全身性強皮症　診療ガイドライン

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3 systemic sclerosis; SSc EBM EBM 2007 SSc SSc 1SSc clinical question CQ CQ evidence-based medicine EBM EBM SSc SSc CQ CQ CQ 2 I VI 6 CQ CQ 3 Minds A D C1 B CQ 1i

4 SSc SSc systemic sclerosis SSc diffuse cutaneous SSc dcssc limited cutaneous SSc lcssc 2

5 1. 3

6 2. a b /RCT 1 3. Minds C1 C2 4

7 Minds i iii iv iv CQ1 modified Rodnan total skin thickness score MRSS 7 CQ2 8 CQ3 8 CQ4 CQ5 D- CQ6 CQ7 CQ8 CQ9 CQ10 CQ11 CQ CQ1 SSc PAH 21 CQ2 PAH 21 CQ3 PH 22 v

8 CQ4 SSc PH 23 CQ5 23 CQ6 24 CQ7 25 CQ8 25 CQ9 WHO PAH 25 CQ10 WHO PAH 26 CQ11 WHO PAH 27 CQ12 WHO PAH 28 CQ13 28 CQ14 29 CQ15 PAH 29 CQ16 ILD PH CQ1 39 CQ2 39 CQ3 40 CQ4 40 CQ CQ CQ CQ CQ1 47 CQ2 47 CQ3 PPI 48 CQ4 48 CQ5 48 CQ6 49 CQ7 49 CQ8 49 CQ9 50 CQ10 50 vi

9 CQ11 50 CQ12 51 CQ13 51 CQ14 51 CQ15 52 CQ16 52 CQ17 52 CQ CQ1 SSc SRC 59 CQ2 SSc SRC 59 CQ3 SRC 60 CQ4 SRC 60 CQ5 SRC 61 CQ6 SRC CQ1 SSc 67 CQ2 SSc 67 CQ3 67 CQ CQ1 73 CQ2 73 CQ3 74 CQ4 74 CQ5 II 75 CQ6 75 CQ7 75 CQ8 76 CQ9 76 vii

10 CQ10 77 CQ11 77 CQ12 77 CQ13 78 CQ CQ1 83 CQ2 83 CQ3 84 CQ4 CO2 84 CQ viii

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12 SSc pseudosclerodermatous disorder SSc 2003 * 1 2** 3 4Scl * ** 1

13 4 4 90% SSc 1 Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis scleroderma. Arthritis Rheum 1980, 23: LeRoy & Medsger SSc diffuse cutaneous SSc dcssc SSc limited cutaneous SSc lcssc 2 1,2 dcssc lcssc dcssc lcssc

14 6 SSc LeRoy Medsger Raynaud diffuse cutaneous SSc (dcssc) 2 RNA limited cutaneous SSc (lcssc) 5 Raynaud LeRoy EC, Black C, Fleischmajer F, Jablonska S, Krieg T, Medsger TA Jr et al.: Scleroderma systemic sclerosis : classification, subsets and pathogenesis, J Rheumatol 1988, 15:

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16 1 5

17 CQ1 CQ2 dcssc * dcssc * 6 6 CQ3-4 PSL mg/ CQ5-11 * I (Scl-70) RNA U3RNP 6

18 1 MRSS Clements modified Rodnan total skin thickness score MRSS MRSS PIP MP MRSS 3 MRSS 1 Clements MRSS 25% 12% 2 37% 43% MRSS Furst MRSS 3 MRSS SSc MRSS Medsger MRSS 0 normal 1 14 mild moderate severe 40 endstage normal 1 9 mild moderate severe 30 very severe 7

19 6 dcssc 1 2 SSc SSc dcssc lcssc 2 dcssc 6 70% 3 6 lcssc dcssc lcssc lcssc 6 dcssc 1 2 lcssc I Scl-70 RNA I/III U3RNP dcssc lcssc SSc Sharada mg 6 5 n 17 MRSS n Takehara 23 MRSS

20 B CQ2 SSc PSL mg/ very severe TSS % 5 mg/ SSc CQ4 3 Steen 6 PSL 15 mg/ 36% 12% OR 95%CI : P PSL 10 mg/ 7 DeMarco 61% 3 RR 95%CI : Helfrich 2 PSL 30 mg/ 64% v.s. 16% 9 Penn RNA RNA 11 SSc RNA D SSc 9

21 D 1966 SSc SSc 1999 dcssc D mg/ D 125 mg/ 14 D D 2008 Derk D 15 D Tashkin 1 mg/kg/ MRSS dcssc lcssc dcssc MRSS 17 SSc MTX MTX 2 Van den Hoogen 29 MTX 15 mg/ 24 P MTX n 19 MRSS 0.7 n

22 Pope 73 MTX 10 mg/ MRSS MTX n n P 0.17 MTX 2 mg/kg/ 1 20 MRSS P mg/kg/ MRSS Nadashkevich 2 mg/kg/ 12 1 mg/kg/ 62.5 mg/kg/ 12 2 mg/kg 630 MRSS 23 MMF 3 Stratton SSc13 MMF 0.5 g g MRSS P Vanthuyne 16 MMF 25 Nihtyanova 109 MMF 63 5 MRSS 26 11

23 γ Grassegger γ 100 g 3 12 γ mm mm mm mm, P 0.01 Black α dcssc 36 1 D 30 SSc SSc Sfikakis mg/ MRSS D Humbert Lafyatis Daoussis 14 1 MRSS Smith 8 24 MRSS Levy 3 dcssc MRSS 36 Ihn 5 dcssc MRSS 37 Nacci 7 SSc 6 MRSS P SSc G-CSF CD34 12

24 dcssc41 25% MRSS 69% 7% 39 17% Vonk 26 25% MRSS 1 73% 5 94% 3.4% 40 Nash MRSS % 23.5% 8 I/II 41 SSc G-CSF 8 Gy 120 mg/kg 90 mg/kg SSc SSc UVA PUVA UVA1 PUVA Morita 42 PUVA 1 Kanekura 43 PUVA 3 Hofer 44 PUVA 4 UVA-1 Morita 4 60 J/cm von Kobyletzki 8 30 J/cm J/cm Kreuter 18 von Kobyletzki 16 25% P Durand 9 48 SSc UVA1 13

25 SSc Mugii HAQ 49 1 Clements PJ, Lachenbruch PA, Seibold JR, Zee B, Steen VD, Brennan P, Silman AJ, Allegar N, Varga J, Massa M, et al.: Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993, 20: Clements P, Lachenbruch P, Siebold J, White B, Weiner S, Martin R, Weinstein A, Weisman M, Mayes M, Collier D, et al.: Inter and intraobserver variability of total skin thickness score modified Rodnan TSS in systemic sclerosis. J Rheumatol 1995, 22: Furst DE, Clements PJ, Steen VD, Medsger TA, Jr., Masi AT, D Angelo WA, Lachenbruch PA, Grau RG, Seibold JR: The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis. J Rheumatol 1998, 25: Medsger TA, Jr., Silman AJ, Steen VD, Black Cm, Akesson A, Bacon PA, Harris CA, Jablonska S, Jayson MI, Jimenez SA, Krieg T, Leroy EC, Maddison PJ, Russell ML, Schachter RK, Wollheim FA, Zacharaie H: A disease severity scale for systemic sclerosis: development and testing. J Rheumatol 1999, 26: Sharada B, Kumar A, Kakker R, Adya Cm, Pande I, Uppal SS, Pande JN, Sunderam KR, Malaviya AN: Intravenous dexamethasone pulse therapy in diffuse systemic sclerosis. A randomized placebo-controlled study. Rheumatol Int 1994, 14: II 6 Takehara K: Treatment of early diffuse cutaneous systemic sclerosis patients in Japan by low-dose corticosteroids for skin involvement. Clin Exp Rheumatol 2004, 22: S87 9. V 7 Steen VD, Medsger TA, Jr.: Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998, 41: IV b 8 DeMarco PJ, Weisman MH, Seibold JR, Furst DE, Wong WK, Hurwitz EL, Mayes M, White B, Wigley F, Barr W, Moreland L, Medsger TA, Jr., Steen V, Martin RW, Collier D, Weinstein A, Lally E, Varga J, Weiner SR, Andrews B, Abeles M, Clements PJ: Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum 2002, 46: IV b 9 Helfrich DJ, Banner B, Steen VD, Medsger TA, Jr.: Normotensive renal failure in systemic sclerosis. Arthritis Rheum 1989, 32: VI b 10 Penn H, Howie AJ, Kingdon EJ, Bunn CC, Stratton RJ, Black Cm, Burns A, Denton CP: Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 2007, 100: VI b 11 Kuwana M, Pandey JP, Silver RM, Kawakami Y, Kaburaki J: HLA class II alleles in systemic sclerosis patients with 14

26 anti-rna polymerase I/III antibody: associations with subunit reactivities. J Rheumatol 2003, 30: Harris ED, Jr., Sjoerdsma A: Effect of penicillamine on human collagen and its possible application to treatment of scleroderma. Lancet 1966, 2: Steen VD, Medsger TA, Jr., Rodnan GP: D-Penicillamine therapy in progressive systemic sclerosis scleroderma : a retrospective analysis. Ann Intern Med 1982, 97: IV b 14 Clements PJ, Furst DE, Wong WK, Mayes M, White B, Wigley F, Weisman MH, Barr W, Moreland LW, Medsger TA, Jr., Steen V, Martin RW, Collier D, Weinstein A, Lally E, Varga J, Weiner S, Andrews B, Abeles M, Seibold JR: Highdose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum 1999, 42: II 15 Derk CT, Huaman G, Jimenez SA: A retrospective randomly selected cohort study of D-penicillamine treatment in rapidly progressive diffuse cutaneous systemic sclerosis of recent onset. J Dermatol 2008, 158: IV a 16 Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M: Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006, 354: II 17 Tashkin DP, Elashoff R, Clements PJ, Roth MD, Furst DE, Silver RM, Goldin J, Arriola E, Strange C, Bolster MB, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel D, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M, Khanna D, Li N, Li G: Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 2007, 176: II 18 Van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB: Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol 1996, 35: II 19 Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, Smith CD, Chalmers IM, Hong P, O Hanlon D, Kaminska E, Markland J, Sibley J, Catoggio L, Furst DE: A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum 2001, 44: II 20 Filaci G, Cutolo M, Scudeletti M, Castagneto C, Derchi L, Gianrossi R, Ropolo F, Zentilin P, Sulli A, Murdaca G, Ghio M, Indiveri F, Puppo F: Cyclosporin A and iloprost treatment of systemic sclerosis: clinical results and interleukin-6 serum changes after 12 months of therapy. Rheumatology Oxford 1999, 38: III 21 Denton CP, Sweny P, Abdulla A, Black Cm: Acute renal failure occurring in scleroderma treated with cyclosporin A: a report of three cases. Br J Rheumatol 1994, 33: V 22 Morton SJ, Powell RJ: Cyclosporin and tacrolimus: their use in a routine clinical setting for scleroderma. Rheumatology Oxford 2000, 39: III 23 Nadashkevich O, Davis P, Fritzler M, Kovalenko W: A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis. Clin Rheumatol 2006, 25: III 24 Stratton RJ, Wilson H, Black Cm: Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology Oxford 2001, 40: IV a 25 Vanthuyne M, Blockmans D, Westhovens R, Roufosse F, Cogan E, Coche E, Nzeusseu Toukap A, Depresseux G, Houssiau FA: A pilot study of mycophenolate mofetil combined to intravenous methylprednisolone pulses and oral lowdose glucocorticoids in severe early systemic sclerosis. Clin Exp Rheumatol 2007, 25: IV a 26 Nihtyanova SI, Brough GM, Black Cm, Denton CP: Mycophenolate mofetil in diffuse cutaneous systemic sclerosis--a retrospective analysis. Rheumatology Oxford 2007, 46: V 27 Grassegger A, Schuler G, Hessenberger G, Walder-Hantich B, Jabkowski J, MacHeiner W, Salmhofer W, Zahel B, Pinter G, Herold M, Klein G, Fritsch PO: Interferon-gamma in the treatment of systemic sclerosis: a randomized 15

27 controlled multicentre trial. Br J Dermatol 1998, 139: II 28 Black Cm, Silman AJ, Herrick AI, Denton CP, Wilson H, Newman J, Pompon L, Shi-Wen X: Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 1999, 42: II 29 Le CH, Morales A, Trentham DE: Minocycline in early diffuse scleroderma. Lancet 1998, 352: IV a 30 Mayes MD, O Donnell D, Rothfield NF, Csuka ME: Minocycline is not effective in systemic sclerosis: results of an open-label multicenter trial. Arthritis Rheum 2004, 50: III 31 Sfikakis PP, Gorgoulis VG, Katsiari CG, Evangelou K, Kostopoulos C, Black Cm: Imatinib for the treatment of refractory, diffuse systemic sclerosis. Rheumatology Oxford 2008, 47: V 32 Humbert P, Dupond JL, Agache P, Laurent R, Rochefort A, Drobacheff C, de Wazieres B, Aubin F: Treatment of scleroderma with oral 1,25-dihydroxyvitamin D3: evaluation of skin involvement using non-invasive techniques. Results of an open prospective trial. Acta Derm Venereol 1993, 73: III 33 Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ, Merkel PA, Simms RW: B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2009, 60: III 34 Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Sirinian C, Karampetsou M, Yiannopoulos G, Andonopoulos AP: Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology Oxford 2010, 49: III 35 Smith VP, Van Praet JT, Vandooren BR, Vander Cruyssen B, Naeyaert JM, Decuman S, Elewaut D, de Keyser F: Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis 2010, 69: III 36 Levy Y, Sherer Y, Langevitz P, Lorber M, Rotman P, Fabrizzi F, Shoenfeld Y: Skin score decrease in systemic sclerosis patients treated with intravenous immunoglobulin--a preliminary report. Clin Rheumatol 2000, 19: V 37 Ihn H, Mimura Y, Yazawa N, Jinnin M, Asano Y, Yamane K, Tamaki K: High-dose intravenous immunoglobulin infusion as treatment for diffuse scleroderma. Br J Dermatol 2007, 156: V 38 Nacci F, Righi A, Conforti ML, Miniati I, Fiori G, Martinovic D, Melchiorre D, Sapir T, Blank M, Shoenfeld Y, Pignone AM, Cerinic MM: Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study. Ann Rheum Dis 2007, 66: V 39 Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, Finke J, Peter HH, van Laar J, Breedveld FC, Fibbe WE, Farge D, Gluckman E, Locatelli F, Martini A, van den Hoogen F, van de Putte L, Schattenberg AV, Arnold R, Bacon PA, Emery P, Espigado I, Hertenstein B, Hiepe F, Kashyap A, Kotter I, Marmont A, Martinez A, Pascual MJ, Gratwohl A, Prentice HG, Black C, Tyndall A: Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis 2001, 60: III 40 Vonk MC, Marjanovic Z, van den Hoogen FH, Zohar S, Schattenberg AV, Fibbe WE, Larghero J, Gluckman E, Preijers FW, van Dijk AP, Bax JJ, Roblot P, van Riel PL, van Laar JM, Farge D: Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis 2008, 67: III 41 Tsukamoto H, Nagafuji K, Horiuchi T, Miyamoto T, Aoki K, Takase K, Henzan H, Himeji D, Koyama T, Miyake K, Inoue Y, Nakashima H, Otsuka T, Tanaka Y, Nagasawa K, Harada M: A phase I-II trial of autologous peripheral blood stem cell transplantation in the treatment of refractory autoimmune disease. Ann Rheum Dis 2006, 65: III 42 Morita A, Sakakibara S, Sakakibara N, Yamauchi R, Tsuji T: Successful treatment of systemic sclerosis with topical PUVA. J Rheumatol 1995, 22: V 43 Kanekura T, Fukumaru S, Matsushita S, Terasaki K, Mizoguchi S, Kanzaki T: Successful treatment of scleroderma with PUVA therapy. J Dermatol 1996, 23: V 44 Hofer A, Soyer HP: Oral psoralen-uv-a for systemic scleroderma. Arch Dermatol 1999, 135: V 16

28 45 Morita A, Kobayashi K, Isomura I, Tsuji T, Krutmann J: Ultraviolet A nm phototherapy for scleroderma in systemic sclerosis. J Am Acad Dermatol 2000, 43: V 46 von Kobyletzki G, Uhle A, Pieck C, Hoffmann K, Altmeyer P: Acrosclerosis in patients with systemic sclerosis responds to low-dose UV-A1 phototherapy. Arch Dermatol 2000, 136: V 47 Kreuter A, Breuckmann F, Uhle A, Brockmeyer N, Von Kobyletzki G, Freitag M, Stuecker M, Hoffmann K, Gambichler T, Altmeyer P: Low-dose UVA1 phototherapy in systemic sclerosis: effects on acrosclerosis. J Am Acad Dermatol 2004, 50: V 48 Durand F, Staumont D, Bonnevalle A, Hachulla E, Hatron PY, Thomas P: Ultraviolet A1 phototherapy for treatment of acrosclerosis in systemic sclerosis: controlled study with half-side comparison analysis. Photodermatol Photoimmunol Photomed 2007, 23: III 49 Mugii N, Hasegawa M, Matsushita T, Kondo M, Orito H, Yanaba K, Komura K, Hayakawa I, Hamaguchi Y, Ikuta M, Tachino K, Fujimoto M, Takehara K, Sato S: The efficacy of self-administered stretching for finger joint motion in Japanese patients with systemic sclerosis. J Rheumatol 2006, 33: III 17

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30 PGI2 ET PDE CQ1 CQ8 CQ4 CQ2 CQ3 CQ6 CQ7 CQ5 CQ16 WHO I WHO II WHO III WHO IV CQ9 CQ10 CQ11 CQ12 CQ14 CQ13 PGI2 ET PDE5 CQ15 20

31 2 PH SSc Koh 1996 PH SSc % 3 20% 1 SSc PH PAH PGI 2 PAH PAH 2 SSc PAH PAH IPAH PAH HPAH SSc PAH IPAH 3 4 lcssc U1RNP PAH SSc 1 ILD PH isolated PH; PAH lcssc 5 ILD PH lcssc 60% ILD PH lcssc 6 lcssc Th/To lcssc ILD PH 7 dcssc ILD PH U3RNP 8 U1RNP SSc ILD PH 9 PAH SSc78 SSc 5 PAH 55% 16% dcssc 10 PAH SSc 5 PAH PAH SSc PAH 1 11 ILD PH dcssc Scl PAH 21

32 PH X BNP N-T probnp Rivero-Carvallo X incident case 30 70% SSc PAH American College of Cardiology Foundation ACCF /American Heart Association AHA 11 TJV TIPGsPAP SSc 570 TJV 3 m/s TJV m/s 18 PAH 14 PAH DLco PAH % %VC %DLco %VC/%DLco PAH 17 BNP NT-proBNP PH SSc 18 PH SSc PAH 19 PAH NT-proBNP %DLco/VA alveolar volume 70% 3 PAH 47.2 PH 2.8 m/s 31 mmhg 36 mmhg TJV TIPGsPAP Evian 2 PH PH TJV m/s TIPG mmhg 5 mmhg spap mmhg 20 3,212 TIPG TJV 2.8 m/s 21 SSc 22

33 TJV 3 m/s TJV m/s 33 mpap 25 mmhg PH Mukerjee SSc 137 spap mpap 15 r PH 31 mmhg 10% TJV 2.8 m/s PH PH mpap 25 mmhg PH Dana Point 4 PH mpap PH mmhg PAH 1 SSc PH PAH PH ILD PH PH PH 4 PH 1 23 SSc PH 1 PAH2 PH3 ILD PH4 PH CTEPH SSc PAH 7 12% SSc 570 SSc 21 dcssc lcssc 22.6% 17.7% 25 SSc ILD ILD PH spap 35 mmhg 44% 12 SSc197 PH ILD 13 ILD PH SSc ILD PH ILD PAH ILD PH CTEPH PAH CT 384 SSc 3 PH PAH 0.61 PH 0.61 ILD PH

34 IPAH 5 95% 26 IPAH 12.6% 27 SSc PAH97 2.6% 28 PAH 92% PAH IPAH/HPAH Fuster IPAH % vs 7% 30 IPAH Rich 3 62% vs 31% 26 Frank IPAH % 32 ACCF/ AHA PT-INR PAH PAH C1 B 4 PH 92% 33 B A 34 24

35 PAH PAH 38% 35 European Society of Cardiology ACCF/AHA PAH % 37 78% 1 IPAH PAH PAH 37 OR 3.7 OR 4.4 U1RNP WHO PAH 1999 PAH 2/3 38 Sanchez PAH-CTD CYC 600 mg/m CYC % PAH SLE MCTD 20 8 SSc 8 SLE MCTD CYC WHO 3.1 L/ /m 2 40 U1RNP 25

36 SSc WHO PAH PAH PGI SSc PAH 6 PAH 2000 PAH 5 PDE5 12 SUPER-1 60 mg/ 120 mg/ 180 mg/ SSc 45% 38% 6 WHO 43 PDE PHIRST mg/ 10 mg/ 20 mg/ 40 mg/ mg/ 6 33 m WHO 40 mg/ 53% 47% % 6 IPAH 6 EARLY EARLY PAH SSc mg/ m 7.9 m P % 107.5% P % P / PAH 2 26

37 ARIES WHO % 72% 47 PGI 2 / PAH SSc 12 6 SSc II WHO PAH WHO PAH SSc78 PGI mpap 50 IPAH/HPAH SSc PAH 33 PGI BREATHE PAH 195 SSc mg/ 250 mg/ m 8 m P P 0.01SSc 6 Joglekar 23 SSc PAH 14 WHO 9 spap 52 Beretta 20 SSc PAH 18 1 spap WHO % 81% 3 47% 71% P 0.02 SSc53 TRUST 48 WHO 16% 68% 92% 55 ARIES % 46 27

38 SUPER-1 61% PHIRST % 44 PAH 70% SSc PAH PAH SSc PAH PAH PGI 2 PDE5 PAH33 SSc5 BREATHE PAH267 SSc31 PACES

39 P IPAH IPAH SSc 6 61 PHIRST 53% 44 6 PAH 2 PGI 2 PDE5 3 WHO 6 IPAH WHO BNP 65 Williams SSc NT-ProBNP NT-ProBNP goal-oriented strategy 66 Hoeper m Grossi WHO m m mmhg 2.5 L/ /m SSc 6 PAH 68 PAH IPAH SSc PAH SSc IPAH

40 ILD PH PAH Mathai SSc PAH39 ILD PH20 ILD PH P ILD 76 ILD PH PGI 2 Minai SSc4 ILD PH19 n 10 n m 77 Ghofrani SSc5 ILD mpap 35 mmhg PH PAH ILD PAH ILD PH 32% 81 PAH PAH 1.1 PAH IPAH 1.2 PAH HPAH 1.3/ PAH 1.4 PAH 1.5 PH 1. / 2. PH 3. / PH 4. PH CTEPH 5. PH 1 PH Dana Point

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44 pulmonary arterial hypertension: a meta-analysis of randomised controlled trials. Ann Rheum Dis 2008, 67: Humbert M, Barst RJ, Robbins IM, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004, 24: Simonneau G, Rubin LJ, Galiè N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008, 149: Burgess G, Hoogkamer H, Collings, et al. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol 2008, 64: Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004, 24: a 61 Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J 2007, 29: a 62 D Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991, 115: Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000, 161: Hinderliter L, Willis PW 4th, Long W, et al. Frequency and prognostic significance of pericardial effusion in primary pulmonary hypertension. Am J Cardiol 1999, 84: Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000, 102: Hoeper MM, Markevych I, Spiekerkoetter E, et al. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005, 26: Grossi M, Palazzini M, Manes A, et al. Results of aggressive follow-up strategy in patients with pulmonary arterial hypertension. Eur Heart J 2007, 28: 308 abstract. 68 Garin MC, Highland KB, Silver RM, et al. Limitations to the 6-minute walk test in interstitial lung disease and pulmonary hypertension in scleroderma. J Rheumatol 2009, 36: Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005: Patterson KC, Weissmann A, Ahmadi T, et al. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med 2006, 145: Souza R, Sitbon O, Parent F, et al. Long-term imatinib treatment in pulmonary arterial hypertension. Thorax 2006, 61: ten Freyhaus H, Dumitrescu D, Bovenschulte H, et al. Significant improvement of right ventricular function by imatinib mesylate in scleroderma-associated pulmonary arterial hypertension. Clin Res Cardiol 2009, 98: Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006, 12: Ghofrani HA, Barst RJ, Benza RL, et al. Future perspectives for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol 2009, 54 1 Suppl : S Mathai SC, Hummers LK, Champion HC, et al. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease. Arthritis Rheum 2009, 60: Hoeper MM, Barberà JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol 2009, 54 1 Suppl : S Minai OA, Sahoo D, Chapman JT, et al. Vaso-active therapy can improve 6-min walk distance in patients with 34

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46 3 37

47 %VC < 50 %VC > 50 CT CQ2-4 CT CQ1 CQ5 6 X 38

48 3 HR CT HRCT SSc HRCT HRCT HRCT 1 2 KL-6 surfactant protein A SP-A SP-D CC chemokine ligand 18 CCL18 KL-6 Krebs von den Lungen-6 II KL-6 SSc HRCT %DLco %VC 3 4 SP-A SP-D II Clara SSc SP-A SP-D HRCT %VC %DLco 4 6 CCL18 pulmonary and activation-related protein SSc %VC

49 dcssc Scl-70 SSc dcssc Scl-70 dcssc 70% RNA III dcssc 9 HRCT SSc HRCT non-specific interstitial pneumonia NSIP HRCT 5 50% 15% 10 alveolitis HRCT BAL SSc alveolitis 13 alveolitis 14 SSc BAL HRCT HRCT BAL BAL HRCT 40

50 2 RCT Scleroderma Lung Study Research Group SLSRG 1 %VC 17 1 %VC 18 SLSRG 2 1 %VC RCT 8 meta 1 %VC SSc % 23 2 MMF MMF TGF-β 2008 SSc MMF 13 SSc 23 1 g/ MMF 61 %VC %DLco %VC 41

51 SSc SSc 24 SSc CQ3 SSc 24 1 Antouniou KM, Margaritopoulos G, Economidou F, et al. Pivotal clinical dilemmas in collagen vascular diseases associated with interstitial lung involvement. Eur Respir J 2009; 33: I 2 Goldin JG, Lynch DA, Strollo DC, et al. High-resolution CT scan findings in patients with symptomatic sclerodermarelated interstitial lung disease. Chest 2008; 134: IV b 3 Hant FN, Ludwicka-Bradley A, Wang H-J, et al. Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J Rheumatol 2009; 36: IV b 4 Yamabe K, Hasegawa M, Takehara K, et al. Comparative study of serum surfactant protein D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis. J Rheumatol 2004; 31: IV b 5 Takahashi H, Kuroki Y, Tanaka H, et al. Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis. Am J Respir Crit Care Med 2000; 162: IV b 6 Asano Y, Ihn H, Yamane K, et al. Clinical significance of surfactant protein D as a serum marker for evaluating pulmonary fibrosis in patients with systemic sclerosis. Arthritis Rheum 2001; 44: IV b 7 Kodera M, Hasegawa M, Komura K, et al. Serum pulmonary and activation-regulated chemokine/ccl18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis. Arthritis Rheum 2005; 52: IV b 8 Prasse A, Pechkovsky DV, Toews GB, et al. CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum 2007; 56: IV b 9 Kuwana M, Kaburaki J, Okano Y, et al. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum 1994; 37: IV b 42

52 10 Launay D, Remy-Jardin M, Michon-Pasturel U, et al. High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol 2006; 33: IV b 11 Goldin JG, Lynch DA, Strollo DC, et al. High-resolution CT scan findings in patients with symptomatic sclerodermarelated interstitial lung disease. Chest 2008; 134: II 12 Goldin J, Elashoff R, Kim HJ, et al. Treatment of scleroderma-interstitial lung disease with cyclophosphamide is associated with less pregressive fibrosis on serial thoracic high-resolution CT scan than placebo. Chest 2009; 136: II 13 Behr J, Bogelmeier C, Beinert T, et al. Bronchoalveolar lavage for evaluation and management of scleroderma disease of the lung. Am J Respir Crit Care Med 1996; 154: IV b 14 Wells AU, Hansell DM, Rubens MB, et al. Fibrosing alveolitis in systemic sclerosis: bronchoalveolar lavage findings in relation to computed tomographic appearnaces. Am J Respir Crit Care Med 1994; 150: IV b 15 Goh NS, Veeraraghavan S, Desai SR, et al. Bronchoalveolar lavage cellular profiles in patients with systemic sclerosisassociated interstitial lung disease are not predictive of disease progression. Arthritis Rheum 2007; 56: IV b 16 Strange C, Bolster MB, Roth MD, et al. Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med 2008; 177: IV b 17 Tashkin DP, Elashoff R, Clements PJ, et al. Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354: II 18 Hoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006; 54: II 19 Tashkin DP, Elashoff R, Clements PJ, et al. Effect of 1-year treatment with cyclophosphamide on outcomes at 2 year in scleroderma lung disease. Am J Respir Crit Care Med 2007; 176: II 20 Nannini C, West CP, Erwin PJ, et al. Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and observational prospective cohort study. Arthrits Res Ther 2008; 10: R124. I 21 Kowal-Bielecka O, Landewe R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group EUSTAR. Ann Rheum Dis 2009; 68: I 22 Hunzelmann N, Moinzadeh P, Genth E, et al. High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy. Arthritis Res Ther 2009; 11: R30. IV a 23 Berezne A, Ranque B, Valeyre D, et al. Therapeutic strategy combining intravenous cyclophosphamide followed by oral azathioprine to treat worsening interstitial lung disease associated with systemic sclerosis: a retrospective multicenter open-label study. J Rheumatol 2008; 35: III 24 Gerbino AJ, Goss CH, Molitor JA. Effects of mycophnolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest 2008; 133: IV b 25 Savarino E, Bazzica M, Zentilin P et al. Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using ph-impedance monitoring. Am J Respir Crit Care Med 2009; 179: IV b 26 Ryu JH, Myers JL, Capizzi SA, et al. Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest 2005; 127: IV a 43

53 4 45

54 CQ1 CQ2 CQ3 CQ4 CQ7 CQ5 CQ6 CQ8 CQ9 CQ10 CQ18 CQ11 CQ14 CQ12 CQ15 CQ13 CQ16 CQ17 46

55 4 SSc C1 A SSc 3 4 PPI 5 PPI 47

56 6 7 C1 B PPI SSc PPI 8 9 PPI SSc SSc 20 mg/ 80 mg/ 140 mg/ PPI 16 B A 2.5 g 3 / SSc

57 SSc SSc 24 SSc 49

58 C1 B C1 A PGF2α 34 50

59 0.1 mg 2 / long-acting-release LAD 20 mg/ SSc mg/ SSc

60 41 2 / 42 SSc mg 1 mg/ SSc mg/ SSc

61 TPN TPN TPN 1 Young MA, Rose S, Reynald JC. Scleroderma, Gastrointestinal manifestations of scleroderma. Rheumatic Dis Clin North Am 1996, 22: V 2 De Vault KR, Castell DO The Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Arch Intern Med 1995, 155: V 3 Sridhar KR, Lange RC, Magyar L, et al. Prevalence of impaired gastric emptying of solids in systemic sclerosis: diagnostic and therapeutic implications. J Lab Clin Med 1998, 132: IV b IV b 5 Vigneri S, Termini R, Leandro G, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 1995, 333: IV b 6 Annese V, Janssens J, Vantappen G, et al. Erythromycin accelerates gastric emptying by inducing antral contractions and improved gastroduodenal coordination. Gastroenterology 1992, 102: IV b 7 Tomomasa T, Kuroume T, Arai H, et al. Erythromycin induces migrating motor complex in human gastrointestinal tract. Dig Dis Sci 1986, 31: IV b 8 Herrick AL. Development of agents for the treatment of systemic sclerosis. Expert Opin Investig Drugs 2001, 10: VI 9 Shoenut JP, Wieler JA, Micflikier AB. The extent and pattern of gastro-oesophageal reflux in patients with scleroderma oesophagus: the effect of low-dose omeprazole. Alimet Pharmacol Ther 1993, 7: IV b 10 Chiba N, De Gara CJ, Wilkinson JM, et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology 1997, 112: IV b 11 Van Pinxteren B, Numans ME, Bonis PA, et al. Short- term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2006, 3: CD IV b 12 Hendel L. Hydroxyproline in the oesophgeal mucosa of pts with progressive systemic sclerosis during omeprazoleinduced healing of reflux oesophagitis. Aliment Pharmacol Ther 1991, 5: IV b 13 Hostein J, Li V, Carpentier P, et al. Omeprazole: crucial progress in the treatment of esophagitis in progressive systemic scleroderma. Gastroenterol Clin Biol 1991, 15: V 14 Kundrotas L, Ward RW. Omeprazole vs ranitidine in pts with progressive systemic sclerosis and symptomatic 53

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64 5 57

65 CQ1 CQ2 CQ3 CQ4 CQ5 CQ2 CQ6 1 ANCA 2 58

66 5 SRC SRC Steen 1 2 Keith-Wagener SRC 1 3 SRC SSc 10 15% 4 5% 4 dcssc 1 3 RNA III SRC SRC mg SRC 1 10 mg SRC 4 6 dcssc RNA III SRC SRC CQ4 SSc ANCA MPO-ANCA SSc SRC Steen SRC SSc D 7 D D 59

67 SSc ANCA MPO-ANCA SRC ANCA 8 9 MPO- ANCA SSc MPO-ANCA SSc ADAMTS SRC SRC SRC normal 1 mild mg/dl moderate : mg/dl severe : 3 mg/dl 4 very severe : 0 normal CQ4 ACE ACE SRC ACE SRC ACE 60

68 SRC ACE 47 8 ACE 1 76% 5 66% 1 15% 5 10% 15 ACE SRC % 8 85% ACE 16 SRC ACE ACE ACE ARB ACE ACE SRC 2 D SRC 6 SRC SRC SRC 1 2 BUN 60 mg/dl Cr 6 mg/dl 3 4 SRC ACE SRC SRC 61

69 SRC SRC 24 SRC 25 1 Steen VD: Scleroderma renal crisis, Rheum Dis Clin North Am 1996, 22: Steen VD: Scleroderma renal crisis, Rheum Dis Clin North Am 2003, 29: Steen VD, Medsger TA, Ziegler GL et al.: Factor predicting development of renal involvment in progressive systemic sclerosis, Am J Med 1984, 76: Helifrich DJ, Banner B, Steen VD, Medsger Jr TA: Normotensive renal crisis in systemic sclerosis, Arthritis Rheum 1989, 32: Steen VD, Medsger Jr TA: Case-control study of corticosteroids and other drugs that either precipitate of protect from the development of scleroderma renal crisis, Arthritis Rheum 1998, 41: DeMarco PJ, Weisman MH, Seibold JR et al.: Predictors and outcome of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse Systemic Sclerosis Trial, Arthritis Rheum 2002, 46: Steen VD, Syzd A, Johnson JP, Greenberg A, Medsger Jr TM: Kideny disease other than renal crisis in patients with diffuse scleroderma, J Rheumatol 2005, 32: Endo H, Hosono T, Kondo H: Antineutrophilic cytoplasmic autoantibodies in 6 patients with renal failure and systemic sclerosis, J Rheumatol 1994, 21: Bartoloni Bocci E, Giordano A, Luccioli F: Crensetic glomerulonephritis and circulating antineutrophilic autoantibodies in scleroderma: a case report and the review of the literature, Clin Exp Rheumatol 2009, 27: Yamanaka K, Mizutani H, Hashimoto K et al.: Scleroderma renal crisis complicated by hemolytic uremic syndrome in a case of elderly onset systemic sclerosis, J Dermatol 1994, 24: Manadan AM, Harris C, Black JA: Thrombotic thrombocytopenic purpura in the setting of systemic sclerosis, Semin Arthritis Rheum 2004, 34: Mannucci PM, Vanoli M, Forza I et al.: von Willebrand factor cleving protease ADAMTS-13 in 123 patients with connective tissue disease systemic lupus erythmatosus and systemic sclerosis, Hematologica 2003, 88: Lopez-Ovejero JA, Saal SD, D Angelo WA, et al.: Reversal of vascular and renal crises of scleroderma by oral angiotensin-converting-enzyme blockade. N Engl J Med 1979, 300: b 15 Steen VD, Castantio JP, Sapiro AP et al.: Outocome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme ACE inhibitors, Ann Intern Med 1990, 113: b 16 Steen VD, Medsger Jr TA: Long-term outcomes of scleroderma renal crisis, Ann Intern Med 2000, 133: b 17 Caskey FJ, Thacker EJ, Jhonston PA et al.: Failure of losartan to control blood pressure in scleroderma renal crisis, Lancet 1997, 349: 620. b 62

70 18 Steen VD, Demarco PJ: Complications in the use of angiotensin receptor blockers in the treatment of scleroderma renal crisis, Arthritis Rheum 2000, 44: b 19 losartan Teixeira L, Servetiz A, Mehrenberger M. et al.: Scleroderma renal crisis, Presse Med 2006, 35: Denton CP, Lapadula, Mounthon L: Renal complications and scleroderma renal crisis, Rheumatology 2009,48: iii32-iii Penn H, Howie AJ, Kingdon EJ, et al.: Scleroderma renal crisis: patient characteristics and long-term outcomes, Q J Med 2007, 100: Teixeira L, Mouthon L, Mahr A, et al. for the Group Francais de Recherche sur ie Sclerodermie GFRS : Motality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients, Ann Rheum Dis 2008, 67: Gibney EM, Parikh CR, Jani A, et al.: Kideny transplantation for systemic sclerosis improves survival and may moderate disease activity, Am J Transplantation 2004, 4: b 25 Pham PTT, Pham PC, Danovith GM, et al.: Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: case report and review of the literature, Am J Transplant 2005, 5:

71 6 65

72 CQ mg/ CQ4 CQ2 SPECT MRI BNP NT-proPBNP CQ2,3 ARB Ca CQ4 CQ1 CQ2 CQ4 CQ1 CQ4 CQ1 CQ2 66

73 6 X MRI X T 24 MRI SSc MRI 39 75% 3 MRI SSc SSc SSc dcssc lcssc 4 5 dcssc lcssc 1 B-type natriuretic peptide BNP 67

74 BNP 6 7 BNP 8 SSc BNP BNP BNP pro-bnp N N-terminal pro-bnp NT-pro-BNP BNP SSc β ARB Ca SSc case-study randomized control trial 9 10 β ARB Ca 1 Hachulla A-L, Launay D, Gaxotte V, et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cress-sectional observational study of 52 patients. Ann Rheum Dis E-publish 3 Dec IV b 2 Kobayashi H, Yokoe I Hirano I, et al. Cardiac magnetic resonance imaging with pharmacological stress perfusion and delayed enhancement in asymptomatic patients with systemic sclerosis. J Rheumatol 2009; 36: IV b 3 Tzelepis GE, Kelekis NL, Plastiras SC, et al. Pattern and distribution of myocardial fibrosis in systemic sclerosis: a delayed enhanced magnetic resonance imaging study. Arthritis Rheum 2007; 56: IV b 4 Kahan A, Allanore Y. Primary myocardial involvement in systemic sclerosis. Rheumatology 2006; 45: iv14-iv17. I 5 Ferri C, Valentini G, Cozzi F, et al. Systemic Sclerosis Study Group of the Italian Society of Rheumatology SIR- GSSSc. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1012 Italian patients. 68

75 Medicine 2002; 81: IV a 6 Maron BJ, Tholakanahalli VN, Zenovich AG, et al. Usefulness of B-type natriuretic peptide assay in the assessment of symptomatic state in hypertrophic cardiomyopathy. Circulation 2004; 109: IV b 7 Binder J, Ommen SR, Chen HH, et al. Usefulness of brain natriuretic peptide levels in the clinical evaluation of patients with hypertrophic cardiomyopathy. Am J Cardiol 2007; 100: IV b 8 Eroglu S, Yildirir A, Bozbas H, et al. Brain natriuretic peptide levels and cardiac functional capacity in patients with dyspnea and isolated diastolic dysfunction. Int Heart J 2007; 48: IV b 9 Sato T, Oominami S, Souma T, et al. A case of systemic sclerosis and Sjogren s syndrome with cardiac tamponade due to steroid-responsive pericarditis. Jpn J Allergol 2006; 55: V 10 Uhl GS, Koppes GM. Pericardial tamponade in systemic sclerosis scleroderma. Br Heart J 1979; 42: V 69

76 7 71

77 CQ1-8 9 CQ

78 7 SSc 101 odds ratio 4.5 odds ratio SSc SSc 29 SSc 16 double blind crossover study 3 SSc meta-analysis mg 3 / 44 SSc mg/

79 SSc open study 107 SSc multicenter double blind prospective study 5 SSc SSc 57 open study 29% 35% 28% 6 43% 43% SSc SSc 10 open study SSc 1 open study 36 SSc 5 / % P % P % P

80 II 10 SSc II 11 SSc P 0.009P SSc P 0.091P SSc SSc 12 SSc 14 SSc 75

81 Korn 122 SSc 17 WHO III IV 18 Fries SSc 16 crossover 19 P P P Markus SSc 2 21 SSc 4 22 SSc 76

82 Deguchi SSc SSc SSc

83 SSc SSc mg 428 VAS 30 E 1 SSc SSc E 1 34 SSc SSc 35 SSc SSc

84 1 Harrison BJ, Silman AJ, Hider SL, et al. Cigarette smoking as a significant risk factor for digital vascular disease in patients with systemic sclerosis. Arthritis Rheum 2002, 46: IV b 2 Caramaschi P, Martinelli N, Volpe A, et al. A score of risk factors associated with ischemic digital ulcers in patients affected by systemic sclerosis treated with iloprost. Clin Rheum 2009, 28: IV b 3 Finch MB, Dawson J, Johnson GD. The peripheral vascular effects of nifedipine in Raynaud s syndrome associated with scleroderma: a double blind crossover study. Clin Rheumatol 1986, 5: II 4 Thompson AE, Shea B, Welch V, et al. Calcium-channel blockers for Raynaud s phenomenon in systemic sclerosis. Arthritis Rheum 2001, 44: I 5 Vayssairat M. Preventive effect of an oral prostacyclin analog, beraprost sodium, on digital necrosis in systemic sclerosis. French Microcirculation Society Multicenter Group for the Study of Vascular Acrosyndromes. J Rheumatol 1999, 26: II IV b IV b 8 Rajagopalan S, Pfenninger D, Somers E, et al. Effects of cilostazol in patients with Raynaud s syndrome. Am J Cardiol 2003, 92: II 9 Gardinali M, Pozzi MR, Bernareggi M, et al. Treatment of Raynaud s phenomenon with intravenous prostaglandin E1acyclodextrin imprioves endothelial cell injury in systemic sclerosis. J Rheumatol 2001, 28: IV b 10 Gliddon AE, Dore CJ, Black CM, et al. Prevention of vascular damage in scleroderma and autoimmune Raynaud s phenomenon. Arthritis Rheum 2007, 56: II 11 Dziadzio M, Denton CP, Smith R, et al. Losartan therapy for Raynaud s phenomenon and scleroderma. Arthritis Rheum 1999, 42: II , 47: V V 14 Argatroban IV b 15 Selenko-Gebauer N, Duschek N, Minimair G, et al. Successful treatment of patients with severe secondary Raynaud s phenomenon with the endothelin receptor antagonist bosentan, Rheumatology 2006, 45: iii45 8. V 16 Garcia de la Pena-Lefebvre P, Rodriguez Rubio S, Valero Exposito M, et al. Long-term experience of bosentan for treating ulcers and healed ulcers in systemic sclerosis. Rheumatology 2008, 47: IV b 17 Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis. Prevention by treatment with bosentan, an oral endothelial receptor antagonist. Arthritis Rheum 2004, 50: II 18 Kumar N, Griffiths B, Allen J. Thermographic and symptomatic effect of a single dose of sildenafil citrate on Raynaud s phenomenon in patients with systemic sclerosis: a potentail treatment. J Rheumatol 2006, 33: V 19 Fries R, Shariat K, von Wilmowsky H, et al. Sildenafil in the treatment of Raynaud s phenomenon resistant to vasodilatory therapy. Circulation 2005, 112: II 20 Colglazier CL, Sutej PG, O Rourke KS, et al. Severe refractory fingertip ulcerations in a patient with scleroderma: successful treatment with sildenafil. J Rheumatol 2005, 32: V 21 Markus YM, Bell MJ, Evans AW, et al. Ischemic scleroderma wounds successfully treated with hyperbaric oxygen therapy. J Rheumatol 2006, 33: IV b

85 IV b 23 Hafner J, Kohler A, Enzler M, et al. Successful treatment of an extended leg ulcer in systemic sclerosis. Vasa 1997, 26: V V 25 Deguchi J, Shigematsu K, Ota S, et al. Surgical result of critical limb ischemia due to tibial arterial occulusion in patients with systemic sclerosis. J Vasc Surg 2009, 49: V 26 Stratton R, Howell K, Goddard N, et al. Digital sympathectomy for ischaemia in scleroderma. Br J Rheumatol 1997, 36: V 27 Hafner J, Della Santa D, Zuber C, et al. Digital sympathectomy microarteriolysis in the treatment of severe Raynaud s phenomenon secondary to systemic sclerosis. Br J Dermatol 1997, 137: V 28 Klyscz T, Junger M, Meyer H, et al. Improvement of acral circulation in a patient with systemic sclerosis with stellate blocks. Vasa 1998, 27: V 29 Taylor MH, McFadden JA, Bolster MB, et al. Ulnar artery involvement in systemic sclerosis scleroderma. J Rheumatol 2002, 29: V 30 Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud s phenomenon and digital ulcers. J Rheumatol 2008, 35: II 31 Yamanaka K, Inaba T, Nomura E et al. Basic fibroblast growth factor treatment for skin ulcerations in scleroderma. Cutis 2005, 76: V V V V VI V 37 Dibutyryl Cyclic AMP V 80

86 8 81

87 CQ1 CQ2 CQ3 CQ4 CQ5 82

88 8 SSc SSc 25% 1 2 SSc SSc a. metastatic calcification b. tumoral calcification c. dystrophic calcification d. idiopathic calcification e. calciphilaxis 5 3 a. metastatic calcification Ca P D b. tumoral calcification P Ca c. dystrophic calcification Ca P SSc X d. idiopathic calcification e. calciphylaxis Ca P 83

89 SSc dystrophic calcification calcium-binding amino acid γ-carboxyglutamic acid γ-carboxyglutamic acid 4 calcification Ca P PTH SSc 5 6 PTH 7 PTH X X CT 8 SSc γ-carboxyglutamic acid K Berger 4 1 mg/ 18 2 SSc 1 / SSc 1 2 γ-carboxyglutamic acid Tc-99m diphosphate mg/ /3 Tc-99m diphosphate Lassoued 6 1 mg / 1 11 Cukierman 3 SSc 1 mg/ 1 2 cm 12 84

90 Bogoch SSc prospective study 11 cross-sectional study 7 retrospective chart review 14 case report CO 2 81% CO 2 B C1 SSc Ca Ca 14 Farah 240 mg/ 5 15 Vayssarirat 23 retrospective uncontrolled study 180 mg/ Palmieri 4 1 CREST mg/ 17 Robertson 9 lcssc mg/ P 18 85

91 Robertson LP, Marshall RW, Hickling P: Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline. Ann Rheum Dis 2003; 62: V 2 Alpoz E, Cankaya H, Guneri P: Facial subcutaneous calcinosis and mandibular resorption in systemic sclerosis: a case report. Dentomaxillofac Radiol 2007; 36: V 3 Boulman N, Slobodin G, Rozenbaum M, et al.: Calcinosis in rheumatic diseases. Semin Arthritis Rheum 2005; 34: Lian JB, Skinner M, Glimcher MJ, et al.: The presence of gamma-carboxyglutamic acid in the proteins associated with ectopic calcification. Biochem Biophys Res Commun 1976; 73: V 5 Avouac J, Guerini H, Wipff J, et al.: Radiological hand involvement in systemic sclerosis. Ann Rheum Dis 2006; 65: V 6 Braun-Moscovici Y, Furst DE, Markovits D, et al.: Vitamin D, parathyroid hormone, and acroosteolysis in systemic sclerosis. J Rheumatol 2008; 35: V 7 Serup J, Hagdrup HK: Parathyroid hormone and calcium metabolism in generalized scleroderma. Increased PTH level and secondary hyperparathyroidism in patients with aberrant calcifications. Prophylactic treatment of calcinosis. Arch Dermatol Res 1984; 276: V 8 Allanore Y, Feydy A, Serra-Tosio G, et al.: Usefulness of multidetector computed tomography to assess calcinosis in systemic sclerosis. J Rheumatol 2008; 35: V 9 Gallop PM, Lian JB, Hauschka PV: Carboxylated calcium-binding proteins and vitamin K. N Engl J Med 1980; 302: Berger RG, Featherstone GL, Raasch RH, et al.: Treatment of calcinosis universalis with low-dose warfarin. Am J Med 1987; 83: II 11 Lassoued K, Saiag P, Anglade MC, et al.: Failure of warfarin in treatment of calcinosis universalis. Am J Med 1988; 84: V 12 Cukierman T, Elinav E, Korem M, et al.: Low dose warfarin treatment for calcinosis in patients with systemic sclerosis. Ann Rheum Dis 2004; 63: Bogoch ER, Gross DK: Surgery of the hand in patients with systemic sclerosis: outcomes and considerations. J Rheumatol 2005; 32: Dolan AL, Kassimos D, Gibson T, et al.: Diltiazem induces remission of calcinosis in scleroderma. Br J Rheumatol 1995; 34: V 15 Farah MJ, Palmieri GM, Sebes JI, et al.: The effect of diltiazem on calcinosis in a patient with the CREST syndrome. Arthritis Rheum 1990; 33: V 16 Vayssairat M, Hidouche D, Abdoucheli-Baudot N, et al.: Clinical significance of subcutaneous calcinosis in patients with systemic sclerosis. Does diltiazem induce its regression? Ann Rheum Dis 1998; 57: V 17 Palmieri GM, Sebes JI, Aelion JA, et al.: Treatment of calcinosis with diltiazem. Arthritis Rheum 1995; 38: V 18 Skuterud E, Sydnes OA, Haavik TK: Calcinosis in dermatomyositis treated with probenecid. Scand J Rheumatol 1981; 10: Rabens SF, Bethune JE: Disodium etidronate therapy for dystrophic cutaneous calcification. Arch Dermatol 1975; 111: V 86

92 20 Vereecken P, Stallenberg B, Tas S, et al.: Ulcerated dystrophic calcinosis cutis secondary to localised linear scleroderma. Int J Clin Pract 1998; 52: V 21 Eddy MC, Leelawattana R, McAlister WH, et al.: Calcinosis universalis complicating juvenile dermatomyositis: resolution during probenecid therapy. J Clin Endocrinol Metab 1997; 82: V 87

93

94 Medsger severity damage activity 1 modified Rodnan total skin thickness score TSS 2 endpoint TSS 1 2 TSS score 1. Medsger TA Jr, Silman AJ, Steen VD, Black CM, Akesson A, et al.: A disease severity scale for systemic sclerosis: development and testing. J Rheumatol 1999, 26: Clements P, Lachenbruch P, Siebold J, White B, Weiner S, et al.:inter and intraobserver variability of total skin thickness score Modified Rodnan TSS in systemic sclerosis. J Rheumatol 1995, 22: Medsger 0 normal normal 1 mild 5% 10% 2 moderate 3 severe 4 very severe LDH HAQ IgG 89

95 Medsger modified Rodnan total skin thickness score TSS Medsger SSc579 0 normal 1 mild 2 moderate 3 severe 4 endstage TSS Medsger TA et al.: J Rheumatol 26: Medsger 151 SSc 0 normal 1 mild 2 moderate 3 severe 4 endstage TSS Medsger SSc 1 mild 3 severe 4 endstage Medsger 1 mild 2 moderate TSS SSc 0 normal 1 mild 2 moderate 3 severe 4 endstage TSS severe 4 endstage 1 mild 1 mild endstage very severe 0 normal 1 mild 2 moderate 3 severe 4 very severe TSS* *modified Rodnan total skin thickness score TSS TSS 90

96 SSc VC/ DLco normal 1 mild 2 moderate 3 severe 4 very severe VC 80 VC VC VC 50 X CT X CT 0 normal 1 mild 2 moderate 3 severe 4 very severe PH PH WHO I PH WHO II PH WHO III PH WHO IV SSc PH PAH PH PH X N-T probnp PH 35 mmhg mmhg 50 mmhg PH 35 mmhg 35 mmhg PH 3 PH 25 mmhg 30 mmhg 15 mmhg 3 PH PH CT 91

97 WHO I II III IV / A. 0. normal 1. mild 2. moderate 3. severe 4. very severe GERD B. 0. normal 1. mild 2. moderate 3. severe 4. very severe Barrett 24 ph CT /1 5 /17.5 /310 /6 / 92

98 / Body mass index 2 D-Xylose Schilling SSc ANCA 0 normal 1 mild 2 moderate 3 severe 4 very severe mg/dl mg/dl mg/dl 0 normal ACE mmHg 2 2 Keith-Wegener RNA 93

99 SSc 1 ANCA P-ANCA MPO-ANCA 2TTP/HUS LDH ADAMTS13 ADAMTS13 0 normal 50 EF 1 mild 45 EF 50 NYHA I 2 moderate 40 EF 45 NYHA II 3 severe EF 40 NYHA III 4 very severe NYHA IV NYHA I II III IV

100 2 0 normal 0 1 mild moderate severe 8 SSc 0 normal normal 1 mild Raynaud s phenomenon 2 moderate digital pitting ulcers 3 severe other skin ulcerations 4 very severe digital gangrene 95

101