Targeted therapies for systemic sclerosis

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Abstract

Pathogenic processes that underlie the development and progression of systemic sclerosis (SSc) are being defined in preclinical, clinical and genetic studies. Important evidence of interplay between the vasculature, connective tissue and specialized epithelial structures is emerging, and abnormalities of both the innate and adaptive immune systems have been identified. In this context, information regarding pivotal mediators, pathways or cell types that could be targets for therapeutic intervention, and that might offer potential for true disease modification, is accruing. Precedent for the regression of some aspects of the pathology has been set in clinical studies showing that potential exists to improve tissue structure and function as well as to prevent disease progression. This article reviews the concept of targeted therapies and considers potential pathways and processes that might be attenuated by therapeutic intervention in SSc. As well as improving outcomes, such approaches will undoubtedly provide information about pathogenesis. The concept of translational medicine is especially relevant in SSc, and we anticipate that the elusive goal of an effective antifibrotic treatment will emerge from one of the several clinical trials currently underway or planned in this disease. Therapeutic advances in SSc would have implications and potential beyond autoimmune rheumatic diseases.

Key Points

  • Therapeutic goals in systemic sclerosis (SSc) include minimization of damage from early inflammation and autoimmunity, restoration of vascular homeostasis, promotion of repair of structural connective tissue and resolution of scarring

  • Cardinal pathogenic processes in SSc—autoimmunity, vascular dysfunction and extracellular matrix overproduction—are interdependent; therapeutic targeting of any of them individually is likely to be of broader benefit

  • Current treatments for SSc, such as broad-spectrum immunosuppression, are adopted from the management of other rheumatic diseases; biologic agents and intracellular signalling inhibitors might also be translated into SSc

  • Increasing understanding of the pathobiology of SSc has identified other relevant biological processes and their signalling pathways, such as stem cell biology and epithelial regeneration, as potential targets for therapy

  • New candidate therapies and advances in clinical trial methodology have made targeted therapy a realistic goal that can be tested robustly, underpinning future progress in SSc management

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Figure 1: Targeting pathogenic processes in SSc.
Figure 2: Targeting multiple pathways of fibroblast activation in SSc.

References

  1. 1

    Shand, L. et al. 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 (2007).

  2. 2

    Nihtyanova, S. I. et al. Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM 103, 109–115 (2010).

  3. 3

    Beyer, C., Schett, G., Distler, O. & Distler, J. H. Animal models of systemic sclerosis: prospects and limitations. Arthritis Rheum. 62, 2831–2844 (2010).

  4. 4

    Pakozdi, A. et al. Clinical and serological hallmarks of systemic sclerosis overlap syndromes. J. Rheumatol. 38, 2406–2409 (2011).

  5. 5

    Koumakis, E. et al. Familial autoimmunity in systemic sclerosis—results of a French-based case–control family study. J. Rheumatol. 39, 532–538 (2012).

  6. 6

    Tyndall, A. J. et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann. Rheum. Dis. 69, 1809–1815 (2010).

  7. 7

    Bhattacharyya, S., Wei, J. & Varga, J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat. Rev. Rheumatol. 8, 42–54 (2011).

  8. 8

    Brooks, W. H. et al. Epigenetics and autoimmunity. J. Autoimmun. 34, 207–219 (2010).

  9. 9

    Hedrich, C. M. & Rauen, T. Epigenetic patterns in systemic sclerosis and their contribution to attenuated CD70 signaling cascades. Clin. Immunol. 143, 1–3 (2012).

  10. 10

    Martín, J. E., Bossini-Castillo, L. & Martín, J. Unraveling the genetic component of systemic sclerosis. Hum. Genet. 131, 1023–1037 (2012).

  11. 11

    Leask, A. Possible strategies for anti-fibrotic drug intervention in scleroderma. J. Cell. Commun. Signal. 5, 125–129 (2011).

  12. 12

    Nihtyanova, S. I. & Denton, C. P. Autoantibodies as predictive tools in systemic sclerosis. Nat. Rev. Rheumatol. 6, 112–116 (2010).

  13. 13

    Riemekasten, G. et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann. Rheum. Dis. 70, 530–536 (2011).

  14. 14

    Chung, L. et al. Clinical trial design in scleroderma: where are we and where do we go next? Clin. Exp. Rheumatol. 30 (Suppl. 71), S97–S102 (2012).

  15. 15

    Elhai, 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. http://dx.doi.org/10.1136/annrheumdis-2012-202657

  16. 16

    Burt, R. 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 378, 498–506 (2011).

  17. 17

    Tyndall, A. Stem cells: HSCT for systemic sclerosis--swallows and summers. Nat. Rev. Rheumatol. 7, 624–626 (2011).

  18. 18

    van Laar, J. M. et al. The ASTIS trial: autologous stem cell transplantation versus IV pulse cyclophosphamide in poor prognosis systemic sclerosis. First results [abstract LB0002]. Ann. Rheum. Dis. 71 (Suppl. 3), 151 (2012).

  19. 19

    Fleming, J. N. et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS ONE 3, e1452 (2008).

  20. 20

    Moinzadeh, P., Khan, K., Ong, V. H. & Denton, C. P. Sustained improvement of diffuse systemic sclerosis following human cytomegalovirus infection offers insight into pathogenesis and therapy. Rheumatology (Oxford) 51, 2296–2298 (2012).

  21. 21

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  22. 22

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  23. 23

    Weingartner, S. et al. Pomalidomide is effective for prevention and treatment of experimental skin fibrosis. Ann. Rheum. Dis. 71, 1895–1899 (2012).

  24. 24

    Khanna, D. et al. Correlation of the degree of dyspnea with health-related quality of life, functional abilities, and diffusing capacity for carbon monoxide in patients with systemic sclerosis and active alveolitis: results from the Scleroderma Lung Study. Arthritis Rheum. 52, 592–600 (2005).

  25. 25

    US National Library of Medicine. ClinicalTrials.gov [online], (2010).

  26. 26

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  27. 27

    Farina, G., Lafyatis, D., Lemaire, R. & Lafyatis, R. A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 62, 580–588 (2010).

  28. 28

    Khan, K. et al. Clinical and pathological significance of interleukin-6 overexpression in systemic sclerosis. Ann. Rheum. Dis. 71, 1235–1242 (2012).

  29. 29

    US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  30. 30

    US National Library of Medicine. ClinicalTrials.gov [online], (2010).

  31. 31

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  32. 32

    Penn, H. et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 100, 485–494 (2007).

  33. 33

    Matucci-Cerinic, M. et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 70, 32–38 (2011).

  34. 34

    Taniguchi, T. et al. Effects of bosentan on nondigital ulcers in patients with systemic sclerosis. Br. J. Dermatol. 166, 417–421 (2012).

  35. 35

    Dhaun, N. et al. Selective endothelin-A receptor antagonism reduces proteinuria, blood pressure, and arterial stiffness in chronic proteinuric kidney disease. Hypertension 57, 772–779 (2011).

  36. 36

    Valerio, C. J. et al. Clinical experience with bosentan and sitaxentan in connective tissue disease-associated pulmonary arterial hypertension. Rheumatology (Oxford) 49, 2147–2153 (2010).

  37. 37

    Kuhn, A. et al. Effect of bosentan on skin fibrosis in patients with systemic sclerosis: a prospective, open-label, non-comparative trial. Rheumatology (Oxford) 49 1336–1345 (2010).

  38. 38

    Giordano, N. et al. Bosentan treatment for Raynauds phenomenon and skin fibrosis in patients with systemic sclerosis and pulmonary arterial hypertension: an open-label, observational, retrospective study. Int. J. Immunopathol. Pharmacol. 23, 1185–1194 (2010).

  39. 39

    Furuya, Y., Kuwana, M. Effect of Bosentan on systemic sclerosis-associated interstitial lung disease ineligible for cyclophosphamide therapy: a prospective open-label study. J. Rheum. 38, 2186–2192 (2011).

  40. 40

    Seibold, J. R. et al. Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis. Arthritis Rheum. 62, 2101–2108 (2010).

  41. 41

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  42. 42

    Dees, C. et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J. Exp. Med. 208, 961–972 (2011).

  43. 43

    Kekewska, A., Görnemann, T., Jantschak, F., Glusa, E. & Pertz, H. H. Antiserotonergic properties of terguride in blood vessels, platelets, and valvular interstitial cells. J. Pharmacol. Exp. Ther. 340, 369–376 (2012).

  44. 44

    Königshoff, M. et al. Increased expression of 5-hydroxytryptamine2A/B receptors in idiopathic pulmonary fibrosis: a rationale for therapeutic intervention. Thorax 65, 949–955 (2010).

  45. 45

    Coleiro, B. et al. Treatment of Raynaud's phenomenon with the selective serotonin reuptake inhibit fluoxetine. Rheumatology (Oxford) 40, 1038–1043 (2001).

  46. 46

    Rabinovitch, M. Molecular pathogenesis of pulmonary arterial hypertension. J. Clin. Invest. 122, 4306–4313 (2012).

  47. 47

    Feoktistov, I., Biaggioni, I. & Cronstein, B. N. Adenosine receptors in wound healing, fibrosis and angiogenesis. Handb. Exp. Pharmacol. 193, 383–397 (2009).

  48. 48

    Perez-Aso, M., Chiriboga, L., Cronstein, B. N. Pharmacological blockade of adenosine A2A receptors diminishes scarring. FASEB J. 26, 4254–4263 (2012).

  49. 49

    Katebi, M., Fernandez, P., Chan, E. S. & Cronstein, B. N. Adenosine A2A receptor blockade or deletion diminishes fibrocyte accumulation in the skin in a murine model of scleroderma, bleomycin-induced fibrosis. Inflammation 31, 299–303 (2008).

  50. 50

    Herrick, A. L. et al. Modified-release sildenafil reduces Raynaud's phenomenon attack frequency in limited cutaneous systemic sclerosis. Arthritis Rheum. 63, 775–782 (2011).

  51. 51

    Udalov, S. et al. Effects of phosphodiesterase 4 inhibition on bleomycin-induced pulmonary fibrosis in mice. Pulm. Med. 10, 1–9 (2010).

  52. 52

    Cortijo, J. et al. Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. Br. J. Pharmacol. 156, 534–544 (2009).

  53. 53

    Zisman, D. A. et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N. Engl. J. Med. 363, 620–628 (2010).

  54. 54

    Rajkumar, V. S. et al. Platelet-derived growth factor-β receptor activation is essential for fibroblast and pericyte recruitment during cutaneous wound healing. Am. J. Pathol. 169, 2254–2265 (2006).

  55. 55

    Baroni, S. S. et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N. Engl. J. Med. 354, 2667–2676 (2006).

  56. 56

    Classen, J. F. et al. Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis Rheum. 60, 1137–1144 (2009).

  57. 57

    Yin, Z. et al. Lysophosphatidic acid-activated C1-current activity in human systemic sclerosis skin fibroblasts. Rheumatology (Oxford) 49, 2290–2297 (2010).

  58. 58

    Pradere, J. P. et al. LPA1 receptor activation promotes renal interstitial fibrosis. J. Am. Soc. Nephrol. 18, 3110–3118 (2007).

  59. 59

    Castelino, F. V. et al. Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheum. 63, 1405–1415 (2011).

  60. 60

    Swaney, J. S. et al. A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br. J. Pharmacol. 160, 1699–1713 (2010).

  61. 61

    Kronke, G. et al. The 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis. Ann. Rheum. Dis. 71, 1081–1087 (2012).

  62. 62

    Ewert, R. et al. Continuous intravenous iloprost to revert treatment failure of first-line inhaled iloprost in patients with idiopathic pulmonary arterial hypertension. Clin. Res. Cardiol. 96, 211–217 (2007).

  63. 63

    Stratton, R. et al. Iloprost suppresses connective growth factor production in fibroblasts and in the skin of scleroderma patients. J. Clin. Invest. 108, 241–250 (2001).

  64. 64

    Wilborn, J. et al. Constitutive activation of 5-lipooxygenase in the lungs of patients with idiopathic pulmonary fibrosis. J. Clin. Invest. 97, 1827–1836 (1996).

  65. 65

    Izumo, T. et al. Cysteinyl-leukotriene 1 receptor antagonist attenuates bleomycin-induced pulmonary fibrosis in mice. Life Sci. 80, 1882–1886 (2007).

  66. 66

    Balistreri, E. et al. The cannabinoid WIN55, 212–2 abrogates dermal fibrosis in scleroderma bleomycin model. Ann. Rheum. Dis. 70, 695–699 (2011).

  67. 67

    Marquart, S. et al. Inactivation of the cannabinoid receptor CB1 prevents leukocyte infiltration and experimental fibrosis. Arthritis Rheum. 62, 3467–3476 (2010).

  68. 68

    Gonzalez, E. G. et al. Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis. Ann. Rheum. Dis. 71, 1545–1551 (2012).

  69. 69

    Du, H., Chen, X., Zhang, J. & Chen, C. Inhibition of COX-2 expression by endocannabinoid-2-arachidonoylglycerol is mediated via PPAR-γ. Br. J. Pharmacol. 163, 1533–1549 (2011).

  70. 70

    Genovese, T. et al. Effect of rosiglitazone and 15-deoxy-δ12, 14-prostaglandin J2 on bleomycin-induced lung injury. Eur. Respir. J. 25, 225–234 (2005).

  71. 71

    Kapoor, M. et al. Loss of peroxisome proliferator-activated receptor γ in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis. Arthritis Rheum. 60, 2822–2829 (2009).

  72. 72

    Samah, M., El-Aidy Ael, R., Tawfik, M. K. & Ewais, M. M. Evaluation of the antifibrotic effect of fenofibrate and rosiglitazone on bleomycin-induced pulmonary fibrosis in rats. Eur. J. Pharmacol. 689, 186–193 (2012).

  73. 73

    Distler, J. H. et al. Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis. Rheumatology (Oxford) 48, 98–103 (2009).

  74. 74

    Gharaee-Kermani, M., McCullumsmith, R. E., Charo, I. F., Kunkel, S. L. & Phan, S. H. CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis. Cytokine 24, 266–276 (2003).

  75. 75

    Gu, L. et al. Control of TH2 polarization by he chemokine monocyte chemoattractant protein-1. Nature 404, 407–411 (2000).

  76. 76

    Carulli, M. T. et al. Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: evidence for autocrine regulation of myofibroblast differentiation. Arthritis Rheum. 52, 3772–3782 (2005).

  77. 77

    Greenblatt, M. B. et al. Interspecies comparison of human and murine scleroderma reveals IL-13 and CCL2 as disease subset-specific targets. Am. J. Pathol. 180, 1080–1094 (2012).

  78. 78

    Tiev, K. P. et al. Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis. Eur. Respir. J. 38, 1355–1360 (2011).

  79. 79

    Reshef, R. et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N. Engl. J. Med. 367, 135–145 (2012).

  80. 80

    Fleishaker, D. L. et al. Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial. Arthritis Res. Ther. 14, R11 (2012).

  81. 81

    Aliprantis, A. O. et al. Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13. Proc. Natl Acad. Sci. USA 104, 2827–2830 (2007).

  82. 82

    Fichtner-Feigl, S., Strober, W., Kawakami, K., Puri, R. K. & Kitani, A. IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis. Nat. Med. 12, 99–106 (2006).

  83. 83

    Kraft, M. Asthma phenotypes and interleukin-13-moving closer to personalized medicine. N. Engl. J. Med. 365, 1141–1144 (2011).

  84. 84

    Yang, L. et al. Periostin facilitates skin sclerosis via PI3K/Akt dependent mechanism in a mouse model of scleroderma. PLoS ONE 7, e41994 (2012).

  85. 85

    US National Library of Medicine ClinicalTrials.gov [online], (2013).

  86. 86

    Valente, A. J. et al. Interleukin-17A stimulates cardiac fibroblast proliferation and migration via negative regulation of the dual-specificity phosphatase MKP-1/DUSP-1. Cell Signal. 24, 560–568 (2012).

  87. 87

    Nakashima, T. et al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J. Immunol. 188, 3573–3583 (2012).

  88. 88

    Kurasawa, K. et al. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum. 43, 2455–2463 (2000).

  89. 89

    Meng, F. et al. Interleukin-17 signalling in inflammatory, kupffer cells and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143, 765–776 (2012).

  90. 90

    Mi, S. et al. Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-β1-dependent and –independent mechanisms. J. Immunol. 187, 3003–3014 (2011).

  91. 91

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  92. 92

    Piguet, P. F. et al. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J. Exp. Med. 170, 655–663 (1989).

  93. 93

    Denton, C. P. et al. An open-label pilot study of infliximab therapy in diffuse cutaneous systemic sclerosis. Ann. Rheum. Dis. 68, 1433–1439 (2009).

  94. 94

    Distler, J. H. et al. Is there a role for TNFα antagonists in the treatment of SSc? EUSTAR expert consensus development using the Delphi technique. Clin. Exp. Rheumatol. 29 (Suppl. 65), S40–S45 (2011).

  95. 95

    Kawaguchi, Y., McCarthy, S. A., Watkins, S. C. & Wright, T. M. Autocrine activation by interleukin 1α induces the fibrogenic phenotype of systemic sclerosis fibroblasts. J. Rheumatol. 31, 1946–1954 (2004).

  96. 96

    Aden, N. et al. Epithelial cells promote fibroblast activation via IL-1α in systemic sclerosis. J. Invest. Dermatol. 130, 2191–2200 (2010).

  97. 97

    Bonniaud, P. et al. TGF-β and Smad3 signaling link inflammatrion to chronic fibrogenesis. J. Immunol. 175, 5390–5395 (2005).

  98. 98

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

  99. 99

    Honda, N. et al. TGF-β mediated downregulation of microRNA-196a contributes to the constitutive upregulated type I collagen expression in scleroderma dermal fibroblasts. J. Immunol. 188, 3323–3331 (2012).

  100. 100

    Hemmatazad, H. et al. Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis. Arthritis Rheum. 60, 1519–1529 (2009).

  101. 101

    Akgedik, R. et al. Effect of resveratrol on treatment of bleomycin-induced pulmonary fibrosis in rats. Inflammation 35, 1732–1741 (2012).

  102. 102

    Li, J., Qu, X., Ricardo, S. D., Bertram, J. F. & Nikolic-Paterson, D. J. Resveratrol inhibits renal fibrosis in the obstructed kidney: potential role in deacetylation of Smad3. Am. J. Pathol. 177, 1065–1071 (2010).

  103. 103

    Horn, A. et al. Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis. Ann. Rheum. Dis. 71, 785–789 (2012).

  104. 104

    Aoyagi-Ikeda, K. et al. Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-β-Smad3 pathway. Am. J. Respir. Cell. Mol. Biol. 45, 136–144 (2011).

  105. 105

    Kavian, N. et al. Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model. Arthritis Rheum. 62, 3477–3487 (2010).

  106. 106

    Djudjaj, S. et al. Notch-3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury. J. Pathol. 228, 286–299 (2012).

  107. 107

    Akhmetshina, A. et al. Activation of canonical Wnt signalling is required for TGF-β mediated fibrosis. Nat. Commun. 3, 735 (2012).

  108. 108

    Dees, C., Zerr. et al. Inhibition of Notch signaling prevents experimental fibrosis and induces regression of established fibrosis. Arthritis Rheum. 63, 1396–1404 (2011).

  109. 109

    Tang, J. Y. et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N. Engl. J. Med. 366, 2180–2188 (2012).

  110. 110

    Ihn, H. et al. Blockade of endogenous transforming growth factor β signaling prevents upregulated collagen synthesis in scleroderma fibroblasts: association with increased expression of transforming growth factor β receptors. Arthritis Rheum. 44, 474–480 (2001).

  111. 111

    Sargent, J. L. et al. A TGF β-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J. Invest. Dermatol. 130, 694–705 (2010).

  112. 112

    Avouac, J. et al. Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis Rheum. 64, 1642–1652 (2012).

  113. 113

    Dees, C. et al. JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis. Arthritis Rheum. 64, 3006–3015 (2012).

  114. 114

    Denton, C. P. et al. Cat-192 Study Group, Scleroderma Clinical Trials Consortium. 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, 323–333 (2007).

  115. 115

    US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  116. 116

    Riser, B. L. et al. CCN3 (Nov) is a negative regulator of CCN2(CTGF) and a novel endogenous inhibitor of the fibrotic pathway in an in vitro model of renal disease. Am. J. Pathol. 174, 1725–1734 (2009).

  117. 117

    Adler, S. G. et al. Phase I study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin. J. Am. Soc. Nephrol. 5, 1420–1428 (2010).

  118. 118

    Asano, Y., Ihn, H., Yamane, K., Jinnin, M. & Tamaki, K : Increased expression of integrin αvβ5 induces the myofibroblastic differentiation of dermal fibroblasts. Am. J. Pathol. 168, 499–510 (2006).

  119. 119

    Katsumoto, T. R., Violette, S. M. & Sheppard, D. Blocking TGFβ via inhibition of the αvβ6 integrin: a possible therapy for systemic sclerosis interstitial lung disease. Int. J. Rheumatol. 208219 (2011).

  120. 120

    Horan, G. S. et al. Partial inhibition of integrin αvβ6 prevents pulmonary fibrosis without exacerbating inflammation. Am. J. Respir. Crit. Care Med. 177, 56–65 (2008).

  121. 121

    Puthawala, K. et al. Inhibition of integrin αvβ6, an activator of latent transforming growth factor-β, prevents radiation-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 177, 82–90 (2008).

  122. 122

    Goodman, S. L., Picard, M. Integrins as therapeutic targets. Trends Pharmacol. Sci. 33, 405–412 (2012).

  123. 123

    Akhmetshina, A. et al. Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis Rheum. 60, 219–224 (2009).

  124. 124

    Spiera, R. F. 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. 70, 1003–1009 (2011).

  125. 125

    Pope, J. et al. Imatinib in active diffuse cutaneous systemic sclerosis: Results of a six-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study at a single center. Arthritis Rheum. 63, 3547–3551 (2011).

  126. 126

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  127. 127

    Gordon, J. K. et al. Nilotinib (Tasigna) in the treatment of early diffuse systemic sclerosis: a single group, open-label pilot clinical trial [abstract 694]. Arthritis Rheum. 64 (Suppl. 10), S298 (2012).

  128. 128

    Ghofrani, H. A. et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am. J. Respir. Crit. Care Med. 182, 1171–1177 (2010).

  129. 129

    Richeldi, L. et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N. Engl. J. Med. 365, 1079–1087 (2011).

  130. 130

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  131. 131

    Keir, G. J. et al. Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy. Eur. Respir. J. 40, 641–648 (2012).

  132. 132

    Murray, L. A. et al. TGF-β driven lung fibrosis is macrophage-dependent and blocked by Serum amyloid P. Int. J. Biochem. Cell. Biol. 43, 154–162 (2011).

  133. 133

    US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  134. 134

    Denton, C. P. et al. Comparative analysis of change in modified Rodnan skin score in patients with diffuse systemic sclerosis receiving imatinib mesylate suggests similar disease course to matched patients receiving standard therapy [abstract]. Arthritis Rheum. 62 (Suppl. 10), 566 (2010).

  135. 135

    Fonseca, C. et al. A polymorphism in the CTGF promoter region associated with systemic sclerosis. N. Engl. J. Med. 357, 1210–1220 (2007).

  136. 136

    Granel, B. et al. Association between a CTGF gene polymorphism and systemic sclerosis in a French population. J. Rheum. 37, 351–358 (2010).

  137. 137

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  138. 138

    US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  139. 139

    US National Library of Medicine. ClinicalTrials.gov [online], (2007).

  140. 140

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  141. 141

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  142. 142

    US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  143. 143

    US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  144. 144

    Herrick, A. L., Lunt, M., Whidby, N. Observational study of treatment outcome in early diffuse cutaneous systemic sclerosis. J. Rheumatol. 37, 116–124 (2010).

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C. P. Denton selected the content of the article. Both authors made substantial contributions to researching data for the article, writing the article, and review and editing of the article before submission.

Correspondence to Christopher P. Denton.

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Competing interests

C. P. Denton declares that he has received consultancy fees, honoraria and research funding from Actelion Pharmaceuticals, and consultancy fees and honoraria from GSK, Pfizer, Novartis, Sanofi-Aventis and Merck-Serono. V. H. Ong declares that he has received consultancy fees and honoraria from Actelion Pharmaceuticals.

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Denton, C., Ong, V. Targeted therapies for systemic sclerosis. Nat Rev Rheumatol 9, 451–464 (2013) doi:10.1038/nrrheum.2013.46

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