Systemic sclerosis (SSc), also called scleroderma, is a chronic autoimmune disorder characterized by fibrosis of the skin and various organs. Early diagnosis and classification are important so that patients can be evaluated for organ involvement and/or damage. However, because SSc is a heterogeneous disease, clinical presentation and disease course vary, and manifestations may overlap with those of other rheumatic disorders, all of which can complicate diagnosis. Clinical subsets of SSc include limited and diffuse cutaneous disease; in addition, some individuals have SSc overlap syndromes, which involve features of different systemic autoimmune rheumatic diseases (SARDs) in addition to those of SSc. Autoantibody formation is characteristic of SSc, and laboratory testing involves assessment for SSc-specific autoantibodies. Criteria antibody tests for the disease include tests for anti-Scl-70 (also known as antitopoisomerase 1), anticentromere antibody (ACA), and anti-RNA polymerase III. Testing for other antibodies associated with SSc may be indicated if criteria test results are negative. See Laboratory Testing below.
Quick Answers for Clinicians
Diagnosis of systemic sclerosis (SSc) involves a combination of clinical findings and autoantibody test results. SSc has a variable disease presentation and prognosis, but many patients will have skin thickening, which is commonly seen in the fingers. Skin thickening extending to the metacarpophalangeal joint is sufficient to classify a patient as having SSc. See Classification Criteria below. Approximately 95% of patients with SSc have antinuclear antibodies (ANAs), so testing for ANAs is an initial step in disease assessment. Subsequent testing for SSc is determined by the ANA patterns observed (eg, centromere, nucleolar, and speckled patterns). See Laboratory Testing below.
Since systemic sclerosis (SSc) is a chronic illness, regular monitoring is needed to assess disease activity and progression. Laboratory tests for monitoring may include erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP); CBC; liver function, creatinine, and urea; and urinary protein tests. Autoantibody tests, although important for diagnosis, are not necessary for monitoring. See Monitoring below.
Indications for Testing
Individuals with skin thickening of the fingers that extends proximal to the metacarpophalangeal joints should be tested for SSc. Patients with puffy fingers or sclerodactyly, fingertip ulcers or pitting scars, abnormal nailfold capillaries, and/or signs of Raynaud phenomenon should also be tested, particularly if these signs are accompanied by pulmonary changes, telangiectasia, or arthritis/arthralgia. See Classification Criteria below.
|Skin thickeningb of the fingers of both hands extending proximal to MCP joints (single criterion sufficient for classification of SSc)||n/a||9|
|Other skin thickeningbc||Puffy fingers||2|
|Sclerodactyly of the fingers (distal to MCP, proximal to PIP joints)||4|
|Fingertip lesionsc||Ulcers on digital tips
|Abnormal nailfold capillaries||n/a||2|
|Pulmonary arterial hypertension and/or interstitial lung disease||n/a||2|
|Scleroderma-related antibodies (any ACA, anti-Scl-70, or anti-RNA polymerase III antibodies)||n/a||3|
|aThese criteria do not apply to patients with an SSc-like disorder that better explains their signs/symptoms.
bPatients with no skin thickening of the fingers cannot be classified as having SSc.
cThe highest score from this category should be used to calculate the total score.
dA total score of ≥9 is diagnostic for SSc.
ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; MCP, metacarpophalangeal; n/a, not applicable; PIP, proximal interphalangeal
Testing for SSc typically starts with a CBC with platelet count and an automated differential, followed by antinuclear antibody (ANA) IgG testing by immunofluorescence assay (IFA). ANAs are seen in the majority of patients with SSc (approximately 95%), although a small subset of patients will be negative for ANAs.
Since ANAs can be found in many conditions, ANA testing is best used when suspicion for SSc or another SARD is high. Subsequent testing is based on the ANA patterns observed (eg, centromere, nucleolar, and speckled patterns). For comprehensive information about ANA patterns and clinical associations, refer to the International Consensus on ANA Patterns website.
Criteria Antibody Tests
- Anti-Scl-70 (also known as antitopoisomerase 1)
- Anti-RNA polymerase III
More than 50% of patients with SSc will have one of these three antibodies, which are generally exclusive of each other. The presence of SSc-specific antibodies may help predict disease phenotype. For example, ACAs are generally associated with limited cutaneous SSc, including CREST (calcinosis, Raynaud syndrome, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome. Anti-Scl and anti-RNA polymerase III antibodies are more common in diffuse disease.
Noncriteria Antibody Tests
Testing for additional antibodies (such as the following) may be indicated in patients with negative criteria antibody tests in whom SSc is still strongly suspected:
- Anti-fibrillarin or anti-u3 ribonucleoprotein (anti-U3 RNP) antibodies
- Anti-PM/Scl (anti-PM/Scl-100) antibodies
- Anti-Th/To antibodies
- Anti-Smith/RNP antibodies
- Anti-Ku antibodies
- Antimitochondrial antigen M2 antibodies (AMAs)
- Antiphospholipid antibodies
- Cyclic citrullinated peptide (CCP)
Because SSc is chronic, patients with the disease require annual follow-up, and those with progressive disease may have need of more frequent follow-up. Some studies associate particular antibodies with clinical manifestations; therefore, detection of particular antibodies early in the disease course may be useful in assessing risks for specific clinical manifestations, including organ involvement and cancer. Other laboratory tests to monitor disease activity include erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP); CBC; liver function tests, creatinine, and urea; and urine protein tests.
ARUP Lab Tests
Comprehensive evaluation for SSc when suspicion for SSc is high and patient presents with features of overlap syndrome
Qualitative Immunoblot/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Components: ANA titer, ANA pattern, anti-Scl-70, anti-RNP III antibody, anti-Smith/RNP antibody, antifibrillarin (U3 RNP), anti-PM/Scl antibody
For use in patients with distinct features of SSc
Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Components: ANA with HEp-2 substrate, IgG by IFA; Scl-70 antibody, IgG; and anti-RNA polymerase III antibody, IgG
Useful for diagnosis of SSc; preferred test is systemic scleroderma comprehensive panel
Useful for diagnosis of SSc; order as secondary screen based on ANA test results or suspicion of SSc
Useful for diagnosis of SSc; preferred test is systemic scleroderma comprehensive panel
Preferred ANA screening test for SARDs
Semi-Quantitative Indirect Fluorescent Antibody
Initial screening test for SARDs; reflex testing depends on ANA pattern detected
Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Multiplex Bead Assay/Qualitative Immunoblot
Useful for diagnosis of SSc in patients with negative criteria antibody tests; use in conjunction with other tests
Useful for diagnosis of SSc in patients with negative criteria antibody tests
Useful for diagnosis of SARDs with or without myopathy; order as secondary screen based on ANA test results
May be useful in the differential evaluation of polymyositis, dermatomyositis, necrotizing autoimmune myopathy, or overlap syndromes associated with SARDs
Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay/Qualitative Immunoblot
Components: SSA 52 and 60 (Ro), SM/RNP (U1) (ENA), Jo-1, Mi-2, PL-7, PL-12, P155/140, EJ, Ku, SRP, OJ, SAE1, MDA5, NXP-2, TIF1-gamma (TIF1-γ), fibrillarin (U3 RNP), and PM/Scl-100 antibodies
Confirmatory test for more common SARDs
May be useful for evaluation of interstitial lung disease in the context of SARDs
Qualitative Immunoprecipitation/Semi-Quantitative Multiplex Bead Assay/Qualitative Immunoblot/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Immunoturbidimetry
Components: SSA 52 and 60 (Ro), Scl-70; Jo-1, PL-7, PL-12, EJ, Ku, SRP, OJ, PM/Scl-100, MDA5, NXP-2, rheumatoid factor, CCP, ANA antibodies, and RNA polymerase III antibody, IgG
May be useful as secondary screen based on results of ANA test or if ANA IFA is negative and SSc, Sjögren syndrome, systemic lupus erythematosus (SLE), or myositis is strongly suspected
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