What to add to methotrexate (MTX) and hydroxychloroquine (HCQ) for a patient with rheumatoid arthritis (RA) that is not adequately managed?

Management of Rheumatoid Arthritis Not Adequately Controlled with Methotrexate and Hydroxychloroquine

For a patient with rheumatoid arthritis not adequately managed on methotrexate and hydroxychloroquine, adalimumab (option C) should be added to the treatment regimen. 1

Treatment Algorithm for Inadequate Response to MTX + HCQ

Step 1: Assess Disease Activity and Response to Current Therapy

• Evaluate disease activity using validated composite measures (DAS28, CDAI, SDAI)
• Confirm adequate dosing of current medications:
  • MTX should be optimized to 20-25 mg/week
  • HCQ typically at 200-400 mg/day

Step 2: Treatment Escalation Options

Based on the 2016 EULAR and 2021 ACR guidelines, when a patient fails to achieve the treatment target with MTX + HCQ, the following options exist in order of preference:

1. Add a biologic DMARD (bDMARD) - particularly a TNF inhibitor like adalimumab 1
2. Add a targeted synthetic DMARD (tsDMARD) like a JAK inhibitor
3. Add sulfasalazine (triple therapy)
4. Switch to another combination of conventional DMARDs

Evidence Supporting Adalimumab Addition

The EULAR recommendations clearly state that when poor prognostic factors are present and a patient has failed to achieve the treatment target with the first csDMARD strategy, "addition of a bDMARD or a tsDMARD should be considered; current practice would be to start a bDMARD" 1. The 2021 ACR guidelines similarly recommend "addition of a bDMARD or tsDMARD over triple therapy for patients taking maximally tolerated doses of methotrexate who are not at target" 1.

Among the TNF inhibitors, adalimumab has been extensively studied in combination with MTX, demonstrating significant improvements in ACR20, ACR50, and ACR70 responses compared to placebo 2. The FDA label for adalimumab confirms its efficacy in combination with methotrexate in patients with active rheumatoid arthritis who have had an inadequate response to methotrexate alone.

Why Not Other Options?

• Cyclophosphamide (A): Not recommended in current guidelines for RA management due to its toxicity profile and the availability of safer alternatives 1, 3.

• Azathioprine (B): Not included in current treatment algorithms for RA. It has been largely replaced by more effective and safer DMARDs 1.

• Sulfasalazine (D): While adding sulfasalazine to create triple therapy (MTX+HCQ+SSZ) is a valid option, the evidence suggests that adding a biologic DMARD like adalimumab provides superior efficacy. The ACR 2021 guideline conditionally recommends adding a bDMARD or tsDMARD over triple therapy for patients taking maximally tolerated doses of methotrexate who are not at target 1.

Important Considerations

• Safety monitoring: Before starting adalimumab, screen for tuberculosis and hepatitis B 3
• Dosing: Adalimumab is typically administered as 40 mg subcutaneously every other week 2
• Evaluation of response: Assess response at 3 months; if no improvement is seen, consider switching to a different class of biologic 1
• Drug interactions: Adalimumab can be safely used with methotrexate; in fact, the combination has synergistic effects 2

Common Pitfalls to Avoid

1. Inadequate dose optimization: Ensure MTX is at optimal dose (20-25 mg/week) before adding a third agent
2. Delayed escalation: Don't wait too long to escalate therapy if the target is not achieved
3. Ignoring poor prognostic factors: Patients with high disease activity, early joint damage, positive RF/ACPA should receive more aggressive therapy
4. Overlooking comorbidities: Consider patient-specific factors that might influence treatment choice

In conclusion, based on the most recent guidelines and evidence, adalimumab is the most appropriate addition to MTX and HCQ for a patient with rheumatoid arthritis that is not adequately managed on this combination.