CONTINUING MEDICAL EDUCATION

Systemic sclerosis in adults. Part I:

Clinical features and pathogenesis
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 cutaneous features of SSc, the importance of their early recognition, their usual evolution in disease course and the
significant impact they have on patients’ Quality-of-Life; categorise patients into the diffuse or limited subtype of SSc according to clinical features; recognise the serological/molecular
associations with different presentations, systemic organ involvement and disease course; describe briefly the current understanding of the molecular mechanisms underlying the
cutaneous and systemic manifestations of SSc and how this may relate to future treatment directions.
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).

Systemic sclerosis (SSc), also referred to as systemic scleroderma or scleroderma, is a rare, complex immune-
mediated connective tissue disease characterized by progressive skin fibrosis and other clinically heterogenous
features. The etiopathogenesis of SSc involves vasculopathy and immune system dysregulation occurring on a
permissive genetic and epigenetic background, ultimately leading to fibrosis. Recent developments in our
understanding of disease-specific autoantibodies and bioinformatic analyses has led to a reconsideration of the
purely clinical classification of diffuse and limited cutaneous SSc subgroups. Autoantibody profiles are predictive
of skin and internal organ involvement and disease course. Early diagnosis of SSc, with commencement of disease-
modifying treatment, has the potential to improve patient outcomes. In SSc, many of the clinical manifestations that
present early signs of disease progression and activity are cutaneous, meaning dermatologists can and should play
a key role in the diagnosis and management of this significant condition. The first article in this continuing medical
education series discusses the epidemiology, clinical characteristics, and pathogenesis of SSc in adults, with an
emphasis on skin manifestations, the important role of dermatologists in recognizing these, and their correlation
with systemic features and disease course. ( J Am Acad Dermatol 2022;87:937-54.)

Key words: clinical features; cutaneous manifestations; differential diagnosis; disease classification;
epidemiology; pathogenesis; systemic sclerosis.

Department of Dermatology, The Alfred Hospital, Melbournea; https://doi.org/10.1016/j.jaad.2021.10.065

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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BMSc, MBBS, PhD, Department of Dermatology, The Alfred
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938 Jerjen et al J AM ACAD DERMATOL
NOVEMBER 2022

d Immunoserologic autoantibody profiles are also

Abbreviations used: used to aid diagnosis, classification, and predict
ACA: anticentromere antibodies disease course.
ACR: American college of rheumatology d Early diagnosis of SSc can improve patient out-
ANA: antinuclear antibodies comes and dermatologists can play a pivotal role
CT: cutaneous telangiectasia
CTD: connective tissue disease in recognizing early cutaneous features.
dcSSc: diffuse cutaneous systemic sclerosis d Dermatologists must be able to differentiate SSc
DU: digital ulcer from morphea and ‘‘scleroderma-like’’ conditions,
GI: gastrointestinal
lcSSC: limited cutaneous systemic sclerosis such as scleromyxoedema, lipodermatosclerosis,
PAH: pulmonary arterial hypertension and nephrogenic systemic fibrosis.
RNAP: RNA polymerase
RP: Raynaud’s phenomenon Given that many early manifestations of SSc are
SSc: systemic sclerosis cutaneous, patients often seek dermatologic services
VEDOSS: very early diagnosis of systemic sclerosis
for initial assessment, leading dermatologists to play
a crucial role in recognizing early SSc, assessing risk
of disease progression, and/or identifying signs
of systemic disease. The potential pivotal role of
EPIDEMIOLOGY dermatologists in making the diagnosis, instituting
Key points multidisciplinary team treatment, and minimizing
d Systemic sclerosis (SSc) has an estimated annual morbidity in SSc should not be underestimated.
incidence of between 0.6 and 5.6 per 100,000 Thus, our collective improved and continued educa-
adults, with a high female predominance. tion and involvement in disease management is vital.
d SSc has one of the highest mortality rates of any The diagnosis of SSc is based on clinical findings,
rheumatic disease; however, the survival rate has autoantibody profiles, and additional specific in-
improved with earlier detection and management vestigations. The classification of and diagnostic
of internal organ involvement. criteria for SSc have evolved significantly. Table I
summarizes the latest joint classification criteria from
The annual incidence of SSc is estimated to be the American College of Rheumatology (ACR) and
between 0.6 and 5.6 per 100,000 adults and preva- the European League Against Rheumatism.17 These
lence between 7.2 and 44.3 per 100,000 adults.1-5 consider a broad spectrum of clinical features and
Women are affected between 3.8 and 15 times more vascular, serologic, and imaging findings. Patients
frequently than men.1 The mean age at diagnosis is with a score of 9 or higher are considered to have SSc
33.5 to 59.8 years.1 Pediatric SSc represents less than (Table I).17
5% of all cases. Although it shares clinical similarities These latest criteria improved sensitivity for
with adult-onset SSc, pediatric SSc is not the focus of the diagnosis of early SSc, which is vital for the
discussion in this article.6 initiation of disease-modifying and outcome-altering
SSc has one of the highest mortality rates of any treatment.17-20 Severe internal organ involvement
connective tissue disease (CTD).7 Survival has typically occurs within 3 years of SSc onset and studies
improved, however, with an estimated cumulative have shown these irreversible manifestations can
5-yearesurvival of 84% in diffuse cutaneous systemic occur before patients meet the ACR diagnostic
sclerosis (dcSSc) and 93% to 96% in limited cuta- criteria.18-20 Knowledge of this has prompted the
neous systemic sclerosis (lcSSc).8-11 The most impor- development of the very early diagnosis of systemic
tant causes of disease-related mortality are interstitial sclerosis (VEDOSS) project. VEDOSS has identified
lung disease, pulmonary artery hypertension (PAH), Raynaud’s phenomenon (RP), puffy fingers, and
renal (scleroderma-renal crisis) and cardiac involve- positive antinuclear antibody (ANA) as early disease
ment.8,10,12-14 Poor prognostic factors include male features that predict progression to established
sex, older age, diffuse cutaneous SSc-subtype, pres- SSc.21,22 The diagnosis is confirmed by the presence
ence of aforementioned organ manifestations, digital of SSc-associated autoantibodies and/or abnormal
ulcers (DUs), and joint involvement.9,12,13,15,16 nailfold capillaries. Patients with puffy fingers and
disease-specific autoantibodies have a predicted 94%
DIAGNOSIS AND CLASSIFICATION probability of satisfying disease classification criteria
Key points within 5 years.21,22 Capturing these early presenta-
d SSc is clinically classified as limited or diffuse, tions can improve long-term outcomes and are
each with a distinct distribution of skin involve- therefore extremely important for dermatologists to
ment, systemic manifestations, and prognosis. recognize.
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VOLUME 87, NUMBER 5

Table I. Classification criteria for systemic sclerosis as per the 2013 ACR/EULAR guidelines17
Main criteria Additional criteria Weighting*
Sclerosis of the hands extending proximal to the 9
metacarpophalangeal joint (sufficient criterion)
Sclerosis of the fingers (only count higher score) Puffy fingers 2
Sclerodactyly (between MCPJ and PIPJ) 4
Fingertip lesions (only count higher score) Digital ulcers 2
Fingertip pitting scars 3
Telangiectasia 2
Abnormal nailfold capillaries 2
Pulmonary involvement (maximum score of 2) PAH 2
ILD 2
Raynaud’s phenomenon 3
SSc-typical autoantibodies (maximum of 3 points) Anti-centromere 3
Anti-topoisomerase I 3
Anti-RNA polymerase III 3

ACR, American college of rheumatology; EULAR, European League Against Rheumatism; ILD, interstitial lung disease; MCPJ,
metacarpophalangeal joint(s); PAH, pulmonary arterial hypertension; PIPJ, proximal interphalangeal joint.
*The total score is determined by adding the maximum weight (score) in each category. Patients with a total score of 9 are classified as
having definite SSc.

Notably, histopathologic findings are not specific clinical features (Table II).11,26-33 Double SSc-
included in the diagnostic criteria for SSc and bi- specific autoantibody positivity is extremely rare.11
opsies are not part of the initial routine work up Overall, skin-ANA classification of SSc (lcSSc vs
because of the low sensitivity of SSc-specific histo- dcSSc, and SSc-specific-autoantibody profile) has
logic alterations.23,24 Skin biopsies are indicated in validated data-driven utility in clinical practice.
case of diagnostic uncertainty to estimate disease Nihtyanova et al11 recently reported the combination
activity and/or for research purposes.24 of autoantibodies and skin involvement predicts
survival, timing, risk, and incidence of systemic
Disease subgroups: lcSSc versus dcSSc complications. Five autoantibodies (ACA, anti-Scl-
The two well-recognized clinical-subsets of SSc 70, anti-RNAP, anti-U3-RNP, other) and 2 skin subsets
(lcSSc and dcSSc) differ based on the distribution of (lcSSc, dcSSc) were identified and each group was
skin involvement.25 Skin thickening in lcSSc is assessed for survival and organ complications (Table
limited to the distal limbs and face, without trunk III). ACA positive patients had the best survival
involvement nor extension proximal to the elbows overall; however, they accrued significant complica-
or knees. In dcSSc, skin thickening involves distal tions over the disease course.
and proximal extremities, the face, and the trunk.
Disease subtyping has important prognostic impli- Emerging classification approaches
cations, as each has a largely predictable pattern of Work to improve the current SSc-classification
internal organ involvement. Although this subtyping further is based on the need to better stratify this
does have clinical utility, it is simplistic when used in multi-organ disease according to the likelihood of
isolation and additional serologic markers should be various clinical manifestations, short- and long-term
considered. prognosis, as well as the prospect of future individ-
ualized targeted treatments. These approaches begin
Autoimmune serology: Associations with to examine the current skin-ANA classification
clinical features and disease course further,34 as well as proteomic and transcriptomic
Autoantibody profiles assist with the diagnosis, classification from skin and blood samples.35,36 The
classification, and prognosis of SSc, and aid in emerging refined, molecular-level perspectives on
excluding scleroderma-like conditions, also called classification need further work, but will likely
scleroderma-mimics or pseudosclerodermas (Fig 1), enable future targeted and personalized therapeutic
which by definition are SSc-specific-autoantibody decision making in SSc.
negative. Approximately 95% of SSc patients are
positive for ANA.26-28 SSc-specific-autoantibodies, Differential diagnosis and diagnostic
including anticentromere antibodies (ACA), antito- considerations
poisomerase I/Scl-70 antibodies, and anti-RNA poly- SSc must be distinguished from other causes of
merase (RNAP) I-III antibodies, are associated with skin thickening, including morphea (localized
940 Jerjen et al J AM ACAD DERMATOL
NOVEMBER 2022

Fig 1. Differential diagnoses to consider in a patient with skin thickening. SSc, Systemic
sclerosis. (Image courtesy of Amanda Saracino, MBBS, PhD.)

scleroderma) and scleroderma-like conditions, also presence of RP, SSc-specific autoantibodies, and
referred to as scleroderma-mimics or pseudoscler- nailfold capillary abnormalities definitively distin-
odermas (Fig 1).17,37-40 guish SSc from these conditions.
The term scleroderma, meaning thick skin, should In the clinical setting of a favored or confirmed
be used as an umbrella-term to encompass both diagnosis of SSc, SSc-overlap syndromes, potential
morphea (localized scleroderma) and SSc (systemic external triggers, and malignancy should also be
scleroderma). Referring to either diagnosis as sclero- considered. SSc can co-exist with other CTDs in
derma is confusing and can cause significant confu- a scleroderma overlap syndrome/overlap-CTD.
sion and anxiety for the patient, especially in the Clinically, features of SSc and another CTD are
setting of a diagnosis of morphea. present, often with autoantibodies of both.
Morphea refers to sclerotic skin disease limited to Autoantibodies against U1-RNP tend to characterize
the skin and underlying connective tissues, such as an overlap-CTD and Pm-Scl antibodies are specific to
subcutaneous tissue, fascia, muscle, and bone. SSc occurring with myositis/dermatomyositis.
Severe forms of generalized morphea can sometimes Environmental and occupational exposures, such
be confused with SSc. It is important for dermatol- as epoxy resins, vinyl chlorides, and silica have been
ogists to have a clear understanding of the distin- implicated in the pathogenesis of SSc. A thorough
guishing features. Histologic features of morphea history to elucidate the potential presence of these
and SSc are indistinguishable. Nailfold capillary may be necessary (Fig 1). There is an overall
abnormalities, sclerodactyly, fibrosis of internal or- increased risk of malignancy in SSc, particularly
gans, and SSc-specific-autoantibodies are never pre- lung, hematologic, liver, bladder, and
sent in morphea (Table IV).41 Severe forms of breast.32,33,42,43 Patients who have negative autoim-
morphea, including linear and generalized subtypes, mune serology and, even more so, those who are
may have extracutaneous manifestations, such as RNAP3 antibody positive, have further increased risk
arthralgia and gastroesophageal reflux disease. of malignancy.5,32,43 Patients with anti-RNAP3 anti-
These are thought to be due to the systemic inflam- bodies have the highest risk of a synchronously
matory nature of the disease, but never due to diagnosed malignancy, usually between 6 months
internal organ fibrosis. Although rare, SSc and before and 12 months after SSc onset.32
morphea can co-exist. Keloidal or localized plaque
morphea are most frequently seen in this setting. PROPOSED PATHOGENIC MECHANISMS
Scleroderma-like diagnoses are broad and include Key points
scleromyxoedema, scleroderma adultorum, nephro- d SSc pathogenesis is complex, multifaceted, and

genic systemic fibrosis, and sclerodermatous-Graft- incompletely elucidated.

versus-host-disease (Fig 1). Relevant features on d SSc pathogenesis involves early vasculopathy,

clinical history, examination, autoimmune serology, innate and adaptive immune system dysfunction,
and histology are needed to exclude or confirm the and, ultimately, abnormal connective tissue for-
diagnosis of SSc in a systematic manner. Simply, the mation (Fig 2).
Table II. Systemic sclerosis serologic findings and their clinical correlations

VOLUME 87, NUMBER 5

J AM ACAD DERMATOL
Estimated Key cutaneous Key systemic Demographic HLA
Antibody target prevalence28 SSc subtype features26-29 features11,26-29 associations26-29 associations30,31
Centromere (ACA) 20% to 25% Limited - Calcinosis - PAH (15-20%) Female predominance. DRB1*01
- RP - Esophageal dysmotility Best prognosis - DRB1*04
- Sclerodactyly and gastrointestinal survival ;96% at DQB1*0501
- Telangiectasia dysfunction 5 years, 65% at DQA1*04:01
- Digital ulcers - Low risk of ILD, cardiac 20 years DRB1*07:01
and renal disease (Europeans)
Topoisomerase 20% to 30% Diffuse or limited - Digital ulcers - High risk of ILD (early) More prevalent in DPB1*13:01
I (Scl-70) (geographical - Joint contractures - PAH Europeans. DPB1*09:01 (Japanese)
variation) - Tendon friction rubs - SRC Poor prognosis (in DRB1*11:04 (European)
- Cardiac combination with DQB1/A1 (African
- Myositis dcSSc). Survival 91% at Americans)
5 years, 46.5% at
20 years
Polymyositis (PM) /Scl 2% to 4% Overlap - Calcinosis - Myositis Younger age at onset. DR3 DRB1*0301-5
Polymyositis/ - ILD (50% by 15 years) Good prognosis. Low risk
limited SSc - PAH (;36% by of death initially (98%
15 years) survival at 5 years) but
- Cardiac increased in
- Renal second decade of
disease (59% survival
at 20 years)
To/Th ribonucleoprotein \5% Limited - Calcinosis - ILD (45%) Higher mortality due to -
- PAH (25%) pulmonary
complications
RNA polymerase III (RNAP3) 1% to 22% Diffuse (rapidly - Joint contractures - Myositis Some have onset of -
progressive) - Tendon friction rubs - SRC (early) diffuse sclerosis prior
- Less cardiac to RP. Survival 88% at
- GAVE 5 years, 47% at
- Moderate risk of ILD 20 years
- PAH (later)
- Increased risk of
malignancy within
3 years of

Jerjen et al 941
diagnosis32,33
U1-ribonucleoprotein (U1-RNP) 5% to 10% Limited, overlap - Joint contractures - Myositis More prevalent in African -
syndromes (MCTD) - PAH Americans and Asians.
- ILD Younger age at onset
Continued
942 Jerjen et al J AM ACAD DERMATOL
NOVEMBER 2022

d An interplay between underlying predisposing

ACA, Anticentromere antibodies; GAVE, gastric antral vascular ectasia; HLA,human leukocyte antigen; ILD, interstitial lung disease; MCTD, mixed connective tissue disease; PAH, pulmonary arterial
More frequent in African HLA- DRB1*08:04 (African
genetic variation and epigenetic changes likely
interact with secondary environmental triggering
associations30,31

with younger age at HLA-DQB1*06:09

factors to influence disease susceptibility and
HLA

onset.
Americans. Associated American)

d The specific role of autoantibodies in disease

pathogenesis is unclear.
Genetic predisposition
Family history of SSc in affected individuals is
Poor prognosis. Survival
85% 5 years, 60% at

rare.44 Nonetheless, studies have demonstrated a

associations26-29
Demographic

genetic predisposition to disease development and

have identified numerous genes associates with SSc
(Table II).45-50
- Small bowel dysmotility 20 years
onset.

Environmental triggers
Postulated triggers for early changes in SSc
include infection, toxins, immune-mediated cytotox-
icity, oxidative stress, toxins, anti-endothelial
Hypo/per-pigmentation - PAH (highest risk)
features11,26-29

antibodies, and ischemia-reperfusion injury.51-53

Early severe organ
Key systemic

involvement:

Environmental and occupational exposures, specif-

ically silica, solvents, pesticides, and epoxy resins,
- Myositis

have been implicated as potential causative factors.54

- Cardiac

Consequently, SSc is recognized as an occupational

- SRC
- ILD

disease in persons with recurrent silica dust

exposure; eg, stonemasons. These environmental
Tendon friction rubs

factors are thought to trigger disease in genetically

Joint contractures
Key cutaneous

susceptible individuals through epigenetic

features26-29

modifications.45,52
Digital ulcers
Calcinosis

Vasculopathy
The aforementioned triggers induce vasculopathy
through various mechanisms. Platelet activation and
-
-
-
-
-

upregulation of adhesion molecules leads to luminal

occlusion, which adds to ischemia and production of
hypertension; RP, Raynaud’s phenomenon; SRC, scleroderma renal crisis.
SSc subtype

reactive oxygen species.53 In response to injury,

endothelial cells may undergo apoptosis,
endothelial-mesenchymal (EM) transition, or activa-
Diffuse

tion to secrete pro-fibrotic and pro-inflammatory

mediators.51,53 Furthermore, there is an imbalance
between vascular tone mediators, promoting vaso-
prevalence28
Estimated

constriction (eg, endothelin), inflammation (eg, su-

4% to 10%

peroxide anions), and vasodilation (eg, nitric

oxide).52,53,55 All these factors contribute to defective
vasculogenesis and impaired vessel repair.51,53,56

Immune dysregulation
Innate and adaptive immune system abnormal-
(U3-RNP) / Fibrillarin
U3-ribonucleoprotein

ities contribute significantly to SSc pathogenesis.

Table II. Cont’d

Skin-infiltrating T cells are predominantly of the T

helper cell 2 subtype with a corresponding increase
Antibody target

in related cytokines (eg, interleukin (IL)-4, IL-13, IL-

5), which have been associated with fibrosis in
animal studies.51 Although the role of SSc-specific
autoantibodies in disease pathogenesis is unclear,
J AM ACAD DERMATOL Jerjen et al 943
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Table III. The seven skin and antibody clusters identified by Nihtyanova et al11 to predict complications and
survival in systemic sclerosis
Classification subgroup
Skin Antibody Prevalence Systemic manifestations Relative prognosis
lcSSc ACA 28.2% Lowest incidence ILD and SRC Best
lcSSc Anti-Scl-70 10.4% Highest incidence ILD, lowest incidence PAH Second best
dcSSc Anti-Scl-70 11.3% Second highest incidence of cardiac SSc and ILD Worst
Any Anti-RNAP 11.1% Lowest incidence cardiac SSc, highest incidence SRC
Any Anti-U3 RNP 4.2% Highest incidence PAH, highest incidence cardiac SSc
lcSSc Other 22.3% Low overall risk of SRC and cardiac SSc
dcSSc Other 12.5% Higher rates of ILD, cardiac SSc and SRC Second worst

Adapted from Nihtyanova et al.11

ACA, Anticentromere antibodies; dcSSc, diffuse cutaneous systemic sclerosis; ILD, interstitial lung disease; lcSSC, limited cutaneous systemic
sclerosis; PAH, pulmonary arterial hypertension; RNAP, RNA polymerase; RNP, ribonucleoprotein; SRC, scleroderma renal crisis; SSc, systemic
sclerosis.

Table IV. Some of the key distinguishing features to assist with differentiating SSc from severe morphea
subtypes
Scleroderma
Feature SSc Morphea
Clinical skin thickening Yes Yes
Raynaud’s phenomenon Yes Possible in severe subtypes,* but uncommon
Puffy fingers / Sclerodactyly Yesepathognomonic No
Nailfold capillary changes Yes No
ANA Yes (95%) Possible in severe subtypes,* approximately 30%
SSc-specific autoantibodies Yesepathognomonic No
Internal organ fibrosis Yes No

ANA, Antinuclear antibodies; SSc, systemic sclerosis.

*Linear and generalized subtypes.

other circulating autoantibodies may be involved via early in the disease course and dermatologists play a
activation of toll like receptors Fc-receptors, and crucial role in diagnosis and care initiation.
direct fibroblast activation.51,53
Cell-cell and cell-matrix interactions between im-
mune cells, endothelial cells, and fibroblasts stimu- CUTANEOUS MANIFESTATIONS
late production and release of cytokines and growth Key points
d Inflammation of the fingers causing early edema
factors. Type-1einterferon and interferon-inducible
genes have been strongly implicated in SSc-patho- (puffy fingers) with subsequent progressive skin
geneses.57,58 Other strong contributors include trans- fibrosis and atrophy (sclerodactyly), is pathogno-
forming growth factor-b (a key driver of fibrosis monic of SSc.
d Orofacial fibrosis results in reduced oral aperture,
pathways), as well as platelet-derived growth factor,
endothelin 1, and insulin-like growth factor 1.51,53 decreased facial expression (amimia), xerostomia,
Ultimately, vasculopathy, coupled with immune and sicca syndrome, with consequences for
dysregulation, promotes excessive deposition of dental health.
d Rapidly progressive, diffuse skin fibrosis is a
extracellular matrix proteins, leading to the character-
istic inflammation and tissue fibrosis of SSc (Fig 2).51,52 predictor of early internal organ involvement.
Varga et al53 have published a detailed overview of the Skin fibrosis
postulated molecular etiopathogenesis of SSc. General. Skin thickening is the uniting feature of
all SSc and pseudoscleroderma disorders. In SSc, this
CLINICAL PRESENTATION is due to fibrosis. In lcSSc, skin fibrosis develops
SSc is clinically heterogeneous. Patients may pre- slowly and shows little variability over time. In dcSSc,
sent with skin, vascular, internal organ-based, and/or 3 disease phases are described: 1) edematous phase
constitutional symptoms. Skin abnormalities occur lasting 6 to 12 months, 2) fibrotic/indurative phase
944 Jerjen et al J AM ACAD DERMATOL
NOVEMBER 2022

Fig 2. Overview of systemic sclerosis (SSc) pathogenesis. SSc etiopathogenesis remains

incompletely understood, however, likely starts with a permissive genetic background,
epigenetic alterations and environmental triggers inciting disease. Resulting abnormalities in
and interplay between vascular, immunologic and fibrotic pathways drive disease progression
and manifestations. BANK1, B Cell Scaffold Protein With Ankyrin Repeats 1; CCL,
CC chemokine ligands; CXCL, chemokine (C-X-C motif) ligand; ECM, extracellular matrix;
EM, endothelial-mesenchymal; ET-1, Endothelin-1; eNOS, endothelial nitric oxide synthase;
HLA, human leukocyte antigen; IFN, interferon; IGF, insulin-like growth factor; IL, interleukin;
IRF, interferon regulatory factor; M1/M2, macrophage type 1/2; PDGF, platelet derived growth
factor; ROS, reactive oxygen species; SMA, smooth muscle actin; STAT4, Signal transducer and
activator of transcription 4; TGF, transforming growth factor; Th1/Th2, T Helper cells 1 and 2;
TLR,toll like receptor. (Image courtesy of Rebekka Jerjen, MChD.)
J AM ACAD DERMATOL Jerjen et al 945
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Fig 3. Skin fibrosis in systemic sclerosis. A and B, Sclerodactyly with symmetrical skin
tightening over the fingers and small joints of the hands with resulting fixed-flexion deformity
at the PIPJ. Note also the involvement of the wrists. C, Fibrosis of the skin over the forearms.
(Photographs courtesy of Thomas Krieg, MD.)

lasting at least 1 to 4 years, and 3) an atrophic phase xerostomia and reduced tear secretion with result-
that continues indefinitely.52,59 These phases may ing sicca syndrome.63,65 Additionally, xerostomia
overlap and, although uncommon, patients may coupled with reduced mouth opening impedes
have recurrence or flare of progressive skin involve- proper oral care and can result in damage to teeth
ment in later disease.59 Importantly, this may be a and gums, as well as weight loss due to reduced
marker of concurrent internal organ progression. food intake.66
Autoantibodies influence the fibrotic process, with Skin overlying joints. Fibrosis of the skin over-
anti-RNAP3 positive patients having a more rapidly lying joints leads to friction rubs, contractures, and
progressing diffuse fibrosis than other autoantibody joint deformities. Patients can experience pain,
groups.60,61 Rapid skin thickness progression is an weakness, and reduced mobility with significant
independent predictor of early mortality and devel- functional impact.67,68
opment of scleroderma renal crisis.60,61
Sclerodactyly. Sclerodactyly refers to tight- CUTANEOUS VASCULOPATHIC CHANGES
ening/thickening of skin over the fingers or toes, Key points
distal to the metacarpophalangeal and metatarso- d Nailfold capillaroscopy is important in the diag-

phalangeal joints but proximal to the proximal nosis of SSc.. Examination can be undertaken
interphalangeal joints.17 It is usually symmetrical using a dermatoscope, enabling rapid detection
and in the early inflammatory stage of the disease of capillary abnormalities.
and fingers often have an edematous appearance d RP occurs in the majority of SSc patients, months

(‘‘puffy fingers’’).62 This is reversible, however, over to years prior to onset of other non-RP features.
time, dermal atrophy occurs, leading to spindle- Association with puffy fingers and nailfold capil-
shaped fingers surrounded by contracted skin (Fig lary changes are red flags in the early diagnosis of
3). The diagnostic sensitivity and specificity of SSc.
sclerodactyly is recognized as part of the ACR/ d Digital ulcers (DU) classically refer to ischemic

European League Against Rheumatism classification fingertip ulcers, but may also occur secondary to
criteria (Table I; 4 of required 9 points). Sclerodactyly trauma or calcinosis. DUs cause significant pain
was present in almost 20% of patients considered to and functional impairment.
have very early onset SSc and thus may serve as a key d Cutaneous telangiectasia (CT) occur on the face,

initial clinical feature to prompt further work up.21 chest, and palms, and are often of cosmetic
Orofacial fibrosis. Fibrosis of the skin around concern as well as a marker of systemic micro-
the mouth can lead to radial perioral furrowing, vascular disease.
microstomia (oral aperture less than 4.5 cm), micro-
cheilia, and impaired speech and mastication.63 Up Nailfold capillary changes
to 80% of patients are affected and there is signif- High-resolution nailfold vidoecapillaroscopy with
icant psychosocial impact.64 Tightening of the skin 200-fold magnification is the gold standard for
on the face can cause a pointed, beaked nose, nailfold capillary assessment, however, it is not
impaired eye opening, and decreased facial expres- available in most clinical settings. Low resolution
sion (amimia).65 Sclerosis of eccrine glands causes (310) visualization using a dermatoscope has
946 Jerjen et al J AM ACAD DERMATOL
NOVEMBER 2022

Fig 4. Nailfold capillaroscopy changes throughout systemic sclerosis. A, Normal, orderly

hairpin capillary architecture. B, Dilated capillaries with preserved density seen in early
systemic sclerosis. C, Dilated capillaries with reduced density seen in active systemic sclerosis.
D, Hemorrhages, neoangiogenesis, avascular areas (‘‘drop out’’) and giant capillaries seen in
late systemic sclerosis. E, Macroscopic appearance. (Photographs courtesy of Dr Kevin Howell,
PhD, and Dr Thomas Krieg, MD.)

comparable sensitivity to nailfold vidoecapillaro- nipples.71,77 Aberrant digital perfusion is character-

scopy and allows clinicians to assess nailfold capil- ized by triphasic color change: initial pallor (vaso-
lary morphology routinely.69 spasm), followed by blue/purple cyanosis
Normally, nailfold capillaries are arranged in (deoxygenation of sequestered blood), and then
orderly ‘‘hairpin’’ rows (Fig 4, A). In SSc, classic erythema (post-ischemic hyperemia).77 At least 2
abnormalities are enlarged capillaries, capillary loss color changes are usually required for the diagnosis.
(‘‘dropout’’), and microhemorrhages (Fig 4, B to Numbness, tingling, and pain may also occur.78 In
E).70,71 A disturbance in the normal arrangement of SSc, these symptoms are often present throughout
these hairpin capillaries is present in approximately most of the year.79
74% of those with SSc and serves as a marker of Identifying patients with possible secondary RP
systemic microcirculation changes.72,73 requires careful assessment for co-existing features.
In recognition of the diagnostic significance and Concurrent puffy fingers, esophageal dysfunction,
insight into disease activity provided by nailfold and/or positive ANA are suggestive of very early
capillary abnormalities, this feature is one of the SSc.21 Detection of specific autoantibodies and
European League Against Rheumatism/ACR classifi- aberrant nailfold capillaroscopy are independent
cation criteria and VEDOSS confirmatory criteria.17,21 predictors of the progression from RP to SSc.80
Nailfold capillaroscopy may be a future outcome Pauling et al77 recently presented a detailed review
measure for clinical trials of SSc-associated vascul- of RP classification and assessment.
opathy.74,75 Smith et al76 have published a rapid
algorithm to facilitate the assessment of nailfold Ischemic Digital Ulcers
capillaries. Approximately 50% of SSc patients experience
DUs, which typically first occur early in the disease
Raynaud’s Phenomenon course, the majority within the first 5 years.67,81-83
More than 90% of patients with SSc experience The term ‘‘digital ulcer’’ usually refers to ulcers of the
RP.17 Time from onset of RP to development of non- distal fingers and toes, which are ischemic in origin
RP symptoms often varies according to SSc subtype due to microvascular pathology and RP (Fig 5). The
(months in dcSSc and years in lcSSc).25 RP affects the key differential diagnoses are ulcers occurring over
fingers and less commonly the toes, ears, lips, and areas of calcinosis or related to trauma, which
J AM ACAD DERMATOL Jerjen et al 947
VOLUME 87, NUMBER 5

Fig 5. Ischemic digital ulcer in the setting of systemic

sclerosis. (Photograph courtesy of Thomas Krieg, MD.)

typically occur over extensor surfaces of the small

joints of the hands that are under increased skin
tension due to sclerodactyly.
Ischemic DU are painful, with a large impact on
function and quality of life.84-86 In a group of patients
meeting VEDOSS criteria, ischemic DU were
observed in those with pulmonary and/or gastroin-
testinal (GI) involvement and not in those without
Fig 6. Calcinosis in systemic sclerosis occurring at finger-
internal organ manifestations.87 A recent European tips with secondary ulceration. (Photograph courtesy of
Scleroderma Trials and Research survey found clas- Thomas Krieg, MD.)
sifying ischemic DU into episodic, recurrent, and
chronic accurately reflects the clinical course.86,88 corresponding ischemia, repetitive trauma, and
DUs can be complicated by secondary infections localized structural damage is postulated to
(particularly with Staphylococcus aureus), which contribute,94 with associated genetic factors.97-99
may progress to osteomyelitis and require Calcinosis is more common in patients who are
amputation.89,90 ACA positive (including lcSSc subtype), have a
history of surgical debridement, osteoporosis, and
Cutaneous telangiectasia longer disease duration.92,96 The size and location of
CT are typically found on the face, chest, and the deposits determine the associated morbidity,
palms, in over half of SSc patients.73 They are a such that patients may be asymptomatic or experi-
marker of microvascular abnormalities; the presence ence significant pain from local pressure, ulceration
of profuse and pseudotumoral (very large) CT is through skin, superimposed infections, and joint
associated with DU, late nailfold vidoecapillaro- contractures.
scopy pattern, and PAH.91 Rapid progression of CT
may serve as a marker of progression of internal Pruritus
vascular abnormalities. Approximately 40% of patients with SSc experi-
ence pruritus, typically in the early, inflammatory
phase of the disease.100,101 This may be due to
CALCINOSIS
inflammatory irritation of nerves and/or fibrotic
Key points
d Calcinosis typically occurs at fingertips and over
nerve ending entrapment. Pruritus is independently
associated with higher modified Rodnan skin scores,
extensor surfaces.
d Calcinosis may be asymptomatic or cause pain
GI involvement, and reduced mental and physical
function.100-102
and ulceration depending on size and location.
Calcinosis is the intradermal or subcutaneous SYSTEMIC MANIFESTATIONS
deposition of insoluble calcified material (mostly d Respiratory manifestations of SSc include intersti-
calcium hydroxyapatite). It occurs in 20% to 40% of tial lung disease and PAH, which require regular
SSc patients73,92-95 and is most commonly found over screening with pulmonary function tests and
the finger tips and extensor surfaces of extremities echocardiography.
(Fig 6).94,96 The etiopathogenesis is poorly under- d Heart failure, pericardial effusions, arrhythmias,
stood. A combination of chronic vasculopathy with and rarely valve sclerosis are known cardiac
Table V. Overview of systemic manifestations in systemic sclerosis

948 Jerjen et al
Organ system affected Complications Prevalence Clinical features Risk factors Screening and monitoring52,119
Respiratory1,11,73,103,104 ILD 30% to 52.3% (usually Dyspnea, decreased exercise dcSSc, antitopoisomerase Pulmonary function tests
within 5 years from tolerance, chronic cough, antibodies, male sex (FVC and diffusion
diagnosis) basal lung crackles on capacity) at baseline and
auscultation every 4-6 months during
first 3 years. Consider
HRCT
PAH 5% to 12% Asymptomatic (early), later: Older age, late disease onset, Use DETECT algorithm105*
dyspnea, decreased exercise digital ulcers, numerous Doppler echocardiography,
tolerance, chronic cough pseudotumoral pulmonary function tests
telangiectasia (FVC and diffusion
capacity) annually, right
heart catheterization may
be needed to confirm
diagnosis
Cardiac111-115 Heart failure 7% to 32% Shortness of breath, decreased Antitopoisomerase antibodies, Annual Doppler echocardio-
Pericardial effusion exercise tolerance, chest older age gram, electrocardiogram,
Valve sclerosis pain, palpitations, syncope, troponin or BNP, cardiac
(rare) fatigue, dizziness, peripheral MRI if high risk
Arrhythmias and edema
conduction
defects
Renal106-109 SRC 2% to 15% (usually Hypertension, pulmonary and Male sex, anti-RNAP3 Measure creatinine clear-
within 5 years peripheral edema, electrolyte antibodies, dcSSc, older age, ance, urea, electrolytes
from diagnosis) disturbances, elevated systemic corticosteroid use and urinalysis at baseline
creatinine, uremia, metabolic ([15 mg prednisolone/day) and at least annually.
acidosis, proteinuria For patients with risk factors:
Renal appoximately 20% Asymptomatic or isolated dcSSc. measure blood pressure 3
vasculopathy proteinuria, increased May or may not progress to times weekly
creatinine and/or SRC
hypertension

J AM ACAD DERMATOL
NOVEMBER 2022
 VOLUME 87, NUMBER 5
J AM ACAD DERMATOL
Gastrointestinal64,110 Impaired 64% to 90% Dysphagia, odynophagia, Older age, dcSSc, anticentro- Symptom based investiga-
esophageal heartburn, regurgitation, mere antibodies, antitopoi- tions eg, barium swallow,
mobility chronic cough somerase I antibodies gastric-emptying study,
(microaspiration), (except GAVE), anti-RNAP3 breath test, esophageal
hoarseness, esophageal (GAVE) manometry, endoscopy
dilatation
GERD Dyspepsia, Barret’s esophagus,
strictures, reflux esophagitis
Intestinal and Malabsorption, bloating, early
gastric satiety, Small intestinal
dysmotility bacterial overgrowth
syndrome, nausea, vomiting,
pain, diarrhea/constipation,
fecal incontinence (sphincter
dysfunction), weight loss
GAVE 5.7% to 22.3% GI bleeding, iron deficiency Gastroscopy (‘‘watermelon
anemia stomach’’)
Urogenital116-118 Male sexual [80% Erectile dysfunction, penile Psychological stress, International Index of
dysfunction deformities, penile rigidity cardiovascular risk factors Erectile Function (IIEF-5)
including older age, smoking, questionnaire
hypercholesterolemia,
arterial hypertension
Female sexual [50% Discomfort, dyspareunia, Longer disease duration, Female Sexual Function
dysfunction impaired sexual activity and depressive symptoms, Index 300 (FSFI), Female
enjoyment relationship distress Sexual Function in SSc
306 (FSFS) questionnaire,
Female Sexual Distress
Scale (FSDS)
Malignancy33,42,43 Lung, 4% to10.8% Organ specific symptoms, Male sex, anti-RNAP3 Symptom directed organ
hematological, 1.75x relative risk constitutional symptoms antibodies, long-term specific investigation.
liver, bladder, (fatigue, weight loss, night immunosuppression Stratify risk based on
breast, non- sweats, lethargy) antibody profile
melanoma skin
cancer

BNP, B-type natriuretic peptide; DLCO, diffusing capacity for carbon monoxide; ECG, electrocardiogram; FSFI, Female Sexual Function Index 300; FSFS, Female Sexual Function in SSc 306; FSDS, Femal

Jerjen et al 949
Sexual Distress Scale; FVC, forced vital capacity; GERD, gastresophageal reflux disease; HRCT, high-resolution computed tomography; GAVE, gastric antral vascular ectasia; IIEF-5, International Index of
Erectile Function; ILD, interstitial lung disease; MRI, magnetic resonance imaging; PAH, pulmonary arterial hypertension; RNAP3, RNA polymerase III; SRC, scleroderma renal crisis.
*The DETECT algorithm is a screening tool for pulmonary artery hypertension that uses pulmonary function tests (FVC and DLCO), serum urate, ECG, serum NTproBNP and other features to provide
a predictive score and guide further investigation. A right heart catheter may be indicated.
950 Jerjen et al J AM ACAD DERMATOL
NOVEMBER 2022

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