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BackgroundPolymyalgia rheumatica (PMR) is an inflammatory disease. But it’s pathophysiology and the impact of the treatments on immune cells are poorly known.ObjectivesOur objectives were to describe the immune cells of patients with PMR dependent from glucocorticoids and to analyze their evolution under tocilizumab.MethodsThe SEMAPHORE trial (NCT02908217, (1)) was a randomized control trial including patients with PMR dependent from glucocorticoids. Between inclusion and week 12, patients were blindly treated with either tocilizumab infusion or placebo infusion every 4 weeks associated to a tapering of glucocorticoids. Age and sex-matched healthy controls (HC) were recruited in the rheumatology department of the Brest University Hospital. HC did not have any history or presence of cancer, auto-immune disease or active infection and did not received treatment with a known impact on the immune system. We analyzed immune cells on whole fresh blood after red cell lysis on flow cytometry (Navios, Cytoflex, Beckmann Coulter) after staining for CD16, CD56, CD19, CD14, CD4, CD8, CD3, CD45, IgD, IgM, CD21, CD27, CD24, CD38, CD5 CD126, CD62L, CD45RA, CD127, CD25, in four different panels.ResultsSamples were obtained for 40 PMR patients and 34 HC. At inclusion, in PMR patients, compared to HC, CD14+CD16- classical monocytes were increased (82±1% vs 77±2%, p=0.01), CD14-CD16+ non-classical monocytes were decreased (4±0.3% vs 7±0.6%, p<0.0001), granulocytes were increased (63±2% vs 52±2%, p<0.0001), natural killer cells were decreased (8±1% vs 13±1%, p=0.007). B cells were decreased (8±0.6% vs 10±0.8%, p=0.03), but with an enrichment in CD27-IgD- senescent B cells (p<0.0001) and in CD21lowB cells (p=0.04). T cells were increased (70±2% vs 64±2%, p=0.02) with an enrichment in CD4+ T cells (p=0.02) and in CD4+CD25highCD127- regulatory T cells (p<0.0001). At week 12, in PMR patients receiving tocilizumab therapy, compared to PMR patients receiving placebo, granulocytes were lower (58±5% vs 73±2%, p=0.006) and monocytes were higher (8±1% vs 5±0.5%, p=0.02).ConclusionIn patients with a PMR dependent from glucocorticoids, immune cells homeostasis is disturbed. Tocilizumab has an impact more pronounced on granulocytes and monocytes. Knowledge about immune disturbance in PMR might help to choose to use a targeted therapy when glucocorticoids are not sufficient.Reference[1]Devauchelle-Pensec V, Carvajal-Alegria G, Dernis E, Richez C, Truchetet ME, Wendling D, et al. Effect of Tocilizumab on Disease Activity in Patients With Active Polymyalgia Rheumatica Receiving Glucocorticoid Therapy: A Randomized Clinical Trial. JAMA. 20 sept 2022;328(11):1053‑62.Acknowledgements:NIL.Disclosure of InterestsGuillermo CARVAJAL ALEGRIA Speakers bureau: Abbvie, Lilly, Novartis, Chugai, Biogen, BMS, Galapagos, Pfizer, Consultant of: Abbvie, Lilly, Novartis, Galapagos, Pfizer, Sara Boukhlal: None declared, Sophie Hillion: None declared, Pierre Pochard: None declared, Emmanuelle Porchet: None declared, Alain Saraux Speakers bureau: Chugai, Consultant of: Chugai, Grant/research support from: Chugai, Sandrine Jousse-Joulin Speakers bureau: Chugai, Consultant of: Chugai, Grant/research support from: Chugai, THIERRY MARHADOUR: None declared, Dewi Guellec: None declared, Divi Cornec Speakers bureau: Chugai, Consultant of: Chugai, Grant/research support from: Chugai, Valerie Devauchelle-Pensec Speakers bureau: Chugai, Consultant of: Chugai, Grant/research support from: Chugai.

Immunological memory is essential for effective immune protection upon antigen rechallenge. Memory B cells encompass multiple subsets, heterogeneous in terms of phenotypes, origins and precursors, anatomical localization, and functional responses. B-cell responses are conditioned by micro-environmental signals, including cytokines. Here, we analyzed in vitro the effects of two cytokines implicated in B-cell differentiation, interferon-alpha (IFN-α) and interleukin (IL)-21, on the early functional response of four different mature B-cell subsets (IgD- CD27- naive, IgD+ CD27+ unswitched, IgD- CD27+ switched and double-negative B cells). The dual response of naive and memory B cells to IL-21 allowed us to uncover a unique IgD+ CD27- CD10- B-cell population (referred to as NARB+) characterized by the expression of marginal zone B-cell markers CD45RB and CD1c. Similar to memory B cells, NARB+ cells were in a pre-activated state, allowing them to rapidly differentiate into plasmablasts upon innate signals while maintaining their susceptibility to IL-21 activation-induced apoptosis as observed for the naive compartment. Both in-depth phenotypic analysis of circulating B cells, and identification of these cells in spleen, tonsil and gut-associated lymphoid tissues, supported that NARB+ are uncommitted precursors of human marginal zone B cells.

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