Effect of stopping methotrexate on covid-19 vaccination

A key challenge at this stage of the Covid-19 pandemic is to improve vaccine-induced immunity in immunocompromised people. Methotrexate, the most prescribed antirheumatic drug worldwide, is the first-line treatment for rheumatological conditions such as rheumatoid arthritis and is often the first-line systemic treatment for skin conditions such as psoriasis.

Withdrawing methotrexate treatment for two weeks after influenza vaccination resulted in increased immunity to vaccination in patients with rheumatoid arthritisno effect of discontinuation of treatment up to four weeks before vaccination in previous studies.


The aim of the study was to assess whether a two-week interruption of methotrexate treatment immediately after the Covid-19 vaccine improved antibody responses against the S1 receptor binding domain (S1-RBD) of the protein. peak Comparison of SARS-CoV-2 with uninterrupted therapy in patients with immune-mediated inflammatory diseases.

This was an open-label, prospective, parallel-group, multicentre, randomised, controlled study conducted in 26 hospitals in the UK. Adults were recruited from rheumatology and dermatology clinics diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, spondyloarthritis axial dermatitis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose methotrexate weekly (≤ 25 mg weekly) for at least three months. Participants were also required to have received two primary doses of vaccine from the UK’s Covid-19 vaccination programme.

The primary endpoint was S1-RBD antibody titer four weeks after receiving the booster dose of the Covid-19 vaccine, assessed in the intent-to-treat population.


Between September 2021 and March 2022, 340 participants were recruited. The mean age was 59.1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titer was 22,750 U/mL (95% CI 19,314-26,796) in the methotrexate suspension group and 10,798 U/mL (8,970-12 997) in the continuous methotrexate group, with a geometric mean ratio of 2.19 (95% CI 1.57–3.04; p<0.0001; mixed effects model).


The increased antibody response in the methotrexate suspension group was consistent regardless of methotrexate dose, route of administration, type of immune-mediated inflammatory disease, age, vaccination platform, and history of SARS-CoV-2 infection. There were no serious adverse events related to the intervention. With this, the study showed that a two-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in an increased increase in antibody responses after vaccination with covid-19. This intervention is simple, inexpensive, easy to implement, and could potentially result in increased vaccine efficacy and duration of protection for susceptible groups.

Practical messages

  • Immunocompromised patients have a poorer immune response to covid-19 vaccines;
  • Patients who are chronic users of methotrexate and who are stable with underlying disease may discontinue treatment for approximately two weeks after the vaccine dose, showing better vaccine booster responses;
  • The combination of vaccines with different platforms does not appear to pose risks for this population, with an apparent better vaccine response.

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