Diagnostic Approach to Scleroderma

Serological Testing

The European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) recommend antinuclear antibody (ANA) testing by immunofluorescence as the initial screening test for suspected scleroderma, as circulating antibodies against antinuclear antigens are present in most patients with systemic scleroderma 1
Scleroderma-specific autoantibodies, including anti-Scl-70/topoisomerase-I, anti-centromere, and anti-RNA polymerase III, are essential for diagnosis and are associated with specific disease manifestations, such as diffuse cutaneous systemic sclerosis and interstitial lung disease 1, 2
Additional autoantibodies, such as anti-U3RNP (fibrillarin), should be considered when evaluating for overlaps, as they are associated with diffuse scleroderma and pulmonary arterial hypertension 2, 3

Inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate, should be obtained to assess disease activity 1
Rheumatoid factor should be tested, as 3% of systemic sclerosis cases overlap with rheumatoid arthritis 2
Testing for other connective tissue disease antibodies, such as anti-SSA/Ro and anti-SSB/La, should be performed when clinical features suggest overlap syndromes 1, 2

Nailfold capillaroscopy is included in the 2013 EULAR/ACR classification criteria for systemic sclerosis and should be performed in all patients with suspected scleroderma, using magnification to detect early microvascular changes characteristic of scleroderma spectrum disorders 4

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 to assess for pulmonary arterial hypertension and other lung diseases 3, 5

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 6
The presence of anti-centromere antibodies is associated with limited cutaneous systemic sclerosis and increased risk of primary biliary cholangitis 2
Anti-RNA polymerase III positivity significantly increases the risk of scleroderma renal crisis and malignancy, requiring enhanced monitoring 2, 7

The European League Against Rheumatism (EULAR) recommends that all patients with systemic sclerosis undergo comprehensive screening for life-threatening organ involvement, as early detection and intervention can modify the natural history of these complications 8, 9
Patients with diffuse cutaneous disease and those positive for anti-topoisomerase 1 (Scl-70) antibodies are at higher risk for interstitial lung disease (ILD) 8
The American College of Rheumatology (ACR) suggests that patients with longer disease duration, older age, and/or low diffusing capacity are at high risk for pulmonary arterial hypertension (PAH) and should be screened with echocardiography, pulmonary function testing, electrocardiography, NT-proBNP, and 6-minute walking distance 8
Patients positive for anti-RNA polymerase III are at high risk for scleroderma renal crisis and require intensive monitoring, including regular blood pressure checks and home blood pressure monitoring 8
The ACR recommends that patients with early diffuse cutaneous disease undergo regular screening for renal involvement, including blood pressure checks and urinalysis 8

The ACR classifies patients with systemic sclerosis by extent of skin involvement, which determines prognosis and treatment approach 9, 10
Diffuse cutaneous SSc (dcSSc) is characterized by skin involvement both distal and proximal to knees/elbows and/or truncal, while limited cutaneous SSc (lcSSc) is characterized by fibrosis distal to elbows/knees without truncal involvement 9
The modified Rodnan skin score (mRSS) is a measure of skin thickness that can be used to assess disease severity and monitor response to treatment, with a minimal clinically important difference of 3.5-5.3 points 8

The ACR recommends screening for cardiac involvement, including arrhythmias and heart failure, in patients with systemic sclerosis 8
Liver function tests, including alkaline phosphatase, should be performed to screen for primary biliary cholangitis, which occurs in 8% of limited cutaneous disease cases 8
Nutritional screening should be performed in patients with severe gastrointestinal involvement, and depression screening should be performed in all patients with systemic sclerosis due to the high prevalence of depression in this population 8