POS1356 PERSISTENCE OF TFH CELLS AFTER RITUXIMAB IS ASSOCIATED WITH IGG4-RELATED DISEASE RELAPSE
Authors: G. Mancuso, T. Jofra, M. Lanzillotta, J. Gerosa, G. DI Colo, L. Dagna, G. Fousteri, E. Della Torre
Journal: Annals of the Rheumatic Diseases (2021)

Background: Clinical improvement after B-cell depletion with rituxmab suggests a prominent pathogenic role of B-lymphcytes in IgG4-related disease (IgG4-RD). IgG4-RD, however, relapses in most cases together with re-expansion of clonally divergent plasmablasts indicating that treatment with rituximab does not completely abrogates T follicular helper (Tfh)-cells dependent germinal center reactions leading to de-novo plasmablast differentiation. Objectives: In the present work we aim to study the effects of B-cell depletion therapy with rituximab on circulating Tfh cells and on the levels of CXCL13 - a chemotactic factor for B-lymphocytes produced by Tfh cells - in patients with IgG4-RD. Methods: Thirty patients with IgG4-RD, diagnosed according to the “Consensus Statement on the Pathology of IgG4-RD” and fulfilling the “2019 ACR/EULAR Classification Criteria” were included in the present study. Ten patients with relapsing disease were treated with the anti-CD20 monoclonal antibody rituximab (two 1g infuxions 15 days apart). Peripheral blood mononuclear cells and serum were collected before rituximab and three months after infusion. Tfh cells subsets in the peripheral blood were measured by flow cytometry and CXCL13 plasma levels were measured by ELISA assay. Results: No changes in total Tfh cells and Tfh cells subsets were observed three months after rituximab neither in absolute counts nor in percentage of CD4+ T cells. In particular, no difference in Tfh1, Tfh2, Tfh17, T follicular regulatory and highly functional Tfh cells counts was observed before and after treatment. The serum level of CXCL13 was significantly higher in active untreated IgG4-RD patients compared to healthy controls (151.94 pg/ml vs 66.98 pg/ml, p value = 0.0026), but was not affected by rituximab treatment (p value = 0.41). Conclusion: In relapsing patients with IgG4-RD rituximab does not affect circulating Tfh cells numbers and serum levels of CXCL13. Persistence of Tfh cells after rituximab and reconstitution of germinal center reactions likely drives IgG4-RD flare. References: [1]Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ. 2020 Jun 16;369:m1067. doi: 10.1136/bmj.m1067. PMID: 32546500. [2]Lanzillotta M, Della-Torre E, Stone JH. Roles of Plasmablasts and B Cells in IgG4-Related Disease: Implications for Therapy and Early Treatment Outcomes. Curr Top Microbiol Immunol. 2017;401:85-92. doi: 10.1007/82_2016_58. PMID: 28091934. [3]Campochiaro C, Ramirez GA, Bozzolo EP, Lanzillotta M, Berti A, Baldissera E, Dagna L, Praderio L, Scotti R, Tresoldi M, Roveri L, Mariani A, Balzano G, Castoldi R, Doglioni C, Sabbadini MG, Della-Torre E. IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients. Scand J Rheumatol. 2016;45(2):135-45. doi: 10.3109/03009742.2015.1055796. Epub 2015 Sep 23. PMID: 26398142. [4]Mattoo H, Mahajan VS, Della-Torre E, Sekigami Y, Carruthers M, Wallace ZS, Deshpande V, Stone JH, Pillai S. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol. 2014 Sep;134(3):679-87. doi: 10.1016/j.jaci.2014.03.034. Epub 2014 May 6. PMID: 24815737; PMCID: PMC4149918. Disclosure of Interests: None declared