Methotrexate Guidelines for Rheumatoid Arthritis and Cancer
Methotrexate should be initiated at 10-15 mg/week orally with escalation of 5 mg every 2-4 weeks up to 20-30 mg/week, with mandatory folic acid supplementation of at least 5 mg weekly, and is the preferred first-line disease-modifying antirheumatic drug for rheumatoid arthritis. 1
Pre-Treatment Work-Up
Before starting methotrexate, obtain the following baseline assessments to identify patients at risk for toxicity 1:
- Laboratory tests: AST, ALT, albumin, complete blood count (CBC), creatinine 1
- Imaging: Chest x-ray (within the previous year) 1
- Clinical assessment: Alcohol intake history, risk factors for methotrexate toxicity 1
- Additional considerations: Hepatitis B/C serology, HIV serology, fasting glucose, lipid profile, pregnancy test 1
Dosing and Administration for Rheumatoid Arthritis
Initial Dosing Strategy
Start with oral methotrexate 10-15 mg/week 1. The 2021 American College of Rheumatology guidelines conditionally recommend titrating to at least 15 mg/week within 4-6 weeks 1.
Dose Escalation Protocol
- Increase by 5 mg every 2-4 weeks based on clinical response and tolerability 1
- Target dose: 20-30 mg/week for optimal efficacy 1
- Evidence shows dose-dependent efficacy: starting doses of 12.5-20 mg/week versus 5-10 mg/week resulted in higher clinical efficacy without increased toxicity 1
Route Optimization
Oral administration is preferred initially, but parenteral (subcutaneous) administration should be considered in specific circumstances 1:
- Inadequate clinical response at oral doses of 20-25 mg/week 1, 2
- Gastrointestinal intolerance to oral formulation 1
- Subcutaneous methotrexate offers greater bioavailability and may reduce gastrointestinal toxicity 1
The 2021 ACR guidelines conditionally recommend switching to subcutaneous methotrexate over adding/switching to alternative DMARDs for patients not at target on oral methotrexate 1, 2.
Mandatory Folic Acid Supplementation
Prescribe at least 5 mg folic acid per week with methotrexate therapy (Grade A recommendation) 1. This is strongly recommended based on meta-analysis evidence showing:
- Reduction in gastrointestinal toxicity (OR 0.42; 95% CI 0.21 to 0.85) 1
- Reduction in hepatotoxicity (OR 0.17; 95% CI 0.09 to 0.32) 1
- No reduction in methotrexate efficacy 1
Monitoring Requirements
Initial Phase (Dose Escalation)
Perform ALT ± AST, creatinine, and CBC every 1-1.5 months until a stable dose is reached 1.
Maintenance Phase
Monitor ALT ± AST, creatinine, and CBC every 1-3 months after reaching stable dosing 1. Clinical assessment for side effects and risk factors should occur at each visit 1.
Managing Liver Function Abnormalities
- Stop methotrexate if ALT/AST >3× upper limit of normal (ULN) on confirmed testing 1
- May reinstitute at lower dose after normalization 1
- If ALT/AST persistently elevated up to 3× ULN: adjust methotrexate dose 1
- If ALT/AST persistently >3× ULN after discontinuation: consider diagnostic procedures 1
Treatment Strategy and Combination Therapy
Monotherapy vs. Combination
In DMARD-naive patients, methotrexate monotherapy is favored over combination with other conventional DMARDs (Grade A recommendation) 1. The efficacy/toxicity balance supports this approach 1.
When Monotherapy Fails
Methotrexate should serve as the anchor for combination therapy when monotherapy does not achieve disease control 1, 2. The 2021 ACR guidelines recommend adding a biologic DMARD or targeted synthetic DMARD rather than switching away from methotrexate entirely 1, 2.
Before declaring methotrexate failure, ensure 2:
- Dose has been escalated to 20-30 mg/week 2
- Trial of subcutaneous administration if oral route inadequate 2
- Adequate folic acid supplementation (at least 5 mg/week) 2
- Adequate trial duration of 3-6 months at optimal dose 2
Treat-to-Target Approach
A treat-to-target approach is strongly recommended over usual care for patients not previously treated with biologics or targeted synthetic DMARDs 1. The minimal initial treatment goal should be low disease activity (conditionally recommended over remission as the initial target) 1.
Long-Term Safety
Methotrexate is appropriate for long-term use based on its acceptable safety profile (Grade B recommendation) 1. The probability of patients continuing methotrexate treatment beyond 5 years is greater than for other slow-acting antirheumatic drugs 3.
Special Populations and Situations
Perioperative Management
Methotrexate can be safely continued in the perioperative period in RA patients undergoing elective orthopedic surgery (Grade B recommendation) 1.
Pregnancy and Fertility
Methotrexate is absolutely contraindicated in pregnancy (Pregnancy Category X) 4. The drug should not be used for at least 3 months before planned pregnancy for both men and women 1. Methotrexate should not be used during breastfeeding 1, 4.
Elderly Patients
Dose selection for elderly patients should be cautious due to 4, 3:
- Greater frequency of decreased hepatic and renal function 4, 3
- Decreased folate stores 4
- Higher risk of bone marrow suppression, thrombocytopenia, and pneumonitis 4
Use creatinine clearance rather than serum creatinine to assess renal function in elderly patients, as serum creatinine may overestimate renal function 4. Consider lower initial doses with eGFR 30-59 mL/minute, with more gradual dose escalation 5. Methotrexate is contraindicated if eGFR <30 mL/minute 5.
Renal Impairment
Methotrexate elimination is reduced in patients with impaired renal function, requiring especially careful monitoring and dose reduction or discontinuation 4. Declining renal function is an important predictor of methotrexate toxicity 3.
Other Rheumatic Indications
Methotrexate as a steroid-sparing agent is recommended (Grade B) for 1:
Methotrexate can be considered for 1:
Cancer Indications
Methotrexate is FDA-approved for 4:
- Gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole 4
- Acute lymphocytic leukemia (prophylaxis and treatment of meningeal leukemia, maintenance therapy) 4
- Breast cancer 4
- Epidermoid cancers of the head and neck 4
- Advanced mycosis fungoides (cutaneous T cell lymphoma) 4
- Lung cancer (squamous cell and small cell types) 4
- Advanced stage non-Hodgkin's lymphomas 4
- Non-metastatic osteosarcoma (high-dose methotrexate with leucovorin rescue in combination with other agents after surgical resection) 4
For intrathecal and high-dose methotrexate therapy, use only the preservative-free formulation because the preserved formulation contains benzyl alcohol, which can cause fatal "gasping syndrome" in neonates 4.
Common Pitfalls to Avoid
Premature Declaration of Treatment Failure
Do not declare methotrexate ineffective if 2:
- Patient is still on oral methotrexate <20 mg/week (dose escalation may provide additional benefit) 2
- Subcutaneous administration has not been tried when oral methotrexate shows inadequate response 2
- Inadequate or absent folic acid supplementation causing intolerance that mimics inefficacy 2
Drug Interactions
Unexpectedly severe bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate with some NSAIDs 4. While interactions between methotrexate and NSAIDs have been reported, they may not be clinically significant in most cases 3. However, exercise extreme caution in patients with reduced renal function 3.
More serious toxicities (e.g., pancytopenia) may result when other folate inhibitors like trimethoprim-sulfamethoxazole are combined with methotrexate 4, 3. Probenecid (inhibitor of renal tubular secretion) can also increase methotrexate toxicity 3.
Discontinuation for Adverse Events
Stop methotrexate immediately if significant drop in blood counts occurs 4. In controlled trials, leukopenia (WBC <3000/mm³) occurred in 2%, thrombocytopenia (platelets <100,000/mm³) in 5%, and pancytopenia in 2% of RA patients 4.
Discontinue methotrexate if vomiting, diarrhea, or stomatitis occurs that may result in dehydration, until recovery 4. Diarrhea and ulcerative stomatitis require interruption of therapy to prevent hemorrhagic enteritis and intestinal perforation 4.
Pulmonary symptoms (especially dry, nonproductive cough) require interruption of treatment and careful investigation, as methotrexate-induced lung disease can occur at any time during therapy and is not always fully reversible 4.
Hepatotoxicity Monitoring
Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, generally only after prolonged use 4. Liver enzyme elevations are frequently seen but are usually transient and asymptomatic 4. However, persistent abnormalities in liver function tests may precede fibrosis or cirrhosis in the RA population 4.
Adverse Event Profile
Up to 60% of patients receiving methotrexate for RA discontinue due to adverse effects, most occurring during the first year 3. In clinical trials, patients in the methotrexate group were twice as likely to discontinue due to adverse events compared to placebo (16% versus 8%; NNT 13) 6.
Common adverse events include 7, 6:
- Gastrointestinal complications (most common) 3, 7
- Hepatotoxicity 3, 7
- Hematological toxicity 3, 7
- Pulmonary toxicity 3, 7
Total adverse event rates at 12 weeks were higher in the methotrexate group compared to placebo (45% versus 15%; NNT 4) 6. However, no statistically significant differences were observed in serious adverse events between methotrexate and placebo at 27-52 weeks 6.
Efficacy in Rheumatoid Arthritis
Methotrexate demonstrates substantial clinical benefit 6:
- ACR 50 response at 52 weeks: RR 3.0 (95% CI 1.5 to 6.0; NNT 7), with 15% absolute treatment benefit 6
- Physical function improvement: MD -0.27 on 0-3 scale (95% CI -0.39 to -0.16; NNT 4), with 9% absolute treatment benefit 6
- Radiographic progression: Lower erosion score progression rates (RR 0.31; 95% CI 0.11 to 0.86; NNT 13), with 8% absolute treatment benefit 6