Managing Leflunomide-Associated Diarrhea in Rheumatoid Arthritis
If diarrhea develops in a patient taking leflunomide, first assess severity and duration, then discontinue leflunomide and initiate cholestyramine washout for severe or persistent cases, while switching to an alternative DMARD such as methotrexate or sulfasalazine. 1, 2
Initial Assessment and Severity Stratification
When diarrhea occurs in a patient on leflunomide, determine:
Duration: Most leflunomide-associated diarrhea occurs within the first 6 months of treatment and is typically mild 1, 3. However, severe cases can develop after 12+ months of therapy 2.
Severity markers: Look for weight loss, electrolyte imbalances, dehydration, or functional impairment requiring hospitalization 2, 4. Severe diarrhea may be associated with high teriflunomide blood concentrations (>50-156 mg/L) 4.
Associated symptoms: Assess for abdominal pain, nausea, loss of appetite, or other gastrointestinal symptoms that commonly accompany leflunomide therapy 1, 3.
Management Algorithm Based on Severity
Mild Diarrhea (No Weight Loss, Functional Impairment Minimal)
- Continue leflunomide with symptomatic management using antidiarrheal agents 3, 5
- Monitor closely for progression over 2-4 weeks 1
- Most mild cases resolve without intervention 3, 5
Moderate to Severe Diarrhea (Weight Loss, Persistent >2-4 Weeks, or Functional Impairment)
- Immediately discontinue leflunomide 2, 4
- Initiate cholestyramine washout: 8 grams three times daily for 11 days to rapidly eliminate the active metabolite teriflunomide 2, 4
- Consider checking teriflunomide blood levels if available (target reduction to <6 mg/L) 4
- Perform colonoscopy to rule out leflunomide-induced colitis (ulcerative or microscopic colitis patterns have been reported) 2
Critical pitfall: Given leflunomide's long half-life (approximately 2 weeks for the active metabolite), simply stopping the drug without cholestyramine washout may result in prolonged symptoms lasting weeks 2.
Alternative DMARD Selection After Discontinuation
Once leflunomide is discontinued, switch to an alternative csDMARD based on EULAR guidelines:
- First choice: Methotrexate (if not previously used or contraindicated), starting at 15-25 mg weekly with folic acid supplementation 6, 7
- Second choice: Sulfasalazine as an alternative csDMARD 6
- If the patient has poor prognostic factors (high disease activity, positive RF/anti-CCP, early joint damage), consider adding a biologic DMARD with methotrexate rather than switching to another csDMARD monotherapy 6
Monitoring During Transition
- Assess disease activity every 1-3 months during the transition to ensure RA remains controlled 6
- Monitor for resolution of diarrhea (typically occurs within 26 days after cholestyramine washout in severe cases) 4
- Check baseline labs (CBC, liver function tests) before initiating the new DMARD 1
Special Considerations
Budesonide may be insufficient: One case series showed that budesonide treatment for leflunomide-induced colitis was ineffective, and symptoms only resolved after drug discontinuation and washout 2. Therefore, do not delay leflunomide discontinuation in favor of symptomatic colitis treatment.
Heterogeneous pathology: Leflunomide-associated diarrhea can manifest as ulcerative colitis or microscopic colitis on biopsy, indicating variable mechanisms of gastrointestinal toxicity 2.