Pausing drugs and spacing vaccines: an open question.

We read with interest the Article by Andrea Rubbert-Roth and colleagues, which reported that among 53 patients with rheumatoid arthritis on various biological, conventional synthetic, and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), antibody responses to COVID-19 vaccination was reduced compared with healthy controls.

The authors reported that their data implied that successful vaccination of patients with rheumatoid arthritis who are taking DMARDs might depend on an interval of 3–6 weeks between vaccinations, but we propose that a longer interval might be of benefit to some patients. Methotrexate is known to reduce the immunogenicity of influenza and pneumococcal vaccinations, and Haberman and colleagues suggested that this fact might also be true of COVID-19 vaccination in patients with immune-mediated inflammatory diseases.

It is possible that a short discontinuation of methotrexate might increase the immune response that is induced by COVID-19 vaccination. Indeed, one study of seasonal influenza vaccination in patients with rheumatoid arthritis receiving methotrexate noted that, in people with stable disease (mean Disease Activity Score 28-CRP=2·3 [SD 1·1]), a discontinuation of the drug for 2 weeks after vaccination resulted in greater humoral responses, without a convincing increase in flares (5·1% vs 10·6%; p=0·070) or use of rescue medications (4·5% vs 6·3%; p=0·49).

For an interval of 3 weeks between vaccine doses, methotrexate would need to be withheld for a total of 5 weeks. An interval of 12 weeks between doses of COVID-19 vaccine (ie, the recommended maximum interval in the UK) would allow methotrexate to be safely discontinued for 2 weeks after to first dose, resumed for 10 weeks, and discontinued for a further 2 weeks after the second dose before returning to usual therapy. Another option would be the use of a single-dose vaccine, such as the Ad26.COV2.S vaccine (Janssen), which would require a pause in methotrexate therapy for just 2 weeks. In stable patients, this pause might allow optimisation of a vaccine-induced immune response without significant risk of disease flare. The external validity of these data is poor, and further research is required, particularly in patients with organ-threatening diseases (eg, antineutrophil cytoplasmic antibody-associated vasculitis and systemic lupus erythematosus). While we await large studies to support these findings, we suggest temporary methotrexate discontinuation as a pragmatic approach to maximising vaccine effectiveness in patients with a low risk of flare.

MR and SD are Medical Research Council Clinical Training Fellows based at the University of Manchester and supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (MR/N025989/1), Roche Pharma, Eli Lilly, UCB Pharma, Novartis, the University of Liverpool, and the University of Manchester. MR and SD have also received support from UCB to attend academic meetings. IB reports having received research support from GlaxoSmithKline; consulting fees from AstraZeneca, Eli Lilly, ILTOO Pharma, Aurinia, and GlaxoSmithKline; speaker fees from UCB; and having participated in an advisory board for AstraZeneca. BP declares no competing interests.