What is the clinical significance of anti-centromere (Anti-CENP) antibodies in patients with systemic scleroderma?

Clinical Significance of Anti-Centromere Antibodies in Systemic Scleroderma

Anti-centromere antibodies (ACA) are strongly associated with limited cutaneous systemic sclerosis (lcSSc), particularly the CREST syndrome variant, and indicate a higher risk for developing pulmonary arterial hypertension but lower risk for interstitial lung disease compared to other scleroderma-specific antibodies.

Association with Disease Subtype

• ACA are present in approximately 49% of patients with CREST syndrome (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) 1
• Only found in about 3% of patients with diffuse cutaneous systemic sclerosis (dcSSc) 1
• ACA are typically the only autoantibody specificity present in sera of patients with the CREST variant 2

Prognostic Significance

Positive Associations:

• Pulmonary Arterial Hypertension (PAH): Patients with long-standing limited scleroderma (CREST syndrome) and ACA are at higher risk for developing isolated PAH 3
• Primary Biliary Cholangitis: Occurs in 8% of lcSSc cases, usually in those positive for ACA 3
• Telangiectasiae: More frequent in ACA-positive patients (93% vs 75% in ACA-negative) 1
• Calcinosis: More common in ACA-positive patients (55% vs 22% in ACA-negative) 1

Negative Associations:

• Interstitial Lung Disease (ILD): Significantly less frequent in ACA-positive patients 1
• Major Organ System Involvement: Patients with ACA have significantly less major organ system involvement compared to those with other ANA patterns 2

Demographic Associations

• More common in females (97% of ACA-positive CREST patients vs 78% of ACA-negative) 1
• Associated with older age at disease onset 1
• HLA-DR1 association has been reported 1

Clinical Algorithm for Interpretation of ACA in Scleroderma

1. If ACA positive in a patient with Raynaud's phenomenon and limited skin involvement:

   • High suspicion for lcSSc/CREST syndrome
   • Implement regular screening for PAH using echocardiography, pulmonary function testing (especially DLCO), NT-proBNP, and 6-minute walk test 3
   • Monitor for primary biliary cholangitis with liver function tests 3
   • Lower suspicion for ILD but still perform baseline HRCT 3

2. If ACA positive in a patient with diffuse skin involvement:

   • Unusual finding (only 3% of dcSSc patients) 1
   • Consider overlapping syndromes or mixed connective tissue disease
   • Perform comprehensive antibody panel including anti-topoisomerase I (Scl-70) and anti-RNA polymerase III

3. If ACA positive without clinical features of scleroderma:

   • Consider early/preclinical scleroderma, especially if Raynaud's phenomenon is present
   • ACA can rarely be found in other conditions like SLE (1.9% prevalence) 4 and localized scleroderma 5
   • Implement close follow-up to monitor for development of scleroderma features

Important Caveats

• The presence of ACA does not exclude the possibility of interstitial lung disease, though the risk is lower compared to anti-topoisomerase I positive patients 3
• Up to 40% of patients with idiopathic PAH have elevated antinuclear antibodies, which can lead to misdiagnosis as scleroderma 3, 6
• ACA can occasionally be found in patients with localized scleroderma (morphea) without systemic involvement 5
• When performing serological testing for suspected scleroderma, a comprehensive panel including anti-topoisomerase I and anti-RNA polymerase III antibodies should be ordered alongside ACA 3

In clinical practice, the presence of ACA should prompt careful and regular screening for pulmonary arterial hypertension, which is a major cause of mortality in lcSSc patients, while recognizing that these patients have a relatively lower risk for progressive interstitial lung disease compared to other antibody subtypes.