ArticleTherapeutic advances in musculoskeletal disease2026
What to do when the first TNF inhibitor fails in rheumatoid arthritis: stratified expert recommendations from a scoping review and Delphi consensus.
Article in Therapeutic advances in musculoskeletal disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Despite widespread use of tumor necrosis factor inhibitors (TNFi) as first-line therapy in rheumatoid arthritis (RA), up to 40% of patients fail initial treatment. Subsequent therapeutic choices remain poorly structured, with limited evidence-based guidance to inform individualized post-TNFi decision-making. Objective: To develop evidence-informed, profile-based recommendations to guide treatment selection after inadequate response to a first TNFi in RA, combining evidence and expert consensus. Design: Delphi-based consensus study informed by a PRISMA-guided scoping review (ScR) and nominal group methodology. Methods: A PRISMA-guided ScR of biologic and targeted synthetic biologic disease-modifying antirheumatic drug (tsDMARDs) after TNFi failure was conducted. Patient profiles were identified by a steering committee, and draft recommendations were evaluated through an anonymized Delphi process. A profile-based decision tree integrated direct and indirect evidence, with evidence strength graded using the Oxford Centre for Evidence-Based Medicine approach. Results: The ScR included 43 studies, mostly exploratory analyses of randomized trials. Scenarios included age ⩾65 years; failure of ⩾2 TNFi; monotherapy; rheumatoid factor/anti-citrullinated peptide antibody status; prominent systemic inflammation; interstitial lung disease (ILD); rheumatoid vasculitis; high cardiovascular (CV) risk or prior CV event; venous thromboembolism (VTE) risk; obesity; high infection risk; osteoporosis; nociplastic pain, depression and fatigue; prior solid cancer; hematologic cancer/lymphoproliferative disease; non-melanoma skin cancer; and pregnancy.Seventeen recommendations were formulated; 15 achieved consensus. Agreed positions included caution with JAK inhibitors (JAKi) in older patients and in those with CV/VTE risk; preference for IL-6 receptor inhibitors or JAKi for monotherapy or prominent systemic inflammation; in RA-ILD, use a b/tsDMARD with a non-TNFi mechanism; rituximab as first choice in rheumatoid vasculitis; abatacept in infection-prone patients; discouraging JAKi in prior malignancy; and TNFi as acceptable during pregnancy. Two statements did not reach consensus: preferential use of non-TNFi in obesity and heightened caution with tofacitinib in osteoporosis or fracture risk. Conclusion: This Delphi-validated, profile-based framework provides a practical tool to support evidence-informed clinical decision-making.
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