From the Journals

Ten-day methotrexate pause after COVID vaccine booster enhances immunity against Omicron variant



People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

A health care provider administers a flu vaccine to a patient Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Dr. Gerd Burmester

The study, published online in RMD Open, included a statistical analysis that determined that a 10-day pause after the vaccination would be optimal, Dr. Burmester said.

Dr. Burmester and coauthors claimed this is the first study to evaluate the antibody response in patients on methotrexate against Omicron variants – in this study, variants BA.1 and BA.2 – after getting a COVID-19 mRNA booster. The study compared neutralizing serum activity of 50 patients taking methotrexate – 24 of whom continued treatments uninterrupted and 26 of whom paused treatments after getting a second booster – with 25 nonimmunosuppressed patients who served as controls. A total of 24% of the patients taking methotrexate received the mRNA-1273 vaccine while the entire control group received the Pfizer/BioNTech BNT162b2 vaccine.

The researchers used SARS-CoV-2 pseudovirus neutralization assays to evaluate post-vaccination antibody levels.

The U.S. Centers for Disease Control and Prevention and other government health agencies have recommended that immunocompromised patients get a fourth COVID-19 vaccination. But these vaccines can be problematic in patients taking methotrexate, which was linked to a reduced response after the second and third doses of the COVID-19 vaccine.

Previous studies reported that pausing methotrexate for 10 or 14 days after the first two vaccinations improved the production of neutralizing antibodies. A 2022 study found that a 2-week pause after a booster increased antibody response against S1 RBD (receptor binding domain) of the SARS-CoV-2 spike protein about twofold. Another recently published study of mRNA vaccines found that taking methotrexate with either a biologic or targeted synthetic disease-modifying antirheumatic drug reduces the efficacy of a third (booster) shot of SARS-CoV-2 mRNA vaccine in older adults but not younger patients with RA.

“Our study and also the other studies suggested that you can pause methotrexate treatment safely from a point of view of disease activity of rheumatoid arthritis,” Dr. Burmester said. “If you do the pause just twice or once only, it doesn’t lead to significant flares.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).


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