Systemic Sclerosis in Adults Part II Management and Therapeutics 2

Systemic sclerosis in adults.
Part II:
management and therapeutics
Rebekka Jerjen, BMSc, MChD,a Mandana Nikpour, MBBS, PhD,b,c Thomas Krieg, MD,d
Christopher P. Denton, PhD,e,f and Amanda M. Saracino, BMSc, MBBS, PhDa,g
Melbourne, Australia; Cologne, Germany; and London, United Kingdom
Learning objectives
After completing this learning activity, participants should recognise the importance of proactive and evidence-based disease monitoring in SSc, especially of skin progression;
describe the evidence-based therapeutic options available for management of the cutaneous manifestations of SSc; contribute to effective management of SSc patients and their
systemic disease, as part of a multidisciplinary team; and discuss emerging therapies in SSc.
Disclosures
Editors
The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with
commercial interest(s).
Authors
The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).
Planners
The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved
with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).
The management of systemic sclerosis (SSc) is complex, evolving, and requires a multidisciplinary approach.
At diagnosis and throughout the disease course, clinical assessment and monitoring of skin involvement is vital
using the modified Rodnan Skin Score, patient-reported outcomes, and new global composite scores (such as
the Combined Response Index for Systemic Sclerosis, which also considers lung function). Immunomodu-
lation is the mainstay of skin fibrosis treatment, with mycophenolate mofetil considered first line.
Meanwhile vasculopathy-related manifestations (Raynaud’s phenomenon, digital ulcers) and calcinosis,
require general measures combined with specific pharmacologic (calcium-channel blockers, phosphodies-
terase type 5 inhibitors, and prostanoids), nonpharmacologic (digital sympathectomy and botulinum toxin
injections), and often multifaceted, management approaches. Patients should be screened at the time of
diagnosis specifically for systemic manifestations and then regularly thereafter, with appropriate treatment.
Numerous targeted therapeutic options for SSc, including skin fibrosis, are emerging and include B-cell
depletion, anti-interleukin 6, Janus kinase, and transforming growth factor b inhibition.
This second article in the continuing medical education series discusses these key aspects of SSc
assessment and treatment, with particular focus on skin involvement. It is vital that dermatologists play a key
role in the multidisciplinary approach to SSc management. ( J Am Acad Dermatol 2022;87:957-78.)
Key words: calcinocic cutis; digital ulcers; management; Raynaud’s phenomenon; systemic sclerosis; treatment.
Department of Dermatology, The Alfred Hospital, Melbournea; https://doi.org/10.1016/j.jaad.2021.10.066

Department of Rheumatology, St Vincent’s Hospital, Melbour- Date of release: November 2022.
neb; Department of Medicine, The University of Melbournec; Expiration date: November 2025.
Department Dermatology and Translational Matrix Biology,
CMMC and CECAD, Faculty of Medicine, University of Cologned;
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Division of Medicine, Centre for Rheumatology and Connective
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Academy of Dermatology’s (AAD) on-
Rheumatology, Royal Free NHS Foundation Trust, Londonf; and
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Department of Medicine, Monash University, Melbourne.g
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Accepted for publication October 26, 2021.
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Correspondence and reprint requests to: Amanda Saracino, BMSc,
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958 Jerjen et al J AM ACAD DERMATOL
NOVEMBER 2022
Abbreviations used:
ACE: angiotensin converting enzyme
CC: calcinosis cutis
CCB: calcium-channel blocker
CRISS: Combined Response Index for Systemic
Sclerosis
dcSSc: diffuse cutaneous systemic sclerosis
DU: digital ulcer
ERA: endothelin receptor-1 antagonists
HAQ-DI: Health Assessment Questionnaire-
Disability Index
IL: interleukin
MMF: mycophenolate mofetil
mRSS: modified Rodnan skin score
PDE5i: phosphodiesterase type 5 inhibitor
PRO: patient-reported outcome
RP: Raynaud’s phenomenon
RCT: randomized controlled trial
SRC: scleroderma renal crisis
SSc: systemic sclerosis
SSc-ILD: systemic sclerosiserelated interstitial
lung disease
DISEASE ASSESSMENT AND MONITORING

Key points
d The modified Rodnan Skin Score (mRSS) is a well-
validated, routinely used clinical tool to measure

and monitor the severity and extent of skin
thickness in systemic sclerosis (SSc). Fig 1. The modified Rodnan Scoring Scale considers the
d Patient-reported outcomes, such as the Health degree and severity of cutaneous fibrosis in 17 anatomic
Assessment Questionnaire-Disability Index sites. Each site is scored between 0 and 3. None (0),
(HAQ-DI), are an important complementary mea- normal, the skin is soft and can be pinched between 2
sure to determine the impact of skin symptoms on fingers. Mild (1). Moderate (2). Severe (3), the skin is
patients’ quality of life. immobile and does not pinch between 2 fingers. (Image
d The Combined Response Index for Systemic
courtesy of Dr Rebekka Jerjen, MChD.)
Sclerosis (CRISS) is a promising tool that allows
and cutometry).7-13 These tools are ideal as comple-
for a comprehensive assessment of disease activ-
mentary quantitative outcome measures in the
ity and burden.
setting of a clinical trial, where reproducibility and
Skin scores consistency across multiple assessors is essential.9
The skin can provide a window into overall sys-
temic disease progression in SSc. The progression of Patient-reported outcomes
skin fibrosis and/or cutaneous vasculopathy provides Patient-reported outcomes (PROs) should be
visible clues to possible internal organ progression. routinely used to complement objective clinical
The mRSS is commonly used to measure and scores (Table I).14-19 The mRSS correlates moderately
monitor the clinical severity and extent of cutaneous with most PROs.20 The skin-specific PRO is a well-
fibrosis (Fig 1).1 The specificity of sclerodactyly in validated measure of the impact of skin manifesta-
SSc is reflected by the fingers and hands (proximal to tions on function and quality of life.15 The HAQ-DI is
the metacarpal-phalangeal joints) being scored as often used in SSc. It contains a series of subjective
distinct body sites in the mRSS. Although the mRSS is questions related to a patient’s physical function and
well validated and sensitive to change, it demon- ability to perform certain tasks.16 Baseline HAQ-DI
strates intra- and interobserver variability.2-5 scores have recently been shown to be a predictor of
To date, other methods for quantifying skin mortality in diffuse cutaneous SSc (dcSSc), thus
thickness are not used routinely in clinical practice, emphasizing the importance of this patient-
but include histopathology (gold standard), a num- centered subjective measure.17
ber of imaging techniques (ultrasonography, mag- To capture the multisystem effects of SSc, Steen and
netic resonance imaging, and computerized skin Medsger developed the Scleroderma Health
scoring),6 and measures of skin hardness (durometry Assessment Questionnaire, which comprises the
J AM ACAD DERMATOL Jerjen et al 959
VOLUME 87, NUMBER 5
Table I. Commonly used patient-reported outcome measures in SSc

Outcome measure Details Reference
SSc Patient-Reported d Composed of 18 questions that assess the physical effects, Man, et al 201715
Outcome (SSPRO) physical limitations, emotional effects, and social effects of SSc
d High degree of internal consistency and moderate-to-high test/
retest reliability
Health Assessment d A series of subjective questions related to patients’ physical Johnson, et al 200516
Questionnaire-Disability function and ability to perform certain tasks Allanore, et al 202017
Index (HAQ-DI) d Frequently used
d Baseline HAQ-DI scores have recently been shown to be a
predictor of mortality in dcSSc
Scleroderma Health d Capture multisystem effects of SSc Steen & Medsger, 199718
Assessment d Comprising the HAQ-DI and 5 additional scleroderma-specific Johnson, et al 200516
Questionnaire (SHAQ) visual analog scales
d Copies of these questionnaires can be found in the appendix
(Johnson et al)15
Dermatology Life d Not commonly used or validated in SSc and has only been Chularojanamontri,
Quality Index reported on in 1 study et al 201114
Almeida, et al 201519
SSc, Systemic sclerosis.
HAQ-DI and 5 additional scleroderma-specific visual highest level of evidence for improving skin
analog scales.16,18 A copy of these questionnaires can scores and good tolerability.
be found in the appendix of the paper by Johnson d Newer therapies targeting molecules implicated
et al.16 A comprehensive overview of various PROs in SSc pathogenesis include B-cell depletion
used in SSc can be found in the paper by Almeida et al.19 therapy with rituximab, antieIL-6 therapy with
tocilizumab, tyrosine kinase inhibition with nin-
Composite measures tedanib, and others.
The CRISS considers 5 core indices of disease d There are currently no targeted therapies
(mRSS, Forced Vital Capacity, HAQ-DI, Patient approved for skin fibrosis in SSc. The tyrosine
Global Assessment, and Physician Global kinase inhibitor, nintedanib, was recently
Assessment).21 Examples of how to apply the approved by the Food and Drug Administration
CRISS to patients is given in the Supplementary for SSc-related interstitial lung disease (SSc-ILD).
Tables 3 to 5 of the study by Khanna et al.21 CRISS Tocilizumab has shown a trend of benefit in
was developed based on an observational cohort of clinical trials and may be helpful in some cases
patients with early-dcSSc. It is demonstrated and with severe skin involvement.
intended for use in clinical trials, and it has been General measures. A nonpharmacologic
provisionally approved by the American College of approach, coupled with comprehensive patient ed-
Rheumatologists. A modified version has recently ucation, is an important foundation for the manage-
been validated externally.21-25 ment of skin fibrosis in SSc. It is important to avoid
cold exposure, apply regular bland emollients, and
Systemic organ monitoring avoid soaps. For sclerodactyly, massage, heat, wax
Organ monitoring protocols are summarized in baths, regular stretching exercises, physiotherapy,
Table V, found in Part 1 of this CME series. splints, and occupational therapy can all help to
reduce the risk of mechanical injury and improve
MANAGEMENT OF DERMATOLOGIC range of motion.26 Specialist scleroderma centers
MANIFESTATIONS often have allied health/nursing teams to assist with
Skin fibrosis these measures. Clinicians and patients without ac-
Key points cess to such specialist services may access similar
d General measures, including physiotherapy, mas- supports via online resource and/or patient support
sage, and stretching exercises, form an essential groups, through organizations such as the
part of skin fibrosis management. Scleroderma Foundation (USA), Scleroderma
d Conventional immunosuppression with myco- Canada, Scleroderma Raynauds United Kingdom,
phenolate mofetil (MMF) is considered first-line Federation of European Scleroderma Association,
treatment for skin and lung fibrosis, with the and Scleroderma Australia.
NOVEMBER 2022
Table II. Scleroderma therapies studied and their Table II. Cont’d
levels of evidence Level of
Level of Treatment evidence
Treatment evidence Laser III
Skin fibrosis Cosmetic camouflage III
HSCT IIa Pruritus
Methotrexate IIb Cannabinoid receptor modulator Ib
Emollients III (Lenabasum)
Systemic corticosteroids III Emollients III
Cyclophosphamide III Antihistamines III
Rituximab III PUVA IV
IPL and CO2 laser for microstomia IV Low-dose oral naltrexone IV
Raynaud’s phenomenon
Calcium-channel blockers Ia ACE, Angiotensin converting enzyme; CTLA4, cytotoxic T-lymphocyte
Intravenous iloprost Ia associated protein 4; CO2, carbon dioxide; DM, dermatomyositis;
ESWT, extracorporeal shock wave lithotripsy; HSCT, hematopoietic
Angiotensin II receptor antagonists Ib
stem cell transplantation; IPL, intense pulsed light; IVIg, intravenous
Phosphodiesterase type 5 inhibitors IIa immunoglobulin; SSc, systemic sclerosis; TNFa, tumour necrosis
Selective serotonin reuptake III factor a; PUVA, psoralen with UV-A.
inhibitors *There is level Ib evidence (from a small RCT) that warfarin does
Alpha-blockers III not improve calcinosis cutis and thus is not recommended.33
Statins III Additionally, warfarin may promote ectopic calcification via
Digital sympathectomy 6botulinum III undercarboxylated matrix gla protein.34
toxin
ACE inhibitors IV
Digital ulcers
Calcium-channel blockers I
Phosphodiesterase type 5 inhibitors I
Intravenous iloprost Ia Topical treatments and phototherapy. Topical
Bosentan Ia corticosteroids and other topical agents do not play a
Statins II major role in the management of SSc skin fibrosis.
Digital sympathectomy 6 botulinum III Occasionally, in the context of significant inflamma-
toxin tion and related pruritus, topical steroids may be used
Aspirin IV anecdotally. Phototherapy is a supportive therapy in
Calcinosis SSc. UV-A1 or UV-A with topical or systemic psoralen
Warfarin Ib - not may be beneficial for fibrosis and pruritus.27 There are
recommended* several other case reports to improve topical treat-
Iontophoresis of acetic IIB (SSc/DM -
ments, including pulsed light and CO2 laser for
acid 1 ultrasound ineffective)
Minocycline IV
perioral fibrosis; however, these are anecdotal obser-
Diltiazem IV (SSc/DM) vations and controlled studies are required.28-30
B-cell depletion therapy (Rituximab) IV (SSc/DM) Immunosuppression for skin fibrosis. Immu-
Topical/intralesional sodium IV (SSc/DM) nomodulation forms the cornerstone of SSc skin
thiosulfate fibrosis management. Systemic corticosteroids have
Intravenous sodium thiosulfate IVenot been used in SSc,31,32 particularly during the initial
recommended edematous phase; however, they can precipitate
Colchicine IV (SSc/DM) scleroderma renal crisis (SRC) and are not recommen-
Surgical excision/physical therapies IV (SSc/DM) ded at high doses (Table II).33-35 MMF is considered
CO2 laser IV (SSc/DM) first-line therapy for skin fibrosis in SSc, including in
Low frequency ultrasound IV (SSc/DM)
those with concomitant SSc-ILD.36-38 At a dose of up to
ESWT IV(SSc/DM)
IVIg IV (DM)
3 g/day, MMF improved mRSS and SSc-ILD in a
Bisphosphonates IV (DM) randomized controlled trial (RCT) (SLS II), as well as
Anti-TNFa (Infliximab) IV (DM) previous case series and open-label studies.36,37,39,40 In
Anti-CTLA4 (Abatacept) IV (DM) this and in a previous RCT (SLS I), cyclophosphamide
Cyclophosphamide IV (DM) also demonstrated significant improvement in mRSS,
Telangiectasia and a modest effect on SSc-ILD; however, this is lost on
IPL III treatment discontinuation.36,37,41,42 Two RCTs showed
Continued methotrexate (15-25 mg/week) improves mRSS in
VOLUME 87, NUMBER 5
early dcSSc, but showed no benefit for lung disease or approved by the Food and Drug Administration after
other organ manifestations.22,43 a positive phase III RCT (SENSCIS), which demon-
Hematopoietic stem cell transplantation. He- strated significant improvement in the primary
matopoietic stem cell transplantation can significantly end point of Forced Vital Capacity.71 However, a
improve both skin and lung fibrosis in SSc (Clinical significant effect of this treatment on mRSS was not
trials: Autologous Stem Cell Transplantation demonstrated.71
International Scleroderma (ASTIS), Scleroderma: The soluble guanylate cyclase stimulator, rioci-
Cyclophosphamide or Transplantation (SCOT), guat, has demonstrated antifibrotic and anti-
Autologous non-myeloablative haemopoietic stem- inflammatory effects in mouse models.76-78
cell transplantation compared with pulse cyclophos- Riociguat is now approved by the Food and Drug
phamide once per month for systemic sclerosis Administration for pulmonary arterial hyperten-
(ASSIST).44-47 This bellicose approach is reserved for sion.80 Further studies are investigating its impact
patients with severe rapidly progressive SSc refractory on fibrosis in SSc, including the phase II study
to other immunosuppression and at risk of poor (RISE-SSc), which demonstrated a trend toward
outcomes.48 Careful patient selection is crucial, due statistically significant improvement in mRSS
to the significant treatment-related toxicities and mor- (Table III).79
tality that makes it an unfeasible option in many These and other emerging targeted treatments for
patients, including those with advanced systemic skin and lung fibrosis in SSc, such as anti-CTLA4
manifestations.47,49 Hematopoietic stem cell transplan- (abatacept), antieIL-13/4 (romilkimab), transform-
tation is only performed at highly specialized centers.50 ing growth factor-b antibody (fresolimumab),
Emerging treatment options for skin cannabinoid receptor analogs (lenabasum), and
fibrosis. There is strong experimental evidence Janus kinase inhibitors (tofacitinib) are described in
for the role of B cells in SSc pathogenesis and their Table III and Fig 2.
depletion or modulation is an attractive treatment
objective.51-54 B-cell depletion therapy with rituxi-
Vasculopathy
mab, an anti-CD20 antibody, has shown a promising
Key points
ability to significantly reduce mRSS and improve d Minimizing cold exposure, preventing trauma,
lung function in a small RCT as well as other larger
and stopping smoking are important in the pre-
European Scleroderma Trial and Research
vention and management of Raynaud’s phenom-
studies,55-63 with concurrent improvement in
enon (RP) and digital ulcers (DUs).
histologic and biochemical markers.57-59 A recent d Pharmacologic management options include vas-
meta-analysis showed generally good tolerability,
olidators and vasoactive medications; calcium-
long-term improvement in mRSS, and stabilization of
channel blockers (CCBs), phosphodiesterase
lung function.64
type 5 inhibitors (PDE5i), and prostanoids. Com-
Treatments targeting interleukin (IL)-6, a key
bination therapy is indicated for DUs and recal-
proinflammatory and profibrotic cytokine implicated
citrant RP.
in SSc pathogenesis, have antifibrotic effects in d DU management entails prevention, treatment
animal models of skin fibrosis.65-67 IL-6 is frequently
of underlying RP, early recognition, ulcer
elevated in the serum of patients with SSc, expressed
classification, meticulous wound care, treat-
by dermal fibroblasts and endothelial cells in patients
ing/preventing infections, and adequate
with dcSSc and associated with progressive skin
analgesia.
fibrosis.68 Tocilizumab, an antieIL-6 antibody, has d In specific cases, digital sympathectomy and bot-
been studied in patients with dcSSc in the early
ulinum toxin injections are nonpharmacologic
inflammatory phase with skin progression and
options for refractory RP and DUs,.
although there was a consistent trend of mRSS
improvement, this was not statistically significant Prevention is vital in the management of periph-
compared to placebo in both a phase II (FasSScinate) eral vasculopathy in SSc. It is important to avoid
and a phase III (FocuSSced) RCT (Table III).55-64,69-95 triggering factors, such as exposure to cold, rapid
Importantly, however, there was a significant reduc- temperature changes, vasoconstrictors (eg, caffeine),
tion in meaningful worsening of mRSS, Forced Vital emotional stress, trauma, and smoking. Patient sup-
Capacity, and CRISS scores in both studies port groups and scleroderma nurse specialists can
(Table III).73 assist patients; eg, with access to double-lined
Recently, the tyrosine kinase inhibitor, ninteda- gloves, silver socks, heat pads, and use of pastes
nib, became the first targeted therapy for SSc-ILD containing zinc oxide to assist with pain and healing
962 Jerjen et al
Table III. Emerging treatments for skin fibrosis in systemic sclerosis
P values for end point data from placebo-controlled trials
Medication Rationale for HAQ-DI
Mechanism name implementation Studies mRSS FVC or SHAQ CRISS
55
Anti-CD20 Rituxumab B cells strongly Has shown promising ability to significantly 0.06 (small 0.002 (small (small No data
implicated in SSc reduce mRSS and improve lung function in RCT)55 RCT)55 RCT)
55
pathogenesis a small RCT as well as other larger 0.03 (Case- 0.02 (Case- Not
(see text) collaborative EUSTAR studies.55-63 control control reported
A recent meta-analysis showed generally analysis)61 analysis)61 Not
good tolerability, long-term improvement 0.029 0.013 reported
in mRSS and stabilization of lung (Comparative (Comparative
function.64 Nonetheless, evidence of study, at 5 study, at 7
efficacy in large RCTs is lacking for years)62 years)59
rituximab, and further studies are needed.
AntieB-cell Belimumab BAFF is a key Phase II trial (NCT01670565) comparing 0.41 0.27 0.04 0.37
activating cytokine for B-cell belimumab with placebo on background of
factor (BAFF) activation and MMF treatment showed reduction in mRSS
antibody increased in the (albeit not statistically significant) and was
serum and skin well tolerated. Decrease in B-cell signaling
of SSc patients.69 and profibrotic genes was demonstrated.70
Combination Rituximab 1 B cells strongly Ongoing phase II study combining patients NA*
of B-cell Belimumab 1 implicated in SSc with dcSSc on MMF with either
depleting MMF pathogenesis rituximab 1 belimumab or placebo and
agents (see text). assessing safety and change in CRISS
(anti-CD20 (NCT03844061).
antibody,
anti-BAFF
antibody)
Small molecule Nintedanib Block signaling Phase III study (SENSCIS, NCT02597933) did 0.58 0.035 NA* NSy
tyrosine pathways with not show significant treatment effect on
kinase downstream mRSS.71
inhibitor transcription Recently approved by the FDA for SSc-ILD.
factors implicated
J AM ACAD DERMATOL
in vasculopathy
and fibrosis
NOVEMBER 2022
(eg, PDGF and
VEGF)
VOLUME 87, NUMBER 5
J AM ACAD DERMATOL
AntieIL-6 Tocilizumab AntieIL-6 A phase II (FaSScinate) and phase III 0.06 (FaSScinate) 0.03 0.53 0.002
treatments (FocuSSED) study of patients with dcSSc in 0.1 (FocuSSed) (FaSScinate) (FaSScinate) (FaSScinate)
have been the early inflammatory phase with skin 0.002 NS 0.02
shown to have progression found a trend toward mRSS (FocuSSed) (FocuSSed) (FocuSSed)
anti-fibrotic improvement.72-74
effects in
animal models
of skin fibrosis.65-67
IL-6 is frequently
elevated in the
serum of SSc
patients,
expressed by
dermal
fibroblasts and
endothelial cells
in patients with
dcSSc and
associated with
skin fibrosis
progression.68
Anti-CTLA4 Abatacept CTLA4 is Phase II trial (ASSET, NCT02161406) showed a 0.28 0.11 0.005 0.03
required for numerically greater but not statistically
T cell co- significant improvement in adjusted mRSS
stimulation in early dcSSc compared with placebo after
and activation. 1 year.75
sGC analog/ Riociguat sGC triggers A small phase II RCT (RISE-SSc, NCT02283762) 0.08 (RISE-SSc) NSy (RISE-SSc) NSy NSy (RISE-SSc)
stimulator signaling cascades in early dcSSc found a trend toward but not (RISE-SSc)
which regulate statistically significant improvement in
vascular tone mRSS. Found potential efficacy for ILD, DUs,
and remodeling.76 and RP.79
sGC attenuates Approved for treatment of PAH after showing
TGF-b signaling efficacy in the phase III Pulmonary Arterial
in animal models Hypertension Soluble Guanylate Cyclase-
and in vitro Stimulator Trial 1 (PATENT-1) study, which
studies thus included a subgroup with PAH-SSc.80
Jerjen et al 963
having
antiproliferative,
anti-inflammatory
and antifibrotic
effects.76-78
Continued
Table III. Cont’d
964 Jerjen et al
AntieTGF-b Fresolimumab Directly target the Phase I open-label study of patients with early Not applicable
antibody key cytokine dcSSc showed an improvement in mRSS, a
involved in fibrosis. reduction in TGF-b related gene expression

and decline in dermal myofibroblast
infiltration.81
AntieTGF-b Pirfenidone Reduce fibroblast Open-label Phase II study in SSc-ILD showed NA*
proliferation, acceptable safety and tolerability.82
inhibit TGF-b. An ongoing phase II trial (SLS III) combing
pirfenidone with MMF for SSc-ILD will also
assess skin fibrosis as a secondary end point
(NCT03221257).
Antie Romilkimab Th2 cytokines A phase II study (NCT02921971) in patients 0.03 0.10 0.4 NSy
IL-4/IL-13 have been with early dcSSc with background
antibody associated immunosuppressive therapy found a
with fibrosis statistically significant decrease in mRSS
in animal with efficacy seen in the most severe
studies.83 disease group as well as those in early
disease stages.84
Cannabinoid Lenabasum CB2 agonists A phase II study (JBT-101-SSc, NCT02465437) 0.085 NSy 0.03 0.04
receptor reduce in patients with dcSSc found lenabasum
type 2 (CB2) expression of was safe, well tolerated and there was a
agonist proinflammatory trend toward improvement in mRSS and
and profibrotic reduction in itch.86
85
genes. An ongoing phase III study (RESOLVE-1,
NCT03398837) will provide further insights
into the safety and efficacy.
J AM ACAD DERMATOL
NOVEMBER 2022
VOLUME 87, NUMBER 5
J AM ACAD DERMATOL
Pan- Lanifibranor Though to Phase II proof of concept trial (FASST, NSy NSy NA* NA*
peroxisome antagonise NCT02503644) found no significant
proliferator- TGF-b improvement in mRSS, complete results
activated profibrotic awaited.89
receptor signaling
(PPAR) pathways.
agonist PPAR-gamma
agonists
ameliorated
dermal fibrosis
in vitro and in
mouse models
of SSc.87
Lanifibranor
prevented lung
fibrosis in
animal models.88
JAK-inhibitor Tofacitinib Prevents Phase I/II study (TOFA-SSc, NCT03274076) of 0.42 NA* 0.35 0.68
proinflammatory tofacitinib at 5 mg twice daily with
and profibrotic background MMF or MTX was well
signaling via tolerated and showed trends in
JAK/STAT pathway. improvement for mRSS and CRISS scores.92
Tofacitinib
prevented
bleomycin induced
fibrosis in mouse
model and
reduced skin
fibrosis in
TSK16 mice.90,91
Anti-CD30 Brentuximab Target activated Ongoing phase I/II dose esclataion study NA*
immune cells. (BRAVOs, NCT03222492) assessing safety
and tolerability in patients with dcSSc on
background immunosuppression.
Continued
Jerjen et al 965
Table III. Cont’d
966 Jerjen et al
Micro Human Reduce localized Previous case series demonstrated a Not applicablez
reinjection of adipose- handicap caused subjective and objective reduction in skin
autologous derived by skin fibrosis. tightening on the face93 and another

adipose stromal cells reported reduction in finger edema and
tissue and Adipose improvement in hand function.94
stromal cells tissue-derived A small open-label study using autologous
stromal stromal bascular fraction of adipose tissue
vascular on fingers of patients with SSc
fraction (SVF) (NCT01813279) reported an improvement
in finger edema, hand disability, pain, RP
and quality of life.95
Ongoing prospective study (FACE,
NCT02206672) assessing efficacy of
micrografting on facial handicap in SSc
patients.
CRISS, Combined Response Index for Systemic Sclerosis; CTLA4, cytotoxic T-lymphocyteeassociated antigen 4; dcSSc, diffuse cutaneous systemic sclerosis; DU, digital ulcer; EUSTAR, The European
Scleroderma Trials and Research; FDA, Food and Drug Administration; FVC, forced vital capacity; sGC, soluble guanylate cyclase; HAQ-DI, Health Assessment Questionnaire-Disability Index; IL,
interleukin; JAK, Janus kinase; MMF, mycophenolate mofetil; mRSS, modified Rodnan Skin Score; MTX, methotrexate; PAH, pulmonary arterial hypertension; PDGF, platelet-derived growth factor; RCT,
randomized controlled trial; RP, Raynaud’s phenomenon; sGC, soluble guanylate cyclase; SHAQ, Scleroderma Health Assessment Questionnaire; SSc, systemic sclerosis; SSc-ILD, systemic
sclerosiserelated interstitial lung disease; STAT, signal transducer and activator of transcription; TGF-b, transforming growth factor beta; VEGF, vascular endothelial growth factor.
*NA, data not available.
y
NS, Result not statistically significant.
z
Not applicable, indicates not a placebo-controlled trial.
J AM ACAD DERMATOL
NOVEMBER 2022
VOLUME 87, NUMBER 5
Fig 2. Illustration of emerging systemic sclerosis therapies and their targets. BAFF, B cell
activating factor; CD28, cluster of Differentiation 28; CD30, cluster of Differentiation 30; CTLA4,
Cytotoxic T-lymphocyteeassociated antigen 4; ECM, extra-cellular matrix; IFN, interferon; IL,
interleukin; PDGF, platelet derived growth factor; ROS, reactive oxygen species; TGF,
transforming growth factor; TH2, T-Helper 2 cell; VEGF, vascular endothelial growth factor.
Image courtesy of Dr Rebekka Jerjen, MChD.
of fissures and wax baths.96 Low-grade evidence Second-line options include PDE5i (eg, sildena-
supports the use of supplements, including antiox- fil)107,109,110 and prostanoids (eg, iloprost).107 PDE5i
idant vitamins C and E, gamolenic acid, ginko biloba, cause vasodilation by preventing cyclic-GMP
ginger, and resveratrol (a natural phenol found in the degradation,111 with efficacy in secondary RP.112
skins of grapes, blueberries, raspberries, and mul- Intravenous iloprost is typically reserved for severe
berries).97-101 RP, resistant to oral therapy, or complicated by
DU.38,107 Prostanoids work through vasodilation
Raynaud’s Phenomenon and by inhibiting platelet aggregation and vascular
Pharmacologic approach. Evidence supports smooth muscle proliferation.113,114 Effects usually
the use of vasodilators and vasoactive therapies to last 4 to 8 weeks and may need to be repeated
reduce the frequency and severity of RP attacks,102 throughout the year. Variations in iloprost adminis-
with CCBs, considered first line (Table II).103-107 Trial tration regimens exist,38,115 but generally no more
data particularly support implementation of non- than 2 mg/kg/min is administered over 1-5 days,
cardioselective, dihydropirine CCBs (eg, nifedipine) with other therapies continued.
to reduce the severity and frequency of RP attacks.104 Third- and fourth-line options include selective
The United Kingdom consensus pathway lists dilti- serotonin reuptake inhibitors,116 angiotensin II
azem (a non-dihydropiridine cardioselective CCB) as receptor antagonists (eg, Losartan),117-119 angio-
a CCB option (together with nifedipine and amlodi- tensin-converting enzyme (ACE) inhibitors,119-123
pine) despite very few studies reporting on its antiplatelets,124 anticoagulants,125 alpha-blockers,126
efficacy.106,108 and statins.127,128 The evidence for these options is
NOVEMBER 2022
less robust and further studies are required to in particular reduces new DU development and is
establish their role in managing RP.103,105,129 potentially associated with improved DU heal-
Combination therapy is often indicated in re- ing.141,142 PDE5i is commonly used first line alone
fractory RP, cases associated with progressive DU or in combination with CCBs in early DUs.102,106,109
or critical digital ischemia, while balancing risks of For DUs resistant to oral therapies or in cases of
hypotension, headaches, and peripheral edema.130 critical ischemia, intravenous prostanoids (iloprost)
Topical vasodilators containing nitroglycerin or can be used to improve DU healing and reduce new
benzyl nicotinate can be used for intermittent and DU formation.143-145
temporary symptom relief; however, little evidence Endothelin-1 receptor antagonists work by in-
supports this approach. hibiting vasoconstriction and smooth muscle and
Procedural options. In some specific cases, fibroblast proliferation.141 Bosentan, a dual ERA, is
nonmedical approaches may be indicated. licensed in Europe for the treatment of pulmonary
Botulinum toxin injections promote local arterial arterial hypertension and the prevention of recur-
vasodilation and a small number of retrospective rent DUs. RCTs have shown it reduces the number
studies report some improvements in primary and of new DUs while not changing healing of existing
secondary RP, but with variable objective change in DUs.146,147 The same efficacy was not found in an
blood flow.103,129-131,133 There are some favorable RCT studying macitentan,148 another dual ERA,
reports for digital sympathectomy, which causes while 2 small studies showed a reduction in new
vasodilation by disrupting sympathetic input to the DUs using ambrisentan, a selective ETA ERA.149,150
digital vessel smooth muscles.103,132,134,135 This Some studies suggest ERAs can be combined with
approach could be particularly beneficial early in PDE5i in severe cases of refractory DUs.149,150
digital ischemia to prevent complications, such as Combination intravenous iloprost and bosentan
DUs, but is rarely used, possibly due to a lack of can reduce the progression of microvascular dam-
available expertise and the recurrence of RP over age in SSc after 1 to 2 years of combination
time.136 therapy.151-154
Up to a third of patients with SSc have refractory
Digital Ulcers DUs.155 Other pharmacologic options include anti-
Assessment. DUs should be classified according platelets and anticoagulants,124,125 ACE inhibitors,129
to size, location, ulcer bed characterization, statins,127 rituximab, and tocilizumab (when used for
exudate, ulcer depth, perilesional skin, and pain.137 SSc-ILD management).156,157 Experimental therapies
Meticulous wound care, including debridement include hyperbaric oxygen, negative pressure ther-
when necessary, is required to minimize further apy, acoustic pressure wound healing, and intermit-
damage and tissue loss and prevent or treat second- tent compression.158-160
ary infection.106,138,139 Dressings should be tailored Procedural options. Surgery is a last resort
to wound character and reviewed regularly. Patients for patients with refractory DUs, severe pain, or
may report significant pain requiring varying degrees osteomyelitis or for the removal of necrotic or
of topical or systemic analgesia.140 underlying calcinotic material. Botulinum toxin in-
Pharmacologic approach. Vasculopathy-asso- jections131,161,162 and digital periarterial sympathec-
ciated DUs usually require a stepwise therapeutic tomy163-165 can prevent and heal DUs and reduce
approach, often with a combination of vasodilatory pain. Other surgical options include debridement (of
and vasoactive medications, including CCBs (nifed- necrotic or calcified material) and amputation (if
ipine/diltiazem), PDE5i (sildenafil), prostanoids gangrenous). More recently, autologous fat grafting
(intravenous iloprost) 6 endothelin receptor-1 an- is being explored.166,167
tagonists (ERA; bosentan). For a systematic guide to Cutaneous telangiectasia. Cutaneous telangi-
medication selection, refer to the UK best practice ectasia can be of significant cosmetic concern for
consensus pathway available in reference Hughes many patients and may warrant treatment for this
et al.106 Figure 3 of these guidelines provides a clear reason. Current treatment options include skin
DU management approach and the implementation camouflage (including green-tinted camouflage
of these treatments is supported by the recently makeup), fine wire diathermy for limited small
updated European league against rheumatism SSc lesions, and laser (ie, potassium titanyl phosphate
treatment recommendations.106,107 or flashlamp pulsed dye laser) or intense pulsed light
Most of these therapies for DUs are supported by therapy for more extensive and/or larger cutaneous
medium- to high-level evidence (Table II).102 PDE5i telangiectasia (Table II).168
VOLUME 87, NUMBER 5
Calcinosis cutis of partial response.174,198 However, there is a possi-

Key points bility of damaging surrounding healthy tissue,
d There is a lack of high-level evidence for the inducing postoperative worsening ischemia through
treatment in calcinosis cutis (CC), with very few neurovascular damage, poor wound healing, and
RCTs and no specific treatment guidelines. skin necrosis, ultimately leading to worse pain and/
d Improving digital circulation and avoiding trauma or functional impairment.199 Physical interventions,
play a key role in prevention. such as CO2 laser and extracorporeal shock wave
d Sodium thiosulphate (topical or intralesional) may lithotripsy, have also been tried in small numbers of
be efficacious. patients with CC with mixed outcomes.200-204
Pruritus. Pruritis is common in SSc and can be
General and pharmacologic management. very troubling for patients.25 Dermatologists should
Thereis an urgent need for controlled studies to play an active role in symptom management.
guide the management of CC. Treating RP, keeping Pruritus is associated with active SSc, indicating the
hands warm, and avoiding trauma are important need for treatment of the systemic condition. Its
preventative measures. Small retrospective, prospec- presence also suggests a greater risk of more severe
tive, and case studies have reported varied success skin and gastrointestinal tract involvement.205
with diverse treatments for CC in SSc, which are All patients should use regular emollients and
described below in brief (Table II). non-soap cleansers, and should avoid overheating
Warfarin (1 mg/day) has been studied in 6 adult and irritants. Studies have reported elevated levels of
SSc patients with CC.169-171 Two patients experi- histamine in SSc patients, particularly dcSSc.206
enced a partial and subsequent complete Therefore, antihistamines are a common first-line
response164 while the others had no improvement. treatment but are often ineffective (Table II).
Retrospective studies of diltiazem in 28 patients with Phototherapy, including psoralen with UV-A, has
CC (12 with SSc) reported no complete re- limited specific evidence for pruritus in SSc, but may
sponders.172-175 B-cell depletion therapy with ritux- be tried in suitable patients.207,208 Montelukast, a
imab has shown conflicting efficacy.175-179 A study of leukotriene receptor antagonist, aims to reduce
3 SSc patients with CC reported 100% response inflammatory irritation of nerve fibers.209
rate176 while another study with 6 SSc patients Neuroactive nerve-stabilizing antipruritic agents,
reported no complete responsers.178 Possibly due such as gabapentin, pregabalin, amitriptyline, and
to its anti-inflammatory effects and chelation of doxepin, tend to be anecdotally more efficacious.
calcium, minocycline (50-100 mg/day) led to a par- Low-dose oral naltrexone, an opioid receptor antag-
tial response in 9 of 12 patients (9 SSc patients) with onist, has demonstrated efficacy in small studies of
CC across 2 studies.174,180 Colchicine reduces inflam- SSc-pruritus and can be considered in the treatment
mation secondary to calcinosis but has shown armamentarium for those with treatment-resistant
variable efficacy across 16 patients (number with and debilitating itch.210,211 Dysregulation of the
SSc unspecified), with only 4 partial and 1 complete endocannabinoid system has also been linked to
responder.174,175,181 pruritus in scleroderma.212 A phase II RCT found an
Topical, intralesional and intravenous sodium oral cannabinoid receptor type 2 agonist,
thiosulfate (STS) has been tried for CC with variable Lenabasum, was safe and resulted in a significant
success.182-188 Topical application to superficial le- improvement in itch scores.213
sions and/or as an adjunct for refractory ulcers
associated with CC is an attractive option as it is
well tolerated.183,188 Twice daily application of 25% OVERVIEW OF SYSTEMIC SSc
sodium thiosulfate compounded in zinc oxide for up MANIFESTATION MANAGEMENT
to 12 months was found to be effective in 19 of 25 Key points
patients (15 SSc patients) with CC in a recent case d Multidisciplinary care is required to manage the
series.188 diverse systemic manifestations of SSc.

Additional treatments have been reported in CC d Immunosuppressive therapies for cutaneous
associated with dermatomyositis, but not in SSc, are fibrosis are often also effective for management
listed in Table II.174,175,189-197 of SSc-ILD.
Procedural options. Surgical removal of calci- d ACE inhibitors have a role in management of
fied deposits should be considered only in specific cardiac dysfunction as well as Scleroderma Renal
suitable cases that are refractory to pharmacologic Crisis (SRC).
therapy and/or due to intractable pain. Studies on d Gastrointestinal manifestations are managed ac-
surgical management of CC have reported high rates cording to symptoms, including proton-pump
NOVEMBER 2022
Table IV. Overview of systemic SSc manifestation management.

Organ system Management approach and considerations
Respiratory
SSc-ILD - Immunosuppressive therapies for cutaneous fibrosis are often also effective for management of SSc-ILD
(with the exception of methotrexate), emphasizing the shared underlying pathogenesis of these
manifestations.
- Mycophenolate mofetil and/or cyclophosphamide are considered first line treatment options for SSc-
ILD.107,214
- Autologous HSCT and lung transplantation are reserved for severe or progressive cases.214-216
- Importantly, nintedanib, a small molecule tyrosine kinase inhibitor, has recently been FDA approved for
SSc-ILD, after positive findings in the Phase III SENSCIS study.71
PAH - High-quality evidence supports the use of PDE5i, ERAs, and sGC analog Riociguat in SSc-related PAH
(see Table III).107,214
- Continuous intravenous epoprostenol and other prostacyclin analogs can be used in refractory cases as
well as lung/heart transplantation.107,214
Cardiac - Standard treatments for ischemic heart disease, valvular disease, arrhythmias, diastolic and/or systolic
dysfunction is indicated, which includes ACE inhibitors, diuretics, and implantable defibrillators.214
- Myocarditis and pericarditis may respond to immunosuppression with MMF or corticosteroids, NSAIDs
and/or colchicine are additional options for the latter condition.107,214
- Interventions such as pericardiocentesis for pericardial effusion and/or creation of a pericardial window
in cases of tamponade may be indicated.
Renal - ACE inhibitors should be used to manage SRC, however, their role in SRC prevention is not
established.107
- Frequent at home blood pressure monitoring is important for those at increased risk of SRC,
particularly those with anti-RNA polymerase III antibodies.217
Gastro-intestinal
GERD - Proton-pump inhibitors, H2 blockers, and antacids are used for GERD.
GI dysmotility - Prokinetic agents; eg, metoclopramide and domperidone
Esophageal - Patients may require endoscopic dilatation.
strictures
Small bowel - Can be treated with various protocols of rotating antibiotics, such as ciprofloxacin, norflaxacin,
bacterial amoxicillin and metronidazole.107
overgrowth
GAVE - Management involves correction of anemia, iron supplementation, and, in some cases, endoscopic
treatment with argon plasma photo-coagulation or with radiofrequency ablation.218
- There are case reports of intravenous cyclophosphamide in refractory GAVE.219
Malabsorption - Chronic severe malabsorption related malnutrition should be prevented and initially addressed with
oral supplementation, including pancreatic enzymes and fat soluble vitamins; however, in severe end
stage cases of refractory weight loss, total parenteral nutrition or percutaneous jejunostomy may be
required.105,214
ACE, Angiotensin converting enzyme; ERA, endothelin receptor-1 antagonists; FDA, Food and Drug Administration; GAVE, gastric antral
vascular ectasia; GERD, gastresophageal reflux disease; GI, gastrointestinal; MMF, mycophenolate mofetil; NSAID, nonsteroidal anti-
inflammatory drug; PAH, pulmonary arterial hypertension; PDE5i, phosphodiesterase 5 inhibitor; sGC, soluble guanylate cyclase; SRC,
scleroderma renal crisis; SSc, systemic sclerosis; SSc-ILD, systemic sclerosiserelated interstitial lung disease.
inhibitors for gastresophageal reflux disease and considered first-line treatment options for SSc-
prokinetic agents for gastroparesis. ILD.107,214 The effectiveness of these agents (with
d It is important for dermatologists, as part of the the exception of methotrexate) emphasizes the
multidisciplinary care team, have a broad under- shared underlying pathogenesis of cutaneous and
standing of individual organ manifestations and pulmonary fibrosis. Meanwhile, PDE5i, ERAs, and
their treatment. the soluble guanylate cyclase analog riociguat are all
effective in SSC-related pulmonary arterial hyperten-
Early screening, treatment and monitoring for
sion. SSc-related cardiac manifestations require
progression of organ-based manifestations in SSc is
standard treatments for ischemic heart disease,
essential and improves mortality (Table V in Part 1 of
valvular disease, arrhythmias, diastolic and/or sys-
this CME). Key management strategies for each organ tolic dysfunction is indicated, which includes ACE
system are summarized in Table IV71,105,107,214-219 in
inhibitors, diuretics, and implantable
this article. MMF and/or cyclophosphamide are
VOLUME 87, NUMBER 5
defibrillators.214 ACE inhibitors should also be used 4. Ionescu R, Rednic S, Damjanov N, et al. Repeated teaching
to manage SRC; however, their role in SRC prevention courses of the modified Rodnan skin score in systemic
sclerosis. Clin Exp Rheumatol. 2010;28(2 suppl 58):S37-S41.
is not established and at-risk patients are required to 5. Czirjak L, Nagy Z, Aringer M, et al. The EUSTAR model for
frequently monitor their blood pressure.107 teaching and implementing the modified Rodnan skin score
Gastrointestinal issues should be investigated and in systemic sclerosis. Ann Rheum Dis. 2007;66(7):966-969.
managed according to symptoms. Strategies include https://doi.org/10.1136/ard.2006.066530
prokinetic agents for gastroparesis, antibiotics for 6. Ch’ng SS, Roddy J, Keen HI. A systematic review of ultraso-
nography as an outcome measure of skin involvement in
bacterial overgrowth, and nutrition supplementation systemic sclerosis. Int J Rheum Dis. 2013;16(3):264-272. https:
for malabsorption (Table IV). Ultimately, a multidis- //doi.org/10.1111/1756-185X.12106
ciplinary approach is vital, and for each organ system 7. Kissin EY, Schiller AM, Gelbard RB, et al. Durometry for the
involved, specialist care is indicated. assessment of skin disease in systemic sclerosis. Arthritis
Rheum. 2006;55(4):603-609. https://doi.org/10.1002/art.22093
8. Merkel PA, Silliman NP, Denton CP, et al. Validity, reliability,
SUMMARY and feasibility of durometer measurements of scleroderma
The early diagnosis, assessment, and initiation skin disease in a multicenter treatment trial. Arthritis Rheum.
2008;59(5):699-705. https://doi.org/10.1002/art.23564
of disease-modifying treatments is vital in the man- 9. De Oliveira MFC, Leopoldo VC, Pereira KRC, et al. Durometry
agement of SSc. Continued regular reassessment for as an alternative tool to the modified Rodnan’s skin score in
the development and/or progression of systemic and the assessment of diffuse systemic sclerosis patients: A cross-
cutaneous complications remains vital and allows sectional study. Adv Rheumatol. 2020;60(1):48. https:
ongoing prompt therapeutic adjustments. Cutaneous //doi.org/10.1186/s42358-020-00152-6
10. Moon KW, Song R, Kim JH, Lee EY, Lee EB, Song YW. The
fibrosis should be monitored using validated correlation between durometer score and modified Rodnan
outcome measures, particularly in the mRSS. skin score in systemic sclerosis. Rheumatol Int. 2012;32(8):
The skin manifestations of SSc are vast and 2465-2470. https://doi.org/10.1007/s00296-011-1993-9
associated with a high degree of morbidity. 11. Enomoto DNH, Mekkes JR, Bossuyt PMM, Hoekzema R,
Management is therefore equally multifaceted and Bos JD. Quantification of cutaneous sclerosis with a skin
elasticity meter in patients with generalized scleroderma. J
complex, and requires a thoughtful systematic multi- Am Acad Dermatol. 1996;35(3 Pt 1):381-387. https:
disciplinary approach. Treatment of skin fibrosis //doi.org/10.1016/S0190-9622(96)90601-5
often overlaps with SSc-ILD, with MMF currently 12. M€uller B, Elrod J, Pensalfini M, et al. A novel ultra-light suction
remaining first line, although targeted therapies are device for mechanical characterization of skin. PLoS One.
on the horizon. In many cases, the skin provides a 2018;13(8):e0201440. https://doi.org/10.1371/journal.pone.0
201440
window to systemic progression in SSc, allowing 13. M€uller B, Ruby L, Jordan S, Rominger MB, Mazza E, Distler O.
dermatologists to contribute to early diagnosis, Validation of the suction device Nimble for the assessment of
treatment initiation, effective disease monitoring, skin fibrosis in systemic sclerosis. Arthritis Res Ther. 2020;
and improved patient outcomes. 22(1):128. https://doi.org/10.1186/s13075-020-02214-y
14. Chularojanamontri L, Sethabutra P, Kulthanan K,
Manapajon A. Dermatology life quality index in Thai patients
Conflicts of interest with systemic sclerosis: a cross-sectional study. Indian J
Dr Nikpour has received research grant support from DermatolVenereol Leprol. 2011;77(6):683-687. https://doi.org/
Actelion, BMS, GSK, Janssen, and UCB and honoraria from 10.4103/0378-6323.86481
Actelion, Boehringer Ingelheim, Janssen, Eli Lilly, Pfizer, 15. Man A, Correa JK, Ziemek J, Simms RW, Felson DT, Lafyatis R.
and UCB. Dr Krieg has received speaking fees from Development and validation of a patient-reported outcome
instrument for skin involvement in patients with systemic
Actelion. Dr Denton reports personal fees or research
sclerosis. Ann Rheum Dis. 2017;76(8):1374-1380. https:
grants to his institution from GlaxoSmithKline, Galapagos, //doi.org/10.1136/annrheumdis-2016-210534
Boehringer Ingelheim, Roche, CSL Behring, Corbus, 16. Johnson SR, Hawker GA, Davis AM. The health assessment
Horizon, and Arxx Therapeutics outside the submitted questionnaire disability index and scleroderma health assess-
work. Dr Saracino has received speaking fees from UCB. ment questionnaire in scleroderma trials: an evaluation of
Dr Jerjen has no conflict of interest to declare. their measurement properties. Arthritis Rheum. 2005;53(2):
256-262. https://doi.org/10.1002/art.21084
REFERENCES 17. Allanore Y, Bozzi S, Terlinden A, et al. Health Assessment
1. Clements P, Meedsger T, Feghali C. Cutaneous involvement Questionnaire-Disability Index (HAQ-DI) use in modelling
in systemic sclerosis. In: Clements P, Furst D, eds. Systemic disease progression in diffuse cutaneous systemic sclerosis:
Sclerosis. 2nd ed. Lippincott Williams & Wilkins; 2004:129-150. an analysis from the EUSTAR database. Arthritis Res Ther.
2. Clements P, Lachenbruch P, Siebold J, et al. Inter and intra- 2020;22(1):257. https://doi.org/10.1186/s13075-020-02329-2
observer variability of total skin thickness score (modified Rodnan 18. Steen VD, Medsger TA. The value of the Health Assessment
TSS) in systemic sclerosis. J Rheumatol. 1995;22(7):1281-1285. Questionnaire and special patient- generated scales to
3. Furst DE, Clements PJ, Steen VD, et al. The modified Rodnan demonstrate change in systemic sclerosis patients over
skin score is an accurate reflection of skin biopsy thickness in time. Arthritis Rheum. 1997;40(11):1984-1991. https://doi.org/
systemic sclerosis. J Rheumatol. 1998;25(1):84-88. 10.1002/art.1780401110
NOVEMBER 2022
19. Almeida C, Almeida I, Vasconcelos C. Quality of life in 726-728. https://doi.org/10.1111/j.1365-4362.1995.tb046

systemic sclerosis. Autoimmun Rev. 2015;14(12):1087-1096. 64.x
https://doi.org/10.1016/j.autrev.2015.07.012 33. Traineau H, Aggarwal R, Monfort JB, et al. Treatment of
20. Ziemek J, Man A, Hinchcliff M, Varga J, Simms RW, Lafyatis R. calcinosis cutis in systemic sclerosis and dermatomyositis: a
The relationship between skin symptoms and the sclero- review of the literature. J Am Acad Dermatol. 2020;82(2):317-
derma modification of the health assessment questionnaire, 325. https://doi.org/10.1016/j.jaad.2019.07.006
the modified Rodnan skin score, and skin pathology in 34. Palaniswamy C, Sekhri A, Aronow WS, Kalra A, Peterson SJ.
patients with systemic sclerosis. Rheumatology (Oxford). Association of warfarin use with valvular and vascular
2016;55(5):911-917. https://doi.org/10.1093/rheumatology/ calcification: a review. Clin Cardiol. 2011;34(2):74-81. https:
kew003 //doi.org/10.1002/clc.20865
21. Khanna D, Berrocal VJ, Giannini EH, et al. The American 35. Steen VD, Medsger TA. Case-control study of corticosteroids
College of Rheumatology provisional composite response and other drugs that either precipitate or protect from the
index for clinical trials in early diffuse cutaneous systemic development of scleroderma renal crisis. Arthritis Rheum.
sclerosis. Arthritis Rheumatol. 2016;68(2):299-311. https: 1998;41(9):1613-1619. https://doi.org/10.1002/1529-0131(19
//doi.org/10.1002/art.39501 9809)41:9\1613::AID-ART11[3.0.CO;2-O
22. Pope JE, Bellamy N, Seibold JR, et al. A randomized, 36. Liossis SNC, Bounas A, Andonopoulos AP. Mycophenolate
controlled trial of methotrexate versus placebo in early mofetil as first-line treatment improves clinically evident
diffuse scleroderma. Arthritis Rheum. 2001;44(6):1351-1358. early scleroderma lung disease. Rheumatology (Oxford). 2006;
https://doi.org/10.1002/1529-0131(200106)44:6\1351::AID- 45(8):1005-1008. https://doi.org/10.1093/rheumatology/kei
ART227[3.0.CO;2-I 211
23. Abignano G, Carriero A, Eng S, Del Galdo F. SAT0262 37. Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate
modified ACR composite response index in systemic sclerosis mofetil versus oral cyclophosphamide in scleroderma-related
score shows sensitivity and external validation to measure interstitial lung disease (SLS II): a randomised controlled,
magnitude of response at 12 months in diffuse cutaneous double-blind, parallel group trial. Lancet Respir Med. 2016;
systemic sclerosis. In: Saturday. vol 8. BMJ Publishing Group 4(9):708-719. https://doi.org/10.1016/S2213-2600(16)30152-7
Ltd and European League Against Rheumatism; June 15 38. De Vries-Bouwstra JK, Allanore Y, Matucci-Cerinic M, Balbir-
2019:1207.2-1208. https://doi.org/10.1136/annrheumdis-201 Gurman A. Worldwide expert agreement on updated rec-
9-eular.7962 ommendations for the treatment of systemic sclerosis. J
24. Tay T, Ferdowsi N, Baron M, et al. Measures of disease status Rheumatol. 2020;47(2):249-254. https://doi.org/10.3899/jrhe
in systemic sclerosis: a systematic review. Semin Arthritis um.181173
Rheum. 2017;46(4):473-487. https://doi.org/10.1016/j.semart 39. Nihtyanova SI, Brough GM, Black CM, Denton CP. Mycophe-
hrit.2016.07.010 nolate mofetil in diffuse cutaneous systemic sclerosisda
25. Melsens K, De Keyser F, Decuman S, Piette Y, retrospective analysis. Rheumatology (Oxford). 2007;46(3):
Vandecasteele E, Smith V. Disease activity indices in systemic 442-445. https://doi.org/10.1093/rheumatology/kel244
sclerosis: a systematic literature review. Clin Exp Rheumatol. 40. Le EN, Wigley FM, Shah AA, Boin F, Hummers LK. Long-term
2016;34(5 suppl 100):186-192. experience of mycophenolate mofetil for treatment of
26. Liem SIE, Vliet Vlieland TPM, Schoones JW, de Vries- diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2011;
Bouwstra JK. The effect and safety of exercise therapy in 70(6):1104-1107. https://doi.org/10.1136/ard.2010.142000
patients with systemic sclerosis: a systematic review. Rheu- 41. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide
matol Adv Pract. 2019;3(2):rkz044. https://doi.org/10.1093/ versus placebo in scleroderma lung disease. N Engl J Med.
rap/rkz044 2006;354(25):2655-2666. https://doi.org/10.1056/NEJMoa05
27. Connolly KL, Griffith JL, McEvoy M, Lim HW. Ultraviolet A1 5120
phototherapy beyond morphea: experience in 83 patients. 42. Tashkin DP, Elashoff R, Clements PJ, et al. Effects of 1-year
PhotodermatolPhotoimmunol Photomed. 2015;31(6):289-295. treatment with cyclophosphamide on outcomes at 2 years in
https://doi.org/10.1111/phpp.12185 Scleroderma Lung disease. Am J Respir Crit Care Med. 2007;
28. Bennani I, Lopez R, Bonnet D, et al. Improvement of micro- 176(10):1026-1034. https://doi.org/10.1164/rccm.200702-32
stomia in scleroderma after carbon dioxide laser treatment. 6OC
Case Rep Dermatol. 2016;8(2):142-150. https://doi.org/10. 43. Van Den Hoogen FHJ, Boerbooms AMT, Swaak AJG,
1159/000445821 Rasker JJ, Van Lier HJJ, Van De Putte LBA. Comparison of
29. Comstedt LR, Svensson A, Troilius A. Improvement of micro- methotrexate with placebo in the treatment of systemic
stomia in scleroderma after intense pulsed light: a case series sclerosis: a 24 week randomized double-blind trial, followed
of four patients. J Cosmet Laser Ther. 2012;14(2):102-106. by a 24 week observational trial. Br J Rheumatol. 1996;35(4):
https://doi.org/10.3109/14764172.2012.672744 364-372. https://doi.org/10.1093/rheumatology/35.4.364
30. Rosholm Comstedt LR, Svensson A, Hesselstrand R, Lehti L, 44. Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloa-
Troilius Rubin A. Effects of intense pulsed light in micro- blative autologous stem-cell transplantation for severe
stomia in patients with systemic sclerosis: A pilot study. J scleroderma. N Engl J Med. 2018;378(1):35-47. https:
Cosmet Laser Ther. 2017;19(3):143-148. https://doi.org/10.10 //doi.org/10.1056/NEJMoa1703327
80/14764172.2016.1262961 45. van Laar JM, Farge D, Sont JK, et al. Autologous hematopoi-
31. Sharada B, Kumar A, Kakker R, et al. Intravenous dexameth- etic stem cell transplantation vs intravenous pulse cyclo-
asone pulse therapy in diffuse systemic sclerosis. A random- phosphamide in diffuse cutaneous systemic sclerosis: a
ized placebo-controlled study. Rheumatol Int. 1994;14(3):91- randomized clinical trial. JAMA. 2014;311(24):2490-2498.
94. https://doi.org/10.1007/BF00300808 https://doi.org/10.1001/jama.2014.6368
32. Pai BS, Srinivas CR, Sabitha L, Shenoi SD, Balachandran CN, 46. Burt RK, Shah SJ, Dill K, et al. Autologous non-myeloablative
Acharya S. Efficacy of dexamethasone pulse therapy in haemopoietic stem-cell transplantation compared with pulse
progressive systemic sclerosis. Int J Dermatol. 1995;34(10): cyclophosphamide once per month for systemic sclerosis
VOLUME 87, NUMBER 5
(ASSIST): an open-label, randomised phase 2 trial. Lancet. 60. Bosello SL, De Luca G, Rucco M, et al. Long-term efficacy of B
2011;378(9790):498-506. https://doi.org/10.1016/S0140-6736 cell depletion therapy on lung and skin involvement in
(11)60982-3 diffuse systemic sclerosis. Semin Arthritis Rheum. 2015;44(4):
47. Sullivan K, Keyes-Elstein L, McSweeney P, et al. Myeloablative 428-436. https://doi.org/10.1016/j.semarthrit.2014.09.002
autologous transplantation of CD34 1 selected hematopoi- 61. Jordan S, Distler JHW, Maurer B, et al. Effects and safety of
etic stem cells (HSCT) vs monthly intravenous cyclophospha- rituximab in systemic sclerosis: an analysis from the European
mide (CY) for severe scleroderma with internal organ Scleroderma Trial and Research (EUSTAR) group. Ann Rheum
involvement: outcomes of a randomized North American Dis. 2015;74(6):1188-1194. https://doi.org/10.1136/annrheum
clinical trial. Biol Blood Marrow Transplant. 2017;23(3):S23- dis-2013-204522
S24. https://doi.org/10.1016/j.bbmt.2017.01.012 62. Daoussis D, Melissaropoulos K, Sakellaropoulos G, et al. A
48. Del Papa N, Onida F, Zaccara E, et al. Autologous hemato- multicenter, open-label, comparative study of B-cell deple-
poietic stem cell transplantation has better outcomes than tion therapy with rituximab for systemic sclerosis-associated
conventional therapies in patients with rapidly progressive interstitial lung disease. Semin Arthritis Rheum. 2017;46(5):
systemic sclerosis. Bone Marrow Transplant. 2017;52(1):53-58. 625-631. https://doi.org/10.1016/j.semarthrit.2016.10.003
https://doi.org/10.1038/bmt.2016.211 63. Fraticelli P, Fischetti C, Salaffi F, et al. Combination therapy
49. Burt RK, Oliveira MC, Shah SJ, et al. Cardiac involvement and with rituximab and mycophenolate mofetil in systemic
treatment-related mortality after non-myeloablative haemo- sclerosis. A single-centre case series study. Clin Exp Rheuma-
poietic stem-cell transplantation with unselected autologous tol. 2018;36(4 suppl 113):142-145. PubMed: 30277864.
peripheral blood for patients with systemic sclerosis: a 64. Tang R, Yu J, Shi Y, et al. Safety and efficacy of rituximab in
retrospective analysis. Lancet. 2013;381(9872):1116-1124. systemic sclerosis: A systematic review and meta-analysis. Int
https://doi.org/10.1016/S0140-6736(12)62114-X Immunopharmacol. 2020;83(87):106389. https://doi.org/10.10
50. Spierings J, van Rhijn-Brouwer FCC, van Laar JM. Hemato- 16/j.intimp.2020.106389
poietic stem-cell transplantation in systemic sclerosis: an 65. Desallais L, Avouac J, Frechet M, et al. Targeting IL-6 by both
update. Curr Opin Rheumatol. 2018;30(6):541-547. https: passive or active immunization strategies prevents
//doi.org/10.1097/BOR.0000000000000541 bleomycin-induced skin fibrosis. Arthritis Res Ther. 2014;
51. Mavropoulos A, Simopoulou T, Varna A, et al. Breg cells are 16(4):R157. https://doi.org/10.1186/ar4672
numerically decreased and functionally impaired in patients 66. Le Huu D, Matsushita T, Jin G, et al. IL-6 blockade attenuates
with systemic sclerosis. Arthritis Rheumatol. 2016;68(2):494- the development of murine sclerodermatous chronic graft-
504. https://doi.org/10.1002/art.39437 versus-host disease. J Invest Dermatol. 2012;132(12):2752-
52. François A, Chatelus E, Wachsmann D, et al. B lymphocytes 2761. https://doi.org/10.1038/jid.2012.226
and B-cell activating factor promote collagen and profibrotic 67. Kitaba S, Murota H, Terao M, et al. Blockade of interleukin-6
markers expression by dermal fibroblasts in systemic scle- receptor alleviates disease in mouse model of scleroderma.
rosis. Arthritis Res Ther. 2013;15(5):R168. https://doi.org/10. Am J Pathol. 2012;180(1):165-176. https://doi.org/10.1016/j.aj
1186/ar4352 path.2011.09.013
53. Sato S, Fujimoto M, Hasegawa M, Takehara K, Tedder TF. 68. Khan K, Xu S, Nihtyanova S, et al. Clinical and pathological
Altered B lymphocyte function induces systemic autoimmu- significance of interleukin 6 overexpression in systemic
nity in systemic sclerosis. Mol Immunol. 2004;41(12):1123- sclerosis. Ann Rheum Dis. 2012;71(7):1235-1242. https:
1133. https://doi.org/10.1016/j.molimm.2004.06.025 //doi.org/10.1136/annrheumdis-2011-200955
54. Hasegawa M, Hamaguchi Y, Yanaba K, et al. B-lymphocyte 69. Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K,
depletion reduces skin fibrosis and autoimmunity in the Sato S. Elevated serum BAFF levels in patients with systemic
tight-skin mouse model for systemic sclerosis. Am J Pathol. sclerosis: enhanced BAFF signaling in systemic sclerosis B
2006;169(3):954-966. https://doi.org/10.2353/ajpath.2006.06 lymphocytes. Arthritis Rheum. 2006;54(1):192-201. https:
0205 //doi.org/10.1002/art.21526
55. Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with 70. Gordon JK, Martyanov V, Franks JM, et al. Belimumab for the
rituximab in scleroderma: results from a 1-year, proof-of- treatment of early diffuse systemic sclerosis: results of a random-
principle study. Rheumatology (Oxford). 2010;49(2):271-280. ized, double-blind, placebo-controlled, pilot trial. Arthritis Rheu-
https://doi.org/10.1093/rheumatology/kep093 matol. 2018;70(2):308-316. https://doi.org/10.1002/art.40358
56. Daoussis D, Liossis SN, Tsamandas AC, et al. Effect of long-term 71. Distler O, Highland KB, Gahlemann M, et al. Nintedanib for
treatment with rituximab on pulmonary function and skin systemic sclerosiseassociated interstitial lung disease. N Engl
fibrosis in patients with diffuse systemic sclerosis. Clin Exp J Med. 2019;380(26):2518-2528. https://doi.org/10.1056/NEJ
Rheumatol. 2012;30(2 suppl 71):S17-S22. PubMed: 22244622. Moa1903076
57. Smith V, Van Praet JT, Vandooren B, et al. Rituximab in diffuse 72. Denton CP, Ong VH, Xu S, et al. Therapeutic interleukin-6
cutaneous systemic sclerosis: an open-label clinical and blockade reverses transforming growth factor-beta pathway
histopathological study. Ann Rheum Dis. 2010;69(1):193-197. activation in dermal fibroblasts: insights from the faSScinate
https://doi.org/10.1136/ard.2008.095463 clinical trial in systemic sclerosis. Ann Rheum Dis. 2018;77(9):
58. Smith V, Piette Y, Van Praet JT, et al. Two-year Results of an 1362-1371. https://doi.org/10.1136/annrheumdis-2018-213031
Open Pilot Study of a 2-treatment Course with rituximab in 73. Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of
Patients with Early Systemic Sclerosis with Diffuse Skin subcutaneous tocilizumab in adults with systemic sclerosis
Involvement. J Rheumatol. 2013;40(1):52-57. https://doi.org/ (faSScinate): a phase 2, randomised, controlled trial. Lancet.
10.3899/jrheum.120778 2016;387(10038):2630-2640. https://doi.org/10.1016/S0140-
59. Bosello S, De Santis M, Lama G, et al. B cell depletion in 6736(16)00232-4
diffuse progressive systemic sclerosis: safety, skin score 74. Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic
modification and IL-6 modulation in an up to thirty-six sclerosis: a randomised, double-blind, placebo-controlled,
months follow-up open-label trial. Arthritis Res Ther. 2010; phase 3 trial. Lancet Respir Med. 2020;8(10):963-974. https:
12(2):R54. https://doi.org/10.1186/ar2965 //doi.org/10.1016/S2213-2600(20)30318-0
NOVEMBER 2022
75. Khanna D, Spino C, Johnson S, et al. Abatacept in early 89. Inventiva. Inventiva announces results from phase IIb clinical
diffuse cutaneous systemic sclerosis: results of a phase II trial with lanifibranor in systemic sclerosis. Accessed March
investigator-initiated, multicenter, double-blind, randomized, 16, 2021. https://inventivapharma.com/results-from-phase-
placebo-controlled trial. Arthritis Rheumatol. 2020;72(1):125- iib-clinical-trial-with-lanifibranor-in-systemic-sclerosis/
136. https://doi.org/10.1002/art.41055 90. Aung WW, Wang C, Xibei J, et al. Immunomodulating role of
76. Matei AE, Beyer C, Gy€ orfi AH, et al. Protein kinases G are the JAKs inhibitor tofacitinib in a mouse model of bleomycin-
essential downstream mediators of the antifibrotic effects induced scleroderma. J Dermatol Sci. 2021;101(3):174-184.
of sGC stimulators. Ann Rheum Dis. 2018;77(3):459-459. https://doi.org/10.1016/j.jdermsci.2020.12.007
https://doi.org/10.1136/annrheumdis-2017-212489 91. Wang W, Bhattacharyya S, Marangoni RG, et al. The JAK/STAT
77. Beyer C, Reich N, Schindler SC, et al. Stimulation of soluble pathway is activated in systemic sclerosis and is effectively
guanylate cyclase reduces experimental dermal fibrosis. Ann targeted by tofacitinib. J Scleroderma Relat Disord. 2020;5(1):
Rheum Dis. 2012;71(6):1019-1026. https://doi.org/10.1136/ 40-50. https://doi.org/10.1177/2397198319865367
annrheumdis-2011-200862 92. Khanna D, Bush E, Nagaraja V, et al. Tofacitinib in early diffuse
78. Beyer C, Zenzmaier C, Palumbo-Zerr K, et al. Stimulation of cutaneous systemic sclerosisdresults of Phase I/II
the soluble guanylate cyclase (sGC) inhibits fibrosis by investigator-initiated, double-blind randomized placebo-
blocking non-canonical TGFb signalling. Ann Rheum Dis. controlled trial [abstract]. Arthritis Rheumatol. 2019;71(suppl
2015;74(7):1408-1416. https://doi.org/10.1136/annrheumdis- 10). Accessed April 30, 2021. https://acrabstracts.org/
2013-204508 abstract/tofacitinib-in-early-diffuse-cutaneous-systemic-sclero
79. Khanna D, Allanore Y, Denton CP, et al. Riociguat in patients with sis-results-of-phase-i-ii-investigator-initiated-double-blind-ran
early diffuse cutaneous systemic sclerosis (RISE-SSc): rando- domized-placebo-controlled-trial/
mised, double-blind, placebo-controlled multicentre trial. Ann 93. Scuderi N, Ceccarelli S, Onesti MG, et al. Human adipose-
Rheum Dis. 2020;79(5):618-625. https://doi.org/10.1136/annr derived stromal cells for cell-based therapies in the treatment
heumdis-2019-216823 of systemic sclerosis. Cell Transplant. 2013;22(5):779-795.
80. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the https://doi.org/10.3727/096368912X639017
treatment of pulmonary arterial hypertension. N Engl J Med. 94. Guillaume-Jugnot P, Daumas A, Magalon J, et al. Autologous
2013;369(4):330-340. https://doi.org/10.1056/NEJMoa1209 adipose-derived stromal vascular fraction in patients with sys-
655 temic sclerosis: 12-month follow-up. Rheumatology (Oxford). 2016;
81. Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab 55(2):301-306. https://doi.org/10.1093/rheumatology/kev323
treatment decreases biomarkers and improves clinical symp- 95. Granel B, Daumas A, Jouve E, et al. Safety, tolerability and
toms in systemic sclerosis patients. J Clin Invest. 2015;125(7): potential efficacy of injection of autologous adipose-derived
2795-2807. https://doi.org/10.1172/JCI77958 stromal vascular fraction in the fingers of patients with
82. Khanna D, Albera C, Fischer A, et al. An Open-label, Phase II systemic sclerosis: an open-label phase I trial. Ann Rheum Dis.
Study of the Safety and Tolerability of pirfenidone in Patients 2015;74(12):2175-2182. https://doi.org/10.1136/annrheum-
with Scleroderma-associated interstitial Lung Disease: the dis-2014-205681
LOTUSS Trial. J Rheumatol. 2016;43(9):1672-1679. https: 96. Scleroderma and Raynaud’s UK. Hands and feet. Published
//doi.org/10.3899/jrheum.151322 online, 2021. Accessed March 25, 2021. https://www.sruk.co.
83. Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis uk/scleroderma/scleroderma-and-your-body/hands-and-feet/
of systemic sclerosis. Annu Rev Pathol. 2011;6(1):509-537. 97. Gabriele S, Alberto P, Sergio G, Fernanda F, Marco MC. Emerging
https://doi.org/10.1146/annurev-pathol-011110-130312 potentials for an antioxidant therapy as a new approach to the
84. Allanore Y, Wung P, Soubrane C, et al. A randomised, double- treatment of systemic sclerosis. Toxicology. 2000;155(1-3):1-15.
blind, placebo-controlled, 24-week, phase II, proof-of-concept https://doi.org/10.1016/S0300-483X(00)00272-9
study of romilkimab (SAR156597) in early diffuse cutaneous 98. Wei J, Ghosh AK, Chu H, et al. The histone deacetylase sirtuin
systemic sclerosis. Ann Rheum Dis. 2020;79(12):1600-1607. 1 is reduced in systemic sclerosis and abrogates fibrotic
https://doi.org/10.1136/annrheumdis-2020-218447 responses by targeting transforming growth factor b
85. Gonzalez EG, Selvi E, Balistreri E, et al. Synthetic cannabinoid signaling. Arthritis Rheumatol. 2015;67(5):1323-1334. https:
ajulemic acid exerts potent antifibrotic effects in experi- //doi.org/10.1002/art.39061
mental models of systemic sclerosis. Ann Rheum Dis. 2012; 99. Volkmann ER, Varga J. Emerging targets of disease-modifying
71(9):1545-1551. https://doi.org/10.1136/annrheumdis-2011- therapy for systemic sclerosis. Nat Rev Rheumatol. 2019;15(4):
200314 208-224. https://doi.org/10.1038/s41584-019-0184-z
86. Spiera R, Hummers L, Chung L, et al. OP0006 Safety and 100. Grygiel-G orniak B, Puszczewicz M. Oxidative damage and
efficacy of lenabasum (JBT-101) in diffuse cutaneous systemic antioxidative therapy in systemic sclerosis. Mediators Inflamm.
sclerosis subjects treated for one year in an open-label 2014;2014:389582. https://doi.org/10.1155/2014/389582
extension of trial jbt101-ssc-001. In: Wednesday, 13 June 101. Cracowski JL, Girolet S, Imbert B, et al. Effects of short-term
2018. BMJ Publishing Group Ltd and European League treatment with vitamin E in systemic sclerosis: A double blind,
Against Rheumatism; 2018:52.1-52. https://doi.org/10.1136/ randomized, controlled clinical trial of efficacy based on urinary
annrheumdis-2018-eular.3512 isoprostane measurement. Free Radic Biol Med. 2005;38(1):98-
87. Wei J, Zhu H, Komura K, et al. A synthetic PPAR-g agonist 103. https://doi.org/10.1016/j.freeradbiomed.2004.09.032
triterpenoid ameliorates experimental fibrosis: PPAR-g-inde- 102. Hachulla E, Clerson P, Launay D, et al. Natural history of
pendent suppression of fibrotic responses. Ann Rheum Dis. ischemic digital ulcers in systemic sclerosis: single-center
2014;73(2):446-454. https://doi.org/10.1136/annrheumdis-20 retrospective longitudinal study. J Rheumatol. 2007;34(12):
12-202716 2423-2430. PubMed: 17985402.
88. Avouac J, Konstantinova I, Guignabert C, et al. Pan-PPAR 103. Pauling JD, Hughes M, Pope JE. Raynaud’s phenomenondan
agonist IVA337 is effective in experimental lung fibrosis and update on diagnosis, classification and management. Clin
pulmonary hypertension. Ann Rheum Dis. 2017;76(11):1931- Rheumatol. 2019;38(12):3317-3330. https://doi.org/10.1007/
1940. https://doi.org/10.1136/annrheumdis-2016-210821 s10067-019-04745-5
VOLUME 87, NUMBER 5
104. Rirash F, Tingey PC, Harding SE, et al. Calcium channel 118. Pancera P, Sansone S, Secchi S, Covi G, Lechi A. The effects of
blockers for primary and secondary Raynaud’s phenomenon. thromboxane A2 inhibition (picotamide) and angiotensin II
Cochrane Database Syst Rev. December 2017;12:CD000467. receptor blockade (losartan) in primary Raynaud’s phenom-
https://doi.org/10.1002/14651858.CD000467.pub2 enon. J Intern Med. 1997;242(5):373-376. https://doi.org/10.10
105. Fernandez-Codina A, Walker KM, Pope JE, Scleroderma 46/j.1365-2796.1997.00219.x
Algorithm Group. Treatment algorithms for systemic sclerosis 119. Wood HM, Ernst ME. Renindangiotensin system mediators
according to experts. Arthritis Rheumatol. 2018;70(11):1820- and Raynaud’s phenomenon. Ann Pharmacother. 2006;
1828. https://doi.org/10.1002/art.40560 40(11):1998-2002. https://doi.org/10.1345/aph.1H201
106. Hughes M, Ong VH, Anderson ME, et al. Consensus best 120. Challenor VF, Waller DG, Hayward RA, Griffin MJ, Roath OS.
practice pathway of the UK Scleroderma Study Group: digital Subjective and objective assessment of enalapril in primary
vasculopathy in systemic sclerosis. Rheumatology (Oxford). Raynaud’s phenomenon. Br J Clin Pharmacol. 1991;31(4):477-
2015;54(11):2015-2024. https://doi.org/10.1093/rheumatolo 480. https://doi.org/10.1111/j.1365-2125.1991.tb05565.x
gy/kev201 121. Rustin MH, Almond NE, Beacham JA, et al. The effect of
107. Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR captopril on cutaneous blood flow in patients with primary
recommendations for the treatment of systemic sclerosis. Raynaud’s phenomenon. Br J Dermatol. 1987;117(6):751-758.
Ann Rheum Dis. 2017;76(8):1327-1339. https://doi.org/10.11 https://doi.org/10.1111/j.1365-2133.1987.tb07356.x
36/annrheumdis-2016-209909 122. Tosi S, Marchesoni A, Messina K, Bellintani C, Sironi G,
108. Kahan A, Amor B, Menkes CJ. A randomised double-blind trial Faravelli C. Treatment of Raynaud’s phenomenon with
of diltiazem in the treatment of Raynaud’s phenomenon. Ann captopril. Drugs Exp Clin Res. 1987;13(1):37-42.
Rheum Dis. 1985;44(1):30-33. https://doi.org/10.1136/ard.44.1.30 123. Janini SD, Scott DGI, Coppock JS, Bacon PA, Kendall MJ.
109. Shenoy PD, Kumar S, Jha LK, et al. Efficacy of tadalafil in Enalapril in Raynaud’s phenomenon. J Clin Pharm Ther. 1988;
secondary Raynaud’s phenomenon resistant to vasodilator 13(2):145-150. https://doi.org/10.1111/j.1365-2710.1988.tb0
therapy: a double-blind randomized cross-over trial. Rheu- 0171.x
matology (Oxford). 2010;49(12):2420-2428. https://doi.org/ 124. Beckett VL, Conn DL, Fuster V, et al. Trial of platelet-inhibiting
10.1093/rheumatology/keq291 drug in scleroderma double-blind study with dipyridamole
110. Fries R, Shariat K, von Wilmowsky H, B€ ohm M. Sildenafil in the and aspirin. Arthritis Rheum. 1984;27(10):1137-1143. https:
treatment of Raynaud’s phenomenon resistant to vasodila- //doi.org/10.1002/art.1780271009
tory therapy. Circulation. 2005;112(19):2980-2985. https: 125. Denton CP, Howell K, Stratton RJ, Black CM. Long-term low
//doi.org/10.1161/CIRCULATIONAHA.104.523324 molecular weight heparin therapy for severe Raynaud’s
111. Andrigueti FV, Ebbing PCC, Arismendi MI, Kayser C. Evalua- phenomenon: a pilot study. Clin Exp Rheumatol. 2000;18(4):
tion of the effect of sildenafil on the microvascular blood 499-502. PubMed: 10949727.
flow in patients with systemic sclerosis: a randomised, 126. Pope J, Fenlon D, Thompson A, et al. Prazosin for Raynaud’s
double-blind, placebo-controlled study. Clin Exp Rheumatol. phenomenon in progressive systemic sclerosis. Cochrane
2017;35(4 suppl 106):151-158. PubMed: 28281457. Database Syst Rev. 2000;2:CD000956. https://doi.org/10.1002/
112. Roustit M, Blaise S, Allanore Y, Carpentier PH, Caglayan E, 14651858.CD000956
Cracowski JL. Phosphodiesterase-5 inhibitors for the treat- 127. Thiers BH. Statins: potentially useful in therapy of systemic
ment of secondary Raynaud’s phenomenon: systematic sclerosis-related Raynaud’s phenomenon and digital ulcers.
review and meta-analysis of randomised trials. Ann Rheum Yearbook of Dermatology and Dermatologic Surgery. 2009;
Dis. 2013;72(10):1696-1699. https://doi.org/10.1136/annr- 2009:234-235. https://doi.org/10.1016/S0093-3619(09)79298-6
heumdis-2012-202836 128. Ladak K, Pope JE. A review of the effects of statins in systemic
113. Mitchell JA, Ali F, Bailey L, Moreno L, Harrington LS. Role of sclerosis. Semin Arthritis Rheum. 2016;45(6):698-705. https:
nitric oxide and prostacyclin as vasoactive hormones //doi.org/10.1016/j.semarthrit.2015.10.013
released by the endothelium. Exp Physiol. 2008;93(1):141- 129. Gliddon AE, Dore CJ, Black CM, et al. Prevention of vascular
147. https://doi.org/10.1113/expphysiol.2007.038588 damage in scleroderma and autoimmune Raynaud’s phe-
114. Falcetti E, Hall SM, Phillips PG, et al. Smooth muscle prolif- nomenon: A multicenter, randomized, double-blind,
eration and role of the prostacyclin (IP) receptor in idiopathic placebo-controlled trial of the angiotensin-converting
pulmonary arterial hypertension. Am J Respir Crit Care Med. enzyme inhibitor quinapril. Arthritis Rheum. 2007;56(11):
2010;182(9):1161-1170. https://doi.org/10.1164/rccm.201001- 3837-3846. https://doi.org/10.1002/art.22965
0011OC 130. Hughes M, Khanna D, Pauling JD. Drug initiation and escalation
115. Ingegnoli F, Schioppo T, Allanore Y, et al. Practical sugges- strategies of vasodilator therapies for Raynaud’s phenomenon:
tions on intravenous iloprost in Raynaud’s phenomenon and can we treat to target? Rheumatology (Oxford). 2020;59(3):464-
digital ulcer secondary to systemic sclerosis: systematic 466. https://doi.org/10.1093/rheumatology/kez522
literature review and expert consensus. Semin Arthritis 131. Iorio ML, Masden DL, Higgins JP. Botulinum toxin A
Rheum. 2019;48(4):686-693. https://doi.org/10.1016/j.semar treatment of Raynaud’s phenomenon: a review. Semin
thrit.2018.03.019 Arthritis Rheum. 2012;41(4):599-603. https://doi.org/10.1016/j.
116. Coleiro B, Marshall SE, Denton CP, et al. Treatment of semarthrit.2011.07.006
Raynaud’s phenomenon with the selective serotonin reup- 132. Hughes M, Allanore Y, Chung L, Pauling JD, Denton CP,
take inhibitor fluoxetine. Rheumatology (Oxford). 2001;40(9): Matucci-Cerinic M. Raynaud phenomenon and digital ulcers
1038-1043. https://doi.org/10.1093/rheumatology/40.9.1038 in systemic sclerosis. Nat Rev Rheumatol. 2020;16(4):208-221.
117. Dziadzio M, Denton CP, Smith R, et al. Losartan therapy for https://doi.org/10.1038/s41584-020-0386-4
Raynaud’s phenomenon and scleroderma: clinical and 133. Bello RJ, Cooney CM, Melamed E, et al. The therapeutic
biochemical findings in a fifteen-week, randomized, efficacy of botulinum toxin in treating scleroderma-
parallel-group, controlled trial. Arthritis Rheum. 1999;42(12): associated Raynaud’s phenomenon: A randomized, double-
2646-2655. https://doi.org/10.1002/1529-0131(199912)42:12 blind, placebo-controlled clinical trial. Arthritis Rheumatol.
\2646::AID-ANR21[3.0.CO;2-T 2017;69(8):1661-1669. https://doi.org/10.1002/art.40123
NOVEMBER 2022
134. Momeni A, Sorice SC, Valenzuela A, Fiorentino DF, Chung L, 149. Parisi S, Peroni CL, Lagana A, et al. Efficacy of ambrisentan in
Chang J. Surgical treatment of systemic sclerosis-is it justified the treatment of digital ulcers in patients with systemic
to offer peripheral sympathectomy earlier in the disease sclerosis: a preliminary study. Rheumatology (Oxford). 2013;
process? Microsurgery. 2015;35(6):441-446. https://doi.org/10. 52(6):1142-1144. https://doi.org/10.1093/rheumatology/ket
1002/micr.22379 019
135. Pollock DC, Li Z, Rosencrance E, Krome J, Koman LA, 150. Chung L, Ball K, Yaqub A, Lingala B, Fiorentino D. Effect of the
Smith TL. Acute effects of periarterial sympathectomy on endothelin type Aeselective endothelin receptor antagonist
the cutaneous microcirculation. J Orthop Res. 1997;15(3):408- ambrisentan on digital ulcers in patients with systemic
413. https://doi.org/10.1002/jor.1100150313 sclerosis: results of a prospective pilot study. J Am Acad
136. Matsumoto Y, Ueyama T, Endo M, et al. Endoscopic thoracic Dermatol. 2014;71(2):400-401. https://doi.org/10.1016/j.jaad.
sympathicotomy for Raynaud’s phenomenon. J Vasc Surg. 2014.04.028
2002;36(1):57-61. https://doi.org/10.1067/mva.2002.123330 151. Moinzadeh P, Hunzelmann N, Krieg T. Combination therapy
137. Amanzi L, Braschi F, Fiori G, et al. Digital ulcers in sclero- with an endothelin-1 receptor antagonist (bosentan) and a
derma: staging, characteristics and sub-setting through phosphodiesterase V inhibitor (sildenafil) for the manage-
observation of 1614 digital lesions. Rheumatology (Oxford). ment of severe digital ulcerations in systemic sclerosis. J Am
2010;49(7):1374-1382. https://doi.org/10.1093/rheumatolo Acad Dermatol. 2011;65(3):e102-e104. https://doi.org/10.10
gy/keq097 16/j.jaad.2011.04.029
138. Hughes M, Herrick AL. Digital ulcers in systemic sclerosis. 152. Ambach A, Seo W, Bonnekoh B, Gollnick H. Low-dose
Rheumatol (Oxf Engl). 2017;56(1):14-25. https://doi.org/10. combination therapy of severe digital ulcers in diffuse
1093/rheumatology/kew047 progressive systemic sclerosis with the endothelin-1 receptor
139. Lebedoff N, Frech TM, Shanmugam VK, et al. Review of local antagonist bosentan and the phosphodiesterase V inhibitor
wound management for scleroderma-associated digital ul- sildenafil. J Dtsch Dermatol Ges. 2009;7(10):888-891. https:
cers. J Scleroderma Relat Disord. 2018;3(1):66-70. https: //doi.org/10.1111/j.1610-0387.2009.07057.x
//doi.org/10.5301/jsrd.5000268 153. Cutolo M, Ruaro B, Pizzorni C, et al. Longterm treatment with
140. Ozgocmen S, Kaya A, Coskun BK. Topical lidocaine helps endothelin receptor antagonist bosentan and iloprost im-
reduce pain of digital ulcers in systemic sclerosis (sclero- proves fingertip blood perfusion in systemic sclerosis. J
derma). Clin Rheumatol. 2006;25(3):378-379. https://doi.org/ Rheumatol. 2014;41(5):881-886. https://doi.org/10.3899/jrh
10.1007/s10067-005-0016-1 eum.131284
141. Tingey T, Shu J, Smuczek J, Pope J. Meta-analysis of healing 154. Trombetta AC, Pizzorni C, Ruaro B, et al. Effects of longterm
and prevention of digital ulcers in systemic sclerosis. Arthritis treatment with bosentan and iloprost on nailfold absolute
Care Res (Hoboken). 2013;65(9):1460-1471. https://doi.org/10. capillary number, fingertip blood perfusion, and clinical
1002/acr.22018 status in systemic sclerosis. J Rheumatol. 2016;43(11):2033-
142. Hachulla E, Hatron PY, Carpentier P, et al. Efficacy of sildenafil 2041. https://doi.org/10.3899/jrheum.160592
on ischaemic digital ulcer healing in systemic sclerosis: the 155. Matucci-Cerinic M, Krieg T, Guillevin L, et al. Elucidating the
placebo-controlled SEDUCE study. Ann Rheum Dis. 2016; burden of recurrent and chronic digital ulcers in systemic
75(6):1009-1015. https://doi.org/10.1136/annrheumdis-2014- sclerosis: long-term results from the DUO Registry. Ann
207001 Rheum Dis. 2016;75(10):1770-1776. https://doi.org/10.1136/
143. Wigley FM, Seibold JR, Wise RA, McCloskey DA, Dole WP. annrheumdis-2015-208121
Intravenous iloprost treatment of Raynaud’s phenomenon 156. Khor CG, Chen XL-F, Lin TS, Lu CH, Hsieh SC. Rituximab for
and ischemic ulcers secondary to systemic sclerosis. J refractory digital infarcts and ulcers in systemic sclerosis. Clin
Rheumatol. 1992;19(9):1407-1414. PubMed: 1279170. Rheumatol. 2014;33(7):1019-1020. https://doi.org/10.1007/
144. Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost s10067-014-2579-1
infusion in patients with Raynaud phenomenon secondary to 157. Fernandes das Neves M, Oliveira S, Amaral MC, Delgado
systemic sclerosis: A multicenter, placebo-controlled, double- Alves J. Treatment of systemic sclerosis with tocilizumab.
blind study. Ann Intern Med. 1994;120(3):199-206. https: Rheumatology (Oxford). 2015;54(2):371-372. https://doi.org/
//doi.org/10.7326/0003-4819-120-3-199402010-00004 10.1093/rheumatology/keu435
145. Badesch DB, Tapson VF, McGoon MD, et al. Continuous 158. Moran ME. Scleroderma and evidence based non-
intravenous epoprostenol for pulmonary hypertension due pharmaceutical treatment modalities for digital ulcers: a
to the Scleroderma spectrum of disease. A randomized, systematic review. J Wound Care. 2014;23(10):510-516.
controlled trial. Ann Intern Med. 2000;132(6):425-434. https: https://doi.org/10.12968/jowc.2014.23.10.510
//doi.org/10.7326/0003-4819-132-6-200003210-00002 159. Mirasoglu B, Bagli BS, Aktas S. Hyperbaric oxygen therapy for
146. Matucci-Cerinic M, Denton CP, Furst DE, et al. Bosentan chronic ulcers in systemic sclerosisdcase series. Int J
treatment of digital ulcers related to systemic sclerosis: Dermatol. 2017;56(6):636-640. https://doi.org/10.1111/ijd.13
results from the RAPIDS-2 randomised, double-blind, 570
placebo-controlled trial. Ann Rheum Dis. 2011;70(1):32-38. 160. Markus YM, Bell MJ, Evans AW. Ischemic scleroderma
https://doi.org/10.1136/ard.2010.130658 wounds successfully treated with hyperbaric oxygen ther-
147. Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in apy. J Rheumatol. 2006;33(8):1694-1696. PubMed: 16881
systemic sclerosis: prevention by treatment with bosentan, 126.
an oral endothelin receptor antagonist. Arthritis Rheum. 2004; _
161. Zebryk P, Puszczewicz MJ. Botulinum toxin A in the
50(12):3985-3993. https://doi.org/10.1002/art.20676 treatment of Raynaud’s phenomenon: a systematic review.
148. Khanna D, Denton CP, Merkel PA, et al. Effect of Macitentan Arch Med Sci. 2016;4:864-870. https://doi.org/10.5114/ao
on the development of new ischemic digital ulcers in ms.2015.48152
patients with systemic sclerosis: DUAL-1 and DUAL-2 ran- 162. Motegi S, Yamada K, Toki S, et al. Beneficial effect of
domized clinical trials. JAMA. 2016;315(18):1975-1988. https: botulinum toxin A on Raynaud’s phenomenon in Japanese
//doi.org/10.1001/jama.2016.5258 patients with systemic sclerosis: A prospective, case series
VOLUME 87, NUMBER 5
study. J Dermatol. 2016;43(1):56-62. https://doi.org/10.1111/ 178. Giuggioli D, Lumetti F, Colaci M, Fallahi P, Antonelli A, Ferri C.
1346-8138.13030 Rituximab in the treatment of patients with systemic sclerosis. Our
163. Chiou G, Crowe C, Suarez P, Chung L, Curtin C, Chang J. experience and review of the literature. Autoimmun Rev. 2015;
Digital sympathectomy in patients with scleroderma: an 14(11):1072-1078. https://doi.org/10.1016/j.autrev.2015.07.008
overview of the practice and referral patterns and percep- 179. Aggarwal R, Loganathan P, Koontz D, Qi Z, Reed AM,
tions of rheumatologists. Ann Plast Surg. 2015;75(6):637-643. Oddis CV. Cutaneous improvement in refractory adult and
https://doi.org/10.1097/SAP.0000000000000614 juvenile dermatomyositis after treatment with rituximab.
164. Bogoch ER, Gross DK. Surgery of the hand in patients with Rheumatology (Oxford). 2017;56(2):247-254. https://doi.org/
systemic sclerosis: outcomes and considerations. J Rheuma- 10.1093/rheumatology/kew396
tol. 2005;32(4):642-648. 180. Robertson LP, Marshall RW, Hickling P. Treatment of cuta-
165. Wasserman A, Brahn E. Systemic sclerosis: bilateral improve- neous calcinosis in limited systemic sclerosis with minocy-
ment of Raynaud’s phenomenon with unilateral digital cline. Ann Rheum Dis. 2003;62(3):267-269. https://doi.org/10.
sympathectomy. Semin Arthritis Rheum. 2010;40(2):137-146. 1136/ard.62.3.267
https://doi.org/10.1016/j.semarthrit.2009.08.002 181. Fuchs D, Fruchter L, Fishel B, Holtzman M, Yaron M.
166. Bene MD, Pozzi MR, Rovati L, Mazzola I, Erba G, Bonomi S. Colchicine suppression of local inflammation due to calci-
Autologous fat grafting for scleroderma-induced digital nosis in dermatomyositis and progressive systemic sclerosis.
ulcers. An effective technique in patients with systemic Clin Rheumatol. 1986;5(4):527-530. PubMed: 3816102.
sclerosis. Handchir Mikrochir Plast Chir. 2014;46(4):242-247. 182. Song P, Fett NM, Lin J, Merola JF, Costner M, Vleugels RA.
https://doi.org/10.1055/s-0034-1376970 Lack of response to intravenous sodium thiosulfate in three
167. Bank J, Fuller SM, Henry GI, Zachary LS. Fat grafting to the cases of extensive connective tissue disease-associated
hand in patients with Raynaud phenomenon: a novel calcinosis cutis. Br J Dermatol. 2018;178(6):1412-1415. https:
therapeutic modality. Plast Reconstr Surg. 2014;133(5):1109- //doi.org/10.1111/bjd.15783
1118. https://doi.org/10.1097/PRS.0000000000000104 183. Karthik S, Bhatt A, Babu T. Sodium thiosulfate dressings
168. Dinsdale G, Murray A, Moore T, et al. A comparison of intense facilitate healing of refractory cutaneous ulcers of calcinosis
pulsed light and laser treatment of telangiectases in patients cutis. J Postgrad Med. 2019;65(2):123-124. https://doi.org/
with systemic sclerosis: A within-subject randomized trial. 10.4103/jpgm.JPGM_500_18
Rheumatology (Oxford). 2014;53(8):1422-1430. https: 184. Baumgartner-Nielsen J, Olesen AB. Treatment of skin calcifi-
//doi.org/10.1093/rheumatology/keu006 cations with intra-lesional injection of sodium thiosulphate: A
169. Berger RG, Featherstone GL, Raasch RH, McCartney WH, case series. Acta Derm Venereol. 2016;96(2):257-258. https:
Hadler NM. Treatment of calcinosis universalis with low-dose //doi.org/10.2340/00015555-2206
warfarin. Am J Med. 1987;83(1):72-76. https://doi.org/10.10 185. Mageau A, Guigonis V, Ratzimbasafy V, et al. Intravenous
16/0002-9343(87)90499-2 sodium thiosulfate for treating tumoral calcinosis associated
170. Lassoued K, Saiag P, Anglade MC, Roujeau JC, Touraine RL. with systemic disorders: report of four cases. Jt Bone Spine.
Failure of warfarin in treatment of calcinosis universalis. Am J 2017;84(3):341-344. https://doi.org/10.1016/j.jbspin.2016.10.
Med. 1988;84(4):795-796. https://doi.org/10.1016/0002-9343 009
(88)90128-3 186. Trysberg E, Werna S, Sakiniene E. AB0617 effect of sodium
171. Cukierman T, Elinav E, Korem M, Chajek-Shaul T. Low dose thiosulfate on calcinosis cutis associated with connective
warfarin treatment for calcinosis in patients with systemic tissue disease. Ann Rheum Dis. 2014;73(Suppl 2):1009.3-
sclerosis. Ann Rheum Dis. 2004;63(10):1341-1343. https: 101010. https://doi.org/10.1136/annrheumdis-2014-eular.
//doi.org/10.1136/ard.2003.014431 4056
172. Farah MJ, Palmieri GMA, Sebes JI, Cremer MA, Massie JD,
187. del Barrio-Dıaz P, Moll-Manzur C, Alvarez-Veliz S, Vera-
Pinals RS. The effect of diltiazem on calcinosis in a patient Kellet C. Topical sodium metabisulfite for the treatment of
with the crest syndrome. Arthritis Rheum. 1990;33(8):1287- calcinosis cutis: a promising new therapy. Br J Dermatol.
1293. https://doi.org/10.1002/art.1780330834 2016;175(3):608-611. https://doi.org/10.1111/bjd.14412
173. Vayssairat M, Hidouche D, Abdoucheli-Baudot N, Gaitz JP. 188. Ma JE, Ernste FC, Davis MDP, Wetter DA. Topical sodium
Clinical significance of subcutaneous calcinosis in patients thiosulfate for calcinosis cutis associated with autoimmune
with systemic sclerosis. Does diltiazem induce its regression? connective tissue diseases: the Mayo Clinic experience, 2012-
Ann Rheum Dis. 1998;57(4):252-254. https://doi.org/10.11 2017. Clin Exp Dermatol. 2019;44(5):e189-e192. https:
36/ard.57.4.252 //doi.org/10.1111/ced.13782
174. Balin SJ, Wetter DA, Andersen LK, Davis MDP. Calcinosis cutis 189. Riley P, McCann LJ, Maillard SM, Woo P, Murray KJ,
occurring in association with autoimmune connective tissue Pilkington CA. Effectiveness of infliximab in the treatment
disease: the Mayo Clinic experience with 78 patients, 1996- of refractory juvenile dermatomyositis with calcinosis. Rheu-
2009. Arch Dermatol. 2012;148(4):455-462. https://doi.org/ matology (Oxford). 2008;47(6):877-880. https://doi.org/
10.1001/archdermatol.2011.2052 10.1093/rheumatology/ken074
175. Fredi M, Bartoli F, Cavazzana I, et al. SAT0469 calcinosis cutis 190. Marco Puche A, Calvo Penades I, Lopez Montesinos B.
in poly-dermatomyositis: clinical and therapeutic study. Ann Effectiveness of the treatment with intravenous pamidronate
Rheum Dis. 2015;74(suppl 2):830-831. https://doi.org/10.11 in calcinosis in juvenile dermatomyositis. Clin Exp Rheumatol.
36/annrheumdis-2015-eular.4163 2010;28(1):135-140. PubMed: 20346254.
176. Moazedi-Fuerst FC, Kielhauser SM, Bodo K, Graninger WB. 191. Fujii N, Hamano T, Isaka Y, Ito T, Imai E. [Risedronate: a
Dosage of rituximab in systemic sclerosis: 2-year results of possible treatment for extraosseous calcification]. Clin Calcium.
five cases. Clin Exp Dermatol. 2015;40(2):211-212. https: 2005;15(suppl 1):75-78; discussion 78-79. doi:CliCa05S-17579..
//doi.org/10.1111/ced.12450 192. Schanz S, Ulmer A, Fierlbeck G. Response of dystrophic
177. Narvaez J, Sancho J, Castellvi I, Al E. Long-term efficacy of calcification to intravenous immunoglobulin. Arch Dermatol.
rituximab in systemic sclerosis. Arthritis Rheum. 2014;66(suppl 2008;144(5):585-587. https://doi.org/10.1001/archderm.144.
10):S737. 5.585
NOVEMBER 2022
193. Kalajian AH, Perryman JH, Callen JP. Intravenous immunoglobulin 2013;52(11):2056-2061. https://doi.org/10.1093/rheumatolo
therapy for dystrophic calcinosis cutis: unreliable in our hands. gy/ket275
Arch Dermatol. 2009;145(3):334; author reply 335. https://doi.org/ 206. Falanga V, Soter NA, Altman RD, Kerdel FA. Elevated plasma
10.1001/archdermatol.2008.620 histamine levels in systemic sclerosis (scleroderma). Arch
194. Galimberti F, Li Y, Fernandez AP. Intravenous immunoglob- Dermatol. 1990;126(3):336-338. https://doi.org/10.1001/arch
ulin for treatment of dermatomyositis-associated dystrophic derm.1990.01670270068011
calcinosis. J Am Acad Dermatol. 2015;73(1):174-176. https: 207. Kroft EBM, Berkhof NJG, van de Kerkhof PCM, Gerritsen RMJP,
//doi.org/10.1016/j.jaad.2015.03.047 de Jong EMGJ. Ultraviolet A phototherapy for sclerotic skin
195. Moraitis E, Arnold K, Wedderburn L, Pilkington C. PReS- diseases: A systematic review. J Am Acad Dermatol. 2008;
FINAL-2130-A: effectiveness of intravenous cyclophospha- 59(6):1017-1030. https://doi.org/10.1016/j.jaad.2008.07.042
mide in severe or refractory juvenile dermatomyositisda 208. Hassani J, Feldman SR. Phototherapy in scleroderma. Derma-
national cohort study UK and Ireland. Pediatr Rheumatol. tol Ther (Heidelb). 2016;6(4):519-553. https://doi.org/10.1007/
2013;11(suppl 2):143. https://doi.org/10.1186/1546-0096-11- s13555-016-0136-3
S2-P143 209. Chwiesko-Minarowska S, Kowal K, Bielecki M, Kowal-
196. DeGuzman M, Singla S, Mizesko M, Sagcal-Gironella AC. Bielecka O. The role of leukotrienes in the pathogenesis of
Abatacept as adjunct therapy for the calcinosis of juvenile systemic sclerosis. Folia Histochem Cytobiol. 2012;50(2):180-
dermatomyositis: A single-center experience. Arthritis Rheum. 185. https://doi.org/10.5603/FHC.2012.0027
2017;69(suppl 4). Accessed June 10, 2021. https:// 210. Bigliardi PL, Stammer H, Jost G, Rufli T, B€ uchner S, Bigliardi-
acrabstracts.org/abstract/abatacept-as-adjunct-therapy-for- Qi M. Treatment of pruritus with topically applied opiate
the-calcinosis-of-juvenile-dermatomyositis-a-single-center- receptor antagonist. J Am Acad Dermatol. 2007;56(6):979-988.
experience/ https://doi.org/10.1016/j.jaad.2007.01.007
197. Boulter E, Beard L, Ryder C, Pilkington C. Effectiveness of 211. Frech T, Novak K, Revelo MP, et al. Low-dose naltrexone for
Anti-TNF-a agents in the treatment of refractory juvenile pruritus in systemic sclerosis. Int J Rheumatol. 2011;2011:
dermatomyositis. Pediatr Rheumatol. 2011;9(suppl 1):O29. 804296. https://doi.org/10.1155/2011/804296
https://doi.org/10.1186/1546-0096-9-S1-O29 212. del Rıo CD, Millan E, Garcıa V, Appendino G, DeMesa J,
198. Fahmy FS, Evans DM, Devaraj VS. Microdrilling of digital Mu~ noz E. The endocannabinoid system of the skin. A
calcinosis. Eur J Plast Surg. 1998;21(7):378-380. https: potential approach for the treatment of skin disorders.
//doi.org/10.1007/s002380050122 Biochem Pharmacol. 2018;157:122-133. https://doi.org/10.10
199. Saddic N, Miller JJ, Miller OF, Clarke JT. Surgical debridement 16/j.bcp.2018.08.022
of painful fingertip calcinosis cutis in CREST syndrome. Arch 213. Spiera R, Hummers L, Chung L, et al. Safety and efficacy of
Dermatol. 2009;145(2):212-213. https://doi.org/10.1001/arch- Lenabasum in a Phase II, randomized, placebo-controlled
derm.145.2.212-b trial in adults with systemic sclerosis. Arthritis Rheumatol.
200. Bottomley WW, Goodfield MJD, Sheehan-Dare RA. Digital 2020;72(8):1350-1360. https://doi.org/10.1002/art.41294
calcification in systemic sclerosis: effective treatment with 214. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;
good tissue preservation using the carbon dioxide laser. Br J 390(10103):1685-1699. https://doi.org/10.1016/S0140-6736
Dermatol. 1996;135(2):302-304. https://doi.org/10.1111/j.13 (17)30933-9
65-2133.1996.tb01166.x 215. Hoffmann-Vold AM, Maher TM, Philpot EE, et al. The
201. Chamberlain AJ, Walker NPJ. Successful palliation and signif- identification and management of interstitial lung disease
icant remission of cutaneous calcinosis in CREST syndrome in systemic sclerosis: evidence-based European consensus
with carbon dioxide laser. Dermatol Surg. 2003;29(9):968-970. statements. The Lancet Rheumatology. 2020;2(2):e71-e83.
https://doi.org/10.1046/j.1524-4725.2003.29261.x https://doi.org/10.1016/S2665-9913(19)30144-4
202. Blumhardt S, Frey DP, Toniolo M, Alkadhi H, Held U, Distler O. 216. McMahan ZH, Volkmann ER. An update on the pharmaco-
Safety and efficacy of extracorporeal shock wave therapy therapeutic options and treatment strategies for systemic
(ESWT) in calcinosis cutis associated with systemic sclerosis. sclerosis. Expert Opin Pharmacother. 2020;21(16):2041-2056.
Clin Exp Rheumatol. 2016;34(5 suppl 100):177-180. PubMed: https://doi.org/10.1080/14656566.2020.1793960
27494629. 217. Nikpour M, Hissaria P, Byron J, et al. Prevalence, correlates
203. Sultan-Bichat N, Menard J, Perceau G, Staerman F, Bernard P, and clinical usefulness of antibodies to RNA polymerase III in
Reguia€ı Z. Treatment of calcinosis cutis by extracorporeal systemic sclerosis: a cross-sectional analysis of data from an
shock-wave lithotripsy. J Am Acad Dermatol. 2012;66(3):424- Australian cohort. Arthritis Res Ther. 2011;13(6):R211. https:
429. https://doi.org/10.1016/j.jaad.2010.12.035 //doi.org/10.1186/ar3544
204. Sparsa A, Lesaux N, Kessler E, et al. Treatment of cutaneous 218. Parrado RH, Lemus HN, Coral-Alvarado PX, Quintana L opez G.
calcinosis in CREST syndrome by extracorporeal shock wave Gastric antral vascular ectasia in systemic sclerosis: current
lithotripsy. J Am Acad Dermatol. 2005;53(5 suppl 1):S263- concepts. Int J Rheumatol. 2015;2015:762546. https:
S265. https://doi.org/10.1016/j.jaad.2005.04.010 //doi.org/10.1155/2015/762546
205. Razykov I, Levis B, Hudson M, Baron M, Thombs BD, Canadian 219. Papachristos DA, Nikpour M, Hair C, Stevens WM. Intravenous
Scleroderma Research Group. Prevalence and clinical corre- cyclophosphamide as a therapeutic option for severe refractory
lates of pruritus in patients with systemic sclerosis: an gastric antral vascular ectasia in systemic sclerosis. Intern Med J.
updated analysis of 959 patients. Rheumatology (Oxford). 2015;45(10):1077-1081. https://doi.org/10.1111/imj.12883

Systemic Sclerosis in Adults Part II Management and Therapeutics 2

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Systemic sclerosis in adults.

Department of Dermatology, The Alfred Hospital, Melbournea; https://doi.org/10.1016/j.jaad.2021.10.066

DISEASE ASSESSMENT AND MONITORING

validated, routinely used clinical tool to measure

Table I. Commonly used patient-reported outcome measures in SSc

SSc, Systemic sclerosis.

involved in fibrosis. reduction in TGF-b related gene expression

autologous derived by skin fibrosis. tightening on the face93 and another

Calcinosis cutis of partial response.174,198 However, there is a possi-

series.188 diverse systemic manifestations of SSc.

Table IV. Overview of systemic SSc manifestation management.

19. Almeida C, Almeida I, Vasconcelos C. Quality of life in 726-728. https://doi.org/10.1111/j.1365-4362.1995.tb046

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