What are the next steps if a Tumor Necrosis Factor (TNF) blocker is not effective?

When a TNF Blocker Fails: Next Steps

The next step depends critically on whether you're dealing with primary non-response (never worked) or secondary non-response (worked initially, then stopped working), and the underlying disease being treated.

For Ankylosing Spondylitis and Axial Spondyloarthritis

Primary Non-Response (Never Worked)

• Switch to an IL-17 inhibitor (secukinumab or ixekizumab) rather than trying another TNF blocker 1
• The rationale is that TNF is likely not the key inflammatory mediator in these patients 1
• Before switching, consider whether the patient has had adequate time to respond, or whether dose optimization (higher dose or shorter dosing interval) might help 1

Secondary Non-Response (Initial Response, Then Loss of Effect)

• Switch to a different TNF blocker rather than immediately changing to another drug class 1
• Observational data show 25-40% of patients achieve meaningful response (50% improvement in Bath AS Disease Activity Index) with a second TNF blocker 1
• This approach preserves other biologic options for future use 1

Critical Contraindications

• Never switch to a biosimilar of the same TNF blocker - the clinical response will not differ 1
• Do not add methotrexate or sulfasalazine to the failed TNF blocker - switch to a new biologic instead 1

For Psoriatic Arthritis

After TNF Blocker Failure

• Switch to another biologic (IL-17i, IL-12/23i, or different TNF blocker) or a JAK inhibitor 1
• Switching within class (to another TNF blocker) is acceptable, but after a second failure within the same class, change to a different mechanism of action 1

Special Considerations for PsA

• If severe skin involvement is present: Prefer IL-17 inhibitors or IL-12/23 inhibitors over another TNF blocker 1
• If predominantly axial disease: Follow the ankylosing spondylitis algorithm above 1
• If concomitant inflammatory bowel disease (IBD): Switch to a monoclonal antibody TNF blocker (not etanercept), NOT to IL-17 inhibitors which are ineffective for IBD 1
• If concomitant uveitis: Prefer TNF monoclonal antibody over IL-17 inhibitors 1

Methotrexate Considerations in PsA

• Consider continuing methotrexate during the transition to IL-12/23 inhibitors to allow the new therapy time to work 1
• May add methotrexate if only partial response to current IL-17 inhibitor 1

For Rheumatoid Arthritis

General Approach

• Switch to another biologic with a different mechanism of action (rituximab, abatacept, tocilizumab) or to a JAK inhibitor 1
• Alternatively, switching to another TNF blocker is also acceptable - even primary non-responders to one TNF blocker may respond to another 1
• The choice between switching within class versus changing class is not definitively established by head-to-head trials 1

Supporting Evidence

• Registry data show that switching TNF blockers can restore response in secondary loss of effectiveness 2, 3
• One- and two-year survival rates for a second TNF blocker are 68% and 60% respectively 3
• Switching works better when the reason is adverse events rather than lack of effectiveness 2, 3

For Ulcerative Colitis

After TNF Blocker Failure

• Switch to tofacitinib (JAK inhibitor) - this is FDA-approved and effective in TNF blocker failures 4
• In clinical trials, 11-12% of patients with prior TNF blocker failure achieved remission at 8 weeks with tofacitinib 10 mg twice daily (induction dose) 4
• Do not use IL-17 inhibitors - they are ineffective for IBD 1

Agents to Avoid

The following should NOT be used even after TNF blocker failure 1:

• Rituximab (for axial disease)
• Abatacept (for axial disease; limited role in PsA after other failures) 1
• Ustekinumab (for axial disease)
• IL-6 inhibitors (for axial disease)
• IL-12/23 inhibitors (for axial disease) 1

Common Pitfalls to Avoid

• Do not simply switch to a biosimilar of the failed TNF blocker 1
• Do not add conventional DMARDs (methotrexate, sulfasalazine) to a failed TNF blocker in ankylosing spondylitis - switch biologics instead 1
• Do not use IL-17 inhibitors in patients with active inflammatory bowel disease 1
• Distinguish between primary and secondary non-response - this fundamentally changes the treatment algorithm in axial disease 1
• Consider disease-specific factors: skin involvement, axial versus peripheral disease, and extraarticular manifestations (IBD, uveitis) all influence the optimal choice 1