Concomitant Methotrexate Linked to Reduced Efficacy of COVID-19 Booster Dose in Elderly Patients with RA

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Recent findings suggest that methotrexate reduces humoral vaccination response against COVID-19 in older, but not younger, patients with rheumatoid arthritis.

An increased risk of insufficient humoral response to the COVID-19 vaccination was seen in elderly patients with rheumatoid arthritis (RA) receiving concomitant methotrexate (MTX). A methotrexate pause of about 2 weeks during the third booster vaccination period may be beneficial for this patient population, according to a study published in Rheumatic & Musculoskeletal Diseases.1

“The SARS-CoV-2 mRNA vaccines BNT162b2 and mRNA-1273 provide efficient protection against severe COVID-19 infections for patients with RA or other rheumatic and musculoskeletal diseases (RMDs),” investigators explained. “However, some antirheumatic drugs have been negatively associated with vaccine immunogenicity, including rituximab and mycophenolate. Recently, it has been shown that MTX reduces humoral vaccination response against SARS-CoV-2 in older but not younger patients with RA.”

In the retrospective analysis, investigators examined the humoral immune response against a third dose of COVID-19 vaccination in 136 patients with RA who were receiving MTX and/or biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). All eligible patients met the American College of Rheumatology (ACR)/ European Alliance of Associations for Rheumatology (EULAR) classification criteria for RA. Immunoglobulin G (IgG) targeting the receptor binding domain (RBD) of the COVID-19 spike protein was evaluated via blood sample at a median of 52.5 (range 2-147) days after the third booster dose. Information collected included age, sex, disease duration, time between second and third doses, and the time between third dose and blood draw for serum-level analysis, which were comparable across treatment groups.

Antibody response to RBD, which was determined using the SARS-CoV-2 IgG II Quant assay on the Alinity i (Abbott), was reported in 97.1% (n =132/136) of patients with RA. In elderly patients receiving concomitant methotrexate, anti-RBD IgG was significantly reduced when compared with elderly patients treated with either monotherapy 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, respectively). There were no differences in humoral anti-RBD response between elderly patients receiving MTX monotherapy and elderly patients receiving bDMARD or tsDMARDs monotherapy. Further, MTX monotherapy had no significant impact on humoral response when compared with patients who were not receiving antirheumatic treatment (1743.8 [659.1, 5091.0] BAU/mL vs 1475.5 [727.1, 5228.4] BAU/mL, respectively).There was no significant impact on humoral immune response in younger patients, defined as < 64.5 years, receiving concomitant methotrexate.

Investigators did not assess treatment modification at the time of vaccination nor pre-vaccination titers, which may have led to the possibility that some patients modified their MTX treatment during the vaccination period without discussing it with their physician.

“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,” instigators concluded. “Moreover, we can confirm earlier results, showing that MTX reduces the humoral vaccination response against SARS-CoV-2 especially in older but not younger 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