Op0299 Dynamics of the B Cell Receptor Repertoire During the Preclinical Phase of Rheumatoid Arthritis: Longitudinal Studies in Untreated Ra-Risk Individuals (Domino Study) and the Effects of Rituximab Treatment (Prairi Study)

Background: In individuals with RA-associated antibodies (RA-risk individuals), B-cell depleting therapy delays the onset of arthritis, pointing to a key role for B-cell clones in the onset of arthritis1. Little is known about the dynamics and phenotype of the dominant B-cell clones in this phase of the disease, and the effect of Rituximab on these clones. Objectives: To study the dynamics and phenotype of dominant B-cell clones in peripheral blood of RA-risk patients, and to evaluate the effect of rituximab on these clones. Methods: Every 6 months we performed adaptive immune receptor sequencing (AIRR-seq) of the BCR-heavy (BCRH) chain on freshly isolated FACS-sorted phenotyped peripheral blood cells in a cohort of untreated RA-risk individuals (DOMINO study). In addition, we performed AIRR-sequencing on peripheral blood samples obtained from RA-risk individuals at screening, baseline, 6 and 12 months after treatment with rituximab (RTX; anti-CD20) or placebo (PRAIRI study). Results: In the DOMINO study we showed that dominant BCRH signatures are encoded by plasmablasts and/or plasma cells. Interestingly, after 6 and 12 months these dominant signatures in peripheral blood are present in low frequences and encoded by memory B cells. RTX induces clonal BCRH depletion in sequential peripheral blood samples, followed by a gradual re-establishment to the pre-treatment BCRH repertoire from 6 months onwards up to 12 months after treatment. Some of the pre-treatment dominant clones do come back in low frequencies, but none resurfaced as dominant clones after 12 months. Conclusion: In RA-risk individuals the BCRH repertoire in peripheral blood continuously changes over time. The most dominant BCRH signatures are encoded by plasmablasts and plasma cells, and intriguingly, over time these clonal BCRH signatures disappear from the plasmablast/plasma cell compartment and reappear as low frequency memory B cell clones. During recovery from RTX-induced B-cell depletion, after approximately 6 months, some of the dominant clones resurfaced, albeit at low frequencies. REFERENCES: 1 Gerlag, D.M., et al., Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study. Ann Rheum Dis, 2019. 78(2): p. 179-185. Acknowledgements: NIL. Disclosure of Interests: Anne Musters: None declared, Aram Al-soudi: None declared, Dornatien Anang: None declared, Ilse Niewold: None declared, Lisa G.M. van Baarsen: None declared, Barbera van Schaik: None declared, Antoine van Kampen: None declared, Danielle Gerlag Current employee of UCB pharma. UCB did not have any role in this project/study, Paul Peter Tak Current employee of Candel therapeutics. Candel therapeutics did not have any role in this study, Sander W. Tas: None declared, Niek de Vries: None declared.