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

Methotrexate Guidelines for Rheumatoid Arthritis and Cancer

Rheumatoid Arthritis Treatment Protocol

Start oral methotrexate at 15 mg weekly and escalate to at least 15 mg within 4-6 weeks, targeting 20-25 mg weekly based on response and tolerability, with mandatory folic acid supplementation of at least 5 mg weekly. 1

Initial Dosing and Escalation

• Begin with oral methotrexate 15 mg once weekly rather than lower starting doses, as this provides superior disease control without compromising safety 2
• Escalate by 5 mg increments every 2-4 weeks until reaching 20-25 mg weekly (maximum 30 mg weekly) 1, 2
• Oral administration is preferred initially over subcutaneous despite moderate evidence suggesting superior subcutaneous efficacy, due to ease of administration and similar bioavailability at typical starting doses 1
• Prescribe at least 5 mg folic acid weekly to reduce gastrointestinal and hepatic toxicity without compromising methotrexate efficacy 1, 2

Optimizing Route of Administration

• If inadequate response persists on oral methotrexate at 20-25 mg weekly, switch to subcutaneous administration at the same dose before adding or switching to other DMARDs 1, 3
• For patients not tolerating oral weekly methotrexate, try split dosing over 24 hours, switch to subcutaneous injections, and/or increase folic acid supplementation before switching to alternative DMARDs 1
• Subcutaneous methotrexate is conditionally recommended over adding/switching to alternative DMARDs for patients taking oral methotrexate who are not at target 1

Treatment Goals and Monitoring

• Assess treatment response at 3 months; if no improvement is seen, modify treatment 2
• The treatment target is remission or low disease activity within 6 months, though a minimal initial treatment goal of low disease activity is conditionally recommended over remission 1, 2
• Full therapeutic effect often requires 12 weeks or longer, though improvement in joint pain and swelling may begin within 3-6 weeks 2
• A treat-to-target approach is strongly recommended over usual care for patients who have not been previously treated with biologic or targeted synthetic DMARDs 1

Combination Therapy Strategy

• Methotrexate monotherapy is conditionally recommended over combination with biologic or targeted synthetic DMARDs in DMARD-naive patients with moderate-to-high disease activity 1, 2
• When methotrexate monotherapy fails at maximally tolerated doses, adding a biologic or targeted synthetic DMARD is conditionally recommended over triple conventional DMARD therapy 1
• Methotrexate should be continued as the backbone when adding biologics, as combination therapy is superior to monotherapy 3, 2
• Short-term glucocorticoids (<3 months) at 5-10 mg prednisone daily are conditionally recommended, with tapering to 5 mg daily by week 8 and discontinuation over 2-4 months total 2

Safety Monitoring Requirements

Before initiating therapy, obtain complete blood count, serum transaminases (ALT/AST), albumin, creatinine with creatinine clearance, chest radiograph (within the previous year), and screening for hepatitis B/C and latent tuberculosis 2, 4

• During therapy, monitor hematology at least monthly and renal/liver function every 1-2 months 1, 4
• ALT/AST with or without creatinine and complete blood count should be performed every 1-1.5 months until stable dose is reached, then every 1-3 months thereafter 1
• Stop methotrexate if confirmed ALT/AST elevation exceeds 3 times upper limit of normal, but may reinstitute at lower dose following normalization 1, 3
• If ALT/AST levels are persistently elevated up to 3 times upper limit of normal, adjust methotrexate dose; consider diagnostic procedures if persistently elevated more than 3 times upper limit of normal after discontinuation 1

Common Pitfalls to Avoid

• Do not declare methotrexate failure prematurely if the patient is still on oral methotrexate <20 mg weekly, as dose escalation may provide additional benefit 3
• Do not start at doses below 10-15 mg weekly, as this delays achieving therapeutic effect and optimal disease control 2
• Ensure adequate folic acid supplementation, as inadequate supplementation may cause intolerance that mimics inefficacy 3
• Mistaken daily use of the recommended weekly dose has led to fatal toxicity; prescriptions should not be written on a PRN basis 4

Defining Treatment Failure

• Methotrexate is considered ineffective when patients fail to achieve low disease activity or remission after dose escalation to 20-30 mg weekly over 4-6 weeks, with consideration of switching to subcutaneous administration 3
• An adequate trial duration of typically 3-6 months at optimal dose is necessary to assess response 3
• Moderate-to-high disease activity persisting despite methotrexate 20-30 mg weekly for 3-6 months indicates treatment failure 3

Special Populations and Contraindications

• Methotrexate must not be used during pregnancy or for at least 3 months before planned pregnancy in both men and women 2, 4
• In patients with estimated glomerular filtration rate between 30-59 mL/minute, use lower initial doses with closer monitoring and more gradual dose escalation 5
• Methotrexate is contraindicated in rheumatoid arthritis patients if estimated glomerular filtration rate is <30 mL/minute 5
• Due to diminished hepatic and renal function in older individuals, relatively low doses should be considered with close monitoring for early signs of toxicity 4, 6

Drug Interactions

• Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with high-dose methotrexate (≥500 mg/m²), as concomitant administration has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity 4
• Caution is advised when NSAIDs and salicylates are used with lower doses of methotrexate, particularly in patients with reduced renal function, as these drugs reduce tubular secretion of methotrexate 4, 6
• More serious toxicities (e.g., pancytopenia) may result when other inhibitors of folate utilization (e.g., cotrimoxazole) or inhibitors of renal tubular secretion (e.g., probenecid) are combined with methotrexate 4, 6

Cancer Treatment Indications

Methotrexate is FDA-approved for gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, acute lymphocytic leukemia (prophylaxis and treatment of meningeal leukemia), breast cancer, head and neck epidermoid cancers, advanced mycosis fungoides, lung cancer (squamous cell and small cell types), advanced stage non-Hodgkin's lymphomas, and non-metastatic osteosarcoma in combination with other chemotherapeutic agents 4

High-Dose Methotrexate for Cancer

• For intrathecal and high-dose therapy, use only the preservative-free formulation of methotrexate; do not use the preserved formulation because it contains benzyl alcohol 4
• High-dose methotrexate is defined as doses of 500 mg/m² or greater 5
• High-dose methotrexate followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation 4
• Caution must be exercised if high-dose methotrexate is administered in combination with potentially nephrotoxic chemotherapeutic agents (e.g., cisplatin) 4

Toxicity Management in Cancer Treatment

• Treatment of severe methotrexate toxicity has three main goals: clearance of methotrexate from the bloodstream, folinic acid therapy, and organ treatment 5
• Leucovorin is highly beneficial in preventing myelosuppression, gastric toxicity, and neurotoxic effects after high-dose methotrexate therapy 5
• Glucarpidase has been licensed for treatment of high plasma methotrexate levels >1 μmol/L in patients with compromised renal function who have delayed methotrexate elimination 5
• Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions, requiring especially careful monitoring for toxicity and dose reduction or discontinuation 4

Serious Toxicities Across All Indications

• Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate along with some nonsteroidal anti-inflammatory drugs 4
• 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; pulmonary symptoms (especially dry, nonproductive cough) require interruption of treatment 4
• Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur 4
• Malignant lymphomas may occur in patients receiving low-dose methotrexate and may regress following withdrawal of methotrexate 4