INTRODUCTION — The term scleroderma is used to describe the presence of thickened, hardened skin (from the Greek "scleros") . 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:
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 .
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 disease.
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 .
The majority of patients with SSc are female, with the female to male ratio ranging from 3:1 to 8:1. There are sex-based 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 . Moreover, the interval from first onset of RP to diagnosis of SSc tends to be longer in women than men .
African American patients tend to have earlier-onset disease and more severe disease phenotypes with increased risk of pulmonary fibrosis and scleroderma renal crisis (SRC) .
CLINICAL FEATURES — In addition to the major organ involvement discussed in detail below, patients with systemic sclerosis (SSc) often experience pain and fatigue . 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 . 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
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) .
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
●Capillary changes at the nail beds
●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
●Degos-like lesions 
●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).
A small subset of patients with SSc have no skin induration (termed SSc sine scleroderma) . Although there is no clinically evident skin sclerosis, these patients have characteristic vascular and/or fibrotic features of SSc, 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 anti-topoisomerase I (anti-Scl-70) . A history of ischemic digital ulcers at presentation has also been associated with cardiovascular worsening and decreased survival . 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 . 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 [16-18]. Destructive small joint involvement 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 calcifications in the skin (calcinosis cutis) (image 1) and other soft tissues, as well as resorption of the distal phalangeal tufts (acro-osteolysis). Articular erosions, joint space narrowing, and demineralization are less common radiographic findings .
Gastrointestinal involvement — Nearly 90 percent of patients with either subtype of SSc (dcSSc or limited cutaneous SSc [lcSSc]) have evidence of gastrointestinal involvement [20,21]. 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 . 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 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 — Cardiac involvement is frequent in SSc but can be entirely asymptomatic. 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). 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 show 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 [23,24]. Impaired kidney reserve may be present in the absence of clinical kidney disease . 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 [26-28].
Life-threatening renal involvement called SRC develops in up to 10 percent of patients and is far more frequent in patients with dcSSc than lcSSc. SRC almost invariably occurs in the early stages of SSc. There is no evidence that the prophylactic use of angiotensin-converting enzyme 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 hemolytic 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.
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 . This was illustrated in a survey that compared 43 SSc patients with 23 patients with rheumatoid arthritis . 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 .
Other disease associations
●Cancer risk – There have been several reports demonstrating an increased risk of malignancy in patients with SSc [32-39].
The most significant cancer association appears to be lung, which accounts for approximately one-third of all cancers in SSc patients ; however, a significantly increased incidence was not noted in a population with a high background rate of lung cancer . In a study of 632 Australian patients with SSc, 19 developed lung cancer . Those who smoked were seven times as likely to develop cancer as those who did not. Pulmonary fibrosis and anti-topoisomerase I antibodies were not risk factors for lung cancer [41,42].
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 . 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 (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 . 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 [43,44]. One study demonstrated that tumors harboring somatic mutations in the POLR3A gene may trigger the development of SSc .
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 [46,47].
●Thromboembolic risk – An increased risk of venous thromboembolism (VTE) has been reported among patients with SSc [48,49]. 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 . 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 patients typically benefit from multispecialty involvement (eg, by rheumatology, dermatology, pulmonology, and gastroenterology).
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:
●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 .
●Anti-topoisomerase 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) [51,52].
●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) [27,53]. These patients may also be at increased risk for concomitant cancer [44,45].
●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 .
The anti-topoisomerase 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) [51,55,56]. 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 [57,58]. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)
To help in the differential diagnosis of SSc, we also order the following when appropriate:
●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 . (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 [60-62]. (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) of the chest is preferred over a chest radiograph in SSc due to the greater sensitivity of the HRCT. In SSc, 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 '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, the skin in SSc shows excessive deposition of compact and organized bundles of collagen in the dermis and expansion of the dermis. In early stages of the disease, skin biopsy shows 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 .
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 . 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.
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 anti-topoisomerase 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") [12,65]. This SSc subset has been described in several case reports and cohort studies [12,65-67]. 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 :
●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 [12,66,67]. The following studies are illustrative:
●An observational study compared the clinical and laboratory features of 507 lcSSc patients with 48 SSc sine scleroderma patients . 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 . 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 . (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes" and "Clinical manifestations and diagnosis of mixed connective tissue disease".)
CLASSIFICATION CRITERIA — The clinical heterogeneity of systemic sclerosis (SSc) highlights the importance of 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) [69,70]. 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 [57,71-74].
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 patients with early SSc who might not display characteristic skin thickening and internal organ involvement . 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 . 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 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".)
●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 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)")
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.)
•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
We also perform the following serologic tests (table 4), which may support the diagnosis if positive:
•Antinuclear antibody (ANA)
•Anti-topoisomerase I (anti-Scl-70) antibody
•Anticentromere antibody (ACA)
•Anti-RNA polymerase III 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.
•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 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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