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 Oct;8(2):e002632. doi: 10.1136/rmdopen-2022-002632.


Background: Several health authorities recommend a third (booster) vaccination to protect patients with rheumatic and musculoskeletal diseases from severe COVID-19. Methotrexate has been shown to reduce the efficacy of the first and second dose of SARS-CoV-2 mRNA vaccines. So far, it remains unknown how concomitant methotrexate affects the efficacy of a COVID-19 booster vaccination.

Methods: We compared the humoral immune response to SARS-CoV-2 vaccination in 136 patients with rheumatoid arthritis (RA) treated with methotrexate and/or biological or targeted synthetic (b/tsDMARDs). IgG targeting the receptor binding domain (RBD) of SARS-CoV-2 spike protein was measured at a median of 52.5 (range 2-147) days after a third dose of the SARS-CoV-2 mRNA vaccines BNT162b2 or mRNA-1273.

Results: Anti-RBD IgG was significantly reduced in elderly patients receiving concomitant treatment with methotrexate as compared with elderly patients receiving monotherapy with b/tsDMARDs or methotrexate (64.8 (20.8, 600.3) binding antibody units per mL (BAU/mL) vs 1106.0 (526.3, 4965.2) BAU/mL vs 1743.8 (734.5, 6779.6) BAU/mL, median (IQR), p<0.001, Kruskal-Wallis test). In younger patients (< 64.5 years), concomitant methotrexate had no significant impact on the humoral immune response.

Conclusions: Concomitant methotrexate increases the risk of an insufficient humoral immune response to SARS-CoV-2 vaccination in elderly patients with RA. Pausing methotrexate during the third vaccination period may be considered for this group of patients.

Keywords: COVID-19; Methotrexate; Rheumatoid Arthritis.

Publication types

  • Letter

MeSH terms

  • Aged
  • Antibodies, Viral
  • Arthritis, Rheumatoid* / drug therapy
  • BNT162 Vaccine
  • COVID-19 Vaccines* / immunology
  • COVID-19* / prevention & control
  • Humans
  • Immunity, Humoral*
  • Immunoglobulin G
  • Methotrexate* / therapeutic use
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus


  • Antibodies, Viral
  • COVID-19 Vaccines
  • Immunoglobulin G
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • BNT162 Vaccine
  • Methotrexate