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2010 the 74 th Annual Scientific Meeting of American College of Rheumatology November 7 11, 2010 at Georgia World Congress Center, Atlanta, GA, USA 2284 SSc 142 Plenary Session: 3 Concurrent Abstract

2 2010 the 74 th Annual Scientific Meeting of American College of Rheumatology November 7 11, 2010 at Georgia World Congress Center, Atlanta, GA, USA 2284 SSc 142 Plenary Session: 3 Concurrent Abstract Session: 21 SSc Systemic Sclerosis: New Therapeutic Approaches Immunopathogenesis of Systemic Sclerosis SSc ACR State-of-the-Art Lecture: Prof. John Varga REF Paul Klemperer Memorial Lectureship: Prof. Frank C. Arnett

3 560. Distler O., et al. A multi-center, open-label, proof of concept study of imatinib mesylate demonstrates no benefit for the treatment of fibrosis in patients with early, diffuse systemic sclerosis Denton CP., et al. Comparative analysis of change in modified Rodnan skin score in patients with diffuse systemic sclerosis receiving imatinib mesylate suggests similar disease course to matched patients receiving standard therapy Spiera RF., et al. Imatinib mesylate (Gleevec ) in the treatment of diffuse cutaneous systemic sclerosis: results of a one year, phase IIa, single arm, open label clinical trial Chung L., et al. Evaluation of an imatinib response gene signature in patients with systemic sclerosis Gordon JK., et al. Does treatment with imatinib modify gene expression in the skin and peripheral blood mononuclear cells of patient with systemic sclerosis? Li Z. and Jimenez SA. Imatinib mesylate and rottlerin abrogate transforming growth factor-induction of endothelial-to-mesenchymal transition in primary lung endothelial cells.

4 560. Distler O., et al. A multi-center, open-label, proof of concept study of imatinib mesylate demonstrates no benefit for the treatment of fibrosis in patients with early, diffuse systemic sclerosis Denton CP., et al. Comparative analysis of change in modified Rodnan skin score in patients with diffuse systemic sclerosis receiving imatinib mesylate suggests similar disease course to matched patients receiving standard therapy. 2 dcssc mg/day 400mg/day 600mg/day, historical control (+9.9%) 48mTSS 21% imatinib dcsscmtss

5 2193. Spiera RF., et al. Imatinib mesylate (Gleevec ) in the treatment of diffuse cutaneous systemic sclerosis: results of a one year, phase IIa, single arm, open label clinical trial. 2 dcssc /- 2.3 years 400mg/day 12 mtss,, X,, mtss(δ= 6.6 +/ 4.7, p < 0.001) %VC(82.9 +/- 21.1% to /- 25.2%, p = 0.008) %DLco(78.0 +/- 22.9% to /- 29.2%, p = 0.12) (80%), (73%), (67%), CK(43%)2

6 573. Chung L., et al. Evaluation of an imatinib response gene signature in patients with systemic sclerosis. SSc Gordon JK., et al. Does treatment with imatinib modify gene expression in the skin and peripheral blood mononuclear cells of patient with systemic sclerosis? PI3 kinase signaing Li Z. and Jimenez SA. Imatinib mesylate and rottlerin abrogate transforming growth factor-induction of endothelial-to-mesenchymal transition in primary lung endothelial cells. TGF-βendothelial mesenchymal transition

7 565. Seibold JR. et al. Combined analysis of outcomes of sitaxentan treatment of pulmonary arterial hypertension associated with systemic sclerosis Bose N. et al. Evaluation of the effect of ambrisentan on digital microvascular flow in patients with systemic sclerosis using laser doppler perfusion imaging Wang Y. et al. Effect of selective and dual endothelin receptor antagonists (ERAs) on SSc and control endothelial cells apoptosis.

8 565. Seibold JR. et al. Combined analysis of outcomes of sitaxentan treatment of pulmonary arterial hypertension associated with systemic sclerosis. STRIDE1, 2, 4 Sitaxentane[100mg] Bosentan[125mg] Sitaxentanebosentan SSc-PAH 54 6 WHO 19% 13% 574. Bose N. et al. Evaluation of the effect of ambrisentan on digital microvascular flow in patients with systemic sclerosis using laser doppler perfusion imaging. lcssc 20 7 PH, digital ulcer (15mg) 15, 5, 1, LDPI RCS, S-HAQ, P-VAS

9 1214. Wang Y. et al. Effect of selective and dual endothelin receptor antagonists (ERAs) on SSc and control endothelial cells apoptosis. type B receptor SSc MVEC type A, type B receptor type A receptor SSc MVEC MVEC selective type A receptor antagonist dual receptor antagonist selective type B receptor antagonist ET ET selective type A receptor antagonist SS

10 Bellando-Randone S., et al. Sildenafil increases vasodilation in systemic sclerosis: an interim analysis from a single centre pilot study. SSc 45 (60mg/day) 15, 15, 15, 3 RCS SF36, S-HAQ, NVC pattern Agarwal V., et al. Efficacy of tadalafil in Raynaud s phenomenon secondary to systemic sclerosis: a double blind randomized placebo controlled parallel group multicentric study. SSc (20mg) 8 ( : 26 : 27 14/18 vs 5/13, p < 0.026) (1/26 vs 9/27, p < 0.004)

11 2192. Le E., et al. Long-Term Benefit of Mycophenolate Mofetil for Treatment of Diffuse Cutaneous Systemic Sclerosis. dcssc / /-77.5 MMF3g/day(range g/day) 12 MMF mtss HAQ disability index, general/muscle Medsger severity score %VC %DLco MMF 12 mtss

12 (GWAS) Gorlova O., et al. Genome-Wide Association Study of Systemic Sclerosis Clinical Features Identifies New Disease Risk Variants. SSc 5471, control (dcssc,lcssc),(aca,topo-i) lcsscsnp IRF8 (rs ) (P=5.42x10-12, OR =0.75) GRB10 (rs ) (P=1.31x10-6, OR =1.15) ACASNP SOX5 (rs ) (P=1.04x10-7, OR =1.36) SScSNP DGKQ (rs ) (P=1.79x10-6, OR=1.12) (cell signal transduction) PSMD1 (rs ) (P=3.27x10-6, OR=1.27) (immuno-proteosome subunit) JAZF1 (rs ) (P=9.44x10-6, OR=1.12) (transcriptional repressor)

13 2011 the 75 th Annual Scientific Meeting of the American College of Rheumatology November 5 9, 2011 at McCormick's Place Convention Center in Chicago, IL, USA

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$‰Łflç‘ÇŁ\”ƒ(’FŁª›ð)-A4$ 1 14163 1611 (2002) 32007 3 3 196 2 1416 ( ) Medsger modified Rodnan total skin thickness score EBM placebo control ACEEBM EBM 3 1611 4 5 (Systemic Sclerosis : SSc) 1980 (1) 1) 200310 (2) 2003 Scl-70 1