Improving COVID-19 vaccine immunogenicity by interrupting methotrexate treatment

People with immune-mediated inflammatory diseases are at increased risk for COVID-19 infection and poor outcomes.¹ This risk might be partly due to immunosuppression from drugs such as methotrexate, commonly used to treat many immune-mediated inflammatory diseases.² Although COVID-19 vaccination has proven to be safe and effective, even for people with immune-mediated inflammatory diseases,3, 4 specific immunosuppressive medications, including methotrexate, have been associated with impaired immunogenicity.⁵ Due to the public health crisis and this at-risk population, the American College of Rheumatology recommends that conventional synthetic disease-modifying anti-rheumatic drugs such as methotrexate should be withheld “for 1–2 weeks (as disease activity allows) after each COVID-19 vaccine dose”.⁶ The only previous clinical trial to support this statement at that time was of methotrexate interruption after seasonal influenza vaccination in patients with rheumatoid arthritis.⁷ Thus, the possible effect on immunogenicity of pausing methotrexate after COVID-19 vaccination among people with other immune-mediated inflammatory diseases was unclear.

In The Lancet Respiratory Medicine, Abhishek Abhishek and colleagues did a randomised controlled trial in patients with immune-mediated inflammatory diseases investigating a 2-week interruption versus no interruption of methotrexate after a COVID-19 booster vaccine.⁸ 127 participants were randomly assigned to the suspend methotrexate group and 127 to the continue methotrexate group of the Vaccine Response On/Off Methotrexate (VROOM) study.⁸ About half of the participants had rheumatoid arthritis; other immune-mediated inflammatory diseases included psoriatic disease, spondyloarthritis, and polymyalgia rheumatica. 82% received the BNT162b2 vaccine (Pfizer–BioNTech) as their booster dose. The primary outcome was the geometric mean ratio (GMR) of the anti-spike-1 receptor-binding domain antibody (anti-S1-RBD) 4 weeks after receiving the vaccine, comparing the suspend and continue methotrexate groups. The suspend group had higher anti-S1-RBD concentrations than the continue group (GMR 2·19 [95% CI 1·57–3·04], p<0·0001) at week 4. This difference was present across many subgroups. At week 12, the suspend group also had higher anti-S1-RBD concentrations than the continue group. However, the suspend group was significantly more likely to report disease flare-ups at week 4 (56% vs 31%) and week 12 (71% vs 45%). Most flare-ups were mild, but systemic glucocorticoid use for flare-ups was numerically higher in the interruption group (18% vs 12%).

These results extend previous findings showing that interruption of methotrexate improves vaccine immunogenicity. Another recent trial among people with rheumatoid arthritis showed that a 2-week interruption of methotrexate after the CoronaVac COVID-19 vaccine (Sinovac) resulted in improved immunogenicity compared with no interruption.⁹ The VROOM study is the first to show that improved vaccine immunogenicity after methotrexate interruption occurs in people with immune-mediated inflammatory diseases other than rheumatoid arthritis. Considering this and the previous trials,7, 8, 9 the improvement in vaccine immunogenicity after methotrexate interruption might be broadly applicable across different vaccine types. However, the precise threshold of humoral response necessary for protection against COVID-19 is unclear. An observational study showed that there was an increased risk of COVID-19 breakthrough infection in patients with rheumatoid arthritis who had an absent humoral vaccine response compared with those with a good humoral vaccine response.¹⁰ Thus, although immunogenicity is clearly improved after methotrexate interruption, the clinical benefits to optimise clinical protection are still somewhat theoretical. Future work should investigate cellular responses and possible improved immunogenicity after interruption of other immunosuppressive medications, different vaccines, and other immune-mediated inflammatory diseases.

Because methotrexate is the anchor drug for control of immune-mediated inflammatory diseases, flare-up and increased disease activity are the risks patients take when interrupting this medication. Indeed, the VROOM study and other trials show short-term increased disease activity.7, 8, 9 Given that VROOM included many immune-mediated inflammatory diseases, a single validated measure of disease activity could not be obtained. The investigators were dependent on patient or provider reports, which might have been influenced by the open-label and unblinded nature of the study. Participants were required to have low disease activity at screening, so results might not generalise to patients with high disease activity. Trials investigating a 2-week versus 1-week interruption would establish whether a similar humoral response is achieved while conferring a lower flare-up risk. An observational study of patients with rheumatoid arthritis showed no difference in disease activity measured weekly pre-vaccination versus post-vaccination in those who interrupted versus continued methotrexate or other immunosuppressants.⁴ However, in routine clinical practice outside of a trial setting, it is difficult to discern whether increased disease activity after vaccination is due to methotrexate interruption, immune activation from the vaccine itself, or idiosyncrasies in these diseases that have a background flare rate. Thus, the VROOM study shows both possible benefit in optimising humoral vaccine response and the possible risk in underlying disease flares.

In summary, this important study shows that a 2-week interruption of methotrexate after booster COVID-19 vaccination results in increased immunogenicity compared with no interruption among patients with several immune-mediated inflammatory diseases. Although this finding adds to the evidence base to support interruption of methotrexate after vaccination, a shared decision process is needed to weigh the possible benefit of optimising protection from COVID-19 and the possible risk of underlying disease flare.

© 2022 Kateryna Kon/Science Photo Library

JAS reports consultancy fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, and Gilead, unrelated to this work. SKT reports consulting fees from NGM Biopharmaceuticals, unrelated to this work, and research grant payments from ModernaTx to her institution for a study of COVID-19 vaccination.