OP0162   SYSTEMIC SCLEROSIS PATIENTS HAVE ACTIVATING ANTIBODIES TARGETING BOTH ENDOTHELIN RECEPTOR TYPE A AND ANGIOTENSIN II TYPE 1 RECEPTOR PREDICTING WORSE PROGNOSIS

G. Riemekasten1, H. Heidecke2, M. Nšther3, M. Mattuci-Cirinic4, M. Worm5, L. Czirjak6, J. Van der Laar7, G. Burmester1, D. Dragun3
1Rheumatology, Charitť Universitštsmedizin, Berlin, 2Rheumatology, CellTrend GmbH, Luckenwalde, 3Nephrology, Charitť Universitštsmedizin, Berlin, Germany, 4Rheumatology, University of Fierence, Fierence, Italy, 5Dermatology, Charitť Universitštsmedizin, Berlin, Germany, 6Rheumatology, University of Pecs, Pecs, Hungary, 7Rheumatology, University of Nejmegen, Nejmegen, Netherlands

Background: Systemic sclerosis (SSc) is characterised by autoimmunity and vasculopathy leading to tissue fibrosis. Several studies indicate a role of angiotensin and endothelin receptor stimulation in the pathogenesis of tissue fibrosis and cardiovascular events.
Objectives: Herein, we tested the hypothesis that SSc patients have activating endothelin and angiotensin receptor antibodies related to severe cardiovascular events.
Methods: 212 patients with systemic sclerosis and 204 controls were analysed for the presence of anti-angiotensin II type 1 and anti-endothelin A receptor antibodies (ab) by a newly developed cellular ELISA based on cell lines transfected for the endothelin A receptor or the angiotensin II type 1 receptor. Patients with systemic sclerosis were assessed for their clinical symptoms. Activating capacity was analysed by a bioassay and by induction of ERK 1/2 kinase phosphorylation. Serial analyses of sera from the ASTIS trial that received either stem cell transplantation or cyclophosphamide were performed.
Results: Reactivities towards the ETAR and AT1T are present in 56.7% and 51.4% of the SSc sera, respectively, but only in 9.3% and in 12.9% of the controls including sera from healthy donors (n = 71), from patients with rheumatoid arthritis (n = 67), primary Raynaudís phenomenon (n = 33), and from 33 patients with morphea. Out of the 131 SSc patients with either anti-ETAR or anti-AT1R antibodies 110 patients (84%) have both antibodies with correlating antibody levels (p < 0.0001, r2 = 0.75). Patients with these antibodies have a more than 5-fold increased risk to suffer from digital ulcers and a more than 10-fold increased risk to develop pulmonary arterial hypertension, death or resuscitation. These antibodies induce ERK1/2 phosphorylation as well as a dose-dependent increase in the frequency of cardiomyocyte contractions that could be blocked by specific receptor blockers. The antibodies are refractory to several immunosuppressive treatments including cyclophosphamide or autologeous stem cell transplantation.

Conclusion: Anti-AT1R and anti-ETAR antibodies are a biomarker for severe disease and worse prognosis and could explain pathogenic features found in systemic sclerosis. The detection of these antibodies could identify SSc patients that might benefit from a receptor blockade or from a specific modulation of the antibody-receptor interaction.
References: The study was supported by EUSTAR, the German network of systemic sclerosis (DNSS), and by the German Scleroderma foundation