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Methotrexate suspension for 2 weeks after COVID-19 vaccination boosts antibody response

Cessation of methotrexate for two weeks after a COVID-19 vaccination boosted antibody levels significantly more than continuing with the drug

Stopping methotrexate (MTX) for as little as two weeks after receipt of a third COVID-19 vaccination dose results in a significantly higher level of antibodies produced in comparison to continuing with the drug, according to a team of UK researchers.

Use of the immunomodulatory drug methotrexate, is known to adversely affect the humoral and cellular immune response to COVID-19 mRNA vaccines. Moreover, it is also recognised that the seroconversion rates after COVID-19 vaccination are significantly lower in immunocompromised patients, especially organ transplant recipients. Therefore strategies to enable immunocompromised patients to mount a satisfactory immune response are urgently required. Interestingly, it has been shown that discontinuation of immunosuppressant drugs such as methotrexate in patients with rheumatoid arthritis, for either 4 weeks before, 2 weeks before and for 2 weeks after vaccination, improves the immunogenicity of seasonal influenza vaccination. In fact, the highest antibody response was achieved when the drug was stopped two weeks after vaccination and this effect was confirmed in another study that specifically focused on stopping the drug two weeks after seasonal influenza vaccination.

As the effectiveness of this strategy has not been formally evaluated for the COVID-19 vaccine, for the present study, the UK undertook a randomised trial among immunocompromised patients prescribed methotrexate. The Vaccine Response On/Off Methotrexate (VROOM) trial, randomised participants 1:1 to either suspension of MTX (suspend methotrexate) for a total of two weeks immediately after their COVID-19 booster dose, or to continue with the drug as usual (continue methotrexate). Included patients were recruited from both rheumatology and dermatology clinics and receiving low dose MTX (< 25 mg/week) for at least 3 months. In addition, the researchers only enrolled participants who had previously received two COVID-19 vaccine doses. The primary outcome of the study was the antibody response against the receptor-binding domain of the COVID-19 spike protein (S1-RBD) 4 weeks after receipt of the third COVID-19 vaccine dose. Secondary outcomes included S1-RBD antibody titres at 12 weeks post-vaccination and self-reported levels of disease activity.

Methotrexate suspension and S1-RBD antibody response

A total of 254 individuals with a mean age of 59.1 years (61% female) were recruited and randomised equally to either strategy. Overall, 51% of participants had rheumatoid arthritis, 34% psoriasis and 20% a skin condition alone. The median dose of methotrexate taken as 20 mg/week.

At week 4, the geometric mean SI-RBD antibody titre was 22,750 U/ml in the suspend methotrexate group and 10,798 U/ml in the continue methotrexate group (p < 0.0001). This increase was independent of the dose and administration route of methotrexate, as well as type of immune-mediated inflammatory disease and age. Moreover, this difference in response remained significant at week 12 (16,520 vs 8094).

One downside of the study was that significantly more patients in the suspend methotrexate group self-reported at least one disease flare over the 12 week period compared to those who continued with the drug (71% vs 45%, odds ratio, OR = 2.83, 95% CI 1.64 – 4.88). However, these flares were generally self-managed and without any major impacts on quality of life.

The authors concluded that their strategy of stopping MTX was both safe and boosted the level of COVID-19 antibodies and called for further studies to examine the effect of stopping other immunosuppressant drugs on the level of antibody response.

Abhishek A et al. Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial. Lancet Resp Med 2022

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