What are alternative disease-modifying antirheumatic drugs (DMARDs) for patients who do not respond to methotrexate?

Alternative DMARDs for Patients Who Do Not Respond to Methotrexate

For patients who do not respond adequately to methotrexate, the addition of a biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) is conditionally recommended over triple therapy, based on the most recent evidence.

First-Line Alternatives After Methotrexate Failure

Conventional Synthetic DMARDs (csDMARDs)

• Leflunomide is the primary alternative csDMARD for patients with contraindication to or intolerance of methotrexate 1
• Sulfasalazine is another recommended alternative when methotrexate cannot be used 1
• Hydroxychloroquine may be considered for patients with milder disease 1

Combination Therapy Options

• Triple therapy (methotrexate + hydroxychloroquine + sulfasalazine) has shown efficacy in patients with inadequate response to methotrexate 1, 2
• Dual combinations that have evidence support include:
  • Methotrexate + hydroxychloroquine
  • Methotrexate + leflunomide
  • Methotrexate + sulfasalazine
  • Sulfasalazine + hydroxychloroquine 1

Biologic and Targeted Synthetic DMARDs

According to the 2020 EULAR recommendations 1, if a patient has an inadequate response to at least one csDMARD:

1. bDMARDs should be initiated, particularly in patients with poor prognostic factors

   • TNF inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab)
   • IL-6 pathway inhibitors (tocilizumab, sarilumab)
   • T-cell co-stimulation modulator (abatacept)
   • B-cell depleting agent (rituximab)
   • IL-17 inhibitors (for psoriatic arthritis with skin involvement)

2. JAK inhibitors (tsDMARDs) may be considered after inadequate response to at least one csDMARD and at least one bDMARD 1

3. PDE4 inhibitors may be considered in patients with mild disease and inadequate response to at least one csDMARD, when neither a bDMARD nor JAK inhibitor is appropriate 1

Treatment Algorithm After Methotrexate Failure

1. Optimize methotrexate first:

   • Consider switching from oral to subcutaneous methotrexate before moving to other options 1, 3
   • Try split dosing over 24 hours or increased folic acid supplementation for patients with intolerance 1

2. If still inadequate response after optimizing methotrexate:

   • For patients with poor prognostic factors: Add a bDMARD or tsDMARD 1
   • For patients without poor prognostic factors: Consider adding another csDMARD or switching to a different csDMARD 1

3. If first bDMARD/tsDMARD fails:

   • Switch to a bDMARD with a different mechanism of action or a tsDMARD 1
   • If TNF inhibitor fails, can try another TNF inhibitor or switch to a different class 1

Special Considerations

• Elderly patients with methotrexate intolerance: Consider hydroxychloroquine or sulfasalazine for mild-to-moderate disease; leflunomide for more severe disease 4

• Patients with heart failure (NYHA class III or IV): Addition of a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended over a TNF inhibitor 1

• Patients with previous lymphoproliferative disorders: Rituximab is conditionally recommended over other DMARDs 1

• Patients with hepatitis B: Prophylactic antiviral therapy is strongly recommended when initiating rituximab or other biologics in hepatitis B core antibody positive patients 1

Monitoring and Follow-up

• Assess response to new therapy at 3 months; if no improvement, adjust therapy 1
• If target has not been reached by 6 months, consider switching therapy again 1
• Continue to monitor for disease activity and adverse effects with any DMARD

Remember that the goal of therapy is to achieve remission or low disease activity, and treatment decisions should be guided by a treat-to-target approach with regular monitoring and adjustment as needed.