What are the best alternative treatments for rheumatoid arthritis (RA) when traditional Disease-Modifying Antirheumatic Drugs (DMARDs) like methotrexate are not effective?

Best Alternatives When Methotrexate Fails in Rheumatoid Arthritis

If methotrexate is ineffective or not tolerated, add a biologic DMARD (TNF inhibitor, abatacept, or tocilizumab) combined with methotrexate if tolerable, or switch to leflunomide monotherapy if methotrexate must be discontinued entirely. 1

First-Line Strategy: Optimize Methotrexate Before Switching

Before abandoning methotrexate entirely, attempt these modifications to improve tolerability and efficacy:

• Switch to subcutaneous methotrexate administration, which reduces gastrointestinal and mucosal side effects while maintaining therapeutic efficacy 2
• Increase folic or folinic acid supplementation to mitigate methotrexate-related toxicity, particularly oral ulcers and nausea 2
• Use split dosing of oral methotrexate over 24 hours to reduce side effects 2
• Escalate to optimal dosing of 25-30 mg weekly with folate supplementation, recognizing that maximum effect requires 4-6 months 1

These strategies are preferred because methotrexate has the best long-term effectiveness, tolerability, and safety profile of any conventional DMARD, with significantly lower cost than biologics 2, 3.

When Methotrexate Optimization Fails: Add Biologic Therapy

For patients with inadequate response to optimized methotrexate monotherapy, adding a biologic DMARD is the preferred next step 1:

Biologic Options (All Combined with Methotrexate):

• TNF inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab) are the most established first biologic choice 1, 3
• Abatacept is equally effective as first-line biologic therapy 1
• Tocilizumab is equally effective as first-line biologic therapy 1

The probability of achieving ACR50 response with methotrexate plus any of these biologics ranges from 56-67%, compared to 41% with methotrexate alone in treatment-naïve patients 3. In methotrexate-inadequate responders, the ACR50 response rate ranges from 27-64% with biologic combinations 3.

Critical Timing Considerations:

• Assess response at 3 months; if no improvement is seen, adjust therapy immediately 1
• Target must be achieved by 6 months (remission or low disease activity); if not, escalate treatment 1
• Monitor disease activity every 1-3 months during active disease 1

When Methotrexate Must Be Discontinued: Alternative Conventional DMARDs

If methotrexate is contraindicated or causes intolerable side effects requiring discontinuation, leflunomide is the preferred alternative conventional DMARD 1, 2:

Leflunomide Dosing:

• Loading dose: 100 mg daily for 3 days 2
• Maintenance dose: 20 mg daily 2
• For elderly or comorbid patients: Start with 10 mg daily and titrate up as tolerated 2
• Monitoring required: Regular liver function tests and complete blood count 2

Leflunomide has similar clinical efficacy to methotrexate and slows radiographic damage progression 2.

Other Conventional DMARD Options (Lower Priority):

• Sulfasalazine is an alternative but less effective than leflunomide 1
• Hydroxychloroquine may be considered for patients with low disease activity due to better tolerability 2
• Injectable gold is rarely used due to toxicity concerns 1

Triple Therapy: A Highly Effective Non-Biologic Option

Methotrexate + sulfasalazine + hydroxychloroquine ("triple therapy") is as effective as methotrexate plus biologic DMARDs 3:

• ACR50 response rate: 61% with triple therapy, comparable to biologic combinations (56-67%) 3
• Significantly fewer withdrawals due to adverse events compared to methotrexate + infliximab (rate ratio 0.26) 3
• Lower cost than biologic therapy while maintaining similar efficacy 3
• Preferred in methotrexate-inadequate responders when biologic therapy is not accessible or desired 3

Special Population Considerations

Heart Failure (NYHA Class III or IV):

• Use non-TNF biologics (abatacept, rituximab, tocilizumab) or JAK inhibitors instead of TNF inhibitors 1
• Switch away from TNF inhibitors if heart failure develops during treatment 1

Previous Lymphoproliferative Disorder:

• Rituximab is preferred over other DMARDs for patients with prior lymphoproliferative disorders for which rituximab is an approved treatment 1

Hepatitis B Core Antibody Positive:

• Strongly recommend prophylactic antiviral therapy when initiating rituximab (regardless of surface antigen status) or any biologic/JAK inhibitor if surface antigen positive 1
• Monitor frequently without prophylaxis for non-rituximab biologics if core antibody positive but surface antigen negative 1

Nontuberculous Mycobacterial Lung Disease:

• Prefer conventional DMARDs over biologics 1
• If biologic needed, use abatacept over other biologics 1

Progressive Subcutaneous Nodules on Methotrexate:

• Switch to non-methotrexate DMARD as methotrexate can paradoxically worsen nodules 1

Algorithm for Treatment Escalation

Phase I (Initial Treatment):

• Start methotrexate (or leflunomide if contraindicated) with short-term low-dose glucocorticoids 1
• Optimize methotrexate dosing and route 2

Phase II (Inadequate Response at 3-6 Months):

• If poor prognostic factors present (high disease activity, early joint damage, positive RF/ACPA at high levels): Add biologic DMARD 1
• If poor prognostic factors absent: Consider triple therapy or switch to leflunomide 1, 3

Phase III (Failure of First Biologic):

• Switch to different biologic class: If TNF inhibitor failed, use abatacept, rituximab, or tocilizumab 1
• JAK inhibitors (tofacitinib) are an option after biologic failure 1

Common Pitfalls to Avoid

• Do not use suboptimal methotrexate dosing (<25 mg weekly) before declaring treatment failure 1
• Do not wait beyond 6 months to escalate therapy if target not achieved 1
• Do not combine biologics with each other or with DMARDs other than methotrexate in routine practice 1
• Do not use TNF inhibitors in patients with NYHA class III/IV heart failure 1
• Do not forget cholestyramine washout for women of childbearing potential on leflunomide if pregnancy is planned 2