Treating RA with Methotrexate

Stanley B. Cohen, MD: As far as initial treatment options for rheumatoid arthritis, I would say that 99% of my patients start with methotrexate. Now, if someone is a premenopausal female unwilling to use birth control, we can’t give them methotrexate because it’s a teratogen, as is leflunomide. So, that would obviously affect our options.

If someone has chronic liver disease or refuses to drink less alcohol—someone who’s a heavy alcohol user—we would not use methotrexate. But 99% of our patients end up starting on methotrexate. We have good clinical trial data from multiple clinical trials, which have shown that we can induce remission, or low disease activity, in about 30% of patients presenting with early rheumatoid arthritis, which may be sustained for a year or 2 or longer.

So, we start with methotrexate in my practice—and rheumatologists vary—I start with 15 mg orally, weekly. I split the dose to try to enhance absorption, to decrease the variability in absorption. We bring them back in 4 to 5 weeks—some will be due in 6 weeks—and at that point, if they’ve shown some initial response but still have active disease, I will escalate the dose to 20 mg. So, by 8 weeks, all of my patients are on 20 mg of methotrexate. Also, concomitantly with that in early disease, we’ll have patients on NSAIDs. Many patients will be on low-dose prednisone to bridge them through those first few months of disease, where they have active disease waiting for methotrexate to work.

Methotrexate can work as early as 1 to 2 weeks, but most people have peak benefit between 12 and 24 weeks of methotrexate. So, we give a therapeutic trial of at least 12 to 16 weeks. If a patient has no response to methotrexate at all by 8 to 12 weeks, they’re not going to respond, and I’m going to move on to another therapy. But most have some improvement, which increases over time.

Methotrexate is the anchor drug for the treatment of rheumatoid arthritis. And many rheumatologists, including myself—if a patient has a partial response but at 12 weeks is still not where we want them to be, and they’re on 20 mg or 25 mg orally of methotrexate—will consider subcutaneous methotrexate because we know that about another one-third of patients will respond by switching from oral to subcutaneous methotrexate. If the patient continues to have active disease between month 3 and month 6, depending on the patient, at that point we will add combination therapy. We will combine biologic therapies, or other conventional synthetic DMARDs with methotrexate to try to induce remission or low disease activity.

There is some issue with the underdosing of methotrexate. Various claims-based databases or observational registries have actually suggested that many of our colleagues are using lower doses of methotrexate than recommended. Now, there are reasons to use low doses of methotrexate. Methotrexate is renally excreted. So, if you have a patient who has underlying kidney disease, you do need to use a lower dose. If you have an elderly patient, they might have a normal serum creatinine/BUN ratio, but the drug may reduce renal function in elderly patients. There are indications for that, but there are some rheumatologists who are risk-adverse and don’t push the dose as far as the dose should be pushed. To be fair, 20% of people on methotrexate, maybe even 30%, do not like methotrexate. They feel poorly for 24 to 48 hours after taking oral methotrexate: upset GI, nausea, fatigue, headaches, or canker sores. Subcutaneous methotrexate can get around that problem in some people, but not all. So, that’s part of the reason the methotrexate is relatively underdosed by some rheumatologists.

We do use subcutaneous methotrexate to try to improve efficacy in patients who had a partial response to oral methotrexate, but we also use it for toxicity. There are reasonable data that subcutaneous methotrexate has less GI toxicity than the oral methotrexate. There are more general data that it might reduce the likelihood of stomatitis, oral ulcers, and so forth. So, we will, in a patient who is responding but having toxicity, try the subcutaneous methotrexate.

Methotrexate could possibly be under dosed by rheumatologists, but I think it is the anchor drug—it is the primary drug—really for 2 reasons. First of all, it’s effective—as I mentioned—in up to 30% of people—very effective. But also, we are not allowed by formularies of insurance companies to get other therapies, such as biologic therapies, unless a patient has been demonstrated to be a non-responder, or a partial responder, to methotrexate.

Generally, what we do is treat a patient for 12 to 16 weeks with methotrexate. At that point, if they’ve had a very good clinical response, we may go to 24 weeks. If they’ve had a marginal clinical response, then I think it’s time to move on. We generally will move on to a biologic or target immunomodulator like tofacitinib, or Xeljanz. And so, it varies to some degree, but it is not appropriate to continue methotrexate past 6 months in someone who continues to have active disease, and is not in low disease activity or remission.