What are the uses and dosing of methotrexate (disease-modifying antirheumatic drug (DMARD)) for various conditions, including rheumatoid arthritis, psoriasis, and cancer?

Methotrexate: Clinical Uses and Dosing

Methotrexate is FDA-approved and guideline-recommended as a first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis, severe recalcitrant psoriasis, psoriatic arthritis, and various malignancies including acute lymphoblastic leukemia, non-Hodgkin's lymphoma, osteogenic sarcoma, choriocarcinoma, and breast carcinoma. 1, 2, 3

Rheumatoid Arthritis

Methotrexate is the cornerstone DMARD for rheumatoid arthritis, with superior efficacy to placebo and comparable efficacy to anti-TNF biologics. 1, 3

Dosing Protocol

• Start at 15 mg weekly orally or subcutaneously, escalating to 15-25 mg weekly based on response. 1, 4
• Subcutaneous administration may be preferred if oral bioavailability is inadequate 1
• At 1 year, one-third of patients show no radiographic progression 3

Mandatory Folate Supplementation

• Administer at least 5 mg folic acid per week (daily dosing except on methotrexate day) to reduce gastrointestinal and hepatic toxicity without compromising efficacy. 1, 5, 4

Monitoring Requirements

• Baseline: CBC with differential, creatinine, liver function tests (including albumin and bilirubin), hepatitis B/C serology, tuberculosis screening (PPD), chest radiograph if pulmonary disease suspected. 1, 4
• Ongoing: CBC and liver enzymes every 1-1.5 months initially, then every 1-3 months once stable; creatinine every 2-3 months. 1, 4
• Withhold methotrexate if WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or MCV >105 fL. 5, 4

Psoriasis and Psoriatic Arthritis

Methotrexate was FDA-approved in 1972 specifically for severe, recalcitrant, disabling psoriasis and is particularly effective for acute generalized pustular psoriasis, psoriatic erythroderma, and extensive chronic plaque psoriasis. 1, 6

Dosing for Psoriasis

• Typical dosing ranges from 7.5-25 mg weekly, achieving 60% PASI 75 response at 16 weeks. 6
• Although only two small controlled trials exist for psoriatic arthritis, methotrexate is commonly used as primary therapy 1

Hepatotoxicity Monitoring (Critical for Psoriasis Patients)

• Baseline liver biopsy only indicated if significant pre-existing liver disease. 1
• For patients without risk factors (diabetes, obesity, excessive alcohol, chronic liver disease): consider liver biopsy after cumulative dose of 3.5-4 g, then after each subsequent 1.5 g. 1
• For high-risk patients: consider baseline or 6-month biopsy, with subsequent biopsies after 1-1.5 g cumulative dose. 1
• If persistently abnormal liver enzymes for 2-3 months, liver biopsy required before continuing therapy 1

Malignancies

Methotrexate is used for acute lymphoblastic leukemia, non-Hodgkin's lymphoma, osteogenic sarcoma, choriocarcinoma, breast carcinoma, lung carcinoma, and intrathecal chemotherapy for CNS prophylaxis. 2, 7

High-Dose Methotrexate (≥500 mg/m²)

• Used in oncology for enhanced efficacy 8
• Requires leucovorin rescue: initial dose up to 100 mg/m² IV, then every 6 hours until methotrexate levels <0.05 µmol/L 1
• Maintain hydration and consider urine alkalinization with sodium bicarbonate to prevent renal tubular precipitation 1

Other Rheumatic and Autoimmune Conditions

Methotrexate serves as a steroid-sparing agent in dermatomyositis, Wegener's granulomatosis, sarcoidosis, systemic scleroderma, and juvenile rheumatoid arthritis (FDA-approved). 1, 2, 7

Critical Contraindications

Absolute Contraindications

• Pregnancy (Category X) or nursing 1, 4
• Cirrhosis 1
• eGFR <30 mL/minute 8

Pregnancy Planning

• Both men and women must discontinue methotrexate 3 months before attempting conception to allow complete elimination and restoration of spermatogenesis. 1
• If pregnancy occurs before 3 months, genetic counseling is mandatory 1

Drug Interactions Increasing Toxicity

The following medications increase methotrexate toxicity by decreasing protein binding or renal excretion: 1

• NSAIDs (salicylates, naproxen, ibuprofen, indomethacin)
• Antibiotics (trimethoprim/sulfamethoxazole, sulfonamides, penicillins, minocycline, ciprofloxacin)
• Diuretics (furosemide, thiazides)
• Other: barbiturates, colchicine, dipyridamole, ethanol, phenytoin, probenecid

Renal Impairment Dosing

• eGFR 30-59 mL/minute: reduce initial dose, monitor closely, use gradual dose escalation with lower weekly maximum. 8
• eGFR <30 mL/minute: contraindicated. 8
• 85% of methotrexate is renally excreted, making renal function critical 1

Pediatric Use

Methotrexate is FDA-approved for juvenile rheumatoid arthritis and well-tolerated in children for various dermatologic and rheumatologic conditions. 1

• Primary side effects: abnormal liver function, stomatitis, gastrointestinal irritation 1
• Most pediatric patients can follow adult monitoring guidelines for those without hepatotoxicity risk factors 1

Combination Therapy

With Biologics

• Methotrexate combined with TNF antagonists (etanercept, adalimumab, infliximab) or ustekinumab improves efficacy and reduces immunogenicity of monoclonal antibodies, though this is off-label. 1, 6
• Significantly more patients achieve PASI 75 with combination therapy versus tapered methotrexate 1

Infection Management

• Temporarily discontinue methotrexate during severe infections or infections not responding to standard treatment; resume after complete resolution. 1, 4
• Opportunistic infections can occur, typically within first 12 weeks but risk persists throughout treatment 1

Overdose Management

If ≥1 mg/kg ingested within 1 hour: 1

• Administer activated charcoal immediately
• Hospital admission with serum methotrexate levels at 4 hours post-ingestion
• Calcium folinate (folinic acid) IV: initial dose up to 100 mg/m², then every 6 hours until levels <0.05 µmol/L
• Most effective when initiated within hours; doubtful efficacy after 24 hours
• Maintain hydration and consider urine alkalinization
• Filgrastim 5 µg/kg/day subcutaneously for bone marrow suppression
• High mortality risk—monitor for sepsis