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Scleroderma therapy: clinical overview of current trends and future perspective

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Abstract

Systemic sclerosis is a chronic autoimmune condition with a complex pathogenesis and a high rate of mortality and morbidity. Internal organ involvement requires interdisciplinary approach in individual patient management. New discoveries in the pathogenesis of scleroderma herald a drastic change in the traditional outlook to therapy and have led to the development of the target-based approach in management. The challenge at present is to translate these advances in molecular mechanisms into well-designed clinical trials that will recognize potential disease-modifying therapies. This article is an evidence-based review of prevailing treatment options and future therapeutic targets in systemic sclerosis.

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Abbreviations

SSc:

Systemic sclerosis

OS:

Oxidative stress

lcSSc:

Limited cutaneous SSc

dcSSc:

Diffuse cutaneous SSc

TGF-ß:

Transforming growth factor-ß

CCB:

Calcium channel blocker

RCT:

Randomized, controlled trial

DHP:

Dihydropyridines

ACE:

Angiotensin-converting enzyme

VCAM-1:

Vascular cell adhesion molecule 1

ICAM-1:

Intercellular adhesion molecule 1

ET-1:

Endothelin 1

PINP:

Procollagen type I N-terminal propeptide

ARB:

Angiotensin receptor blocker

PAH:

Pulmonary hypertension

SMW distance:

6-min walk distance

VAS:

Visual analog scale

DU:

Digital ulcer

PDE5:

Phosphodiesterase

RCS:

Raynaud’s condition score

5 HT:

5 hydroxytryptamine [serotonin]

IL-1:

Interleukin 1

TNF-α:

Tumor necrosis factor α

MTX:

Methotrexate

TSS:

Total skin score

ILD:

Interstitial lung disease

MMF:

Mycophenolate mofetil

IVIG:

Intravenous immunoglobulin

HSCT:

Hematopoietic stem cell transplantation

TGF β:

Transforming growth factor β

PDGF:

Platelet-derived growth factor

Rock:

Rho kinase

ECM:

Extracellular matrix

(PPAR)-γ:

Peroxisome proliferator-activated receptor

ROS:

Reactive oxygen species

References

  1. Murrell DF (1993) A radical proposal for the pathogenesis of scleroderma. J Am Acad Dermatol 28:78–85

    Article  PubMed  CAS  Google Scholar 

  2. Tikly M, Channa K, Theodorou P et al (2006) Lipid peroxidation and trace elements in systemic sclerosis. Clin Rheumatol 25:320–324

    Article  PubMed  Google Scholar 

  3. Herrick AL, Rieley F, Schofield D et al (1992) Micronutrient antioxidant status in patients with primary Raynaud’s phenomenon and systemic sclerosis. J Rheumatol 21:1477–1483

    Google Scholar 

  4. Veale DJ, Collidge TA, Belch J (1995) Increased prevalence of symptomatic macrovascular disease in systemic sclerosis. Ann Rheum Dis 54:853–855

    Article  PubMed  CAS  Google Scholar 

  5. Ho M, Veale DJ, Eastmond C et al (2000) Macrovascular disease in systemic sclerosis. Ann Rheum Dis 59:39–43

    Article  PubMed  CAS  Google Scholar 

  6. Shoenfeld Y, Gerli R, Doria A et al (2005) Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 112:3337–3347

    Article  PubMed  Google Scholar 

  7. Sherer Y, Shoenfeld Y (2006) Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat Clin Pract Rheumatol 2:1–8

    Article  Google Scholar 

  8. LeRoy CE (1996) Systemic sclerosis: a vascular perspective. Rheum Dis Clin N Am 22:675

    Article  CAS  Google Scholar 

  9. Matucci Cerinic M, Fiori G, Grenbaum E et al (2003) Macrovascular disease in systemic sclerosis. In: Furst D, Clements P (eds) Systemic sclerosis. Lippincott Williams and Wilkins, Baltimore

  10. Shand L, Lunt M, Nihtyanova S et al (2007) Relationship between change in skin score and disease outcome in diffuse cutaneous systemic sclerosis: application of a latent linear trajectory model. Arthritis Rheum 56:2422–2431

    Article  PubMed  Google Scholar 

  11. Kowal-Bielecka O, Landewe′ R, Avouac J et al (2009) EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 68:620–628

    Google Scholar 

  12. Kawakami T, Ihn H, Xu W et al (1998) Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype. J Invest Dermatol 110(1):47–51

    Article  PubMed  CAS  Google Scholar 

  13. Leask A (2006) Scar wars: is TGFbeta the phantom menace in scleroderma? Arthritis Res Ther 8(4):213

    Article  PubMed  CAS  Google Scholar 

  14. Wei, Jun, Leng et al (2009) Profibrotic Wnt signaling in human mesenchymal cells: implications for scleroderma. Arthritis Rheumatism, vol 60, Abstract Supplement

  15. Julie B, Jennifer F, Kimberly J et al (2008) Increased expression of Wnt2 and SFRP4 in Tsk Mouse Skin: role of Wnt signaling in altered dermal fibrillin deposition and systemic sclerosis. J Investigat Dermatol 128:871–881

    Google Scholar 

  16. Ayumi Y, Yohei I, Kazuhiro K et al (2008) CD19 Regulates skin and lung fibrosis via toll-like receptor signaling in a model of Bleomycin-induced scleroderma. Am J Pathol 172(6):1650–1663

    Google Scholar 

  17. Fineschi S, Goffin L, Rezzonico R et al (2008) Antifibroblast antibodies in systemic sclerosis induce fibroblasts to produce profibrotic chemokines, with partial exploitation of toll-like receptor 4. Arthritis Rheum 58(12):3913–3923

    Google Scholar 

  18. Agarwal SK, Wu M, Livingston CK (2011) Toll-like receptor 3 upregulation by type I interferon in healthy and scleroderma dermal fibroblasts. Arthritis Res Therapy 13:R3

    Google Scholar 

  19. Silverstein JL, Steen VD, Medsger TA et al (1988) Cutaneous hypoxia in patients with systemic sclerosis (Scleroderma). Arch Dermatol 124(9):1379–1382

    Article  PubMed  CAS  Google Scholar 

  20. Hong K-H, Yoo S-A, Kang S–S et al (2006) Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts. Clin Exp Immunol 146(2):362–370

    Article  PubMed  CAS  Google Scholar 

  21. Schild C, Trueb B (2002) Mechanical stress is required for high-level expression of connective tissue growth factor. Exp Cell Res 274(1):83–91

    Google Scholar 

  22. Wei J, Bhattacharyya S, Tourtellotte WG, Varga J (2010) Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy. Autoimmun Rev 10(5):267–275

    Article  PubMed  CAS  Google Scholar 

  23. Flavahan NA, Flavahan S, Mitra S, Chotani MA (2003) The vasculopathy of Raynaud’s phenomenon and scleroderma. Rheum Dis Clin North Am 29:275–291

    Article  PubMed  Google Scholar 

  24. Rajkumar VS, Sundberg C, Abraham DJ, Rubin K, Black CM (1999) Activation of microvascular pericytes in autoimmune Raynaud’s phenomenon and systemic sclerosis. Arthritis Rheum 42:930–941

    Article  PubMed  CAS  Google Scholar 

  25. Prescott RJ, Freemont AJ, Jones CJP et al (1992) Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 166:255–263

    Article  PubMed  CAS  Google Scholar 

  26. Thompson AE, Shea B, Welch V, Fenlon D, Pope JE (2001) Calcium-channel blockers for Raynaud’s phenomenon in systemic sclerosis. Arthritis Rheum 44:1841–1847

    Article  PubMed  CAS  Google Scholar 

  27. Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Herve P, Simonneau G (2005) Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111:3105–3111

    Article  PubMed  CAS  Google Scholar 

  28. Wollersheim H, Thien T (1991) Double-blind placebo-controlled crossover study of oral nicardipine in the treatment of Raynaud’s phenomenon. J Cardiovasc Pharmacol 18:813–818

    Article  PubMed  CAS  Google Scholar 

  29. Schmidt JF, Valentin N, Neilsen SL (1989) The clinical effect of felodipine and nifedipine in Raynaud’s phenomenon. Eur J Clin Pharmacol 37:191–192

    Article  PubMed  CAS  Google Scholar 

  30. La Civita L, Pitaro N, Rossi M et al (1997) Amlodipine in the treatment of Raynaud’s phenomenon. A double-blind placebo-controlled crossover study. Clin Drug Invest 13:126–131

    Article  Google Scholar 

  31. Kahan A, Amor B, Menkes CJ (1985) A randomised double-blind trial of diltiazem in the treatment of Raynaud’s phenomenon. Ann Rheumat Dis 44:30–33

    Google Scholar 

  32. Da costa J, Gomesja, Espirito Santo J et al (1987) Inefficacy of diltiazem in the treatment of Raynaud’s phenomenon with associated connective tissue disease: a double blind placebo controlled study. J Rheumatol 14:858–859

    Google Scholar 

  33. Kinney EL, Nicholas GG, Gallo J (1982) The treatment of severe Raynaud’s phenomenon with verapamil. J Clin Pharmacol 22(1):74–76

    Google Scholar 

  34. Allanore Y, Borderie D, Lemaréchal H, Ekindjian OG, Kahan A (2004) Nifedipine decreases sVCAM-1 concentrations and oxidative stress in systemic sclerosis but does not affect the concentrations of vascular endothelial growth factor or its soluble receptor 1. Arthritis Res Ther 6:R309–R314

    Google Scholar 

  35. Pope J, Fenlon D, Thompson A, Shea B, Furst D, Wells G et al (2000) Iloprost and cisaprost for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev (2):CD000953

  36. Wigley FM, Korn JH, Csuka ME, Medsger TA Jr, Rothfield NF, Ellman M et al (1998) Oral iloprost treatment in patients with Raynaud’s phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study. Arthritis Rheum 41:670–677

    Article  PubMed  CAS  Google Scholar 

  37. Black CM, Halkier SA, Rensen L, Belch JJ, Ullman S, Madhok R et al (1998) Oral iloprost in Raynaud’s phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study. Br J Rheumatol 37:952–960

    Article  PubMed  CAS  Google Scholar 

  38. Rademaker M, Cooke ED, Almond NE, Beacham JA, Smith RE, Mant TG et al (1989) 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 298:561–564

    Article  PubMed  CAS  Google Scholar 

  39. Scorza R, Caronni M, Mascagni B et al (2001) Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud’s phenomenon. A randomized, controlled study. Clin Exp Rheumatol 19:503–508

    PubMed  CAS  Google Scholar 

  40. Wigley FM, Seibold JR, Wise RA, McCloskey DA, Dole WP (1992) Intravenous iloprost treatment of Raynaud’s phenomenon and ischemic ulcers secondary to systemic sclerosis. J Rheumatol 19:1407–1414

    PubMed  CAS  Google Scholar 

  41. Hunzelmann N, Scleroderma TK (2010) From pathophysiology to novel therapeutic approaches. Exp Dermatol 19:393–400

    Google Scholar 

  42. Olschewski H, Ghofrani HA, Schmehl T, Winkler J, Wilkens H, Hoper MM et al (2000) Inhaled Iloprost to treat severe pulmonary hypertension. An uncontrolled trial. German PPH study group. Ann Intern Med 132:435–443

    PubMed  CAS  Google Scholar 

  43. Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM et al (2000) Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized controlled trial. Ann Intern Med 132:425–434

    PubMed  CAS  Google Scholar 

  44. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve′ P et al (2002) Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 40:780–788

    Article  PubMed  CAS  Google Scholar 

  45. McLaughlin VV, Shillington A, Rich S (2002) Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 106:1477–1482

    Article  PubMed  CAS  Google Scholar 

  46. Oudiz RJ, Schilz RJ, Barst RJ, Galie N, Rich S, Rubin LJ et al (2004) Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease. Chest 126:420–427

    Article  PubMed  CAS  Google Scholar 

  47. Vayssairat M (1996) Controlled multicenter double blind trial of an oral analog of prostacyclin in the treatment of primary Raynaud’s phenomenon. J Rheumatol 23:1917–1920

    PubMed  CAS  Google Scholar 

  48. Vayssairat M (1999) 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 26(10):2173–2178

    PubMed  CAS  Google Scholar 

  49. Galie` N, Humbert M, Vachie′ry J-L et al (2002) Effects of Beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 39:1496–1502

    Google Scholar 

  50. Gliddon AE, Doré CJ, Black CM (2007) Prevention of vascular damage in scleroderma and autoimmune Raynaud’s phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 56(11):3837–3846

    Article  PubMed  CAS  Google Scholar 

  51. Dziadzio M, Denton CP, Smith R et al (1999) Losartan therapy for Raynaud’s phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 42(12):2646–2655

    Article  PubMed  CAS  Google Scholar 

  52. Yatsyshyn N, Yatsyshyn R, Neyko YE (2010) Telmisartan improves endothelial function in scleroderma patients with pulmonary hypertension. J Hypertens 28:e550

    Google Scholar 

  53. Pope J, Fenlon D, Thompson A et al (2000) Prazosin for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2:CD000956

    Google Scholar 

  54. Chung L, Shapiro L, Fiorentino D et al (2009) MQX-503, a novel formulation of nitroglycerin, improves the severity of Raynaud’s phenomenon. Random Control Trial Arthritis Rheumatism 60(3):870–877

    Google Scholar 

  55. Badesch DB, Hill NS, Burgess G et al (2007) Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol 34:2417–2422

    PubMed  Google Scholar 

  56. Xiong C-M, Lu X-L, Shan G-L et al (2011) Oral Sildenafil therapy for chinese patients with pulmonary arterial hypertension: a multicenter study. J Clin Pharm, PMID 21415281

  57. Lee AJ, Chiao TB, Tsang MP (2005) Sildenafil for pulmonary hypertension. Ann Pharmacother 39(5):869–884

    Article  PubMed  CAS  Google Scholar 

  58. Herrick AL, van den Hoogen F, Gabrielli A et al (2011) Modified-release sildenafil reduces Raynaud’s phenomenon attack frequency in limited cutaneous systemic sclerosis. Arthritis Rheumatism 63(3):775–782

    Google Scholar 

  59. Brueckner CS, Becker MO, Kroencke T (2010) Effect of sildenafil on digital ulcers in systemic sclerosis: analysis from a single centre pilot study. Ann Rheum Dis 69:1475–1478

    Article  PubMed  CAS  Google Scholar 

  60. Yung A, Reay N, Goodfield MD (2005) Improvement in digital flexibility and dexterity following ingestion of sildenafil citrate in limited systemic sclerosis. Arch Dermatol 141:831–883

    Google Scholar 

  61. Shenoy P, Agarwal V, Kumar S et al (2008) Efficacy of tadalafil in secondary Raynaud’s phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial [abstract]. Arthritis Rheum 58(9 Suppl):S402

    Google Scholar 

  62. Galiè N, Brundage BH, Ghofrani HA et al (2009) Pulmonary arterial hypertension and response to tadalafil (PHIRST) study group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 119:2894–2903 [PubMed]

    Article  PubMed  CAS  Google Scholar 

  63. Ghofrani HA, Voswinckel R, Reichenberger F et al (2004) Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol 44:1488–1496

    Google Scholar 

  64. Toque HA, Teixeira CE, Priviero FB (2008) Vardenafil, but not sildenafil or tadalafil, has calcium-channel blocking activity in rabbit isolated pulmonary artery and human washed platelets. Br J Pharmacol 154(4):787–796

    Google Scholar 

  65. Caglayan E, Huntgeburth M, Karasch T (2006) Phosphodiesterase Type 5 inhibition is a novel therapeutic option in Raynaud disease. Arch Intern Med 166:231–233

    Google Scholar 

  66. Rajagopalan S, Pfenninger D, Somers E et al (2003) Effects of cilostazol in patients with Raynaud’s syndrome. Am J Cardiol 92(11):1310–1315

    Article  PubMed  CAS  Google Scholar 

  67. Korn JH, Mayes M, Matucci CM, Rainisio M, Pope J, Hachulla E et al (2004) Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50:3985–3993

    Article  PubMed  CAS  Google Scholar 

  68. Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, Wigley FM, Black CM, Fessler BJ, Merkel PA, Pope JE, Sweiss NJ, Doyle MK, Hellmich B, Medsger TA Jr, Morganti A, Kramer F, Korn JH, Seibold JR (2011) Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 70(1):32–38

    Google Scholar 

  69. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A et al (2002) Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346:896–903

    Article  PubMed  CAS  Google Scholar 

  70. Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A et al (2004) Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 24:353–359

    Article  PubMed  CAS  Google Scholar 

  71. King Jr. TE, Behr J, Brown KK et al (2008) BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respirat Crit Care Med 177:75–81

  72. King Jr. TE, Brown KK, Raghu G (2011) BUILD-3: a randomized, controlled trial of Bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med (Published ahead of print on April 7, 2011)

  73. Silver RM (2008) Endothelin and scleroderma lung disease. Rheumatology 47:v25–v26

    Google Scholar 

  74. Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S et al (2004) Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 169:441–447

    Article  PubMed  Google Scholar 

  75. Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S et al (2006) Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 47:2049–2056

    Article  PubMed  CAS  Google Scholar 

  76. Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA et al (2008) Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 117:3010–3019

    Article  PubMed  CAS  Google Scholar 

  77. Eddahibi S, Guignabert C, Barlier-Mur AM et al (2006) Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Circulation 113:1857–1864

    Article  PubMed  CAS  Google Scholar 

  78. Coleiro B, Marshall SE, Denton CP et al (2001) Treatment of Raynaud’s phenomenon with the selective serotonin reuptake inhibitr fluoxetine. Rheumatology (Oxford) 40:1038–1043

    Article  CAS  Google Scholar 

  79. Marcos E, Adnot S, Pham MH et al (2003) Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am J Respir Crit Care Med 168:487–493

    Article  PubMed  Google Scholar 

  80. Kawut SM, Horn EM, Berekashvili KK et al (2006) Selective serotonin reuptake inhibitor use and outcomes in pulmonary arterial hypertension. Pulm Pharmacol Ther 19:370–374

    Article  PubMed  CAS  Google Scholar 

  81. Sambo P, Amico D, Giacomelli R et al (2001) Intravenous N-acetylcysteine for treatment of Raynaud’s phenomenon secondary to systemic sclerosis: a pilot study. J Rheumatol 28:2257–2262

    PubMed  CAS  Google Scholar 

  82. Nevskaya T, Ananieva L, Bykovskaia S et al. Autologous progenitor cell implantation as a novel therapeutic intervention for ischaemic digits in systemic sclerosis. Rheumatology 48(1):61–64

  83. Quillinan NP, Denton CP (2009) Disease-modifying treatment in systemic sclerosis: current status. Curr Opin Rheumatol 21:636–641

    Article  PubMed  Google Scholar 

  84. Das SN, Alam MR, Islam N et al (2005) Placebo controlled trial of methotrexate in systemic sclerosis. Mymensingh Med J: MMJ 14:71–74

    PubMed  CAS  Google Scholar 

  85. van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB (1996) 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 35:364–372

    Article  PubMed  Google Scholar 

  86. Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S et al (2001) A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum 44:1351–1358

    Article  PubMed  CAS  Google Scholar 

  87. Hennessa S, Wigley FM (2007) Current drug therapy for scleroderma and secondary Raynaud’s phenomenon: evidence-based review. Curr Opin Rheumatol 19:611–618

    Article  CAS  Google Scholar 

  88. Tashkin DP, Elashoff R, Clements PJ et al (2006) Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354:2655–2666

    Article  PubMed  CAS  Google Scholar 

  89. Hoyles RK, Ellis RW, Wellsbury J et al (2006) A multicenter prospective, randomised, double-blind, placebo controlled trial of corticosteroids and intravenous cyclophosphamide, followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 54:3962–3970

    Article  PubMed  CAS  Google Scholar 

  90. Tashkin DP, Elashoff R, Clements PJ et al (2007) Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 176:1026–1034

    Article  PubMed  CAS  Google Scholar 

  91. Berezne A, Ranque B, Valeyre D et al (2008) 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 35:1064–1072

    PubMed  CAS  Google Scholar 

  92. Nihtyanova SI, Brough GM, Black CM et al (2007) Mycophenolate mofetil in diffuse cutaneous systemic sclerosis: a retrospective analysis. Rheumatology 46:442–445

    Article  PubMed  CAS  Google Scholar 

  93. Swigris JJ, Olson AL, Fischer A et al (2006) Mycophenolate mofetil is safe, well tolerated and preserves lung function in patients with connective tissue disease related interstitial lung disease. Chest 130:30–36

    Article  PubMed  CAS  Google Scholar 

  94. Clements PJ, Lachenbruch PA, Sterz M et al (1993) Cyclosporine in systemic sclerosis. Results of a forty-eight-week open safety study in ten patients. Arthritis Rheum 36(1):75–83

    Article  PubMed  CAS  Google Scholar 

  95. Filaci G, Cutolo M, Basso M et al (2001) Long-term treatment of patients affected by systemic sclerosis with cyclosporin A. Rheumatology (Oxford) 40:1431–1432

    Article  CAS  Google Scholar 

  96. Zachariae H, Halkier-Sorensen L, Heickendorff L, Zachariae E, Hansen HE (1990) Cyclosporin A treatment of systemic sclerosis. Br J Dermatol 122:677–681

    Article  PubMed  CAS  Google Scholar 

  97. Shegogue D, Trojanowska M (2004) Mammalian target of rapamycin positively regulates collagen Type I production via a phosphatidylinositol 3-kinase-independent pathway. J Biol Chem 279:23166–23175

    Article  PubMed  CAS  Google Scholar 

  98. Karleen Su T-I, Khanna D, Furst DE et al (2009) Rapamycin (rapa) vs methotrexate (mtx) in early diffuse systemic sclerosis (ssc): a 48-week randomized, single-blind pilot safety study. Arthritis Rheum 60(12):3821–3830

    Google Scholar 

  99. Asano N, Fujimoto M, Yazawa N et al (2004) B lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse. Am J Pathol 165:641–650

    Article  PubMed  CAS  Google Scholar 

  100. Saito E, Fujimoto M, Hasegawa M et al (2002) CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest 109:1453–1462

    PubMed  CAS  Google Scholar 

  101. Hasegawa M, Hamaguchi Y, Yanaba K et al (2006) B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol 169:954–966

    Article  PubMed  CAS  Google Scholar 

  102. Yoshizaki A, Iwata Y, Komura K et al (2008) CD19 regulates and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma. Am J Pathol 172:1650–1663

    Article  PubMed  CAS  Google Scholar 

  103. Bosello S, De Santis M, Lama G et al (2010) B cell depletion in diff use progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow up open-label trial. Arthritis Res Ther 12:R54

    Article  PubMed  CAS  Google Scholar 

  104. Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ, Merkel P, Simms RW (2009) B cell depletion with rituximab in patients with diff use cutaneous systemic sclerosis. Arthritis Rheum 60:578–583

    Article  PubMed  Google Scholar 

  105. Smith V, Van Praet JT, Vandooren B et al (2010) Rituximab in diff use cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis 69:193–197

    Article  PubMed  CAS  Google Scholar 

  106. Daoussis D, Liossis SC, Tsamandas AC et al (2010) Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology 49:271–280

    Article  PubMed  CAS  Google Scholar 

  107. Sato S, Hasegawa M, Takehara K (2001) Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci 27:140–146

    Article  PubMed  CAS  Google Scholar 

  108. Koch AE, Kronfeld-Harrington LB, Szekanecz et al (1993) In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease. Pathobiology 61:239–246

  109. Shima Y, Kuwahara Y, Murota H et al (2010) The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology 49:2408–2412

    Article  PubMed  CAS  Google Scholar 

  110. Distler JHW, Schett G, Gay S, Distler O (2008) The controversial role of tumour necrosis factor a in fibrotic diseases. Arth Rheum 58:2228–2235

    Article  CAS  Google Scholar 

  111. Lam GK, Hummers LK, Woods A et al (2007) Efficacy and safety of etanercept in the treatment of scleroderma-associated joint disease. J Rheumatol 34:1636–1637

    PubMed  Google Scholar 

  112. Denton CP, Engelhart M, Tvede N et al (2008) An open-label pilot study of infliximab therapy in diffuse cutaneous systemic sclerosis. Ann Rheum Dis 68(9):1433–1439

    Article  PubMed  CAS  Google Scholar 

  113. Phumethum V, Jamal S, Johnson SR (2011) Biologic therapy for systemic sclerosis: a systematic review. J Rheumatol 38(2):289–296

    Google Scholar 

  114. Levy Y, Sherer Y, Langevitz P et al (2000) Skin score decrease in systemic sclerosis patients treated with intravenous immunoglobulin: a preliminary report. Clin Rheumatol 19:207–211

    Article  PubMed  CAS  Google Scholar 

  115. Levy Y, Amital H, Langevitz P et al (2004) Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study. Arthritis Rheum 50:1005–1007

    Article  PubMed  CAS  Google Scholar 

  116. Nacci F, Righi A, Conforti ML et al (2007) Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study. Ann Rheum Dis 66:977–979

    Article  PubMed  CAS  Google Scholar 

  117. Ihn H, Mimura Y, Yazawa N et al (2007) High-dose intravenous immunoglobulin infusion as treatment for diffuse scleroderma. Br J Dermatol 156:1058–1060

    Article  PubMed  CAS  Google Scholar 

  118. Blank M, Levy Y, Amital H, Shoenfeld Y, Pines M, Genina O (2002) The role of intravenous immunoglobulin therapy in mediating skin fibrosis in tight skin mice. Arthritis Rheum 46:1689–1690

    Article  PubMed  CAS  Google Scholar 

  119. Amital H, Rewald E, Levy Y et al (2003) Fibrosis regression induced by intravenous gammaglobulin treatment. Ann Rheum Dis 62:175–177

    Google Scholar 

  120. Postlethwaite AE, Wong WK, Clements P et al (2008) 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 58:1810–1822

    Article  PubMed  CAS  Google Scholar 

  121. Ghosh AK, Yuan W, Mori Y, Chen S, Varga J (2001) Antagonistic regulation of type I collagen gene expression by interferon-gamma and transforming growth factor-beta. Integration at the level of p300/CBP transcriptional coactivators. J Biol Chem 276:11041–11048

    Article  PubMed  CAS  Google Scholar 

  122. Varga J, Olsen A, Herhal J, Constantine G, Rosenbloom J, Jimenez SA (1990) Interferon-gamma reverses the stimulation of collagen but not fibronectin gene expression by transforming growth factor-beta in normal human fibroblasts. Eur J Clin Invest 20:487–493

    Article  PubMed  CAS  Google Scholar 

  123. Carbone LD, Warrington KJ, Barrow KD, Pugazhenthi M, Watsky MA, Somes G et al (2006) Pamidronate infusion in patients with systemic sclerosis results in changes in blood mononuclear cell cytokine profiles. Clin Exp Immunol 146:371–380

    Article  PubMed  CAS  Google Scholar 

  124. Vonk MC, Marjanovic Z, van den Hoogen FHJ et al (2008) Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis 67:98–104

    Article  PubMed  CAS  Google Scholar 

  125. Nash RA, McSweeney PA, Corfford LJ et al (2007) High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood 110:1388–1396

    Article  PubMed  CAS  Google Scholar 

  126. Clements PJ, Furst DE, Wong WK, Mayes M, White B, Wigley F et al (1999) High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum 42:1194–1203

    Article  PubMed  CAS  Google Scholar 

  127. Derk CT, Huaman G, Jimenez SA (2008) A retrospective randomly selected cohort study of D-penicillamine treatment in rapidly progressive diffuse cutaneous systemic sclerosis of recent onset. Br J Dermatol 158(5):1063–1068

    Google Scholar 

  128. Grassegger A, Schuler G, Hessenberger G et al (1998) Interferon-gamma in the treatment of systemic sclerosis: a randomized controlled multicentre trial. Br J Dermatol 139:639–648

    Article  PubMed  CAS  Google Scholar 

  129. Black CM, Silman AJ, Herrick AI et al (1999) 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 42:299–305

    Article  PubMed  CAS  Google Scholar 

  130. Kreuter A, Breuckmann F, Uhle A et al (2004) Low dose UVA1 phototherapy in systemic sclerosis: effects on acrosclerosis. J Am Acad Dermatol 50(5):740–747

    Article  PubMed  Google Scholar 

  131. Kanekura T, Fukumaru S, Matsushita S et al (1996) Successful treatment of scleroderma with PUVA therapy. J Dermatol 23:455–459

    PubMed  CAS  Google Scholar 

  132. Hofer A, Soyer HP (1999) Oral psoralen-UV-A for systemic scleroderma. Arch Dermatol 135:603–604

    Article  PubMed  CAS  Google Scholar 

  133. Pasic A, Ceovic R, Lipozencic J et al (2003) Phototherapy in pediatric patients. Pediatr Dermatol 20(1):71–77

    Article  PubMed  Google Scholar 

  134. Knobler RM, French LE, Kim Y, Bisaccia E, Graninger W (2006) A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis. J Am Acad Dermatol 54(5):793–799

    Article  PubMed  Google Scholar 

  135. Sunderkotter C, Kuhn A, Hunzelmann N, Beissert S (2006) Phototherapy: a promising treatment option for skin sclerosis in scleroderma? Rheumatology 45:iii52–iii54

  136. Unemori EN, Amento EP (1990) Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J Biol Chem 265:10681–10685

    PubMed  CAS  Google Scholar 

  137. Seibold JR, Korn JH, Simms R, Clements PJ, Moreland LW, Mayes MD et al (2000) Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo controlled trial. Ann Intern Med 132:871–879

    PubMed  CAS  Google Scholar 

  138. Nagler A, Miao HQ, Aingorn H et al (1997) Inhibition of collagen synthesis, smooth muscle cell proliferation, and injury-induced intimal hyperplasia by halofuginone. Arterioscler Thromb Vasc Biol 17:194–202

    Article  PubMed  CAS  Google Scholar 

  139. Pines M, Snyder D, Yarkoni S, Nagler A (2003) Halofuginone to treat fibrosis in chronic graft-versus-host disease and scleroderma. Biol Blood Marrow Transplant 9:417–425

    Article  PubMed  CAS  Google Scholar 

  140. Salikhov IG, Bodrova RA, Ziganshina LE (2002) Ximedon-electrophoresis in rehabilitation of patients with systemic scleroderma. Vopr Kurortol Fizioter Lech Fiz Kult 5:33–36

    Google Scholar 

  141. Nagai S, Hamada K, Shigematsu M, Taniyama M, Yamauchi S, Izumi T (2002) Open-label compassionate use one year treatment with pirfenidone to patients with chronic pulmonary fibrosis. Intern Med 41:1118–1123

    Article  PubMed  CAS  Google Scholar 

  142. Taniguchi H, Ebina M, Kondoh Y, Ogura T et al (2010) Pirfenidone in idiopathic pulmonary fibrosis. ERJ 35(4):821–829

    Google Scholar 

  143. Simone NL, Soule BP, Gerber L, Augustine E, Smith S, Altemus RM, Mitchell JB, Camphausen KA (2007) Oral pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study. Radiat Oncol 2:19

    Google Scholar 

  144. Alarcon-Segovia D, Ramos-Niembro F, Ibanez de Kasep G (1979) Long-term evaluation of colchicine in the treatment of scleroderma. J Rheumatol 6(6):705–712

    Google Scholar 

  145. Guttadauria M, Diamond H, Kaplan D (1977) Colchicine in the treatment of scleroderma. J Rheumatol 4(3):272–276

    Google Scholar 

  146. Le CH, Morales A, Trentham DEK (1998) Minocycline in early diffuse scleroderma. Lancet 352:1755–1756

    Article  PubMed  CAS  Google Scholar 

  147. Mayes MD, O’Donnell D, Rothfield NF, Csuka ME (2004) Minocycline is not effective in systemic sclerosis: results of an open-label multicenter trial. Arthritis Rheum 50(2):553–557

    Article  PubMed  CAS  Google Scholar 

  148. Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18:816–827

    Article  PubMed  CAS  Google Scholar 

  149. Trojanowska M, Varga J (2007) Molecular pathways as novel therapeutic targets in systemic sclerosis. Curr Opin Rheumatol 19:568–573

    Article  PubMed  CAS  Google Scholar 

  150. Ihn H, Yamane K, Kubo M, Tamaki K (2001) Blockade of endogenous transforming growth factor beta signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: association with increased expression of transforming growth factor beta receptors. Arthritis Rheum 44:474–480

    Article  PubMed  CAS  Google Scholar 

  151. Kawakami T, Ihn H, Xu W, Smith E, LeRoy C, Trojanowska M (1998) Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype. J Invest Dermatol 110:47–51

    Article  PubMed  CAS  Google Scholar 

  152. McCormick LauraL, Zhang Yan et al (1999) Anti-TGF-ß treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol 163:5693–5699

    PubMed  CAS  Google Scholar 

  153. Denton CP, Merkel PA, Furst DE (2007) 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 56(1):323–333

    Article  PubMed  CAS  Google Scholar 

  154. Kubo M, Czuwara-Ladykowska J, Moussa O et al (2003) Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. Am J Pathol 163:571–581

    Article  PubMed  CAS  Google Scholar 

  155. Asano Y, Stawski L (2010) Faye Hant Endothelial Fli1 deficiency impairs vascular homeostasis: a role in scleroderma vasculopathy. Am J Pathol 176(4):1983–1998

    Google Scholar 

  156. Czuwara-Ladykowska J, Shirasaki F, Jackers P, Watson DK, Trojanowska M (2001) Fli-1 inhibits collagen type I production in dermal fibroblasts via an Sp1-dependent pathway. J Biol Chem 276:20839–20848

    Article  PubMed  CAS  Google Scholar 

  157. Schermuly RT, Dony E, Ghofrani HA et al (2005) Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115:2811–2821

    Article  PubMed  CAS  Google Scholar 

  158. Ghofrani HA, Seeger W, Grimminger F (2005) Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 29:353

    Google Scholar 

  159. Bailey SR, Eid AH, Mitra S, Flavahan S et al (2004) Rho kinase mediates cold-induced constriction of Cutaneous Arteries role of α2C-adrenoceptor translocation Circul Res 94:1367

    Google Scholar 

  160. Dees C, Pileckyte M et al (2008) Rho-associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts. Arthritis Rheumatism 58(8):2553–2564

    Google Scholar 

  161. Essig M, Vrtovsnik F, Nguyen G, Sraer JD, Friedlander G (1998) Lovastatin modulates in vivo and in vitro the plasminogen activator/plasmin system of rat proximal tubular cells: role of geranylgeranylation and Rho proteins. J Am Soc Nephrol 9:1377–1388

    PubMed  CAS  Google Scholar 

  162. Abou-Raya A, Abou-Raya S, Helmii M (2008) Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon and digital ulcers. J Rheumatol 35(9):1801–1808

    Google Scholar 

  163. Wei J, Bhattacharyya S, Varga J (2010) Peroxisome proliferator-activated receptor γ: innate protection from excessive fibrogenesis and potential therapeutic target in systemic sclerosis. Curr Opin Rheumatol 22(6):671–676

    Article  PubMed  CAS  Google Scholar 

  164. Ghosh AK, Bhattacharyya S, Lakos G, Chen SJ, Mori Y, Varga J (2004) Disruption of transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator-activated receptor gamma. Arthritis Rheum 50:1305–1318

    Article  PubMed  CAS  Google Scholar 

  165. Ghosh AK, Bhattacharyya S, Wei J, Kim S, Barak Y, Mori Y et al (2009) Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator. FASEB J 23(9):2968–2977

    Article  PubMed  CAS  Google Scholar 

  166. Shi-wen X, Eastwood M, Stratton RJ et al (2010) Rosiglitazone alleviates the persistent fibrotic phenotype of lesional skin scleroderma fibroblasts. Rheumatology 49:259–263

    Google Scholar 

  167. Sambo P, Baroni SS, Luchetti M et al (2001) Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum 44(11):2653–2664

    Article  PubMed  CAS  Google Scholar 

  168. Denton CP, Bunce TD, Dorado MB et al (1999) Probucol improves symptoms and reduces lipoprotein oxidation susceptibility in patients with Raynaud’s phenomenon. Rheumatology (Oxford) 38(4):309–315

    Article  CAS  Google Scholar 

  169. Herrick AL, Hollis S, Schofield D et al (2000) A double-blind placebo-controlled trial of antioxidant therapy in limited cutaneous systemic sclerosis. Clin Exp Rheumatol 18(3):349–356

    Google Scholar 

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  1. T.N.M.C & BYL Nair Hospital, OPD 16, OPD building, Mumbai Central, Mumbai, 400 008, India

    Afsha A. Topal & Rachita S. Dhurat

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Topal, A.A., Dhurat, R.S. Scleroderma therapy: clinical overview of current trends and future perspective. Rheumatol Int 33, 1–18 (2013). https://doi.org/10.1007/s00296-012-2486-1

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