What are the considerations for immunotherapy in patients with a positive Antinuclear Antibody (ANA) result?

Management of Positive ANA in the Context of Cancer Immunotherapy

A positive ANA result alone does not contraindicate cancer immunotherapy with checkpoint inhibitors, and routine ANA screening before starting immunotherapy is not indicated. 1

Pre-Treatment Screening Recommendations

Do not routinely test for ANA or other autoantibodies before initiating checkpoint inhibitor therapy. 1 The presence of baseline ANA does not predict the development of immune-related adverse events (irAEs), except for colitis where some association has been noted. 1

Exceptions Requiring Pre-Treatment Antibody Testing

• Patients with thymoma: Test for anti-acetylcholine receptor and anti-striated muscle antibodies before starting checkpoint inhibitors, as all patients with thymoma who develop checkpoint inhibitor-induced myositis have these antibodies present at baseline. 1
• Symptomatic patients: If unexplained rheumatic, musculoskeletal, or systemic symptoms are present before treatment, perform a complete rheumatologic assessment including appropriate autoantibody testing. 1

Management of Patients with Pre-Existing Autoimmune Disease and Positive ANA

Pre-existing autoimmune disease with positive ANA is not a contraindication to checkpoint inhibitor therapy, provided the patient is well-informed and closely monitored. 1 This represents a shared decision between oncologist, rheumatologist, and patient, with consideration of whether checkpoint inhibitors will be used in metastatic versus adjuvant settings. 1

Baseline Immunosuppression Strategy

• Keep baseline glucocorticoids below 10 mg prednisone equivalent per day if possible, as higher doses may impair checkpoint inhibitor efficacy. 1
• Minimize other immunosuppressive medications to the lowest effective dose at checkpoint inhibitor initiation. 1
• No preventive immunosuppressive treatment is needed for patients with positive ANA starting checkpoint inhibitors. 1

Expected Outcomes in Autoimmune Disease Patients

• Disease flares occur in approximately 47% of patients with pre-existing autoimmune conditions during checkpoint inhibitor therapy. 1
• New immune-related adverse events occur in approximately 43% of these patients. 1
• Only 8-10% require checkpoint inhibitor discontinuation due to flares or irAEs. 1
• 79% of patients can continue checkpoint inhibitor therapy despite flares or irAEs with appropriate management. 1

Monitoring During Checkpoint Inhibitor Therapy

Clinical Surveillance

• Establish facilitated access to rheumatology consultation for prompt evaluation of new rheumatic or systemic symptoms. 1
• Monitor for rheumatic irAEs including inflammatory arthritis (most common), myositis, sicca syndrome, polymyalgia rheumatica-like syndrome, and vasculitis. 1
• Recognize that autoantibodies are often absent in checkpoint inhibitor-induced rheumatic diseases—only 20% test positive for rheumatoid factor and 14% for anti-citrullinated peptide antibodies in checkpoint inhibitor-induced arthritis. 1

Management of Flares and Immune-Related Adverse Events

• First-line treatment: Glucocorticoids for most flares and rheumatic irAEs. 1
• Second-line options: Conventional synthetic DMARDs (hydroxychloroquine, methotrexate, sulfasalazine) as monotherapy or combination therapy. 1
• TNF inhibitors: Reserved primarily for inflammatory bowel disease flares or refractory colitis. 1

Interpretation of ANA Results in This Context

Understanding ANA Specificity

• ANA at 1:80 has only 74.7% specificity for systemic lupus erythematosus, meaning many positive results at this titer are not clinically significant. 1
• ANA at 1:160 has 86.2% specificity while maintaining 95.8% sensitivity for systemic autoimmune rheumatic diseases. 1
• Healthy individuals show ANA positivity in 31.7% at 1:40,13.3% at 1:80, and 5.0% at 1:160. 1, 2

When to Pursue Further Testing

• If ANA titer ≥1:160 with compatible clinical symptoms: Order specific extractable nuclear antigen (ENA) panel and anti-dsDNA antibodies. 3
• If clinical suspicion for specific autoimmune disease exists: Test for disease-specific antibodies regardless of ANA titer or result. 1
• Report both ANA pattern and titer, as different patterns suggest different autoantibodies and associated conditions. 1, 3

Common Pitfalls to Avoid

• Do not delay or withhold checkpoint inhibitor therapy based solely on positive ANA without clinical autoimmune disease. 1
• Do not perform routine serial ANA testing during checkpoint inhibitor therapy, as ANA is for diagnosis, not monitoring. 1, 3
• Do not assume checkpoint inhibitor-induced rheumatic disease will be autoantibody-positive—most cases lack traditional autoantibodies. 1
• Do not interpret low-titer ANA (1:40-1:80) as clinically significant without strong clinical correlation, given high prevalence in healthy individuals. 1, 2