Initial Testing to Rule Out Scleroderma
The initial diagnostic workup for suspected scleroderma should include antinuclear antibody (ANA) testing by immunofluorescence, followed by scleroderma-specific autoantibodies (anti-Scl-70/topoisomerase-I, anti-centromere, anti-RNA polymerase III), and nailfold capillaroscopy, which is part of the EULAR/ACR classification criteria for systemic sclerosis. 1, 2
Serological Testing
First-Line Antibody Testing
Antinuclear antibodies (ANA) by immunofluorescence should be performed as the initial screening test, as circulating antibodies against antinuclear antigens are present in most patients with systemic scleroderma 1, 3
Scleroderma-specific autoantibodies are essential for diagnosis and include 1:
- Anti-Scl-70/topoisomerase-I (associated with diffuse cutaneous systemic sclerosis and interstitial lung disease)
- Anti-centromere antibodies (associated with limited cutaneous systemic sclerosis)
- Anti-RNA polymerase III (associated with diffuse disease and renal crisis risk)
- Anti-U1RNP, anti-Th/To, anti-PM/Scl75, anti-PM/Scl100, and anti-Ku
Additional autoantibodies to consider when evaluating for overlaps include anti-U3RNP (fibrillarin), which is associated with diffuse scleroderma and pulmonary arterial hypertension 1
Supporting Laboratory Tests
Inflammatory markers including C-reactive protein (CRP) and erythrocyte sedimentation rate should be obtained 1
Rheumatoid factor should be tested, as 3% of systemic sclerosis cases overlap with rheumatoid arthritis 1
Testing for other connective tissue disease antibodies (anti-SSA/Ro, anti-SSB/La, Smith, Jo1, other myositis antibodies) should be performed when clinical features suggest overlap syndromes 1
Nailfold Capillaroscopy
Nailfold capillaroscopy is included in the 2013 EULAR/ACR classification criteria for systemic sclerosis and should be performed in all patients with suspected scleroderma 2
The examination should be performed using magnification (otoscope, ophthalmoscope, dermatoscope, or formal capillaroscopy) focusing on the nailfold of the 2nd through 5th digits 2
Patients with puffy fingers or specific SSc-associated antibodies should undergo nailfold capillaroscopy as it can detect early microvascular changes characteristic of scleroderma spectrum disorders 2
Capillary density is a sensitive measure of disease activity and persistent capillary abnormalities are associated with longer time to remission 2
Clinical Assessment Considerations
For Localized Scleroderma (Morphea)
While localized scleroderma is primarily a clinical diagnosis, antinuclear antibodies are frequently detected using indirect immunofluorescence on cultured cells, with histones being the major autoantigens 4
Anti-topoisomerase II alpha antibody has been found frequently in localized scleroderma, whereas anti-topoisomerase I (Scl-70) is not detected in localized forms 4
All children with suspected localized scleroderma should be referred to a specialized pediatric rheumatology center 1
For Systemic Sclerosis
A detailed history of medication use and environmental exposures should be obtained to exclude other causes of interstitial lung disease that may mimic scleroderma 1
Pulmonary function testing including diffusing capacity for carbon monoxide (DLCO) should be performed, as isolated decrease in DLCO can be an early finding and predictor of pulmonary arterial hypertension 1, 5
Important Caveats
Up to 40% of patients with idiopathic pulmonary arterial hypertension have elevated antinuclear antibodies, so positive ANA alone is not diagnostic of scleroderma and must be interpreted in clinical context 1
SSc-specific autoantibodies at strong titers (not medium titers) are independently associated with disease activity and organ involvement 6
The presence of anti-centromere antibodies is associated with limited cutaneous systemic sclerosis and increased risk of primary biliary cholangitis (8% of cases) 1
Anti-RNA polymerase III positivity significantly increases the risk of scleroderma renal crisis and malignancy, requiring enhanced monitoring 1