Methotrexate

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 slowly. 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, not 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 that gets abandoned does no good. It's worth reading alongside the first one.

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.

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. How you feel doesn't tell you which group you'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 is 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 ranging 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.

Common misconceptions.

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 are covered.
• Antirheumatic, the wider word your notes may use.