SAT0026 IMPACT OF TOCILIZUMAB ON IMMUNE PHENOTYPES IN PATIENTS WITH LARGE VESSEL VASCULITIS

Abstract

Background The pathogenesis of large vessel vasculitis (LVV) such as Takayasu arteritis (TAK) and giant cell arteritis (GCA) consists of the immune abnormalities including the interaction between vascular dendritic cells, macrophages and T cells. It is reported that genetic polymorphisms in the immune-modulating cytokine genes such as IL6 and IL12B are associated with LVV. However, little is known about pathological immune cell subsets targeted by immunosuppressants and/or molecular-target therapy such as IL-6 blockade. Objectives The aim of this study was to assess the relationship between the phenotype of peripheral immune cells with clinical manifestations and responsiveness to the treatment in patients with LVV. Methods Peripheral blood mononuclear cells were obtained from 22 patients with active LVV (TAK 7, GCA 15) and 19 healthy donors (HD). All patients were treated with high dose glucocorticoid (GC). The study included the patients treated with immunosuppressive agents such as azathioprine and methotrexate (n=8) or with anti-IL-6 receptor antibody tocilizumab (n=7). The blood samples were taken at baseline and week 24 after treatment. The peripheral immune cell subset was defined based on comprehensive 8-color flow cytometric analysis for human immune system termed “the Human Immunology Project” by NIH and FOCIS (1), and the correlation with clinical characteristics and responsiveness to the therapies were evaluated. Results The proportion of CD3+CD4+CXCR3-CCR6+CD38+HLA-DR+ activated Th17 cells and CD3+CD4+CXCR5+ICOS+CD38+ activated Tfh cells in patients with TAK and that of activated Th17 cells and CD19+CD20+CD27-IgD- double negative effector B cells in patients with GCA were significantly higher compared with HD. At baseline, the frequency of activated Tfh cells showed positive correlation and that of CD4+CCR4+CD25+CD127low T regulatory (Treg) cells showed negative correlation with disease activity scores such as Indian Takayasu Activity Index (ITAS)2010 (2) and ITAS.A (CRP) in both TAK and GCA. The immunosuppressive therapy improved the disease activity in all patients. The frequency of activated Tfh cells was reduced by 24-week treatment with high dose GC and immunosuppressants in TAK and GCA. However, the frequency of Th17 cells was not changed by those treatments. Of note, tocilizumab decreased the proportion of activated Th17 cells and increased the proportion of Treg cells in both TAK and GCA. Conclusion The results indicated that the abnormal T cell differentiation correlated with disease activity of LVV. Although Tfh cell activation was improved, Th17 cell activation was not changed by the conventional immunosuppressive agents. By contrast, tocilizumab reduced Th17 cells and increased Treg cells, indicating that IL-6 blockade may correct the impaired balance of Th17 and Treg cells in patients with LVV.