Involvement of functional autoantibodies against vascular receptors in systemic sclerosis
Running head: Functional vascular autoantibodies
Gabriela Riemekasten1*, Aurélie Philippe2,4, Melanie Näther2,4, Torsten Slowinski3,
Dominik N. Müller5, Harald Heidecke6, Marco Matucci-Cerinic7*, László Czirják8*,
Ivo Lukitsch2,4, Mike Becker1*, Angela Kill1*, Jacob M. van Laar5*,
Rusan Catar2,4, Friedrich C. Luft5, Gerd R. Burmester1,
Björn Hegner2,4,Duska Dragun 2,4
1From the Medical Faculty of the Charité, Departments of Rheumatology and Clinical Immunology, German Rheumatology Research Centre, a Leibnitz institute, and 2Nephrology and Intensive Care Medicine, CVK, 3Department of Nephrology, CCM, 4the Center for Cardiovascular Research; 5the Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine – all in Berlin, Germany; 6CellTrend GmbH Luckenwalde, Germany; Department ofRheumatology and Immunology, 7Department of Rheumatology, University of Florence, 8Department of Rheumatology and Immunology, University of Pecs, Hungary, 9Institute of Cellular Medicine, Newcastle University, United Kingdom (JMvL). *EUSTAR investigators.
Key words: Angiotensin type 1 receptor (AT1R), Endothelin type A receptor (ETAR), autoimmune G-protein receptor (GPCR) activation, obliterative vasculopathy, anti-endothelial cell antibodies
Address reprint requests to Dr. D. Dragun, at the Department Nephrology and Intensive Care Medicine, Charité University Hospital Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany, tel. +4930450553485, fax. +4930450565925 or at .
SSc(N= 203) / Diffuse SSc
(N= 93) / Limited SSc
(N= 110) / RA
(N= 97) / Control
(N= 302)
Female sex (%) / 75.9 / 66.7 / 83.6 / 74.3 / 75.8
Age (y) / 50.8
(49.0-52.5) / 49.2
(46.5-51.8) / 52.1
(49.8-54.4) / 58.7
(56.0-61.5) / 50.2
(48.0-52.5)
Duration of Disease (y) / 6.5
(5.6-7.4) / 6.1
(4.7-7.5) / 6.9
(5.7-8.1) / 8.9
(7.0-10.9) / N/A
Anti-Scl70 ab (% pos) / 30.7 / 60.9 / 5.5 / N/A / N/A
Anti-centromere ab
(% pos) / 30.7 / 5.4 / 51.8 / N/A / N/A
Proven PAH (%) / 11.8 / 17.2 / 7.3 / N/A / N/A
Scleroderma renal crisis (%) / 5.9 / 12.9 / 0 / N/A / N/A
Digital ulcers (%) / 34.0 / 52.7 / 18.2 / N/A / N/A
Anti-AT1R Ab (units) / 21.0
(19.0-22.9) / 25.0
(21.8-28.2) / 17.6
(15.4-19.8) / 10.8
(9.5-12.2) / 9.5
(8.5-10.4)
Anti-ETAR Ab (units) / 22.3
(20.3-24.3) / 25.7
(22.8-28.6) / 9.4
(16.9-21.8) / 11.0
(9.7-12.2) / 9.0
(8.0-10.0)
Supplemental Table 1. Demographic characteristics of the age-matched patients with systemic sclerosis (SSc) and control patients with rheumatoid arthritis (RA), as well as healthy subjects and anti-AT1R and anti-ETAR antibody levels for each group studied. Data are presented as frequency (%) or means (95%CI). N/A stands for not applicable.
Anti-AT1R- and ETAR-autoantibodies in independent cohorts
Separate analyses in control cohorts were conducted. Comparison of autoantibody values obtained in patients from our center to two independent SSc cohorts from two different European regions and EUSTAR centers (Hungary and Italy) showed similar values (supplemental Fig. A and B andsupplemental Table 2).
Supplemental Figure. Diagnostic value of anti-AT1R- and ETAR- autoantibodies in age-matched and independent cohorts. Anti-AT1R- (Panel A) and anti-ETAR-autoantibodies (Panel B) serumlevels in study cohort (Germany) compared to two independent cohorts (Italy and Hungary).
Germany / Italy / HungarySSc (N=298) / Diffuse SSc (N=175) / Limited SSc (N=123) / SSc (N=43) / Diffuse SSc (N=27) / Limited SSc (N=16) / SSc (N=137) / Diffuse SSc (N=89) / Limited SSc (N=58)
Female sex (%) / 83.8 / 74.8 / 89.7 / 90.9 / 81.3 / 96.3 / 89.8 / 81.3 / 94.4
Age (y) / 56.0 (54.5-57.5) / 53.5 (51.0-56.0) / 57.8 (55.9-59.7) / 65.3 (61.9-68.8) / 60.2 (51.9-68.6) / 68.0 (65.0-71.0) / 54.4 (52.3-56.4) / 51.0 (46.8-55.3) / 56.0 (53.9-58.2)
Duration of Disease (y) / 6.8 (6.0-7.5) / 6.4 (5.2-7.6) / 7.1 (6.1-8.1) / 10.8 (9.3-12.3) / 11.0 (8.0-14.0) / 10.7 (8.8-12.6) / 6.2 (5.0-7.3) / 5.3 (3.4-7.2) / 6.7 (5.3-8.2)
Anti-Scl70 ab (% pos) / 27.3 / 58.2 / 5.7 / 27.9 / 62.5 / 7.4 / 42.3 / 72.9 / 25.8
Anti-centromere ab (% pos) / 36.8 / 5.8 / 58.3 / 55.8 / 25.0 / 74.1 / 19.0 / 2.1 / 28.1
Proven PAH (%) / 13.8 / 17.9 / 10.9 / 34.9 / 56.3 / 19.2 / 8.0 / 4.2 / 10.1
Scleroderma renal crisis (%) / 5.7 / 13.8 / 0.0 / N/A / N/A / N/A / 1.5 / 2.1 / 1.1
Digital ulcers (%) / 29.9 / 46.3 / 18.3 / 48.8 / 87.5 / 25.9 / 16.1 / 20.8 / 13.5
Anti-AT1R Ab (units) / 20.5 (19.0-22.1) / 24.5 (21.8-27.2) / 17.7 (16.0-19.4) / 23.0 (12.3-33.7) / 20.4 (16.1-24.6) / 15.4 (9.7-21.0) / 29.3 (20.1-38.6) / 31.5 (19.0-44.0) / 28.7 (15.8-41.6)
Anti-ETAR Ab (units) / 21.8 (20.3-23.4) / 25.4 (22.8-27.9) / 19.3 (17.4-21.2) / 24.6 (13.5-35.6) / 21.8 (17.6-26.5) / 16.6 (9.7-23.6) / 32.7 (22.1-43.3) / 36.2 (22.6-50.0) / 31.3 (16.4-46.3)
Supplemental Table 2. Demographic characteristics of the study cohort and independent systemic sclerosis (SSc) cohorts with and anti-AT1R and anti-ETAR antibody levels. Data are presented as frequency (%) or means (95%CI). N/A stands for not applicable.