Antimetabolites, folic acid analogues
ATC code: L01BA01 (Methotrexate)
Brand names
Trexall, Otrexup, Rasuvo
Competitive dihydrofolate reductase inhibitor. At high doses (oncology), suppresses DNA synthesis and cell proliferation. At low weekly doses (rheumatic disease), the anti-inflammatory effect predominates via adenosine accumulation and suppressed T-cell activation. Low-dose weekly therapy mandates concurrent folic acid 5 mg weekly the day after methotrexate — reduces hepatotoxicity, nausea, and stomatitis without losing efficacy.
First line
In psoriasis and psoriatic arthritis, methotrexate is first-line systemic therapy for moderate-to-severe disease per 2020 and GRAPPA 2021. In juvenile idiopathic arthritis — first-line disease-modifying therapy. Used in protocols for ANCA-associated vasculitis and giant cell arteritis.
Psoriasis and psoriatic arthritis, juvenile idiopathic arthritis, vasculitides.
First line
Per 2023 and 2021, methotrexate is the first-line anchor drug for rheumatoid arthritis. Start 7.5–15 mg weekly orally; with inadequate response or oral intolerance — subcutaneous 15–25 mg weekly. Concomitant folic acid 5 mg weekly the day after methotrexate is mandatory. Effect develops over 6–12 weeks.
Second line
In Crohn disease, methotrexate is used as a thiopurine alternative when those agents are intolerated or ineffective per 2021 and 2020. Evidence is weaker in ulcerative colitis, where methotrexate is rarely used. Dose 25 mg subcutaneously weekly.
Not recommended
Use of methotrexate in viral URI or cold is not described in any international source. The drug is an immunosuppressant with a serious side-effect profile; use outside rheumatologic, dermatologic, gastrointestinal, or oncologic indications is unacceptable.
1 pair found. Sorted from critical to minor.
Mechanism
снижают почечную элиминацию метотрексата, риск миелосупрессии и нефротоксичности резко возрастает, особенно при высокодозовых режимах.
Management
При высокодозовом метотрексате – противопоказано. При низкодозовой ревматологической терапии – контроль ОАК, креатинина, печеночных ферментов.
Boxed warning
FDA boxed warning: methotrexate is a teratogen and abortifacient, contraindicated in pregnancy (category X). Inadvertent daily dosing (instead of weekly) has caused fatal overdoses. Hepatotoxicity, myelosuppression, severe pulmonary complications, severe cutaneous reactions, and tumors (including lymphomas) occur with long-term therapy.
FDA categories were retired in 2015 (historically X). The drug is teratogenic and abortifacient. Use in pregnancy is absolutely contraindicated. Women of reproductive age require reliable contraception during therapy and for at least 6 months after discontinuation. Men: at least 3 months before planned conception. Inadvertent pregnancy on therapy — immediate discontinuation and genetic counseling.
Contraindicated during breastfeeding — the drug transfers into milk.
methotrexate is evaluated for the following indications with varying evidence strength: Rheumatoid arthritis (evidence tier A), Autoimmune conditions (evidence tier A), Inflammatory bowel disease (IBD) (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of methotrexate (≥ 1 in 100): Nausea, post-dose discomfort, Stomatitis, oral ulcers, Fatigue, Transaminase elevation, Alopecia (mild, reversible), Decreased appetite. See the Safety section for uncommon and serious reactions.
FDA categories were retired in 2015 (historically X). The drug is teratogenic and abortifacient. Use in pregnancy is absolutely contraindicated. Women of reproductive age require reliable contraception during therapy and for at least 6 months after discontinuation. Men: at least 3 months before planned conception. Inadvertent pregnancy on therapy — immediate discontinuation and genetic counseling.
Contraindicated during breastfeeding — the drug transfers into milk.
methotrexate is contraindicated in: Pregnancy and breastfeeding; Severe hepatic impairment; Severe renal impairment (eGFR below 30); Active severe infections; Active tuberculosis. Full list in the Safety section.
FDA boxed warning: methotrexate is a teratogen and abortifacient, contraindicated in pregnancy (category X). Inadvertent daily dosing (instead of weekly) has caused fatal overdoses. Hepatotoxicity, myelosuppression, severe pulmonary complications, severe cutaneous reactions, and tumors (including lymphomas) occur with long-term therapy.
rheumatic doses are 100–500 fold lower than oncology doses. The side-effect profile at these doses is fundamentally different — manageable and largely preventable.
moderate occasional intake (1–2 drinks weekly) is acceptable; regular heavy drinking raises hepatotoxicity risk and is contraindicated.
folic acid 5 mg is taken once weekly on the day after methotrexate — this regimen reduces adverse effects without compromising therapeutic effect per EULAR.