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A bottle of methotrexate being "attacked" by the coronavirus.
Credit: Tatiana Ayazo

If you have rheumatoid arthritis, you’re likely familiar with methotrexate — a disease-modifying antirheumatic drug (DMARD) that’s often prescribed when someone is first diagnosed with rheumatoid arthritis. This drug, which can affect immune system function, is also used to treat psoriatic arthritis and other types of inflammatory arthritis.

Many patients on methotrexate have had concerns about whether it can impact the effectiveness of the COVID-19 vaccine, and preliminary research is starting to provide some answers.

A new study published in the journal Annals of the Rheumatic Diseases shows that methotrexate may reduce the body’s immune response to the COVID-19 vaccine.

Researchers assessed the immune response of 51 patients with immune-mediated inflammatory diseases (IMID) at NYU Langone Health in New York City at a baseline and after they received the second dose of the Pfizer COVID-19 vaccine, along with 26 healthy subjects who served as controls. The researchers also analyzed a second group of patients with IMID (31 total) and healthy controls (182 total) from Germany.

All of the IMID patients were either taking methotrexate or TNF inhibitors and other biologics.

More than 90 percent of healthy subjects and inflammatory disease patients on biologic treatments showed robust antibody responses, but only 62 percent of those on methotrexate achieved an adequate response. Patients taking methotrexate also did not show an increase in CD8+ T cell activation — another part of the immune system that may be important in fending off the coronavirus — after receiving the vaccine.

“Although precise cut-offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines,” note the authors.

In other words, researchers don’t know for sure what level of immune system response corresponds to adequate protection from getting sick with COVID-19. But it’s likely that some patients may benefit from additional steps to achieve a better response to the vaccine, whether that’s temporarily pausing their dosage of methotrexate for one to two weeks after getting the vaccine or getting a booster shot.

The IMID diagnoses of patients in the study were mostly rheumatoid arthritis and psoriatic arthritis.

“It’s a small study but not a huge surprise, because this has been seen for other vaccines like flu,” 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 American College of Rheumatology COVID-19 Vaccine Clinical Guidance. “It’s why the American College of Rheumatology COVID-19 Vaccine Guidance Task Force recommended holding methotrexate for one to two weeks after each vaccine dose.”

It’s worth noting that the study was observational rather than a randomized controlled clinical trial, in which researchers would be able to better show causality. It also only looked at one of three COVID-19 vaccines authorized for use in the United States. Plus, people taking methotrexate in the study were older on average than those on other medications or healthy controls. (Being older is associated with having a lower response to some vaccines.)

Should You Temporarily Pause Methotrexate When You Get the Vaccine?

If you take methotrexate and have not yet gotten the COVID-19 vaccine, talk to your doctor before your vaccine. They may recommend following the ACR’s guidance by holding methotrexate for one week after each dose of the Pfizer or Moderna vaccines or for two weeks after the single-dose Johnson & Johnson vaccine if you have well-controlled disease.

However, you shouldn’t make any changes to your medication without consulting your health care provider first.

Get the COVID-19 Vaccine, But Follow Precautions Afterward

These findings shouldn’t stop you from getting the COVID-19 vaccine. Experts agree that some protection from the vaccine is better than none, particularly since chronic disease patients may have a higher risk of severe outcomes from COVID-19 than the general public. And keep in mind that two-thirds of individuals on methotrexate still had a robust vaccine response.

“The reassuring aspect of these data is that methotrexate users generally can mount vaccine responses,” says Alfred Kim, MD, PhD, Assistant Professor of Medicine, Pathology, and Immunology at Washington University in St. Louis, Missouri. “It’s not as devastating as B cell depleting agents [like rituximab] or medications used for transplantation. Having said this, there are the 40 percent who mount poor responses and this will certainly cause trepidation for methotrexate users, but the key point is that over half will mount responses.”

The FDA does not recommend using antibody tests after getting the vaccine to determine your antibody levels, since experts aren’t sure yet what levels correlate with protection. Plus, antibody tests may only check for a certain type of antibody, and several parts of the immune system play a role in building immunity to COVID-19. That’s why we can’t tell yet what the reduced antibody response for patients on methotrexate in this study means in terms of actual protection from COVID-19.

“It’s impossible to answer,” says Dr. Kim. “We only can report on correlates of protection like antibody titers, neutralization titers, and T cell responses, but true protection data will take months if not a year to obtain.”

However, this new study does provide more proof that it’s important for people on methotrexate to continue to exercise caution when it comes to wearing a mask, social distancing, and avoiding high-risk situations, like crowded indoor spaces.

Experts still urge immunocompromised patients to continue to mask and practice social distancing. Here’s how immunocompromised patients in our community plan to continue wearing masks.

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Haberman RH, 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 Professor of Medicine at the University of Alabama at Birmingham who led the task force that created the ACR COVID-19 Vaccine Clinical Guidance

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