This is the first large-scale demonstration of mRNA vaccine responsiveness in Asian patients with rheumatic diseases. For an accurate evaluation of the effect of treatments on antibody titer, the background of each group was made as uniform as possible. The absence of a history of COVID-19 was assessed not only by patient interviews but also by measuring antibody titers before vaccination. Patients treated with high-dose glucocorticoids and belimumab were excluded. Low racial diversity is suitable for assessing purely drug-induced effects. Our study findings demonstrate that drugs elicit different adaptive immune responses in patients with rheumatic diseases, with some keeping the antibody response while others markedly diminishing it.
CNI is one of the most used drugs for rheumatoid arthritis and other rheumatic diseases in the Asia-Pacific region. [4-6] To the best of our knowledge, this is the first report to examine the effect of CNI on humoral response to the mRNA vaccine in patients with rheumatic diseases. Rozen-Zvi et al. reported lower CNI blood level (less than ≤7 ng/ml) was associated with antibody response to SARS-CoV-2 mRNA vaccine among kidney transplant recipients.  In our report, the CNI group showed good humoral response; the median dose of tacrolimus was 3 mg/day (IQR, 2-3), and that of cyclosporine was 150 mg/day (IQR, 150-200). These results suggest that low doses of CNI used for rheumatic diseases do not reduce humoral response.
In most studies on seroconversion rates of mRNA vaccination in patients with rheumatic disease, MMF and RTX have been reported to reduce seroconversion rates after the second vaccination [3, 8, 9], which is consistent with the results of our study. ABT has also been reported to reduce the seroconversion rate in two large-scale studies [3, 8], whereas the seroconversion rate remained at 90.5% in our patients. Furer et al. reported a seroconversion rate of 40% (2/5) for ABT with MTX and 71% (5/7) for ABT monotherapy . Inconsistencies in our findings from those in previous reports may be largely owing to the exclusion of patients with concomitant MTX use in our study.
Whether MTX reduces the seroconversion rate remains controversial. Although Haberman et al. reported a decrease in adequate vaccine response to MTX, the adequate response in the study was assessed by the presence of antibody production above a certain level, not by true non-response . Bugatti et al. also reported that MTX was associated with a lower seroconversion rate after the first mRNA vaccination, but this was not evaluated after the second vaccination . On the other hand, in large-scale studies referring to seroconversion rate after the second mRNA vaccination, univariate analysis of seroconversion rates showed significant differences, and these differences disappeared in multivariate analysis [3, 8]. In our study, we also observed a high seroconversion rate in MTX monotherapy after the second vaccination. In the present study, MTX alone failed to reduce the seroconversion rate because of a lower dose of MTX used in Japan than that in other countries. For example, the median MTX dose was 10 mg/week (IQR, 8-12). We also revealed that the antibody titer significantly decreased in patients treated with TNFi in combination with MTX, which was not observed with TNFi alone. MTX in combination with other drugs may further reduce the antibody titer and seroconversion rate after the second mRNA vaccination.
Anti-SARS-CoV-2 RBD antibody titer measured by the Elecsys assay correlates with the effectiveness in preventing viral infections in ex vivo experiments , although it remains unclear what level of anti-SARS-CoV-2 RBD antibody titer would be effective in preventing severe disease or disease onset in the general population and in immunosuppressed patients. In a large observational study that included patients receiving immunosuppressive treatment, a third vaccination administered five months after the second vaccination was also reported to reduce the risk of severe illness and death . Even in post-renal transplant patients without antibody response to the second mRNA vaccination, seroconversion was observed in 27-38% after a third mRNA vaccination was received one month after the second vaccination [14, 15]. Our results indicate that an early third vaccination is desirable in patients under treatment that significantly reduce antibody titers.
There are limitations to this study. Foremost, this is an observational study. There may be bias relating to the type of mRNA vaccine used, as more than 90% of vaccinations in this study used BNT162b2, healthy controls were not included, and confounding factors other than sex, age, and glucocorticoid dose have not been considered. Additionally, although the Bonferroni-Dunn test is a robust method of analysis, it is difficult to achieve statistical significance. No significant differences were observed in treatments other than those in the five groups outlined previously; however, other study designs may have observed differences in other treatments, especially MTX.