What is the significance of an anticentromere (antibody) pattern in multiple sclerosis (MS)?

Anticentromere Antibodies in Multiple Sclerosis: Clinical Significance and Differential Diagnosis

Anticentromere antibodies (ACA) are not typically associated with multiple sclerosis (MS) and their presence should prompt consideration of alternative diagnoses, particularly limited cutaneous systemic sclerosis (lcSSc) or other connective tissue diseases.

Understanding Anticentromere Antibodies

• Anticentromere antibodies are primarily associated with limited cutaneous systemic sclerosis (lcSSc), present in 50-80% of these cases, and generally indicate a better prognosis compared to other scleroderma subtypes 1.
• ACA are detected through indirect immunofluorescence testing, producing a characteristic centromere pattern, and can be confirmed by specific ELISA or Western blot testing for CENP-A and CENP-B proteins 2.
• The diagnostic specificity of ACA for systemic sclerosis is high (>97%), making it a valuable biomarker for differentiating between autoimmune conditions 2.

Clinical Significance in Multiple Sclerosis

• ACA are not part of the typical autoantibody profile in MS patients and are not included in the diagnostic criteria for MS 1.
• The presence of ACA in a patient with suspected MS should be considered a "red flag" that warrants investigation for alternative diagnoses 1.
• MS diagnosis relies on specific MRI findings (periventricular, juxtacortical, infratentorial, or spinal cord lesions) and clinical presentation, not on ACA or other autoantibodies 1.

Differential Diagnosis When ACA is Present

Systemic Sclerosis Consideration

• ACA positivity strongly suggests limited cutaneous systemic sclerosis (lcSSc), especially when accompanied by Raynaud's phenomenon 1.
• Patients with ACA should be evaluated for other features of scleroderma spectrum disorders, including:
  • Skin thickening, particularly of the fingers and face 1
  • Pulmonary arterial hypertension (PAH), which is more common in ACA-positive patients 1
  • Digital ulcers or telangiectasias 1

Other Connective Tissue Diseases

• ACA can be found in approximately 23.5% of rheumatology patients without scleroderma or Raynaud's phenomenon 3.
• Other conditions associated with ACA include:
  • Sjögren's syndrome 3
  • Primary biliary cholangitis (occurs in 8% of lcSSc cases, usually ACA-positive) 1
  • Systemic lupus erythematosus (rarely) 3
  • Seronegative polyarthritis 3

Diagnostic Approach for MS Patients with Positive ACA

1. Re-evaluate MS diagnosis:

   • Review MRI findings for typical MS lesions (ovoid periventricular lesions, Dawson's fingers) 1
   • Check CSF for oligoclonal bands (present in up to 98% of MS patients in Central/Northern Europe) 1

2. Screen for scleroderma and other connective tissue diseases:

   • Assess for Raynaud's phenomenon, skin thickening, and telangiectasias 1, 4
   • Consider pulmonary function testing and echocardiography to evaluate for PAH 1
   • Check liver function tests to rule out primary biliary cholangitis 1

3. Consider MOG-IgG testing:

   • MOG (myelin oligodendrocyte glycoprotein) antibody-associated disease can mimic MS but has distinct treatment implications 1
   • MOG-EM (MOG-IgG-associated encephalomyelitis) has different MRI patterns than typical MS 1

4. Evaluate for other antibody-mediated neurological conditions:

   • AQP4-IgG testing for neuromyelitis optica spectrum disorders 1
   • Consider testing for other neuronal surface antibodies if presentation includes encephalopathy 1

Clinical Implications and Management

• If ACA is positive and features of scleroderma are present, referral to rheumatology is warranted for appropriate management 1, 5.
• ACA-positive patients should be monitored for development of pulmonary arterial hypertension, which requires specific treatment approaches 1.
• MS-specific disease-modifying therapies may not be appropriate if the diagnosis is revised to another condition based on ACA positivity and clinical features 1.
• Some immunomodulatory treatments used for MS may be ineffective or potentially harmful in antibody-mediated conditions like MOG-EM or connective tissue diseases 1.

Important Caveats

• The mere presence of ACA does not definitively rule out MS, as some patients may have both conditions concurrently, though this is uncommon 1, 3.
• ACA titers in patients without scleroderma can be similar to those with the disease, so titer alone cannot distinguish between conditions 3.
• Anticentromere antibodies have high concordance between CENP-A and CENP-B subtypes (94.3%), so testing for both may only slightly increase diagnostic sensitivity 2.
• Early detection of scleroderma spectrum disorders is important for appropriate management and monitoring for complications 4, 5.