When to Perform an Autoimmune Workup
An autoimmune workup should only be performed when there is sufficient clinical suspicion of an autoimmune disease, as indiscriminate testing leads to false-positive results and unnecessary follow-up testing. 1
Clinical Indications for Testing
Symptoms and Signs That Warrant Testing
- Unexplained systemic inflammation
- Joint pain and swelling (particularly symmetric polyarthritis)
- Skin manifestations (rash, photosensitivity, urticaria-like lesions)
- Unexplained fever episodes
- Raynaud's phenomenon
- Sensorineural hearing loss
- Chronic aseptic meningitis
- Skeletal abnormalities
- Myalgia or muscle weakness
- Gastrointestinal symptoms with systemic features
Specific Clinical Scenarios
- For suspected CAPS (cryopyrin-associated periodic syndromes): urticaria-like rash, cold/stress-triggered episodes, sensorineural hearing loss 2
- For suspected TRAPS (tumor necrosis factor receptor-associated periodic syndrome): long-lasting fever episodes, migratory rash, periorbital edema, myalgia 2
- For suspected immune checkpoint inhibitor-related rheumatic adverse events: new-onset joint pain, muscle weakness, or stiffness during cancer immunotherapy 2
Components of an Autoimmune Workup
Initial Screening Tests
- Antinuclear antibody (ANA) testing
- Inflammatory markers: ESR and CRP
- Complete blood count with differential
Follow-up Testing Based on Positive ANA
If ANA is positive, proceed with specific autoantibody testing:
- Anti-dsDNA antibodies
- Anti-Ro/SSA and anti-La/SSB antibodies
- Anti-RNP antibodies
- Anti-Sm antibodies
- Anti-phospholipid antibodies
- Complement levels (C3, C4) 2, 1
Rheumatoid Arthritis-Specific Testing
- Rheumatoid factor (RF)
- Anti-cyclic citrullinated peptide (anti-CCP) antibodies 3
Interpretation of Results
ANA Testing
- ANA titers ≤1:320 may be present in healthy individuals and should not be considered definitive evidence of autoimmune disease
- High ANA titers (≥1:640) increase specificity for autoimmune disease
- Multiple positive autoantibodies (≥3) significantly increase likelihood of systemic lupus erythematosus 1
Inflammatory Markers
- ESR and CRP have modest positive correlation with each other across autoimmune diseases
- Both markers show weak correlation with clinical disease activity measures in rheumatoid arthritis, systemic lupus erythematosus, and osteoarthritis 4
- CRP may better reflect acute inflammation, while ESR can be influenced by immunoglobulins, rheumatoid factor, and hemoglobin levels 5
- In rheumatoid arthritis, subjective and semi-objective criteria correlate more significantly with CRP levels than with ESR 6
Pitfalls and Caveats
Avoiding False Positives
- Include pertinent clinical information with laboratory requests
- Use appropriate screening dilutions for ANA testing
- Interpret positive results within clinical context 1
Monitoring Considerations
- For patients with established autoimmune disease but no current activity, assessments every 6-12 months are recommended
- More frequent monitoring is needed for active disease or patients on immunosuppressive therapy 2
- Monitor for infection risk in patients on immunosuppressive therapy by checking neutrophil count, lymphocyte count, and IgG levels 2
Drug Effects on Test Results
- Specific medications can affect correlation between inflammatory markers
- CRP and ESR correlation varies based on treatment (strongest with penicillamine, weakest with steroids) 7
Referral Guidelines
- Patients with positive ANA and specific disease antibodies should be referred to a rheumatologist
- Early referral is particularly important for patients with suspected inflammatory myositis, polymyalgia rheumatica, or giant cell arteritis 2, 1
Remember that autoimmune workup should be guided by clinical presentation and not performed indiscriminately, as false-positive results can lead to unnecessary anxiety, additional testing, and potential overtreatment.