What is methotrexate?

What is Methotrexate

Methotrexate is a folic acid antagonist that functions as an antimetabolite, immunosuppressant, and disease-modifying antirheumatic drug (DMARD), FDA-approved in 1972 for psoriasis and widely used for rheumatoid arthritis, inflammatory bowel disease, and other autoimmune conditions. 1, 2

Mechanism of Action

Methotrexate works through multiple pathways depending on the dose administered:

• At low doses (<25 mg/week), methotrexate primarily acts as an immunosuppressant by inhibiting dihydrofolate reductase, which decreases folate cofactors required for DNA and RNA synthesis, ultimately suppressing lymphocyte proliferation rather than affecting keratinocytes directly 1

• Polyglutamate derivatives of methotrexate potently inhibit 5-aminoimidazole-4-carboxamide ribonucleotide transformylase, resulting in increased endogenous adenosine—a key anti-inflammatory molecule 1

• Recent evidence suggests methotrexate inhibits JAK/STAT pathway activity, which is central to both inflammatory and immune system signaling, potentially explaining much of its DMARD activity 3

Clinical Indications

FDA-Approved Uses

• Neoplastic diseases (as chemotherapy at high doses) 2
• Severe psoriasis (moderate-to-severe plaque psoriasis, pustular psoriasis, psoriatic erythroderma) 1
• Adult rheumatoid arthritis (as first-line DMARD therapy) 1, 4

Off-Label Uses Supported by Guidelines

• Atopic dermatitis at 10-25 mg/week 5
• Crohn's disease at 25 mg/week intramuscularly for induction, 15 mg/week for maintenance 1, 5
• Psoriatic arthritis (peripheral arthritis, though less effective than TNF-inhibitors) 1
• Steroid-refractory chronic graft-versus-host disease at 5-10 mg/m² 1
• Giant-cell arteritis, polymyalgia rheumatica, systemic lupus erythematosus, and dermatomyositis as steroid-sparing agents 1

Standard Dosing Regimens

Rheumatoid Arthritis

• Start at 10-15 mg orally once weekly, escalate by 5 mg every 2-4 weeks up to 20-30 mg/week based on clinical response and tolerability 1, 5
• Parenteral administration (subcutaneous or intramuscular) should be considered if inadequate response or intolerance to oral dosing 1

Psoriasis

• Typical range is 7.5-25 mg weekly as a single dose or divided into 3 doses over 24 hours 1
• A test dose of 2.5 mg should be considered, especially in patients with impaired kidney function 1
• 10 mg weekly dosing is slower-acting than 25 mg weekly but causes fewer severe adverse effects 1

Crohn's Disease

• Induction: 25 mg intramuscularly once weekly for 16-24 weeks 1
• Maintenance: 15 mg intramuscularly once weekly for up to 40 weeks 1

Mandatory Folic Acid Supplementation

All patients on methotrexate must receive folic acid supplementation to reduce gastrointestinal, hepatic, and hematologic toxicity without compromising efficacy:

• At least 5 mg folic acid per week (strong recommendation) 1, 5
• Alternative dosing: 1 mg daily (except on the day of methotrexate administration) 5, 6
• Large doses of folic acid may reduce methotrexate efficacy, so dosing should remain within recommended ranges 1

Common Adverse Effects

Gastrointestinal (Most Common)

• Nausea, vomiting, diarrhea, stomatitis occur in up to 25-32% of patients 1, 5, 6
• Management strategies include splitting the weekly dose over 12-24 hours, administering with food or at bedtime, ensuring folic acid supplementation, or switching to parenteral administration 1, 6

Hepatotoxicity

• Liver enzyme elevations are common but often transitory; only 5% require permanent discontinuation 6
• Methotrexate should be stopped if transaminases exceed 3× upper limit of normal on repeat testing 1
• Baseline liver biopsy is not recommended regardless of risk factors 1

Hematologic Toxicity

• Myelosuppression accounts for the majority (67 of 164 cases) of methotrexate-associated fatalities 6
• Withhold methotrexate if WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L 6

Pulmonary Toxicity

• Pneumonitis and fibrosis are rare but serious, accounting for 30 of 164 methotrexate-associated fatalities 6
• Baseline chest x-ray should be obtained for all patients starting methotrexate 1, 6
• Monitor for dyspnea, dry cough, and fever as warning signs 6

Monitoring Requirements

Initial Phase (First 3 Months)

• Complete blood count, liver function tests (AST, ALT, albumin), and creatinine at least monthly 1, 5
• Weeks 2,4,8, and 12 after initiation per British Society of Gastroenterology 6

Maintenance Phase

• CBC and liver function tests every 1-3 months depending on dose stability 1, 5
• Renal function (creatinine, eGFR) every 2-3 months 5
• Annual hepatotoxicity screening with noninvasive methods (vibration-controlled transient elastography) for high-risk patients 1

Absolute Contraindications

• Pregnancy and breastfeeding (methotrexate is teratogenic at all gestational ages) 1, 5
• Women must wait at least 3 months after discontinuation before attempting conception 1, 5
• Men should wait 3 months after discontinuation before attempting to father children 5, 6
• Severe renal impairment (eGFR <20 mL/min) 1, 5
• Significant hepatic damage or cirrhosis 5
• Bone marrow suppression (anemia, leukopenia, thrombocytopenia) 5

Critical Drug Interactions

• Trimethoprim-sulfamethoxazole is absolutely contraindicated due to severe bone marrow suppression risk 1, 6
• NSAIDs reduce renal elimination of methotrexate, particularly dangerous with any dose; however, some NSAIDs like celecoxib do not interact 1, 6
• Other high-risk interactions include salicylates, sulfonamides, penicillins, probenecid, and colchicine 6

Dose Adjustments for Renal Impairment

eGFR (mL/min/1.73 m²)	Dose Adjustment
>90	Normal dose
20-50	Half dose
<20	Avoid methotrexate

1, 5

Comparative Efficacy

• Methotrexate is less effective than adalimumab and infliximab for cutaneous psoriasis 1
• In rheumatoid arthritis, methotrexate monotherapy has comparable efficacy to other DMARDs and should be considered the anchor for combination therapy when monotherapy fails 1, 4
• At 1 year, one-third of RA patients on methotrexate have no radiographic progression 7
• ACR 50 response rate at 52 weeks is 3 times higher with methotrexate versus placebo (RR 3.0,95% CI 1.5-6.0) 4

Long-Term Safety Profile

• Methotrexate is appropriate for long-term use based on its acceptable safety profile when properly monitored 1
• Can be safely continued perioperatively in RA patients undergoing elective orthopedic surgery 1
• Risk of malignancy (particularly lymphoma) appears consistent with background population rates in psoriasis patients, though vigilance is advisable 1