Methotrexate Break Prevents Impairment of Variant Neutralization After COVID-19 Booster Dose

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The neutralizing serum activity against variants in patients receiving methotrexate only increased 20-23-fold after booster vaccination, while the serum activity in those in the non-immunosuppressed group increased 67-73-fold.

Patients who paused methotrexate (MTX) after receiving a COVID-19 booster dose had a similar vaccine response when compared with non-immunosuppressed persons (NIP). Those who continued MTX reported an impaired response, which indicates the potential benefits of a second booster vaccination. Results suggest that a 1-week MTX break is adequate if the last administration of the drug occurs between 1 and 3 days before COVID vaccination, according to a study published in Rheumatic & Musculoskeletal Diseases.1

“Various immunosuppressants reduce the immune response after COVID-19 vaccination,” investigators explained. “MTX is the most commonly prescribed disease-modifying antirheumatic drug in the world. MTX reduces the humoral vaccination response and CD8+T cell activation after second vaccination against COVID-19. Pausing MTX therapy 10 or 14 days after both vaccinations of the basic immunization against COVID-19 significantly improves the production of neutralizing antibodies.”

The observational cohort study, a continuation of a subanalysis analyzing factors that may influence humoral response of COVID-19 immunization in patients receiving MTX therapy, evaluated neutralizing serum activity against COVID-19 wild-type (Wu01) and the variants Omicron BA.1 and BA.2 via pseudovirus neutralization assay prior to mRNA booster immunization, and at 4 and 12 weeks after. At week 4 post booster vaccination, patients were asked whether MTX was paused. Of the 50 patients with rheumatic disease receiving MTX therapy, 26 paused the medication (defined as an interval longer than 7 days surrounding vaccination). Forty-four NIP were included in the control cohort.

The neutralizing serum activity against Wu01 and Omicron variants in patients receiving MTX only increased 20-23-fold after booster vaccination, while the serum activity in the NIP group increased 67-73-fold. Those who continued treatment with MTX had significantly lower neutralization against variants at both week 4 and week 12 when compared with patients who paused MTX as well as the control cohort, with the exception of BA.2 at week 12. Those who paused MTX had comparably high neutralizing capacities when compared with those in the NIP group, except for Wu01 at week 12. Pausing MTX after booster vaccination, as opposed to before, was linked to a significantly higher neutralization capacity for all variants. The optimal duration was 10 days after vaccination.

The study was strengthened by its closely selected timeline for collection of samples, a follow-up period of over 12 weeks, a similar age and sex distribution among cohorts, and a rigorous selection of MTX co-therapy. The use of virus neutralization assays against Omicron BA.1 and BA.2 is also considered the “gold standard” for the determination of COVID-19 neutralizing serum activity.

However, the lack of systemic recording of disease activity and safety, potential MTX pause recall bias, and the low number of cases limited the study. Further, although the entire control cohort was vaccinated with BTN162b2, 24% of patients in the MTX group were vaccinated with mRNA-1273. Lastly, investigators did not evaluate T-cell function within the cohort, therefore leaving questions regarding immunogenicity unanswered.

“Defining the aim of booster vaccinations as the induction of neutralizing capacities against variants comparable to that of NIP, then there is a need for a fourth vaccination in patients that continued MTX during first booster vaccination,” investigators concluded. “Further studies are needed to clarify whether a 1-week pause of MTX is not inferior to a 2-week pause.”


Habermann E, Gieselmann L, Tober-Lau P, et al. Pausing methotrexate prevents impairment of Omicron BA.1 and BA.2 neutralisation after COVID-19 booster vaccination. RMD Open. 2022;8(2):e002639. doi:10.1136/rmdopen-2022-002639