OP0282 RITUXIMAB ASSOCIATED WITH SEVERE COVID-19 AMONG PATIENTS WITH INFLAMMATORY ARTHRITIDES: A 1-YEAR MULTICENTER STUDY IN 1116 SUCCESSIVE PATIENTS RECEIVING BIOLOGIC AGENTS
Authors: R. Felten, P. M. Duret, E. Bauer, M. Ardizzone, H. J. Djossou, J. H. Salmon, C. Fabre, J. Walther, I. Chary Valckenaere, M. Geoffroy, L. Messer, F. Berenbaum, M. Soubrier, J. Sellam, J. E. Gottenberg
Journal: Annals of the Rheumatic Diseases (2021)

Background: At a time when vaccines are being prioritized for individuals most at risk, there is currently no clear evidence that risk of SARS-CoV-2 infection is higher for patients with than without inflammatory arthritides (IA). Biologic use was not associated with worse COVID-19 outcomes for yet but the case of rituximab (RTX) remains an issue, given its immunological long term effect, the role of humoral response against SARS-CoV-2 and its indirect effect on T-cell response. A potential association between rituximab and worse COVID-19 outcomes was raised by case reports and retrospective, declarative studies (with few data on the total number of patients exposed). Objectives: To address differently the issue of the risk of COVID-19 related to RTX and limit biases, we examined the occurrence of severe COVID-19 in all patients receiving intravenous biologic agents at day-hospitals during the pandemic in France. Methods: From 1st September 2019 to 1st January 2021, we analyzed patients with IA prospectively treated with intravenous biologic agents (RTX, abatacept, infliximab or tocilizumab) in 7 clinical centers in France. We obtained the list of patients receiving intravenous biologic agents in each center from the pharmacist of the hospitals. Therefore, all consecutive patients receiving 1 of the 4 drugs at the time of the study were included in each center. Patients with no follow-up after September 2020 were systematically contacted by phone. The occurrence of a severe COVID -19 (i.e. resulting in death, hospitalization or increase in length of hospitalization related to COVID-19) was the primary outcome criteria. Results: In total, 1116 patients receiving intravenous biologic agents were included: 449 with infliximab, 392 RTX, 170 tocilizumab and 105 abatacept. From 1st September 2019, the median follow-up time was 15 months (interquartile range 14-16). In total, 10 cases of severe COVID-19 occurred, 9 treated with RTX and 1 with infliximab (supplementary Table 1). Four deaths occurred in our cohort during follow-up but none was related to COVID-19 (1 patient treated by tocilizumab, 1 by RTX and 2 by infliximab). In univariate analysis, the proportion of severe COVID-19 was significantly higher for patients receiving RTX than other biologic agents (9/392 vs 1/724, p=0.0003, OR [95%CI] 17.0 [2.1-134.6]). To take into account potential confounders, we performed multivariate analysis accounting for baseline parameters that differed between RTX and other biologic groups. RTX remained significantly associated with risk of severe COVID-19 (p=0.019) (Table 1). Patient characteristics Rituximab (n= 392 ) Other bDMARDs (n= 724 ) Univariate analysis, p-value Multivariate analysis, p-value Median age (years ), — [IQR] 64 [56-71] 57.3 [47.0-67.0] &lt; 0.0001 0.51 Female — n (%) 285 (72.7) 426 (58.8) &lt; 0.0001 0.58 IA diagnosis &lt; 0.0001 0.12 Median follow-up from 1st September to last news 14 [13-15] 15 [14-16] &lt; 0.0001 0.86 Confirmed severe COVID-19 cases —n (%) 9 (2.3) 1 (0.1) 0.0003 0.019 Comorbidities ** (history of) — n (%) Cardiovascular disease 60 (15.4) 167 (23.1) 0.0025 0.77 Chronic lung disease, 92 (23.5) 84 (11.6) 0.0001 0.88 Median BMI (kg/m 2 ) — [IQR] 25.8 [23.2-29.4] 27.3 [23.4-31.2] 0.015 0.80 Treatments — n (%) Methotrexate 179 (45.8) 322 (44.5) 0.71 Leflunomide 41 (10.5) 39 (5.4) 0.0023 0.43 Hydroxychloroquine 35 (8.9) 24 (3.3) 0.0001 0.15 Glucocorticoids 127 (41.8) 100 (19.4) &lt; 0.0001 0.36 Median dose (mg/day ) — [IQR] 1 [0-5] 0 [0-0] &lt; 0.0001 No significant difference in terms of baseline gammaglobulins (p=0.46) or number of previous RTX infusions (p=0.57) was observed among patients receiving RTX with or without a severe COVID-19. Conclusion: The present results highly indicate increased risk of severe COVID-19 with RTX. Among patients with inflammatory arthritides, those receiving RTX should be prioritized for vaccination against SARS-CoV-2, sufficiently long before infusion/reinfusion and the immunization checked, or an alternative targeted therapy proposed. Acknowledgements: We thank Dr. Karine Demesmay and all the pharmacists who helped us for this study. Disclosure of Interests: Renaud FELTEN Speakers bureau: Abbvie, Biogen, BMS, Lilly, Novartis, Pfizer, Pierre-Marie Duret: None declared, Elodie BAUER: None declared, Marc Ardizzone: None declared, H Julien Djossou: None declared, Jean-Hugues Salmon: None declared, Cassandre Fabre: None declared, Julia Walther: None declared, Isabelle CHARY VALCKENAERE: None declared, marion geoffroy: None declared, Laurent Messer: None declared, Francis Berenbaum: None declared, Martin SOUBRIER: None declared, Jérémie SELLAM Speakers bureau: MSD, Pfizer, Abbvie, Roche, BMS, Lilly, Janssen, Novartis, Galapagos, Sandoz, Fresenius Kabi, Grant/research support from: Roche, MSD, Pfizer, Jacques-Eric Gottenberg: None declared