What is a positive Antinuclear Antibody (ANA) nucleolar pattern associated with?

Positive ANA Nucleolar Pattern Associations

A positive ANA nucleolar pattern is most strongly associated with systemic sclerosis (scleroderma), particularly in patients with anti-U3-RNP antibodies, and is frequently seen in diffuse scleroderma with pulmonary involvement. 1

Clinical Significance of Nucleolar Pattern

The nucleolar pattern is one of the standardized ANA patterns recognized in the International Consensus on ANA Patterns (ICAP) classification and can be further subdivided into:

• AC-8 homogeneous nucleolar pattern: Associated with anti-Th/To, anti-PM-Scl, anti-nucleophosmin/B23, and anti-nucleolin/C23 antibodies 2
• AC-9 clumpy nucleolar pattern: Associated with anti-fibrillarin/U3RNP antibodies 2
• AC-10 punctate nucleolar pattern: Associated with anti-RNA polymerase I and anti-hUBF/NOR-90 antibodies 2

Disease Associations

Primary Associations:

1. Systemic Sclerosis (Scleroderma)

   • Particularly common in diffuse scleroderma with anti-U3-RNP antibodies 1
   • Associated with pulmonary involvement and moderate interstitial fibrosis 1
   • Patients with scleroderma and nucleolar antibodies often develop pulmonary hypertension out of proportion to their degree of fibrosis 1

2. Pulmonary Arterial Hypertension (PAH)

   • Nucleolar pattern is seen in scleroderma patients who develop PAH 1
   • Associated with a marked decrease in diffusing capacity of the lung for carbon monoxide (DLCO) 1

Other Associations:

• Systemic Autoimmune Rheumatic Diseases (SARDs) 2
• Malignancies 2
• Graft versus Host Disease (GVHD) 2
• Localized Scleroderma (in a minority of cases) 3, 4

Specific Antibody Associations

The nucleolar pattern can be produced by several specific antibodies:

• Anti-fibrillarin/U3RNP: Strongly associated with diffuse scleroderma 2, 5
• Anti-Th/To: Associated with limited cutaneous systemic sclerosis 2
• Anti-PM-Scl: Associated with polymyositis/scleroderma overlap syndrome 2
• Anti-RNA polymerase I: Associated with systemic sclerosis 2
• Anti-hUBF/NOR-90: Less specific association with various conditions 2

Clinical Implications

• The presence of a nucleolar pattern in a patient with Raynaud's phenomenon should raise suspicion for systemic sclerosis 6
• In patients with limited scleroderma (formerly CREST syndrome), PAH is the cause of death in up to 50% of patients who die of scleroderma-related complications 1
• Patients with diffuse scleroderma and nucleolar antibodies should be monitored closely for pulmonary involvement 1

Diagnostic Considerations

• According to international recommendations, ANA patterns should be reported using standardized terminology 1
• Both nuclear and nucleolar patterns should be reported when present 1
• The pattern and highest dilution demonstrating reactivity should be included in reports 1
• A positive ANA with nucleolar pattern should prompt consideration of specific antibody testing based on clinical presentation 1, 7

Monitoring Implications

• Patients with scleroderma and nucleolar antibodies should have regular monitoring of pulmonary function, particularly DLCO 1
• A progressive decline in DLCO may predict development of PAH in these patients 1

Pitfalls and Caveats

• The nucleolar pattern is relatively uncommon, seen in only 5-9% of positive ANA tests 2
• Not all patients with nucleolar pattern will develop systemic sclerosis or PAH
• The pattern alone is insufficient for diagnosis and must be correlated with clinical findings
• Commercial assays for specific nucleolar antibodies have varying sensitivity and specificity 2
• In localized scleroderma, nucleolar antibodies are less common than in systemic sclerosis 3, 4

When a nucleolar pattern is identified, clinicians should consider the possibility of systemic sclerosis and evaluate for specific clinical features, particularly pulmonary involvement and pulmonary hypertension.