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Methotrexate Withdrawal and RA Flares

Posted on July 15, 2022
Medically reviewed by
Diane M. Horowitz, M.D.
Article written by
Maureen McNulty

Many people with rheumatoid arthritis (RA) try methotrexate (Trexall) as a treatment option. This medication is a disease-modifying antirheumatic drug (DMARD) that can slow disease progression, or prevent joints from being damaged further. Methotrexate calms the immune system to prevent inflammation. It is often the first DMARD prescribed to treat RA.

About two-thirds of people who use methotrexate say that it helps keep their RA from getting worse. However, most people who use it also experience side effects such as fatigue, nausea, diarrhea, abdominal pain, mouth sores, hair loss, or shortness of breath. It can also lead to more serious side effects like lymphoma (a type of blood cancer) or liver disease.

Because of the side effects, cost, or other concerns about methotrexate, some people may want to stop taking it. However, your RA could worsen if you stop treatment.

Methotrexate Withdrawal

Some drugs and medications can lead to dependence — when you have been taking some drugs for a long time, your body begins to rely on them in order to function properly. When you stop using them, you go through withdrawal and experience physical or mental symptoms.

Researchers aren’t yet sure whether people can go through withdrawal from stopping methotrexate treatment. Clinical studies haven’t reported any major methotrexate withdrawal symptoms from people stopping this therapy. However, it is clear that stopping methotrexate treatment can increase the risk of RA flare-ups.

RA Flares and Methotrexate

Flare-ups — periods of time in which symptoms worsen — are common when living with RA. Flare-ups can last days, weeks, or months. They often lead to symptoms like joint stiffness, pain, and swelling, as well as fatigue and fevers.

Some clinical trials have found that people with RA can experience disease flares when they stop using methotrexate. One small study compared people taking methotrexate with people taking a placebo (a “fake” treatment that mimics a real medication) for their RA. Within one month, all of the participants taking the placebo experienced a flare-up.

Other studies have analyzed whether taking methotrexate less often could lead to flare-ups. Studies have found that anywhere from 8 percent to 48 percent of people have an RA flare when they go from taking methotrexate once every week to once every two weeks. This treatment plan may work best for people with early-stage RA who have gone into remission. It can also help when people are using methotrexate in combination with other DMARDs that are working to help control the disease.

This research was conducted many years ago, before biologics became a common RA treatment option. More recently, researchers have found that some people may be able to stop using methotrexate when they are also using biologics. Studies have looked at people who had stable RA after taking tofacitinib (Xeljanz) or etanercept (Enbrel) along with methotrexate. Researchers found that when people stopped using methotrexate but continued taking the biologic drug, they did not have a higher risk of a flare-up.

Is It a Good Idea to Taper Off of Methotrexate?

Methotrexate can help many people with RA go into remission. People in remission have dramatically improved RA symptoms. For example, your doctor may consider you to be in remission if you have just a single swollen joint or if your blood tests show that you have low levels of inflammation.

If you are in remission from RA, your doctor may give you the option of stopping methotrexate therapy or reducing your dose. Some guidelines recommend slowly tapering off methotrexate if your RA is well controlled. Before trying to switch to a lower dose, talk to your rheumatologist to see if it’s the right choice for you. Your doctor will consider factors like:

  • Whether you experience side effects from using methotrexate
  • How long you’ve been in remission
  • Whether you’re concerned about experiencing a disease flare-up if you lower your dose

Your rheumatologist may be OK with you stopping methotrexate altogether. They may also suggest changing your dosage or taking the medication less frequently. This may help prevent flare-ups and help you stay in remission.

Treating Flare-Ups

If you experience a flare-up after stopping or reducing methotrexate, your RA may become active again. In this case, your doctor may suggest going back on your previous treatment plan.

In one study, 36 percent of people who took etanercept and methotrexate for at least six months and then stopped using methotrexate needed to go back to their original therapy. Out of this group, 75 percent were able to get back into remission and 92 percent had low disease activity after restarting methotrexate.

There are also other strategies you may be able to use to treat flare-ups. You may want to try:

  • Lowering your stress levels
  • Getting more sleep
  • Relieving pain with hot water bottles, heated blankets, warm baths, or ice packs
  • Getting very light exercise, if your doctor says it’s OK
  • Distracting yourself with a fun or interesting activity
  • Taking over-the-counter or prescription medications to ease flare symptoms, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids

These strategies may not be enough to treat a flare-up that occurs after you stop taking methotrexate. You may feel better if you go back to your original medication. Work with your health care team to weigh the benefits and risks of your treatment options.

Talking To Your Doctor About Methotrexate

Make sure to talk to your doctor before you stop taking methotrexate or try to change your dose. If you don’t like methotrexate because of its side effects or if you want to try a different treatment, your doctor can help you change your treatment plan. They may also be able to suggest other ways to ease methotrexate side effects, such as:

  • Taking methotrexate after a meal, when your stomach is full
  • Receiving methotrexate therapy on Friday or Saturday, so you have the weekend to recover
  • Taking a folic acid (folate) supplement
  • Using other medications to treat side effects like nausea

You should keep taking methotrexate even if you’re feeling good, unless you and your doctor discuss otherwise. Having fewer RA symptoms means that your medication is working — if you stop taking it, your condition could worsen.

Connect With Others Who Understand

On myRAteam, the social network for people with RA and their loved ones, members come together to ask questions, give advice, and share their stories with others who understand life with rheumatoid arthritis.

Have you used methotrexate? Have you experienced flare-ups when stopping this medication? Share your experience in the comments below, or start a conversation by posting on your Activities page.

All updates must be accompanied by text or a picture.
Diane M. Horowitz, M.D. is an internal medicine and rheumatology specialist. Review provided by VeriMed Healthcare Network. Learn more about her here.
Maureen McNulty studied molecular genetics and English at Ohio State University. Learn more about her here.

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