Pharmacotherapy of systemic sclerosis

Expert Opinion on Pharmacotherapy

Volumn 11, Issue 5, 2010, Pages 789-806

  Postlethwaite, Arnold E ^a,b   Harris, L Jeff ^b,c   Raza, Syed H ^a,b   Kodura, Swapna ^a,b   Akhigbe, Titilola ^a,b  

^a UNIVERSITY OF TENNESSEE HEALTH SCIENCE CENTER   (United States)

^b DEPARTMENT OF VETERANS AFFAIRS   (United States)

^c VANDERBILT UNIVERSITY   (United States)

Author keywords

Autoimmunity; Fibrosis; Platelets; Scleroderma; Systemic sclerosis

Indexed keywords

ABATACEPT; ACETYLSALICYLIC ACID; ANALGESIC AGENT; ANTIBIOTIC AGENT; ATORVASTATIN; BOSENTAN; CALCIUM CHANNEL BLOCKING AGENT; CYCLOPHOSPHAMIDE; DASATINIB; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIPYRIDAMOLE; DISEASE MODIFYING ANTIRHEUMATIC DRUG; ERYTHROMYCIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; ILOPROST; IMATINIB; METELIMUMAB; METHOTREXATE; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; OCTREOTIDE; PHOSPHODIESTERASE V INHIBITOR; PLACEBO; PRAVASTATIN; PROSTACYCLIN DERIVATIVE; PROTON PUMP INHIBITOR; PRUCALOPRIDE; RAPAMYCIN; SILDENAFIL; SIMVASTATIN; UNINDEXED DRUG;

ARTHRITIS; AUTOIMMUNITY; AUTOLOGOUS STEM CELL TRANSPLANTATION; BLIND LOOP SYNDROME; CELL FUNCTION; CLINICAL FEATURE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; DIGITAL ULCER; DRUG MECHANISM; DRUG MEGADOSE; DRUG PULSE THERAPY; ESOPHAGUS FUNCTION DISORDER; FIBROGENESIS; GASTROINTESTINAL SYMPTOM; HEART MUSCLE FIBROSIS; HUMAN; HYPOTENSION; INTESTINAL DYSMOTILITY; INTRACTABLE PAIN; KIDNEY DISEASE; LOW DRUG DOSE; LUNG FIBROSIS; MAST CELL; MEDICAL CARE; MORTALITY; MUSCULOSKELETAL DISEASE; MYOCARDITIS; MYOFIBROBLAST; NONHUMAN; PATHOGENESIS; PNEUMATOSIS INTESTINALIS; PROTEIN FUNCTION; PULMONARY HYPERTENSION; QUALITY OF LIFE; RAYNAUD PHENOMENON; REVIEW; SCLERODERMA RENAL CRISIS; SKIN FIBROSIS; SYSTEMIC SCLEROSIS; THROMBOCYTE; ULCER; ULTRAVIOLET A RADIATION; UNSPECIFIED SIDE EFFECT; VASCULAR DISEASE; VASOSPASM;

ANIMALS; AUTOIMMUNITY; CLINICAL TRIALS AS TOPIC; DRUG DELIVERY SYSTEMS; FIBROSIS; HUMANS; QUALITY OF LIFE; SCLERODERMA, SYSTEMIC;

EID: 77949454176     PISSN: 14656566     EISSN: None     Source Type: Journal    
DOI: 10.1517/14656561003592177     Document Type: Review

References (118)

1. Sgonc R, Gruschwitz MS, Boeck G, et al. Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 2000;43(11):2550-2562
2. Giacomelli R, Matucci-Cerinic M, Cipriani P, et al. Circulating Vdelta1+ T cells are activated and accumulate in the skin of systemic sclerosis patients. Arthritis Rheum 1998;41(2):327-334
3. Nash RA, McSweeney PA, Crofford LJ, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood 2007;110(4):1388-1396
4. Raghow R, Postlethwaite AE, Keski-Oja J, et al. Transforming growth factor-beta increases steady state levels of type I procollagen and fibronectin messenger RNAs posttranscriptionally in cultured human dermal fibroblasts. J Clin Invest 1987;79(4):1285-1288
5. Tan FK, Hildebrand BA, Lester MS, et al. Classification analysis of the transcriptosome of nonlesional cultured dermal fibroblasts from systemic sclerosis patients with early disease. Arthritis Rheum 2005;52(3):865-876
6. Sargent JL, Milano A, Bhattacharyya S, et al. A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J Invest Dermatol 2009 [Epub ahead of print]
7. Gruschwitz M, Muller PU, Sepp N, et al. Transcription and expression of transforming growth factor type beta in the skin of progressive systemic sclerosis: a mediator of fibrosis? J Invest Dermatol 1990;94(2):197-203
8. Gabrielli A, Di Loreto C, Taborro R, et al. Immunohistochemical localization of intracellular and extracellular associated TGF beta in the skin of patients with systemic sclerosis (scleroderma) and primary Raynaud's phenomenon. Clin Immunol Immunopathol 1993;68(3):340-349
9. Sfikakis PP, McCune BK, Tsokos M, et al. Immunohistological demonstration of transforming growth factor-beta isoforms in the skin of patients with systemic sclerosis. Clin Immunol Immunopathol 1993;69(2):199-204
10. Postlethwaite AE, Holness MA, Katai H, Raghow R. Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J Clin Invest 1992;90(4):1479-1485
11. Dziadzio M, Smith RE, Abraham DJ, et al. Circulating levels of active transforming growth factor beta1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score. Rheumatology (Oxford) 2005;44:1518-1524
12. Denton CP, Merkel PA, Furst DE, et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum 2007;56:323-333
13. Postlethwaite AE, Seyer JM. Fibroblast chemotaxis induction by human recombinant interleukin-4. Identification by synthetic peptide analysis of two chemotactic domains residing in amino acid sequences 70-88 and 89-122. J Clin Invest 1991;87:2147-2152
14. Alaibac M, Berti E, Chizzolini C, et al. Role of cellular immunity in the pathogenesis of autoimmune skin diseases. Clin Exp Rheumatol 2006;24:S14-19
15. Parel Y, Aurrand-Lions M, Scheja A, et al. Presence of CD4+CD8+ double-positive T cells with very high interleukin-4 production potential in lesional skin of patients with systemic sclerosis. Arthritis Rheum 2007;56(10):3459-3467
16. Salmon-Ehr V, Serpier H, Nawrocki B, et al. Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis. Arch Dermatol 1996;132:802-806
17. Scaletti C, Vultaggio A, Bonifacio S, et al. Th2-oriented profile of male offspring T cells present in women with systemic sclerosis and reactive with maternal major histocompatibility complex antigens. Arthritis Rheum 2002;46:445-450
18. Makhluf HA, Stepniakowska J, Hoffman S, et al. IL-4 upregulates tenascin synthesis in scleroderma and healthy skin fibroblasts. J Invest Dermatol 1996;107:856-859
19. Brinckmann J, Kim S, Wu J, et al. Interleukin 4 and prolonged hypoxia induce a higher gene expression of lysyl hydroxylase 2 and an altered crosslink pattern: important pathogenetic steps in early and late stage of systemic scleroderma? Matrix Biol 2005;24:459-468
20. Bhogal RK, Stoica CM, McGaha TL, Bona CA. Molecular aspects of regulation of collagen gene expression in fibrosis. J Clin Immunol 2005;25:592-603
21. McGaha TL, Le M, Kodera T, et al. Molecular mechanisms of interleukin-4-induced up-regulation of type I collagen gene expression in murine fibroblasts. Arthritis Rheum 2003;48:2275-2284
22. Rishikof DC, Ricupero DA, Kuang PP, et al. Interleukin-4 regulates connective tissue growth factor expression in human lung fibroblasts. J Cell Biochem 2002;85:496-504
23. McGaha TL, Bona CA. Role of profibrogenic cytokines secreted by T cells in fibrotic processes in scleroderma. Autoimmun Rev 2002;1:174-181
24. Ong C, Wong C, Roberts CR, et al. Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol 1998;28:2619-2629
25. Baroni SS, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006;354:2667-2676
26. Loizos N, Lariccia L, Weiner J, et al. Lack of detection of agonist activity by antibodies to platelet-derived growth factor receptor alpha in a subset of normal and systemic sclerosis patient sera. Arthritis Rheum 2009;60:1145-1151
27. Arnett FC. Is scleroderma an autoantibody mediated disease? Curr Opin Rheumatol 2006;18:579-581
28. Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2009;60:578-583
29. Rajkumar VS, Howell K, Csiszar K, et al. Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis. Arthritis Res Ther 2005;7:R1113-1123
30. Kirk TZ, Mark ME, Chua CC, et al. Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. J Biol Chem 1995;270:3423-3428
31. Ahmed SS, Tan FK, Arnett FC, et al. Induction of apoptosis and fibrillin 1 expression in human dermal endothelial cells by scleroderma sera containing anti-endothelial cell antibodies. Arthritis Rheum 2006;54:2250-2262
32. Guiducci S, Distler O, Distler JH, Matucci-Cerinic M. Mechanisms of vascular damage in SSc-implications for vascular treatment strategies. Rheumatology (Oxford) 2008;47 (Suppl 5):v18-20
33. Postlethwaite AE, Chiang TM. Platelet contributions to the pathogenesis of systemic sclerosis. Curr Opin Rheumatol 2007;19:574-579
34. Nomura S, Inami N, Ozaki Y, et al. Significance of microparticles in progressive systemic sclerosis with interstitial pneumonia. Platelets 2008;19:192-198
35. Friedhoff LT, Seibold JR, Kim HC, Simester KS. Serotonin induced platelet aggregation in systemic sclerosis. Clin Exp Rheumatol 1984;2:119-123
36. Chiang TM, Postlethwaite AE. A cell model system to study regulation of phosphotidylinositol 3-kinase and protein kinase B activity by cytokines/growth factors produced by type I collagen stimulated immune cells from patients with systemic sclerosis. Biochim Biophys Acta 2007;1770:1181-1186
37. Tokumura A, Carbone LD, Yoshioka Y, et al. Elevated serum levels of arachidonoyl-lysophosphatidic acid and sphingosine 1-phosphate in systemic sclerosis. Int J Med Sci 2009;6:168-176
38. Akhmetshina A, Dees C, Pileckyte M, et al. Rho-associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts. Arthritis Rheum 2008;58:2553-2564
39. Chanez P, Lacoste JY, Guillot B, et al. Mast cells' contribution to the fibrosing alveolitis of the scleroderma lung. Am Rev Respir Dis 1993;147:1497-1502
40. Yamamoto T, Katayama I, Nishioka K. Expression of stem cell factor in the lesional skin of systemic sclerosis. Dermatology 1998;197:109-114
41. Gailit J, Marchese MJ, Kew RR, Gruber BL. The differentiation and function of myofibroblasts is regulated by mast cell mediators. J Invest Dermatol 2001;117:1113-1119
42. Salamon P, Shoham NG, Gavrieli R, et al. Human mast cells release Interleukin-8 and induce neutrophil chemotaxis on contact with activated T cells. Allergy 2005;60:1316-1319
43. Salamon P, Shoham NG, Puxeddu I, et al. Human mast cells release oncostatin M on contact with activated T cells: possible biologic relevance. J Allergy Clin Immunol 2008;121:448-455 e445
44. Mazzoni A, Siraganian RP, Leifer CA, Segal DM. Dendritic cell modulation by mast cells controls the Th1/Th2 balance in responding T cells. J Immunol 2006;177:3577-3581
45. Kambayashi T, Allenspach EJ, Chang JT, et al. Inducible MHC class II expression by mast cells supports effector and regulatory T cell activation. J Immunol 2009;182:4686-4695
46. Randone SB, Guiducci S, Cerinic MM. Musculoskeletal involvement in systemic sclerosis. Best Pract Res Clin Rheumatol 2008;22:339-350
47. Furst DE, Clements PJ, Steen VD, et al. The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis. J Rheumatol 1998;25:84-88
48. Kissin EY, Merkel PA, Lafyatis R. Myofibroblasts and hyalinized collagen as markers of skin disease in systemic sclerosis. Arthritis Rheum 2006;54:3655-3660
49. Thompson AE, Shea B, Welch V, et al. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum 2001;44:1841-1847
50. Rademaker M, Cooke ED, Almond NE, et al. Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study. BMJ 1989;298:561-564
51. Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004;50:3985-3993
52. Seibold JR, Matucci Cerinic M, Denton CP. Bosentan reduces the number of new digital ulcers in patients with systemic sclerosis. Ann Rheum Dis 2006;65 (Suppl II):90
53. Hettema ME, Zhang D, Stienstra Y, et al. No effects of bosentan on microvasculature in patients with limited cutaneous systemic sclerosis. Clin Rheumatol 2009;28:825-833
54. Fries R, Shariat K, von Wilmowsky H, Bohm M. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation 2005;112:2980-2985
55. Caglayan E, Huntgeburth M, Karasch T, et al. Phosphodiesterase Type 5 inhibition is a novel therapeutic option in Raynaud disease. Arch Intern Med 2006;166:231-233
56. 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;35:1801-1808
57. Del Papa N, Cortiana M, Vitali C, et al. Simvastatin reduces endothelial activation and damage but is partially ineffective in inducing endothelial repair in systemic sclerosis. J Rheumatol 2008;35:1323-1328
58. Furukawa S, Yasuda S, Amengual O, et al. Protective effect of pravastatin on vascular endothelium in patients with systemic sclerosis: a pilot study. Ann Rheum Dis 2006;65:1118-1120
59. Wigley FM, Korn JH, Csuka ME, et al. Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study. Arthritis Rheum 1998;41:670-677
60. Black CM, Halkier-Sorensen L, Belch JJ, et al. Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study. Br J Rheumatol 1998;37:952-960
61. Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med 1994;120:199-206
62. Denton CP, Lapadula G, Mouthon L, Muller-Ladner U. Renal complications and scleroderma renal crisis. Rheumatology 2009;48 (Suppl 3):iii32-35
63. DeMarco PJ, Weisman MH, Seibold JR, et al. Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum 2002;46:2983-2989
64. Steen V. Scleroderma renal crisis. Indian J Med Sci 2007;61:71-72
65. Forbes A, Marie I. Gastrointestinal complications: the most frequent internal complications of systemic sclerosis. Rheumatology (Oxford) 2009; 48 (Suppl 3):iii36-39
66. Howe S, Eaker EY, Sallustio JE, et al. Antimyenteric neuronal antibodies in scleroderma. J Clin Invest 1994;94:761-770
67. Singh J, Mehendiratta V, Del Galdo F, et al. Immunoglobulins (IgGs) from scleroderma patients inhibit muscarinic receptor in Internal Anal Sphincter (IAS) smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 2009;297(6):G1206-13
68. Marie I, Ducrotte P, Denis P, et al. Oesophageal mucosal involvement in patients with systemic sclerosis receiving proton pump inhibitor therapy. Aliment Pharmacol Ther 2006;24:1593-1601
69. Derk CT, Rasheed M, Artlett CM, Jimenez SA. A cohort study of cancer incidence in systemic sclerosis. J Rheumatol 2006;33:1113-1116
70. Marie I. Gastrointestinal involvement in systemic sclerosis. Presse Med 2006;35:1952-1965
71. Calamia KT, Scolapio JS, Viggiano TR. Endoscopic YAG laser treatment of watermelon stomach (gastric antral vascular ectasia) in patients with systemic sclerosis. Clin Exp Rheumatol 2000;18:605-608
72. Marie I, Levesque H, Ducrotte P, et al. Manometry of the upper intestinal tract in patients with systemic sclerosis: a prospective study. Arthritis Rheum 1998;41:1874-1883
73. Battle WM, Snape WJ Jr, Wright S, et al. Abnormal colonic motility in progressive systemic sclerosis. Ann Intern Med 1981;94:749-752
74. Ebert EC. Gastric and enteric involvement in progressive systemic sclerosis. J Clin Gastroenterol 2008;42:5-12
75. Govoni M, Muccinelli M, Panicali P, et al. Colon involvement in systemic sclerosis: clinical-radiological correlations. Clin Rheumatol 1996;15:271-276
76. Madsen JL, Hendel L. Gastrointestinal transit times of radiolabeled meal in progressive systemic sclerosis. Dig Dis Sci 1992;37:1404-1408
77. Wegener M, Adamek RJ, Wedmann B, et al. Gastrointestinal transit through esophagus, stomach, small and large intestine in patients with progressive systemic sclerosis. Dig Dis Sci 1994;39:2209-2215
78. Budd DC, Nirdlinger EL, Sturtz DL, Fouty WJ Jr. Transverse colon volvulus associated with scleroderma. Am J Surg 1977;133:370-372
79. Robinson JC, Teitelbaum SL. Stercoral ulceration and perforation of the sclerodermatous colon: report of two cases and review of the literature. Dis Colon Rectum 1974;17:622-632
80. Miercort RD, Merrill FG. Pneumatosis and pseudo-obstruction in scleroderma. Radiology 1969;92:359-362
81. Ritchie M, Caravelli J, Shike M. Benign persistent pneumoperitoneum in scleroderma. Dig Dis Sci 1986;31:552-555
82. Trezza M, Krogh K, Egekvist H, et al. Bowel problems in patients with systemic sclerosis. Scand J Gastroenterol 1999;34:409-413
83. Basilisco G, Barbera R, Vanoli M, Bianchi P. Anorectal dysfunction and delayed colonic transit in patients with progressive systemic sclerosis. Dig Dis Sci 1993;38:1525-1529
84. Kenefick NJ, Vaizey CJ, Nicholls RJ, et al. Sacral nerve stimulation for faecal incontinence due to systemic sclerosis. Gut 2002;51:881-883
85. 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;56:3827-3836
86. D'Angelo WA, Fries JF, Masi AT, Shulman LE. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med 1969;46:428-440
87. Perera A, Fertig N, Lucas M, et al. Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti-topoisomerase I antibody. Arthritis Rheum 2007;56:2740-2746
88. Meune C, Avouac J, Wahbi K, et al. Cardiac involvement in systemic sclerosis assessed by tissue-doppler echocardiography during routine care: a controlled study of 100 consecutive patients. Arthritis Rheum 2008;58:1803-1809
89. Cremers B, Flesch M, Kostenis E, et al. Modulation of myocardial contractility by lysophosphatidic acid (LPA). J Mol Cell Cardiol 2003;35:71-80
90. Kahan A, Allanore Y. Primary myocardial involvement in systemic sclerosis. Rheumatology (Oxford) 2006;45 (Suppl 4):iv14-17
91. Allanore Y, Vignaux O, Arnaud L, et al. Effects of corticosteroids and immunosuppressors on idiopathic inflammatory myopathy related myocarditis evaluated by magnetic resonance imaging. Ann Rheum Dis 2006;65:249-252
92. Liangos O, Neure L, Kuhl U, et al. The possible role of myocardial biopsy in systemic sclerosis. Rheumatology (Oxford) 2000;39:674-679
93. Al-mashaleh M, Bak H, Moore J, et al. Resolution of sclerodermatous myocarditis after autologous stem cell transplantation. Ann Rheum Dis 2006;65:1247-1248
94. Champion HC. The heart in scleroderma. Rheum Dis Clin North Am 2008;34:181-90, viii
95. Steen V. The heart in systemic sclerosis. Curr Rheumatol Rep 2004;6:137-140
96. Kahan A, Coghlan G McLaughlin V. Cardiac complications of systemic sclerosis. Rheumatology (Oxford) 2009;48 (Suppl 3):iii45-48
97. Wells AU, Steen V, Valentini G. Pulmonary complications: one of the most challenging complications of systemic sclerosis. Rheumatology (Oxford) 2009;48 (Suppl 3):iii40-44
98. Desai SR, Veeraraghavan S, Hansell DM, et al. CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology 2004;232:560-567
99. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655-2666
100. Tashkin DP, Elashoff R, Clements PJ, et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 2007;176:1026-1034
101. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000;132:425-434
102. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296-302
103. Oudiz RJ, Schilz RJ, Barst RJ, et al. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest 2004;126:420-427
104. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800-804
105. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-329
106. Denton CP, Pope JE, Peter HH, et al. Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases. Ann Rheum Dis 2008;67:1222-1228
107. Barst RJ, Langleben D, Badesch D, et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006;47:2049-2056
108. Galie N, Olschewski H, Rubin L, The ARIES study group. Ambrisentan therapy for pulmonary arterial hypertension: an integrated analysis of the ARIES-2 and ARIES-2 studies. Am J Respir Crit Care Med 2007;175:A397
109. Badesch DB, Hill NS, Burgess G, et al. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol 2007;34:2417-2422
110. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894-2903
111. Santiago B, Gutierrez-Canas I, Dotor J, et al. Topical application of a peptide inhibitor of transforming growth factor-beta1 ameliorates bleomycin-induced skin fibrosis. J Invest Dermatol 2005;125:450-455
112. Das SN, Alam MR, Islam N, et al. Placebo controlled trial of methotrexate in systemic sclerosis. Mymensingh Med J 2005;14:71-74
113. Denton CP, Black CM. Targeted therapy comes of age in scleroderma. Trends Immunol 2005;26:596-602
114. Hasegawa M, Hamaguchi Y, Yanaba K, et al. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol 2006;169:954-966
115. Matsushita T, Hasegawa M, Yanaba K, et al. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum 2006;54:192-201
116. Knobler RM, French LE, Kim Y, et al. A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis. J Am Acad Dermatol 2006;54:793-799
117. Postlethwaite AE, Wong WK, Clements P, et al. A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I. oral type I collagen does not improve skin in all patients, but may improve skin in late-phase disease. Arthritis Rheum 2008;58:1810-1822
118. Scherer HU, Burmester GR, Riemekasten G. Targeting activated T cells: successful use of anti-CD25 monoclonal antibody basiliximab in a patient with systemic sclerosis. Ann Rheum Dis 2006;65:1245-1247