AB0171 THE IMMUNOMODULATORY AND ANTI-INFLAMMATORY EFFECTS OF BOSENTAN IN SYSTEMIC SCLEROSIS
Authors: M. G. Tinti, T. Mazza, L. D’agruma, A. De Cata
Journal: Annals of the Rheumatic Diseases (2020)

Background: Plasma endothelin-1 (ET-1) levels are increased in patients with systemic sclerosis (SSc), playing a central role in the development of fibrosis, vasoconstriction and inflammation 1 . While the beneficial effect of Bosentan, the endothelin receptor antagonists, have been demonstrated on vasoconstriction and fibrosis, its potential anti-inflammatory and immunomodulatory activity needs to be further investigated. Objectives: To assess whether Bosentan can modulate the gene expression profile of immune cells in sample of patients with limited and diffuse SSc and active digital ulcers. Methods: We enrolled 34 patients affected by SSc. Twenty-four patients were affected by limited SSc and 12 by diffuse SSc. Blood samples were collected from patients before and after 24 weeks of treatment with Bosentan, in the absence of immunosuppressive therapies. All patients received Bosentan 125 mg twice a day for 24 weeks. Gene expression profiles were assessed by GeneChip® Human Transcriptome Array 2.0 microarray technology. Significantly (p-value&lt;0.05) and differentially (|FC|&gt;1.5) expressed genes pre/post treatment were obtained by paired t-statistics, as implemented in Partek Genomics Suite ver. 6.6. These genes were subjected to functional enrichment analysis by Ingenuity Pathway Analysis. The effect of Bosentan on patients was studied on the “diffuse” and “limited” sub-cohorts, individually, as well as on the whole cohort. Results: Contrary to the limited cohort where differentially expressed genes resulted to be all non-coding genes which are almost all over-expressed before treatment, the diffuse cohort was characterized by 19 differentially expressed genes that enrich biological functions and pathways related to the immune system and its organic response (in particular T-cells). Comparing the limited to the diffuse cohort, pre- and post- treatment, a distinct genetic fingerprint emerges, that characterizes the response to Bosentan by the latter cohort as increased apoptosis of lymphocytes (z-score=3.28) and a decreased quantity of antigen presenting cells (from z-score=1.06 (pre) to -0.75 (post)). Conclusion: The presence of an inflammatory microenvironment, as occur in SSc, influence the relative expression of ET-1 receptors on immune cells, which in turn further contribute to the amplification of cellular responses to inflammation. The observed difference response to therapy between the two cohorts of patients was attributed to influence of ET-1 levels on the relative expression of ET-1 receptors on immune cells surface. Interestingly Bosentan, beside the already-known effect on promoting antigen presenting cells apoptosis, seem to exert its immunomodulatory activity also by deregulating functions that mainly involves the T cells and by promoting their apoptosis, which in turn reflect also its anti-inflammatory proprieties. References: [1]Tinazzi E, Puccetti A, Patuzzo G, et al. Endothelin receptors expressed by immune cells are involved in modulation of inflammation and in fibrosis: relevance to the pathogenesis of systemic sclerosis. J Immunol Res. 2015;2015:147616. Disclosure of Interests: None declared