
parotid enlargement; a transient seventh-nerve paralysis may also occur [171, 172]. In most
cases, facial paralysis is abrupt in onset, and can occur days to weeks after the appearance of
parotitis. Facial palsy may clear spontaneously but also responds to corticosteroids.
Indications for treatment of SGS depend mainly on the severity of symptoms. Because SGS is
usually associated with a good prognosis and may be asymptomatic, systemic treatment may not
be required. When treatment is needed, oral corticosteroids are most frequently prescribed.
The diagnosis of ROS

The diagnosis of sarcoidosis can be challenging, as the disease can mimic several other
conditions [173–177]. Diagnosis may be especially problematic when ROS is isolated without
evidence of concomitant involvement of more common organs involved with sarcoidosis.
The recently published American Thoracic Society Practice Guideline on the diagnosis of
sarcoidosis stated that the diagnosis of sarcoidosis is based on three major criteria: 1) a
compatible clinical presentation, 2) the finding of noncaseating granulomatous inflammation in
tissue, and 3) exclusion of alternative causes of granulomatous inflammation [147]. As there are
no standard criteria to determine whether these three conditions are satisfied, the diagnosis of
sarcoidosis is never fully secure [147]. This document stated that only a few presentations are
viewed as so specific for sarcoidosis that histological confirmation is not required for diagnosis:
Löfgren syndrome, Heerfordt syndrome and lupus pernio. Other presentations, although deemed
highly probable for the diagnosis of sarcoidosis, require histopathological confirmation of
noncaseating granulomas, particularly if they appear as isolated abnormalities.
In terms of applying these diagnostic criteria to ROS, it appears necessary to biopsy these organs
to establish a diagnosis when there is no evidence of sarcoidosis in other locations. In the situation
of a known case of sarcoidosis with evidence of potential ROS, the clinician needs to weigh the
risk of missing an alternative diagnosis. If the risk is small, such as if there is minimal chance of
serious infection of malignancy, then the organ abnormality may be observed. A “diagnostic
treatment approach” may even be considered where a short treatment course that reduces or
eliminates the organ abnormality may strongly suggest ROS involvement [178]. When the risk of
serious alternative diagnosis is significant, a biopsy should be performed. In cases when sarcoidosis
is suspected in common organs with concomitant evidence of ROS, the diagnosis of sarcoidosis
can be established by standard methods. After the diagnosis of sarcoidosis is established, the
decision as to whether to histologically confirm ROS becomes identical to the situation described
above where observation of the rare manifestations may be justified.
Obviously, the approach to the diagnosis of sarcoidosis and ROS is highly nuanced and dependent
on the exact clinical situation. Key factors in the diagnostic approach include the probability of the
correct diagnosis, the risk of potential alternative diagnoses and, in the case of considering
sarcoidosis treatment, the risk of such treatment if an alternative diagnosis is present [179].
The differential diagnosis of rare organ manifestations of sarcoidosis

Distinguishing sarcoidosis organ involvement from alternative diagnoses is problematic because
of the lack of a gold-standard diagnostic test [147]. Even a tissue biopsy revealing noncaseating
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TABLE 2 Causes of granulomatous inflammation
Site Common Less common Rare
GIT Crohn disease GIT malignancy Fungi

Tuberculosis Whipple disease
Foreign body (including barium, Bacteria (Salmonella, Yersinia,
cholesterol embolisation) Campylobacter,
Parasites (Schistosoma) Helicobacter pylori)
Sarcoidosis Syphilis
Common variable
immunodeficiency
Chronic granulomatous disease
Hyaline ring granuloma
Lymphoma
Vasculitis
Drugs (NSAIDs, drug-induced
sarcoidosis-like reactions)
Idiopathic
Genitourinary tract Post-surgical/foreign body Xanthogranulomatous Intravesicular BCG
(prostatitis) Tuberculosis/other
mycobacteria
Fungi and other infections
(syphilis, parasites)
Sarcoidosis
Malignancy
Serosal surfaces Tuberculosis and other Lymphoma Solid-organ malignancy
mycobacteria Sarcoidosis (peritoneal keratin
Fungi Post-surgical/foreign body granuloma)
Other infections (parasitic, viral) Vasculitis/connective tissue
disease
Muscle Sarcoidosis Vasculitis Thymoma
Granulomatous myositis Connective tissue diseases Myasthenia gravis
Infections (tuberculosis, syphilis, Idiopathic
Pneumocystis jiroveccii) Lymphoma
Foreign body reaction TNF-α inhibitor-induced
granulomatous myositis
Bone or bone Tuberculosis/other mycobacteria Solid-organ malignancy BCG vaccination
marrow Fungi (histoplasmosis) Bacteria (Salmonella Typhi, Silicosis/coal workers’
Lymphoma brucellosis, Q fever, parasites) pneumoconiosis
Sarcoidosis Drugs
Herpesviruses (CMV, EBV) Vasculitis/connective tissue
diseases
Upper respiratory Granulomatosis with polyangiitis Tuberculosis Atypical mycobacteria
tract Allergic fungal sinusitis Other infections
(Aspergillus species) Foreign body
Eosinophilic granulomatosis with Granulomatous cheilitis
polyangiitis Crystalloid granulomas
Cholesterol granuloma associated with tumours
Sarcoidosis or cysts
Klebsiella rhinoscleromatis
infection
Intranasal cocaine/
narcotic-induced
Salivary glands Calculus duct obstruction Tuberculosis Atypical mycobacteria
Duct obstruction by malignancy Other infections
Sarcoidosis Foreign body
Granulomatous cheilitis
Crystalloid granulomas
associated with tumours
or cysts
GIT: gastrointestinal tract; NSAID: nonsteroidal anti-inflammatory drug; BCG: bacille Calmette–Guérin;
CMV: cytomegalovirus; EBV: Epstein–Barr virus.
308 https://doi.org/10.1183/2312508X.10033320
granulomatous inflammation is not specific for sarcoidosis, as alternative medical conditions

may display a similar histology [147, 180]. In the case of ROS, this diagnostic challenge is
amplified because the statistical likelihood of the diagnosis is low. Table 2 lists the differential
diagnoses of granulomatous inflammation in organs that are rarely involved with sarcoidosis.
Infections need to be considered in the differential diagnosis of ROS. These include organisms
that commonly cause a granulomatous inflammatory response such as Mycobacterium
tuberculosis, atypical mycobacteria and fungi. Stains and cultures for these organisms should
routinely be obtained. The various bacterial, viral and parasitic infections listed in table 2 should
also be considered, depending on the organ involved. As mentioned, the histological
characteristics of the granulomatous inflammation are inadequately specific to reliably distinguish
sarcoidosis from an infectious cause of disease. In addition, the presence of constitutional
symptoms such as fever, weight loss and night sweats are common with both sarcoidosis and
infections, and are unreliable indicators of the cause of granulomatous inflammation [181].
Malignancy should also be considered as an alternative diagnosis to ROS, particularly in the

case of bone lesions or lymphadenopathy. 18F-FDG PET/CT cannot differentiate granulomatous
inflammation from malignancy. PET scanning with one other radiotracer specific for
malignant-cell hypermetabolism has been proposed to do so, such as 18F-α-methyltyrosine,
18
F-fluoroboronophenylalanine or 18F-deoxyfluorothymidine [182–184]. For bone and spinal
lesions, MRI, often in combination with PET/CT, may be useful to differentiate sarcoid lesions
from metastasis [185].
General approach to the treatment of organs rarely involved with sarcoidosis

The approach to the treatment of ROS is not significantly different from the treatment of organs
commonly involved with sarcoidosis. Treatment is indicated for sarcoidosis conditions that
significantly affect quality of life or functional status, or that cause organ-threatening or
life-threatening situations [186, 187]. As many forms of ROS are asymptomatic without
significant health consequences, treatment is often not indicated. When treatment is required,
standard anti-sarcoidosis therapies with standard dosing is usually sufficient. Corticosteroids at
doses of 20–40 mg·day−1 of prednisone equivalent are usually adequate in most cases, and
antimetabolites and TNF-α antagonists have also been useful as corticosteroid-sparing or
corticosteroid-replacing therapies [11, 35, 49, 188].
Conclusion
ROS is often asymptomatic. It is most commonly present in patients with systemic sarcoidosis
who have manifestations of the disease in more common organs. The diagnosis of ROS is
problematic, because usually there are several alternative clinical considerations, and many of
these may lead to poor outcomes if they are not treated appropriately. Therefore, it is necessary
to exclude such alternative conditions, and this may require a tissue biopsy. ROS usually does
not require treatment unless the patient is symptomatic, and in such cases, effective therapy is
identical to that used for other forms of sarcoidosis. Knowledge of the manifestations of ROS
can aid the clinician in administering appropriate sarcoidosis care.
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Disclosures: M.A. Judson is a consultant for Star Therapeutics and his institution has received grant funding from
Mallinckrodt and the Foundation for Sarcoidosis Research. J. Pastre has nothing to disclose. D. Israël-Biet reports
receiving: consulting fees from Boehringer Ingelheim; honoraria for educational events from Boehringer Ingelheim
and Roche; payments from Galapagos as a member of an adjudication committee; and support for attending
meetings and/or travel from Boehringer Ingelheim.
Acknowledgements: The authors wish to acknowledge Sooyeon Kwon (Albany Stratton Veterans Affairs Medical
Center; Albany, NY, USA) for her expert assistance with the preparation of the tables in this manuscript. The
authors also wish to acknowledge Gaetano Pastina (Albany Medical Center, Albany, NY, USA) who reviewed and
assisted in the preparation of figure 5 of this manuscript.
https://doi.org/10.1183/2312508X.10033320 315
Chapter 21
When to treat sarcoidosis

Daniel A. Culver1 and Athol U. Wells2,3
1
Dept of Pulmonary Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA. 2Royal Brompton
Hospital, London, UK. 3Imperial College, London, UK.
Corresponding author: Daniel A. Culver (culverd@ccf.org)
Cite as: Culver DA, Wells AU. When to treat sarcoidosis. In: Bonella F, Culver DA, Israël-Biet D, eds. Sarcoidosis (ERS
10033520].
@ERSpublications
Sarcoidosis treatment decisions must be individualised, accounting for the likelihood of organ-threatening
disease and potential impact of treatment on quality of life. Patient-centred decisions are crucial to
developing an effective therapeutic alliance. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis treatment is initiated for two major reasons: threat of severe organ dysfunction (danger) or
to improve quality of life when bothersome symptoms dominate the presentation. While there are few
data to suggest a major impact of treatment on the likelihood of long-term disease remission, reducing
inflammation with prednisone and other therapies is likely to prevent progressive, organ-threatening
disease, and may be useful to restore symptomatic organ dysfunction. As most death and major
morbidity from sarcoidosis occur in patients with extensive pulmonary disease, pulmonary
hypertension, cardiac sarcoidosis, neurological disease, uveitis and calcium derangements, danger
indications for treatment are typically present when these organs are substantially affected. Management
involves prognostic assessment of the likely natural history of the disease and often entails relatively
aggressive immunosuppressive therapy, with a more proscriptive role for the physician in the decision
to treat. In contrast, treatment of bothersome symptoms typically revolves around a patient-centred,
individualised discussion, considering the relationship of the symptoms to granulomatous inflammation,
likelihood of response to therapy and risks of medications. Therapy may be much less aggressive when
treating quality of life. Corticosteroid therapy is associated with significant toxicity, probably
accounting for a proportion of sarcoidosis mortality. Longitudinal care of the patient includes recurring
assessments of the risk–benefit balance of treatment, likelihood of remission, screening for new
evidence of dangerous sarcoidosis and consideration of emergent comorbidities.
Introduction
Historically, approaches to the treatment of sarcoidosis have varied widely from the moment that
it was first understood that steroid therapy effectively suppresses inflammation in most patients,
resulting in short-term improvements in symptoms and radiographs [1, 2]. In some centres, a
very vigorous approach was taken in which treatment was introduced and maintained as long as
there was evidence of persistent sarcoidosis, even when the disease was not considered to be
dangerous or associated with major loss of quality of life (QoL) [2, 3]. The deleterious effects of
prolonged steroid therapy were not at first fully appreciated in sarcoidosis and other inflammatory
diseases. Even with time and the use of steroid-sparing agents, a vigorous standardised approach
continued to be advocated by some physicians, almost to the present day.
316 https://doi.org/10.1183/2312508X.10033520
WHEN TO TREAT | D.A. CULVER AND A.U. WELLS
The opposing view, which is that sarcoidosis therapies do not alter the natural history of the
disease, was influenced by the observation of early relapse with discontinuation of
corticosteroid therapy [1, 4–7]. A number of short-term observational studies, in which
outcomes were compared in patients receiving and not receiving corticosteroid therapy,
established that the benefits were not sustained, with the disease status rapidly returning to
levels equivalent to those in untreated patients. It was often stated, based on these studies, that
sarcoidosis therapies do not alter the natural history of the disease, and this caused some
clinicians to adopt a minimalist approach. It is important to stress, however, that in most of
these studies, the use of steroid therapy was not overtly selective but included many patients
with often minor chest radiographic abnormalities in isolation. More importantly, most of the
studies were very short in duration with a duration of treatment of 3 or 6 months: in only two
studies was steroid therapy continued for longer periods, ranging from 6 months to a minimum
of 18 months [8, 9]. Thus, from this data, it could reasonably be concluded that steroid therapy,
when used nonselectively for 3–6 months, did not result in enduring benefits.
Reviews of the available controlled treatment trials suggest a more nuanced truth: treatment
may, in fact, positively alter the natural history and lung function, but the effect size is small
when averaged across heterogeneous groups and is not evident for the short-term likelihood of
spontaneous remission. Additionally, some authors have postulated that treatment could reduce
the immune responses necessary for spontaneous resolution [10, 11]. For example,
corticosteroids could prevent effective antigen clearance, resulting in T-cell exhaustion and
chronic inflammation [12, 13]. In a cohort of 88 HLA-DRB1*03-negative Swedish patients with
acute sarcoidosis, 37% of untreated versus 20% of corticosteroid-treated patients resolved their
disease by 2 years [14]. A prospective observational US study noted that 74% of treated patients
experienced a relapse of their disease after tapering, whereas only 8% of initially untreated patients
required treatment during follow-up [11]. Similar findings have been observed in Japan [15].
Randomised controlled trials with adequate follow-up, however, have not generally demonstrated
either an adverse or a beneficial effect of treatment on the overall likelihood of remission (table 1)
[5–9, 16]. It is possible, but currently unproven, that therapies targeting putative aetiological triggers
of sarcoidosis might improve the likelihood of disease resolution [18–20].
It was concluded by most clinicians, based on accumulated experience and clinical reasoning,
that treatment should be instituted selectively, based on specific indications, without the
expectation that very early withdrawal of treatment may be realistic. This amounted to a
management approach that was intermediate between the indiscriminate use of therapy and
therapeutic nihilism. It became evident that in many patients with progressive disease associated
with worsening pulmonary physiology who required a course of treatment, eventual cessation of
treatment was not accompanied by relapse or additional progression of disease [21], and in other
patients, long-term, low-dose maintenance therapy was effective in maintaining stability [22]. The
debate as to whether sarcoidosis therapy alters the natural history of disease has not been resolved:
however, it became increasingly accepted that treatment was often effective in preventing or
minimising irreversible damage and in improving symptoms in nonremitting disease. In other
words, the judicious use of treatment could attenuate the adverse consequences of the natural
history of sarcoidosis (whether or not the natural history was, itself, influenced by therapy).
However, this compromise was not without major uncertainties, including the optimal duration
of therapy, the balance between treatment benefits and treatment comorbidities and, above all,
the lack of consensus on the “big picture” goals of treatment. In many texts, long lists of
indications for treatment were constructed, including symptomatic indications and various
measures of major organ damage; in pulmonary sarcoidosis, for example, there was no overall
https://doi.org/10.1183/2312508X.10033520 317
318

TABLE 1 Controlled studies with long-term follow-up for treatment of pulmonary sarcoidosis
First author Patients, Design Treatment Population Stage 1/ Follow-up Outcomes Relapse/long-term
[ref.] n stage 2–3 outcome
(n/n)
ISRAEL [5] 83 DBRPC PDN 15 mg daily for New diagnosis 37/46 3 months and 54% (PDN) versus 24% 59% (PDN) improved
3 months 5.3 years (PLCB) improved versus 47% (PLCB);
(mean) progression in 38%
(PDN) versus 16%
(PLCB)
SELROOS [7] 37 Open label, MP, various doses for Persistent, <5 years 0/37 7, 24 and 89% (MP) versus 61% No CXR, PFT or clinical
random 7 months since diagnosis 48 months (PLCB) had improved differences persisted at
CXR at 7 months 48 months
HARKLEROAD [6] 25 Alternating PDN 60 mg tapering Recent disease and 8/14 ⩾10 years No PFT or mortality All four patients with
to 20 mg for 6 months abnormal gas differences normal CXR were
transfer untreated
EULE [8] 172 Open label, PDN 40 mg tapering Asymptomatic 67/105 Minimum All three patients with Relapse 22% in
random to 10 mg for 6 or 5 years, mean progression of disease treated, 16% in
12 months 8.9 years in treated group untreated
GIBSON [9] 58 Alternating Titrated to normalise Persistent infiltrates 0/58 5 years Mean VC 100% versus Six out of 31 initially
https://doi.org/10.1183/2312508X.10033520
CXR, for ⩾18 months after 6 months 91% for treated versus untreated patients
without progression selectively treated; required steroids
other end-points no during follow-up
different
PIETINALHO [16] 149 DBRPC Prednisolone for Newly diagnosed 79/70 5 years FVC and DLCO both 16 out of 18 relapses
3 months followed by better at 18 months and were in placebo group
inhaled budesonide 5 years in treated group
for 15 months
DBRPC: double-blind, randomised, placebo-controlled; PDN: prednisone; PLCB: placebo; MP: methylprednisolone; CXR: chest radiograph; PFT: pulmonary function test;
VC: vital capacity. Reproduced and modified from [17] with permission.
consensus on the balance of symptoms, pulmonary function impairment and chest radiographic
findings, or the integration of baseline and serial data, in determining whether treatment should
be introduced [17]. Reports of treatment outcomes were dominated by corticosteroid data, but
outcomes were, by and large, not linked to reasons to treat, nor were attempts made to
distinguish between high- and low-dosage algorithms according to treatment goals.
Reasons to institute treatment: danger and unacceptable loss of QoL

Over the last 5 years, there has been an increasing consensus that treatment goals should be
distilled into the goals that matter to patients, which are to live longer and enjoy a better QoL
[23]. In other words, treatment should be instituted when: 1) there is an immediate increased
risk of mortality due to sarcoidosis or of progression to severe disabling disease, or 2) there is
unacceptable loss of QoL due to sarcoidosis. These indications were the basis for the recently
published European Respiratory Society (ERS) clinical practice guidelines for the treatment of
sarcoidosis [24]. It should be acknowledged from the outset that there are many patients in
whom this distinction is blurred or in whom both indications exist. Furthermore, treatment
instituted for QoL reasons can be deconstructed into treatment given for existing symptoms and
therapies used when ongoing progression is likely to result in unacceptable loss of QoL, even
when the disease is not overtly dangerous.
The separation between treatment indications is helpful on several levels. For example, it provides
a framework that is more readily understood by patients; all too often, the broad treatment goals
are not understood and this sometimes undermines the development of partnerships between
doctors and patients in the management of this complex disease [25–27]. As discussed later, the
nature of doctor–patient conversations on management is sometimes profoundly influenced by
knowledge of whether or not sarcoidosis is perceived as dangerous on medical grounds, with a
clearer understanding of the risk–benefit considerations when treatment is introduced.
Risk stratification for dangerous sarcoidosis

Accurate risk stratification is central to identifying patients at increased risk of death due to
sarcoidosis. It has been estimated that up to 5% of sarcoidosis patients die due to sarcoidosis
[28–32]. In the subset of patients with severe phenotypes, mortality is much higher [31, 33, 34].
The most frequent causes of direct sarcoidosis mortality by far consist of severe fibrosis, with or
without associated pulmonary hypertension, accounting for ⩾50% of deaths, and cardiac
disease, responsible for ⩾25% of deaths (except in Japanese patients, in whom cardiac disease
is the most frequent cause of death due to sarcoidosis) [35–39]. Risk stratification has been most
closely studied in pulmonary and cardiac disease.
For many decades, the Scadding chest radiographic staging system was the cardinal means of risk
stratification in pulmonary sarcoidosis, based on cohort studies in which mortality increased with
increasing stage, especially in patients with stage 4 disease (overt fibrotic abnormalities) [28, 40].
The Scadding system offered the advantage of easy accessibility using a routine and inexpensive
test. However, its limitations must be understood. Outcome separations apply to average effects in
cohorts of patients but are not reliable in individual patients. Even in stage 4 disease, the excess
mortality amounted to an increase in mortality of only 10% above the mortality seen in sarcoidosis
patients in general in a carefully constructed French study; thus, the presence of overt fibrosis does
not, in itself, establish that disease is progressive, nor does it account for major variation in the
extent of fibrotic disease in the lungs [29]. Furthermore, major interobserver variation exists in the
designation of stage 4 disease [41]. In recent years, more accurate risk stratification has been
achieved using CT evaluation (fibrosis extent >20% of the total lung volume, increases in the
https://doi.org/10.1183/2312508X.10033520 319
pulmonary artery diameter/aorta diameter ratio), severe reduction in pulmonary function test (PFT)
indices (especially severe reductions in gas transfer and major increases in the composite
physiological index) and the presence of pulmonary hypertension [28, 42, 43].
In cardiac sarcoidosis, it has long been recognised that severe impairment of left ventricular function
and major rhythm disturbances (including complete heart block and ventricular tachycardia) have
major adverse prognostic significance [44–48]. The considerable reduction in mortality due to
cardiac sarcoidosis in recent series may be due largely to the timely insertion of intracardiac devices
and better management of heart failure, especially in patients with apparently isolated cardiac
sarcoidosis, often presenting with severe disease. Advanced imaging has made a considerable
contribution: extensive cardiac scarring (e.g. late gadolinium enhancement ⩾20% of total cardiac
volume) and a high burden of cardiac inflammation (as shown by considerable 18F-FDG uptake on
cardiac PET scanning) are both associated with increased mortality [45, 49–51].
Risk stratification is less developed in other dangerous forms of sarcoidosis, although

hypercalcaemia is universally acknowledged as a dangerous complication [31]. Severe renal or
hepatic involvement, optic neuritis and other major organ involvements should all be considered
on a case-by-case basis, although thresholds for severity have not been designated. Optic
neuritis and active central nervous system involvement are widely considered as dangerous
forms of the disease (although this can be debated in Bell’s palsy).
Treatment of dangerous sarcoidosis

In general, in these various scenarios, high-dose “induction” therapy is appropriate, most
commonly high doses of corticosteroids initially (typically 20–60 mg·day−1 depending on the
indication). The various strategies, including prednisone dosing strategy, second-line
immunosuppressive agents and anti-TNF therapy, and their timing, lie beyond the scope of this
chapter but are discussed in detail in the recent ERS treatment guideline [24] and elsewhere in
this Monograph [52]. Two important conclusions can be drawn. First, patient acceptance of
high-dose treatment is critically dependent on clear discussion of the risk of nonintervention:
the reasons to treat are primarily informed by medical expertise. Second, treatment should not
be delayed until thresholds associated with increased mortality are reached: earlier treatment of
potentially dangerous disease is appropriate when the disease is progressive and the level of
severity lies close to a dangerous level.
In all treatment decisions, the risk of treatment-related comorbidities is a major consideration, and
this problem will be reviewed in detail later in this chapter. However, in patients with overtly
dangerous disease, we take the view that treatment is imperative. Existing comorbidities such as
diabetes and hypertension may influence the choice and dose of initial therapy; for example,
lower doses of corticosteroid may be combined with immunosuppressive therapy, based on
case-by-case evaluation [17]. However, we argue that when a rapid treatment response is required
in dangerous disease, initial high-dose steroid therapy is often appropriate, even when
comorbidities are present. In this scenario, short-term difficulties with, for example, control of
diabetes or hypertension must be anticipated and managed proactively. As an example, table 2
outlines an approach for considering initiation of treatment for cardiac sarcoidosis.
Screening for dangerous disease

The presence of extant or threatened danger should be considered in all patients, but certain
scenarios make danger more likely. When considering all patients, routine baseline testing
should include detailed symptom assessment, physical examination, chest radiography, PFTs,
320 https://doi.org/10.1183/2312508X.10033520
TABLE 2 Key variables that influence the aggressiveness of initial therapy for cardiac sarcoidosis
Cardioprotective therapy or Induction therapy

meticulous observation
PET signal Low grade (<3 SUV max); limited Intensive (>7 SUV max); extensive;
in extent RV uptake
Comorbidities Diabetes, hypertension, Absence of major
elevated BMI treatment-associated comorbidities
Age Older age Younger age
CMR signal Limited or no LGE Extensive LGE
Cardiac function Normal function Major loss of function
(echocardiogram/CMR/PET)
AV nodal/infra-Hisian disease Absent High-grade heart block
Other rhythm disturbance Absent Sustained VT, or VF
Systemic disease activity Absent Major (including intense PET signal)
Patient wishes Prefers low-dose treatment Favours aggressive treatment
Integration of the prognostic features, including advanced imaging study evidence of more intense
inflammation or more extensive disease, facilitates discussion with the patient about whether to pursue an
initial aggressive induction strategy. For patients with less risk of danger, a cardioprotective strategy with
low-dose immunosuppression, or close observation alone, may be a reasonable option. The likelihood of
dangerous cardiac involvement should be serially assessed during follow-up. CMR: cardiac MRI;
AV: atrioventricular; SUV: standardised uptake value; max: maximum; RV: right ventricle; BMI: body mass index;
LGE: late gadolinium enhancement; VT: ventricular tachycardia; VF: ventricular fibrillation.
ECG, complete blood count, and some assessment of liver and renal function [53]. Chest CT
scanning is routinely available in the modern era, with lower radiation exposure, and a baseline
CT scan is standard practice in most centres. Patients with multiorgan disease, of black race, age
>40 years and with symptoms are all more likely to experience progressive disease, and merit
closer longitudinal scrutiny [31, 32, 54]. In patients with more severe dyspnoea or markedly
impaired PFTs, HRCT should be considered to screen for fibrosis. A CT scan may also reveal
complications of fibrosis such as mycetoma, large-airways obstruction and bronchiectasis [55].
Risk factors for sarcoidosis-associated pulmonary hypertension (SAPH) include the presence of
pulmonary fibrosis, more severe impairment of PFTs, hypoxaemia and increasing levels of
dyspnoea [56, 57]. An impaired 6-min walk distance or exertional desaturation is typically present
with SAPH [58], and a distance of <400 m should prompt consideration of additional testing [58].
A mean pulmonary artery diameter/ascending aorta diameter ratio of >1.0 is a useful marker to
suggest the need for further evaluation with echocardiography or right heart catheterisation [59,
60]. The evaluation of SAPH is discussed in another chapter in this Monograph [61].
Treatment for unacceptable loss of QoL

Current data do not allow for a clear exposition of how treatment can best be instituted in this
setting: decisions here must be made on a case-by-case basis, using clinical reasoning, common
sense and, above all, very clear communication between the patient and medical advisers [25].
However, certain considerations are often helpful in decisions on whether treatment should be
started. First and foremost, loss of QoL is not easy to quantify: only the patient has a clear
sense of the impact of sarcoidosis on their daily life [62, 63]. Clear communication that disease
is not overtly dangerous allows the patient to make a judgement on whether they would choose
to accept treatment on symptomatic grounds alone. It is essential that thoughtful advice be given
as to whether symptoms are ascribable to sarcoidosis: in many instances, this is not the case and
the introduction of sarcoidosis therapies may result in a net loss of QoL. Furthermore, the nature
https://doi.org/10.1183/2312508X.10033520 321
of initial therapy must be negotiated with the patient: the high-dose induction regimens typically
used in dangerous disease are often inappropriate, with the treatment worse than the disease.
Discussions related to treatment for QoL reasons are often prolonged, with the choice and level
of treatment often modified by patient wishes. Early review of therapy, with titration of
treatment levels against side-effects and efficacy (in effect, confirmation that intervention has
resulted in a net improvement in QoL) is essential.
Although sarcoidosis patients may experience severe loss of QoL, the association of symptoms
with granulomatous inflammation is frequently uncertain. Symptoms can broadly be
conceptualised in four overlapping domains (table 3). It is useful at the outset to consider the
provenance of the symptoms as a guide to the aggressiveness of immunosuppressive and other
therapies. Some features that increase the likelihood that symptoms are related to granulomatous
inflammation include the specificity of symptoms and signs, the presence of disease activity
markers (e.g. elevated soluble IL-2 receptor level, 18F-FDG uptake on PET scan), results of
therapeutic trials and the absence of other explanations for the symptoms [64–66]. Despite the
lack of evidence of active granulomatous organ involvement, symptoms such as arthralgias and
fatigue can be a manifestation of sarcoidosis, and a trial of prednisone or other medications can
be useful. It is helpful to educate the patient that symptoms that have developed since the onset
of sarcoidosis may not relate to sarcoidosis per se [67].
Whether or not symptoms are clearly related to active granulomatous inflammation, it is often
beneficial to involve other disciplines in the comprehensive care of the patient. For example,
nonexertional fatigue may persist after apparent resolution of inflammation [68]. The diagnosis
and management of fatigue may be optimised by engaging rehabilitation specialists, primary
care providers, nutritionists and psychologists, as it is unlikely that a single intervention will
completely reverse the symptom and restore premorbid energy levels [69]. In these settings,
shared decision making about the goals of therapy, how to balance the expected risks and
benefits of therapy, and expectation setting about the limits of modern medicine are important.
TABLE 3 Categories of symptoms experienced by sarcoidosis patients
Category Examples
Granulomatous inflammation Exertional limitation due to impaired pulmonary

physiology
Vision loss due to optic neuritis
Distress due to lupus pernio
Nongranulomatous consequences of sarcoidosis Fatigue despite absence of active granulomas
Brain fog
Small-fibre neuropathy causing dysautonomia
Depression
Therapy toxicities Depression
Dyspnoea due to weight gain or myopathy after steroid
treatment
Vision loss due to cataracts
Hair loss due to immunosuppressive medications
Unrelated to sarcoidosis Depression
Weight gain
Difficulty concentrating
Any other symptom that can occur in non-sarcoidosis
populations
322 https://doi.org/10.1183/2312508X.10033520
Stopping treatment
The ideal duration of therapy has not been defined, but, in general, treatment for ⩾6–12 months
is recommended for most patients [70]. Historically, relapses are thought to occur in 20–74% of
treated individuals [11, 71], but there are few contemporary data to guide clinicians. In a large
Italian series, relapses occurred in 37% of treated individuals, with extrapulmonary disease and
a requirement for higher initial doses of steroids independently associated with higher risk for
relapse [72]. Approximately 50% of relapses occur in the first 6 months after stopping therapy
[11], and almost all relapses occur within 36 months of steroid cessation. The large majority
involve the same organs as at presentation [72]. Besides the presenting mode, the need for
therapy at the outset of disease is a powerful predictor of the need for ongoing treatment [11, 73].
Taken together, these data suggest that patients with worse prognosis at the outset are the most
likely to relapse, and that the label “remission” should not be conferred until 3 years after
stopping therapy.
Treatment toxicity
Treatment regimens focused primarily on QoL or symptoms may be conceptualised differently
from those focused on dangerous sarcoidosis, as the risk–benefit calculations necessarily differ
in the two settings. Although some data suggest that corticosteroid therapy is associated with a
lower QoL, these data may be misleading due to residual confounding, or may not reflect the
benefits of treatment with lower doses in patients who do not have organ-threatening disease.
For example, a cross-sectional survey in a US clinic found clinically and statistically significant
decrements in general (36-Item Short Form Survey) and pulmonary (St George’s Respiratory
Questionnaire) health-related QoL in treated individuals [63]. The annual steroid dose has also
been associated with QoL [74]. The worse QoL exhibited in these studies may be explained by
patterns of organ involvement but could also reflect the toxicities of corticosteroids.
Toxicities related to corticosteroids can be broadly divided into two groups: 1) side-effects
easily noted by the patient, and 2) longer-term consequences that may lead to additional
comorbidities. Overtly discernible side-effects may occur at a threshold dose (e.g. hypertension,
weight gain, glaucoma), or the risk may be linear (oedema, cataracts), with no theoretical “safe”
dose [75]. It is not uncommon that the typical maintenance dose of corticosteroids in practice
exceeds the threshold dose shown to confer risk, with many patients managed at ⩾10 mg·day−1
in some cohorts [76, 77]. In a single-centre review, no safe dose of corticosteroids could be
identified [78], but the inability to identify a safe dose of corticosteroids may be related to usage
patterns in usual practice, as very few patients were managed with daily doses of ⩽5 mg. Thus,
the risk–benefit analysis of low-dose prednisone for management of bothersome symptoms
remains unclear.
Despite uncertainty about the long-term risk profile of low-dose corticosteroids, it is clear that
higher doses may be harmful to patients. Data from a large patient survey suggested that the
majority of sarcoidosis patients experience new comorbidities after the diagnosis of sarcoidosis,
and many of these are most likely due to steroid toxicities [79]. For example, hypertension,
obesity and obstructive sleep apnoea each developed in about one-fifth of patients after the
diagnosis of sarcoidosis, with older age, lower income, disease duration, non-white race and
multiple organ involvement all independently conferring risk for steroid-related toxicities [79].
Sarcoidosis treatment with corticosteroids was associated with a >2-fold increased risk for
diabetes in the Swedish National Patient Register [80]. In population-based studies, the hazard
ratio for cardiovascular disease in sarcoidosis patients is 1.4–1.6 compared with age- and
sex-matched controls [81, 82]. While cardiovascular disease could be a result of uncontrolled
https://doi.org/10.1183/2312508X.10033520 323
systemic inflammation, it is also likely that a proportion of the excess comorbidities is due to
the deleterious metabolic effects of corticosteroids. In several observational studies, increasing
numbers of comorbidities have been associated with mortality in sarcoidosis populations [83, 84].
Taken together, the data support the hypothesis that corticosteroids account for excess morbidity
and mortality in sarcoidosis patients, and that greater cumulative doses are riskier.
Longitudinal screening for new signs of dangerous sarcoidosis

While most dangerous sarcoidosis is evident around the time of diagnosis, patients should have
periodic surveillance for new organ involvement. There are few data examining the ideal
longitudinal screening strategy, and thus the most recent sarcoidosis guidelines rely mainly on
symptom-based screening after the initial organ assessment [53]. The intensity of history taking
should be guided by the patient’s unique sarcoidosis history, the individual and cultural
predilection of the patient to mention symptoms without specific solicitation, and the presence
of other testing. For example, facial droop and syncope are commonly unrecognised as
manifestations of sarcoidosis, and their presence should be specifically queried at each
follow-up visit. The only routine follow-up tests to screen for new organ involvement
recommended in the American Thoracic Society guideline are serum calcium, creatinine and
alkaline phosphatase [53].
The follow-up screening strategy should also be dictated by risk. Most overt or bothersome
organ involvement will be evident in the first 6 months after diagnosis, with an additional 16%
occurring in the first 24 months in the ACCESS (A case control etiologic study of sarcoidosis)
study cohort [85]. Black race and extrapulmonary involvement are associated with a higher
chance of developing new organ involvement [85, 86]. As there are notable associations of
ocular, neurological and cardiac involvement, when any of these organs is affected, screening
strategies for the others may be more intense [87–89]. After 2–3 years, new overt bothersome
organ involvement is rare, except for cardiac disease, which can manifest years after the initial
diagnosis, even in patients without a treatment indication at diagnosis [86].
Conclusion
Treatment of sarcoidosis depends on assessment of the prognosis (likelihood of present or
threatened danger) and the impact of sarcoidosis on QoL. In practice, these two indications for
therapy frequently overlap, but decision making about treatment strategy and communication
with the patient are facilitated by dichotomising, using the danger/QoL paradigm. Ideally,
biomarkers or clinical indicators suggesting a high likelihood of threatened danger will be
identified in the future, allowing more precise decisions about when to initiate therapy. At
present, however, markers of poor prognosis, as well as evidence of severe organ dysfunction,
remain the best guides to identify threatened or extant danger. In dangerous sarcoidosis,
concomitant treatment with more than one immunosuppressive agent may be appropriate at the
outset. For QoL indications, treatment can be less aggressive, with a focus on shared therapeutic
decision making between patients and physicians. Biomarkers that more clearly pinpoint which
symptoms are attributable to granulomatous inflammation are needed.
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Disclosures: D.A. Culver reports receiving the following, outside the submitted work: grants or contracts to his
institution from Boehringer Ingelheim, Genentech, Mallinkrodt, aTyr, the Foundation for Sarcoidosis Research, the
Ann Theodore Foundation and the NHLBI; personal consulting fees from Boehringer Ingelheim and Mallinkrodt;
and support from Roche for attending meetings and/or travel; and fees for participation in a data safety
monitoring board or advisory board from Boehringer Ingelheim, Xentria and Roivant. D.A. Culver is the President
of the World Association for Sarcoidosis and Other Granulomatous Disorders (WASOG). A.U. Wells reports receiving
the following, outside the submitted work: personal fees and nonfinancial support from Boehringer Ingelheim,
Bayer and Roche Pharmaceuticals; and personal fees from Blade.
https://doi.org/10.1183/2312508X.10033520 327
Chapter 22
Treating sarcoidosis and potential new drugs

Canay Caliskan1 and Antje Prasse 1,2
1
Dept of Respiratory Medicine, Hannover Medical School and Biomedical Research in End-stage and Obstructive
Lung Disease Hannover, German Lung Research Center (DZL), Hannover, Germany. 2Fraunhofer Institute for
Toxicology and Experimental Medicine, Hannover, Germany.
Corresponding author: Antje Prasse ( prasse.antje@mh-hannover.de)
Cite as: Caliskan C, Prasse A. Treating sarcoidosis and potential new drugs. In: Bonella F, Culver DA, Israël-Biet D,
eds. Sarcoidosis (ERS Monograph). Sheffield, European Respiratory Society, 2022; pp. 328–336 [https://doi.org/10.
1183/2312508X.10033620].
@ERSpublications
This chapter summarises current concepts in established pharmacological therapy in sarcoidosis and
highlights potential new drugs currently being tested in trials https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis manifests with inflammatory granulomas in multiple organs, most commonly the lungs and
lymph nodes. The diverse range of organ manifestations and the variety of disease-modifying factors
such as environmental, genetic and patient-related factors all add to the clinical heterogeneity of the
disease and make it difficult to find the best pharmacological treatment. Every patient appears to be
different, and an individualized therapy is required. Immunosuppressive therapy is the cornerstone of
the management of sarcoidosis. Current treatment options focus on suppressing immune responses by
inhibiting macrophages, T-cells and cytokine signalling. Our knowledge of the pathogenesis of this
heterogeneous disease has improved, and new drugs are currently being tested in clinical trials. This
chapter reviews the current approaches to pharmacological treatment of sarcoidosis and highlights
potential new drugs.
Introduction
One sarcoidosis patient does not look like another, causing difficulties in identifying universal
treatment concepts. Development of new medications is hindered by the heterogeneity of the
disease and the need for individualised treatment concepts, which is thwarted by inflexible
study designs. Most of the current treatment concepts used by many experts in the field are
empirical rather than evidence based. Only a few placebo-controlled, randomised, multicentre
trials have been conducted in patients with sarcoidosis. Many failed and were underpowered,
unfortunately, but all of them revealed something to us and may help us to improve and
avoid pitfalls in study design in the future. Considering the lack of new developments in the
field, it is therefore no wonder that it took >20 years to publish a revised European
Respiratory Society (ERS) guideline for the treatment of sarcoidosis [1, 2]. However, many of
the current treatment recommendations are still tagged with a very low confidence level and
should rather be considered expert opinions. The aim of this chapter is to summarise current
concepts on established pharmacological therapy and highlight potential new drugs. In the
end, there is good news: never have so many drug candidates been tested for their efficacy in
sarcoidosis as currently.
328 https://doi.org/10.1183/2312508X.10033620
TREATING SARCOIDOSIS | C. CALISKAN AND A. PRASSE
Second-line treatment with antimetabolites

For those patients requiring high glucocorticoid doses to control their symptoms and who are
unable to taper, or those who suffer from unacceptable side-effects of glucocorticoid treatment, it is
recommended to start second-line therapy with an immunosuppressive drug [1]. MTX, azathioprine
and leflunomide are therapeutic options in this context [1, 3]. In the current guideline, the use of
MTX is particularly favoured, because the most compelling evidence exists for this compound [1].
MTX is a folic acid antagonist that has anti-inflammatory effects. Two clinical studies showed a
significantly better outcome with MTX therapy for sarcoidosis patients. While tapering
glucocorticoids, a dosage of 10–15 mg·week−1 of MTX is sufficient [1, 4]. Clinical trials are
also ongoing to investigate patients with cardiac sarcoidosis (e.g. ClinicalTrials.gov identifier
NCT03593759).
Azathioprine is a purine metabolism inhibitor. The average dosage is 150–200 mg·day−1. One
prospective open-label study documented azathioprine treatment as being of benefit in patients
with sarcoidosis [5]. To compare second-line agents, a retrospective study by VORSELAARS et al.
[6] tested the safety and efficacy of either MTX or azathioprine on top of prednisolone
treatment in two centres treating patients with pulmonary sarcoidosis [7, 8]. While the centre in
Nieuwegein, Netherlands, treated their patients preferentially with MTX, the centre in Leuven,
Belgium, treated their patients preferentially with azathioprine. With regard to the ability to
taper down prednisolone, both compounds worked similarly well. Improvement in pulmonary
function, especially FVC and DLCO, was only mild, but again similar with both [7, 8]. The
major difference reported was the number of infectious complications, which was significantly
higher in Belgium, where azathioprine was used. Numbers of infections were identified, among
other things, by use of antibiotics. As the use of antibiotics differs in both countries, it remained
unclear whether azathioprine is associated with a higher infection rate. Recently, however,
another retrospective study reported very similar results. The data of a Swedish registry
including 926 patients with sarcoidosis indicated again that treatment with azathioprine harbours
a higher risk of infection compared with MTX [9]. Both MTX and azathioprine have similar
side-effects, such as gastrointestinal distress, which can be fulminant and may occur at the
beginning of the therapy. Moreover, both drugs can induce myelosuppression and infections.
MTX, but not azathioprine, is potentially teratogenic, which must be considered when treating
young adults [6]. Recent data suggest that azathioprine therapy is safe even during pregnancy.
Long-term safety data of patients treated with azathioprine after organ transplantation or in the
context of rheumatic diseases showed an increase in nonmelanoma skin cancer [10]. It is
currently unclear whether this is a specific side-effect of distinct immunosuppressants or an
effect of immunosuppression per se. A recent publication also reported an increase in
nonmelanoma skin cancer after treatment with MTX [11].
Leflunomide, a dihydroorotate inhibitor, is commonly used to treat rheumatoid arthritis. It was

tested in a small retrospective study and showed good efficacy in controlling symptoms,
including in patients who did not respond to MTX treatment [12].
MMF is a purine nucleotide synthesis inhibitor and was tested in a small study showing a
sufficient steroid-sparing effect for patients with neurosarcoidosis [13].
TNF-α inhibitors
TNF-α inhibitors are recommended by the current ERS practical guidelines as a third-line
therapy and should be considered in patients with symptomatic pulmonary sarcoidosis who are
https://doi.org/10.1183/2312508X.10033620 329
believed to be at a higher risk of future mortality or permanent disability and who have already
been treated with antimetabolites and glucocorticoids [1, 14, 15]. TNF-α plays a key role in
granulomatous formation and is produced by macrophages as well as T-cells [16].
The monoclonal anti-TNF-α antibody infliximab (IFX) was tested in two double-blind,
placebo-controlled multicentre phase II trials in patients with sarcoidosis [17, 18]. In the larger
trial, the effect of IFX was tested on 138 patients with chronic pulmonary sarcoidosis and a
significant increase of 2.5% was reported in the FVC % predicted in the IFX arm compared
with placebo [18]. Of note, patients with cutaneous or neurological involvement benefited
most [19]. Starting with a loading dose of 5 mg·kg−1 at weeks 0, 2 and 6, IFX can be combined
with prednisolone or MTX/azathioprine [20]. The maintenance dose should be adjusted to
3–5 mg·kg−1 every 4–8 weeks.
Some patients treated with IFX may develop intolerance or a loss in efficacy due to anti-IFX
antibodies [15, 21, 22]. In these cases, adalimumab is often chosen as an alternative TNF-α
inhibitor, for which a significant improvement in patients with cutaneous or ophthalmic
involvement has been reported [23, 24]. In one double-blind, randomised clinical trial with
cutaneous sarcoidosis, adalimumab showed an amelioration of cutaneous affections [25].
Furthermore, sarcoidosis patients with refractory chronic noninfectious uveitis demonstrated an
improvement of intraocular inflammatory signs after taking adalimumab [23]. However, more
randomised studies are needed to evaluate the dosage and duration of treatment.
Currently, IFX is the favourite biological agent [26]. Of note, other TNF-α inhibitors such as
etanercept and golimumab have failed in sarcoidosis [27, 28]. Prior to the commencement of
TNF-α inhibitors, several infectious diseases must be ruled out, especially tuberculosis and
aspergillosis. Active and latent tuberculosis should be detected by IFN-γ release tests and
hepatitis infections by the respective serological tests. Moreover, patients treated with TNF-α
inhibitors have an increased risk of viral infections, particularly varicella-zoster virus and
papillomaviruses. Vaccination against varicella-zoster virus is recommended prior to the start of
treatment. Other contraindications are recent malignancies and severe heart failure.
Other treatments
Rituximab
Rituximab is also classed as a biological and is a recombinant anti-human CD20 monoclonal
antibody. Although CD20 is expressed mainly on B-cells and rituximab serves as a CD20+
B-cell-depleting treatment, the compound also has beneficial effects in diseases such as
granulomatosis with polyangiitis, which is considered to be T-cell driven. The effect of
rituximab on T-cells remains unclear, but rituximab may improve regulatory T-cell function as
studies in patients with systemic lupus erythematosus have suggested [29]. One small
prospective open-label phase I/II trial, which included 10 patients with pulmonary sarcoidosis,
showed inconsistent data, but in a subset of five patients, an improvement in pulmonary
function tests with rituximab treatment was noted [30].
Antifibrotics
Patients with progressive fibrosing sarcoidosis may benefit from antifibrotic treatment. The
INBUILD (Efficacy and safety of nintedanib in patients with progressive fibrosing interstitial
lung disease) trial tested the efficacy of nintedanib in various progressive fibrotic ILDs,
including a small number of patients with sarcoidosis [31]. The number of patients was,
however, too low to draw any meaningful conclusion with regard to sarcoidosis [32]. Fibrotic
remodelling in sarcoidosis is not well understood and may differ among patients. While some
330 https://doi.org/10.1183/2312508X.10033620
patients predominantly develop vast bronchiectasis in former zones of inflammatory

conglomerates, others suffer from predominantly basilar and subpleural fibrosis of a usual
interstitial pneumonitis (UIP) type. It is unknown whether UIP can evolve in the context of
sarcoidosis or whether it should be considered a comorbidity in line with a coincidence of IPF
and sarcoidosis. For sarcoidosis patients presenting with a UIP type of fibrosis [33], it is
conceivable to start treatment with antifibrotics, although their benefit is currently unclear in
patients with bronchiectasis.
Potential new treatments

Several new compounds are currently being tested or planned to be tested in the near future
within clinical trials (table 1). In this section, we will give a short overview.
Janus kinase inhibitors

Janus kinases ( JAKs) are intracellular tyrosine kinases that transduce cytokine-triggered signals
and activate the JAK-signal transducer and activator of transcription protein (STAT) pathway
[36]. The JAK-STAT pathway can be stimulated through multiple inflammatory cytokines,
especially IFN-γ, which plays a major role in many inflammatory disorders and granuloma
formation [37, 38]. IFN-γ is produced mainly by lymphocytes and is highly upregulated in the
lungs and BAL of sarcoidosis patients [39, 40]. Four JAK isoforms have been detected: JAK1,
JAK2, JAK3 and TYK2. JAK inhibitors can selectively interfere in the JAK-STAT pathway and
were recently approved for the treatment of rheumatoid arthritis and other diseases. Tofacitinib,
a JAK1/3 inhibitor, was tested in several patients with cutaneous, pulmonary and multiorgan
sarcoidosis [41–44]. The dosage was 5 mg twice daily. All case reports showed clinical,
histological and pulmonary improvement. One case series of five patients even noted a
corticoid-sparing effect [42]. Tofacitinib is currently being tested for its efficacy in an
open-label trial for pulmonary and cutaneous sarcoidosis (ClinicalTrials.gov identifier
NCT03910543). Several case reports have also underlined the effectiveness of ruxolitinib, a
selective JAK1/2 inhibitor. Ruxolitinib was examined in patients with JAK2-mutated
polycythemia vera and refractory multiorgan sarcoidosis and showed an improvement in skin
and pulmonary findings [45, 46]. The dosage was 5 mg twice daily. Moreover, data from a case
report indicate that treatment with baricitinib, another selective JAK1/2 inhibitor, was also of
benefit in a patient with steroid-resistant sarcoidosis [47].
IL-6 receptor inhibitors (tocilizumab/sarilumab)

IL-6 is upregulated in the lung and BAL fluid of patients with sarcoidosis and is produced
mainly by macrophages [48, 49]. The IL-6 receptor (IL-6R) is widely distributed on immune
cells including T-cells, B-cells and macrophages. The effects of the recombinant monoclonal
anti-human IL-6R antibody tocilizumab has to date only been tested in a small case series [50].
An additional anti-human IL-6R monoclonal antibody, sarilumab, is currently being tested in a
small, phase II, single-site, placebo-controlled withdrawal study (ClinicalTrials.gov identifier
NCT04008069). Both biologicals have been approved for the treatment of rheumatoid arthritis.
ATYR1923
Recently, ATYR1923, a selective modulator of neuropilin-2 (NRP2), was tested in a placebo-
controlled, multicentre, phase IIa clinical trial (ClinicalTrials.gov identifier NCT03824392).
NRP2 is a cell-surface receptor that associates with vascular endothelial growth factor receptor-1
(VEGFR-1) and regulates inflammatory responses [51]. Data suggest that certain haplotypes of
the VEGF gene are associated with sarcoidosis [52] and VEGF-A may be involved in
granuloma formation [53]. The clinical trial had a multiple dose-ascending design and tested the
https://doi.org/10.1183/2312508X.10033620 331
332

TABLE 1 Potential new treatments
Treatment Condition Study Status Primary Estimated ClinicalTrials.

design outcome enrolment gov identifier
Tofacitinib (JAK1/3 Cutaneous sarcoidosis Phase I; nonrandomised, Awaiting Change in CSAMI score 15 patients NCT03910543
inhibitor) single group, open label results
Ruxolitinib (JAK1/ Multiorgan sarcoidosis Case report
2 inhibitor)
Baricitinib (JAK1/2 Steroid-resistant sarcoidosis Case report
inhibitor)
Tocilizumab (IL-6R Pulmonary sarcoidosis Case series Four patients who failed
antibody) multiple steroid-sparing
treatments
Sarilumab (IL-6R Glucocorticoid-dependent Phase II, randomised, placebo- Recruiting Flare-free survival 15 patients NCT04008069
antibody) sarcoidosis controlled withdrawal study
ATYR1923 Pulmonary sarcoidosis Phase I/phase II, randomised, Press Improvement in PFT 37 patients NCT03824392
(selective NRP2 double blind, placebo release values and decline in
modulator) controlled, multiple [34] inflammatory biomarker
ascending dose levels
Abatacept Pulmonary sarcoidosis Phase II, multicentre, open Awaiting Infectious complications 30 patients DRKS00011660
(CTLA-4–Ig label single arm results
fusion protein)
Canakinumab Pulmonary sarcoidosis Phase II, randomised, placebo Awaiting Change in pulmonary 40 patients NCT02888080
https://doi.org/10.1183/2312508X.10033620
(anti-IL-1β controlled, multiple dose results function between

antibody) baseline and week 24
Anakinra (IL-1R Cardiac sarcoidosis Phase II, randomised, Recruiting Change in inflammation 28 patients NCT04017936
antagonist) double blind marker
CMK389 (anti-IL-18 Pulmonary sarcoidosis Phase II, randomised, placebo Recruiting Change in FVC 66 patients NCT04064242
antibody) controlled, multicentre
Inhaled sirolimus Pulmonary and cutaneous Planned
sarcoidosis for 2022
Gimsilumab Pulmonary sarcoidosis Planned
(GM-CSF for 2022
antibody)
JAK: Janus kinase; IL-6R: IL-6 receptor; NRP2: neuropilin-2; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; GM-CSF: granulocyte–macrophage colony-stimulating factor;
CSAMI: Cutaneous Sarcoidosis Activity and Morphology Instrument; PFT: pulmonary function test. Reproduced and modified from [35] with permission.
effect of three different doses of intravenously administered ATYR1923 (1.0–5.0 mg·kg−1) in

37 patients with pulmonary sarcoidosis. All recruited patients underwent a protocol-guided oral
glucocorticoid tapering regimen, and the study was completed in July 2021. According to a
press release by the company (aTyr Pharma), the dose of 5 mg·kg−1 was well tolerated and led
to a statistically significant higher steroid reduction, improvements in pulmonary function test
values and a decline in inflammatory biomarker levels [34].
Abatacept
Abatacept is a biological that was developed by Bristol Myers Squibb as a fusion protein and
functions like an antibody [54]. The protein is composed of the Fc region of an
immunoglobulin fused to the extracellular part of cytotoxic T-lymphocyte-associated protein 4
(CTLA-4). CTLA-4 is highly expressed on regulatory T-cells and is the natural ligand of CD80
and CD86, which are expressed on antigen-presenting cells such as macrophages and provide
costimulatory signals during T-cell activation [55, 56]. Binding of abatacept to CD80 or CD86
masks these receptors and exhibits immunoregulatory functions [54]. Macrophages and other
antigen-presenting cells without functionally active CD80 or CD86 can no longer fully activate
T-cells [57]. In 2005, abatacept was already approved for the treatment of rheumatoid arthritis.
An investigator-initiated open-label clinical trial recently tested the effect of abatacept in 30
patients with pulmonary sarcoidosis over a period of 6 months in Germany [58]. The study
investigated safety aspects, changes in lung function values, quality of life and BAL parameters.
IL-1β inhibitors (canakinumab/anakinra)

The biological canakinumab is an anti-IL-1β antibody, which was tested in a small, multicentre,
placebo-controlled clinical trial for the treatment of 40 patients with pulmonary sarcoidosis
because several studies suggested a role for IL-1β in sarcoidosis and increased IL-1β levels in
progressive pulmonary sarcoidosis [59]. IL-1β is produced by macrophages after inflammasome
activation [60]. The clinical trial studied the effect of once monthly, s.c.-administered
canakinumab (300 mg) on pulmonary function parameters and 18F-FDG PET uptake over a
period of 6 months, and lasted until 2019. Data from the trial (ClinicalTrials.gov identifier
NCT02888080) have not yet been published. The study size may have been too small to draw
any conclusions and the study design did not include a pre-specified strict protocol on how to
taper glucocorticoids or antimetabolites.
Anakinra is an IL-1 receptor antagonist and therefore inhibits IL-1α and IL-1β. It is currently
being tested in a phase II, double-blind, randomised trial in patients with cardiac sarcoidosis
(ClinicalTrials.gov identifier NCT04017936). The examined dose is 100 mg administered once
a day by s.c. injection. This two-centre trial is examining the influence on systemic
inflammatory biomarkers and inflammation activity in PET and MRI scans. Anakinra is already
approved for the treatment of moderate-to-severe rheumatoid arthritis.
IL-18 inhibitor (CMK389)

The same pharmaceutical company that ran the clinical trial testing canakinumab recently
initiated an additional clinical trial testing the effect of the anti-IL-18 antibody CMK389. Like
IL-1β, IL-18 is also produced following NLR family pyrin domain containing 3 (NLRP3)
inflammasome activation [61]. Its role in humans and granuloma formation has not been studied
in detail, but elevated serum levels have been reported [62].
Inhaled sirolimus
Sirolimus, also known as rapamycin, was originally developed as an antibiotic and belongs to
the substance class of macrolides [63]. Because of its immunosuppressive properties, it is
https://doi.org/10.1183/2312508X.10033620 333
widely used after organ transplants to prevent allograft rejection [64]. Sirolimus is especially
known to inhibit mTOR activation and downstream signalling [65]. A recently published study
showed that macrophage-specific mTOR overexpression is associated with granuloma formation
in mice and increased phospho-mTOR expression in lung tissues from sarcoid patients [66, 67].
There are plans for a pharmaceutical company to initiate a multicentre clinical trial testing the
efficacy of inhaled sirolimus (Rapamune) in 2022. In addition, the same company will also test
the effect of locally administered Rapamune in skin sarcoidosis.
Granulocyte–macrophage colony-stimulating factor inhibitor (gimsilumab)

Gimsilumab is a recombinant anti-human granulocyte–macrophage colony-stimulating factor
(GM-CSF) antibody that was recently tested in severe respiratory failure due to coronavirus
disease 2019 and will be tested soon in a multicentre, placebo-controlled clinical trial in patients
with pulmonary sarcoidosis. GM-CSF gene expression levels in BAL fluid of patients with
pulmonary sarcoidosis were reported to be elevated and correlated with disease activity [68].
Conclusion
Finding the best medication for an individual sarcoidosis patient is a difficult task. Sarcoidosis
is such a heterogeneous disease that every patient appears to be different. The complexity of the
disease is driven by its systemic nature and the multitude of possible organ manifestations.
Moreover, the heterogeneity of sarcoidosis is probably also caused by multiple inducing factors,
which may lead to different underlying immunological conditions. Of note, the majority of
patients will recover spontaneously and should not be treated with any immunosuppressive
compound, considering the potential side-effects. Only in patients at risk of organ dysfunction
or severe impairment in their quality of life should immunosuppressive treatment be started. So
far, immunosuppressive treatment options have been restricted to only a few drugs and do not
adequately address the heterogeneity of the disease. However, with the plethora of new medical
compounds on the horizon, most of them currently being tested in clinical trials, we are
optimistic that we will soon have more effective compounds, which will enable physicians to
establish more individualised therapy approaches in patients with sarcoidosis.
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Disclosures: C. Caliskan has nothing to disclose. A. Prasse has received lecture fees from Boehringer Ingelheim
and Novartis.
336 https://doi.org/10.1183/2312508X.10033620
Chapter 23
Quality-of-life assessment
Timothy Tully1,2, Marc A. Judson3, Amit Suresh Patel1,2 and Surinder S. Birring1,2
1
Centre for Human & Applied Physiological Sciences, School of Basic & Medical Biosciences, Faculty of Life
Sciences & Medicine, King’s College London, UK. 2Dept of Respiratory Medicine, King’s College Hospital, London,
UK. 3Division of Pulmonary and Critical Care Medicine, Albany Medical College, Albany, NY, USA
Corresponding author: Surinder S. Birring (surinder.birring@nhs.net)
Cite as: Tully T, Judson MA, Patel AS, et al. Quality-of-life assessment. In: Bonella F, Culver DA, Israël-Biet D, eds.
2312508X.10033720].
@ERSpublications
Sarcoidosis is a heterogeneous disease that has wide-ranging effects on health including quality of life. The
assessment of quality of life is an important aspect of sarcoidosis care and can be measured with validated
tools. https://bit.ly/3ozzgsF
ISSN: 2312-5098.
Sarcoidosis is a heterogeneous disease with numerous clinically relevant end-points. Quality-of-life

assessment is an increasingly used end-point in sarcoidosis that evaluates the impact of the condition
from the patient’s perspective. Quality-of-life assessment incorporates the sarcoidosis patient directly
into the management of the disease through an emphasis on patient-centred care and shared decision
making. Sarcoidosis-specific quality-of-life assessment tools have been designed, studied and validated,
and their minimal clinically importance difference established. However, further research is needed with
respect to this novel approach to assist with sarcoidosis management decisions.
Introduction
Quality of life is an abstract and highly subjective concept. It is also a dynamic concept, as
quality of life changes over time in response to many factors including psychological, social,
spiritual, physical health, wealth, employment, safety, security and freedom [1]. These factors
are affected by the culture and customs by which people live [2, 3].
Quality-of-life questionnaires allow the patient to evaluate the impact of disease states and
treatments on various aspects of their life. These aspects include their mood, activities of daily
living and personal relationships (figure 1). Quality-of-life assessment is particularly helpful in
sarcoidosis where the heterogeneity of the disease can impact the clinical usefulness of
traditional objective measures such as radiological tests and lung function tests, whereas quality
of life is an end-point applicable to all patients [4].
In this chapter, we examine some of the main features of health-related quality of life (HRQoL)
in sarcoidosis and the tools that are used to assess HRQoL. We analyse the relationship between
HRQoL and other measures of sarcoidosis. We also explore more recent advances in HRQoL
assessment tools and consider how they may play a more significant role in future research.
https://doi.org/10.1183/2312508X.10033720 337
HRQoL assessment
Patient
Friends and values and
family input preferences
Patient-centred
care
Objective Access to
clinical and healthcare
physiological services
data
Comorbidities
FIGURE 1 The role of health-related quality-of-life (HRQoL) assessment in sarcoidosis.
Factors affecting HRQoL in sarcoidosis and their measurement

Sarcoidosis is a complex, multisystem, inflammatory disease of unknown aetiology. It is
characterised by the presence of noncaseating granulomas and most commonly affects the lungs
and mediastinal and hilar lymph nodes causing symptoms of cough and dyspnoea. It may affect
any organ in the body and frequently involves the eyes, skin, heart, liver, spleen, kidneys and
nervous system. Sarcoidosis can also cause life-threatening and severe organ involvement,
which includes cardiomyopathy, end-stage lung disease and neurological impairment including
painful small-fibre neuropathy. These are “organ-related symptoms” causing organ scarring and
dysfunction from granulomatous inflammation that are measureable objectively. Sarcoidosis also
has more general or “non-organ-related symptoms”. The disease has a significant impact on a
patient’s HRQoL with potentially debilitating symptoms such as fatigue and reduced physical
activity, depression, anxiety and chronic pain. These symptoms are often not related to
granulomatous inflammation or organ dysfunction. They are subjective but can be measureable
with patient-reported outcome measures (PROs), such as HRQoL tools. HRQoL assessment
should be considered complimentary to standard objective medical investigations.
Predictors of poor quality of life in sarcoidosis include increased disease severity at

presentation, black race, low income and poor access to healthcare [5–7]. Other factors, which
either directly or indirectly impact quality of life, include depression, multisystem involvement
and the side-effects of treatments [8].
Fatigue and reduced physical activity

Approximately 80% of patients with sarcoidosis will report fatigue, and this is the most
common symptom of this disease [9]. Fatigue is multifactorial and should be investigated
338 https://doi.org/10.1183/2312508X.10033720
QUALITY-OF-LIFE ASSESSMENT | T. TULLY ET AL.
thoroughly to ensure that there are no other treatable or reversible causes. The cause of fatigue
is often difficult to elucidate but may be broadly divided into fatigue caused directly by
manifestations of sarcoidosis that are organ related, side-effects of treatments, and non-organ
related fatigue such as poor sleep quality, sleep apnoea or depression. There is often more than
one cause of fatigue, making management more complex.
Assessment of fatigue in sarcoidosis research is well established, and questionnaires such as the
Fatigue Assessment Scale (FAS) have been used extensively [10–12]. The FAS is a 10-item
sarcoidosis-specific PRO questionnaire. It is a reliable and validated tool in assessment of
sarcoidosis-related fatigue and HRQoL [11]. It is available in 21 languages and is simple, easy
to complete and not time consuming. The minimal clinically importance difference (MCID) is
4 points or ⩾10% change in the baseline value [13, 14].
Sarcoidosis-specific HRQoL assessment tools such as the Sarcoidosis Assessment Tool (SAT)
and the King’s Sarcoidosis Questionnaire (KSQ) include fatigue items within their modules.
The General Health module within the KSQ (KSQ-GH) enquires about tiredness and how this
impacts the patient’s recreational activities. An MCID of 8 has been established for the overall
KSQ-GH module. The SAT uses a fatigue module PFI (PROMIS Fatigue Instrument), which
was created from the Patient Reported Outcomes Measurement Information Systems (PROMIS)
items. PROMIS was developed to aid the evolution of HRQoL assessment in chronic disease
and consists of an extensive cache of PRO items [15]. The MCID for the SAT has been
established (2–5 points, depending on the module). In one study, 107 patients were assessed
using both the FAS and PFI. The PFI showed superior internal consistency using Cronbach’s α
(0.96 versus 0.74), but a very high coefficient also suggests that the PFI may contain more
items than is necessary [16]. Fatigue is the major symptom of sarcoidosis and is considered in
depth in another chapter in this Monograph [17].
Physical inactivity, like fatigue, is multifactorial and is reduced in patients with sarcoidosis [18].
In one study of 29 patients (15 patients with sarcoidosis versus 14 age-matched healthy controls),
physical inactivity was associated with a reduced functional exercise capacity using the 6-min
walk test (6MWT). No association between reduced physical activity and HRQoL was found,
although the small sample size should be noted [19]. In a further small study (n=18) of patients
with advanced sarcoidosis, exercise training improved parameters such as functional capacity,
muscle strength and HRQoL assessment using the St George’s Respiratory Questionnaire (SGRQ)
[20]. Further research is required to determine the factors that cause physical inactivity in
sarcoidosis and to better understand what interventions may improve long-term outcomes.
Dyspnoea and cough

After fatigue, dyspnoea and cough are the next most commonly reported symptoms in
sarcoidosis, with a prevalence of ∼70% and ∼50%, respectively [21]. As with many symptoms
in sarcoidosis, dyspnoea may be present even when other markers of disease are normal [22].
The Modified Medical Research Council (mMRC) Dyspnoea Scale is a widely used tool in
medicine. It has been validated in COPD and has frequently been used as a means of assessing
dyspnoea in patients with sarcoidosis [23, 24]. It grades breathlessness from 0 to 4, with 4 being
most severe. A patient decides which one of five statements best describes their breathlessness.
It is quick and easy to use. Its MCID in sarcoidosis is not known.
The Borg Dyspnoea Score is a scale of 0–10, whereby a patient can grade the intensity of their
breathlessness before, during and after exercise. It has been used as a PRO in sarcoidosis.
https://doi.org/10.1183/2312508X.10033720 339
Overall, the mMRC Dyspnoea Scale and Borg Dyspnoea Score are useful tools in assessment of
breathlessness, but they are nonspecific and fail to assess the amount of effort needed to
complete a task or reliably monitor changes in dyspnoea over time in patients with chronic
respiratory disease [25].
The Baseline Dyspnoea Index (BDI) and Transitional Dyspnoea Index (TDI) have also been
studied in patients with sarcoidosis [25]. The BDI evaluates a patient’s dyspnoea at baseline,
while the TDI assesses the change in dyspnoea from baseline. These PROs assess dyspnoea
across three domains: the level of functional impairment involved, the magnitude of the task
and the magnitude of effort that evokes dyspnoea. Consequently, they are more specific and
potentially more useful at detecting significant change compared with the mMRC Dyspnoea
Scale or Borg Dyspnoea Score. One study investigated use of the BDI and TDI in 387 patients
from the Registry for Advanced Sarcoidosis [26]. BDI scores correlated with pulmonary
function, 6MWD and HRQoL measures (all domains of the KSQ). They had a strong
correlation with the FAS. The TDI needs further evaluation, as it did not correlate with these
measures, nor did it show any significant mean change. The similarities between the
components of the BDI and mMRC Dyspnoea Scale may explain its correlation in this study.
The BDI may be more useful, as it is a multidimensional PRO and may detect changes in
patient-reported dyspnoea after treatment.
Impact of sarcoidosis on mental health

The impact of chronic disease on mental health is well recognised. For instance, in sarcoidosis,
studies estimate that ∼60% of patients will have depressive symptoms [27, 28]. This is
compared with a prevalence of about 14–48% in a condition such as rheumatoid arthritis,
depending on the PRO that is used to assess [29]. The prevalence of depression in the general
population is ∼5% of people [30].
Depression has been shown to be associated with poorer health outcomes over time in patients
with chronic disease [31]. The high prevalence of depressive symptoms in sarcoidosis may also
relate to the associated symptoms of fatigue, pain and dyspnoea, and the impact of common
treatments such as corticosteroids. In a study by CHANG et al. [28], depression was more common
in those patients of low income and female sex. Further studies are needed to understand the
impact of socioeconomic factors and comorbidities on depression associated with sarcoidosis.
Anxiety has also been recognised in patients with sarcoidosis with a prevalence of ∼33–37% of
patients [32, 33]. In the study by SHARP et al. [32] of 112 patients, those with moderate-to-severe
symptoms of depression or anxiety were more likely to visit the emergency department in the
last 6 months (eight and 13 times higher odds for emergency department visits). Patients with
significant anxiety or depression had worse HRQoL, assessed using the KSQ and SGRQ.
Assessing the impact of sarcoidosis on mental health thus plays an important role in assessment
of HRQoL in sarcoidosis, and tools such as the Beck Depression Inventory, Hospital Anxiety
and Depression Scale (HADS) and the Centre for Epidemiological Studies – Depression Scale
(CES-D) have been used in sarcoidosis research [4, 27]. The KSQ and SAT also have mental
health components. Recognising depressive symptoms is important and warrants further
assessment in the clinic; appropriate treatment may improve HRQoL and outcomes in patients
with chronic respiratory disease [34].
Impact of sarcoidosis on career, family and relationships

Sarcoidosis can have a significant impact on a patient’s career. A study of Swedish patients with
sarcoidosis demonstrated more sick days versus controls in the year of diagnosis (57 versus
340 https://doi.org/10.1183/2312508X.10033720
31 days) and 5 years after diagnosis (45 versus 34 days), with a loss of 8% of their annual
income [35]. A similar pattern of work loss was seen in commercially insured patients with
sarcoidosis in the USA (16 versus 11 days), and was associated with significant healthcare costs
[36]. These factors can impact career progression and earning potential, and subsequently may
be indirect causes of anxiety and depression, compounding the link discussed earlier [37]. All
of these factors create a potentially high symptom burden and may lead to an impact on
patients’ social life, relationships with family and loved ones, and maintaining intimate
relationships, as may occur in any chronic disease [8].
Neurosarcoidosis
Neurosarcoidosis occurs in ∼5% of patients with sarcoidosis. It is suspected that its prevalence
is likely to be higher, given that it can be difficult to diagnose in some patients [38]. Whether
there is a correlation between central nervous system involvement and depression is not known
[39]. Neurosarcoidosis may affect any aspect of the central or peripheral nervous system.
Common neurological manifestations include facial nerve palsy and optic neuritis, meningitis,
encephalitis, psychosis and even hydrocephalus as a consequence of a granulomatous mass
lesion in the brain [40].
Impact of treatments in sarcoidosis

The most commonly used treatment in sarcoidosis is glucocorticoids. These medications are
usually effective and result in better symptom management, but they are not without potentially
serious and detrimental side-effects [41]. Weight gain, effect on mood, psychosis, skin changes,
myopathy, hyperglycaemia, hypertension and a subsequent increased cardiovascular risk are
well-recognised problems with the chronic use of glucocorticoids [42]. While some studies have
reported poorer HRQoL in patients taking high-dose corticosteroids, it is difficult to establish
the contribution of medication side-effects to overall HRQoL, as these patients often have more
severe disease with more extensive organ involvement [43].
Steroid-sparing agents and biological therapies are used in select patients with sarcoidosis under
close supervision. The European Respiratory Society has recently published clinical practice
guidelines for the treatment of sarcoidosis with detailed analysis of these treatments [44].
Sarcoidosis is recognised as a challenging condition to treat, and HRQoL plays an important
role in the management plans. Some examples of recent clinical trials reporting HRQoL benefits
of therapies are reviewed in the Sarcoidosis-specific HRQoL assessment tools section.
HRQoL assessment in sarcoidosis

HRQoL assessment in sarcoidosis is becoming more important and should be considered for
use as a major end-point in clinical trials [45]. It is also important to note, however, that another
reason to initiate treatment in sarcoidosis is to prevent disease progression and end-organ
damage, and the clinician’s experience and interpretation of overall disease status and holistic
care cannot be understated.
Over the past two decades in particular, a large body of work has been devoted to broadening
our understanding and use of HRQoL assessment in sarcoidosis. Assessment tools or PROs are
developed through a meticulous design and validation process. Translations of the PRO must
also be validated to allow for cross-cultural use. Reliability must be demonstrated. These are
lengthy and rigorous processes and have been undertaken in recent years. The PRO must also
be capable of detecting significant change in what it is measuring, the MCID [46]. In a large
study of 660 patients with sarcoidosis, it was demonstrated that patients who presented with
https://doi.org/10.1183/2312508X.10033720 341
symptoms at the onset of the disease had a worse HRQoL at long-term follow-up (up to
7 years) [7]. As impaired quality of life is an indication for treatment in sarcoidosis, this finding
has clinical relevance.
MCID in sarcoidosis HRQoL assessments

The MCID is the smallest difference or change in HRQoL that a patient has perceived that
would encourage initiating or changing treatment or deciding whether treatment has been
effective or not. Highlighting the importance of the MCID, a review of a recent study to
establish an MCID in a sarcoidosis-specific PRO, the KSQ, described the work as “a missing
piece” that would allow the KSQ to be an effective research outcome measure [47, 48].
Assessment tools in sarcoidosis HRQoL

Before the development of sarcoidosis-specific HRQoL assessment tools, clinicians used
well-established, generic and system-specific HRQoL assessment tools when studying quality of
life in sarcoidosis. The PROs differ in construct and administration, and therefore care should be
taken to administer PROs in the way they were intended to minimise variability of assessment
between studies. Generic and disease-specific PROs are summarised in table 1.
Generic tools
Medical Outcomes Study 36-item Short Form
The Medical Outcomes Study 36-item Short Form (SF-36) assessment tool has been used in
quality-of-life research across all aspects of medicine since its development in 1992. It has
proven to be an excellent and sustainable tool for use in HRQoL research. The tool comprises
36 questions, which assess eight health domains in a bio-psycho-social approach including a
question on perceived general health. The SF-36 is simple, patient friendly and can be
completed within a few minutes. It has been translated and validated in different languages and
cultures. The MCID for the SF-36 has been established and is a change in score of 4 points.
Studies of its reliability and validity have been mixed [50]. It has been used in sarcoidosis
research alongside other PROs. It is a useful tool in this respect, but practically its use may be
limited in a clinical setting for an individual as it is not specific for their condition. It has a role
in detecting treatment-related improvements at a group level within a study and when comparing
against other chronic disorders [51].
The World Health Organization Quality Of Life-100

The World Health Organization Quality Of Life-100 (WHOQoL-100) was developed in the
early 1990s for cross-cultural use and is available in 28 different languages. It can be used to
assess quality of life in any aspect of healthcare. It has been tested for reliability and validity.
The questionnaire comprises 100 questions related to the patient’s health and well-being over
the past 2 weeks. These questions are based on six domains: physical, psychological, level of
independence, social relations, environment and spirituality. There is an abbreviated 26-item
version of the questionnaire, the WHOQoL-BREF, which merges some of the six domains and
uses four domains instead. The questionnaires take ∼20 min and <10 min to complete,
respectively [52]. The WHOQoL-100 has been used in sarcoidosis HRQoL assessment and
shows good reliability and validity [53]. In one study of the effects of fatigue on HRQoL in 145
patients with sarcoidosis, tired patients reported worse HRQoL in all domains of the
WHOQoL-100 [54]. To support this finding, another study of fatigue and exercise capacity in
88 patients with sarcoidosis used the WHOQoL-BREF to assess HRQoL. Patients with
sarcoidosis again had a reduced quality of life in comparison with healthy controls [55]. The
MCIDs of the WHOQoL-100 and the WHOQoL-100 in sarcoidosis have not yet been studied.
342 https://doi.org/10.1183/2312508X.10033720
https://doi.org/10.1183/2312508X.10033720
TABLE 1 Overview of frequently used patient-reported outcome measures in health-related quality-of-life assessment in sarcoidosis
Measure Items, n Scoring Time to MCID Domains

complete, min determined
Generic
SF-36 36 0–100 (higher score better) 5–10 Yes (not in sarcoidosis) Physical functioning
Physical role limitations
Bodily pain
General health perceptions
Energy/vitality
Social functioning
Emotional role limitations
Mental health
WHOQOL-100 100 0–100 (facet scores and 10 Yes (not in sarcoidosis) Physical health
domain scores) Psychological independence
Level of independence
Social relationships

Environment
Spirituality/religion/personal
beliefs
FAS 10 0–50 (higher score is worse, 1–2 Yes Mental fatigue
<22 is normal) 4 points or a 10% change from Physical fatigue
baseline value
Pulmonary specific
SGRQ 50 (76 weighted 0–100 (higher score is worse) 10–20 Yes Symptoms
responses) 4–12 units (in asthma and COPD) Activity
Impact
Continued
343
344

TABLE 1 Continued
Measure Items, n Scoring Time to MCID Domains

complete, min determined
Sarcoidosis specific
SAT 51 T-scores scaled to mean of 50 and 10–15 Yes Physical functioning
SD of 10 2–5 points depending on the Satisfaction with roles and
module activities
Pain interference
Sleep disturbance
Fatigue
Lung problems
Skin problems
Skin stigma
KSQ 29 0–100 (higher score is better) 10 Yes General health status
KSQ General=8 Lung
https://doi.org/10.1183/2312508X.10033720
KSQ Lung=4 Medication

Skin
Eyes
MCID: minimal clinically important difference; SF-36: 36-item Short Form; WHOQOL-100: World Health Organization Quality of Life-100; FAS: Fatigue Assessment Scale; SGRQ:
St George’s Respiratory Questionnaire; SAT: Sarcoidosis Assessment Tool; KSQ: King’s Sarcoidosis Questionnaire. Reproduced and modified from [49] with permission.
Pulmonary-specific tools: the SGRQ

The SGRQ is a pulmonary-specific HRQoL questionnaire. It has been used extensively in
sarcoidosis research [45, 56]. The questionnaire was developed in the early 1990s, initially as
a PRO in COPD. It focuses on three domains of health: frequency and severity of symptoms,
activities that may be affected by these symptoms, and the impact this has on a patient’s
physical and psychological state. There are 50 questions in total in the questionnaire [57].
This PRO has been validated for use in a wide range of pulmonary diseases including
asthma, COPD, bronchiectasis and sarcoidosis [4, 58, 59]. A mean change score of 4 units on
the SGRQ is the MCID in patients with COPD [60]. MCID estimates in IPF are 5–8 [61]. LO
et al. [45] analysed the correlation between the SGRQ and other established assessments in
sarcoidosis including the SF-36, FVC, FEV1 and 6MWT. The SGRQ was directly compared
with the SF-36. Improvement in SGRQ total score correlated with improvement in FVC %
predicted (r= −0.25), FEV1 (r= −0.20) and 6MWT (r= −0.20). The strongest correlation between
SGRQ total score and other parameters studied was the SF-36 physical component summary
score (r= −0.80 for baseline scores, r= −0.45 for changes from baseline). This study further
emphasised the importance of the SGRQ and HRQoL assessment in sarcoidosis. The SGRQ has
also been studied as a secondary outcome measure in a phase II clinical trial of the efficacy of
antimycobacterial therapy in chronic pulmonary sarcoidosis [62]. The limitations of using the
SGRQ in sarcoidosis are that it is a lengthy questionnaire, it does not assess some health issues
relevant to sarcoidosis, it contains items that are not so relevant to sarcoidosis and the MCID has
not been defined in sarcoidosis.
Sarcoidosis-specific HRQoL assessment tools

Generic questionnaires, such as the WHOQoL-100, offer a comprehensive assessment of a
patient’s health and well-being by measuring a large number of health domains. Although this
can allow for a fair assessment of the overall quality of life, a more precise measurement may
be obtained using a disease-specific HRQoL tool [63]. Consequently, sarcoidosis-specific
HRQoL tools have been developed.
SAT
The SAT was developed in the USA in 2015. The authors had originally developed a
Sarcoidosis Health Questionnaire (SHQ) in 2003 and it was well studied in sarcoidosis.
However, it was not divided into domains or modules and so it could not be tailored to the
organ involved, such as skin, for example. The questionnaire did not assess treatment
side-effects, which is an important aspect of HRQoL assessment in sarcoidosis.
The authors of the SAT used the PROMIS item pool bank to develop a disease-specific
questionnaire. The health domains included physical function, fatigue, pain, sleep, and
interference with activities and roles. Importantly, the questionnaire addressed specific concerns
related to skin and lungs. This addressed the limitations of the SHQ. The reliability and
validity of the questionnaire was then demonstrated in a double-blind, randomised controlled
clinical trial in the use of golimumab and ustekinumab in lung and skin sarcoidosis. In this
study, the SAT showed good internal consistency and correlated well with established
questionnaires such as the SGRQ and SF-36 (Cronbach’s α ⩾0.87 across all modules). The
SAT was also able to discriminate patients based on the severity of dyspnoea (mMRC
Dyspnoea Scale) and lung function (DLCO/gas transfer) [64]. The questionnaire has a fatigue
module (SAT-PFI) and, importantly, an MCID has been established (range of 2–5 points,
depending on the module) [65].
https://doi.org/10.1183/2312508X.10033720 345
An important difference between the SAT and KSQ is that each module is analysed individually.
There are no total scores or combination scores in the SAT. This may allow recognition of
changes in specific modules, such as a patient with skin-predominant sarcoidosis. The SAT also
only takes 5–10 min to complete and therefore it may be favoured in clinical settings.
KSQ
The KSQ is the other sarcoidosis-specific HRQoL PRO. It was developed in 2012 in a study of
207 patients with sarcoidosis with involvement of various organs [66]. The KSQ also consists of
modules: general health status, lung, medication, skin and eyes. Total scores can be calculated,
including combination scores, allowing assessment of patients with single- or multiple-organ
involvement. There is a fatigue item included in the general health status module. This module
correlates strongly with the FAS (r2=0.74). Concurrent validity was demonstrated by assessing the
relationship with the SGRQ and SF-36 (r= −0.66 to −0.83 for the SGRQ). Internal consistency
was high (Cronbach’s α=0.93 for general health status). The KSQ has been validated and
translated across cultures. As of 2021, it is available in 28 different languages [67]. Adapting
PROs for cross-cultural use may be a challenging task in terms of ensuring accurate translation of
questions [68]. The KSQ performed well and had good construct validity and internal consistency
(Cronbach’s α=0.72–0.93) in a Dutch population. All modules of the KSQ showed this range of
consistency [69]. Bland–Altman plots showed good repeatability, and interclass coefficients were
0.70–0.90. The translated KSQ was simple and brief, taking only a few minutes to complete.
A recent study evaluated the KSQ MCID in sarcoidosis HRQoL, which has emphasised its
importance in sarcoidosis research and supports its use as a clinically meaningful outcome
measure in clinical trials [47]. The MCID for KSQ General Health is 8 and for KSQ Lung is 4.
The study used both anchor and distribution methods to calculate the MCID. The “anchors”
were the previously established MCIDs of SGRQ, SF-36 and FAS. A 0.5 SD of baseline KSQ
scores was used for the distribution-based method.
The KSQ has shown potential for use in patient registries. A group of leading researchers in
sarcoidosis have developed the Registry for Advanced Sarcoidosis Associated Pulmonary
Hypertension (ReSAPH). The registry has almost 500 patients from a number of international
centres. Its goal is to help clinicians gain a better understanding of this condition and to study
the effects of therapy. The KSQ Lung module has been utilised as an effective tool in clinical
trials. It was used to demonstrate improvements in HRQoL associated with roflumilast in
patients with fibrotic sarcoidosis [70]. The KSQ General Health module has also been utilised
in clinical trials: in a trial of respiratory corticotropin in chronic sarcoidosis, there was an
improvement in general health status and fatigue scores [71].
Currently, the KSQ is being used in the development of an online sarcoidosis assessment
platform (ClinicalTrials.gov identifier NCT04342403). The aim of this platform is to assess
phenotypes in sarcoidosis and to monitor disease burden longitudinally. These advances further
underline the growing importance of HRQoL assessment in sarcoidosis.
Limitations of HRQoL assessment tools

Quality-of-life assessment is challenging both methodically and conceptually [72]. Factors such
as recall bias, some lengthy and time-consuming questionnaires, irrelevant questions for certain
patients, incomplete questionnaires and poor guidance on how to complete the tool are all
potential problems that need to be overcome. There is a need for simple tools for everyday
clinical practice; the assessment of symptoms with visual analogue scales or numerical rating
scales should be explored further.
346 https://doi.org/10.1183/2312508X.10033720
Conclusion
HRQoL assessment is an important aspect of care in patients with sarcoidosis. Improvement in
HRQoL has been reported as the most important outcome of therapy for the patient. Significant
advances have been made in this area in the last two decades. Sarcoidosis-specific assessment
tools have been designed and validated, and their MCID established. Clinicians are now in a
position where these assessment tools can be used reliably as major outcome measures in
sarcoidosis clinical trials and can play a more important role in the management of sarcoidosis
in clinic practice.
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(ERS Monograph) Fransesco Bonella, Daniel Culver, Dominique Israel - Biet - Sarcoidosis ERS Monograph-European Respiratory Society (2022)

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ERS monograph

Recent reports indicate that the prevalence of sarcoidosis is rising

This book is one in a series of ERS Monographs. Each individual issue

ERS Monographs are available online at books.ersjournals.com and print

Managing Editor: Rachel Gozzard

Published by European Respiratory Society ©2022

Guest Editors vii

1. Definition and history 1

2. Epidemiology: solving the jigsaw puzzle 8

3. Aetiopathogenesis, molecular determinants and immunological features 25

4. Unravelling the genetic basis of sarcoidosis 41

6. Conventional and nuclear imaging techniques 75

7. Pathological features and differential diagnosis 91

8. Serum and imaging biomarkers 107

9. Pulmonary sarcoidosis 122

10. Cardiac sarcoidosis 142

11. Granulomatous and nongranulomatous neurological sarcoidosis 160

13. The calcium–kidney–bone axis 193

14. Non-organ-specific manifestations 206

15. Hepatic and splenic involvement 223

16. Sarcoidosis-associated pulmonary hypertension 234

17. Rheumatological manifestations 256

18. Ocular sarcoidosis 267

19. Paediatric sarcoidosis 285

20. The manifestations of rare organ sarcoidosis 295

21. When to treat sarcoidosis 316

22. Treating sarcoidosis and potential new drugs 328

23. Quality-of-life assessment 337

It’s a pleasure to introduce this latest edition of the ERS

Francesco Bonella is Associate Professor of Medicine and Head of

His research interests include sarcoidosis, IPF, autoimmune ILD,

Francesco founded EuPAPNet, the European Network for

Francesco is the recipient of several honours and awards, including

Daniel A. Culver is the Chair of the Department of Pulmonary

Dominique Israël-Biet is Professor Emeritus of pulmonary

Dominique graduated from the Faculté de Médecine Cochin-Port

She was trained in pulmonary medicine under the guidance of

Dominique’s research interests mainly focus on sarcoidosis and

Dominique was a member of the ERS Task Force on

She is actively involved in WASOG. As an elected member of its

Dominique is on the Editorial Board of Respiratory Medicine and

Sarcoidosis is a systemic, multi-pathway disease and a clinical chameleon. Recent reports

Definition and history

Sarcoidosis is a multisystem disorder of unknown cause(s). It commonly affects young

The diagnosis is established when clinico-radiological findings are supported by

Frequently observed immunological features are depression of cutaneous delayed-type

Corticosteroids relieve symptoms, suppress the formation of granulomas and normalize

In the American Thoracic Society (ATS)/European Respiratory Society (ERS)/WASOG

Historical development of sarcoidosis

Immunology of sarcoidosis: change of dogmas

TABLE 1 Milestones in the history of sarcoidosis

TABLE 2 Milestones in the immunology of sarcoidosis

The search for potential aetiological agents

With the application of modern molecular techniques, Mycobacterium tuberculosis and

Changing diagnostic tools in sarcoidosis

The sarcoidosis movement around the world: change in research topics

TABLE 3 The changing tools for diagnosing sarcoidosis

TABLE 4 International conferences on sarcoidosis#

Year City Organiser(s)

1958 London D. Geraint James

Disclosures: U. Costabel has nothing to disclose. S. Nagai has nothing to disclose.

Epidemiology: solving the jigsaw puzzle

TABLE 1 Epidemiological challenges associated with sarcoidosis