What is the recommended workup for a patient suspected of having CREST (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) syndrome?

CREST Syndrome Workup

In patients with suspected CREST syndrome (limited cutaneous systemic sclerosis), obtain serologic testing for anticentromere antibodies and antinuclear antibodies as the primary diagnostic step, combined with systematic clinical assessment for the five cardinal features, as anticentromere antibodies are present in 98% of CREST cases and represent a highly specific diagnostic marker. 1

Initial Clinical Assessment

Cardinal Features to Document

Systematically evaluate for the five defining features that form the CREST acronym:

• Calcinosis: Examine digits, extensor surfaces, and pressure points for subcutaneous calcium deposits; obtain plain radiographs of hands and feet if palpable masses present 2, 3
• Raynaud's phenomenon: Document color changes (white-blue-red triphasic response) in digits with cold exposure or stress 2, 4
• Esophageal dysmotility: Query for dysphagia, heartburn, regurgitation, and epigastric discomfort 2, 3
• Sclerodactyly: Assess for skin thickening and tightness limited to fingers distal to metacarpophalangeal joints 2, 3
• Telangiectasia: Examine face, hands, oral mucosa, and upper trunk for dilated superficial blood vessels 3

Note that only three of five features are required for diagnosis, though full manifestation may develop over time. 2, 4

Essential Laboratory Testing

Autoantibody Panel (First-Line)

• Anticentromere antibodies (ACA): This is the hallmark serologic marker, producing discrete speckled immunofluorescence pattern on HEp-2 cells, positive in 98% of CREST patients at titers >1:80 1
• Antinuclear antibodies (ANA): Obtain as part of initial screening; typically positive with centromere pattern 2, 3

Additional Serologic Studies

• Complete blood count to assess for anemia and inflammatory markers 5
• Comprehensive metabolic panel for baseline organ function 2
• Do not expect anti-DNA, anti-RNP, or anti-SS-B antibodies in CREST syndrome, as these are characteristically absent 1

Organ-Specific Evaluation

Pulmonary Assessment

Given the high prevalence of pulmonary arterial hypertension (PAH) in limited scleroderma:

• Doppler echocardiography: Essential to screen for PAH, assess right ventricular function, and evaluate for left-sided heart disease 5
• Pulmonary function tests with DLCO: Marked isolated decrease in DLCO (mean 52% predicted) is highly predictive of PAH development; serial measurements show linear decline years before PAH diagnosis 5
• High-resolution chest CT: Evaluate for interstitial lung disease, though less common in limited versus diffuse scleroderma 5

Critical pitfall: Patients with limited scleroderma and isolated DLCO <55% predicted have 35% risk of developing PAH; annual echocardiographic screening is warranted in this population 5

Gastrointestinal Evaluation

• Esophageal manometry: Gold standard for documenting esophageal dysmotility if symptoms present 2
• Upper endoscopy: Consider if severe reflux symptoms or dysphagia to assess for complications (strictures, Barrett's esophagus) 2
• Barium esophagram: Alternative if manometry unavailable, shows aperistalsis and dilated esophagus 2

Vascular Assessment

• Nailfold capillaroscopy: Documents microvascular changes characteristic of systemic sclerosis (dilated capillary loops, capillary dropout, hemorrhages) 2

Diagnostic Criteria Application

Use the 2013 ACR/EULAR classification criteria for systemic sclerosis to confirm diagnosis:

• Skin thickening of fingers extending proximal to MCPs (sufficient alone) OR
• Combination of skin thickening of fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, PAH/ILD, Raynaud's phenomenon, and SSc-related autoantibodies (anticentromere) with weighted scoring system 2

The diagnosis requires clinical-laboratory correlation; no single test is definitive 2

Imaging Studies

Radiographic Evaluation

• Plain radiographs of hands and feet: Document calcinosis when present; shows subcutaneous calcifications 3, 6
• Chest radiograph: Baseline assessment for pulmonary involvement 5

Advanced Imaging (When Indicated)

• CT chest without contrast: If DLCO reduced or clinical suspicion for ILD 5
• Cardiac MRI: If echocardiography suggests PAH or right ventricular dysfunction 5

Risk Stratification

High-Risk Features Requiring Closer Monitoring

• Anticentromere antibodies with anti-U3-RNP or anti-nucleolar antibodies: Higher PAH risk 5
• Disease onset after menopause: Associated with isolated PAH development 5
• DLCO <55% predicted: 35% will develop PAH 5
• Rapidly progressive symptoms within first year: Atypical presentation requiring aggressive monitoring 3

When to Refer

• Rheumatology: All suspected cases for confirmation and long-term management 2
• Pulmonology: If DLCO <60% predicted or echocardiographic evidence of PAH 5
• Gastroenterology: Severe esophageal symptoms or complications 2
• Cardiology: Elevated pulmonary artery pressures on echocardiography (sPAP >30 mmHg) 5
• Hand surgery: Painful or functionally limiting calcinosis requiring debridement 6

Common Diagnostic Pitfalls

• Assuming all five features must be present: Only three are required for diagnosis, and full manifestation may take years 2, 4
• Overlooking early PAH: Anticentromere-positive patients can develop severe PAH even with minimal skin involvement; DLCO is the most sensitive early marker 5
• Misclassifying as diffuse scleroderma: CREST is limited cutaneous SSc; skin involvement does not extend proximal to elbows/knees 2, 4
• Ignoring calcinosis as key distinguishing feature: While Raynaud's, sclerodactyly, and esophageal dysmotility occur in both limited and diffuse SSc, calcinosis is the characteristic element that defines CREST syndrome 4