Methotrexate is a disease-modifying antirheumatic drug (DMARD) and antimetabolite used weekly at low doses to treat rheumatoid arthritis and psoriasis, and at higher doses for certain cancers. It works by blocking folate metabolism and reducing inflammatory cell activity. It requires regular blood monitoring for liver and bone marrow toxicity and is absolutely contraindicated in pregnancy.
Methotrexate
What Is Methotrexate?
Methotrexate (MTX) has a long history spanning more than 70 years. Originally developed as a chemotherapy agent in the late 1940s and used to treat childhood leukemia, it was later found — at much lower once-weekly doses — to be a powerful anti-inflammatory agent for autoimmune diseases. Today it occupies two distinct roles in medicine: as a conventional immunosuppressive DMARD for rheumatic and dermatologic conditions, and as a chemotherapy backbone for certain malignancies.
In rheumatology, methotrexate is the anchor DMARD — the first disease-modifying drug tried in most patients with rheumatoid arthritis and many other inflammatory joint diseases. It is inexpensive, widely available, extensively studied, and effective both as a monotherapy and in combination with biologic agents. Its once-weekly schedule (taken on the same day each week) distinguishes it from most other oral medications taken daily.
For psoriasis, both oral and injectable methotrexate can produce significant clearance of plaques and is considered alongside biologic therapies in moderate-to-severe cases. At chemotherapy doses, it is used in protocols for acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, and other cancers — at exposures far higher than those used in rheumatology.
Uses & Indications
FDA-approved indications for methotrexate span rheumatology, dermatology, and oncology. In inflammatory disease, it is used for its ability to slow or halt disease progression — not just to control symptoms. In cancer treatment it is used for its cytotoxic properties at higher exposures.
- Rheumatoid arthritis (RA) — first-line DMARD; reduces joint inflammation, slows structural damage (erosions), and improves physical function
- Psoriatic arthritis — treats both joint and skin manifestations
- Plaque psoriasis — reduces skin cell turnover and inflammation; used in moderate-to-severe disease
- Juvenile idiopathic arthritis (JIA) — widely used in children with polyarticular disease
- Inflammatory myopathies (polymyositis, dermatomyositis) — as a steroid-sparing agent
- Ectopic pregnancy — medical treatment to terminate ectopic implantation
- Acute lymphoblastic leukemia (ALL) — component of induction, consolidation, and maintenance regimens
- Non-Hodgkin lymphoma, osteosarcoma, meningeal cancer — high-dose protocols with leucovorin rescue
How It Works
Methotrexate is a folate antagonist. It competitively inhibits dihydrofolate reductase (DHFR), the enzyme that converts dihydrofolate to tetrahydrofolate — the active form cells need for purine and thymidylate synthesis. Without adequate tetrahydrofolate, rapidly dividing cells cannot replicate their DNA. In cancer treatment, this cytotoxic effect is the primary mechanism. In inflammatory disease, the same anti-proliferative action slows the expansion of activated immune cells.
Inside cells, methotrexate is converted to polyglutamated forms (MTX-PGs) that are retained intracellularly for weeks. These polyglutamates inhibit additional folate-dependent enzymes, including AICAR transformylase. Inhibition of AICAR transformylase leads to accumulation of AICAR, which promotes the release of adenosine — a potent endogenous anti-inflammatory mediator. This adenosine pathway is thought to be responsible for much of methotrexate's anti-inflammatory effect at the low doses used in rheumatology, rather than direct cytotoxicity.
Folic acid supplementation (taken on non-MTX days) does not meaningfully reduce methotrexate's efficacy in RA and psoriasis, but substantially reduces the risk of common side effects including nausea, mouth sores, and certain blood count changes. Most rheumatologists prescribe folic acid routinely with methotrexate.
Side Effects
Common Side Effects
- Nausea and GI upset — most common early complaint; often improves over time or with subcutaneous injection instead of oral tablets
- Oral mucositis (mouth sores) — ulcers or soreness in the mouth; folic acid supplementation reduces risk
- Fatigue — many patients report a "methotrexate day" of low energy the day after their dose
- Headache and dizziness — typically transient after each dose
- Increased sun sensitivity (photosensitivity) — especially relevant for psoriasis patients
- Hair thinning — diffuse, usually mild; not the same as chemotherapy-level hair loss
Serious Side Effects
SERIOUS RISKS — REGULAR MONITORING REQUIRED: Methotrexate can cause life-threatening liver damage (hepatotoxicity), lung inflammation (methotrexate pneumonitis), and bone marrow suppression. It is a known teratogen — it causes fetal death or severe birth defects and must be stopped well before any planned pregnancy in both men and women. Patients must have regular blood tests (CBC, liver enzymes, creatinine) throughout treatment. Alcohol must be strictly avoided due to additive hepatotoxicity.
- Hepatotoxicity — cumulative liver damage is the primary long-term concern at low doses; risk increased significantly by alcohol use, obesity, diabetes, and pre-existing liver disease. Periodic liver enzyme monitoring is required; guidelines recommend liver biopsy or FibroScan evaluation after significant cumulative doses in high-risk patients
- Methotrexate pneumonitis — an idiosyncratic, potentially serious lung reaction; presents as dry cough, shortness of breath, and fever, usually within the first year. Not dose-related. Requires immediate discontinuation
- Bone marrow suppression — suppression of white blood cells, red blood cells, and platelets; risk greatly increased by renal impairment (methotrexate is renally cleared) and drug interactions (especially trimethoprim-sulfamethoxazole)
- Teratogenicity — methotrexate is a known human teratogen; causes spontaneous abortion, fetal death, and major fetal abnormalities. Contraindicated in pregnancy; contraception required during treatment and for a period afterward
- Opportunistic infections — immune suppression increases risk of infections including Pneumocystis pneumonia (PCP) in some protocols
Drug Interactions
Methotrexate has several clinically important drug interactions, primarily related to competition for renal tubular secretion and additive toxicity. Patients must inform all healthcare providers they are taking methotrexate before starting any new medication.
| Drug / Class | Interaction | Clinical Significance |
|---|---|---|
| Trimethoprim-sulfamethoxazole (Bactrim) | Both drugs inhibit folate metabolism; combination dramatically increases risk of bone marrow suppression and mucositis | High — generally avoid; if antibacterial coverage is needed, use alternatives |
| NSAIDs (ibuprofen, naproxen, etc.) | NSAIDs reduce renal blood flow and compete for tubular secretion, reducing methotrexate clearance and raising plasma levels | Moderate–High — chronic combined use warrants careful monitoring; acute short courses are often used but patients should be aware |
| Proton pump inhibitors (omeprazole, etc.) | PPIs may reduce renal tubular secretion of methotrexate, increasing exposure; primarily a concern at higher doses | Moderate — monitor at higher doses; H2 blockers are an alternative |
| Penicillins (amoxicillin, etc.) | Penicillins compete with methotrexate for renal tubular secretion, potentially raising MTX levels | Moderate — monitor for toxicity signs if combined |
| Leflunomide | Additive hepatotoxicity; combination increases risk of liver damage | High — combination requires careful monitoring; sometimes used intentionally in RA with close surveillance |
| Alcohol | Additive hepatotoxicity; significantly increases risk of liver fibrosis and cirrhosis | High — alcohol should be strictly avoided during methotrexate therapy |
Warnings & Contraindications
Contraindications
- Pregnancy — teratogen; absolute contraindication
- Breastfeeding
- Significant renal impairment (methotrexate is primarily renally cleared; accumulation causes severe toxicity)
- Pre-existing significant hepatic disease or cirrhosis
- Active serious infections
- Immunodeficiency syndromes
- Bone marrow hypoplasia or significant blood count abnormalities
- Hypersensitivity to methotrexate
Required Monitoring
- CBC with differential and platelets — baseline and periodically throughout therapy
- Hepatic function panel (AST, ALT, albumin, bilirubin) — baseline and periodically
- Serum creatinine / estimated GFR — baseline and periodically
- Chest X-ray at baseline (pulmonary baseline for pneumonitis comparison)
Frequently Asked Questions
Why is methotrexate taken only once a week for arthritis?
At low doses used in rheumatology, methotrexate is given once weekly — a critically important schedule. The weekly interval allows the body time to recover from the transient effects on normal rapidly-dividing cells (gut lining, bone marrow), reducing toxicity while maintaining the anti-inflammatory benefit. Taking it daily at these doses would substantially increase the risk of serious side effects. Missing a dose or accidentally taking a double dose can be dangerous — patients should always confirm the once-weekly schedule with their provider.
What is methotrexate used for?
Methotrexate treats rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, and juvenile idiopathic arthritis at low weekly doses. At higher doses used in oncology, it treats acute lymphoblastic leukemia, certain lymphomas, and osteosarcoma. It is also used medically to treat ectopic pregnancy.
How does methotrexate work?
Methotrexate blocks dihydrofolate reductase (DHFR), disrupting DNA synthesis in rapidly dividing cells. At anti-inflammatory doses, it also promotes adenosine release — a potent anti-inflammatory mediator — through inhibition of AICAR transformylase. Its intracellular polyglutamate forms persist for weeks, which partly explains its weekly dosing schedule in arthritis.
What are the side effects of methotrexate?
Common side effects include nausea, fatigue, mouth sores, and mild hair thinning — most can be reduced by taking folic acid on non-methotrexate days and switching to subcutaneous injection if oral causes GI upset. Serious risks include liver damage (worsened by alcohol), lung inflammation, and bone marrow suppression. Regular blood test monitoring is essential.
Can I drink alcohol while taking methotrexate?
No. Alcohol should be strictly avoided during methotrexate therapy. Both methotrexate and alcohol are independently hepatotoxic, and their combination significantly increases the risk of serious liver damage, fibrosis, and cirrhosis — even at the low doses used for arthritis. This is one of the most important lifestyle restrictions for patients taking methotrexate long-term.