Methotrexate Discontinuation May Improve Influenza Vaccine Response During the COVID-19 Pandemic

elderly man receiving vaccine, injection, influenza
Study authors evaluated the effects of methotrexate discontinuation on influenza vaccine response during the COVID-19 pandemic.

A temporary discontinuation of methotrexate (MTX) after receiving the influenza vaccine may improve vaccine response in patients with rheumatic disease, according to a comment published in Lancet Rheumatology. Study authors noted that a 2-week period of MTX interruption was not associated with significant worsening of disease activity, though longer drug-free periods were associated with disease flares.

Methotrexate is often used as the first-line treatment for rheumatoid arthritis (RA); however, the immunosuppressive effects of the disease-modifying antirheumatic drug may compromise vaccine response. Study authors reviewed the current literature evaluating the effects of temporary MTX discontinuation on antibody titers to the trivalent influenza vaccine.

In a 2017 randomized clinical trial, patients receiving MTX for RA were randomly assigned to continue MTX (n=54); suspend MTX for 4 weeks before vaccination (n=44); suspend MTX for 2 weeks prior to and 2 weeks after vaccination (n=49); or suspend MTX for 4 weeks after vaccination (n=52). Satisfactory vaccine response (defined as a ≥4-times increase in antibody titer) was achieved by the majority of all groups. However, antibody titers were highest in the group that suspended MTX for 4 weeks after vaccination.

In a subsequent prospective, multicenter study, patients with RA were randomly assigned to continue MTX (n=156) or withhold MTX for 2 weeks (n=160) after receiving the quadrivalent influenza vaccine. Results of this analysis indicated that a satisfactory antibody titer was achieved by 75.5% of the MTX-withholding group compared with 54.5% of the control group (P <.001). Neither group experienced significant disease flares.

In a post-hoc analysis of both studies, discontinuation for a 4-week period was associated with a moderate increase in disease flares. However, a discontinuation of MTX for 2 weeks did not induce higher disease activity.

These data may suggest that a brief discontinuation of MTX after influenza vaccination may increase antibody titer.

However, the studies had limited generalizability; both were conducted in South Korea, with low baseline MTX doses. In addition, factors such as patient age, MTX administration route, duration, and degree of disease activity were unclear. An international prospective cohort is necessary to better explore the effect of MTX interruption on vaccine response.

Study authors noted that vaccination was an important tool to prevent co-infection with seasonal influenza and COVID-19. “[W]e feel that the available evidence merits individualized discussions with patients with well-controlled disease the potential benefits and risks of omission of 1 [to] 2 doses of methotrexate, influenza vaccine efficacy, and perhaps COVID-19 vaccination when available,” they wrote.

Disclosure: Study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Mehta P, Sanchez E, Moraitis E, et al. Influenza vaccination and interruption of methotrexate in adult patients in the COVID-19 era: an ongoing dilemma. Lancet Rheumatol. Published online November 10, 2020. doi:10.1016/S2665-9913(20)30392-1