[ Diffuse Lung Disease CHEST Reviews ]

Diagnosis and Management of

Myositis-Associated Lung Disease
Robert W. Hallowell, MD; and Sonye K. Danoff, MD, PhD

Although interstitial lung disease (ILD) is a leading cause of morbidity and mortality in patients
with inflammatory myopathies, the current definition and diagnostic criteria of autoimmune
myositis remain inadequate to capture the large proportion of patients with lung-dominant
disease. As a result, these patients present unique diagnostic and treatment challenges for
even the most experienced clinicians. This article highlights the emerging role of autoantibodies
in the diagnosis, classification, and management of patients with ILD. We propose alternative
nomenclature to facilitate research on this unique patient population. Additionally, evidence
supporting the various therapies used in the treatment of myositis-associated ILD is reviewed.
The classification and treatment of patients with myositis-associated ILD remains challenging.
A standardized therapeutic approach to these patients is lacking, and prospective studies in the
field are needed to determine optimal treatment regimens. CHEST 2023; 163(6):1476-1491

KEY WORDS: antisynthetase syndrome; idiopathic pneumonia with autoimmune features;

interstitial lung disease; myopathy

Interstitial lung disease (ILD) is a common significant, occurring in up to one-third of

complication of the inflammatory
myopathies, with a reported prevalence
reaching 42.6%, depending on the series and
the definition used,1-7 although this number
can double in the presence of certain
antisynthetase antibodies.8,9 While it can
occur at any point in the course of disease,
ILD frequently precedes manifestations of
myositis,3,4,10-12 with a presentation that
ranges from subclinical to fulminant.5,13,14
Although many patients respond favorably
to immunosuppressive therapy, the risk of
relapse and long-term progression remains
all patients.15 Moreover, ILD is the primary
cause of death and hospitalization in
patients with inflammatory myositis.5,16
Despite the impact of ILD on patients with
myositis, Bohan and Peter17,18 did not
consider ILD a defining clinical feature in
their proposed classification criteria for
polymyositis and dermatomyositis in 1975.
Even after multiple subsequent updates, ILD
remains excluded from the first validated
classification criteria approved by the
American College of Rheumatology (ACR)/
European Alliance of Associations for

ABBREVIATIONS: ACR = American College of Rheumatology; anti-
MDA-5 = anti-RNA helicase encoded by melanoma differentiation-
associated gene 5 antibody; ARS-Ab = antisynthetase antibody;
CADM = clinically amyopathic dermatomyositis; DLCO = diffusing
capacity of the lungs for carbon monoxide; EULAR = European Alli-
ance of Associations for Rheumatology; IIM = idiopathic inflammatory
myositis; ILD = interstitial lung disease; IPAF = idiopathic pneumonia
with autoimmune features; IVIG = IV immunoglobulin; MAA =
myositis-associated antibody; MSA = myositis-specific antibody; PFT =
pulmonary function test; TPE = therapeutic plasma exchange
AFFILIATIONS: From the Division of Pulmonary and Critical Care
Medicine (R. W. H.), Massachusetts General Hospital and Harvard
Medical School, Boston, MA; and the Division of Pulmonary Critical
Care Medicine (S. K. D.), Johns Hopkins University School of Medi-
cine, Baltimore, MD.
CORRESPONDENCE TO: Sonye K. Danoff, MD, PhD; email: sdanoff@
jhmi.edu
Copyright Ó 2023 The Author(s). Published by Elsevier Inc under li-
cense from the American College of Chest Physicians. This is an open
access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
DOI: https://doi.org/10.1016/j.chest.2023.01.031

1476 CHEST Reviews [ 163#6 CHEST JUNE 2023 ]

Rheumatology (EULAR) in 2017.19 The purpose of this an expanded MSA panel. In their study, one of the four
review is to discuss the diagnostic and treatment distinct patient clusters to emerge was characterized by
challenges surrounding ILD in patients with idiopathic patients who showed positive results for an antisynthetase
inflammatory myopathies and myositis-associated and antibody and the presence of ILD, although lung
myositis-specific autoantibodies. involvement also was found in > 50% of patients in two of
the three additional clusters. Their data provide growing
Deciphering Autoantibodies in Patients With evidence for the importance of both MSAs and ILD in the
classification of patients with IIM.
Myositis-Associated ILD
The role of autoantibodies in the diagnosis of myositis and
their implication for patients with concurrent ILD has The Antisynthetase Antibodies
evolved over several decades. The prevalence of
By far, the MSAs with the greatest pulmonary
recognized autoantibodies in patients with idiopathic
implications include the antisynthetase antibodies
inflammatory myositis (IIM) exceeds 50%, and these
(Table 1) and those directed against an RNA helicase
autoantibodies classically are categorized as being either
encoded by melanoma differentiation-associated gene 5
myositis-specific antibodies (MSAs) or myositis-
(anti-MDA-5). Based on a large meta-analysis that
associated antibodies (MAAs).20-23 Myositis-associated
included 27 studies and 3,487 patients, the prevalence of
ILD is highly associated with the presence of an MSA. One
antisynthetase antibodies (ARS-Abs) in patients with
study involving 257 consecutive patients with IIM
dermatomyositis or polymyositis is 20% and 29%,
demonstrated the presence of an MSA in 93% of the
respectively, making them the most common
patients with ILD.7 In 1997, Targoff et al24 proposed the
autoantibodies in patients with IIM.21 ARS-Abs are
inclusion of various MSAs into the classification criteria
associated with an increased risk of ILD developing; the
for IIM. However, it was not until the 2017 EULAR/ACR
prevalence of a parenchymal lung abnormality can range
statement that any MSA was included in an official
from 56% to 100%, depending on the specific
validation classification for IIM, although only anti-Jo-1
autoantibody in question and the method for
was listed in that criteria.19 Subsequently, Mariampillai
determining the presence of lung disease.21,26-30
et al,25 using unsupervised correspondence and
hierarchical clustering analysis, demonstrated the Between 1990 and 1991, Marguerie et al48 and Love
usefulness of classifying IIM based on clinical features and et al22 used a respective series of patients to describe

TABLE 1 ] Antisynthetase Antibodies

Patients With Patients With
Lung Muscle
ARS-Abs Involvement,a Involvement,a
Detected, %11,12,26-28, %11,12,26-28, Distinct Clinical
Antibody Target Antigen %23,26,27,31,32 33–37,31,38–45 33–37,31,38–45
Features21,26,27,36,37,31,46,47
Anti-Jo-1 Histidyl-tRNA synthetase 22-73 69 84 Arthralgias, mechanics
hands, myositis
Anti-PL-12 Alanyl-tRNA synthetase 6-17 91 33 Raynaud’s, isolated ILD
Anti-PL-7 Threonyl-tRNA 10-18 75 66 Heliotrope rash, severe
synthetase ILD, myositis, pericardial
effusions
Anti-EJ Glycyl-tRNA synthetase 2-23 98 56
Anti-OJ Isoleucyl-tRNA 2-5 100 44 Severe myopathy, lower
synthetase incidence of Raynaud’s
Anti-KSb Asparaginyl-tRNA 3-8 100% 5% Isolated ILD
synthetase
Anti-ZOb Phenylalanyl-tRNA Rare . . .
synthetase
Anti-HA/YRSb Tyrosyl-tRNA synthetase Rare . . .

ARS-Ab ¼ antisynthetase antibody; ILD ¼ interstitial lung disease.

a
Values shown are the average of studies listed.
b
These antibodies are not commercially available.

chestjournal.org 1477
what would come to be known as the antisynthetase
syndrome, characterized predominantly by some
combination of ILD, myositis, arthritis, Raynaud’s
phenomenon, fevers, and mechanic’s hands in the
presence of ARS-Abs. However, the clinical validity of
an antisynthetase syndrome recently was challenged,
largely because patients with an ARS-Ab are not
clinically homogenous, and it is common to see ILD in
the absence of the other classic clinical features,
particularly at the onset of disease.26,27,31,33–37,49
Furthermore, these clinical features may occur with a
similar frequency in patients positive for an MAA, but
lacking an ARS-Ab.9
A growing number of case series have attempted to
distinguish the ARS-Abs phenotypically, suggesting
their association with distinct clinical features, including
the rate of myositis, rapidly progressive ILD (RP-ILD),
or mortality.8,21,26,31 In many cases, characteristic
systemic features may take months or years to develop,
resulting in clinical profiles that differ greatly between
study onset and end of follow-up.50–52 Given the
dynamic clinical course of these patients, studies relying
on limited periods or disease characteristics described
only at initial presentation to characterize the clinical
phenotype of these antibodies may be of limited value
when it comes to truly defining a link between specific
ARS-Abs and clinical phenotypes.51
Anti-MDA-5
Anti-MDA-5 is an MSA associated with a phenotype
frequently resembling that of the ARS-Abs and the
antisynthetase syndrome.53–55 However, palmar papules,
deep ulcerations with punched-out borders, and areas of
frank skin necrosis are considered highly specific for the
presence of this antibody.54–56 The prevalence of anti-
MDA-5 antibodies ranges from 6.9% to 40.6% in
patients with dermatomyositis and is more common in
both Asian cohorts and patients with clinically
amyopathic dermatomyositis (CADM) compared with
those with classic dermatomyositis.53,54,56–61 Anti-
MDA-5 is associated with worse ILD scores,55 the
development of acute or rapidly progressive
ILD,53,55,57,59,60 and death.53,60–62 Furthermore, evidence
that anti-MDA-5 titers may correlate with the severity of
skin ulcerations55 and ILD55,63–65 is growing. However,
the clinical significance of anti-MDA-5 may differ based
on patient ethnicity, with severe disease more frequently
reported in Asian studies compared with North
American studies.66
1478 CHEST Reviews
Additional MSAs and MAAs
Anti-polymyositis-Scl and anti-Ku are two MAAs
usually found in patients with overlap myositis and
concurrent features of systemic sclerosis or systemic
lupus erythematosus.67,68 Both are associated with
characteristic clinical findings frequently seen in patients
with ARS antibodies, including arthralgias, fevers, and
Raynaud’s phenomenon.9 The rate of ILD in patients
with polymyositis-Scl antibodies is reported to range
from 38% to 78%9,69–71; the rate in patients with anti-Ku
antibodies may be as high as 27% based on one large
meta-analysis.9
The anti-SS-A 52-kD IgG antibody is an MAA
frequently found in patients with IIM, with an estimated
prevalence exceeding 20%, and higher rates in patients
demonstrating ILD.72–75 Co-occurrence of SS-A 52-kD
IgG antibody with antisynthetase antibodies and MDA-
5 is not uncommon,8,26,76 and its presence has been
linked to more aggressive pulmonary and
extrapulmonary disease.8,77,78 One study assessing a
cohort of 83 patients with positive results for anti-MDA-
5 with CADM found that the rate of both rapidly
progressive ILD (54.8% vs 23.8%) and the classic
cutaneous ulcerations typically considered
pathognomonic for the presence of anti-MDA-5
antibodies (27.4% vs 4.8%) were significantly higher in
patients with concurrently positive results for anti-SS-A
52-kD IgG antibodies.76
Anti-signal recognition particle (SRP), anti-Mi-2, anti-
NXP-2, and anti-TIF1g (formerly anti-p155/140)
antibodies have not been associated with an increased
risk of ILD developing,62,79–85 although they can occur
concurrently in patients with myositis-associated ILD
and antisynthetase antibodies, with clinical implications.
Patients with anti-SRP antibodies are at an increased
risk of severe myositis developing with markedly
elevated muscle enzymes.86 Anti-Mi-2 antibodies tend to
be associated with a lower incidence of ILD and
malignancy and more favorable outcomes compared
with other patients with dermatomyositis.87 Anti-TIF1g
and NXP-2 both are highly associated with the presence
of malignancy that perhaps exceeds the already elevated
risk seen in patients with IIM and the presence of an
ARS antibody.26,79,88 One study including > 200
patients with dermatomyositis reported that 83% of the
patients found to have a malignancy showed positive
results for anti-TIF1g or NXP-2; the presence of either
antibody was associated with an OR of 3.78 for the
presence of malignancy.89
[ 163#6 CHEST JUNE 2023 ]
Challenges With the Current Nomenclature
More recently, the commercialization of comprehensive
myositis panels and growing awareness of the role that
autoantibodies play in the diagnosis of ILD increasingly
has resulted in patients whose blood work performed as
part of an initial evaluation of ILD demonstrates
positivity for one or more MSAs or MAAs, often with
minimal or no appreciable muscle involvement. As an
example, Fidler et al90 retrospectively studied 165
patients with idiopathic ILD and no confirmed or
suspected connective tissue disease; they found an MAA
or MSA in 26.7% of patients. The antisynthetase
antibodies frequently are associated with pulmonary-
dominant disease or ILD that precedes the development
of clinically apparent myositis by months to
years.26,31,51,55,60 Aggarwal et al27 demonstrated that
among patients with non-Jo-1 antisynthetase antibodies,
40% never demonstrated any evidence of muscle
involvement. In another study by Misra et al91 that
included 40 patients who showed positive results for an
MSA, the rates of ILD or muscle or skin disease were
86%, 39%, and 28%, respectively. In their study, ILD was
the most dominant clinical feature in patients with
positive results for an MSA. Moreover, half of the
patients with positive results MSAs had a diagnosis of
isolated ILD and did not fulfill ACR/EULAR criteria for
an IIM.91
Despite being labeled as myositis specific, the MSAs
frequently exist in the absence of overt muscle
involvement, thus making the nomenclature and their
role in diagnosing a myositis-associated ILD confusing
for many providers. Indeed, one of the most severe and
rapidly progressive forms of ILD associated with anti-
MDA-5 (an MSA) often is in patients with amyopathic
disease.6,76 Even when patients with ILD demonstrate
some degree of extrapulmonary symptoms suggestive of
an underlying autoimmune process, they may not meet
ACR criteria for a defined connective tissue disease
(CTD). Historically, the disease of these patients has
received various labels: lung-dominant CTD,92
undifferentiated CTD-associated ILD,93 autoimmune-
featured ILD,94 or idiopathic pneumonia with
autoimmune features (IPAF).95
Although the term IPAF was intended as a research
designation, it has gained traction in clinical
terminology. This designation remains problematic
clinically, because it potentially obscures the
characteristic features of patients with MSA-associated
ILD by combining them with other patients having
chestjournal.org
unrelated antibodies into one heterogeneous group. It
seems likely that not all patients with IPAF are created
equal, and the MSAs may be associated with different
outcomes than less specific antibodies (eg, rheumatoid
factor, antinuclear antibodies) currently included in the
IPAF classification criteria. As an example, Takato et al96
demonstrated no significant difference in the CT scan
patterns, baseline pulmonary function test (PFT) results,
or treatment response in a group of 36 patients with ILD
and positive results for anti-ARS either with or without
features of inflammatory myositis. Additionally, one
recent retrospective study demonstrated that patients
with IPAF harboring MSAs showed better survival
compared with patients with IPAF and negative results
for MSAs and outcomes similar to patients with overt
myositis-associated ILD.97
Depending on the practice setting, patients with isolated
lung disease, subtle myositis, or late-onset
extrapulmonary symptoms may be more likely to
experience a delay in diagnosis with resultant delayed or
inadequate therapy and higher mortality rates.27,91
Nomenclature that accurately captures the relationship
between MSA positivity and the clinical presentation of
many patients with ILD currently is inadequate. The
classification system for IIM fails to recognize lung
disease as a cardinal feature of these disorders. The
catchall term IPAF serves as a miscellaneous category
with the potential to obscure the characteristic features
of patients with emerging myositis-associated ILD by
combining them into a heterogeneous group carrying
less risk of ILD progression or flare than some of the
patients with MSAs. The potential consequences include
delays in diagnosis or crucial lifesaving therapy and the
prevention of more targeted studies on patients with
myositis-associated ILD and MSA-associated ILD as
distinct clinical entities.
To emphasize the most salient clinical feature of these
patients—their pulmonary involvement—and the fact
that they are unified collectively by some combination of
serologic, muscle, or skin findings suggesting the
presence of an underlying inflammatory myopathy, we
propose the term pneumomyositis. Such nomenclature
does not exclude patients with concurrent overt muscle
involvement, nor does it exclude patients with MSAs in
the absence of clinical or subclinical myositis. Rather, it
highlights the unifying organ system associated with the
greatest morbidity and mortality, while preserving the
myositis phraseology that has become associated with
commercial serologic panels and the spectrum of clinical
1479
features. Furthermore, more precise nomenclature will
facilitate focused research into this rare and potentially
heterogeneous group of patients. As an example, some
interest has been expressed in categorizing the ARS-Abs,
which frequently have lung-dominant features, as a
distinct group in patients with myositis. However, this
approach ignores the fact that the lung can be the
predominant site of clinical presentation with other
MSA and MAA, notably MDA-5. Conversely, some
patients with myositis-associated ILD lack recognized
autoantibodies and patients with severe myositis lack
any form of lung involvement. By having a more
pulmonary-centric nomenclature, research and clinical
trials focused on the lung powered to stratify patients
based on phenotypic profiles we hope will become more
feasible.
Clinical Presentation
The presentation of ILD in patients with IIM can range
from asymptomatic, incidentally discovered lung
abnormalities to rapidly progressive respiratory failure
mimicking ARDS (Fig 1). In cases of the latter, patients
often demonstrate a progressive cough or dyspnea that
initially is misdiagnosed as a viral infection or
pneumonia. By the time they seek treatment from a
primary care physician or an urgent care facility a few
weeks later, they frequently show a significant oxygen
requirement necessitating hospital admission. Given the
high prevalence of ILD in patients with IIM, we
recommend conducting full PFTs when IIM is
diagnosed and annually, even in the absence of overt
respiratory symptoms. PFTs are known to have a
suboptimal sensitivity for detecting the presence of ILD
in patients with an underlying CTD,98 and any change
in respiratory symptoms or appreciable decline in FVC
or diffusing capacity of the lungs for carbon monoxide
(DLCO; 5% or 10%, respectively)99 should prompt the
acquisition of chest CT scan imaging. Dyspnea in
patients with severe myositis rarely may be caused by
respiratory muscle weakness, and interpretation of
spirometric values must be taken in the context of the
muscle disease of such patients. On occasion, maximal
inspiratory pressures or maximal expiratory pressures
may provide insight into underlying diaphragm
weakness.
Pulmonary hypertension is a recognized complication in
patients with myositis and ARS-Abs and is associated
with increased mortality.100,101 Echocardiography
should be considered as a screening tool in the following
situations: a change in respiratory symptoms not readily
1480 CHEST Reviews
explained by progressive interstitial changes on CT scan
imaging, dyspnea out of proportion to the degree of ILD,
pulmonary artery enlargement on CT scan imaging, a
decline in DLCO out of proportion to the decline in FVC,
an initial DLCO of > 40% predicted, or any physical
examination findings suggestive of pulmonary
hypertension (eg, peripheral edema, jugular venous
distension, or loud second heart sound).102,103
Radiologic Findings
The parenchymal abnormalities in patients with IIM tend
to have predominantly subpleural and basilar distribution,
although patchy or diffuse disease can be seen.5,11,35
Although patterns consistent with cellular nonspecific
interstitial pneumonia, organizing pneumonia, or a
combination of the two are seen most frequently, other
patterns such as usual interstitial pneumonia (UIP) can be
present.12,13,35,104 Patients with a more chronic course of
disease often have reticulations, traction bronchiectasis, or
honeycombing; superimposed ground-glass changes or
frank consolidations may be seen in acute presentations or
exacerbations of pre-existing disease.5,11,105,106 Although
the prognostic implications of the presence of consolidative
changes remain unclear, the presence of ground-glass
opacities seems to portend a worse prognosis.105,106
Pneumomediastinum is a rare complication of patients
with myositis-associated ILD, with an incidence ranging
from 2.2% to 8.6% and most cases occurring in patients
with dermatomyositis or CADM.6,107–109 In one study of
70 patients with dermatomyositis or polymyositis-
associated ILD, pneumomediastinum occurred
spontaneously in four patients and was associated with
mechanical ventilation in two patients; all six patients
died.6 Additional series have demonstrated a mortality
rate ranging from 25% to 75% in the presence of this
complication,107–109 suggesting that it may be associated
with poor outcomes.
Histopathologic Features
Surgical biopsies are performed rarely in patients with
known IIM or underlying antisynthetase antibodies,
largely because of concerns that the procedure itself may
incite a disease flare15,16 and in light of the fact that the
predetermined need for immunosuppression obviates
the need for a tissue diagnosis. That being said, when a
lung biopsy sample is obtained in these patients, it is not
uncommon for the histopathologic results to be
discordant with the CT scan interpretation.17-19,35,85
[ 163#6 CHEST JUNE 2023 ]
 A B C

Figure 1 – Case vignettes. A, CT scan from a 48-y-old woman referred to the rheumatology clinic for 4 mo of severe fatigue, proximal muscle weakness, and
shortness of breath. She reported arthralgias in her hands and knees and had experienced Raynaud’s phenomenon and peeling of the skin on her hands for the
previous 9 mo, despite the arrival of warmer weather. Examination findings were notable for fine bibasilar crackles, Raynaud’s phenomenon, and mechanic’s
hands. The serologic panel revealed positive anti-Jo1 antibody, anti-Sjogren’s Syndrome A antibody, a creatine kinase (CK) of 3,400, and an aldolase of 17. CT
scan findings were consistent with a fibrotic nonspecific interstitial pneumonia, or NSIP, pattern. She was treated with a prednisone taper starting at 0.75 mg/kg/
d and mycophenolate 3,000 mg/d. Six mo after the initiation of therapy, muscle enzyme levels had normalized, the mechanic’s hands had almost completely
resolved, and repeat CT imaging revealed a slight reduction in reticulations and ground-glass opacities. Pulmonary function test results have remained stable for
the past year with minimal changes on imaging. Given that she describes her breathing as “acceptable,” the immunosuppression was not augmented, despite
persistence of CT scan abnormalities. B, CT scan from a 60-y-old woman referred to our center for a second opinion regarding progressive interstitial lung
disease (ILD) and significant dyspnea refractory to 6 mo of prednisone at a dose of 40 mg/d. She did not have any symptoms consistent with an underlying
connective tissue disease. The following antibodies were negative on initial testing: antinuclear antibody, anti-Smith, anti-ribonucleoprotein, anti-Scl-70, anti-
Sjogren’s Syndrome A/B, rheumatoid factor, anti-cyclic citrullinated peptide, and antineutrophil cytoplasmic antibodies. Surgical lung biopsy findings were
most consistent with a mixed cellular and fibrotic NSIP pattern. Physical examination findings at the time were notable only for fine bibasilar crackles. She had
no rashes, joint effusions, or skin changes. Additional testing revealed the presence of an anti-PL-12 antibody in a high titer; CK and aldolase levels were within
normal limits. Mycophenolate 3,000 mg/d was initiated with significant improvement in respiratory symptoms and imaging findings. Over the course of several
months, as prednisone was weaned to a dose of 5 mg/d, arthralgias, muscle weakness, an erythematous rash on her face and hands, and a CK elevation to 2,000
developed. Monthly IV immunoglobulin was initiated, and the skin and muscle manifestations resolved. Breathing and repeat CT imaging findings remained at
the improved baseline. C, CT scan from a 50-y-old woman who was in her usual state of health until 2 mo before presentation, when she experienced low-grade
fevers, a dry cough, and progressive dyspnea with moderate exertion. COVID-19 polymerase chain reaction testing showed negative results, but chest radi-
ography performed at an urgent care center revealed bibasilar infiltrates, and she was treated with a course of amoxicillin/clavulanate. The symptoms failed to
improve, and she received a second course of antibiotics (levofloxacin) via a telehealth visit 2 wk later. However, the dyspnea progressed, and she sought
treatment at the ED, where oxygen saturation was 79% on room air at rest. On further questioning, she reported a new erythematous rash developing on the
extensor surface of her arms and hands roughly 7 wk previously. CT scan imaging revealed extensive dense, bilateral consolidations. Subsequent serologic testing
eventually showed positive results for anti-MDA-5 and anti-Ro-52 antibodies. She demonstrated no weakness on examination, and levels of CK and aldolase
were within normal limits, thus confirming a diagnosis of rapidly progressive ILD in the setting of clinically amyopathic dermatomyositis clinically amyopathic
dermatomyositis. She required intubation and was treated with a methylprednisolone pulse followed by high- dose steroids, IV immunoglobulin, and
tacrolimus. Her course was complicated by methicillin-resistant Staphylococcus aureus pneumonia, sepsis, and renal failure requiring continuous venovenous
hemodialysis. Her family ultimately withdrew care and she died on hospital day 17.

Nonspecific interstitial pneumonia is the most common Management of Myositis-Associated ILD

pathologic pattern in patients with myositis-associated
ILD,10,110 with a prevalence of 41% in one review that
included 310 patients with a known antisynthetase
antibody. UIP, organizing pneumonia, and diffuse
alveolar damage were seen in 24%, 19%, and 14.5% of
patients, respectively. DIP, respiratory bronchiolitis, and
lymphocytic interstitial pneumonia each were reported
in < 6% of patients. Furthermore, evidence suggested
that the frequency of each pattern may be influenced by
the underlying antisynthetase antibody.111
Some evidence suggests that the underlying
histopathologic features may relate to disease outcomes
in patients with myositis-associated ILD and known
antisynthetase antibodies.19,20,112 Based on the data by
Flashner et al,111 future investigations attempting to link
outcomes to the presence of a specific MSA should
account for the fact that these antibodies may be
associated with histopathologic trends.
Immunosuppression
Strategies for therapy based on the acuity of presentation
are discussed after reviewing the range of therapies
currently available (Table 2). Immunosuppression is the
mainstay of therapy, and evidence suggests that patients
with polymyositis have a better response rate than those
with dermatomyositis.10,113,114 A strategy for treatment
based on disease severity is shown in Figure 2, and a
detailed discussion of the agents is provided below. To
date, no prospective trials have compared the efficacy of
the various immunosuppressant agents for the treatment
of ILD, and the limited data available suggest that the most
commonly used agents likely are interchangeable.113,115,116
Corticosteroids
Because of their rapid onset of action, low cost, easy
accessibility, and provider familiarity, corticosteroids

chestjournal.org 1481
1482 CHEST Reviews

TABLE 2 ] Primary Therapy for the Treatment of Myositis-Associated ILD

Medication Typical Dosage Monitoring Adverse Effects
Corticosteroids 0.5-1.0 mg/kg/d prednisone Annual bone density, glucose monitoring Osteoporosis, glaucoma, hyperglycemia, insomnia,
equivalent; methylprednisolone weight gain, bruising, mood changes, myopathy,
pulse 500-1,000 mg/d for 3 d risk for PJP
Azathioprine 2-2.5 mg/kg/d TPMT activity before initiation; CBC count and CMP every Transaminitis, leukopenia, GI intolerance,
2 wk during dose titration and every 8 wk thereafter; increased risk of malignancy
yearly skin examination by a dermatologist
Mycophenolate 2,000-3,000 mg/d in two doses CBC count and CMP every 2 wk during dose titration and Transaminitis, leukopenia, GI intolerance,
mofetil every 8 wk thereafter; yearly skin examination by a increased risk of malignancy, difficulty
dermatologist concentrating
Tacrolimus Typical starting dose is 0.5-1.0 mg CBC count, CMP, TAC trough every week for the first Renal toxicity, hypertension, hyperlipidemia,
bid; titrate to a trough of month and every 4 wk thereafter; lipid panel and yearly tremors, hyperglycemia, increased risk of
5-10 ng/mL skin examination by a dermatologist malignancy
Methotrexate 15-25 mg po weekly; concurrent CBC count and CMP every 2 wk during dose titration and Transaminitis, leukopenia, GI intolerance, hair
use of folic acid 1 mg/d to reduce every 8 wk thereafter thinning, tooth decay
the risk of myelosuppression
Cyclophosphamide 2 mg/kg po daily; 600 mg/m2 IV CBC count and CMP every 2 wk, UA monthly, urine Myelosuppression, malignancy, hemorrhagic
monthly cytologic analysis yearly for life cystitis, infertility
Rituximab 1,000 mg day 0 and day 14; repeat Hepatitis serologic examination before screening; Hepatitis reactivation, increased risk of severe
about every 6 mo immunoglobulin levels before redosing SARS-CoV-2 infection, infusion reactions,
progressive multifocal leukoencephalopathy
(rare)
[
163#6 CHEST JUNE 2023

IVIG 2 g/kg/mo divided over 3-5 d Screen for IgA deficiency before initiation VTE, volume overload, headaches (aseptic
meningitis), antibody-mediated cytopenias,
anaphylaxis, infusion reactions

ILD ¼ interstitial lung disease; IVIG ¼ IV immunoglobulin; PJP ¼ Pneumocystis jirovecii pneumonia; CMP ¼ comprehensive metabolic panel; TAC ¼ tacrolimus; TPMT ¼ Thiopurine S-methyltransferase; UA ¼
urinalysis.
]
 Assess disease severity at initial
presentation
• PFTs
• Extent of CT involvement
• Hypoxemia

Moderate disease Acute exacerbation/Severe disease

Mild disease • Abnormal PFTs • Hospitalization
• Preserved PFTs • Evidence of disease progression • Hypoxemia
• Minimal symptoms • > 10% involvement on CT
• d 10% involvement on CT
• No oxygen requirement
• Solumedrol lg x 3 d; then prednisone taper
• Prednisone taper starting at 1 mg/kg (max 60 mg) daily
Observe starting at 1 mg/kg
• Initiate concurrent MMF or AZA
PFTs q3-4 mo • IVIG 400 mg/kg x 5 d

• If immunosuppression-naive, start concurrent

Persistent MMF, AZA, or TAC
Clinically Disease Disease Acute
inflammatory • If already receiving MMF/AZA prior to
stable progression progression exacerbation
disease/ disease flare, consider adding TAC/RTX
Marginal response
after 4-6 mo

Failure to improve after 7 d; progression

towards respiratory failure
• Consider transition • Add TAC or RTX
to TAC/RTX • Consider adding IVIG
• Consider adding IVIG
• Ensure receiving either TAC/RTX
• Consider PLEX for respiratory failure

Figure 2 – Diagram showing treatment approach to myositis-associated interstitial lung disease (ILD). The decision to use chronic immunosuppression
in patients with myositis-associated ILD and the agent of choice is influenced by the severity of disease at diagnosis, disease trajectory, response to initial
therapy, patient comorbidities, and provider familiarity with the treatment methods available at a given institution. AZA ¼ azathioprine; IVIG ¼ IV
immunoglobulin; MMF ¼ mycophenolate; PFT ¼ pulmonary function test; PLEX ¼ plasma exchange; RTX ¼ rituximab; TAC ¼ tacrolimus.

represent the most common initial therapy worldwide. Calcineurin Inhibitors

Typical starting doses range from 0.75 to 1.0 mg/kg,
with reported response rates for monotherapy ranging
from 37.5% to 52% (lower in patients with
dermatomyositis vs polymyositis).114,117 Given that
prolonged therapy often is anticipated in these patients,
and to minimize side effects, steroid-sparing agents as
discussed below typically are added either concurrently
or soon after steroid initiation.
Azathioprine and Mycophenolate
Small, retrospective studies generally have suggested that
these antimetabolites can stabilize lung function with an
effective steroid-sparing ability and clinical response rate
on the order of approximately 50% for patients treated
with either azathioprine or mycophenolate,12,113,118–121
although the studies were not designed for a head-to-
head comparison. In a retrospective analysis of 110
patients with myositis-associated ILD treated with either
azathioprine or mycophenolate, a significant steroid-
sparing effect and improvement in FVC % predicted was
seen in both groups. DLCO % predicted was improved
only in the azathioprine group, although this agent
also was associated with a higher rate of drug
discontinuation and adverse events, particularly LFT
abnormalities.122
Most of the evidence supporting the use of calcineurin
inhibitors comes from Asia, where cyclosporin A and
tacrolimus have been used with greater frequency than
in Europe or the United States. Retrospective data
suggest that cyclosporin A and tacrolimus are effective
steroid-sparing agents for the treatment of myositis-
associated ILD,123,124 and it has been suggested that
outcomes are improved when patients receive therapy
with a calcineurin inhibitor earlier in the course of the
disease.125 Furthermore, reports exist of tacrolimus
being effective in patients with disease progression
despite various steroid-sparing agents.126–129 In a
retrospective analysis by Sharma et al,113 23 patients
with myositis-associated ILD who did not show a
response to prednisone and either methotrexate,
mycophenolate, or azathioprine subsequently were
treated with adjunct tacrolimus. ILD improved in 94% of
the patients, 81% reported a decrease in prednisone dose
by 12 months, and several patients were weaned off the
original steroid-sparing agent. Although it is possible
that a similar response might have been realized with the
addition of any type of concurrent immunosuppression,
the calcineurin inhibitors are being used with increasing
frequency worldwide, particularly for more severe or
refractory disease.

chestjournal.org 1483
Methotrexate
Although historically considered a potentially
pneumotoxic drug, more recent evidence suggests that
methotrexate does not increase the incidence of ILD or
mortality when used to treat connective tissue
disease.130–132 A study that included 52 patients with
antisynthetase syndrome treated exclusively with
methotrexate, reversible drug-induced pneumonitis
occurred with a frequency of (4%).133 Methotrexate
produces good joint activity for the arthritis that
frequently accompanies the antisynthetase syndrome,
and limited retrospective data suggest it to be at least as
effective as azathioprine when used as a steroid-sparing
agent to treat myositis in patients with the
antisynthetase syndrome.133 In one trial that included 17
patients with myositis-associated ILD, the combination
of steroids and methotrexate resulted in a 47% clinical
response rate.113
Cyclophosphamide
In a retrospective study including 34 patients receiving
IV cyclophosphamide induction with a median of six
infusions followed by continued immunosuppression
with an additional steroid-sparing agent, FVC and
DLCO both increased at 6 months and 2 years.134 Ge
et al135 performed a review of five nonrandomized
studies, including 193 patients with myositis-associated
ILD treated with cyclophosphamide. On average,
roughly two-thirds of the patients showed an
improvement in PFT results and CT scan scores. As
with other forms of immunosuppression, data for the
use of cyclophosphamide in patients with RP ILD are
limited to small case series in which patients are
treated with concurrent therapy and the outcomes are
poor.64,136,137 Mira-Avendano et al115 performed one
of the few direct comparisons of azathioprine,
mycophenolate, and cyclophosphamide as first-line
steroid-sparing monotherapy. Although the study was
small and retrospective (46 patients in total), all three
agents demonstrated a similar efficacy as measured by
improvement in dyspnea scores, steroid-sparing effect,
and PFT results stabilization. The Scleroderma Lung
Study II was the only prospective randomized trial
directly comparing the efficacy of immunosuppressant
agents in patients with systemic sclerosis-associated
ILD, and mycophenolate was found to be noninferior
to cyclophosphamide.138 To date, no evidence exists
that cyclophosphamide is more effective or faster
acting than any other steroid-sparing agent for the
1484 CHEST Reviews
treatment of myositis-associated ILD.115,134
Nevertheless, misconceptions about its increased
potency for the treatment of ILD persist, perhaps
because it is available in an IV formulation or is
associated with greater toxicity. Additionally, much of
the literature surrounding the treatment of myositis-
associated RP ILD is from Asia, where alternatives to
cyclophosphamide and the calcineurin inhibitors more
commonly used in the United States (eg,
mycophenolate and rituximab) may be less popular or
less available. Because we find cyclophosphamide to be
associated with greater toxicity than other readily
available forms of immunosuppression, it is not our
first-line therapeutic choice for monotherapy or
combination therapy.
Rituximab
Most of the limited literature on the use of rituximab for
myositis-associated ILD is in combination with other
immunosuppressant agents for refractory cases.139,140
Bauhammer et al139 reported a significant improvement
in FVC and DLCO in 10 patients with anti-J01-positive
ILD treated with rituximab, including those with
positive results for anti-Ro-52. A retrospective study that
included 24 patients with either myositis or
antisynthetase syndrome demonstrated a clinically
significant improvement in PFT results and CT scan
appearance for the entire group after the addition of
rituximab, despite the fact that most of the patients had
refractory disease with alternative steroid-sparing
agents. However, the results of this and similar studies
need to be interpreted with caution, because concurrent
immunosuppressant agents may have been used around
the time of rituximab administration.140 A study by
Allenbach et al141 evaluating 10 patients with
antisynthetase antibodies and ILD also demonstrated
improvement or stabilization in FVC in most patients,
despite disease progression with corticosteroids plus two
other immunosuppressive drugs. Finally, Langlois
et al134 performed an observational study in patients
with antisynthetase antibody-positive ILD, in which 34
patients received induction with IV cyclophosphamide
and 28 patients received rituximab. Eighty-eight percent
of the patients who received cyclophosphamide and
54% of the patients who received rituximab received
additional immunosuppression. At 6 months and at 2
years, both groups demonstrated a slight but similar
improvement in FVC and DLCO. However, progression-
free survival was better in the rituximab group (hazard
ratio, 0.263; P ¼ .011).
[ 163#6 CHEST JUNE 2023 ]
IV Immunoglobulin
Although the vast majority of evidence supporting the
use of IV immunoglobulin (IVIG) in patients with
inflammatory myositis is focused on the skin and muscle
findings,142–146 case reports147,148 and case series
suggesting the usefulness of IVIG as adjunct therapy in
patients with pulmonary involvement are
increasing.149,150 Huapaya et al151 performed a
retrospective analysis of 17 patients with myositis-
associated ILD, most of whom (82%) had refractory
disease despite treatment with two steroid-sparing
agents. A 10% increase in FVC was achieved in roughly
40% of patients who received IVIG, with a mean
reduction in prednisone dose exceeding 50%. Like in
many ILD studies, the use of concurrent
immunosuppression confounds the interpretation of
these results. Wang et al152 performed a retrospective
review of 48 patients with MDA-5 seeking treatment
with RP ILD, 31 of whom received IVIG in addition to
standard immunosuppressive therapy that typically
involved one or two steroid-sparing agents. The IVIG
group demonstrated increased survival and remission at
3 months.
Tofacitinib
Tofacitinib is a pan-JAK inhibitor initially shown to
improve cutaneous disease in patients with refractory
dermatomyositis.153–157 More recently, two small studies
suggested a potential benefit in patients with pulmonary
involvement. Chen et al158 demonstrated a mortality
benefit in 18 patients with MDA-5-associated ILD
receiving tofacitinib compared with historical control
participants. Kurasawa et al159 demonstrated a mortality
benefit in five patients with MDA-5-associated ILD and
three predetermined poor prognostic factors compared
with six similar patients who received standard-of-care
immunosuppression as control participants. Given the
paucity of data and new concerns about the current
black box warning surrounding the risk of heart-related
events, additional data are required before tofacitinib is
recommended as routine therapy for patients with
myositis-associated ILD.
Antifibrotic Therapy in Progressive Fibrotic
Phenotypes
Although immunosuppression remains the primary
therapy for patients with myositis-associated ILD, a UIP
pattern of disease can be present in up to one-quarter of
patients,111 and a progressive fibrotic phenotype can
develop despite aggressive immunosuppressive therapy.
The most robust data supporting the use of antifibrotic
chestjournal.org
agents in patients with CTD-associated ILD comes from
the Nintedanib for Systemic Sclerosis-Associated
Interstitial Lung Disease, or SENSCIS, trial, which
randomized 576 patients with systemic sclerosis and ILD
to receive either nintedanib or placebo.160 In the largest
non-IPF trial, Nintedanib Progressive Fibrosing
Interstitial Lung Disease, or INBUILD, patients with
autoimmune ILD constituted roughly 25% of the cohort.
However, standard immunosuppression as is used
typically in the treatment of myositis was prohibited on
enrollment, and patients with myositis-associated ILD
were not well represented in the study.161,162 To date, the
only studies evaluating the role of either nintedanib or
pirfenidone for the treatment of myositis-associated ILD
have been small, open-label, or retrospective.163,164
Plasma Exchange
In patients with fulminant respiratory failure despite
aggressive immunosuppressive therapy, therapeutic
plasma exchange (TPE) has been considered as adjunct
therapy. Ning et al109 retrospectively evaluated 18
patients with refractory myositis-associated ILD
resulting in ICU admission for respiratory failure treated
with at least four sessions of TPE. They found that 11 of
18 patients (61%) survived and demonstrated an average
improvement in CT scan scores. Poor prognostic factors
predicting lack of treatment response were increased
serum ferritin levels and subcutaneous or mediastinal
emphysema. Komai et al165 performed a retrospective
case-control study in patients with CADM-associated
ILD refractory to combination therapy with high-dose
steroids, cyclophosphamide, and calcineurin inhibitors.
Of 19 patients, eight patients received
immunosuppression only and 11 patients received
immunosuppression plus TPE. Posttreatment levels of
MDA-5 antibody titers, ferritin, and anti-Krebs von den
Lungen-6 (KL-6) antibody titers were significantly lower
in the TPE group. Additionally, survival was higher in
the TPE group (91% vs 50%; P < .05). However, it
should be noted that although the differences were not
necessarily statistically significant, the TPE group did
have more exposure overall to tofacitinib (36% vs 0%),
rituximab (27% vs 0%), and abatacept (18% vs 0%),
whereas the traditional group had more exposure to
IVIG (50% vs 0%).
Our Treatment Approach
The decision to treat and how aggressively to do so is
determined by the progression and severity of disease, in
addition to patient age and comorbidities. In the
1485
situation of stable and mild disease, in which PFT results
are preserved, symptoms are minimal, and < 10% of the
lung parenchyma is involved on CT scan imaging, it
may be reasonable simply to monitor patients closely
with serial PFTs every 3 to 4 months. However, in the
setting of worsening symptoms not explained by
underlying heart disease, radiographic progression, or a
decline in PFTs (5% or 10% for FVC and DLCO,
respectively), we use a very low threshold for initiating a
prednisone taper with a concurrent steroid-sparing
agent (Fig 2).
Although anecdotes touting the benefits of each drug
abound at centers of excellence around the world,
convincing data that one agent is more efficacious or
rapidly acting are nonexistent. Therefore, the comfort
level of the prescribing provider, the availability of
specific medications in different regions of the world, the
interplay between the comorbidities of each patient, and
the most common side effects of the different agents all
factor into the ultimate treatment choice. For example,
we tend to favor the use of rituximab in patients with
concurrent inflammatory arthritis; we use IVIG more
judiciously in patients in whom a risk of
thromboembolism or volume overload is a concern;
alternatives to tacrolimus may be preferred in cases of
significant renal impairment; and in patients who are
pregnant or who express the desire to conceive,
azathioprine may be the safest option.
Patients with ILD progressing to severe hypoxemia and
respiratory failure pose a particular challenge, because
outcomes remain poor despite aggressive therapy with
multiple agents.137,166,167 We treat these patients with a
combination of pulse-dose methylprednisolone followed
by 1 mg/kg of prednisone in combination with IVIG
(2 g/kg in divided doses) and at least one additional
steroid-sparing agent (mycophenolate, azathioprine, or
tacrolimus) chosen based on comorbidities. We prefer to
use tacrolimus, particularly in patients with known ARS
or MDA-5 positivity, because our own anecdotal
experience has been that greater efficacy is achieved with
a faster onset of action, and some low-quality data
suggest its usefulness in refractory disease.126–129 We
tend to avoid azathioprine in the setting of significant
transaminitis and tacrolimus in patients with known
chronic kidney disease. In patients who fail to stabilize
within the first 7 days or who demonstrate fulminant
respiratory failure at presentation, we typically initiate a
second steroid-sparing agent from an alternative drug
class. Although the use of cyclophosphamide in critically
1486 CHEST Reviews
ill patients is practiced in various centers, we do not
consider this approach to be based on strong evidence.
Moreover, we consider cyclophosphamide to be more
toxic than other steroid-sparing agents, with a higher
incidence of cytopenias, infertility, and hemorrhagic
cystitis being of primary concern. It is also important to
consider that systemic exposure to cyclophosphamide
fluctuates with renal function, so critically ill patients in
whom renal failure develops are at increased risk of
experiencing complications.
Although consensus exists within the medical
community to limit long-term steroid exposure, formal
guidelines on the duration of steroid and steroid-sparing
therapy are lacking. It has been our experience that most
steroid-sparing agents take several months to realize
their full effect. Additionally, we have observed patients
who experience severe, sometimes refractory, ILD flares
on tapering of immunosuppression. For these reasons,
we routinely overlap therapy with prednisone and a
steroid-sparing agent, with the goal of weaning off the
former or decreasing to a prednisone equivalent of #
10 mg/d within 3 months. We then continue treatment
with the target dose of steroid-sparing agent(s) until the
perceived improvement in lung function or CT scan
abnormalities has plateaued. On average, we do not
consider tapering these agents for at least 18 to
24 months. Even then, we do so slowly and we closely
monitor PFT results, ambulatory saturations, and
patient symptoms with each dose adjustment.
Patients with myositis-associated ILD are at risk of
glucocorticoid-induced osteoporosis and opportunistic
infections developing, particularly Pneumocystis jirovecii
pneumonia.168 In addition to calcium and vitamin D
supplementation, we follow the American College of
Rheumatology guidelines for the use of oral
bisphosphonates in those anticipated to continue
receiving at least 2.5 mg/d of prednisone for > 3 months
and at least a moderate fracture risk.169 We typically
prescribe P jirovecii pneumonia prophylaxis in patients
receiving prednisone at a dose of 20 mg/d for $ 4 weeks,
rituximab, or any combination of two or more steroid-
sparing agents. Measurement of CD4 levels of < 200/
mm3 also may help to guide the decision to prescribe P
jirovecii pneumonia prophylaxis.
Conclusions
ILD is a frequent complication of the inflammatory
myopathies and is associated with significant morbidity
[ 163#6 CHEST JUNE 2023 ]
and mortality. The presence of various MSAs may be
associated with the phenotypic variance and outcomes
of these patients with ILD. However, updated
nomenclature and diagnostic criteria incorporating these
antibodies and emphasizing pulmonary involvement as
the most salient clinical feature will be necessary to
facilitate more precise research focused on pulmonary
outcomes of treatment in this rare disease. To date,
immunosuppression with prednisone and various
steroid-sparing agents is the mainstay of therapy.
However, convincing data supporting the use of one
agent over another are lacking, and prospective studies
in the field are needed to determine optimal treatment
regimens.
Financial/Nonfinancial Disclosures
The authors have reported to CHEST the following: R.
W. H. reports the following conflicts of interest: indirect
clinical trial research funding from Boehringer
Ingelheim, Regeneron, Galapagos, Hoffmann-
LaRocheHoffman-La Roche, and Nitto Denko;
authorship fees from Dynamed and UpToDate;
consulting fees from Teladoc, ImpactNetwork,
Boehringer Ingelheim, and Paradigm Medical; and
advisory board of Boehringer Ingelheim. S. K. D. reports
the following conflicts of interest: research grants from
Genentech/Roche, Bristol Myers Squibb, Boehringer
Ingelheim, and United Therapeutics; speaker and
advisory board fees from Boehringer Ingelheim and CSL
Behring; DSMB service for Galapagos and Galectic;
development of education materials for MCM Education
and the France Foundation; royalties from UpToDate;
and employment from the Pulmonary Fibrosis
Foundation.
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