Glossary
Methotrexate
What the research found.
One two-year trial covered 799 people with early rheumatoid arthritis who had never taken methotrexate. At one year, 46 percent on methotrexate alone reached a 50 percent improvement, against 62 percent on methotrexate plus adalimumab and 41 percent on adalimumab alone. Both comparisons came in at P under 0.001.
One review pooled 30 randomized trials and 3858 people taking methotrexate with folic acid. Anemia of any degree occurred in 2.55 percent, from 0.60 to 5.47, and a low white cell count occurred in 1.17 percent, from 0.16 to 2.80. Low platelets occurred in 0.19 percent, from 0.00 to 0.86. So the rates are low without being zero.
One trial re-randomized people who had reached low disease activity on a three-drug scheme. At 65 weeks, 81 percent were still on methotrexate against 55 percent on leflunomide, at P equals 0.025, while low disease activity was reached by 32 of 32 against 23 of 27, at P equals 0.024. Both of those measures favored the older drug.
One trial followed 289 people whose response to methotrexate had been poor. At one year, 78 percent were still on the conventional three-drug combination against 63 percent on methotrexate plus etanercept. Disease activity didn't differ between the two treatments.
One Swedish study matched 3642 people starting methotrexate for psoriatic arthritis against 3642 with rheumatoid arthritis. At six months, remission judged by the assessor was reached by 20 percent against 27 percent, at an adjusted odds ratio of 0.54, from 0.39 to 0.75. One drug, two diseases, and a worse result in the first.
One trial extension followed people for five years. Among those staying on one drug alone, 43 percent on methotrexate reached remission on the Clinical Disease Activity Index at week 260. On the two upadacitinib doses it was 53 and 59 percent.
Van Vollenhoven and colleagues, Arthritis Research and Therapy, 2024
What it is
Methotrexate is a disease-modifying antirheumatic drug, which gets shortened to DMARD. It works on the way your body handles folate, and on several inflammatory signal routes as well, and the result in an inflammatory arthritis is less immune activity in the joints. It has been in rheumatology use for decades. It's still the drug most rheumatologists reach for first in rheumatoid arthritis.
The words disease-modifying mean something specific here, because they separate this drug from a painkiller. Methotrexate doesn't only reduce symptoms while you take it. It slows or prevents the joint damage that rheumatoid arthritis causes, which is why rheumatologists press patients to stay with it through the early weeks when the benefit isn't obvious yet.
What the trials show it does
One trial covered 799 people with early rheumatoid arthritis who had never taken it, split three ways over two years, with one group on methotrexate alone, one on adalimumab alone, and one on both drugs together. That three-way design is what makes it worth reading rather than skimming. It answers the question people ask.
At one year, 46 percent on methotrexate alone reached a 50 percent improvement, against 62 percent on both drugs together and 41 percent on adalimumab alone, with both comparisons against the pair coming in at P under 0.001. Joint damage told a similar story. The pair progressed 1.3 points at year one and 1.9 at year two, while methotrexate alone progressed 5.7 and 10.4 and adalimumab alone progressed 3.0 and 5.5.
Read that as two findings rather than as one. Methotrexate alone does real work, and it does a good deal less than the pair does. That's the reason so many people end up on more than one drug in the end.
The other measure, which is staying on it
Trials usually report who got better, and they also report who was still taking the drug at the end. That second figure holds its own information, because a drug nobody stays on helps nobody. It's worth reading alongside the first one rather than after it.
One trial re-randomized people who had reached low disease activity on a three-drug scheme, with half continuing on methotrexate and half on leflunomide. At 65 weeks, 81 percent were still on methotrexate against 55 percent on leflunomide, at P equals 0.025. That trial also found low disease activity in 32 of 32 people on methotrexate against 23 of 27 on leflunomide, at P equals 0.024. Remission came in at 90.6 percent against 74.1 percent, at P equals 0.091, which doesn't clear the usual bar.
One other trial makes the point from a different angle. It followed 289 people whose response to methotrexate had been poor, and at one year 78 percent were still on a conventional three-drug combination against 63 percent on methotrexate plus etanercept. Disease activity didn't differ between them.
Why the cancer comparison misleads people
Many people look this drug up, find it's used in chemotherapy, and get alarmed. Methotrexate is used in cancer care, and the dose there is many times higher than the dose used in an inflammatory arthritis. Rheumatology doses are low and usually taken once a week rather than daily, and the side effects at that dose differ in kind rather than only in size.
The once-a-week schedule is the most important safety point about this drug. Taking methotrexate daily by mistake causes serious harm, and that mistake has killed people. So if you take it, be sure you understand the schedule and be sure anyone who helps with your medicines understands it too.
What it's like to take
Most people get on with methotrexate. The common side effects are nausea and mouth ulcers, with tiredness for a day or two after the dose being common too, and folic acid cuts several of those down a great deal. It gets prescribed alongside as standard, and some people do better on an injection under the skin than on tablets, because it can settle the nausea and it gets absorbed better.
The benefit takes time to appear, and this is where people give up on it. It commonly takes six to twelve weeks before the effect on joints is clear, so judging the drug after two weeks of feeling queasy is unfair to it, because you get the costs without the benefit. Tell your rheumatology team about side effects rather than stopping on your own, because there's usually something they can adjust.
Monitoring
Methotrexate needs regular blood tests, checking your liver, your blood counts, and your kidneys. The drug can affect the liver, and it can also slow the bone marrow down, and both problems are manageable when they're caught early. Routine testing is how they get caught, which makes missing blood tests the main avoidable risk with this drug.
One review put numbers on the blood count side of that. It pooled 30 randomized trials and 3858 people taking methotrexate alongside folic acid. Anemia of any degree came in at 2.55 percent, from 0.60 to 5.47, and a low white cell count came in at 1.17 percent, from 0.16 to 2.80. Low neutrophils came in at 1.77 percent, from 0.33 to 4.00, and low platelets at 0.19 percent, from 0.00 to 0.86.
Across all 3858 people there were four cases of severe anemia and three of severe low neutrophils, and no case of pancytopenia was reported. Read those two ways at once, because the rates are low and they aren't zero. Nobody can tell from how they feel which group they're in, which is the whole argument for testing on a schedule rather than when something feels wrong.
Alcohol counts here too, because both alcohol and methotrexate load the liver. There isn't one safe amount that fits everybody, so this needs an honest conversation with the rheumatologist who prescribes it. Playing down how much you drink makes the plan less safe without making it any more comfortable.
It doesn't behave alike in every disease
Methotrexate gets used in several illnesses, and one Swedish study asked whether it performs equally well in two of them. It's the largest comparison we hold. The answer is worth knowing if psoriatic arthritis is the one you have.
The study matched 3642 people starting methotrexate for psoriatic arthritis against 3642 with rheumatoid arthritis, all of them new to disease-modifying drugs. Two years on, similar shares were still taking it, at 71 percent against 76 percent. The response measures were a different story, where at six months pain scores of 15 mm or less were reached by 26 percent against 36 percent and remission judged by the assessor came in at 20 percent against 27 percent.
Adjusted for the differences between the groups, the odds ratios for psoriatic arthritis against rheumatoid arthritis were 0.63 for pain, from 0.47 to 0.85. Global health came in at 0.57, from 0.42 to 0.76, and remission came in at 0.54, from 0.39 to 0.75. All three point in one direction.
Where it sits against the newer drugs
One trial extension followed people for five years on a single drug. At week 260, 43 percent on methotrexate were in remission on the Clinical Disease Activity Index, against 53 and 59 percent on the two upadacitinib doses. One review pooled 10 trials of biologics used on their own, where tocilizumab came out ahead of methotrexate across every response measure, at odds ratios running from 2.1 to 3.89.
So the newer drugs do beat it in these comparisons, and what they haven't done is displace it. Methotrexate is still the drug nearly every new treatment gets measured against. It's still the first one most rheumatologists reach for.
Pregnancy
Methotrexate causes birth defects and pregnancy loss, so it has to be stopped well before conception, and that applies to anyone who could become pregnant. Current guidance also covers men planning to father a child, so both prospective parents should discuss timing with the prescriber. Reliable contraception is needed throughout treatment.
If you're planning a pregnancy, raise it early rather than waiting until you're close to trying. There are other treatments that go with pregnancy, and switching takes planning so your disease stays controlled through the change. An unplanned pregnancy on methotrexate needs an urgent conversation with your rheumatology team.
Common misconceptions.
Myth. It's chemotherapy, so it must be dangerous.
Reality. The dose is the whole of the difference, because cancer care uses many times the dose used in an inflammatory arthritis. One review pooled 30 randomized trials and 3858 people taking it with folic acid, where anemia of any degree came in at 2.55 percent and low platelets at 0.19 percent. Across all 3858 of those people there were four cases of severe anemia and three of severe low neutrophils, and no case of pancytopenia was reported at all.
Myth. If it were any good I wouldn't need anything else.
Reality. Needing more than one drug is normal here rather than a verdict on this one. In one trial of 799 people, 46 percent on methotrexate alone reached a 50 percent improvement at one year, and adding a biologic lifted that to 62 percent. Another trial ran the comparison the other way round, where three conventional drugs together stayed in use longer than methotrexate plus a biologic, at 78 percent against 63 percent, with disease control coming out level.
Myth. The newer drugs have made it obsolete.
Reality. They haven't, and the trials show why. One five-year extension found 43 percent on methotrexate alone in remission at week 260, while the two newer single-drug arms reached 53 and 59 percent, which is better and isn't a rout. Methotrexate is also the drug nearly every new treatment gets tested against, which is why it turns up in almost every trial on this site.
Myth. Missing a blood test now and then is no big deal.
Reality. The blood problems are uncommon rather than absent, and testing is how they get found at all. Across 30 trials and 3858 people, low neutrophils of any degree came in at 1.77 percent, from 0.33 to 4.00, and three of those 3858 had a severe drop. Nobody can tell from how they feel which group they are in, which is the whole argument for routine testing.
Myth. It behaves alike in every disease it's used for.
Reality. One Swedish study put that to the test cleanly. It matched 3642 people starting methotrexate for psoriatic arthritis against 3642 with rheumatoid arthritis, and two years on similar shares were still taking it, at 71 percent against 76 percent. At six months, though, every response measure was lower in psoriatic arthritis, with remission judged by the assessor coming in at an odds ratio of 0.54, from 0.39 to 0.75.
Related terms.
- DMARDs, the family this drug belongs to.
- Biologics, the injected drugs it gets compared against.
- Biologics against DMARDs, where those head-to-head trials sit.
- Antirheumatic, the wider word your notes may use.
Questions patients ask.
Why is methotrexate given once a week?
Because that's the schedule it was tested and licensed on for this use, as a weekly tablet or a weekly injection. Taking it daily by mistake causes serious harm, and that mistake has killed people, so anyone who helps with your medicines needs to know the schedule too. If you're ever unsure which day you took it, ask your team rather than guessing.
How well does it work on its own?
Reasonably, and worse than a combination does. In one trial of 799 people new to it, 46 percent reached a 50 percent improvement at one year on methotrexate alone, and adding a biologic lifted that to 62 percent, with joint damage also progressing less on the pair. So it does real work by itself, and it's often a starting point rather than the whole plan.
Is it safer than the newer drugs?
Our sources don't rank them against each other, and they do give you one figure worth having. One review pooled 30 randomized trials and 3858 people taking methotrexate with folic acid, where anemia of any degree came in at 2.55 percent and low platelets at 0.19 percent, and no case of pancytopenia was reported. That's a low rate in trial conditions, and everyday use is a different setting.
Why do I need blood tests?
The drug can affect the liver and it can slow the bone marrow down, and both of those are manageable when they're found early. A blood test is how they get found, because neither one announces itself. In the pooled trial data, low neutrophils of any degree came in at 1.77 percent, from 0.33 to 4.00, and your team sets the interval for your own tests.
Why does it take so long to work?
It commonly takes six to twelve weeks before the effect on joints is clear, and that stretch is where people give up on it. The queasiness comes first and the benefit comes later. Judging it after two weeks means taking the cost without ever seeing the benefit, so tell your team about side effects rather than stopping on your own, because there's usually something they can change.
Does it work as well in psoriatic arthritis?
Worse, on the largest comparison we hold. One Swedish study matched 3642 people with psoriatic arthritis against 3642 with rheumatoid arthritis, all of them starting methotrexate, and similar shares stayed on it at two years. At six months, though, remission judged by the assessor came in at an odds ratio of 0.54, from 0.39 to 0.75, and pain response at 0.63, from 0.47 to 0.85.
What about pregnancy?
Methotrexate causes birth defects and pregnancy loss, so it has to be stopped well before conception, and current guidance also covers men planning to father a child. If you're thinking about a pregnancy, raise it early, because switching treatment takes planning and waiting until you're close to trying makes it harder. An unplanned pregnancy while taking it needs an urgent conversation with your rheumatology team.
References.
- Breedveld FC; Weisman MH; Kavanaugh AF et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26-37. 10.1002/art.21519PREMIER: two-year
- Vanni KMM; Lyu H; Solomon DH. Cytopenias among patients with rheumatic diseases using methotrexate: a meta-analysis of randomized controlled clinical trials. Rheumatology (Oxford). 2020;59:709-717. 10.1093/rheumatology/kez343Systematic literature review and meta-analysis of randomised controlled trials with a methotrexate monotherapy arm
- Stouten V; Michiels S; Westhovens R et al. Effectiveness of maintenance therapy with methotrexate compared with leflunomide for patients with RA having achieved disease control with both these drugs: results of a predefined sub-analysis of CareRA, a pragmatic RCT. Clin Rheumatol. 2020;39:2593-2601. 10.1007/s10067-020-05008-4Predefined sub-analysis of CareRA
- Peper SM; Lew R; Mikuls T et al. Rheumatoid Arthritis Treatment After Methotrexate: The Durability of Triple Therapy Versus Etanercept. Arthritis Care Res (Hoboken). 2017;69:1467-1472. 10.1002/acr.23255Open-label extension of a 48-week double-blinded noninferiority randomised trial
- Lindström U; di Giuseppe D; Exarchou S et al. Methotrexate treatment in early psoriatic arthritis in comparison to rheumatoid arthritis: an observational nationwide study. RMD Open. 2023;9. 10.1136/rmdopen-2022-002883Observational nationwide study from Swedish national registers
- van Vollenhoven R; Strand V; Takeuchi T et al. Upadacitinib monotherapy versus methotrexate monotherapy in patients with rheumatoid arthritis: efficacy and safety through 5 years in the SELECT-EARLY randomized controlled trial. Arthritis Res Ther. 2024;26:143. 10.1186/s13075-024-03358-xLong-term extension of the SELECT-EARLY phase 3 randomised controlled trial
- Migliore A; Bizzi E; Egan CG et al. Efficacy of biological agents administered as monotherapy in rheumatoid arthritis: a Bayesian mixed-treatment comparison analysis. Ther Clin Risk Manag. 2015;11:1325-35. 10.2147/TCRM.S89678Bayesian mixed-treatment comparison meta-analysis of 10 double-blind randomised controlled trials of biologic agents used as monotherapy in rheumatoid arthritis
This page gathers the published research on this subject into one place. The studies behind it were published between 1989 and 2026, and every figure links to the paper it came from. Those studies were peer reviewed. This summary of them was not. Dr. Sarah Luebker is reviewing these pages one at a time and has not reached this one yet, so it carries no medical review date and nothing here is her opinion or her advice to you. Each page gets updated as she reaches it. It is here in the meantime because the science is worth having in one organized place that is easy to find and easy to read. Talk to your own clinician before acting on any of it.