Methotrexate: How a Low Weekly Dose Works in Rheumatoid Arthritis and Other Conditions

Table of Contents

1. One Drug at Two Very Different Doses
2. How the Low Weekly Dose Is Thought to Work
3. What the Trials Show in Rheumatoid Arthritis
4. Psoriasis and Psoriatic Arthritis
5. The Once-Weekly Schedule and the Daily-Dosing Error
6. Tablets and Injections Compared
7. Folic Acid Alongside Methotrexate
8. Side Effects and Monitoring on the Label
9. Alcohol and the Liver
10. Pregnancy, Contraception and Breastfeeding
11. Drug Interactions Named on the Label
12. Key Research Papers
13. Connections
14. Featured Videos

One Drug at Two Very Different Doses

Methotrexate is a folate antagonist. Folate (vitamin B9) has to be converted by an enzyme called dihydrofolate reductase into its working form before cells can use it to build the purines and thymidine that go into new DNA. Methotrexate blocks that enzyme. The prescribing information describes the result plainly: methotrexate “interferes with DNA synthesis, repair, and cellular replication,” and fast-dividing tissues — cancer cells, bone marrow, the lining of the mouth and gut, the cells of a developing baby, and the bladder lining — are the most sensitive to it.

That single fact explains both of the drug’s lives:

• Cancer use. In cancer care, methotrexate is used to stop dividing cells. High-dose intravenous regimens in hospital use hundreds of milligrams or more per square metre in a single treatment. Even the tablet label lists cancer uses: as part of maintenance chemotherapy for acute lymphoblastic leukemia (a recommended dosage of 20 mg per square metre of body surface once weekly), for mycosis fungoides (a skin lymphoma), and in a low-dose “metronomic” combination for relapsed non-Hodgkin lymphoma.
• Inflammatory disease. The label’s other indications are adults with rheumatoid arthritis, children with polyarticular juvenile idiopathic arthritis, and adults with severe psoriasis. Here the recommended starting dosage in rheumatoid arthritis is 7.5 mg once weekly — a small fraction of a cancer dose, taken on one day of the week.

Rheumatologists also prescribe it widely for psoriatic arthritis and other inflammatory conditions. Psoriatic arthritis is not one of the indications listed on the US tablet label, and the trial evidence for it is weaker than for rheumatoid arthritis (see below).

The tablet is absorbed incompletely: the label gives a mean bioavailability of about 60% at doses of 30 mg per square metre or less, with peak blood levels 0.75 to 6 hours after a dose. Food delays absorption and lowers the peak. Methotrexate itself leaves the blood quickly — the label gives an elimination half-life of about 3 to 10 hours — but inside cells it is converted into “polyglutamate” forms that, in the label’s words, “may remain in tissues for extended periods.” That long tail inside cells is part of why a dose once a week is enough, and part of why a daily dose is dangerous. The kidneys clear most of the drug, which is why kidney function matters so much (see side effects and monitoring).

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How the Low Weekly Dose Is Thought to Work

The prescribing information is candid: “The mechanism of action in rheumatoid arthritis and in psoriasis is unknown.” The doses used in arthritis are low enough that it is hard to explain the benefit purely as cell killing, and researchers have spent four decades looking for the real reason.

The adenosine explanation. The best-studied idea came from Bruce Cronstein’s laboratory. In a 1993 study in mice, animals given methotrexate for three to four weeks built up a molecule called AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) inside their cells. When an inflammatory irritant was injected into a small air pocket under the skin of these mice, the fluid contained more adenosine, and far fewer white blood cells gathered there. Adenosine is a natural “calm down” signal: it acts on receptors on white blood cells and damps their inflammatory activity. Two experiments in the same mice pointed to adenosine as the cause: breaking down the adenosine with an enzyme partly reversed methotrexate’s effect, and a drug blocking the adenosine A2 receptor reversed it completely. The authors concluded that methotrexate’s anti-inflammatory action in that model was due to increased adenosine release at inflamed sites.

This explains a few practical observations: why benefit takes weeks to build (the label notes that most responses in rheumatoid arthritis appeared between 3 and 6 weeks, and some as late as 12 weeks), and why the drug can calm inflammation without destroying the immune system.

Several mechanisms at once. A 2020 review by Cronstein and Aune describes adenosine release as one of several candidate mechanisms, alongside inhibition of purine and pyrimidine synthesis, effects on methylation reactions, reduced movement of the inflammatory switch NF-κB (nuclear factor kappa B) into the cell nucleus, effects on JAK-STAT (Janus kinase–signal transducer and activator of transcription) signalling and nitric oxide production, and changes in certain long non-coding RNAs. The same review states that low-dose methotrexate “remains the gold standard in RA therapy” and that it enhances the effect of most biologic agents. The honest summary is that no single mechanism has been proven to be the whole story in people.

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What the Trials Show in Rheumatoid Arthritis

The first convincing trial. In 1985 Weinblatt and colleagues published a 24-week double-blind crossover trial in 28 people with rheumatoid arthritis that had not responded to earlier treatments. The trial gave oral methotrexate as 2.5 to 5 mg every 12 hours for three doses each week. Compared with placebo, it reduced tender and painful joints, morning stiffness and disease activity; swollen joints and walking time improved too. Side effects during methotrexate included raised liver enzymes (21%), nausea (18%) and diarrhea (12%). The authors noted that “the mechanism of action is unknown” and that longer trials would be needed.

The pooled placebo evidence. A 2014 Cochrane review pooled seven trials with 732 participants, all of whom had failed an earlier treatment, at weekly doses of 5 to 25 mg for 12 to 52 weeks. At 52 weeks, a major (50%) improvement by American College of Rheumatology criteria was three times more likely on methotrexate than on placebo — 15 more people out of 100 reached it. Physical function and the physical part of quality-of-life scores improved, and fewer people had worsening joint erosions on X-ray (8 fewer per 100). The cost was tolerability: 16% of people on methotrexate stopped because of side effects against 8% on placebo, and any side effect at 12 weeks was reported by 45% versus 15%. Serious adverse events were 3% versus 2%, a difference that was not statistically significant.

The anchor drug. The 2022 EULAR (European Alliance of Associations for Rheumatology) recommendations state that treatment initially starts with methotrexate plus a glucocorticoid. If the response within 3 to 6 months is not enough and poor prognostic factors are present, a biologic is added to the conventional drug rather than replacing it. The 2021 American College of Rheumatology guideline, with 44 recommendations (7 strong and 37 conditional), also covers how these drugs are used in people with liver disease, lung disease and other high-risk conditions.

NORD-STAR. The clearest modern test of how far methotrexate-based treatment goes is the NORD-STAR trial, run by doctors (not by a manufacturer) in 29 rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands and Iceland between 2012 and 2018. It enrolled 812 people with newly diagnosed rheumatoid arthritis who had never been treated; their mean age was 54.3 years and 68.8% were women. Every participant started methotrexate. They were randomly assigned to add one of four partners:

• active conventional treatment — either prednisolone tapered to 5 mg a day, or sulfasalazine plus hydroxychloroquine plus steroid injections into swollen joints;
• certolizumab pegol (a tumour necrosis factor blocker);
• abatacept (which blocks a T-cell activation signal);
• tocilizumab (an interleukin-6 blocker).

The main outcome was strict remission by the Clinical Disease Activity Index at 24 weeks. Adjusted remission rates were:

Only abatacept showed a higher remission rate than conventional treatment (a 9.4 percentage-point difference, with a confidence interval running from 0.1 to 18.7). Conventional treatment was shown to be non-inferior to certolizumab pegol and tocilizumab, though not to abatacept. The authors concluded that the results “highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids” in early, untreated rheumatoid arthritis. In plain terms: in this trial, roughly four in ten newly diagnosed people reached strict remission at six months with methotrexate plus inexpensive conventional partners, and of the three biologics only abatacept added a measurable improvement on top.

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Psoriasis and Psoriatic Arthritis

Psoriasis. Severe psoriasis is a labelled indication; the label’s recommended tablet dosage is 10 to 25 mg once weekly, not exceeding 30 mg per week, reduced to the lowest effective dose once the skin responds. For many years the trial evidence was thin. The METOP trial (2017) tested injected methotrexate under the skin in 120 adults with moderate to severe plaque psoriasis who had never taken it. The trial gave a starting dose of 17.5 mg per week, with an increase to 22.5 mg allowed after 8 weeks, together with folic acid 5 mg per week. At 16 weeks, a 75% improvement in the Psoriasis Area and Severity Index was reached by 41% on methotrexate versus 10% on placebo. Over 52 weeks there were no deaths, serious infections, cancers or major heart events in the trial, and serious adverse events were recorded in 3% of those treated for the full year.

The label carries skin-specific findings for psoriasis: ultraviolet light exposure while taking methotrexate may aggravate psoriasis; the drug can cause photosensitivity and reactivation of old sunburn; and in two published psoriasis series, hair loss, photosensitivity and “burning of skin lesions” occurred in 3% to 10% each. It also states that in psoriasis, liver scarring may occur without symptoms or abnormal liver tests (see alcohol and the liver).

Psoriatic arthritis. Here the evidence is mixed. The MIPA trial, published in 2012 as the first large placebo-controlled trial of methotrexate in psoriatic arthritis, randomised 221 people to 15 mg per week or placebo for 6 months. It found no significant effect on its main joint outcome or on tender and swollen joint counts, blood inflammation markers, function or pain. Methotrexate did improve the patients’ and assessors’ overall ratings and the skin scores. The authors wrote that the trial “found no evidence for MTX improving synovitis” (joint-lining inflammation) and raised questions about classing it as disease-modifying in psoriatic arthritis. Forty-four patients were lost to follow-up (21 on methotrexate, 23 on placebo). Methotrexate nevertheless remains in common use for psoriatic arthritis, and the 2020 Cronstein and Aune review describes it as generally first-line there; the full picture is on the psoriatic arthritis page.

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The Once-Weekly Schedule and the Daily-Dosing Error

The most important practical fact about low-dose methotrexate is printed in the drug’s boxed warning, the strongest warning the US Food and Drug Administration (FDA) requires: “Methotrexate tablets when inadvertently administered once daily have resulted in death.” The warnings section adds that deaths from medication errors occurred “most commonly” in patients “taking methotrexate daily when a weekly dosing regimen was prescribed.” The patient Medication Guide puts it in everyday words: for rheumatoid arthritis, juvenile arthritis and severe psoriasis, the dose is taken one time each week, on the same day of the week, and “severe side effects and death have happened in people who have mistakenly taken methotrexate tablets every day instead of 1 time each week.”

Why is the error so dangerous? Almost every other tablet people take is daily, so a weekly drug is easy to misread — by the patient, by a carer filling a pill organiser, or by a professional renewing a prescription or giving a dose in hospital. Seven days of a weekly dose means a week’s exposure becomes seven weeks’ worth, and because the drug lingers inside cells as polyglutamates, the bone marrow and the lining of the mouth and gut take the full force.

What the error looks like in real cases. French poison-control and drug-safety centres reviewed 74 people with low-dose methotrexate errors (more than twice the intended weekly dose, or 30 mg or more in a week). The causes were:

• misunderstanding of the weekly schedule by patients or home carers — 56.2%;
• an erroneous prescription renewal — 23.3%;
• a wrong dose given by a health professional — 20.5%.

Seventy of the 74 had taken methotrexate daily, at a mean of 9.6 mg a day for a mean of 11.7 days. Sixty-one (82%) developed complications, 46 of them severe, and nine people died between 11 and 45 days after the first wrong dose. Those with severe outcomes were older on average (75.6 versus 69.5 years) and had taken a higher cumulative dose. The authors noted that the errors persisted “despite several warnings from drug agencies.”

The antidote. The label’s overdose section names leucovorin and levoleucovorin (active forms of folate that bypass the blocked enzyme), given as soon as possible after an overdose and guided by blood creatinine and methotrexate levels. Glucarpidase, an enzyme that breaks methotrexate down, is named for toxic blood concentrations when the kidneys are clearing the drug too slowly. The label lists the signs of overdose as mainly blood and gut effects — low white cells and platelets, anemia, mouth sores and ulcers, nausea, vomiting and gut bleeding — and notes that some people had no symptoms at first.

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Tablets and Injections Compared

Methotrexate can be swallowed or injected under the skin. Because tablet absorption is incomplete and becomes less efficient at higher doses, an injection delivers more of the same dose into the body. The tablet label notes that when switching from tablets to an injected form, “an alternative dosing regimen may be necessary.”

The head-to-head trial. A six-month double-blind trial by Braun and colleagues (2008) randomised 375 people with active rheumatoid arthritis who had never taken methotrexate to 15 mg per week either as tablets or as an injection under the skin, each with a dummy of the other form. At 24 weeks:

• a 20% improvement by American College of Rheumatology criteria was reached by 78% with the injection versus 70% with tablets;
• a 70% improvement was reached by 41% versus 33%;
• in people who had had the disease for 12 months or longer, the 20% response rates were 89% versus 63%.

Non-responders at week 16 were switched (tablets to injection, or 15 to 20 mg by injection), and 30% and 23% of them then responded. The rate of adverse events was similar in all groups.

The wider literature. A 2009 systematic review of 38 publications by Visser and van der Heijde found that starting at 25 mg per week, or escalating quickly by 5 mg a month to 25–30 mg, gave larger clinical effects but more gut side effects than starting at 5–15 mg or escalating slowly. In early rheumatoid arthritis, starting with 15 mg per week by injection rather than by mouth was associated with higher efficacy but also more withdrawals due to toxicity. In long-standing disease, switching people who had failed 15–20 mg by mouth to 15 mg by intramuscular injection did not improve efficacy. The review’s authors described a regimen of starting at 15 mg orally, escalating by 5 mg per month to 25–30 mg or the highest tolerated dose, with a switch to injection for an insufficient response, as the evidence-based approach. The US tablet label, by contrast, starts at 7.5 mg and states that doses above 20 mg once weekly carry an increased risk of serious adverse reactions, including bone-marrow suppression.

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Folic Acid Alongside Methotrexate

It sounds contradictory to give a vitamin alongside a drug that blocks that vitamin, and in cancer care it is: the label states that folic acid products “may decrease the clinical effectiveness of methotrexate” in cancer, where they are taken only when the treating team directs it. In rheumatoid arthritis, juvenile arthritis and psoriasis the label says the opposite: “Folate deficiency may increase methotrexate adverse reactions. Administer folic acid or folinic acid” for these conditions.

The Cochrane evidence. A 2013 Cochrane review (Shea and colleagues) pooled six double-blind placebo-controlled trials with 624 adults with rheumatoid arthritis taking up to 25 mg of methotrexate weekly, with folic or folinic acid at a low starting dose of 7 mg a week or less. Compared with placebo, supplementation:

• reduced gut side effects such as nausea, vomiting or abdominal pain by 26% in relative terms (9 percentage points absolute);
• reduced abnormal liver-enzyme rises by 76.9% relative (16 percentage points absolute);
• reduced withdrawal from methotrexate for any reason by 60.8% relative (15.2 percentage points absolute).

Mouth sores showed a trend toward reduction that was not statistically significant, and the trials reported too few blood-count problems to draw conclusions about the bone marrow. Importantly, supplementation did not appear to have a statistically significant effect on how well methotrexate controlled the arthritis — it reduced side effects without blunting the benefit. The review rated the evidence as moderate quality for most outcomes.

Folic acid is the synthetic form of folate; the natural form in food, and why the two differ, is explained on the vitamin B9 (folate) page. Folinic acid (leucovorin) is already in the reduced form the blocked enzyme would normally make.

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Side Effects and Monitoring on the Label

The boxed warning states that serious adverse reactions, including death, have been reported with methotrexate, and lists the organs to monitor: bone marrow, gut, liver, lungs, skin and kidneys. In the label’s 12- to 18-week placebo-controlled rheumatoid arthritis studies (128 patients on 7.5 to 15 mg weekly), the reactions that exceeded placebo were:

Blood counts. The label states that methotrexate can cause “severe and life-threatening” falls in red cells, white cells and platelets, and lists blood counts at baseline, periodically during treatment and as clinically indicated. The complete blood count page explains what those numbers mean.

Liver. The label describes “severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure,” states that the drug’s safety in people with liver disease is unknown, and lists liver tests at baseline and periodically.

Lungs. Pulmonary toxicity, including acute or chronic interstitial pneumonitis and “irreversible or fatal cases,” is a labelled warning. A 2014 meta-analysis of 22 randomised trials with 8,584 participants (Conway and colleagues) put this in proportion: methotrexate slightly raised the risk of any respiratory adverse event (relative risk 1.10) and of respiratory infection (1.11), and the trials that recorded pneumonitis showed a clearly higher risk (relative risk 7.81). Death from lung disease was not significantly increased (relative risk 1.53, with a wide confidence interval from 0.46 to 5.01), nor were non-infectious respiratory events overall. The label lists new or worsening cough, fever or shortness of breath as symptoms patients report to their prescriber, and the Medication Guide singles out a dry cough. Rheumatoid arthritis can itself affect the lungs; see interstitial lung disease.

Infections. The label states that people treated with methotrexate are at increased risk of “life-threatening or fatal bacterial, fungal, or viral infections,” naming among them Pneumocystis pneumonia, invasive fungal infection, hepatitis B reactivation, tuberculosis and disseminated shingles. It states that live vaccines are not recommended during treatment and that immunisations are brought up to date before starting.

Kidneys. Because the kidneys remove most of the drug, the label lists kidney function at baseline and periodically and calls for close monitoring when creatinine clearance is below 90 mL/min. Fluid collections such as ascites or a pleural effusion hold methotrexate and prolong its elimination.

Other labelled warnings. Severe skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis), nerve toxicity, secondary cancers (the label notes that some lymphoproliferative disease that arose on low-dose methotrexate regressed completely after the drug was withdrawn), impaired fertility, and severe allergic reactions including anaphylaxis, which is a contraindication.

Gut effects — diarrhea, vomiting, nausea and mouth sores — occurred in up to 10% of people treated for non-cancer conditions, according to the label, with a higher risk of severe gut reactions in people with peptic ulcer disease or ulcerative colitis.

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Alcohol and the Liver

The label’s liver warning contains one sentence about drinking: “The risk of hepatotoxicity is increased with heavy alcohol consumption.” The patient Medication Guide lists drinking alcohol-containing beverages — and any change in the amount during treatment — among the things a prescriber is told about. The label does not set a numeric limit; individual specialist societies have published their own limits, which vary from country to country.

Two further label facts bear on the liver:

• In psoriasis, liver fibrosis or cirrhosis “may occur in the absence of symptoms or abnormal liver tests,” and the risk appears to rise with the total cumulative dose, generally after 1.5 g or more. At 15 mg a week that total is reached in about two years.
• The label lists other liver-toxic medicines as a reason for close monitoring (see interactions).

In the Cochrane folic-acid review above, supplementation cut abnormal liver-enzyme rises by about three-quarters, which is one reason liver-test results on methotrexate are read alongside folate use, alcohol intake and conditions such as fatty liver disease. How the liver handles alcohol is shown step by step in the alcohol metabolism animation.

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Pregnancy, Contraception and Breastfeeding

The first point of the boxed warning is embryo-fetal toxicity: methotrexate “can cause embryo-fetal toxicity, including fetal death,” and for non-cancer conditions it is contraindicated in pregnancy. The label lists a pregnancy check in females who could become pregnant before the first dose.

The intervals on the label.

Why the long tail. The label explains that because methotrexate “is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.” Exposure in the first trimester is associated with miscarriage and with skull, face, brain, limb and sometimes heart abnormalities.

The numbers the label quotes. In a prospective multicentre study of women who took 30 mg a week or less after conception, the rate of miscarriage was 42%, compared with 22% in unexposed women with autoimmune disease and 17% in unexposed women without autoimmune disease. Among live births, the label gives adjusted odds ratios for major birth defects of 1.8 (confidence interval 0.6 to 6) against the unexposed autoimmune group and 3.1 (1 to 10) against the unexposed non-autoimmune group, with a defect rate of 2.9% after exposure. For context, the label gives the background risk in the US general population as 2% to 4% for major birth defects and 15% to 20% for miscarriage.

Breast milk. The label reports that methotrexate appears in breast milk in low amounts — the highest milk-to-plasma ratio reported was 0.08 to 1 — and that there are no data on its effects on a breastfed child or on milk production.

Fertility. The label states that methotrexate can impair fertility and cause low sperm counts and menstrual changes, and that it is not known whether this is reversible in everyone affected. How rheumatic diseases and their treatment interact with pregnancy is covered for related conditions on the lupus and pregnancy page.

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Drug Interactions Named on the Label

Most methotrexate interactions work the same way: the other medicine slows the kidneys’ removal of methotrexate, pushes it off its carrier proteins in the blood, or adds a second hit to folate metabolism. The label lists medicines that “may increase methotrexate plasma concentrations” and the risk of severe adverse reactions, and calls for close monitoring when they are combined:

• oral antibiotics (including neomycin), and penicillin or sulfonamide antibiotics;
• highly protein-bound drugs such as oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas and tetracyclines;
• probenecid;
• other antifolate drugs such as dapsone, pemetrexed, pyrimethamine and sulfonamides;
• aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs);
• proton pump inhibitors (the stomach-acid blockers);
• medicines that are toxic to the liver or to the kidneys.

Separately, the label states that nitrous oxide anesthesia potentiates methotrexate’s effect on folate pathways and advises against it in people receiving methotrexate.

Trimethoprim-sulfamethoxazole. This common antibiotic combination sits in the label’s sulfonamide category (sulfamethoxazole is a sulfonamide, a group the label names both as protein-bound drugs and as antifolates), and trimethoprim also works by blocking folate metabolism. Case reports describe severe toxicity, including one report of mouth and skin ulceration, low white cells and kidney insufficiency after the two were combined. Population data are more mixed. An Ontario study of 1,602 older adults on low-dose methotrexate who were newly given trimethoprim-sulfamethoxazole, matched to 1,602 given a cephalosporin antibiotic, found no difference in 30-day deaths (0.87% versus 0.94%), but a higher risk of hospital admission for any cause (relative risk 1.49) and of admission with a persistent infection (relative risk 2.78). A Korean study of the low preventive (“prophylactic”) dose of trimethoprim-sulfamethoxazole found cytopenia in 5.7% with the combination versus 5.0% with methotrexate alone, a difference that was not significant.

Nonsteroidal anti-inflammatory drugs. These appear on the label’s interaction list, yet the label also notes that most patients in its own rheumatoid arthritis trials were taking nonsteroidal anti-inflammatory drugs alongside methotrexate. The interaction is a reason for monitoring rather than a contraindication in the label’s wording.

Proton pump inhibitors. The clearest data come from high-dose cancer treatment. A Dutch cohort of 89 high-dose methotrexate cycles found delayed elimination in 27 (30.3%), and proton pump inhibitor use was significantly more frequent in the delayed group; low-dose aspirin showed no effect on elimination in the same study. How proton pump inhibitors work is shown in the stomach acid and proton pump inhibitor animation.

The label also cautions that folic acid lowers methotrexate’s effectiveness in cancer, and that the risk of skin cancers is further increased when cyclosporine is given to people with psoriasis who previously received methotrexate.

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Key Research Papers

1. Hetland ML, Haavardsholm EA, Rudin A, Nordström D, Nurmohamed M, Gudbjornsson B, et al. Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial. BMJ. 2020;371:m4328. PubMed PMID: 33268527
2. Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, Bombardier C, Wells GA, Tugwell P. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;2013(5):CD000951. PubMed PMID: 23728635
3. Braun J, Kästner P, Flaxenberg P, Währisch J, Hanke P, Demary W, et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008;58(1):73-81. PubMed PMID: 18163521
4. Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009;68(7):1094-9. PubMed PMID: 19033290
5. Cronstein BN, Naime D, Ostad E. The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest. 1993;92(6):2675-82. PubMed PMID: 8254024
6. Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol. 2020;16(3):145-154. PubMed PMID: 32066940
7. Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, Trentham DE. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med. 1985;312(13):818-22. PubMed PMID: 3883172
8. Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2014;2014(6):CD000957. PubMed PMID: 24916606
9. Smolen JS, Landewé RBM, Bergstra SA, Kerschbaumer A, Sepriano A, Aletaha D, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82(1):3-18. PubMed PMID: 36357155
10. Fraenkel L, Bathon JM, England BR, St Clair EW, Arayssi T, Carandang K, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2021;73(7):1108-1123. PubMed PMID: 34101376
11. Vial T, Patat AM, Boels D, Castellan D, Villa A, Theophile H, Torrents R, Kassai B. Adverse consequences of low-dose methotrexate medication errors: data from French poison control and pharmacovigilance centers. Joint Bone Spine. 2019;86(3):351-355. PubMed PMID: 30243781
12. Conway R, Low C, Coughlan RJ, O'Donnell MJ, Carey JJ. Methotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheumatol. 2014;66(4):803-12. PubMed PMID: 24757133
13. Kingsley GH, Kowalczyk A, Taylor H, Ibrahim F, Packham JC, McHugh NJ, et al. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology (Oxford). 2012;51(8):1368-77. PubMed PMID: 22344575
14. Warren RB, Mrowietz U, von Kiedrowski R, Niesmann J, Wilsmann-Theis D, Ghoreschi K, et al. An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10068):528-537. PubMed PMID: 28012564
15. Sadeghi H, Ahmadi F, McArthur E, Sontrop JM, Abdullah SS, Urquhart BL, et al. Co-prescription of low-dose methotrexate and trimethoprim-sulfamethoxazole and the 30-day risk of death among older adults: A cohort study. Br J Clin Pharmacol. 2025;91(4):1263-1271. PubMed PMID: 39647844
16. Kwon OC, Lee JS, Kim YG, Lee CK, Yoo B, Hong S. Safety of the concomitant use of methotrexate and a prophylactic dose of trimethoprim-sulfamethoxazole. Clin Rheumatol. 2018;37(12):3215-3220. PubMed PMID: 29383453
17. Hamid M, Lashari B, Ahsan I, Micaily I, Sarwar U, Crocetti J. A deadly prescription: combination of methotrexate and trimethoprim-sulfamethoxazole. J Community Hosp Intern Med Perspect. 2018;8(3):149-151. PubMed PMID: 29915656
18. Boerrigter E, Crul M. A non-interventional retrospective cohort study of the interaction between methotrexate and proton pump inhibitors or aspirin. Ann Pharm Fr. 2017;75(5):344-348. PubMed PMID: 28705331
19. US National Library of Medicine, DailyMed. Methotrexate tablets, for oral use — full prescribing information and Medication Guide (boxed warning revised 2/2026). DailyMed: methotrexate tablets

PubMed Topic Searches

1. PubMed: low-dose methotrexate in rheumatoid arthritis trials
2. PubMed: methotrexate and adenosine
3. PubMed: methotrexate weekly-to-daily dosing errors
4. PubMed: injected versus oral methotrexate
5. PubMed: folic acid with methotrexate
6. PubMed: methotrexate drug interactions

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Connections

• Drugs — the parent section for every drug page
• Rheumatoid Arthritis — the disease methotrexate anchors the treatment of
• Disease-Modifying Antirheumatic Drugs and Biologics — the wider treatment decision
• Psoriatic Arthritis — where the methotrexate evidence is mixed
• Psoriasis — a labelled indication
• Tocilizumab — one of the NORD-STAR comparison drugs
• Vitamin B9 (Folate) — the vitamin methotrexate blocks
• Liver Function Tests — the monitoring the label lists
• Complete Blood Count — the other routine check
• Acute Lymphoblastic Leukemia — the cancer use on the tablet label

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