Diagnosis and prognosis

Early diagnosis of SSc is important to delay, mitigate, or avoid irreversible end-organ damage. The diagnosis is based primarily on the presence of characteristic clinical findings and autoantibodies. Classification criteria are available from the American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) and have 91% sensitivity and 92% specificity for SSc (Table 2).6 Autoantibody positivity may be present early in the course of the disease and assist in diagnosis of patients with nonspecific signs and symptoms. Autoantibody patterns can also help distinguish the various types of SSc (ie, lcSSc, dcSSc, sine scleroderma, overlap syndrome) and the organ(s) likely to be involved, which is important for determining prognosis and optimal treatment.7,8

Table 2. ACR-EULAR Systemic Sclerosis Classification Criteria6 [return to contents]

The following sections describe the autoantibodies associated with SSc and their relevance for diagnosis and prognosis. A summary of the autoantibodies, their prevalences, and their clinical associations is provided in Table 3. An algorithm showing the use of antibody testing for SSc diagnosis is presented in the Figure.

Table 3. Clinical Characteristics Associated With Autoantibodies Used in the Diagnosis and Classification of Systemic Sclerosisa [return to contents]

Figure. Autoantibody Testing for Systemic Sclerosis Diagnosis and Determination of Prognosis
[return to contents]

Antinuclear antibody

Antinuclear antibody (ANA) immunofluorescence assay (IFA) is the initial test for detecting autoantibodies in a patient presenting with nonspecific symptoms, including Raynaud phenomenon. ANA is present in 85% to 95% of patients with SSc; however, ANA is also present in many other autoimmune disorders.9,19 Thus, a positive ANA IFA test should be followed with testing for more specific antibodies such as centromere B, Scl-70 (topoisomerase I), and RNA polymerase III antibodies.20 A negative ANA IFA test decreases the likelihood of SSc but does not rule it out.

Centromere antibodies

Centromere antibodies can be directed against a number of centromere proteins (CENP), including CENP-A, -B, and -C, though CENP-B is thought to be the main target.7,21 These antibodies are found in 20% to 40% of patients with SSc and are associated with the lcSSc subtype.7 Furthermore, centromere antibodies are included in the 2013 ACR-EULAR classification criteria.6 However, these antibodies can occur in other connective tissue diseases, including systemic lupus erythematosus (SLE), primary biliary cholangitis, rheumatoid arthritis, and Sjögren syndrome.7

Presence of centromere antibodies is considered predictive of SSc development in patients with Raynaud phenomenon.21 The antibodies are associated with lower risk of cardiac and renal involvement but higher risk of PAH.7,21 For patients without PAH, centromere antibodies are associated with a better prognosis overall than are other autoantibodies.21

PM/Scl antibodies

PM/Scl antibodies target the PM/Scl exosome complex, and most reactivity is against 2 proteins, PM/Scl-75 and PM/Scl-100. They are present in 2% to 11% of SSc patients and are associated with SSc-myositis overlap syndrome and lcSSc.7,8 PM/Scl antibodies also occur in other autoimmune diseases such as polymyositis and dermatomyositis.

The presence of either PM/Scl-75 or PM/Scl-100 antibody is associated with calcinosis, and the co-occurrence of both antibodies is associated with inflammatory myositis.11,12 However, each antibody may be associated with a distinct clinical phenotype; gastrointestinal symptoms and ILD are common in patients with PM/Scl-75 antibodies but less so in those with PM/Scl-100 antibodies.11,12 Internal organ involvement generally remains mild in patients with any PM/Scl antibodies, and the presence of these antibodies is associated with an overall favorable prognosis.7

RNA polymerase III antibodies

RNA polymerase III antibodies target RNA polymerase epitopes 11 and 155 and are thus also known as anti-RP11 and anti-RP155. These antibodies are found in 7% to 41% of patients with SSc and occur most often in dcSSc.8,14 They are diagnostic for SSc, as they are rarely found in other autoimmune diseases, and are included in the 2013 ACR-EULAR classification criteria.6

The presence of RNA polymerase III antibodies is associated with progressive skin thickening, gastric antral vascular ectasia (GAVE), and renal crisis.7,8 In addition, these antibodies are associated with onset of cancer within a 2-year timeframe before or after onset of SSc skin changes.13 Historically, RNA polymerase III antibodies indicated a poor prognosis, but mortality rates improved after the introduction of ACE inhibitors to treat renal crisis; the prognosis for patients with RNA polymerase III antibodies is now better than for those with Scl-70 or U3-RNP antibodies.8

Scl-70 (topoisomerase I antibody)

Topoisomerase I antibodies were initially named Scl-70 based on immunoblot detection of a 70-kDa protein.21 The prevalence of Scl-70 antibodies in SSc varies widely across geographies and ethnicities, ranging from 9% to 71%.7 These antibodies are strongly associated with dcSSc but also occur in lcSSc.7,8 Furthermore, they are highly specific to SSc and are included in the 2013 ACR-EULAR classification criteria.6,7

The presence of Scl-70 antibodies is associated with pulmonary and cardiac involvement as well as renal crisis and vascular complications.7,8 Therefore, these antibodies indicate a poor prognosis.15 The increased mortality associated with Scl-70 antibodies results primarily from the higher risk for severe ILD.7,8

Th/To antibodies

Th/To antibodies target RNase P and mitochondrial RNase ribonucleoprotein complexes. These antibodies are found in 2% to 5% of SSc patients and are primarily associated with lcSSc.7,8 Th/To antibodies are rarely found in other autoimmune diseases but can occur in patients with localized scleroderma.8

Patients with Th/To antibodies often develop both ILD and PAH and thus have a poorer prognosis than other patients with lcSSc.7,8

U1-snRNP (Sm/RNP) antibodies

U1-snRNP antibodies, also referred to as U1-RNP and Smith (Sm)/RNP, target 3 components of the U1 small nuclear ribonucleoprotein complex: U1-snRNP RNP A, U1-snRNP RNP C, and U1-snRNP RNP-70kd. These antibodies, found in 2% to 14% of SSc patients, are more frequent in lcSSc than in dcSSc.16 The antibodies are also found in patients with other autoimmune diseases, including approximately 90% of patients with mixed connective tissue disease.7,16

Patients with U1-snRNP antibodies tend to have less prominent skin thickness and less renal involvement, but have increased risk of PAH, arthritis, and esophageal dysfunction.8,16 Overall, the presence of U1-snRNP antibodies is associated with a good response to corticosteroids and a favorable prognosis.16

U3-RNP (fibrillarin) antibodies

U3-RNP antibodies target the U3 small nucleolar ribonucleoprotein (U3-RNP) complex, which consists of the protein fibrillarin and U3 RNA.7 These antibodies are found in about 4% to 10% of patients with SSc, and are especially common in African American SSc patients (approximately 30%).7,8 U3-RNP antibodies are rarely found in patients with other autoimmune disorders; thus, the presence of these antibodies supports a SSc diagnosis.8,21 These antibodies occur most often in dcSSc, but they can also occur in lcSSc.7,8

U3-RNP antibodies are associated with multiorgan involvement, including the heart, kidneys, muscle, lungs, and gastrointestinal system. Their presence is an independent risk factor for the development of PAH, and PAH is the most common cause of death in U3-RNP–positive patients.7,8 Therefore, their presence indicates a poorer prognosis.

Supportive testing

Once a diagnosis of SSc is established, and clinical findings and autoantibody testing have established the type, further laboratory testing is performed to support evaluation of end-organ function and overall health. Testing may include examination of liver and kidney function, complete blood count, and inflammation assessment.22 Since SSc is a chronic disease, follow-up assessment at least annually is recommended.22