Infections
of effector distal cytokines, exerted deleterious effects, as described with another vaccines. 15 When comparing humoral response, we observed substantial reductions in seroconversion and antibody titres in patients with ISP+ compared with to patients with ISP−. The lowest seroconversion rate was observed in patients receiving abatacept compared with patients with IMRD ISP− and the rest of patients with IMRD ISP+, that was also associated with the lowest T-cell responses. BMB and RTX-treated patients showed reduction in seroconversion and antibody titres after vaccination. Nevertheless, in these patients, T-cell responses were successfully induced in most, suggesting that humoral response is more affected than cellular response, as previ- ously reported in patients treated with B-cell depleting therapies vaccinated with influenza and pneumococcal vaccines. 16 17 We observed a positive correlation between mean interval from last RTX dose and immunogenicity and found that most patients vaccinated within 9 months after RTX treatment showed lower seroconversion and antibody levels. These findings are consistent with previous studies regarding the influence of anti-CD20 therapy on humoral response and as predictor of failure to seroconvert. 18–21 As already reported with other types of vaccines, 15 22 LFM, anti-TNF and IL-6i agents and antimalarials did not significantly affect mRNA vaccine’s humoral and cellular immune responses. In our study, the effect of MFM on humoral and cellular vaccine’s immunogenicity was milder than the observed with AZA. These data contrast with a study reporting lower serological responses to mRNA SARS- CoV-2 vaccines in recipients of solid organ transplants under immunosuppression (MFM or AZA), and also with another study in patients with rheumatic diseases under MFM. But in both studies, responses were measured after a single dose of vaccine, and cellular responses were not mentioned. 23 24 Seroconversion and anti-spike titres were moderately decreased, but T-cell responses mostly preserved, in patients treated with MTX. Consistent with our data, two other studies showed lower levels of spike-specific IgG in patients receiving MTX versus immunocompe- tent controls and patients receiving biologic agents, but cellular immunity was not hampered. 25 26 We did not observe decreased vaccine’s immunogenicity in patients on combined therapy with anti-TNF/IL-6i and MTX. In multivariate analysis, a negative correlation between humoral response and age >65 years was found, despite no association in univariate analysis. It is well-known that immunosenescence brought on by natural ageing leads to T-cell exhaustion and intrinsic B-cell defects, which alter immunogenicity. 27 Furthermore, since functional immunosuppression is related with length of disease and therapies, we also considered the influence of cumulative glucocorticoid and MTX dose. Interestingly, we found that disease duration >10 years, accumulated dose of glucocorticoids and MTX and treatment with abatacept
were also independent predictors of dimmed immunoge- nicity. But it has to bear in mind that collinearity among variables cannot be fully excluded. On the contrary, surprisingly, hydroxychloroquine had a positive effect on immune response to the vaccines. Our study has several strengths: we have included homogeneous study groups matched by age and gender, patients with different diseases and treatments, and have determined the effects on both humoral and functional cellular (CD4 and CD8) immune responses to this new vaccine strategy. While we still don’t understand the importance of cellular immune responses in COVID- 19, it is recognised that in immunosuppressed patients, vaccine-induced cellular immunity is a better surrogate for protection. 28–30 Cellular immunity has a crucial role in SARS-CoV-2, as specific CD4 and CD8 responses have been identified in healthy COVID-19-recovered indi- viduals, but also in recovered agammaglobulinemic patients. 31 32 Moreover, since our study is prospective, all patients will be followed for 1 year to assess vaccine’s clin- ical efficacy and duration related to their humoral and cellular immune responses. In addition, the effect of a booster dose will be evaluated. On the other hand, important limitations of the study also exist. Distinction between immunosuppressive and immunomodulatory drugs is at present far from clear, 33 rendering the choice of cohorts difficult. We reasoned that this weakness could be appropriately overcome by using a composite of objective features (online supple- mental material 2). The small number of patients treated with some drugs does not allow generalisation of conclu- sions. It has also to be recognised that even with a multi- factorial analysis, the net effect of any single characteristic analysed is difficult to envision. In light of our findings, it would be advisable to consider cell-mediated responses after vaccination in patients with immune-mediated inflammatory diseases. However, its clinical utility warrants further research with a greater number of vaccinated immunosuppressed patients. Contributors CSS, SC, JGRdM contributed to study design and developed the study protocol. CSS, SC, JGH and JGRdM contributed to sample preparation and performed the assays. CSS, CMM and EDA selected and recruited patients. CSS, SC, CMM, EDA, JGH, FR and JGRdM contributed to analysis and clinical interpretation of the data. CSS, FR and JGRdM performed the statistical analysis. CSS, SC, CMM, JGH, EDA, FR and JGRdM contributed to drafting and editing the final manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Funding CAULE'S Research funding 2021. Competing interests None declared. Patient consent for publication Not applicable. Ethics approval This study involves human participants and was approved by CAULE's Ethical Committee. Participants gave informed consent to participate in the study before taking part. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available in a public, open access repository. Not applicable. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially,
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Sieiro Santos C, et al . RMD Open 2022; 8 :e001898. doi:10.1136/rmdopen-2021-001898
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