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Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)

Christopher P Denton, MD
Section Editor
John S Axford, DSc, MD, FRCP, FRCPCH
Deputy Editor
Monica Ramirez Curtis, MD, MPH


The etiology and pathogenesis of the scleroderma disorders are poorly understood. As a result, treatment of these conditions is difficult, incomplete, and not curative. (See "Risk factors for and possible causes of systemic sclerosis (scleroderma)" and "Pathogenesis of systemic sclerosis (scleroderma)".)

Patients with diffuse as opposed to limited cutaneous involvement are the most likely to have early and sometimes severe internal organ involvement. These patients are classified as having diffuse cutaneous systemic sclerosis (dcSSc). This is the subset of patients for whom systemic approaches to treatment are most often used.

This topic reviews the systemic approaches to the treatment of systemic sclerosis (SSc, scleroderma). An overview of the treatment of scleroderma disorders and a discussion of the clinical manifestations and diagnosis of SSc are presented separately. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults" and "Overview of the clinical manifestations of systemic sclerosis (scleroderma) in adults" and "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults".)


Clinical trials that evaluate the effectiveness of therapies for systemic sclerosis (SSc) are hampered because of the following problems [1,2]:

The disease is rare with heterogeneous clinical manifestations


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Literature review current through: Sep 2016. | This topic last updated: May 25, 2016.
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  1. Pope JE, Bellamy N. Outcome measurement in scleroderma clinical trials. Semin Arthritis Rheum 1993; 23:22.
  2. Leighton C. Drug treatment of scleroderma. Drugs 2001; 61:419.
  3. White B, Bauer EA, Goldsmith LA, et al. Guidelines for clinical trials in systemic sclerosis (scleroderma). I. Disease-modifying interventions. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis. Arthritis Rheum 1995; 38:351.
  4. Black CM, Denton CP. Scleroderma. In: Role of Cytokines in Autoimmunity, Brennan FM, Feldmann M. (Eds), 1996. p.153.
  5. Furst DE, Clements PJ, Hillis S, et al. Immunosuppression with chlorambucil, versus placebo, for scleroderma. Results of a three-year, parallel, randomized, double-blind study. Arthritis Rheum 1989; 32:584.
  6. Casas JA, Saway PA, Villarreal I, et al. 5-fluorouracil in the treatment of scleroderma: a randomised, double blind, placebo controlled international collaborative study. Ann Rheum Dis 1990; 49:926.
  7. O'Dell JR, Steigerwald JC, Kennaugh RC, et al. Lack of clinical benefit after treatment of systemic sclerosis with total lymphoid irradiation. J Rheumatol 1989; 16:1050.
  8. Valentini G, Paone C, La Montagna G, et al. Low-dose intravenous cyclophosphamide in systemic sclerosis: an open prospective efficacy study in patients with early diffuse disease. Scand J Rheumatol 2006; 35:35.
  9. Akesson A, Wollheim FA, Thysell H, et al. Visceral improvement following combined plasmapheresis and immunosuppressive drug therapy in progressive systemic sclerosis. Scand J Rheumatol 1988; 17:313.
  10. 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; 41:1613.
  11. 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.
  12. 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; 33:90.
  13. Appelboom T, Itzkowitch D. Cyclosporine in successful control of rapidly progressive scleroderma. Am J Med 1987; 82:866.
  14. Clements PJ, Lachenbruch PA, Sterz M, et al. Cyclosporine in systemic sclerosis. Results of a forty-eight-week open safety study in ten patients. Arthritis Rheum 1993; 36:75.
  15. Su TI, Khanna D, Furst DE, et al. Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Arthritis Rheum 2009; 60:3821.
  16. van den Hoogen FH, Boerbooms AM, Swaak AJ, et al. 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; 35:364.
  17. Pope JE, Bellamy N, Seibold JR, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum 2001; 44:1351.
  18. Henness S, Wigley FM. Current drug therapy for scleroderma and secondary Raynaud's phenomenon: evidence-based review. Curr Opin Rheumatol 2007; 19:611.
  19. Johnson SR, Feldman BM, Pope JE, Tomlinson GA. Shifting our thinking about uncommon disease trials: the case of methotrexate in scleroderma. J Rheumatol 2009; 36:323.
  20. Kowal-Bielecka O, Landewé 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; 68:620.
  21. Stratton RJ, Wilson H, Black CM. Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology (Oxford) 2001; 40:84.
  22. Nihtyanova SI, Brough GM, Black CM, Denton CP. Mycophenolate mofetil in diffuse cutaneous systemic sclerosis--a retrospective analysis. Rheumatology (Oxford) 2007; 46:442.
  23. Le EN, Wigley FM, Shah AA, et al. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2011; 70:1104.
  24. Derk CT, Grace E, Shenin M, et al. A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis. Rheumatology (Oxford) 2009; 48:1595.
  25. Herrick AL, Lunt M, Whidby N, et al. Observational study of treatment outcome in early diffuse cutaneous systemic sclerosis. J Rheumatol 2010; 37:116.
  26. Farge D, Passweg J, van Laar JM, et al. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis 2004; 63:974.
  27. McSweeney PA, Nash RA, Sullivan KM, et al. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood 2002; 100:1602.
  28. 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; 110:1388.
  29. Farge D, Marolleau JP, Zohar S, et al. Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study. Br J Haematol 2002; 119:726.
  30. Miniati I, Guiducci S, Conforti ML, et al. Autologous stem cell transplantation improves microcirculation in systemic sclerosis. Ann Rheum Dis 2009; 68:94.
  31. Burt RK, Shah SJ, Dill K, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 2011; 378:498.
  32. Burt RK, Oliveira MC, Shah SJ, et al. Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis. Lancet 2013; 381:1116.
  33. van Laar JM, Tyndall A. Adult stem cells in the treatment of autoimmune diseases. Rheumatology (Oxford) 2006; 45:1187.
  34. Farge D, Gluckman E. Autologous HSCT in systemic sclerosis: a step forward. Lancet 2011; 378:460.
  35. Van Laar J, Farge D, Sont J, et al. High dose immunoablation and autologous hematopoietic stem cell transplantation versus monthly intravenous pulse therapy cyclophosphamide in severe systemic sclerosis. Arthritis Rheum 2012; 64:4167.
  36. van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014; 311:2490.
  37. Snowden JA, Akil M, Kiely DG. Improving safety in autologous HSCT for systemic sclerosis. Lancet 2013; 381:1081.
  38. Casciola-Rosen L, Wigley F, Rosen A. Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis. J Exp Med 1997; 185:71.
  39. Steen VD, Medsger TA Jr, Rodnan GP. D-Penicillamine therapy in progressive systemic sclerosis (scleroderma): a retrospective analysis. Ann Intern Med 1982; 97:652.
  40. Jimenez SA, Sigal SH. A 15-year prospective study of treatment of rapidly progressive systemic sclerosis with D-penicillamine [see comment]. J Rheumatol 1991; 18:1496.
  41. Clements PJ, Furst DE, Wong WK, et al. 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 1999; 42:1194.
  42. Freundlich B, Jimenez SA, Steen VD, et al. Treatment of systemic sclerosis with recombinant interferon-gamma. A phase I/II clinical trial. Arthritis Rheum 1992; 35:1134.
  43. Stevens W, Vancheeswaran R, Black CM. Alpha interferon-2a (Roferon-A) in the treatment of diffuse cutaneous systemic sclerosis: a pilot study. UK Systemic Sclerosis Study Group. Br J Rheumatol 1992; 31:683.
  44. Black CM, Silman AJ, Herrick AI, et al. 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; 42:299.
  45. Stratton R, Shiwen X, Martini G, et al. Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients. J Clin Invest 2001; 108:241.
  46. Seibold JR, Korn JH, Simms R, et al. Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000; 132:871.
  47. Khanna D, Clements PJ, Furst DE, et al. Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2009; 60:1102.
  48. Shi-wen X, Kennedy L, Renzoni EA, et al. Endothelin is a downstream mediator of profibrotic responses to transforming growth factor beta in human lung fibroblasts. Arthritis Rheum 2007; 56:4189.
  49. Distler JH, Schett G, Gay S, Distler O. The controversial role of tumor necrosis factor alpha in fibrotic diseases. Arthritis Rheum 2008; 58:2228.
  50. Denton CP, Engelhart M, Tvede N, et al. An open-label pilot study of infliximab therapy in diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2009; 68:1433.
  51. 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.
  52. Denton CP, Abraham DJ. Transforming growth factor-beta and connective tissue growth factor: key cytokines in scleroderma pathogenesis. Curr Opin Rheumatol 2001; 13:505.
  53. Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 2004; 15:255.
  54. Spiera RF, Gordon JK, Mersten JN, et al. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis 2011; 70:1003.
  55. Distler JH, Jüngel A, Huber LC, et al. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 2007; 56:311.
  56. Pannu J, Asano Y, Nakerakanti S, et al. Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate. Arthritis Rheum 2008; 58:2528.
  57. van Daele PL, Dik WA, Thio HB, et al. Is imatinib mesylate a promising drug in systemic sclerosis? Arthritis Rheum 2008; 58:2549.
  58. Distler JH, Manger B, Spriewald BM, et al. Treatment of pulmonary fibrosis for twenty weeks with imatinib mesylate in a patient with mixed connective tissue disease. Arthritis Rheum 2008; 58:2538.
  59. Kay J, High WA. Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum 2008; 58:2543.
  60. Chung L, Fiorentino DF, Benbarak MJ, et al. Molecular framework for response to imatinib mesylate in systemic sclerosis. Arthritis Rheum 2009; 60:584.
  61. Distler J, Distler O. Novel treatment approaches to fibrosis in scleroderma. Rheum Dis Clin North Am 2008; 34:145.
  62. Lafyatis R, O'Hara C, Feghali-Bostwick CA, Matteson E. B cell infiltration in systemic sclerosis-associated interstitial lung disease. Arthritis Rheum 2007; 56:3167.
  63. 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.
  64. Daoussis D, Liossis SN, Tsamandas AC, et al. Is there a role for B-cell depletion as therapy for scleroderma? A case report and review of the literature. Semin Arthritis Rheum 2010; 40:127.
  65. Smith V, Van Praet JT, Vandooren B, et al. Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. Ann Rheum Dis 2010; 69:193.
  66. Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford) 2010; 49:271.
  67. Daoussis D, Andonopoulos AP, Liossis SN. Wnt pathway and IL-17: novel regulators of joint remodeling in rheumatic diseases. Looking beyond the RANK-RANKL-OPG axis. Semin Arthritis Rheum 2010; 39:369.
  68. Daoussis D, Liossis SN, Tsamandas AC, et al. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol 2012; 30:S17.
  69. McQueen FM, Solanki K. Rituximab in diffuse cutaneous systemic sclerosis: should we be using it today? Rheumatology (Oxford) 2015; 54:757.
  70. Keir GJ, Maher TM, Ming D, et al. Rituximab in severe, treatment-refractory interstitial lung disease. Respirology 2014; 19:353.
  71. Jordan S, Distler JH, Maurer B, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis 2015; 74:1188.
  72. Rituximab versus cyclophosphamide in connective tissue disease-ILD (RECITAL). ClinicalTrials.gov Identifier: NCT01862926. Available at https://clinicaltrials.gov/ct2/show/NCT01862926 (Accessed on June 2, 2015).
  73. Poelman CL, Hummers LK, Wigley FM, et al. Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. J Rheumatol 2015; 42:236.
  74. 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.
  75. Khan K, Xu S, Nihtyanova S, et al. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis 2012; 71:1235.
  76. De Lauretis A, Sestini P, Pantelidis P, et al. Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J Rheumatol 2013; 40:435.
  77. Barnes TC, Spiller DG, Anderson ME, et al. Endothelial activation and apoptosis mediated by neutrophil-dependent interleukin 6 trans-signalling: a novel target for systemic sclerosis? Ann Rheum Dis 2011; 70:366.
  78. Elhai M, Meunier M, Matucci-Cerinic M, et al. Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis 2013; 72:1217.
  79. Shima Y, Kuwahara Y, Murota H, et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford) 2010; 49:2408.
  80. Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 2016; 387:2630.
  81. Quillinan NP, McIntosh D, Vernes J, et al. Treatment of diffuse systemic sclerosis with hyperimmune caprine serum (AIMSPRO): a phase II double-blind placebo-controlled trial. Ann Rheum Dis 2014; 73:56.