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Official reprint from UpToDate®

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Clinical manifestations and diagnosis of systemic

sclerosis (scleroderma) in adults
Author: John Varga, MD
Section Editor: John S Axford, DSc, MD, FRCP, FRCPCH
Deputy Editor: Philip Seo, MD, MHS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2023. | This topic last updated: Nov 04, 2022.

INTRODUCTION

The term scleroderma is used to describe the presence of thickened, hardened skin (from the
Greek "scleros") [1]. Scleroderma is the hallmark feature of systemic sclerosis (SSc).

SSc is a chronic multisystem disease characterized by widespread vascular dysfunction and

progressive fibrosis of the skin and internal organs. The diagnosis of SSc and related disorders
is based primarily upon the presence of characteristic clinical findings and supported by specific
serologic abnormalities.

SSc is a heterogeneous disease, which is reflected by a broad range of organ involvement,

disease progression and severity, and outcomes.

This topic will review the clinical manifestations and diagnosis of SSc in adults. Localized
scleroderma, scleroderma-like conditions, and scleroderma disorders in childhood are
presented separately. (See "Juvenile localized scleroderma" and "Juvenile systemic sclerosis
(scleroderma): Classification, clinical manifestations, and diagnosis".)

Separate topic reviews related to SSc include the following:

● (See "Pathogenesis of systemic sclerosis (scleroderma)".)

● (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in
adults".)
● (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)".)

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● (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in

systemic sclerosis (scleroderma)".)
● (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis
(scleroderma)".)
● (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk
factors, and screening".)
● (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and
prognosis".)
● (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal
crisis".)
● (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)".)
● (See "Cardiac manifestations of systemic sclerosis (scleroderma)".)
● (See "Systemic sclerosis (scleroderma) and pregnancy".)

BACKGROUND

Major disease subsets — Systemic sclerosis (SSc) is traditionally classified based on the extent
of skin involvement and the accompanying pattern of internal organ involvement ( table 1),
as well as the presence of overlapping features with other systemic rheumatic diseases. The
different disease subtypes are also associated with different patterns of organ involvement and
disease evolution.

● Limited cutaneous systemic sclerosis – Patients typically present with puffy fingers
distal to the metacarpophalangeal joints (MCP) and ultimately develop skin sclerosis distal
to the elbows and knees, and, to a lesser extent, the face and neck, while the trunk and
proximal extremities are spared. These patients generally have prominent vascular
manifestations, including severe Raynaud phenomenon (RP) and mucocutaneous
telangiectasia, sometimes followed by a later onset of pulmonary arterial hypertension
(PAH). Many patients with limited cutaneous SSc (lcSSc) have manifestations of the CREST
syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly,
and telangiectasia).

● Diffuse cutaneous systemic sclerosis – Patients typically present with puffy hands and
develop skin thickening that extends proximally to the upper arms, thighs, and/or trunk.
Analysis of a large patient cohort indicates that many patients with SSc cannot readily be
classified into lcSSc or diffuse cutaneous SSc (dcSSc), and multiple distinct additional
disease subsets with shared features may exist [2].

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Patients with dcSSc are more likely to have a rapid progression of skin thickening with
early development of lung fibrosis and an increased risk of renal crisis and cardiac
involvement.

● Systemic sclerosis sine scleroderma – A small subset of patients have no detectable skin
involvement but have clinical features such as RP, digital ulcers, and PAH, along with
autoantibodies specific for SSc.

● Systemic sclerosis with overlap syndrome – Patients with SSc (of any of the above
subsets) may have overlap or features of another systemic rheumatic disease such as
systemic lupus erythematosus (SLE), rheumatoid arthritis, polymyositis, or Sjögren's
syndrome.

Epidemiology — The reported incidence and prevalence rates of SSc vary widely across studies.
This may be due in part to the differences in disease classification as well as possibly true
temporal and geographic differences. The overall incidence rates range globally from 8 to 56
new cases per million persons per year, and the prevalence rates fall between 38 and 341 cases
per million persons [3].

The majority of patients with SSc are female, with the female to male ratio ranging from 3:1 to
8:1. There are differences in disease presentation, with women trending towards more limited
disease, younger age of onset, and increased frequency of peripheral vascular disease and risk
for PAH. Men have an increased risk of diffuse cutaneous disease, more frequent interstitial
lung disease (ILD), cardiac involvement, and renal crisis [4]. Moreover, the diagnostic delay from
first onset of RP tends to be longer in women than men [5].

African Americans tend to have earlier-onset disease and more severe disease phenotypes with
increased risk of pulmonary fibrosis and scleroderma renal crisis (SRC) [6].

CLINICAL FEATURES

In addition to the major organ involvement discussed in detail below, patients with systemic
sclerosis (SSc) often experience pain and fatigue [7]. The level of fatigue that has been
described is comparable to that in rheumatoid arthritis, systemic lupus erythematosus (SLE), or
cancer patients in active treatment [8]. The presence of fatigue has been associated with poorer
physical function and greater pain [7,9]. Causes of pain include skin-related discomfort, joint
pain, Raynaud phenomenon (RP), and ischemic digital ulcers.

Major organ involvement

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Cutaneous manifestations — Skin involvement is a nearly universal feature of SSc. It is

characterized by variable extent and severity of skin thickening and hardening. The fingers,
hands, and face are generally the earliest involved areas of the body. Edematous swelling and
erythema may precede skin induration ( figure 1). Progressive skin fibrosis has been
associated with worsening lung function in patients with diffuse cutaneous SSc (dcSSc) [10].

Other prominent skin manifestations include:

● Pruritus in the early stages

● Edema in the early stages
● Skin hyperpigmentation or depigmentation ("salt and pepper")
● Loss of appendicular hair
● Dry skin
● Capillary changes at the nail beds
● Lipoatrophy
● Ulcerations over the distal interphalangeal joints (DIP) and proximal interphalangeal joints
(PIP) related to repetitive microtrauma over tightened skin
● Digital tip ulcers and/or pitting at the fingertips
● Telangiectasia
● Calcinosis cutis ( image 1)

The skin distribution forms the basis for the widely used binary classification system of SSc into
limited and diffuse forms of the disease ( table 2).

Only a small subset of patients with SSc have no skin induration (termed SSc sine scleroderma)
[11]. Although there is no clinically evident skin sclerosis, these patients have characteristic
vascular and/or fibrotic features of systemic disease, including RP, nailfold capillary alterations,
gastrointestinal involvement, renal crisis, pulmonary hypertension, and/or interstitial lung
disease (ILD).

Digital vasculopathy — RP is virtually always present in patients with SSc and can predate
other disease symptoms by years, particularly in limited SSc. RP is classically viewed as
reversible vasospasm due to functional changes in the digital arteries of the hands and feet.
However, over time, many patients with SSc develop progressive structural changes in the small
blood vessels, with permanently impaired flow. In such patients, episodes of RP may be
prolonged, lasting 30 minutes or even longer, and can result in ischemic pain, digital ulceration,
trophic changes, and in extreme cases, refractory or progressive ischemia and infarction. (See
"Clinical manifestations and diagnosis of Raynaud phenomenon".)

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Ischemic digital ulcers ultimately develop in up to 50 percent of patients. In general, digital

ulcers are associated with a worse disease course. The early occurrence of digital ulcerations is
more commonly seen in patients with diffuse disease and in patients who are positive for
antitopoisomerase I (anti-Scl-70) [12]. A history of ischemic digital ulcers at presentation has
also been associated with cardiovascular worsening and decreased survival [13]. Digital
ischemia can result in infection, gangrene, and amputation.

Musculoskeletal manifestations — The musculoskeletal manifestations of SSc are diverse

and include arthralgia, arthritis, tendinitis, tendon friction rubs, and small and large joint
contractures. For patients with dcSSc, swelling and stiffness of the fingers, arthralgia, myalgia,
and fatigue are among the earliest disease manifestations.

Joint pain, immobility, and contractures of both small and large joints develop as the result of
fibrosis around tendons and other periarticular structures. Contractures of the fingers are
common, but large joint contractures involving the wrists, elbows, and ankles may also occur.
The process is sometimes associated with palpable and/or audible deep tendon friction rubs,
characteristically in patients with dcSSc. The most common sites of involvement are the
extensor and flexor tendons of the fingers and wrist, tendons over the elbow (triceps), knee
(patellar), and ankle (anterior and posterior tibial, peroneal and Achilles).

Frank inflammatory arthritis is uncommon in SSc. When present, it is usually accompanied by

joint contractures and tendon friction rubs and is more likely to occur in patients with dcSSc
[14]. Analysis of synovial fluid generally reveals a mildly inflammatory fluid, and synovial biopsy
may show inflammation in the absence of pannus formation. The pattern of arthritis is most
commonly polyarticular, but oligoarticular and monoarticular patterns can also be observed. In
some patients, an erosive polyarticular arthritis of the small joints, particularly the
metacarpophalangeal joints and wrists, can be seen. The distal interphalangeal joints are
generally not affected. The pattern of articular involvement in the hands is similar to that in
rheumatoid arthritis, and some patients have an overlap of SSc and rheumatoid arthritis, with
positive anti-cyclic citrullinated peptide (CCP) antibodies. In such cases, it can be difficult to
distinguish an overlap syndrome from an SSc-related primary arthropathy.

Several studies suggest that the presence of tendon friction rubs in patients with SSc is a
marker for aggressive disease and increased risk of internal organ involvement including renal
crisis [15-17]. Destructive joint disease in a patient with SSc may suggest an overlap syndrome
with rheumatoid arthritis. (See "Undifferentiated systemic rheumatic (connective tissue)
diseases and overlap syndromes".)

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Radiographs of the hands may reveal soft tissue calcifications (calcinosis cutis) ( image 1) and
resorption of the distal phalangeal tufts (acro-osteolysis). Articular erosions, joint space
narrowing, and demineralization are less common radiographic findings [18].

Gastrointestinal involvement — Nearly 90 percent of patients with either subtype of SSc

(dcSSc or limited cutaneous SSc [lcSSc]) have evidence of gastrointestinal involvement [19,20].
Nearly half of these patients may have no symptoms. Although the esophagus is the most
frequently affected part of the gastrointestinal tract, any part of the gastrointestinal tract may
be involved.

Common symptoms of gastrointestinal involvement include dysphagia and choking, heartburn,

hoarseness, cough after swallowing, early satiety, bloating, alternating constipation and
diarrhea, episodic pseudo-obstruction and bacterial small bowel overgrowth with
malabsorption, and fecal incontinence. Chronic gastroesophageal reflux and recurrent episodes
of microaspiration may contribute to the development or progression of ILD [21]. Vascular
ectasia (angiodysplasia) in the antrum of the stomach ("watermelon stomach") is frequent and
may be a cause of chronic unexplained gastrointestinal bleeding and anemia. The
gastrointestinal manifestations of SSc are discussed in detail separately. (See "Gastrointestinal
manifestations of systemic sclerosis (scleroderma)".)

Pulmonary involvement — Some degree of pulmonary involvement is present in more than

80 percent of patients with SSc. The two principal clinical manifestations are ILD (also called
fibrosing alveolitis or pulmonary fibrosis) and pulmonary vascular disease, leading to
pulmonary arterial hypertension (PAH) ( table 3). These issues are discussed in detail
separately but will be briefly reviewed here. (See "Overview of pulmonary complications of
systemic sclerosis (scleroderma)" and "Clinical manifestations, evaluation, and diagnosis of
interstitial lung disease in systemic sclerosis (scleroderma)" and "Pulmonary arterial
hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening".)

The most common symptoms of pulmonary involvement in SSc are breathlessness on exertion
(which may progress to dyspnea at rest) and a nonproductive cough. However, patients may
have evidence of radiologic alveolitis and early pulmonary fibrosis in the absence of respiratory
symptoms or physical findings of functional abnormalities on pulmonary function testing (PFT).
Chest pain is infrequent and hemoptysis is rare. In advanced disease, auscultation over the
lungs reveals "velcro" rales most prominent at the lung bases.

Pulmonary vascular disease, primarily PAH, occurs in 10 to 40 percent of patients with SSc. It is
common in patients with longstanding limited cutaneous disease without associated ILD. It can
also happen secondary to ILD, particularly in those with diffuse SSc. Dyspnea with exertion and

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diminished exercise tolerance are the most common initial symptoms, but are commonly
absent until the disease is fairly advanced.

PAH is typically progressive and, if severe, can lead to cor pulmonale and right-sided heart
failure. Thrombosis of the pulmonary vessels is a common late-stage complication and is a
frequent cause of death. (See "Pulmonary hypertension due to lung disease and/or hypoxemia
(group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in
adults".)

Cardiac involvement — All anatomic domains of the heart can be affected in patients with
SSc, including the myocardium, pericardium, and conduction system. Cardiac complications of
SSc can be primary, but can also occur secondary to PAH, ILD, or scleroderma renal crisis (SRC).
Cardiac involvement is frequent in SSc but might be entirely asymptomatic. A detailed
discussion of the cardiac manifestations of SSc can be found elsewhere. (See "Cardiac
manifestations of systemic sclerosis (scleroderma)".)

Kidney involvement — Autopsy studies suggest that 60 to 80 percent of patients with dcSSc
have pathologic evidence of kidney damage. In patients who have not developed SRC, kidney
biopsy may show vascular fibrosis and interstitial collagen accumulation. Glomerulonephritis is
uncommon, although antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has
been rarely reported [22,23]. Impaired kidney reserve may be present in the absence of clinical
kidney disease [24]. Microalbuminuria, a mild elevation in the plasma creatinine concentration,
and/or hypertension is observed in as many as 50 percent of patients, but generally does not
progress to chronic kidney failure [25-27].

Severe and life-threatening renal involvement called SRC develops in approximately 10 to 15

percent of patients. It is far more frequent in patients with dcSSc than lcSSc and almost
invariably occurs in the early stages of the disease. There is no evidence that the prophylactic
use of angiotensin-converting inhibitor therapy can reduce the frequency, or mitigate the
outcome, of SRC. This form of kidney involvement is characterized by:

● Abrupt onset of marked or malignant hypertension (although some patients remain

normotensive)
● Acute onset of oliguric renal failure
● Urinalysis that reveals only mild proteinuria with few cells or casts
● Microangiopathic hemolysis anemia and thrombocytopenia

Other features of SRC may be secondary to severe hypertension or vasculopathy and include
pulmonary edema, headache, blurred vision, retinal microhemorrhages, and hypertensive
encephalopathy, sometimes complicated by generalized seizures.
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Kidney disease in SSc, including SRC, is discussed in detail separately. (See "Kidney disease in
systemic sclerosis (scleroderma), including scleroderma renal crisis".)

Neuromuscular involvement — Muscle atrophy (sarcopenia), muscle weakness, and

myopathy are increasingly recognized as major contributors to the morbidity and mortality of
the disease. Other neurologic abnormalities in SSc that are less common include central,
peripheral, and autonomic neuropathies. The neuromuscular manifestations of SSc are
discussed in detail separately. (See "Neuromuscular manifestations of systemic sclerosis
(scleroderma)".)

Genitourinary involvement — SSc in men is very commonly associated with erectile

dysfunction, which can be an early and even initial manifestation of disease [28]. This was
illustrated in a survey that compared 43 SSc patients with 23 patients with rheumatoid arthritis
[29]. Among the SSc patients, 81 percent had self-reported erectile dysfunction versus 48
percent of those with rheumatoid arthritis. While RP was more prevalent in SSc than in
rheumatoid arthritis (86 versus 19 percent), it was not an independent predictor of erectile
dysfunction.

Women with SSc may also have sexual dysfunction. This is related to decreased vaginal
lubrication or constriction of the vaginal introitus. In one study, dyspareunia was present in 56
percent of 60 women with SSc [30].

Other disease associations

● Cancer risk – There have been several reports demonstrating an increased risk of
malignancy in patients with SSc [31-38].

The most significant association appears to be with lung cancer, which accounts for
approximately one-third of the cancers seen in SSc patients [33]; however, a significantly
increased incidence was not noted in a population with a high background rate of lung
cancer [36]. In a study of 632 Australian patients with SSc, 19 developed lung cancer [39].
Those who smoked were seven times as likely to develop cancer as those who did not.
Pulmonary fibrosis and antitopoisomerase I antibodies were not risk factors for lung
cancer [40,41].

The issue of malignancy in SSc was assessed in a nationwide population-based,

retrospective cohort analysis from Denmark performed between 1977 and 2006; 2046
patients with SSc were evaluated [37]. Patient records were compared with a cohort from
the Danish Cancer Registry. The ratio of cancers in SSc patients to expected cancers (the
standardized incidence ratio [SIR]) was 1.5 overall. The most frequent cancers were lung
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(SIR 1.6), hematologic (SIR 2.5), and immune-related (SIR 1.4). A similar, modest increase in
the overall risk of malignant disease (SIR 1.55) was also seen in a cohort of 769 patients
seen from 1987 to 2002 [38]. There was, however, a marked increase in the risk of
esophageal carcinoma (SIR 15.9 [95% CI 4.2-27.6]) and oropharyngeal carcinoma (SIR 9.63
[95% CI 2.97-16.3]).

The cause of an increased cancer risk in SSc is not well understood. The association with
lung and skin cancers suggests that sites of disease activity may be prone to malignant
transformation.

A close temporal relationship between the onset of cancer and SSc has been observed
among patients with autoantibodies to ribonucleic acid (RNA) polymerase I/III [42,43]. One
study demonstrated that tumors harboring somatic mutations in the POLR3A gene may
trigger the development of SSc [44].

There are conflicting data regarding whether the presence of antibodies to

topoisomerase-I (Scl-70) identifies a population of SSc patients who are more likely to
have, or to develop, cancer [45,46].

● Thromboembolic risk – An increased risk of venous thromboembolism (VTE) has been

reported among patients with SSc [47,48]. A large population-based study observed a
threefold increased risk of pulmonary embolism, deep vein thrombosis, and VTE among
1245 patients with incident SSc, compared with matched non-SSc controls, after adjusting
for relevant risk factors such as age, sex, and recent hospitalizations [47]. The increased
risk of VTE was highest during the first year after SSc diagnosis.

EVALUATION FOR SUSPECTED SYSTEMIC SCLEROSIS

Systemic sclerosis (SSc) should be suspected in patients presenting with Raynaud Phenomenon
(RP), skin thickening, puffy or swollen fingers, hand stiffness, and painful distal finger ulcers.
Symptoms of gastroesophageal reflux are often present. (See "Clinical manifestations and
diagnosis of Raynaud phenomenon".)

Early referral to specialists, depending upon the pattern of organ involvement and severity of
disease, is often appropriate, and multidisciplinary specialty involvement (eg, by rheumatology,
dermatology, pulmonology, and gastroenterology) is often required.

Physical examination — With the physical examination, the clinician should look for evidence
of the following findings:

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● Puffy swollen fingers and/or nonpitting edema of the hands ( figure 1). This is more
commonly observed in the early stages of the disease.

● Skin thickening, either diffuse or limited to the hands, feet, face, and forearms. The
assessment of skin involvement includes semiquantitative estimation of skin thickness,
pliability (hardness), and fixation to underlying structures (tethering). The modified
Rodnan skin score is commonly used as an outcome measure in clinical trials
( figure 2A-B). This semiquantitative score rates the severity of these features from 0
(normal) to 3 (most severe) in 17 distinct areas of the body and shows an acceptable
degree of intra-rater variability.

● Perioral skin tightening with decreased oral aperture ( figure 3).

● Digital pitting with loss of fingertip tissue and superficial digital ulcerations under or close
to the nailbed due to underlying vascular disease. Ulcerations over the distal or proximal
interphalangeal joints may also be observed, but these are usually due to trauma as a
complication of avascular or thinned skin ( figure 4).

● Abnormal nailfold capillaroscopy with scleroderma pattern. This is particularly useful for
clinicians skilled at identifying characteristic nailfold capillary abnormalities, such as
dilated capillary loops, capillary dropout, microhemorrhages, and architectural
derangement. (See "Clinical manifestations and diagnosis of Raynaud phenomenon",
section on 'Nailfold capillary microscopy'.)

● Calcinosis cutis (of the hands, elbows, and knees), mucocutaneous telangiectasias
( figure 3), and/or cutaneous hyperpigmentation.

● Tendon friction rubs, which can be felt as coarse crepitus over joints or areas with adjacent
joint involvement. The most common sites of involvement are the tendons of the fingers
and wrists, elbows, knees, and ankles.

Laboratory testing — We obtain the following routine laboratory tests, some of which may
provide information about specific organ involvement:

● Complete blood count and differential, which may reveal anemia due to malabsorption,
iron deficiency, or gastrointestinal blood loss
● Serum creatinine level, which may indicate renal dysfunction
● Creatine kinase (CK), which may be elevated in patients with myopathy or myositis
● Urinalysis with urine sediment, which may reveal proteinuria and/or cellular casts

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We also perform the following serologic tests ( table 4), which may support the diagnosis if
positive:

● Antinuclear antibody (ANA). ANA test is positive in approximately 95 percent of patients

with SSc, and therefore a negative test should prompt consideration of other fibrosing
illnesses [49].

● Antitopoisomerase I (anti-Scl-70) antibody. Anti-deoxyribonucleic acid (DNA)

topoisomerase I (Scl-70) antibodies are generally associated with diffuse cutaneous SSc
(dcSSc) and a higher risk of severe interstitial lung disease (ILD) [50,51].

● Anticentromere antibody (ACA). The presence of ACA is usually associated with limited
cutaneous SSc (lcSSc); only 5 percent of patients with dcSSc have ACA.

● Anti-RNA polymerase III antibody. Antibodies to RNA polymerase III are found in patients
with dcSSc and are generally associated with rapidly progressive skin involvement as well
as an increased risk for scleroderma renal crisis (SRC) [26,52]. These patients may also be
at increased risk for concomitant cancer [43,44].

● Antibodies to Th/To, which recognize two RNA-processing enzymes plus associated

proteins, are seen in 5 percent of patients with SSc, and present with a nucleolar pattern
of immunofluorescence. The presence of anti-Th/To autoantibodies is associated with
limited skin disease, a greater frequency of ILD, and substantially increased risk of
developing pulmonary arterial hypertension (PAH). In a retrospective study of 204 SSc
patients with anti-Th/To antibodies and 408 SSc patients without these antibodies,
antibody positivity was associated with a 3.3-fold increased risk of developing pulmonary
hypertension, with 37 percent of the patients developing World Health Organization
(WHO) Group I PAH within 10 years, and reduced cumulative 5-year survival [53].

The antitopoisomerase I (anti-Scl-70), ACA, and anti-RNA polymerase III tests are highly specific
(>99.5 percent in some studies) for SSc but are only moderately sensitive (20 to 50 percent)
[50,54,55]. The autoantibodies are almost always mutually exclusive. Among those with RP but
without definite SSc or a related autoimmune rheumatic disease, the presence of one of these
antibodies predicts an increased risk of progression to SSc, particularly in combination with
puffy fingers and/or abnormal nailfold capillaroscopy [56,57]. (See "Clinical manifestations and
diagnosis of Raynaud phenomenon".)

To help in the differential diagnosis of SSc, we also may order the following when appropriate:

● Rheumatoid factor

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● Antibodies to citrullinated peptides (anti-CCP)

● Systemic lupus erythematosus (SLE)-associated antibodies (eg, anti-double-stranded DNA
and/or anti-Smith)
● Antibodies associated with overlap connective tissue diseases (eg, RNP antibodies)

Since these antibodies are relatively uncommon in patients with SSc, their presence points
toward overlap syndromes with other systemic rheumatic diseases. These syndromes are
characterized by a more prominent arthritis than seen in SSc [58]. (See "Undifferentiated
systemic rheumatic (connective tissue) diseases and overlap syndromes".)

A variety of other SSc-associated serologic tests may also inform the diagnosis, but their
availability is generally limited to specialized research centers ( table 5). These relatively
uncommon autoantibodies have distinct clinical associations and prognostic implications.

Antineutrophil cytoplasmic antibodies (ANCA) are often ordered indiscriminately in patients

with suspected SSc. However, they are not associated with SSc, and we do not routinely order
this test [59-61]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

Additional studies — In addition to a careful history, physical examination, nailfold

capillaroscopy, and laboratory testing, studies targeting specific organ involvement are useful
for confirmation of the diagnosis and determining the presence and extent of extracutaneous
involvement.

All patients with suspected SSc should be evaluated for ILD and pulmonary hypertension, which
are the most frequent types of lung involvement in SSc patients. A more detailed discussion of
the initial evaluation for lung disease in patients with SSc is presented separately (see "Clinical
manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis
(scleroderma)", section on 'Evaluation'). However, we will briefly present here the studies that
we obtain as part of the initial diagnostic workup:

● Pulmonary function testing (PFT) – This should be done to assess for the presence or
absence of a restrictive ventilatory defect or a decrease in the single breath diffusion
capacity for carbon monoxide (DLCO).

● Radiographic imaging of the lung – High-resolution computed tomography (HRCT) is

preferred to a chest radiograph in SSc due to the greater sensitivity of the HRCT. HRCT
frequently reveals interstitial lung abnormalities even in patients with normal PFT results.

● Doppler echocardiography – This is recommended for initial screening for PAH. (See
"Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on

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'Echocardiography'.)

Evaluation for gastrointestinal involvement, which to varying degrees is present in almost all
patients with SSc, should be guided by patient symptoms. A more detailed discussion on the
gastrointestinal manifestations of SSc and appropriate diagnostic studies is presented
separately. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)".)

In occasional patients with SSc, visceral organ involvement may be the predominant clinical
manifestation at the time of presentation. As an example, a patient may present with SRC even
prior to developing characteristic skin changes (see "Kidney disease in systemic sclerosis
(scleroderma), including scleroderma renal crisis", section on 'Clinical presentation'). However,
in our experience, these clinical scenarios are atypical and often represent cases in which the
cutaneous findings or other characteristic manifestations of SSc were subtle or overlooked.

The approach to the differential diagnosis of ischemic or fibrotic involvement limited to a

particular organ is presented separately in topic reviews. (See "Approach to the adult with
interstitial lung disease: Clinical evaluation" and "Kidney disease in systemic sclerosis
(scleroderma), including scleroderma renal crisis" and "Clinical features and diagnosis of
pulmonary hypertension of unclear etiology in adults".)

Skin biopsy in selected cases — Skin biopsy is rarely indicated for making the diagnosis of SSc.
However, in some cases, a skin biopsy may be necessary to help differentiate SSc from other
syndromes such as eosinophilic fasciitis, scleredema, or scleromyxedema. (See 'Causes of
scleroderma-like skin changes' below.)

Histologically, SSc cutaneous involvement is characterized by excessive deposition of compact

and organized bundles of collagen in the dermis. Skin biopsy shows expansion of the dermis,
and in early stages, dermal edema, variable degrees of perivascular mononuclear inflammatory
cell infiltration, and fibrosis. The intradermal white adipose layer shows progressive atrophy
and even complete absence and displacement by fibrotic tissue [62].

Additional common features include atrophic eccrine and pilosebaceous glands, and loss of
intradermal fat. In patients with early-stage disease, sparse mononuclear cell infiltrates may be
found around the dermal blood vessels [63]. Direct immunofluorescence studies are usually
negative in SSc patients. These lesions may be histologically indistinguishable from other
diseases characterized by collagen deposition, such as morphea.

DIAGNOSIS

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Systemic sclerosis — We diagnose limited or diffuse systemic sclerosis (SSc) in patients with
skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal
joints. The presence of the following additional findings and/or abnormalities support the
diagnosis of SSc:

● Raynaud phenomenon (RP).

● Ischemic fingertip ulcerations (digital tip pitting scars) ( figure 4), calcinosis cutis,
hyperpigmentations, and/or mucocutaneous telangiectasia ( figure 3). However, these
findings are often absent in patients with early disease.
● Heartburn and/or dysphagia of recent onset.
● Characteristic nailfold capillary changes.
● Erectile dysfunction in men.
● Acute onset of hypertension and renal insufficiency.
● Dyspnea on exertion associated with restrictive changes on pulmonary function tests
(PFTs) or evidence of interstitial pulmonary changes on radiography or high-resolution CT
(HRCT).
● Dyspnea on exertion associated with evidence of pulmonary arterial hypertension (PAH)
on Doppler echocardiography.
● Diarrhea with malabsorption or intestinal pseudo-obstruction.
● Positive antitopoisomerase I (anti-Scl-70) antibody, anticentromere antibody (ACA), and/or
anti-RNA polymerase III antibody; or a positive antinuclear antibody (ANA) with a nucleolar
immunofluorescence pattern.

Systemic sclerosis sine scleroderma — Approximately 10 percent of patients in whom a

diagnosis of SSc is eventually made do not have clinically evident skin induration ("sine
scleroderma") [11,64]. This SSc subset has been described in several case reports and cohort
studies [11,64-66]. The diagnosis of SSc in these patients rests upon the presence of other
characteristic clinical features (eg, RP, esophageal hypomotility, nailfold capillary changes,
digital tip pitting, evidence of pulmonary and/or renal involvement) and specific serum
autoantibodies.

In the absence of another autoimmune rheumatic disease, we diagnose SSc sine scleroderma
in patients with each of the following [11]:

● RP or a peripheral vascular equivalent (digital tip pitting scars or ulcers, gangrene,

abnormal nailfold capillaries)

● Positive ANA with a speckled or nucleolar immunofluorescence pattern

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● Any one of the following: pulmonary interstitial fibrosis, primary PAH without fibrosis,
characteristic esophageal motility alterations, or renal failure consistent with scleroderma
renal crisis (SRC)

Early referral to a rheumatologist is recommended when SSc sine scleroderma is suspected in

order to avoid delay in diagnosis and treatment.

The pattern of extracutaneous clinical features and laboratory findings observed in these
patients is most similar to that seen in the limited cutaneous SSc (lcSSc) subset [11,65,66]. The
following studies are illustrative:

● An observational study compared the clinical and laboratory features of 507 lcSSc patients
with 48 SSc sine scleroderma patients [11]. Other than the absence of skin thickening,
there were no significant differences in the type of individual internal organ involvement,
serum autoantibodies, or survival rate.

● In the largest observational study, which included 947 consecutive patents with SSc, 79 (8
percent) of whom were classified as having SSc sine scleroderma, there were also no
significant differences in the pattern of organ involvement compared with that observed
in lcSSc [66]. In this cohort, esophageal hypomotility was the most frequent
extracutaneous manifestation of SSc sine scleroderma (83 percent), followed by interstitial
lung disease (ILD; 57 percent), and pulmonary hypertension (23 percent). Cardiac
manifestations attributed to SSc were present in 11 percent of patients. While skin
thickening was undetectable, other cutaneous manifestations, including telangiectasia (29
percent), ischemic digital ulcers (24 percent), and calcinosis cutis (8 percent), were
observed.

Systemic sclerosis overlap syndrome — Typical scleroderma skin changes occur in some
patients with systemic lupus erythematosus (SLE), inflammatory arthritis, and inflammatory
muscle diseases. An "overlap syndrome" is present if there is clear-cut SSc together with
sufficient clinical and/or laboratory features to support a concurrent diagnosis of another
defined connective tissue disease. In some cases, a diagnosis of mixed connective tissue
disease is made, but this may reflect a temporary state. Many patients who are given the
diagnosis of mixed connective tissue disease "differentiate" over time by evolving into SSc, SLE,
or dermatomyositis, while some retain features of multiple diseases [67]. (See "Undifferentiated
systemic rheumatic (connective tissue) diseases and overlap syndromes" and "Clinical
manifestations and diagnosis of mixed connective tissue disease".)

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CLASSIFICATION CRITERIA

The clinical heterogeneity of systemic sclerosis (SSc) highlights the importance of defining
robust and pragmatic criteria used for disease classification to permit consistency across
different centers. Several classification systems for SSc have been developed for research
purposes. Although the items generally included in classification criteria reflect those used for
the clinical diagnosis, there are other findings used in clinical practice that inform the diagnosis.
Rare patients who do not fulfill the formal classification criteria may be diagnosed with SSc,
and, conversely, other patients who do fulfill criteria may still have an alternative diagnosis. A
major international effort developed classification criteria that reflect advances in assessment
and understanding of the disease.

● 2013 Classification Criteria – The 2013 Classification Criteria for Systemic Sclerosis were
developed by a joint committee of the American College of Rheumatology (ACR) and the
European Alliance of Associations for Rheumatology (EULAR; formerly known as European
League Against Rheumatism) in order to identify patients with SSc for inclusion in clinical
studies.( table 6A-B) [68,69]. This system addressed the shortcomings of previously used
classification systems by capturing a broader spectrum of SSc patients, and also
incorporated disease-specific autoantibodies and nailfold capillaroscopy [56,70-73].

The 2013 criteria incorporate disease manifestations of the three hallmarks of SSc: fibrosis
of the skin and/or internal organs, production of specific autoantibodies, and evidence of
vasculopathy. Skin thickening of the fingers extending proximal to the
metacarpophalangeal joints is sufficient for the patient to be classified as having SSc. If
that is not present, seven additive items with varying weights for each should be used:
skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold
capillaries, interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH),
Raynaud phenomenon (RP), and SSc-related autoantibodies.

The sensitivity and specificity for the 2013 criteria were 0.91 and 0.92, respectively.
However, these criteria have yet to be validated in ethnic groups that are not common in
North America and in Europe.

It must be noted that strict adherence to these classification criteria will still exclude some
patients in whom a clinical diagnosis of SSc would likely be made. As an example, a patient
with early-stage SSc presenting with RP, an SSc-specific autoantibody (described above),
and abnormal nailfold capillaroscopy would not have enough features to be classified as
SSc.

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● Preliminary criteria for early diagnosis – Preliminary criteria for very early diagnosis of
SSc (VEDOSS) have been proposed in order to identify patients with early SSc who might
not display characteristic skin thickening and internal organ involvement [73]. Key features
(or "red flags") whose presence should raise suspicion for early SSc include RP, puffy
swollen digits, and the presence of a positive antinuclear antibody (ANA). The prevalence
of these proposed diagnostic features was evaluated in a cohort of 469 patients with RP.
Almost 90 percent of ANA-positive patients with RP and puffy swollen digits also had SSc-
specific autoantibodies and/or a scleroderma pattern on nailfold capillaroscopy, and
fulfilled the VEDOSS preliminary criteria for early SSc [74]. Validation of the predictive
value of these preliminary criteria for progression to full-blown SSc and guidelines for
appropriate monitoring and management of these patients are still needed.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of systemic sclerosis (SSc) is related to the predominant clinical
features of the particular patient. In some cases, the differential includes conditions with
scleroderma-like skin changes, whereas in others, the differential of Raynaud phenomenon
(RP), interstitial lung disease (ILD), or pulmonary hypertension may need to be considered.

Causes of scleroderma-like skin changes — Indurated skin (scleroderma) may be a

manifestation of conditions other than SSc. These include exposures to certain drugs, toxins, or
environmental factors. Some endocrine disorders (eg, diabetes mellitus and hypothyroidism),
renal disease, and amyloidosis and other infiltrative disorders can also cause scleroderma-like
skin changes.

● Scleredema – Scleredema can be idiopathic or associated with diabetes or infection. It is

characterized by prominent symmetrical skin thickening predominantly on the trunk,
particularly the nape, shoulders, and upper back. The face may also be affected, while the
fingers are spared. In severe cases, mobility of the shoulders and chest is markedly
impaired. Patients with longstanding insulin-dependent diabetes mellitus may develop a
type of scleredema called scleredema of Buschke (see "Cutaneous manifestations of
internal malignancy", section on 'Scleredema'). RP, nailfold microvascular changes, and
autoantibodies are not present in these patients, and ILD and other forms of internal
organ involvement are rare.

● Scleromyxedema – Scleromyxedema, also called papular mucinosis, is characterized by

waxy, yellow-red papules on the head, neck, arms, and upper trunk, commonly occurring
over thickened and indurated skin. Middle-aged adults are most commonly affected. The

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presence of a monoclonal protein, often immunoglobulin G (IgG) lambda, detected in the

serum or urine by immunofixation supports the diagnosis of scleromyxedema. Skin biopsy
is frequently diagnostic. Scleromyxedema may be associated with, and even be the
presenting features of, immunoglobulin light chain (AL) amyloidosis and multiple
myeloma. (See "Cutaneous manifestations of internal malignancy", section on
'Scleromyxedema'.)

● Endocrine disorders – Diabetes mellitus and myxedema due to hypothyroidism can be

accompanied by skin induration. Endocrine disorders may also occur in some patients
with monoclonal gammopathies, for example, in the POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). (See
"POEMS syndrome".)

Sclerodactyly due to diabetes mellitus ("diabetic cheiroarthropathy") occurs in individuals

with longstanding type I diabetes. It is characterized by thickening and waxiness of the
skin, mostly marked on the dorsa of the fingers. Diabetic cheiroarthropathy is often
associated with limited mobility and flexion contractures of the proximal interphalangeal
joints. RP, ischemic ulceration, calcinosis cutis, and tapering of the digits are absent, and
autoantibodies are not detected. (See "Overview of the musculoskeletal complications of
diabetes mellitus", section on 'Diabetic sclerodactyly'.)

Myxedema is seen in hypothyroidism and is characterized by thickening and coarseness of

the skin (see "Clinical manifestations of hypothyroidism", section on 'Skin'). The increased
incidence of hypothyroidism in SSc complicates the differential diagnosis.

● Nephrogenic systemic fibrosis – Among patients with advanced renal failure (dialysis-
dependent or estimated glomerular filtration rate of less than 15 mL/min), the
administration of gadolinium-containing contrast media for magnetic resonance imaging
(MRI) has been associated with nephrogenic systemic fibrosis (previously called
nephrogenic fibrosing dermopathy). Nephrogenic systemic fibrosis is characterized by
thickening and hardening of the skin overlying the extremities and trunk. On histologic
examination, there is marked expansion and fibrosis of the dermis with accumulation of
CD34-positive fibroblasts. The clinical appearance of the affected limbs resembles
eosinophilic fasciitis, but is distinguished by involvement of hands and feet, which are
typically spared in eosinophilic fasciitis. Internal organ fibrosis may also occur. (See
"Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney
disease".)

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● Amyloidosis – Amyloid infiltration of the skin may produce thickening and stiffness. This is
characteristic of AL amyloid, due to a plasma cell disorder. Skin biopsy reveals
accumulation of amyloid with characteristic staining properties, and polarizing
microscopic examination of Congo red-stained skin or subcutaneous fat reveals apple-
green birefringence. Immunofixation of serum or urine reveals a monoclonal component.
(See "Overview of amyloidosis".)

● Eosinophilic fasciitis – Eosinophilic fasciitis (diffuse fasciitis with eosinophilia) leads to

adherence of skin to underlying thickened fascia. Skin changes are prominent proximal to
the wrists and ankles and usually spare the hands and feet. The disorder is associated with
transient peripheral blood eosinophilia and a variable degree of inflammatory cell
infiltration in the fascia. Skin changes suggestive of eosinophilic fasciitis are an orange
peel (peau d'orange) appearance and the groove sign (visible collapse of the superficial
veins when the limb is elevated). In order to observe the characteristic changes in the
fascia, a surgical excisional biopsy of skin, including subcutaneous tissue and fascia, is
necessary. (See "Eosinophilic fasciitis".)

● Chronic graft-versus-host disease – Both localized and generalized scleroderma-like skin

changes can occur in chronic graft-versus-host disease (GVHD). This disorder typically
follows allogeneic hematopoietic transplantation but may also occur following
transfusions in immunosuppressed hosts. Autoantibodies, particularly antinucleolar and
antimitochondrial antibodies, may be present. RP is generally absent. Characteristic
findings on skin biopsy may help in differentiating chronic GVHD from scleroderma. (See
"Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

● Drug-induced scleroderma – Use of some drugs has been linked to the development of
scleroderma or scleroderma-like disorders. Reports include SSc-like changes in patients
who have received the cancer chemotherapeutic drugs, bleomycin and docetaxel, and
localized scleroderma-like injection site reactions to vitamin K, vitamin B12, and the
analgesic pentazocine. (See "Risk factors for and possible causes of systemic sclerosis
(scleroderma)", section on 'Drugs' and "Cutaneous adverse effects of conventional
chemotherapy agents", section on 'Subacute cutaneous lupus erythematosus and
scleroderma-like changes'.)

● Environmental exposure – Use of vibrating tools may lead to RP, dissolution of the bone
at the fingertips (acroosteolysis), and sclerodactyly. Exposures to organic solvents,
petroleum distillates, a contaminant of L-tryptophan, and adulterated cooking oil have
also been related to diseases with scleroderma-like skin thickening. (See "Risk factors for

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and possible causes of systemic sclerosis (scleroderma)", section on 'Noninfectious

environmental factors'.)

Raynaud phenomenon — RP occurs in over 90 percent of patients with SSc but does not occur
in the other disorders associated with scleroderma-like skin changes discussed above (see
'Causes of scleroderma-like skin changes' above). On the other hand, cold-induced digital
vasospasm associated with characteristic color changes may occur in isolation (primary RP, also
called Raynaud disease), in other disease states, and in response to drugs and/or
environmental exposures (see "Clinical manifestations and diagnosis of Raynaud
phenomenon"). Primary RP occurs in up to 5 percent of the general population and more
commonly in women; in these individuals, it generally develops in the first three decades of life,
is frequently familial, and is not associated with ischemic digital ulcers or infarction.

RP is not a feature of localized scleroderma (or morphea).

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Systemic sclerosis
(scleroderma)".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Systemic sclerosis (scleroderma) (The Basics)")

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SUMMARY AND RECOMMENDATIONS

● Definitions – Systemic sclerosis (SSc) is a chronic multisystem disease with variable clinical
presentations and disease course, characterized by autoimmunity, widespread vascular
dysfunction, and variable fibrosis of the skin and internal organs. Most patients with SSc
can generally be classified based on the extent of skin involvement and the accompanying
pattern of internal organ involvement, as well as the presence of overlapping features
with other systemic rheumatic diseases. The major subsets of SSc include limited
cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc), SSc sine scleroderma, and SSc
overlap syndrome. (See 'Introduction' above and 'Major disease subsets' above.)

● Clinical manifestations – Major clinical manifestations of SSc include the following (see
'Clinical features' above):

• Cutaneous manifestations – Skin involvement is a nearly universal feature of SSc and

is characterized by variable extent and severity of skin thickening and hardening. The
fingers, hands, and face are generally the earliest areas of the body involved. (See
'Cutaneous manifestations' above.)

• Digital vasculopathy – Raynaud phenomenon (RP) is essentially universally present in

patients with SSc. RP is classically viewed as reversible vasospasm due to functional
changes in the digital arteries of the hands and feet. However, over time, many
patients with SSc develop progressive structural changes in the small blood vessels,
with permanently impaired flow resulting in digital ulcers and tissue loss. (See 'Digital
vasculopathy' above.)

• Musculoskeletal manifestations – The musculoskeletal manifestations of SSc are

diverse and include arthritis, tendinitis, and joint contractures. (See 'Musculoskeletal
manifestations' above.)

• Gastrointestinal involvement – Nearly 90 percent of patients with SSc have evidence

of gastrointestinal involvement. Nearly half of these patients may have no symptoms.
Although the esophagus is the most frequently affected part of the gastrointestinal
tract, any part of the gastrointestinal tract may be involved. Common symptoms of
gastrointestinal involvement include dysphagia and choking, heartburn, hoarseness,
cough after swallowing, bloating, alternating constipation and diarrhea, pseudo-
obstruction and bacterial small bowel overgrowth with malabsorption, and fecal
incontinence. (See 'Gastrointestinal involvement' above.)

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• Pulmonary involvement – Evidence for pulmonary involvement is observed in more

than 70 percent of patients with SSc. The two principal clinical manifestations are
interstitial lung disease (ILD) and pulmonary vascular disease, leading to pulmonary
arterial hypertension (PAH). (See 'Pulmonary involvement' above.)

• Cardiac involvement – All anatomic domains of the heart can be affected in patients
with SSc, including the myocardium, pericardium, and conduction system. Primary
cardiac involvement is frequent and can be asymptomatic. Cardiac manifestations can
also occur secondary to PAH, ILD, or scleroderma renal crisis (SRC). (See 'Cardiac
involvement' above.)

• Kidney involvement – Clinical kidney disease is observed in up to half of patients.

Findings may include albuminuria, a mild elevation in the plasma creatinine
concentration, and/or hypertension. SRC, the most serious kidney complication, occurs
in up to 10 to 15 percent of patients, generally among those with early-stage disease
and diffuse cutaneous involvement, and is associated with a poor prognosis. (See
'Kidney involvement' above.)

• Neuromuscular involvement – Myopathy is increasingly recognized as a major

contributor to the morbidity and mortality of the disease. Other neurologic
abnormalities in SSc that are less common include central, peripheral, and autonomic
neuropathies. (See 'Neuromuscular involvement' above.)

• Genitourinary involvement – SSc in men is very commonly associated with erectile

dysfunction, which can be an early and even initial manifestation of disease. Women
with SSc may also have sexual dysfunction. (See 'Genitourinary involvement' above.)

● Evaluation – The diagnosis of SSc should be suspected in patients with skin thickening,
puffy or swollen fingers, RP, hand stiffness, and/or painful distal finger ulcers. Symptoms
of gastroesophageal reflux are often present. (See 'Evaluation for suspected systemic
sclerosis' above.)

● Laboratory testing – We obtain the following routine laboratory tests in patients with
suspected SSc, some of which may provide information about specific organ involvement
(see 'Laboratory testing' above):

• Complete blood count and differential, which may reveal anemia due to malabsorption
of iron or gastrointestinal blood loss
• Serum creatinine level, which may indicate renal dysfunction
• Creatine kinase (CK), which may be elevated in patients with myopathy or myositis
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• Urinalysis

We also perform the following serologic tests ( table 4), which may support the
diagnosis if positive:

• Antinuclear antibody (ANA)

• Antitopoisomerase I (anti-Scl-70) antibody
• Anticentromere antibody (ACA)
• Anti-RNA polymerase III antibody
• Anti-Th/To antibody

● Additional studies – Additional studies focusing on specific organ involvement are useful
for confirmation of the diagnosis and determining the extent of extracutaneous
involvement (see 'Additional studies' above):

• All patients with suspected SSc should be evaluated for ILD and pulmonary
hypertension, which are the most frequent types of lung involvement in SSc patients.
Studies that we obtain as part of the initial diagnostic workup include radiographic
imaging of the lung (preferably high-resolution CT [HRCT]), pulmonary function testing
(PFT), and Doppler echocardiography.

• Evaluation for gastrointestinal involvement, which is present in almost all patients with
SSc to varying degrees, should be guided by patient symptoms.

● Diagnosis – We diagnose limited or diffuse SSc in patients with skin thickening of the
fingers of both hands extending proximal to the metacarpophalangeal joints. Among
patients with such involvement, the presence of the following additional findings and/or
abnormalities support the diagnosis of SSc (see 'Diagnosis' above):

• Ischemic fingertip ulcerations (digital tip pitting scars) ( figure 4), calcinosis cutis, skin
hyperpigmentations, and/or mucocutaneous telangiectasia ( figure 3). However,
these findings are often absent in patients with early disease.
• Characteristic nailfold capillary changes.
• Heartburn and/or dysphagia of new onset.
• Erectile dysfunction in men.
• RP.
• Acute onset of hypertension and renal insufficiency.
• Dyspnea on exertion associated with evidence of interstitial pulmonary changes on
radiography or HRCT.
• Dyspnea on exertion associated with evidence of PAH on Doppler echocardiography.
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• Diarrhea with malabsorption or intestinal pseudo-obstruction.

• Positive anti-Scl-70 antibody, ACA, and/or anti-RNA polymerase III antibody; or a
positive ANA with a nucleolar immunofluorescence pattern.

● Systemic sclerosis sine scleroderma – Approximately 10 percent of patients in whom a

diagnosis of SSc is eventually made do not have clinically apparent skin induration ("sine
scleroderma"). The diagnosis of SSc in these patients rests upon the presence of other
characteristic clinical features (eg, RP, esophageal hypomotility, nailfold microvascular
changes, evidence of pulmonary and/or renal involvement) and specific serum
autoantibodies. (See 'Systemic sclerosis sine scleroderma' above.)

● Differential diagnosis – The differential diagnosis in SSc includes scleredema,

scleromyxedema, overlap syndromes, diabetes and other endocrine disorders,
nephrogenic systemic fibrosis, amyloidosis, eosinophilic fasciitis, chronic graft-versus-host
disease (GVHD), drug-induced scleroderma, and environmental exposures. (See
'Differential diagnosis' above.)

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74. Minier T, Guiducci S, Bellando-Randone S, et al. Preliminary analysis of the very early
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Topic 7539 Version 37.0

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GRAPHICS

Clinical features of the major systemic sclerosis subsets

Diffuse Early (<3 years after

Late (>3 years after onset)
cutaneous onset)

Constitutional Fatigue and weight loss Minimal, weight gain typical

Vascular Raynaud often relatively Raynaud more severe, more telangiectasia

mild

Cutaneous Rapid progression Stable or regression

involving arms, trunk, face

Musculoskeletal Prominent arthralgia, Flexion contractures and deformities, joint/muscle

stiffness, myalgia, muscle symptoms less prominent
weakness, tendon friction
rubs

Gastrointestinal Dysphagia, heartburn More pronounced symptoms, midgut and

anorectal complications more common

Cardiopulmonary Maximum risk for Reduced risk of new involvement but progression
myocarditis, pericardial of existing established visceral fibrosis
effusion, interstitial
pulmonary fibrosis

Renal Maximum risk for renal Renal crisis less frequent, uncommon after 5 years
crisis within the first 5
years

Limited Early (<10 years after

Late (>10 years after onset)
cutaneous onset)

Constitutional None Only secondary to visceral complications

Vascular Raynaud typically severe Raynaud persists, often causing digital ulceration
and longstanding or gangrene
telangiectasia

Cutaneous Mild sclerosis with little Stable, calcinosis more prominent

progression on trunk, face

Musculoskeletal Occasional joint stiffness Mild flexion contractures

Gastrointestinal Dysphagia, heartburn More pronounced symptoms, midgut and

anorectal complications more common

Cardiopulmonary Usually no involvement Lung fibrosis may develop, but often progresses
slowly, anti-SCL-70 predicts increased risk of severe
fibrosis. Maximum risk for developing isolated
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pulmonary hypertension and secondary right

ventricular failure.

Renal No involvement Rarely involved, anti-RNA polymerase predicts

increased risk of renal involvement.

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Puffy hands and shiny skin in early systemic sclerosis

(A) Diffusely puffy fingers are a common initial presentation.

(B) Shiny skin suggests impending skin thickening.

Reprinted with permission from Systemic Sclerosis/Scleroderma: A Treatable Multisystem Disease, October 15, 2008, Vol 78,
No 8, American Family Physician. Copyright © 2008 American Academy of Family Physicians. All Rights Reserved.

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Calcinosis cutis in scleroderma on radiograph

A-P view of the hands in a patient with scleroderma shows extensive calcification involving the soft tissues
of the distal phalanges of both hands.

A-P: anteroposterior.

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Systemic sclerosis subtypes

Limited cutaneous systemic sclerosis

Raynaud phenomenon for years, occasionally decades

Skin involvement limited to hands, face, feet, and forearms (acral distribution)

Nailfold capillary pattern typical of systemic sclerosis (predominantly nailfold capillary loops with
capillary dropout)

A significant (10 to 15%) late incidence of pulmonary hypertension, with or without skin
calcification, gastrointestinal disease, telangiectasias (CREST syndrome), or interstitial lung disease

Renal disease rarely occurs

Anticentromere antibody (ACA) in 50 to 60%, but other patterns also occurring in 5 to 10%
(especially anti-PM/Scl and anti-Scl-70)

Diffuse cutaneous systemic sclerosis

Raynaud phenomenon followed, within 1 year, by puffy or hidebound skin changes

Truncal and acral skin involvement; tendon friction rubs

Nailfold capillary pattern typical of systemic sclerosis with dilatation (early), dilatation and dropout
(active), and tortuosity with dropout (late)

Early and significant incidence of renal, interstitial lung, diffuse gastrointestinal, and myocardial
disease

Anti-Scl-70 (30%) and anti-RNA polymerase I, II, or III (12 to 15%) antibodies

Systemic sclerosis sine scleroderma

Presentation with pulmonary fibrosis or renal, cardiac, or gastrointestinal disease

No skin involvement

Raynaud phenomenon may be present

Antinuclear antibodies may be present (anti-Scl-70, ACA, or anti-RNA polymerase I, II, or III)

Overlap syndromes
Features of systemic sclerosis that coexist with those of another autoimmune rheumatic disease,
such as systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, vasculitis, or
Sjögren's syndrome

CREST syndrome: calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and

telangiectasia syndrome, also called limited scleroderma or limited cutaneous form of systemic
sclerosis; anti-PM/Scl: anti-polymyositis/scleroderma antinuclear antibodies, also called anti-
exosome antibodies; anti-Scl-70: antinuclear autoantibody to the scleroderma 70 kD antigen
fragment, also called the anti-topoisomerase I antibody; RNA: ribonucleic acid.

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Clinical manifestations of lung disease in scleroderma

Disease Symptoms Signs

Pulmonary fibrosis Dyspnea Chest expansion

Dry cough Basal crepitations (rales)

Clubbing (late, very

uncommon)

Pulmonary hypertension Dyspnea Loud P2

Ankle edema Right ventricular heave

Pleural involvement Pleuritic chest pain Pleural rub

Dyspnea Pleural effusion (rare)

Bronchiectasis Cough with purulent Basal crepitations

sputum

Dyspnea

Spontaneous pneumothorax Chest pain Resonant percussion

Dyspnea Reduced breath sounds

Lung cancer (scar type), especially alveolar Cough Possible signs of collapse
cell
Hemoptysis

Respiratory failure due to respiratory muscle Dyspnea Hypoventilation

involvement
Reduced chest
expansion

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Modified Rodnan skin score for systemic sclerosis

Method used to semiquantify skin thickness in scleroderma. The

modified Rodnan skin score is obtained by clinical palpation of 17
different body areas (fingers, hands, forearms, upper arms, face,
chest, abdomen, thighs, lower legs, and feet) and subjective
averaging of the thickness of each specific site: 0 = normal (A); 1 =
mild (B); 2 = moderate (C); and 3 = severe (D). The maximum
total score is 51.

Reproduced from: Firestein GS, Budd RC, Gabriel SE, et al. Kelley's Textbook of
Rheumatology, 9th ed, Saunders, Philadelphia 2012. Illustration used with the
permission of Elsevier Inc. All rights reserved.

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Clinical assessment of skin thickening

The modified Rodnan skin score. Semiquantitative estimates by clinical

palpation of the extent and severity of scleroderma skin change. The total skin
surface is divided into 17 different areas, and in each of these areas the skin
score is estimated by manual palpation. The total skin score is the sum of the
skin scores of the individual areas.

Original figure modified for this publication. Bolster MB, Silver RM. Clinical features of systemic
sclerosis. In: Hochberg MC, Silman AJ, Smolen JS, et al. Rheumatology, 5th ed, Mosby (Elsevier),

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Philadelphia 2010. Illustration used with the permission of Elsevier Inc. All rights reserved.

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Oral manifestations of systemic sclerosis

Oral manifestations.

(A) Perioral skin tightening with decreased oral aperture, furrowing around the lips, and dry
mucous membranes.

(B) Periodontal disease with regression of gum and loosening of teeth.

(C, D) Telangiectasias on lips and tongue.

Reproduced from: Firestein GS, Budd RC, Gabriel SE, et al. Kelley's Textbook of Rheumatology, 9th ed, Saunders,
Philadelphia 2012. Illustration used with the permission of Elsevier Inc. All rights reserved.

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Digital ulcerations and ischemia in systemic sclerosis

Scleroderma and Raynaud phenomenon can be associated with ischemic and traumatic
digital ulcerations and digital ischemia.

(A) Traumatic ulcers over the proximal interphalangeal joints.

(B, C) Ischemic digital tip ulcerations secondary to small arterial disease.

(D) Digital gangrene secondary to vascular disease.

Reproduced from: Firestein GS, Budd RC, Gabriel SE, et al. Kelley's Textbook of Rheumatology, 9th ed,
Saunders, Philadelphia 2012. Illustration used with the permission of Elsevier Inc. All rights reserved.

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Serum autoantibodies in systemic sclerosis

Approximate
ANA staining frequency in Clinical Organ
Antigen
pattern all patients associations involvement
(%)

Scl-70 Speckled 10 to 40 dcSSc Lung fibrosis,

(topoisomerase-1) isolated
pulmonary
hypertension less
likely

Centromere Centromere 15 to 40 lcSSc Pulmonary

(kinetochore) hypertension,
esophageal
disease,
"protection" from
lung fibrosis and
renal disease

RNA polymerase Fine speckled 4 to 25 dcSSc Renal, skin,

III nucleolar malignancy

Characteristics and clinical associations of the different autoantibodies that may be seen in
scleroderma. dcSSc and lcSSc refer to diffuse and limited cutaneous systemic sclerosis, respectively.

ANA: antinuclear antibody; dcSSc: diffuse cutaneous systemic sclerosis; lcSSc: limited cutaneous
systemic sclerosis.

Adapted from: Nihtyanova SI, Denton CP. Autoantibodies as predictive tools in systemic sclerosis. Nat Rev Rheumatol 2010;
6:112.

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Serum autoantibodies in scleroderma

Approximate
ANA staining frequency in Clinical Organ
Antigen
pattern all patients associations involvement
(%)

Scl-70 Speckled 10 to 40 dcSSc Lung fibrosis,

(topoisomerase-1) isolated
pulmonary
hypertension less
likely

Centromere Centromere 15 to 40 lcSSc Pulmonary

(kinetochore) hypertension,
esophageal
disease,
"protection" from
lung fibrosis and
renal disease

RNA polymerase Fine speckled 4 to 25 dcSSc Renal, skin,

III nucleolar malignancy

U3 RNP Nucleolar 1 to 5 dcSSc, poor Pulmonary

(fibrillarin) outcome, Black hypertension,
males muscle

PM-Scl Nucleolar 3 to 6 Overlap, mixed Muscle

U1 RNP Speckled 5 to 35 lcSSc, Black Muscle

patients,
polymyositis
overlap

Th/To Nucleolar 1 to 7 lcSSc Pulmonary

hypertension,
lung fibrosis,
small bowel

Anti-U11/U12 Nucleolar 1 to 5 lcSSc and dcSSc Lung fibrosis

Anti-Ku 1 to 3 Overlap SSc Muscle and joint

involvement, SLE
overlap

Characteristics and clinical associations of the different autoantibodies that may be seen in
scleroderma. dcSSc and lcSSc refer to diffuse and limited cutaneous systemic sclerosis, respectively.

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ANA: antinuclear antibody; dcSSc: diffuse cutaneous systemic sclerosis; lcSSc: limited cutaneous
systemic sclerosis; SLE: systemic lupus erythematosus.

Adapted from: Nihtyanova SI, Denton CP. Autoantibodies as predictive tools in systemic sclerosis. Nat Rev Rheumatol 2010;
6:112.

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The ACR/EULAR criteria for the classification of SSc*

Item Sub-item(s) Weight/score ¶

Skin thickening of the fingers of both – 9

hands extending proximal to the
metacarpophalangeal joints (sufficient
criterion)

Skin thickening of the fingers (only Puffy fingers 2

count the higher score)
Sclerodactyly of the fingers (distal to 4
the metacarpophalangeal joints but
proximal to the proximal
interphalangeal joints)

Fingertip lesions (only count the higher Digital tip ulcers 2

score)
Fingertip pitting scars 3

Telangiectasia – 2

Abnormal nailfold capillaries – 2

Pulmonary arterial hypertension Pulmonary arterial hypertension 2

and/or interstitial lung disease
(maximum score is 2) Interstitial lung disease 2

Raynaud phenomenon – 3

SSc-related autoantibodies Anticentromere 3

(anticentromere, anti-topoisomerase I
Anti-topoisomerase I
[anti-Scl-70], anti-RNA polymerase III)
(maximum score is 3) Anti-RNA polymerase III

ACR/EULAR criteria for the classification of systemic sclerosis.

ACR: American College of Rheumatology; EULAR: European League Against Rheumatism; SSc:
systemic sclerosis.

* These criteria are applicable to any patient considered for inclusion in an SSc study. The criteria are
not applicable to patients with skin thickening sparing the fingers or to patients who have a
scleroderma-like disorder that better explains their manifestations (eg, nephrogenic sclerosing
fibrosis, generalized morphea, eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema,
erythromyalgia, porphyria, lichen sclerosis, graft-versus-host disease, diabetic cheiroarthropathy).

¶ 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.

From: van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification Criteria for Systemic Sclerosis: An American College
of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum 2013; 65:2737. Copyright

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© 2013 by the American College of Rheumatology. Reproduced with permission from John Wiley & Sons, Inc. All rights
reserved.

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Definitions of items in the ACR/EULAR criteria for the classification of SSc

Item Definition

Skin thickening Skin thickening or hardening not due to scarring after injury, trauma, etc.

Puffy fingers Swollen digits—a diffuse, usually nonpitting increase in soft tissue mass of the
digits extending beyond the normal confines of the joint capsule. Normal digits
are tapered distally with the tissues following the contours of the digital bone
and joint structures. Swelling of the digits obliterates these contours. Not due to
other causes such as inflammatory dactylitis.

Fingertip ulcers Ulcers or scars distal to or at the proximal interphalangeal joint not thought to
or pitting scars be due to trauma. Digital pitting scars are depressed areas at digital tips as a
result of ischemia, rather than trauma or exogenous causes.

Telangiectasia Telangiectasiae are visible macular dilated superficial blood vessels, which
collapse upon pressure and fill slowly when pressure is released. Telangiectasiae
in a scleroderma-like pattern are round and well demarcated and found on
hands, lips, and inside of the mouth, and/or are large mat-like telangiectasiae.
Distinguishable from rapidly filling spider angiomas with central arteriole and
from dilated superficial vessels.

Abnormal nailfold Enlarged capillaries and/or capillary loss with or without pericapillary
capillary pattern hemorrhages at the nailfold. May also be seen on the cuticle.
consistent with
systemic sclerosis

Pulmonary Pulmonary arterial hypertension diagnosed by right-sided heart catheterization

arterial according to standard definitions.
hypertension

Interstitial lung Pulmonary fibrosis seen on high-resolution computed tomography or chest

disease radiography, most pronounced in the basilar portions of the lungs, or occurrence
of "Velcro" crackles on auscultation, not due to another cause such as congestive
heart failure.

Raynaud's Self-reported or reported by a physician, with at least a two-phase color change

phenomenon in finger(s) and often toe(s) consisting of pallor, cyanosis, and/or reactive
hyperemia in response to cold exposure or emotion; usually one phase is pallor.

SSc-related Anticentromere antibody or centromere pattern seen on antinuclear antibody

autoantibodies testing, anti-topoisomerase I antibody (also known as anti-Scl-70 antibody), or
anti-RNA polymerase III antibody. Positive according to local laboratory
standards.

Definitions of the items/sub-items in the ACR/EULAR criteria for the classification of systemic
sclerosis.

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ACR: American College of Rheumatology; EULAR: European League Against Rheumatism; SSc:
systemic sclerosis.

From: van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification Criteria for Systemic Sclerosis: An American College
of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum 2013; 65:2737. Copyright
© 2013 by the American College of Rheumatology. Reproduced with permission from John Wiley & Sons, Inc. All rights
reserved.

Graphic 91165 Version 2.0

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Contributor Disclosures
John Varga, MD Equity Ownership/Stock Options: Emerald Pharma [Scleroderma]; TeneoBio [Fibrosis,
scleroderma]. Grant/Research/Clinical Trial Support: GSK [Scleroderma]; Pfizer [Scleroderma]; Roche
[Scleroderma]; TeneoBio [Scleroderma]. Consultant/Advisory Boards: APIE Therapeutics [Pulmonary
Fibrosis]; Arxx Therapeutics [Scleroderma]; Boehringer Ingelheim [Pulmonary fibrosis]; Emerald
[Scleroderma]; TeneoBio [Scleroderma]. All of the relevant financial relationships listed have been
mitigated. John S Axford, DSc, MD, FRCP, FRCPCH No relevant financial relationship(s) with ineligible
companies to disclose. Philip Seo, MD, MHS No relevant financial relationship(s) with ineligible companies
to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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