What are the guidelines for using methotrexate (disease-modifying antirheumatic drug (DMARD)) in treating conditions like rheumatoid arthritis and cancer?

Methotrexate for Rheumatoid Arthritis and Cancer

Primary Indication and Role

Methotrexate is the anchor disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis and is indicated for severe, recalcitrant, disabling psoriasis and various malignancies including gestational choriocarcinoma, acute lymphocytic leukemia, breast cancer, head and neck cancers, lung cancer, non-Hodgkin's lymphomas, and osteosarcoma. 1

For rheumatoid arthritis specifically, methotrexate is indicated for patients with severe, active disease who have had insufficient response to or are intolerant of first-line therapy including full-dose NSAIDs. 1

Dosing Strategy for Rheumatoid Arthritis

Initial Dosing

• Start with oral methotrexate 15 mg once weekly rather than lower doses, as this provides superior disease control without compromising safety. 2, 3
• Escalate by 5 mg increments every 2-4 weeks to reach 20-25 mg weekly within 4-6 weeks based on clinical response and tolerability. 2, 3
• Maximum weekly dose is 25-30 mg. 2, 3

Route of Administration

• Oral methotrexate is conditionally recommended over subcutaneous administration for patients initiating therapy, despite moderate evidence suggesting superior efficacy of subcutaneous injections, due to ease of oral administration and similar bioavailability at typical starting doses. 2
• If inadequate response persists on oral methotrexate at 20-25 mg/week, switch to subcutaneous administration before adding or switching to other DMARDs. 2, 4, 3

Folic Acid Supplementation

• Prescribe at least 5 mg of folic acid per week to reduce gastrointestinal and other adverse effects without compromising methotrexate efficacy. 2, 3
• Higher doses of folic acid (or low-dose folinic acid) may be needed if tolerability issues arise, though high-dose folinic acid (>5 mg/week) may reduce efficacy. 2

Monitoring Requirements

Baseline Assessment

• Complete blood count (CBC) with differential and platelet counts 2, 1
• Hepatic enzymes (ALT/AST), albumin 2, 1
• Serum creatinine with creatinine clearance calculation 2, 1
• Chest radiograph (within the previous year) 1
• Screen for hepatitis B/C and latent tuberculosis 3

Ongoing Monitoring

• ALT/AST, creatinine, and CBC should be performed every 1-1.5 months until a stable dose is reached, then every 1-3 months thereafter. 2
• For rheumatoid arthritis and psoriasis: hematology at least monthly, renal function and liver function every 1-2 months. 1
• Clinical assessment for side effects and risk factors should be performed at each visit. 2

Laboratory Thresholds for Action

• Stop methotrexate if there is a confirmed increase in ALT/AST greater than 3 times the upper limit of normal (ULN), but may reinstitute at a lower dose following normalization. 2
• If ALT/AST levels are persistently elevated up to 3 times ULN, adjust the methotrexate dose. 2
• Consider diagnostic procedures if ALT/AST remains elevated more than 3 times ULN after discontinuation. 2

Treatment Response and Targets

Timeline for Assessment

• Assess treatment response at 3 months; if no improvement is seen, modify treatment. 3
• Full therapeutic effect often requires 12 weeks or longer, though improvement in joint pain and swelling may begin within 3-6 weeks. 3
• The treatment target is remission or low disease activity within 6 months. 3

Treat-to-Target Approach

• A treat-to-target (TTT) approach is strongly recommended over usual care for patients who have not been previously treated with biologic or targeted synthetic DMARDs. 2
• A minimal initial treatment goal of low disease activity is conditionally recommended over a goal of remission. 2

Managing Inadequate Response or Intolerance

Optimizing Methotrexate Before Switching

Methotrexate should be considered ineffective only after dose escalation to 20-30 mg/week over 4-6 weeks, with consideration of switching to subcutaneous administration before declaring treatment failure. 4

Strategies for Intolerance

• Try split dosing of oral methotrexate over 24 hours, or switch to weekly subcutaneous injections, and/or increase folic acid supplementation before switching to alternative DMARDs. 2
• Switching to subcutaneous methotrexate is conditionally recommended over adding/switching to alternative DMARDs for patients taking oral methotrexate who are not at target. 2

Adding Other Therapies

• Addition of a biologic DMARD or targeted synthetic DMARD is conditionally recommended over triple therapy (methotrexate + sulfasalazine + hydroxychloroquine) for patients taking maximally tolerated doses of methotrexate who are not at target. 2
• Methotrexate monotherapy is conditionally recommended over combination with biologics or targeted synthetic DMARDs in DMARD-naive patients with moderate-to-high disease activity, as many patients will reach their treatment goal on methotrexate alone. 2, 3
• When adding biologics, methotrexate should be continued as the backbone, as combination therapy is superior to monotherapy. 4, 3

Glucocorticoid Use

• Short-term glucocorticoids (<3 months) are conditionally recommended, with the goal of tapering to 5 mg daily by week 8 and continuing to taper over 2-4 months total. 3
• Initial dosing of 5-10 mg prednisone daily combined with methotrexate provides superior disease control and slows radiographic progression. 3
• Longer-term glucocorticoid therapy (≥3 months) is strongly discouraged due to significant toxicity. 3

Safety Considerations and Contraindications

Major Warnings

• Methotrexate must not be used during pregnancy or for at least 3 months before planned pregnancy in both men and women. 3, 1
• Deaths have been reported with methotrexate use in malignancy, psoriasis, and rheumatoid arthritis. 1
• Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions, requiring careful monitoring and dose reduction or discontinuation. 1

Renal Function Considerations

• In patients with renal deficiency, a lower initial dose is considered with an estimated glomerular filtration rate (eGFR) between 30 and 59 mL/minute. 5
• Methotrexate is contraindicated in patients with rheumatoid arthritis if the eGFR is <30 mL/minute. 5
• Declining renal function with age increases the risk of methotrexate toxicity, likely due to drug accumulation. 6

Drug Interactions

• Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with high doses of methotrexate. 1
• Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate, as these drugs may reduce tubular secretion and enhance toxicity. 1
• Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate along with some NSAIDs. 1
• More serious toxicities may result when other inhibitors of folate utilization (e.g., cotrimoxazole) or inhibitors of renal tubular secretion (e.g., probenecid) are combined with methotrexate. 6

Common Adverse Effects

• Gastrointestinal complications are the most common adverse effects. 6, 7
• Patients in the methotrexate group are twice as likely to discontinue due to adverse events compared to placebo (16% versus 8%). 8
• Up to 60% of all patients who receive methotrexate for rheumatoid arthritis discontinue taking it because of adverse effects, most of which occur during the first year of therapy. 6

Serious Toxicities

• Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, may occur acutely at any time during therapy and has been reported at low doses. 1
• Pulmonary symptoms (especially a dry, nonproductive cough) require interruption of treatment and careful investigation. 1
• Hepatotoxicity, fibrosis and cirrhosis may occur, but generally only after prolonged use. 1
• Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. 1
• Malignant lymphomas may occur in patients receiving low-dose methotrexate and may regress following withdrawal. 1

Special Populations

Older Patients

• Due to diminished hepatic and renal function as well as decreased folate stores in older individuals, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity. 1
• Decreased renal function as a result of disease and/or aging appears to be an important determinant of hepatic, lymphoproliferative and hematological toxicity. 6

Efficacy Data for Rheumatoid Arthritis

• Methotrexate monotherapy showed a clinically important and statistically significant improvement in the ACR 50 response rate when compared with placebo at 52 weeks (RR 3.0,95% CI 1.5 to 6.0; NNT 7). 8
• Statistically significant improvement in physical function was observed in patients receiving methotrexate alone compared with placebo at 12 to 52 weeks (MD -0.27,95% CI -0.39 to -0.16; NNT 4). 8
• Radiographic progression rates were statistically significantly lower for patients in the methotrexate group compared with placebo-treated patients (RR 0.31,95% CI 0.11 to 0.86; NNT 13). 8
• The probability of patients continuing methotrexate treatment beyond 5 years is greater than for other slow-acting antirheumatic drugs. 6

Critical Pitfalls to Avoid

• Do not start at doses below 10-15 mg weekly, as this delays achieving therapeutic effect and optimal disease control. 3
• Do not declare methotrexate failure prematurely if the patient is still on oral methotrexate <20 mg/week, as dose escalation may provide additional benefit. 4
• Do not switch to alternative DMARDs without first trying subcutaneous administration when oral methotrexate shows inadequate response. 4, 3
• Inadequate folic acid supplementation or absence of supplementation may cause intolerance that mimics inefficacy. 4
• Patients should be informed that the recommended dose is taken weekly, as mistaken daily use of the recommended dose has led to fatal toxicity. 1
• Prescriptions should not be written or refilled on a PRN basis. 1