Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases

Abstract

Objective: To study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).

Methods: In this retrospective study, neutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 patients with AIRD on MTX therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 patients with AIRD without immunosuppressive medication.

Results: Patients on MTX showed a significantly lower mean antibody response compared with patients with AIRD without immunosuppressive therapy (71.8% vs 92.4%, p<0.001). For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001). All nine patients with antibody levels below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher mean neutralising antibody levels after second vaccination, compared with patients who continued MTX therapy during both vaccinations (83.1% vs 61.2%, p=0.001). This effect was particularly pronounced in patients older than 60 years (80.8% vs 51.9%, p=0.001). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.

Conclusion: MTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age.

Keywords: COVID-19; autoimmune diseases; methotrexate; vaccination.

Figure 1

Comparison of neutralising capacity in patients with autoimmune rheumatic diseases (AIRD) without immunosuppression and with methotrexate (MTX) therapy. Neutralising capacity measured using surrogate virus neutralisation test after second vaccination in patients on MTX (n=64) represented by red dots versus patients with AIRD who were under no immunosuppressive therapy during both vaccinations (n=21) represented by green dots. P values were calculated using the parametric unpaired t-test with Welch’s correction.

Figure 2

Comparison of patients with autoimmune rheumatic diseases (AIRD) who continued or held their methotrexate (MTX) during the COVID-19 vaccination. (A) Neutralising capacity measured using surrogate virus neutralisation test compared between patients who held MTX during vaccination (n=31) and patients who continued MTX therapy (n=33). (B) Neutralising capacity differentiated by age groups <60 years and ≥60 years. P values were calculated using the parametric unpaired t-test with Welch’s correction. Dotted line marks the cut-off value following manufacturer’s protocol (≥30%). Yellow squares represent patients who continued MTX therapy, purple dots represent patients who held MTX for at least one vaccination.

Figure 3

Correlation of age and neutralising capacity measured using surrogate virus neutralisation test. Purple dots represent patients who held methotrexate (MTX) during vaccination (n=31), yellow squares represent patients who continued MTX therapy (n=33). Neutralising antibodies were measured using a surrogate virus neutralisation test. Dotted lines mark the cut-off value following manufacturer’s protocol (≥30%) and the cut-off age used for further analysis at 60 years. P value and correlation coefficient were calculated using the Spearman’s rank correlation.

Figure 4

Visualisation of analysed time intervals. Time between methotrexate (MTX) intakes and COVID-19 vaccinations were assessed for each vaccination and added together to receive the total time before vaccinations (T_BV=T_BV1+T_BV2) and after vaccinations (T_AV=T_AV1+T_AV2). The MTX interval was defined as the total durations between two MTX intakes at the time of vaccination (T_AV+T_BV).