Methotrexate Dose Reduction When Starting Rituximab
When initiating rituximab, methotrexate dose reduction should be considered to decrease the risk of infections and other adverse effects related to combined immunosuppression, though the evidence does not mandate complete discontinuation. 1
Evidence-Based Approach to Dose Management
Primary Recommendation from Dermatology Guidelines
The British Association of Dermatologists explicitly states that adjuvant systemic immunosuppressive drugs can be continued with concomitant use of rituximab, but dose reduction should be considered to decrease the risk of infections and other adverse effects related to immunosuppression. 1 This represents the most direct guideline-level evidence addressing your question.
Context from Rheumatoid Arthritis Literature
The combination of rituximab with methotrexate is well-established and effective:
Rituximab (2×1000 mg) combined with methotrexate is significantly more efficacious than methotrexate alone for rheumatoid arthritis, with ACR50 response rates of 29% versus 9% at 24 weeks (NNT=6). 2
In early active RA, rituximab 2×1000 mg plus methotrexate reduced joint damage progression compared to methotrexate alone (mean change in Sharp score 0.359 vs 1.079, p=0.0004). 3
The combination can be used successfully without necessarily reducing methotrexate dose in many patients, as demonstrated in multiple controlled trials. 2, 3
Disease-Specific Considerations
For vasculitis (GPA/MPA): When rituximab is used for remission maintenance after achieving remission, it is conditionally recommended over methotrexate or azathioprine, suggesting these agents serve different roles rather than being used simultaneously. 1
For pemphigus: Rituximab has been used with concomitant corticosteroids and immunosuppressants (including methotrexate) in 79-97% of cases, though specific dosing guidance for methotrexate reduction is not provided. 1
Practical Algorithm for Dose Adjustment
When to Consider Dose Reduction:
Patient has risk factors for infection:
Patient is on high-dose methotrexate (≥15-20 mg/week):
- Consider reducing to 10-15 mg/week when adding rituximab 1
Patient develops signs of excessive immunosuppression:
- Leukopenia (WBC <3.5×10^9/L)
- Neutropenia (neutrophils <2×10^9/L)
- Recurrent infections 5
When Full-Dose Methotrexate May Be Continued:
- Young, otherwise healthy patients
- Well-controlled disease requiring both agents
- No history of infection complications
- Normal renal function
- Close monitoring capability 2, 3
Monitoring Requirements
Enhanced surveillance is essential when combining these agents:
- Complete blood count every 2-4 weeks initially after starting rituximab 4
- Liver function tests and renal function monitoring 4
- Watch for signs of methotrexate toxicity: mucositis, fever, diarrhea, skin reactions 4, 5
- Ensure adequate folic acid supplementation (1-5 mg daily except on methotrexate day) 4
Critical Pitfalls to Avoid
Drug interactions: Both rituximab and methotrexate impair vaccine responses, with rituximab having a greater effect (pooled OR for non-seroconversion 4.91-13.06) compared to methotrexate (OR 2.0-5.41). 1 Vaccinations should ideally be completed before starting rituximab.
Infection risk: The combination increases infection risk beyond either agent alone. Temporarily discontinue methotrexate if serious infection develops requiring antibiotics. 5
Renal function: Methotrexate toxicity risk increases dramatically with renal impairment. If creatinine clearance is 20-50 mL/min, reduce methotrexate dose by 50%; if <20 mL/min, avoid methotrexate entirely. 1, 4