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Reviews

Immunotherapy of systemic sclerosis

, , &
Pages 2559-2567 | Received 04 May 2018, Accepted 18 Jun 2018, Published online: 16 Jul 2018

References

  • Desbois AC, Cacoub P. Systemic sclerosis: An update in 2016. Autoimmun Rev. 2016;15(5):417–26. doi:10.1016/j.autrev.2016.01.007.
  • Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, Goulet JR, Rich E, Grodzicky T, Raymond Y, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum. 2008;58(12):3902–12. doi:10.1002/art.24038.
  • Sakkas LI, Chikanza IC, Platsoucas CD. Mechanisms of Disease: the role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol. 2006;2(12):679–85. doi:10.1038/ncprheum0346.
  • Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012 Mar;24(2):165–70 doi:10.1097/BOR.0b013e32834ff2e8.
  • Nikpour M, Stevens WM, Herrick AL, Proudman SM. Epidemiology of systemic sclerosis. Best Pract Res Clin Rheumatol. 2010 Dec;24(6):857–69. doi:10.1016/j.berh.2010.10.007.
  • Nguyen C, Bérezné A, Baubet T, Mestre-Stanislas C, Rannou F, Papelard A, Morell-Dubois S, Revel M, Guillevin L, Poiraudeau S et al. Groupe Français de Recherche sur la Sclérodermie. Association of gender with clinical expression, quality of life, disability, and depression and anxiety in patients with systemic sclerosis. PLoS One. 2011 Mar9;6(3):e17551. doi:10.1371/journal.pone.0017551.
  • Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis. 2007 Jul;66(7):940–4 doi:10.1136/ard.2006.066068.
  • Sakkas LI, Simopoulou T, Daoussis D, Liossis SN, Potamianos S. Intestinal involvement in systemic sclerosis: A clinical review. Dig Dis Sci. 2018 Apr;63(4):834–44. doi:10.1007/s10620-018-4977-8.
  • Rubio-Rivas M, Corbella X, Pestaña-Fernández M, Tolosa-Vilella C, Guillen-Del Castillo A, Colunga-Argüelles D, Trapiella-Martínez L, Iniesta-Arandia N, Castillo-Palma MJ, Sáez-Comet L et al. First clinical symptom as a prognostic factor in systemic sclerosis: results of a retrospective nationwide cohort study. Clin Rheumatol. 2018 Apr;37(4):999–1009 doi:10.1007/s10067-017-3936-7.
  • Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, Bancel DF, Allanore Y, Müller-Ladner U, Distler O, 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. 2010 Oct;69(10):1809–15. doi:10.1136/ard.2009.114264.
  • Kalogerou A, Gelou E, Mountantonakis S, Settas L, Zafiriou E, Sakkas L. Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis. 2005;64(8):1233–5. doi:10.1136/ard.2004.027094.
  • Sakkas LI, Platsoucas CD. Is systemic sclerosis an antigen-driven T cell disease? Arthritis Rheum. 2004;50(6):1721–33. doi:10.1002/art.20315.
  • Sakkas LI, Tourtelotte C, Myers A, Berney S, Platsoucas CD. Increased levels of alternatively spliced interleukin-4 (IL-4d2) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis. Clin Diagn LabImmunol 1999;6(5):660–4.
  • Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, Takabayashi K, Iwamoto I. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum. 2000;43(11):2455–63. doi:10.1002/1529-0131(200011)43:11%3c2455::AID-ANR12%3e3.0.CO;2-K.
  • Moudgil KD, Choubey D. Cytokines in autoimmunity: role in induction, regulation, and treatment. J Interferon Cytokine Res. 2011 Oct;31(10):695–703. doi:10.1089/jir.2011.0065.
  • Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J. 2004 May;18(7):816–27. doi:10.1096/fj.03-1273rev.
  • Sakkas LI, Bogdanos DP. Systemic sclerosis: New evidence re-enforces the role of B cells. Autoimmun Rev. 2016;15(2):155–61. doi:10.1016/j.autrev.2015.10.005.
  • Hasegawa M. B lymphocytes: shedding new light on the pathogenesis of systemic sclerosis. J Dermatol. 2010;37(1):3–10. doi:10.1111/j.1346-8138.2009.00763.x.
  • Luchetti MM, Moroncini G, Jose Escamez M, Svegliati Baroni S, Spadoni T, Grieco A, Paolini C, Funaro A, Avvedimento EV, Larcher F, et al. Induction of scleroderma fibrosis in skin-humanized mice by administration of anti-platelet-derived growth factor receptor agonistic autoantibodies. Arthritis Rheumatol. 2016;68(9):2263–73. doi:10.1002/art.39728.
  • Moroncini G, Svegliati Baroni S, Gabrielli A. Agonistic antibodies in systemic sclerosis. Immunol Lett. 2018;195:83–87. doi:10.1016/j.imlet.2017.10.007.
  • François A, Chatelus E, Wachsmann D, Sibilia J, Bahram S, Alsaleh G, Gottenberg JE. B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis. Arthritis Res Ther. 2013;15(5):R168. doi:10.1186/ar4352.
  • van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, MatucciCerinic M, Naden RP, Medsger TA Jr, Carreira PE, et al. 2013 classification criteria for systemic sclerosis: An American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737–47. doi:10.1002/art.38098.
  • Sakkas LI, Simopoulou T, Katsiari C, Bogdanos D, Chikanza IC. Early systemic sclerosis-opportunities for treatment. Clin Rheumatol. 2015;34(8):1327–31. doi:10.1007/s10067-015-2902-5.
  • Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M et al. Scleroderma lung study research group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655–66. doi:10.1056/NEJMoa055120.
  • Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, Roberts C, Desai S, Herrick AL, McHugh NJ et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006;54:3962–70. doi:10.1002/art.22204.
  • Mendoza FA, Mansoor M, Jimenez SA. Treatment of rapidly progressive systemic sclerosis: Current and future prospective. Expert Opinion Orphan Drugs 2016;4(1):31–47. doi:10.1517/21678707.2016.1114454.
  • Herrick AL, Pan X, Peytrignet S, Lunt M, Hesselstrand R, Mouthon L, Silman A, Brown E, Czirják L, Distler JHW et al. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS). Ann Rheum Dis 2017;76:1207–18. doi:10.1136/annrheumdis-2016-210503.
  • Saigusa R, Asano Y, Nakamura K, Yamashita T, Ichimura Y, Takahashi T, Toyama T, Taniguchi T, Yoshizaki A, Miyazaki M, et al. Plasma plasmin-α2-plasmin inhibitor complex levels may predict the effect of cyclophosphamide for systemic sclerosisrelated interstitial lung disease. Mod Rheumatol. 2017;27(4):618–22. doi:10.1080/14397595.2016.1226472.
  • van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, van de Putte LB. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br J Rheumatol. 1996;35(4):364–72. doi:10.1093/rheumatology/35.4.364.
  • Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, Smith CD, Chalmers IM, Hong P, O'Hanlon D, et al. A randomized controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001;44(6):1351–8. doi:10.1002/1529-0131(200106)44:6%3c1351::AID-ART227%3e3.0.CO;2-I.
  • 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(2):323–9.
  • Lateef O, Shakoor N, Balk RA. Methotrexate pulmonary toxicity. Expert Opin Drug Saf. 2005;4(4):723–30. doi:10.1517/14740338.4.4.723.
  • Nadashkevich O, Davis P, Fritzler M, Kovalenko W. A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis. Clin Rheumatol. 2006;25(2):205–12. doi:10.1007/s10067-005-1157-y.
  • Poormoghim H, Rezaei N, Sheidaie Z, Almasi AR, Moradi-Lakeh M, Almasi S, Andalib E. Systemic sclerosis: comparison of efficacy of oral cyclophosphamide and azathioprine on skin score and pulmonary involvement-a retrospective study. Rheumatol Int. 2014;34(12):1691–9. doi:10.1007/s00296-014-3026-y.
  • Baqir M, Makol A, Osborn TG, Bartholmai BJ, Ryu JH. Mycophenolate mofetil for scleroderma-related interstitial lung disease: A real world experience. PLoS One. 2017;12(5):e0177107. doi:10.1371/journal.pone.0177107.
  • Koutroumpas A, Ziogas A, Alexiou I, Barouta G, Sakkas LI. Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease. Clin Rheumatol. 2010;29(10):1167–8. doi:10.1007/s10067-010-1498-z.
  • Shenoy PD, Bavaliya M, Sashidharan S, Nalianda K, Sreenath S. Cyclophosphamide versus mycophenolate mofetil in scleroderma interstitial lung disease (SSc-ILD) as induction therapy: a single-centre, retrospective analysis. Arthritis Res Ther. 2016;18(1):123. doi:10.1186/s13075-016-1015-0.
  • Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, Goldin J, Arriola E, Volkmann ER, Kafaja S, et al. Sclerodema Lung Study II Investigators. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016;4(9):708–19. doi:10.1016/S2213-2600(16)30152-7.
  • Volkmann ER, Tashkin DP, Li N, Roth MD, Khanna D, Hoffmann-Vold AM, Kim G, Goldin J, Clements PJ, Furst DE, et al. Mycophenolate mofetil versus placebo for systemic sclerosis-related interstitial lung disease: An analysis of scleroderma lung studies I and II. Arthritis Rheumatol. 2017;69(7):1451–60. doi:10.1002/art.40114.
  • Namas R, Tashkin DP, Furst DE, Wilhalme H, Tseng CH, Roth MD, Kafaja S, Volkmann E, Clements PJ, Khanna D, Participants in the Scleroderma Lung Study I and members of the Scleroderma Lung Study II Research Group. Efficacy of mycophenolate mofetil and oral cyclophosphamide on skin thickness: Post hoc analyses from two randomized placebo-controlled trials. Arthritis Care Res (Hoboken). 2018;70(3):439–44. doi:10.1002/acr.23282.
  • Tsukamoto H, Nagafuji K, Horiuchi T, Mitoma H, Niiro H, Arinobu Y, Inoue Y, To K, Miyamoto T, Iwasaki H, et al. Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4+ T cells. Rheumatology (Oxford). 2011;50(5):944–52. doi:10.1093/rheumatology/keq414.
  • Tyndall A, Saccardi R. Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions. Clin Exp Immunol. 2005;141(1):1–9. doi:10.1111/j.1365-2249.2005.02806.x.
  • Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, Gooley TA, Holmberg L, Henstorf G, LeMaistre CF, 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):1388–96. doi:10.1182/blood-2007-02-072389.
  • Vonk MC, Marjanovic Z, van den Hoogen FH, Zohar S, Schattenberg AV, Fibbe WE, Larghero J, Gluckman E, Preijers FW, van Dijk AP, et al. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis. 2008;67(1):98–104 doi:10.1136/ard.2007.071464.
  • Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, Molitor JA, Henstorf G, Lafyatis R, Pritchard DK, et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS One. 2008;3(1):e1452. doi:10.1371/journal.pone.0001452.
  • Miniati I, Guiducci S, Conforti ML, Rogai V, Fiori G, Cinelli M, Saccardi R, Guidi S, Bosi A, Tyndall A, et al. Autologous stem cell transplantation improves microcirculation in systemic sclerosis. Ann Rheum Dis. 2009;68(1):94–98. doi:10.1136/ard.2007.082495.
  • Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, Craig R, Hirano I, Marshall K, Ruderman E, 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(9790):498–506. doi:10.1016/S0140-6736(11)60982-3.
  • van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, Schuerwegh AJ, Marijt EW, Vonk MC, Schattenberg AV, et al. EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014;311(24):2490–8. doi:10.1001/jama.2014.6368.
  • Host L, Nikpour M, Calderone A, Cannell P, Roddy J. Autologous stem cell transplantation in systemic sclerosis: a systematic review. Clin Exp Rheumatol. 2017; 35 Suppl 106(4):198–207.
  • Sullivan KM, Goldmuntz EA, Furst DE. Autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018 Mar 15;378(11):1066–7. doi:10.1056/NEJMc1801275.
  • Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980 23(5):581–90.
  • Bellando-Randone S, Matucci-Cerinic M. From Raynaud's Phenomenon to Very Early Diagnosis of Systemic Sclerosis- The VEDOSS approach. Curr Rheumatol Rev. 2013;9(4):245–8. doi:10.2174/157339710904140417124819.
  • WHO Expert Committee on Biological Standardization. Fifty-sixth report. WHO Technical Report Series, No. 941, 2007 (352 pages), p: 202 http://apps.who.int/iris/bitstream/handle/10665/43594/WHO_TRS_941.pdf?sequence=1&isAllowed=y
  • Cantarini L, Rigante D, Vitale A, Napodano S, Sakkas LI, Bogdanos DP, Shoenfeld Y. Intravenous immunoglobulins (IVIG) in systemic sclerosis: a challenging yet promising future. Immunol Res. 2015;61(3):326–37. doi:10.1007/s12026-014-8615-z.
  • Blank M, Levy Y, Amital H, Shoenfeld Y, Pines M, Genina O. The role of intravenous immunoglobulin therapy in mediating skin fibrosis in tight skin mice. Arthritis Rheum. 2002;46(6):1689–90. doi:10.1002/art.10363.
  • Levy Y, Amital H, Langevitz P, Nacci F, Righi A, Conforti L, Generini S, Matucci Cerinic M, Shoenfeld Y. Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study. Arthritis Rheum. 2004;50(3):1005–7. doi:10.1002/art.20195.
  • Nacci F, Righi A, Conforti ML, Miniati I, Fiori G, Martinovic D, Melchiorre D, Sapir T, Blank M, Shoenfeld Y, et al. Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study. Ann Rheum Dis. 2007;66(7):977–9. doi:10.1136/ard.2006.060111.
  • Takehara K, Ihn H, Sato S. A randomized, double-blind, placebo-controlled trial: intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis. Clin Exp Rheumatol. 2013;31(2 Suppl 76):151–6.
  • Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol. 2005 Dec;29(3):173–84. doi:10.1385/CRIAI:29:3:173.
  • Matsushita T, Fujimoto M, Hasegawa M, Matsushita Y, Komura K, Ogawa F, Watanabe R, Takehara K, Sato S. BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice. J Invest Dermatol. 2007;127(12):2772–80 doi:10.1038/sj.jid.5700919.
  • Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K, Sato S. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 2006;54(1):192–201. doi:10.1002/art.21526.
  • Gordon JK, Martyanov V, Franks JM, Bernstein EJ, Szymonifka J, Magro C, Wildman HF, Wood TA, Whitfield ML, Spiera RF. Belimumab for the treatment of early diffuse systemic sclerosis: Results of a randomized, double-blind, placebo-controlled, pilot trial. Arthritis Rheumatol. 2018;70(2):308–16. doi:10.1002/art.40358.
  • Khan K, Xu S, Nihtyanova S, Derrett-Smith E, Abraham D, Denton CP, Ong VH. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis. 2012;71(7):1235–42. doi:10.1136/annrheumdis-2011-200955.
  • Sakkas LI. Spotlight on tocilizumab and its potential in the treatment of systemic sclerosis. Drug Des Devel Ther. 2016;10:2723–8. doi:10.2147/DDDT.S99696.
  • Shima Y, Kuwahara Y, Murota H, Kitaba S, Kawai M, Hirano T, Arimitsu J, Narazaki M, Hagihara K, Ogata A, et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford). 2010;49(12):2408–12. doi:10.1093/rheumatology/keq275.
  • Fernandes das Neves M, Oliveira S, Amaral MC, Delgado Alves J. Treatment of systemic sclerosis with tocilizumab. Rheumatology (Oxford). 2015;54(2):371–2. doi:10.1093/rheumatology/keu435.
  • Shima Y, Hosen N, Hirano T, Arimitsu J, Nishida S, Hagihara K, Narazaki M, Ogata A, Tanaka T, Kishimoto T, et al. Expansion of range of joint motion following treatment of systemic sclerosis with tocilizumab. Mod Rheumatol. 2015;25(1):134–7. doi:10.3109/14397595.2013.874749.
  • Frech TM, Hudson M. Protective role of interleukin-6 in systemic sclerosis gastrointestinal tract involvement: case report and review of the literature. Clin Exp Rheumatol. 2015;33(4) (Suppl 91):S179–81.
  • Elhai M, Meunier M, Matucci-Cerinic M, Maurer B, Riemekasten G, Leturcq T, Pellerito R, Von Mühlen CA, Vacca A, Airo P, et al. EUSTAR (EULAR Scleroderma Trials and Research group). Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis. 2013;72(7):1217–20. doi:10.1136/annrheumdis-2012-202657.
  • Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, Baron M, Chung L, Fierlbeck G, Lakshminarayanan S, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–40. doi:10.1016/S0140-6736(16)00232-4.
  • Khanna D, Denton CP, Lin CJF, van Laar JM, Frech TM, Anderson ME, Baron M, Chung L, Fierlbeck G, Lakshminarayanan S, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis. 2018;77(2):212–20. doi:10.1136/annrheumdis-2017-211682.
  • Chakravarty EF, Martyanov V, Fiorentino D, Wood TA, Haddon DJ, Jarrell JA, Utz PJ, Genovese MC, Whitfield ML, Chung L. Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis Res Ther. 2015;17:159. doi:10.1186/s13075-015-0669-3.
  • de Paoli FV, Nielsen BD, Rasmussen F, Deleuran B, Søndergaard K. Abatacept induces clinical improvement in patients with severe systemic sclerosis. Scand J Rheumatol. 2014;43(4):342–5. doi:10.3109/03009742.2013.812238.
  • Wehner Fage S, Arvesen KB, Olesen AB. Abatacept improves skin-score and reduces lesions in patients with localized scleroderma: A case series. Acta Derm Venereol. 2018;98(4):465–6. doi:10.2340/00015555-2878.
  • Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, Pergamenschikov A, McCalmont TH, Brown PO, Botstein D, Connolly MKSystemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003;100(21):12319–24. doi:10.1073/pnas.1635114100.
  • Lafyatis R, O'Hara C, Feghali-Bostwick CA, Matteson E. B cell infiltration in systemic sclerosis-associated interstitial lung disease. Arthritis Rheum. 2007; 56(9):3167–8 doi:10.1002/art.22847.
  • Hasegawa M, Hamaguchi Y, Yanaba K, Bouaziz JD, Uchida J, Fujimoto M, Matsushita T, Matsushita Y, Horikawa M, Komura 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(3):954–66. doi:10.2353/ajpath.2006.060205.
  • Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Sirinian C, Karampetsou M, Yiannopoulos G, Andonopoulos AP. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford). 2010;49(2):271–80. doi:10.1093/rheumatology/kep093.
  • Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Paliogianni F, Sirinian C, Yiannopoulos G, Andonopoulos AP. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol. 2012;30(2 Suppl 71):S17–22.
  • Daoussis D, Melissaropoulos K, Sakellaropoulos G, Antonopoulos I, Markatseli TE, Simopoulou T, Georgiou P, Andonopoulos AP, Drosos AA, Sakkas L, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2017;46(5):625–31. doi:10.1016/j.semarthrit.2016.10.003.
  • Jordan S, Distler JH, Maurer B, Huscher D, van Laar JM, Allanore Y, Distler O, EUSTAR Rituximab study group. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015;74(6):1188–94. doi:10.1136/annrheumdis-2013-204522.
  • Boonstra M, Meijs J, Dorjée AL, Marsan NA, Schouffoer A, Ninaber MK, Quint KD, Bonte-Mineur F, Huizinga TWJ, Scherer HU, et al. Rituximab in early systemic sclerosis. RMD Open. 2017;3(2):e000384. eCollection 2017. PubMed PMID: 28879049; PubMed Central PMCID: PMC5574444. doi:10.1136/rmdopen-2016-000384.
  • Thiebaut M, Launay D, Rivière S, Mahévas T, Bellakhal S, Hachulla E, Fain O, Mekinian A. Efficacy and safety of rituximab in systemic sclerosis: French retrospective study and literature review. Autoimmun Rev. 2018;17(6):582–87. doi:10.1016/j.autrev.2017.12.010.
  • Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ, Merkel P, Simms RW. B cell depletion with rituximab in patients patients with diffuse systemic cutaneous sclerosis. Arthritis Rheum 2009;60(2):578–83. doi:10.1002/art.24249.
  • Bosello SL, De Luca G, Rucco M, Berardi G, Falcione M, Danza FM, Pirronti T, Ferraccioli G. Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum. 2015;44(4):428–36. doi:10.1016/j.semarthrit.2014.09.002.
  • Melsens K, De Keyser F, Decuman S, Brusselle G, De Pauw M, Deschepper E, De Wilde K, Elewaut D, Piette Y, Vandecasteele E, et al. Assessment of sensitivity to change of the European scleroderma study group activity index. Clin Exp Rheumatol. 2016;34(Suppl 100):148–51
  • Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta. 2008;1782(4):197–228. doi:10.1016/j.bbadis.2008.01.006.
  • Sonnylal S, Denton CP, Zheng B, Keene DR, He R, Adams HP, Vanpelt CS, Geng YJ, Deng JM, Behringer RR, et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum. 2007;56(1):334–44. doi:10.1002/art.22328.
  • Sargent JL, Milano A, Bhattacharyya S, Varga J, Connolly MK, Chang HY, Whitfield ML. A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J Invest Dermatol. 2010;130(3):694705. doi:10.1038/jid.2009.318.
  • Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K. Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts. J Clin Invest. 2004;113(2):253–64. doi:10.1172/JCI16269.
  • Asano Y, Ihn H, Yamane K, Jinnin M, Mimura Y, Tamaki K. Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts. J Immunol. 2005;175(11):7708–18. doi:10.4049/jimmunol.175.11.7708.
  • Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane K, Tamaki K. Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-beta signaling in cultured scleroderma fibroblasts. Am J Pathol. 2005;166(5):1451–63. doi:10.1016/S0002-9440(10)62362-0.
  • Shi-wen X, Kennedy L, Renzoni EA, Bou-Gharios G, du Bois RM, Black CM, Denton CP, Abraham DJ, Leask A. Endothelin is a downstream mediator of profibrotic responses to transforming growth factor beta in human lung fibroblasts. Arthritis Rheum. 2007;56(12):4189–94. doi:10.1002/art.23134.
  • Silver RM. Endothelin and scleroderma lung disease. Rheumatology (Oxford). 2008 Oct;47 Suppl 5:v25–26. doi:10.1093/rheumatology/ken283.
  • Denton CP, Merkel PA, Furst DE, Khanna D, Emery P, Hsu VM, Silliman N, Streisand J, Powell J, Akesson A, 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. 2007;56(1):323–33. doi:10.1002/art.22289.
  • Rice LM, Padilla CM, McLaughlin SR, Mathes A, Ziemek J, Goummih S, Nakerakanti S, York M, Farina G, Whitfield ML, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest. 2015;125(7):2795–807. doi:10.1172/JCI77958.
  • Tamaki Z, Asano Y, Kubo M, Ihn H, Tada Y, Sugaya M, Kadono T, Sato S. Effects of the immunosuppressant rapamycin on the expression of human α2(I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts. J Dermatol Sci. 2014;74(3):251–9. doi:10.1016/j.jdermsci.2014.02.002.
  • Yanaba K. Strategy for treatment of fibrosis in systemic sclerosis: Present and future. J Dermatol. 2016;43(1):46–55. doi:10.1111/1346-8138.13026.
  • Su TI, Khanna D, Furst DE, Danovitch G, Burger C, Maranian P, Clements PJ. Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Arthritis Rheum. 2009;60(12):3821–30. doi:10.1002/art.24986.
  • Gomez-Puerta JA, Mócsai A. Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Curr Top Med Chem. 2013;13(6):760–73. doi:10.2174/15680266113139990094.
  • Sfikakis PP, Gorgoulis VG, Katsiari CG, Evangelou K, Kostopoulos C, Black CM. Imatinib for the treatment of refractory, diffuse systemic sclerosis. Rheumatology (Oxford). 2008;47(5):735–7. doi:10.1093/rheumatology/ken104.
  • Khanna D, Saggar R, Mayes MD, Abtin F, Clements PJ, Maranian P, Assassi S, Saggar R, Singh RR, Furst DE. A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease. Arthritis Rheum. 2011;63(11):3540–6. doi:10.1002/art.30548.
  • Pope J, McBain D, Petrlich L, Watson S, Vanderhoek L, de Leon F, Seney S, Summers K. 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. 2011;63(11):3547–51. doi:10.1002/art.30549.
  • Spiera RF, Gordon JK, Mersten JN, Magro CM, Mehta M, Wildman HF, Kloiber S, Kirou KA, Lyman S, Crow MK. 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(6):1003–9. doi:10.1136/ard.2010.143974.
  • Prey S, Ezzedine K, Doussau A, Grandoulier AS, Barcat D, Chatelus E, Diot E, Durant C, Hachulla E, de Korwin-Krokowski JD et al. Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. Br J Dermatol. 2012;167(5):1138–44. doi:10.1111/j.1365-2133.2012.11186.x.
  • Gordon JK, Martyanov V, Magro C, Wildman HF, Wood TA, Huang WT, Crow MK, Whitfield ML, Spiera RF. Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial. Arthritis Res Ther. 2015;17:213. doi:10.1186/s13075-015-0721-3.
  • Martyanov V, Kim GJ, Hayes W, Du S, Ganguly BJ, Sy O, Lee SK, Bogatkevich GS, Schieven GL, Schiopu E, et al. Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease. PLoS One. 2017;12(11):e0187580. doi:10.1371/journal.pone.0187580.
  • Wermuth PJ, Piera-Velazquez S, Rosenbloom J, Jimenez SA. Existing and novel biomarkers for precision medicine in systemic sclerosis. Nat Rev Rheumatol. 2018;14(7):421–32. doi:10.1038/s41584-018-0021-9.

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