key: cord-0838739-1men8pke authors: Auroux, Maxime; Laurent, Benjamin; Coste, Baptiste; Massy, Emmanuel; Mercier, Alexandre; Durieu, Isabelle; Confavreux, Cyrille B; Lega, Jean-Christophe; Mainbourg, Sabine; Coury, Fabienne title: Serological response to SARS-CoV-2 vaccination in patients with inflammatory rheumatic disease treated with disease modifying anti-rheumatic drugs: a cohort study and a systematic review with meta-analysis date: 2022-04-28 journal: Joint Bone Spine DOI: 10.1016/j.jbspin.2022.105380 sha: 788afc965c61c1070713f220248f1707166a1a8e doc_id: 838739 cord_uid: 1men8pke Introduction: Vaccination is considered as a cornerstone of the management of COVID-19 pandemic. However, while vaccines provide a robust protection in immunocompetent individuals, the immunogenicity in patients with inflammatory rheumatic diseases (IRD) is not well established. Methods: A monocentric observational study evaluated the immunogenicity of a two-dose regimen vaccine in adult patients with IRD (n=123) treated with targeted or biological therapies. Serum IgG antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins were measured after the second vaccination. In addition, a search for observational studies performed in IRD under biologic or targeted therapies up to September 31, 2021 (PROSPERO registration number: CRD42021259410) was undertaken in publication databases, preprint servers, and grey literature sources. Studies that reported sample size, study date, location, and seroprevalence estimate were included. A meta-analysis was conducted to identify demographic differences in the prevalence of SARS-CoV-2 antibodies. Results: Of 123 patients (median age 66 IQR 57-75), 69.9% have seroconverted after vaccination. Seroconverted patients were older than non-seroconverted ones in our cohort. Rituximab was associated with a significantly low antibody response. Besides, we identified 20 seroprevalence studies in addition to our cohort including 4423 participants in 11 countries. Meta-analysis confirmed a negative impact of rituximab on seroconversion rate and suggested a less substantial effect of abatacept, leflunomide and methotrexate. Conclusion: Rituximab impairs serological response to SARS-CoV-2 vaccines in patients with IRD. This work suggests also a negative impact of abatacept, methotrexate or leflunomide especially when associated to biological therapy. Patients treated with immunosuppressive therapies have an increased risk of infections. International guidelines recommend the update of vaccinal calendar before starting an immunosuppressive treatment [1] . Previous works regarding pneumococcal or influenza vaccination have shown a decreased immunogenicity of vaccines in patients treated with immunosuppressive agents [2] [3] [4] [5] . A recent review by Friedman MA et al. has highlighted the negative impact of conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) such Methotrexate and biological treatments such rituximab or abatacept on immunogenicity of different vaccines [6] . Efficacy and safety of COVID-19 vaccines have been assessed in large clinical trials [7] [8] [9] [10] but inflammatory rheumatic diseases (IRD) patients have been largely excluded from these clinical trials, because of a theoretical risk of disease flare, induced inflammatory diseases [11] and a potential impaired immune response to vaccine due to the use of immunosuppressive agents. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection does not occur necessarily more frequently than in healthy subjects [12] , it has been shown to be more severe in patients treated with rituximab, mycophenolate mofetil or high-dose glucocorticoids [13] [14] [15] [16] [17] [18] . Despite limited data on efficacy and safety of SARS-CoV-2 vaccines, patients with inflammatory diseases treated with immunosuppressive agents have been prioritized to receive SARS-CoV-2 vaccination according American College of Rheumatology (ACR) guidelines [19] . Several studies report the serological response to SARS-CoV-2 vaccines in IRD patients [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] . We aimed to synthesize immunogenicity data to identify high-risk groups and inform public health decision making. Adult patients with IRD were recruited from May 2021 to September 2021 from rheumatology and internal medicine departments of our Lyon Sud University Hospital (France). Patients who underwent a serological assessment of response to SARS-CoV-2 vaccine after a full vaccination scheme were retrospectively included in this study. Patients with a history of symptomatic RT-PCR-confirmed COVID-19 were are presented with their 95% confidence interval (95% CI). A p-value lower than 0.05 was considered statistically significant. All analyses were performed using R 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). The study protocol was approved by local etic committee (Hospices Civils de Lyon Scientific and ethic committee, Number 21_572, September 6, 2021). The protocol of the present study was registered before in the International prospective J o u r n a l P r e -p r o o f 7 three board areas: selection, comparability, and ascertainment of the exposure or outcome of interest in cohort studies [42] . Studies with a score ≥ 5 stars were considered high quality, while studies with a score < 5 stars were rated as low quality. The proportion of patients with positive SARS-CoV-2 serology and its 95% confidence interval (95%CI) were estimated using arcsine transformation for all treatments and each of them. Heterogeneity between study-specific estimates was assessed using inconsistency index I 2 [43] , and random-effects models were a priori chosen because of expected heterogeneity. The risk of publication bias was determined by funnel plot aspect. All analyses were performed with R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria) with package 'meta' and 'metafor'. Overall, 123 patients (76.4% of female) were included with a median age of 66 Finally, we found in our cohort that the mean antibody titer (n=106) was also significantly lower in patients treated with biologic in combination with methotrexate compared to biologic monotherapy (767 BAU/mL vs 359 BAU/mL, Wilcoxon test P<0.05). A total of 1179 publications were identified. Thirty-five records were assessed for eligibility and finally 20 articles coming from 11 different countries were included in the meta-analysis in addition to our cohort ( Figure 1 ). The characteristics of these studies are shown in Table 3 The impact of DMARDs on the immune response to vaccine is clearly variable. The main factor implicated in impaired response to SARS-CoV-2 mRNA vaccine in patients with IRD was the immunotherapeutic agents rather than the underlying disease itself. An overall seroconversion rate of 84.8% was found in our meta-analysis. As a comparator, the seroconversion rate in healthy individuals enrolled in control groups of studies included in our meta-analysis was analysed. We found that 730/733 (99.5%) had seroconverted (excluding control group of Meideros-Ribeiro et al. [27] which received Coronavac and not mRNA based vaccine). In our cohort, rituximab was clearly associated with deeply reduced immune response, consistently with our meta-analysis. 10 Consistent with findings of Furer et al. [22] , Chung et al. [44] or Verhoeven et al. [45] , the delay between the last infusion of rituximab and the first injection of vaccine seems to have a critical impact on antibody response: a short delay between last rituximab infusion and first vaccination dose was shown to be associated with an impaired serological response to SARS-COV-2 vaccination. We found in our cohort a smaller delay between last infusion and first dose of vaccination in non-responders than in responders (respectively median time 174 (IQR 161-240) days in responders vs 121 (IQR 73-188) days in non-responders). Our work also suggests an impact of the rituximab dose on seroconversion rate, with more responders when patients are treated with 1G each cycle compared to 1G on day 1 and day 15. In our cohort, we have shown that the number of CD19+ cells was lower (unless the statistical significance was not obtained due to small effectives) in patients without seroconversion in the rituximab subgroup. This is consistent with previous findings of Mrak et al. [28] and more recently by Stefanski et al. [46] . We know that rituximab treatment is associated with a long immunosuppression duration, at least 6 to 9 months [47] . Therefore, the ACR guidelines [19] recommend to vaccine patients 2 to 4 weeks before the next rituximab infusion (i.e at least 5 months after the last injection). It might be interesting to measure the number of CD19+/CD20+ cells and vaccinate patients only when they are detectable if the disease is controlled at that time. Few studies have investigated the effect of the rituximab dose. In our cohort, we demonstrated that the proportion of serological response in patients receiving rituximab 1g on day 1 and day 15 every 6 months was lower than in patients receiving 1g only at day 1. We didn't investigate the cellular response to mRNA vaccination in our population. Methotrexate has been shown to negatively affect response to influenza and pneumococcal vaccine [4, 52, 53] . Regarding SARS-COV-2 vaccination, results are conflicting. Ammitzboll et al. found a lower response rate in patients treated with MTX in combination with a biologic treatment compared to biologic monotherapy [20] . Furer et al. found that MTX monotherapy was associated with a lower seroconversion rate compared to healthy controls but in a smaller magnitude than observed with rituximab [22] . In addition, in the study of Braun-Moscovici et al., antibody titers were lower when MTX was used [21] . In our cohort, methotrexate when combined with biological or targeted agents was associated with a significant decreased antibody titer. In meta- weeks MTX to improve serological response [19] . This approach needs to take in consideration the risk of disease flare in our patients. Regarding the type of vaccine, ACR guidelines [19] recommend only mRNA-based vaccines for immunosuppressed patients. This is consistent with results from the inactivated vaccine CoronaVac showing a significantly decreased response rate in immunosuppressed patients compared to seroconversion rate observed in cohort vaccinated with mRNA-based vaccines [27] . In our meta-analysis, this study contributed in part to the heterogeneity we observed, but the results we have presented remained similar when this study was excluded from the analyses. This meta-analysis confirmed the negative impact of rituximab on seroconversion rate and suggested a negative impact of abatacept, methotrexate and leflunomide. A strength of our study is that we choose to investigate the impact of treatment in reallife conditions. We were very selective regarding the pathologies included and the treatment studied. In comparison to other meta-analysis that have been published so far in other diseases [54] , we also selected only studies reporting seroconversion rate after a complete vaccinal schema of 2 doses and therefore analysed data on more than 4500 patients. On the other hand, we also know that studies included in this metaanalysis are mainly retrospective and non-exhaustive. Moreover, the populations are sometimes heterogeneous in terms of age or co-morbidities. In conclusion, we found that patients treated with immunosuppressive agents have a decreased serological response to mRNA vaccines especially when treated with rituximab and probably with abatacept, leflunomide or methotrexate. In this population, a third dose of vaccination is highly recommended. Prospective works are in progress to evaluate the effectiveness of this protection in immunosuppressed patients and the persistence of it during time, this will be of peculiar interest. MA has received consulting fees from Bristol-Myers Squibb outside from this work. Contributors: All authors contributed to manuscript preparation. 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