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Methotrexate

If you have an autoimmune or inflammatory condition, you’ve likely had a number of questions about getting the COVID-19 vaccine. Many of these concerns are specific to immunosuppressive medications (like methotrexate) because they may also make the COVID-19 vaccine less effective.

Guidance from the American College of Rheumatology provides some answers for patients and their providers about these concerns. You can read more about the guidance here.

We also encourage you to check out our main guide: Getting a COVID-19 Vaccine: What to Know If You’re Immunocompromised for a basic overview of the COVID-19 vaccine landscape for people with inflammatory and autoimmune health conditions. You can also read these other resources on COVID-19 vaccines for people who are immunocompromised:

This article will focus specifically on methotrexate, a disease-modifying antirheumatic drug (DMARD) that affects immune system function. It is a first-line treatment for rheumatoid arthritis (meaning, it is prescribed to most RA patients when they are first diagnosed) and also used to treat psoriatic arthritis and psoriasis and other types of inflammatory arthritis.

Can You Get the COVID-19 Vaccine If You Take Methotrexate for an Autoimmune or Inflammatory Disease?

The answer is generally yes. The American College of Rheumatology encourages people with rheumatic diseases to get vaccinated against COVID-19. “We want patients to get a COVID-19 vaccine — hard stop,” says rheumatologist Jeffrey Curtis, MD, MPH, a Professor of Medicine at the University of Alabama at Birmingham who led the task force that created the ACR COVID-19 vaccine guidance.

“Beyond known allergies to vaccine components, there are no known additional contraindications to COVID-19 vaccination” for people with rheumatic diseases, the guidance states. This means that simply having an autoimmune or inflammatory rheumatic disease — or taking medication like methotrexate to treat it — is not a reason to not get a COVID-19 vaccine.

The general consensus for most immunosuppressed patients — based on what is known about how COVID-19 vaccines work — is that COVID-19 vaccines should be safe for people on immunosuppressant therapy but may be some degree less effective.

Concerns have largely stemmed from the fact that people who take medications like methotrexate or other medications that affect immune system function were not included in the clinical trials that led to the vaccines’ authorization.

In the months since, preliminary data from various studies about how such medications affect the immune response to the vaccine has started to emerge. While more research is needed, the news about methotrexate and the COVID-19 vaccine is so far mostly reassuring, says Alfred Kim, MD, PhD, Assistant Professor of Medicine, Pathology, and Immunology at Washington University in St. Louis, Missouri. His research team recently found that people taking methotrexate had a “modest impairment” in their response to the vaccine. Read more here about the research.

Similarly, a small study just published in the journal Annals of the Rheumatic Diseases found that about one-third of people with inflammatory arthritis or related conditions taking methotrexate had a reduced response to the COVID-19 vaccine.

Researchers looked at vaccine responses in 82 patients (most had rheumatoid arthritis and psoriatic arthritis/psoriasis) and compared them with a control group of 208 patients. They found that more than 90 percent of the healthy controls or people taking medications other than methotrexate (such as TNF biologics) had adequate antibodies after getting the vaccine, but only 62 percent of those taking methotrexate did.

This may sound alarming, but keep in mind that it means that the majority of people on MTX did mount an adequate response to the vaccine.

And even if the vaccine is less effective, that doesn’t necessarily mean that the COVID-19 vaccine doesn’t work at all — it may just work less well than in people who don’t take medications like methotrexate. But even a slightly less effective vaccine may still help prevent severe disease that requires hospitalization (or worse).

Think of it this way: If you had a choice between being in a snowstorm wearing a winter coat, hat, gloves, and scarf (fully effective vaccine) versus a just a winter coat (less effective vaccine) versus just a T-shirt (no vaccine), of course you’d prefer having all the winter attire. But having the coat is way better than just the T-shirt.

More research on how a decreased immune response to the vaccine actually affects rates of COVID-19 infections and outcomes is needed.

How Methotrexate Affects the Immune System

Before methotrexate was widely used to treat rheumatologic conditions, it was originally approved as (and is still used as) a form of chemotherapy for cancer. But it works in the body differently when used in much lower doses to treat inflammatory rheumatic conditions like rheumatoid arthritis than higher doses used for cancer treatment.

For rheumatic conditions, methotrexate is taken as pills or a subcutaneous injection, usually once per week.

Methotrexate is considered an “antiproliferative” medication, which means it stops cells from replicating. It reduces the activity of several types of proteins and cells involved in immune system function, including T cells and B cells.

This description from Dr. Kim helps explain how methotrexate affects the immune system:

Let’s say your immune system is an army fighting a virus enemy. It needs to be able to quickly increase the number of its troops. For a typical virus, the immune system can expand its army by a million-fold. But methotrexate limits your immune system’s ability to scale its troops. Instead of expanding by a million, maybe it can only increase by a thousand. This inability to increase your troops makes you less able to fight off an infection.

But when you have an autoimmune condition like rheumatoid arthritis, you wouldn’t want your immune system to be able to mount lots of troops. “In this case, expanding the army is a bad thing, because it’s contributing to the inflammation and disease flares,” Dr. Kim explains. That’s why methotrexate can be so effective at managing inflammatory diseases like RA.

What Happens If You Take Methotrexate and Get a Vaccine

Because methotrexate prevents the immune system from having as robust a response to “invaders,” it can weaken the body’s response to vaccines. This means someone who is on methotrexate and gets a vaccine may not get as much protection from it as someone who is not taking methotrexate.

This was studied a few years ago in a randomized controlled trial of about 300 rheumatoid arthritis patients in South Korea after they received the flu vaccine. Half of the patients were randomized to continue taking their methotrexate as usual after getting the vaccine. The other half stopped taking methotrexate for two weeks after getting the flu vaccine. When researchers measured levels of the patients’ antibodies to flu virus strains four weeks later, they found that more patients in the group who stopped methotrexate (76 percent) had satisfactory levels of antibodies to at least two of the four flu virus strains in the vaccine than those in the group who kept taking methotrexate (55 percent).

Antibodies recognize germs and foreign invaders in order to help the body get rid of them before they infect or harm you.

This data has led some rheumatologists to advise patients to skip methotrexate for two weeks after getting a flu vaccine in order to increase the immune system’s response to the flu vaccine.

“Your body develops the immune response after you get the vaccination, so you would think that trying to not suppress your immune system in the time you’re developing the immune response would be the most important time period,” rheumatologist Michael Putman, MD, recently said about this study in an episode of EBRheum, The Evidence-Based Rheumatology Podcast.

And some rheumatologists are extrapolating data from studies like this to recommend that patients also pause methotrexate after getting a COVID-19 vaccine.

Should You Pause Methotrexate After Getting a COVID-19 Vaccine?

Initial studies have found that some patients on methotrexate have a decreased response to the COVID-19 vaccine. While more research is needed, some experts and medical organizations have recommended that patients hold methotrexate after getting the vaccine; others have not.

  • The American College of Rheumatology’s COVID-19 Vaccine guidance recommends that patients with well-controlled disease hold methotrexate for one week after each COVID-19 vaccine dose (for Pfizer and Moderna vaccines) or for two weeks after a single-dose vaccine (Johnson & Johnson).
  • The National Psoriasis Foundation’s COVID-19 Task Force Guidance recommends “that patients who are to receive a mRNA-based COVID-19 vaccine continue their biologic or oral therapies for psoriasis and/or psoriatic arthritis in most cases.” However, it also says that for people who are 60 or older or have comorbidities linked with poor COVID-19 outcomes and have well-controlled disease could consider holding methotrexate for two weeks after getting the one-dose Johnson & Johnson vaccine.

Experts who recommend pausing methotrexate temporarily after getting a COVID-19 vaccine suggest this because it may help the vaccine protect you as much as possible.

Experts who recommend continuing to take methotrexate after getting a COVID-19 vaccine may have concerns that patients could flare if they stop taking it, or are not as worried about the potential decrease in vaccine effectiveness.

Stopping Methotrexate for One Week vs. Two Weeks

The reason the ACR guidance recommends holding for one week versus the two-week period used in the South Korean study has to do with scheduling issues related to the two-dose vaccines from Pfizer and Moderna. If you were to stop taking methotrexate for two weeks after each vaccine dose, you would be off the medication much longer than if you were getting just a one-dose vaccine. Skipping methotrexate for one week instead of two might be a happy medium that may allow patients to have a stronger immune response without as much of a risk of flaring.

If you get a single-dose vaccine from Johnson & Johnson, the ACR guidance suggests holding methotrexate for two weeks afterward.

The Role of Shared Decision-Making

But keep in mind that recommendations about whether to continue or stop methotrexate need to be individualized for every patient. For example:

  • If a patient is in remission or has very low disease activity and is doing very well on methotrexate, their doctor may advise that they skip taking it for two weeks after each COVID-19 vaccine rather than just one.
  • If a patient does not have well-controlled disease and is worried about flaring if they stop methotrexate, their doctor may advise that they keep taking methotrexate after they get the COVID-19 vaccine.

As Dr. Curtis points out, the increase in patients’ immune response to the flu vaccine in the South Korean study was dependent on their methotrexate dose. Those on higher doses of methotrexate who stopped taking it had a better response to the flu vaccine than those on a lower dose of methotrexate. In other words, people on lower doses of methotrexate may not benefit as much from skipping it after getting a vaccine than those on higher doses.

Another thing to consider: We don’t actually know whether decreases in the immune system response to a vaccine actually translates to whether or not someone is more likely to get COVID-19 infection or severe disease.

“Even if you have a lower antibody response to a COVID-19 vaccine because of taking a medication like methotrexate, you could still be adequately protected against infection or severe disease,” says Dr. Kim, who explains that there just isn’t data yet to know this. He is advising patients to keep taking methotrexate after the COVID-19 vaccine.

So, when it comes to deciding whether to keep taking or temporarily pause taking methotrexate after getting a COVID-19 vaccine, there is no right answer for every patient. The choice depends on a number factors, including how well your underlying disease is controlled, whether you’re more concerned about the potential for disease flares vs. trying to maximize your body’s response to the vaccine, and whether you and your doctor together think it’s a good idea for you.

The bottom line: 

  • You should get a COVID-19 vaccine unless you have any known allergies to the vaccine or ingredients in it.
  • The COVID-19 vaccine will likely not work as well in people on methotrexate compared to people who don’t take it, but the vaccine will likely still provide some protection.
  • Some organizations and doctors advise that patients — especially those whose diseases are well-controlled — pause methotrexate for one to two weeks after getting a COVID-19 vaccine; other organizations and doctors do not.
  • The choice about whether or not to stop methotrexate after getting a COVID-19 vaccine is one you should make with your doctor based on your health and personal situation.

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COVID-19 Task Force Guidance Statements. NPF COVID-19 Task Force. National Psoriasis Foundation. April 27, 2021. https://www.psoriasis.org/covid-19-task-force-guidance-statements.

COVID-19 Vaccination Considerations for Persons with Underlying Medical Conditions. COVID-19. U.S. Centers for Disease Control and Prevention. May 14, 2021. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/underlying-conditions.html.

COVID-19 Vaccine Clinical Guidance Summary for Patients with Rheumatic and Musculoskeletal Disease. American College of Rheumatology. April 28, 2021. https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Guidance-Rheumatic-Diseases-Summary.pdf.

Current and Future Role of Methotrexate in the Therapeutic Armamentarium for Rheumatoid Arthritis. International Journal of Clinical Rheumatology. Medscape. 2012. https://www.medscape.com/viewarticle/761828_1.

Episode 71: MTX Discontinuation Post… Influenza Vaccinatio‪n. The Evidence Based Rheumatology Podcast. January 27, 2021. https://podcasts.apple.com/us/podcast/e71-mtx-discontinuation-post-influenza-vaccination/id1331528750?i=1000506839264.

Haberman R, et al. Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease. Annals of the Rheumatic Diseases. May 25, 2021. doi: http://dx.doi.org/10.1136/annrheumdis-2021-220597.

Interview with Alfred Kim, MD, PhD, Assistant Professor of Medicine, Pathology, and Immunology at Washington University in St. Louis, Missouri

Interview with Jeffrey Curtis, MD, MPH, a rheumatologist and Professor of Medicine at the University of Alabama at Birmingham

Methotrexate (Rheumatrex, Trexall, Otrexup, Rasuvo). American College of Rheumatology. December 2020. https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Treatments/Methotrexate-Rheumatrex-Trexall.

Park JK, et al. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial. Annals of the Rheumatic Diseases. June 2018. doi: http://dx.doi.org/10.1136/annrheumdis-2018-213222.