Which laboratory tests should be ordered to confirm CREST (limited systemic sclerosis) in a patient?

Laboratory Testing for CREST Syndrome (Limited Systemic Sclerosis)

Order antinuclear antibody (ANA) testing by immunofluorescence as the initial screening test, followed immediately by anti-centromere antibody (ACA) testing, which is the hallmark serological marker for CREST syndrome with 57% sensitivity in limited cutaneous systemic sclerosis. 1, 2, 3

Primary Serological Tests

First-Line Antibody Testing

• ANA by indirect immunofluorescence is the mandatory initial screening test, as circulating antinuclear antibodies are present in 90-95% of systemic sclerosis patients 1, 4
• Anti-centromere antibody (ACA) is the specific diagnostic marker for CREST/limited cutaneous systemic sclerosis, present in 57% of patients with this subset 3
• The centromere staining pattern on HEp-2 cells is highly selective for CREST syndrome and strongly associated with this clinical variant 5, 6

Scleroderma-Specific Autoantibody Panel

• Anti-topoisomerase I (anti-Scl-70) should be tested to exclude diffuse cutaneous disease, as this antibody is mutually exclusive with ACA in 97% of cases 3, 7
• Anti-RNA polymerase III testing is essential because positivity indicates high risk for scleroderma renal crisis and malignancy, requiring enhanced monitoring 1, 2
• Anti-U3RNP (fibrillarin) should be considered when evaluating for pulmonary arterial hypertension risk 1

Supporting Laboratory Tests

Baseline Screening Panel

• Complete blood count, glucose, electrolytes, kidney function, and liver enzymes are required in all patients 2
• Inflammatory markers (CRP and ESR) should be obtained to assess disease activity 1
• Rheumatoid factor should be tested, as 3% of systemic sclerosis cases overlap with rheumatoid arthritis 1

Overlap Syndrome Screening

• Anti-SSA/Ro and anti-SSB/La antibodies should be performed when clinical features suggest overlap syndromes 1
• Anti-U1RNP antibodies suggest mixed connective tissue disease or systemic sclerosis overlap syndrome 2

Organ-Specific Screening Tests

Pulmonary Assessment

• Pulmonary function tests (PFTs) including forced vital capacity and diffusing capacity for carbon monoxide (DLCO) should be performed at baseline 1, 2
• High-resolution CT of the chest should be used to screen for interstitial lung disease, particularly in high-risk patients 2

Cardiac and Renal Screening

• N-terminal pro-B-type natriuretic peptide (NT-proBNP) should be tested if arrhythmias or heart failure are present 2
• Urinalysis for proteinuria should be performed annually 2
• Blood pressure monitoring is essential, especially in anti-RNA polymerase III positive patients 1

Additional Screening

• Liver function tests, including alkaline phosphatase, should be performed to screen for primary biliary cholangitis, which occurs in 8% of limited cutaneous disease cases 1

Critical Diagnostic Caveats

• Up to 40% of patients with idiopathic pulmonary arterial hypertension have elevated ANA, so positive ANA alone is not diagnostic and must be interpreted in clinical context 1
• 40% of systemic sclerosis patients may have neither ACA nor anti-Scl-70 antibodies present, so negative results do not exclude the diagnosis 3
• ACA and anti-Scl-70 antibodies are mutually exclusive in 97% of cases, with both antibodies present in only 3 patients out of 670 studied 3
• Anti-centromere antibodies are associated with increased risk of primary biliary cholangitis, warranting liver function monitoring 1

Monitoring Strategy

• Repeat PFTs every 3-6 months in early disease or if interstitial lung disease is present 2
• Monitor CBC and liver enzymes if on immunosuppressive therapy 2
• Age-appropriate malignancy screening within 3 years of diagnosis if anti-RNAP III positive 2