Clinical Manifestations and Diagnosis of Systemic Sclerosis (Scleroderma) in Adu

Author: John Varga, MD
Section Editor: John S Axford, DSc, MD, FRCP, FRCPCH

Deputy Editor: Monica Ramirez Curtis, MD, MPH
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2020. | This topic last updated: Jan 03, 2020.
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 heterogenous disease, which is reflected by a broad range of organ

involvement, disease 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 "Localized scleroderma in childhood" and
"Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and
diagnosis".)
Separate topic reviews related to SSc include the following:
https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

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● (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)".)
● (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, classification, risk factors, and screening".)
● (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma):
Treatment and prognosis".)
● (See "Renal 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 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 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,

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esophageal dysmotility, sclerodactyly, and telangiectasia).
● Diffuse cutaneous systemic sclerosis – Patients typically present with puffy

hands and have 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].
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 per year [3].
The majority of patients with SSc are female. There are differences in disease
presentation, with women trending towards more limited disease, younger age of onset,
increased peripheral vascular disease, and risk for pulmonary arterial hypertension
(PAH). Men have an increased risk of diffuse disease, more severe interstitial lung
disease (ILD), and increased cardiovascular complications [4].
African Americans tend to have earlier-onset disease and more severe disease
phenotypes with increased risk of pulmonary fibrosis and scleroderma renal crisis
(SRC) [5].

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CLINICAL FEATURES
In addition to the major organ involvement discussed in detail below, patients with
systemic sclerosis (SSc) often experience pain and fatigue [6]. 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 [7]. The presence of fatigue
has been associated with poorer physical function and greater pain [6]. Causes of pain
include skin-related discomfort, joint pain, Raynaud phenomenon (RP), and ischemic
digital ulcers.
Major organ involvement
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 areas of the body
involved. 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) [8].
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 distribution of skin lesions forms the basis for the widely used binary classification

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system of SSc into limited and diffuse forms of the disease (table 2).
Only a small percentage of patients with SSc have no skin induration (termed SSc sine
scleroderma) [9]. 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".)
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) [10]. A history of ischemic
digital ulcers at presentation has also been associated with cardiovascular worsening
and decreased survival [11]. Digital ischemia can result in infection, gangrene, and
amputation.
Musculoskeletal manifestations — The musculoskeletal manifestations of SSc are

diverse and include arthritis, tendinitis, tendon friction rubs, and joint contractures. For
patients with dcSSc, swelling of the hands, 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. Tendon friction rubs occur predominantly in patients

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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 [12]. 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 [13-15]. 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".)
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 [16].
Gastrointestinal involvement — Nearly 90 percent of patients with either subtype

of SSc (dcSSc or limited cutaneous SSc [lcSSc]) have evidence of gastrointestinal
involvement [17,18]. 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

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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 [19]. 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 seen 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, classification, 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. 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 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

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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 manifestations can also occur secondary to PAH, ILD, or scleroderma renal
crisis (SRC). A detailed discussion of the cardiac manifestations of SSc can be found
elsewhere. (See "Cardiac manifestations of systemic sclerosis (scleroderma)".)
Renal 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 [20,21]. Impaired renal
reserve may be present in the absence of clinical renal disease [22]. 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 [23-25].
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. This form of renal
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.
Renal disease in SSc, including SRC, is discussed in detail separately. (See "Renal
disease in systemic sclerosis (scleroderma), including scleroderma renal crisis".)

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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
[26]. This was illustrated in a survey that compared 43 SSc patients with 23 patients
with rheumatoid arthritis [27]. 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 [28].
Other disease associations
● Cancer risk – There have been several reports demonstrating an increased risk of
malignancy in patients with SSc [29-36]. The most significant association appears
to be with lung cancer, which accounts for approximately one-third of the cancers
seen in SSc patients [31]; however, a significantly increased incidence was not
noted in a population with a high background rate of lung cancer [34]. In a study of
632 Australian patients with SSc, 19 developed lung cancer [37]. Those who
smoked were seven times as likely to develop cancer as those who did not.
Pulmonary fibrosis and antitopoisomerase antibodies were not risk factors for lung
cancer.
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 [35]. 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

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most frequent cancers were lung (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 [36].
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 RNA polymerase I/III [38,39]. One
study demonstrated that tumors harboring somatic mutations in the POLR3A gene
may trigger the development of SSc [40].
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 [41,42].
● Thromboembolic risk – An increased risk of venous thromboembolism (VTE) has

been reported among patients with SSc [43,44]. 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 [43]. 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".)

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

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● 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
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 [45].
● Antitopoisomerase I (anti-Scl-70) antibody. Anti-DNA topoisomerase I (Scl-70)

antibodies are generally associated with diffuse cutaneous SSc (dcSSc) and a
higher risk of severe interstitial lung disease (ILD) [46,47].
● 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) [24,48].
These patients may also be at increased risk for concomitant cancer [39,40].
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) [46,49,50]. The autoantibodies are almost always mutually
exclusive. Among those with RP but without definite SSc or a related autoimmune
rheumatic disease, the presence of these antibodies predicts an increased risk of
progression to SSc, particularly in combination with puffy fingers and/or abnormal
nailfold capillaroscopy [51]. (See "Clinical manifestations and diagnosis of Raynaud
phenomenon".)
To help in the differential diagnosis of SSc, we also may order the following when
appropriate:

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● Rheumatoid factor
● 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 [52]. (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
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 [53-55]. (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

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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

pulmonary arterial hypertension (PAH). (See "Overview of pulmonary complications
of systemic sclerosis (scleroderma)", section on '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 some 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 "Renal disease in
systemic sclerosis (scleroderma), including scleroderma renal crisis", section on
'Clinical features'). However, in our experience, these clinical scenarios are atypical and
often represent cases in which the cutaneous findings 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 "Renal 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.)

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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 [56].
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 [57]. 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
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 computed tomography (HRCT).
● Dyspnea on exertion associated with evidence of pulmonary arterial hypertension
(PAH) on Doppler echocardiography.

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● 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") [9,58]. This SSc subset has been described in several
case reports and cohort studies [9,58-60]. 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 [9]:
● 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
● 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
[9,59,60]. The following studies are illustrative:
● An observational study compared the clinical and laboratory features of 507 lcSSc
patients with 48 SSc sine scleroderma patients [9]. 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.

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● 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 [60]. 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 [61]. (See "Undifferentiated systemic rheumatic (connective tissue)
diseases and overlap syndromes" and "Definition and diagnosis of mixed connective
tissue disease".)
CLASSIFICATION CRITERIA
The clinical heterogeneity of systemic sclerosis (SSc) highlights the importance of

defining robust and pragmatic criteria 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

Page 17 of 35
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 League Against Rheumatism (EULAR) in
order to identify patients with SSc for inclusion in clinical studies.(table 6A-B)
[62,63]. This system addressed the shortcomings of previously used classification
systems by capturing a broader spectrum of SSc patients, and also incorporated
several diagnostic advances, particularly disease-specific autoantibodies and
nailfold capillaroscopy [51,64-67].
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.
● Preliminary criteria for early diagnosis – Preliminary criteria for very early
diagnosis of SSc (VEDOSS) have been proposed in order to identify features of
early disease that may precede characteristic skin thickening and internal organ
involvement, and facilitate earlier diagnosis [67]. 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

Page 18 of 35
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 scleroderma-specific autoantibodies and/or a scleroderma pattern
on nailfold capillaroscopy, and fulfilled the VEDOSS preliminary criteria for early
SSc [68]. Validation of the predictive value of these preliminary criteria is 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

Page 19 of 35
trunk, commonly occurring over thickened and indurated skin. Middle-aged adults
are most commonly affected. The 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

Page 20 of 35
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".)
● 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, diagnosis, and
grading 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-

Page 21 of 35
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 side 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 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

Page 22 of 35
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 scleroderma (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Systemic sclerosis (SSc) is a chronic multisystem disease characterized by

autoimmunity, widespread vascular dysfunction, and variable fibrosis of the skin
and internal organs. Most 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.)
● Major clinical manifestations of SSc include the following (see 'Clinical features'
above):
• 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.)

Page 23 of 35
• 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.)
• The musculoskeletal manifestations of SSc are diverse and include arthritis,

tendinitis, and joint contractures. (See 'Musculoskeletal manifestations' above.)
• 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.)
• 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.)
• All anatomic domains of the heart can be affected in patients with SSc,
including the myocardium, pericardium, and conduction system. Cardiac
manifestations can also occur secondary to PAH, ILD, or scleroderma renal
crisis (SRC). (See 'Cardiac involvement' above.)
• Clinical renal 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 renal 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 'Renal involvement' above.)

Page 24 of 35
• 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.)
• 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.)
● 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.)
● 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
• 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
● 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):

Page 25 of 35
• 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 computed
tomography [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.
● 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, 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.
• Diarrhea with malabsorption or intestinal pseudo-obstruction.
• Positive antitopoisomerase I (anti-Scl-70) antibody, ACA, and/or anti-RNA
polymerase III antibody; or a positive ANA with a nucleolar pattern.
● 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,

Page 26 of 35
evidence of pulmonary and/or renal involvement) and specific serum
autoantibodies. (See 'Systemic sclerosis sine scleroderma' above.)
● 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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Topic 7539 Version 31.0

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Clinical Manifestations and Diagnosis of Systemic Sclerosis (Scleroderma) in Adu

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Clinical Manifestations and Diagnosis of Systemic Sclerosis (Scleroderma) in Adu

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Author: John Varga, MD

Section Editor: John S Axford, DSc, MD, FRCP, FRCPCH

SSc is a chronic multisystem disease characterized by widespread vascular dysfunction

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

Separate topic reviews related to SSc include the following:

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

Major disease subsets — Systemic sclerosis (SSc) is traditionally classified based on

● Limited cutaneous systemic sclerosis – Patients typically present with puffy

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

● Diffuse cutaneous systemic sclerosis – Patients typically present with puffy

● Systemic sclerosis sine scleroderma – A small subset of patients have no

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

Major organ involvement

Cutaneous manifestations — Skin involvement is a nearly universal feature of

Other prominent skin manifestations include:

● Pruritus in the early stages

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

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

Musculoskeletal manifestations — The musculoskeletal manifestations of SSc are

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

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

Gastrointestinal involvement — Nearly 90 percent of patients with either subtype

Common symptoms of gastrointestinal involvement include dysphagia and choking,

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

Pulmonary involvement — Some degree of pulmonary involvement is seen in more

The most common symptoms of pulmonary involvement in SSc are breathlessness on

Pulmonary vascular disease, primarily PAH, occurs in 10 to 40 percent of patients with

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

Cardiac involvement — All anatomic domains of the heart can be affected in

Renal involvement — Autopsy studies suggest that 60 to 80 percent of patients

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

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

Other features of SRC may be secondary to severe hypertension or vasculopathy and

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

Genitourinary involvement — SSc in men is very commonly associated with

Other disease associations

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

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

There are conflicting data regarding whether the presence of antibodies to

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

EVALUATION FOR SUSPECTED SYSTEMIC SCLEROSIS

Systemic sclerosis (SSc) should be suspected in patients presenting with Raynaud

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

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

● Abnormal nailfold capillaroscopy with scleroderma pattern. This is particularly

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

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

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

● Anticentromere antibody (ACA). The presence of ACA is usually associated with

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

Antineutrophil cytoplasmic antibodies (ANCA) are often ordered indiscriminately in

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

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

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

● Doppler echocardiography – This is recommended for initial screening for

Evaluation for gastrointestinal involvement, which to varying degrees is present in

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

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

Systemic sclerosis — We diagnose limited or diffuse systemic sclerosis (SSc) in

● Raynaud phenomenon (RP).

https://www.uptodate.com/contents/clinical-manifestations-a…le=1~150&usage_type=default&display_rank=1#H3899918791 04/02/2020, 07:51

Systemic sclerosis sine scleroderma — Approximately 10 percent of patients in

In the absence of another autoimmune rheumatic disease, we diagnose SSc sine

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