When are Connective Tissue Disease (CTD) screens, Perinuclear Anti-Neutrophil Cytoplasmic Antibodies (pANA), and Centromere Anti-Neutrophil Cytoplasmic Antibodies (cANA) necessary?

From the Guidelines

Connective tissue disease (CTD) screen, peripheral antinuclear antibody (pANA), and cellular antinuclear antibody (cANA) testing should be performed when evaluating patients with suspected autoimmune disorders, particularly systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, scleroderma, or mixed connective tissue disease, as indicated by symptoms such as unexplained joint pain, skin rashes, photosensitivity, oral ulcers, serositis, unexplained fatigue, Raynaud's phenomenon, or multi-system involvement suggesting autoimmune etiology 1.

When to perform these tests is crucial for early diagnosis and management of autoimmune diseases. The following symptoms and conditions warrant CTD screen, pANA, and cANA testing:

• Unexplained joint pain
• Skin rashes (particularly malar or discoid rashes)
• Photosensitivity
• Oral ulcers
• Serositis
• Unexplained fatigue
• Raynaud's phenomenon
• Multi-system involvement suggesting autoimmune etiology

The CTD screen typically includes a panel of autoantibody tests that help identify specific autoimmune conditions, while ANA testing serves as an initial screening tool with high sensitivity but lower specificity. A positive ANA result (typically at titers ≥1:80) should prompt further specific antibody testing such as anti-dsDNA, anti-Smith, anti-Ro/SSA, anti-La/SSB, anti-RNP, or anti-Scl-70 antibodies to narrow the diagnosis, as recommended by international guidelines for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies 1.

These tests should be ordered in the context of clinical findings rather than as isolated screening tools in asymptomatic individuals, as false positives can occur in healthy people, particularly at low titers, and in elderly patients. Interpretation should always be done in conjunction with clinical presentation, as the pattern and titer of antibodies can provide valuable diagnostic information. Additionally, screening for interstitial lung disease (ILD) is recommended in patients with systemic autoimmune rheumatic diseases, particularly those with risk factors such as anti-Scl-70 positivity, diffuse cutaneous subtype, and elevated acute phase reactants 1.

In patients with early diffuse cutaneous systemic sclerosis, blood pressure should be monitored to detect and treat scleroderma renal crisis early, especially if the patient has anti-RNA polymerase III antibodies 1. Selected screening can also be performed when the index of suspicion of certain manifestations, such as cardiac involvement, is high.

The most recent and highest quality study, published in 2024, provides guidelines for the screening and monitoring of interstitial lung disease in people with systemic autoimmune rheumatic diseases, emphasizing the importance of shared decision-making between the rheumatologist and patient 1.

From the Research

CTD Screen, pANA, and cANA

• The CTD screen is used to identify comorbidities of connective tissue diseases in subjects with systemic lupus erythematosus (SLE) 2.
• pANA (perinuclear anti-neutrophil cytoplasmic antibodies) and cANA (cytoplasmic anti-neutrophil cytoplasmic antibodies) are types of autoantibodies that can be present in various autoimmune diseases.
• A positive ANA (anti-nuclear antibody) test, which includes pANA and cANA, may be seen in non-autoimmune inflammatory diseases, including acute and chronic infections 3.
• The likelihood of a positive ANA result due to infection increases when the test is used as an initial screen in patients with non-specific clinical symptoms, such as fever, joint pain, myalgias, fatigue, rash, or anemia 3.

Indications for CTD Screen, pANA, and cANA

• The CTD screen is indicated in patients with SLE to identify additional connective tissue diseases, such as Sjögren's syndrome, scleroderma, rheumatoid arthritis, dermatomyositis/polymyositis, and mixed connective tissue disorder 2.
• pANA and cANA testing may be indicated in patients with symptoms suggestive of autoimmune disorders, such as fever, fatigue, joint pain, rash, ulcers, and muscle weakness 4.
• Autoimmune serology testing, including pANA and cANA, may be useful in the assessment of uncharacterized interstitial lung disease to identify connective-tissue disease-related ILD (CTD-ILD) 5.

Clinical Considerations

• A detailed history and careful physical examination play an important role in guiding laboratory evaluation for autoimmune disorders, including CTD screen, pANA, and cANA 4.
• The presence of suggestive clinical signs or symptoms, such as fever, joint pain, and rash, can increase the yield of autoimmune serology testing, including pANA and cANA 5.
• The diagnosis and treatment of autoimmune disorders, including those associated with pANA and cANA, require a comprehensive approach, including clinical evaluation, laboratory testing, and treatment with immunosuppressants, vasodilators, and biologic agents 6.