Efficacy of COVID-19 Booster Reduces With Methotrexate in Older Patients With RA

Concomitant administration of methotrexate increases the risk for an inadequate immune response to the mRNA COVID-19 vaccines in older patients with RA.

Among older patients with rheumatoid arthritis (RA), pausing concomitant methotrexate (MTX) during the third booster dose of the SARS-CoV-2 mRNA vaccine may improve the humoral response to the vaccine, according to results of a retrospective analysis published in RMD Open.

Although MTX has been shown to decrease the efficacy of the first and second doses of the COVID-19 mRNA vaccines, the effect of concomitant MTX on the efficacy of the third SARS-CoV-2 booster dose remain unknown.

Researchers studied the humoral immune response to the third dose of the COVID-19 mRNA vaccines in individuals with RA receiving treatment with MTX and/or biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs).

Blood samples from all participants were collected at a median of 52.5 days (range, 2-147 days) after the third dose of the mRNA vaccine. Antibody response to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein was determined using an immunoglobulin G (IgG) assay and reported in binding antibody units per mL (BAU/mL).

A total of 136 patients with RA were included in the study. Anti-RBD antibodies were detected in 97.1% (n=132) of the participants.

To our knowledge, this is the first report showing that a concomitant MTX therapy reduces the efficacy of a booster shot of SARS-CoV-2 mRNA vaccines in elderly patients with RA.

Older patients with RA (ie, ≥64.5 years) receiving concomitant MTX therapy along with b/ts DMARDs had significantly lower serum levels of anti-RBD SARS-CoV-2 IgG compared with those receiving b/ts DMARD monotherapy or those receiving MTX monotherapy (64.8 vs 1106.0 vs 1743.8 BAU/mL, respectively; P <.001).

No differences were observed in humoral anti-RBD response between older participants receiving bDMARD monotherapy and those receiving tsDMARD monotherapy.

Among the younger subgroup of patients (ie, <64.5 years), as well, the researchers did not observe any differences in anti-SARS-CoV-2 IgG serum levels between those receiving MTX monotherapy and b/tsDMARDs.

Of note, MTX monotherapy had no significant impact on humoral anti-SARS-CoV-2 response among patients receiving vs not receiving antirheumatic treatment (1743.8 vs 1475.5 BAU/mL, respectively; P =.982).

Study limitations included that fact that treatment modification at the time of
SARS-CoV-2 vaccination and prevaccination titers were not evaluated and the possibility that some patients may have modified their MTX treatment during vaccination without consulting their physicians.

According to the study authors, “…discontinuation of concomitant MTX treatment for about 2 weeks might help to improve vaccine immunogenicity of booster shots in this group of [older] patients . . . .” This appears to be “the first report” to demonstrate that “a concomitant MTX therapy reduces the efficacy of a booster shot of SARS-CoV-2 mRNA vaccines in [older] patients with RA.


Stahl D, tho Pesch C, Brück C, et al. Reduced humoral response to a third dose (booster) of SARS-CoV-2 mRNA vaccines by concomitant methotrexate therapy in elderly patients with rheumatoid arthritis. RMD Open. 2022;8(2):e002632. doi:10.1136/rmdopen-2022-002632