What to start for rheumatoid arthritis after developing methotrexate (Disease-Modifying Antirheumatic Drug (DMARD))-induced mucositis?

Treatment Options for Rheumatoid Arthritis After Methotrexate-Induced Mucositis

For patients who develop methotrexate-induced mucositis in rheumatoid arthritis, leflunomide should be considered as the next DMARD of choice.

Understanding Methotrexate-Induced Mucositis

Methotrexate (MTX) is the anchor drug for rheumatoid arthritis treatment, but mucositis is a recognized adverse effect:

• Mucositis occurs due to MTX's inhibition of rapid cell turnover, which can lead to significant oral lesions and pain 1
• Severe cases may require temporary discontinuation of MTX and supportive care including pain management 1, 2
• Folic acid supplementation is crucial for preventing MTX toxicity - non-compliance with folic acid can worsen mucositis 1

Alternative DMARD Options After MTX Intolerance

First-Line Alternative: Leflunomide

• In cases of MTX contraindications or early intolerance, leflunomide should be considered as part of the first treatment strategy 3
• Leflunomide has similar clinical efficacy to methotrexate in established and recent rheumatoid arthritis 4
• It is as effective as methotrexate in slowing radiographic damage progression 4

Other Conventional Synthetic DMARD Options

• Sulfasalazine can be considered as an alternative when MTX cannot be used 3
• For patients with moderate-to-high disease activity, combination therapy may be needed 3

Treatment Algorithm After MTX-Induced Mucositis

1. First step: Switch to leflunomide monotherapy 3

   • Starting dose: 100mg daily for 3 days (loading dose), followed by 20mg daily
   • Monitor liver function tests and complete blood count regularly

2. If inadequate response to leflunomide monotherapy:

   • Consider adding hydroxychloroquine 3, 5
   • Triple therapy (sulfasalazine + hydroxychloroquine + leflunomide) can be considered 5

3. If still inadequate response:

   • Addition of a biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) should be considered 3
   • TNF inhibitors, abatacept, IL-6 inhibitors, or JAK inhibitors can be used in combination with leflunomide 3

Monitoring and Treatment Targets

• Follow a treat-to-target approach with regular monitoring every 1-3 months during active disease 3
• Aim for remission or low disease activity 3
• If no improvement is seen within 3 months or target not reached by 6 months, adjust therapy 3

Important Considerations and Pitfalls

• Avoid reintroducing methotrexate in patients who experienced significant mucositis, as recurrence is likely 2
• Consider route of administration if attempting to retry methotrexate - subcutaneous administration may reduce gastrointestinal side effects but may not prevent mucositis 3
• Ensure adequate folate supplementation with any DMARD therapy to minimize toxicity 1
• Monitor for overlapping toxicities when switching between DMARDs, particularly hepatotoxicity with leflunomide 3, 6
• Consider washout period when transitioning between DMARDs to prevent additive toxicity 6

Special Situations

• For patients with very high disease activity or poor prognostic factors, consider earlier introduction of biologics in combination with leflunomide 3
• In elderly patients or those with comorbidities, start with lower doses of leflunomide (10mg daily) and titrate up as tolerated 3
• For patients with childbearing potential, discuss the teratogenic risks of leflunomide and need for cholestyramine washout if pregnancy is planned 3

Remember that the goal of treatment is to achieve remission or low disease activity to prevent structural damage and long-term disability while minimizing medication toxicity 3, 4.