What is the CREST (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) variant on Antinuclear Antibody (ANA)?

CREST Variant on ANA Testing

The CREST variant on ANA testing refers to a specific anti-centromere antibody pattern that is highly associated with limited cutaneous systemic sclerosis (formerly called CREST syndrome), appearing as a discrete speckled pattern on immunofluorescence testing and reacting with the centromeric region of metaphase chromosomes.

What is CREST Syndrome?

CREST syndrome is a limited cutaneous form of systemic sclerosis characterized by five clinical features that form the acronym:

• Calcinosis: Calcium deposits in the skin and subcutaneous tissues
• Raynaud's phenomenon: Episodic vasospasm of fingers and toes
• Esophageal dysmotility: Impaired esophageal function
• Sclerodactyly: Skin thickening limited to fingers and toes
• Telangiectasia: Dilated small blood vessels visible on the skin

ANA Pattern in CREST Syndrome

When testing for antinuclear antibodies (ANA) in patients with CREST syndrome:

• The characteristic pattern is a discrete speckled pattern on immunofluorescence testing using HEp-2 cells 1
• This pattern specifically targets the centromeric region of chromosomes 2
• Anti-centromere antibodies are present in over 50% of CREST syndrome cases 3
• The pattern is highly specific for limited cutaneous systemic sclerosis 4

Clinical Significance

The presence of anti-centromere antibodies has important clinical implications:

• Diagnostic value: Found in approximately 98% of patients with CREST syndrome 2
• Prognostic indicator: Helps predict the pattern of scleroderma that will evolve 4
• Disease specificity: Rarely found in patients with rapidly advancing or diffuse scleroderma 4
• Early detection: May appear before the full clinical syndrome develops, sometimes preceding diagnosis by years 2

Associated Conditions

Anti-centromere antibodies may also be found in:

• Raynaud's disease (without other scleroderma features) 2
• Primary biliary cirrhosis 4
• Less commonly in other connective tissue diseases:
  • Systemic lupus erythematosus (rare)
  • Mixed connective tissue disease (rare)
  • Active digital vasculitis 5
  • Seronegative polyarthritis 5

Clinical Relevance and Screening Recommendations

• Screening for anti-centromere antibodies is recommended in all patients with:

  • Raynaud's phenomenon
  • Suspected scleroderma
  • Primary biliary cirrhosis 4

• The presence of anti-centromere antibodies in a patient with limited scleroderma is associated with:

  • Better prognosis than diffuse scleroderma
  • Longer disease duration (>10 years) 3
  • Risk of specific complications: digital gangrene and pulmonary hypertension (3-14% of cases) 3

Laboratory Testing Considerations

• ANA testing should be performed using indirect immunofluorescence on HEp-2 cells as the gold standard method 1
• A titer of ≥1:80 is considered positive 1
• The centromere pattern is one of the most commonly recognized nuclear patterns on HEp-2 substrates 1
• When anti-centromere antibodies are detected, specific follow-up testing may be warranted even if the patient doesn't have classic CREST features, as it may indicate another serious rheumatic or connective tissue disease 5

Pulmonary Complications

Patients with CREST syndrome, particularly those with anti-centromere antibodies, should be monitored for:

• Pulmonary arterial hypertension, which occurs most frequently in systemic sclerosis 1
• Pulmonary hypertension, which is the cause of death in up to 50% of patients who die of scleroderma-related complications 1
• Decreased diffusing capacity (DLCO), which may precede the development of pulmonary arterial hypertension by years 1

The detection of anti-centromere antibodies on ANA testing should prompt careful clinical evaluation and appropriate follow-up to monitor for the development of CREST syndrome features or other associated conditions.