What laboratory tests are recommended for diagnosing and managing CREST (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) syndrome?

Laboratory Testing for CREST Syndrome

The essential laboratory workup for CREST syndrome centers on autoantibody testing, with anticentromere antibody (ACA) being the hallmark serologic marker, present in 98% of cases, alongside complete blood count, comprehensive metabolic panel, and screening for pulmonary arterial hypertension with DLCO and echocardiography. 1, 2

Core Serologic Testing

Antinuclear Antibody Panel

• Anticentromere antibody (ACA) is the defining serologic marker, producing a discrete speckled pattern on immunofluorescence and present in 98% of CREST syndrome patients 2
• ACA reacts specifically with the centromeric region of metaphase chromosomes, distinguishing CREST from diffuse systemic sclerosis 2
• Antinuclear antibody (ANA) testing should be performed as the initial screening test, with subsequent specific antibody identification 3, 2
• Anti-U3-RNP or anti-nucleolar antibodies in combination with ACA indicate higher risk for pulmonary arterial hypertension and warrant closer monitoring 1

Additional Autoantibody Testing

• Anti-Th RNP antibodies occur in 13% of scleroderma-spectrum illnesses and should be assessed 4
• Anti-DNA, anti-RNP, and anti-SS-B antibodies are typically absent in CREST syndrome, helping differentiate from other connective tissue diseases 2
• The presence of ACA without clinical CREST features may indicate underlying rheumatic disease, active digital vasculitis, or systemic lupus erythematosus 5

Baseline Hematologic and Metabolic Assessment

Complete Blood Count

• CBC should be performed to assess for anemia and inflammatory markers as part of initial screening 1
• Thrombocytosis may be present and requires monitoring for thrombotic risk 6

Comprehensive Metabolic Panel

• Liver function tests, renal function, and electrolytes should be evaluated at baseline 1
• Corrected calcium levels should be assessed, particularly when calcinosis is present or suspected 7

Cardiopulmonary Screening (Critical for Morbidity/Mortality)

Pulmonary Function Testing

• DLCO measurement is mandatory, as marked isolated decrease is highly predictive of pulmonary arterial hypertension development 1
• Serial DLCO measurements show linear decline years before PAH diagnosis, making this the most important prognostic laboratory test 1
• Patients with DLCO <55% predicted have a 35% risk of developing PAH and require annual echocardiographic screening per American College of Chest Physicians guidelines 1
• Referral to pulmonology is indicated when DLCO <60% predicted 1

Echocardiographic Assessment

• Doppler echocardiography is essential to screen for PAH, assess right ventricular function, and evaluate left-sided heart disease 1
• Referral to cardiology is required for elevated pulmonary artery pressures (sPAP >30 mmHg) 1
• Cardiac MRI should be performed if echocardiography suggests PAH or right ventricular dysfunction 1

Risk Stratification Markers

High-Risk Features Requiring Enhanced Surveillance

• Disease onset after menopause is associated with isolated PAH development 1
• Anticentromere antibodies combined with anti-U3-RNP or anti-nucleolar antibodies confer higher PAH risk 1
• DLCO <55% predicted mandates annual echocardiographic screening 1

Imaging Studies

Chest Imaging

• High-resolution chest CT should be performed to evaluate for interstitial lung disease, though this is less common in limited versus diffuse scleroderma 1
• CT chest without contrast is indicated if DLCO is reduced or clinical suspicion for ILD exists 1
• Baseline chest radiograph is recommended by the American College of Cardiology for pulmonary involvement assessment 1

Common Pitfalls to Avoid

• Do not assume ACA negativity excludes CREST syndrome, as 2% of cases may be ACA-negative; clinical diagnosis with three of five features remains valid 2
• The appearance of anticentromere antibody may precede full clinical manifestation, sometimes presenting only with Raynaud's phenomenon initially 2
• ACA positivity without CREST features should prompt evaluation for other serious rheumatic diseases, particularly active digital vasculitis or systemic lupus erythematosus 5
• Never delay DLCO testing, as this is the single most important predictor of life-threatening PAH development 1
• Patients with rapidly progressive symptoms may develop complete clinical manifestation within one year, requiring aggressive monitoring 3