One-quarter of people who take the drug methotrexate for common immune system disorders—from rheumatoid arthritis to multiple sclerosis—mount a weaker immune response to a coronavirus disease (COVID-19) vaccine, a new study shows.

Published recently in Annals of the Rheumatic Diseases, the study addressed disorders that result when the immune system, meant to fight disease and drive healing, is triggered abnormally. This in turn causes inflammation, the pain and swelling that come as immune cells rush into damaged or infected tissue, but often in the wrong amount or context. Called immune-mediated inflammatory disorders, they are typically treated with drugs that reduce inflammation, including methotrexate.

Led by researchers at NYU Grossman School of Medicine, the new study looked specifically at patients’ responses to the Pfizer–BioNTech mRNA COVID-19 vaccine, which they measured by looking at the antibodies produced in each patient by the vaccine. Once injected into the body, vaccine ingredients are meant to trigger the production of antibodies, immune proteins that specifically glom onto this viral target protein, disabling it and tagging it for removal from the body.

The lower antibody response in patients who take methotrexate does not necessarily mean that these patients are not protected against COVID-19, cautions co-first study author Rebecca Haberman, MD, clinical instructor in the Department of Medicine at NYU Langone Health.

“It is most important to state that patients should not be concerned about our study findings as the majority of patients with immune system disorders are responding well to the mRNA vaccines,” Dr. Haberman says. “It is also possible that methotrexate is delaying, rather than preventing, an adequate immune response against COVID-19.”

Researchers have known that patients with rheumatoid arthritis who take methotrexate have a reduced response to seasonal flu vaccines. Because mRNA vaccines use a new mechanism of action that patients with these common immune disorders have not seen before, the researchers wanted to determine how well these patients are protected.

The research was conducted at NYU Langone and at Friedrich-Alexander University Erlangen Nuremberg in Germany and enrolled healthy people and patients treated for common immune-mediated disorders, including rheumatoid arthritis, psoriatic arthritis, and psoriasis. Study participants received two doses of Pfizer–BioNTech mRNA COVID-19 vaccine. The researchers analyzed blood samples to determine the amount of antibodies patients produced after receiving the vaccine and measured the activation of key immune system cells, including CD8 killer T cells, which are generated as part of the body’s immune response.

The researchers found that more than 90 percent of healthy subjects and patients taking drugs other than methotrexate to control inflammation in both the New York and German study groups mounted strong antibody responses. Patients with immune-mediated inflammatory disorders who were taking methotrexate achieved an adequate response in only 62 percent of cases. Similarly, while healthy patients and those with common immune disorders who were taking anti-inflammatory drugs other than methotrexate produced CD8 T cells, patients taking methotrexate did not show an increase in CD8 T cell activation after vaccination.

“More research is needed to understand why such a significant proportion of people with common immune disorders who take methotrexate have deficiencies in mounting an antibody and cellular response,” says study co-senior author Jose U. Scher, MD, an associate professor in the Department of Medicine at NYU Langone. “This may not necessarily mean that the vaccine is not efficacious, but that alternate vaccine strategies need to be investigated.”

These alternate vaccine strategies include potentially discontinuing methotrexate during the time these patients receive the vaccine, changing the dosage of methotrexate, or possibly administering a booster shot to the vaccine, says Dr. Scher, who is also director of the Psoriatic Arthritis Center at NYU Langone. The research team is currently leading studies to determine the best course of action for these patients.

This work was supported by National Institutes of Health grants R01 AR074500, T32 AR069515, and UM1 AI148574; a Rheumatology Research Foundation Scientist Development Award; the Bloomberg Philanthropies COVID-19 Initiative; the Pfizer COVID-19 Competitive Grant Program; The Beatrice Snyder Foundation; and The Riley Family Foundation.

Dr. Scher has served as a consultant for Janssen, Novartis, Pfizer, Bristol Myers Squibb, Sanofi and UCB, and Abbvie, and he has received funding for investigator-initiated studies from Novartis, Sanofi, Pfizer, and Janssen. Dr. Haberman has received consulting fees from Janssen. Study co-investigators Peter M. Izmirly, MD, has received consulting fees from GSK and Momenta/Janssen; and Steven B. Abramson, MD, has received grants from Johnson and Johnson. Study co-corresponding author Mark J. Mulligan, MD, has received grants from Eli Lilly, Pfizer, and Sanofi and personal fees from Meissa Vaccines. All of these relationships are being managed in accordance with the policies and procedures of NYU Langone.

In addition to Dr. Scher, Dr. Haberman, Dr. Izmirly, Dr. Abramson, and Dr. Mulligan, other NYU Langone investigators are co-first authors Ramin Herati, MD, and Marie Samanovic-Golden, MD; and study co-investigators Rebecca B. Blank, MD, PhD; Michael Tuen, PhD; Sergei B. Koralov, PhD; Joseph R. Allen; Rochelle L. Castillo, MD; Amber R. Cornelius; Paula J. Rackoff, MD; Gary E. Solomon, MD; Samrachana Adhikari, PhD; Natalie E. Azar, MD; Pamela Rosenthal, MD; Jonathan Samuels, MD; Brian D. Golden, MD; and Soumya M. Reddy, MD. Other researchers involved in the study are co-corresponding author Georg Schett, MD, PhD; co-first author David Simon, MD; and study co-investigators Raja Atreya, MD; Koray Tascilar, MD; and Markus Neurath, MD, at Friedrich-Alexander University Erlangen Nuremberg.

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