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

Methotrexate Guidelines for Rheumatic Disorders and Cancer

Initial Dosing and Administration

Start oral methotrexate at 10-15 mg/week and escalate by 5 mg every 2-4 weeks up to 20-30 mg/week based on clinical response and tolerability. 1 This dosing strategy balances efficacy with toxicity, as higher starting doses (25 mg/week versus 15 mg/week) show greater effectiveness but trend toward more gastrointestinal side effects. 1

• Target a weekly dose of at least 15 mg within 4-6 weeks to achieve optimal therapeutic benefit, with further escalation often providing additional efficacy. 1, 2
• If inadequate response occurs at oral doses of 20-25 mg/week, switch to subcutaneous or intramuscular administration before declaring treatment failure, as parenteral routes offer higher bioavailability and reduced gastrointestinal toxicity. 1, 2
• For intolerance to oral methotrexate, consider split dosing over 24 hours or subcutaneous injections before switching to alternative DMARDs. 1

Mandatory Pre-Treatment Work-Up

Before initiating methotrexate, obtain the following baseline assessments 1:

• Clinical assessment of risk factors including alcohol intake and patient education
• Laboratory tests: AST, ALT, albumin, complete blood count (CBC), creatinine
• Chest radiograph (within the previous year)
• Consider: HIV serology, hepatitis B/C serology, fasting glucose, lipid profile, pregnancy test

Essential Folic Acid Supplementation

Prescribe at least 5 mg folic acid per week with methotrexate therapy (Grade A recommendation). 1 This supplementation reduces gastrointestinal and liver toxicity without compromising efficacy. 1 Meta-analysis data shows folic acid at 7-35 mg/week significantly reduces gastrointestinal side effects (OR 0.42), and 1 mg/day protects against hepatotoxicity (OR 0.17). 1

Monitoring Requirements

Perform ALT (with or without AST), creatinine, and CBC every 1-1.5 months until a stable dose is reached, then every 1-3 months thereafter. 1 Clinical assessment for side effects and risk factors should occur at each visit. 1

Managing Liver Function Abnormalities

• Stop methotrexate immediately if confirmed ALT/AST elevation exceeds 3 times the upper limit of normal (ULN), but may reinstitute at lower dose after normalization. 1
• If ALT/AST persistently elevated up to 3 times ULN, adjust the methotrexate dose. 1
• For persistent elevation >3 times ULN after discontinuation, pursue diagnostic procedures. 1

Treatment Strategy for Rheumatoid Arthritis

In DMARD-naive patients, methotrexate monotherapy is preferred over combination with other conventional DMARDs (Grade A recommendation). 1 The efficacy/toxicity balance favors monotherapy initially. 1

• When monotherapy fails to achieve disease control, use methotrexate as the anchor for combination therapy rather than switching away entirely. 1, 2
• For patients not at target on maximally tolerated oral methotrexate, add a biologic DMARD or targeted synthetic DMARD rather than triple therapy. 1
• If a biologic or targeted synthetic DMARD fails, switch to a different class rather than another agent in the same class. 1

Defining Treatment Failure

Methotrexate is considered ineffective when 2:

• Moderate-to-high disease activity persists despite 20-30 mg/week for 3-6 months
• Failure to achieve low disease activity or remission using validated measures after adequate dose optimization
• Inadequate response persists even after switching to subcutaneous administration at optimal doses

Critical Pitfalls to Avoid

• Do not declare methotrexate failure prematurely if the patient remains on oral doses <20 mg/week, as dose escalation may provide additional benefit. 2
• Do not overlook subcutaneous administration when oral methotrexate shows inadequate response. 1, 2
• Ensure adequate folic acid supplementation, as deficiency may cause intolerance mimicking inefficacy. 2

Long-Term Safety and Special Populations

Methotrexate is appropriate for long-term use based on its acceptable safety profile (Grade B recommendation). 1 However, specific precautions apply:

Perioperative Management

Continue methotrexate in the perioperative period for RA patients undergoing elective orthopedic surgery (Grade B recommendation). 1

Pregnancy and Fertility

Discontinue methotrexate at least 3 months before planned pregnancy for both men and women, and do not use during pregnancy or breastfeeding. 1, 3 Methotrexate causes embryotoxicity, abortion, and fetal defects. 3

Elderly Patients

Use caution in elderly patients due to 3, 4:

• Greater frequency of decreased hepatic and renal function
• Decreased folate stores
• Higher risk of bone marrow suppression, thrombocytopenia, and pneumonitis with advancing age
• Consider more accurate renal function assessment (creatinine clearance) rather than serum creatinine alone, as measurements may overestimate function in elderly patients. 3

Renal Impairment

• Contraindicated if eGFR <30 mL/minute in RA patients. 5
• For eGFR 30-59 mL/minute, use lower initial doses with more gradual escalation and closer monitoring. 5
• Methotrexate elimination is reduced in renal impairment, ascites, or pleural effusions, requiring dose reduction or discontinuation. 3

Serious Toxicities and Management

Hematologic Toxicity

Stop methotrexate immediately if significant drop in blood counts occurs in psoriasis or RA patients. 3 Methotrexate can cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and thrombocytopenia. 3

Pulmonary Toxicity

Interrupt treatment immediately if pulmonary symptoms develop, particularly dry, nonproductive cough, as methotrexate-induced lung disease may occur at any time and is not always reversible. 3 Fatalities have been reported. 3

Gastrointestinal Toxicity

Discontinue methotrexate until recovery if vomiting, diarrhea, or stomatitis causes dehydration. 3 Diarrhea and ulcerative stomatitis require interruption to prevent hemorrhagic enteritis and intestinal perforation. 3

Hepatotoxicity

Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis after prolonged use. 3 Liver enzyme elevations are frequently transient and asymptomatic but do not predict subsequent hepatic disease. 3

Drug Interactions

High-Risk Combinations

• Avoid concomitant NSAIDs in high-dose methotrexate, as unexpectedly severe bone marrow suppression and gastrointestinal toxicity have been reported. 3
• Exercise extreme caution with trimethoprim/sulfamethoxazole, which increases bone marrow suppression through decreased tubular secretion and additive antifolate effects. 3
• Avoid nitrous oxide anesthesia, which potentiates methotrexate effects on folate-dependent pathways, increasing risk of stomatitis, myelosuppression, and neurotoxicity. 3
• Monitor theophylline levels closely, as methotrexate decreases theophylline clearance. 3

Moderate-Risk Interactions

• Monitor closely when combining with other hepatotoxic drugs (azathioprine, retinoids, sulfasalazine). 3
• High-dose leucovorin may reduce efficacy of intrathecally administered methotrexate. 3

Other Rheumatic Indications

Methotrexate as a steroid-sparing agent is recommended (Grade B) for 1:

• Giant cell arteritis
• Polymyalgia rheumatica

Consider methotrexate for:

• Systemic lupus erythematosus
• Juvenile dermatomyositis

Cancer Indications

Methotrexate is indicated for 3:

• Gestational choriocarcinoma, chorioadenoma destruens, and hydatidiform mole
• Acute lymphocytic leukemia (prophylaxis of meningeal leukemia and maintenance therapy)
• Meningeal leukemia
• Breast cancer
• Epidermoid cancers of the head and neck
• Advanced mycosis fungoides (cutaneous T cell lymphoma)
• Lung cancer (particularly squamous cell and small cell types)
• Advanced stage non-Hodgkin's lymphomas
• Non-metastatic osteosarcoma (high-dose with leucovorin rescue post-surgical resection)

For intrathecal and high-dose therapy, use only preservative-free formulation as the preserved formulation contains benzyl alcohol, which has caused fatal "gasping syndrome" in neonates. 3

Discontinuation Rates and Efficacy

Methotrexate demonstrates substantial clinical benefit with 6:

• ACR 50 response rate 3 times higher than placebo at 52 weeks (RR 3.0; NNT 7)
• Physical function improvement (MD -0.27 on 0-3 scale; NNT 4)
• Reduced radiographic progression (RR 0.31 for erosion score increase; NNT 13)

However, 16% discontinue due to adverse events (RR 2.1 versus placebo; NNT 13), with total adverse event rates of 45% versus 15% for placebo at 12 weeks. 6 Despite this, the probability of continuing methotrexate beyond 5 years is greater than for other slow-acting antirheumatic drugs. 4