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Review

An update on the pharmacotherapeutic options and treatment strategies for systemic sclerosis

&
Pages 2041-2056 | Received 01 Apr 2020, Accepted 06 Jul 2020, Published online: 17 Jul 2020

References

  • Fernández-Codina A, Walker KM, Pope JE, et al. Treatment algorithms for systemic sclerosis according to experts. Arthritis Rheumatol. 2018 Nov;70(11):1820–1828.
  • Volkmann ER, Varga J. Emerging targets of disease-modifying therapy for systemic sclerosis. Nat Rev Rheumatol. 2019 Apr;15(4):208–224.
  • Zhang YDJ. Therapeutic molecular targets of SSc-ILD. J Scleroderma Related Disord. 2020;5(25):17–30.
  • Peoples C, Medsger TA Jr., Lucas M, et al. Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes. J Scleroderma Relat Disord. 2016 May-Aug;1(2):177–240.
  • Steen VD. The many faces of scleroderma. Rheum Dis Clin North Am. 2008 Feb;34(1):1–15;v.
  • Sierra-Sepulveda A, Esquinca-Gonzalez A, Benavides-Suarez SA, et al. Systemic sclerosis pathogenesis and emerging therapies, beyond the fibroblast. Biomed Res Int. 2019;2019:4569826.
  • Volkmann ER, Furst DE. Management of systemic sclerosis-related skin disease: a review of existing and experimental therapeutic approaches. Rheum Dis Clin North Am. 2015 Aug;41(3):399–417.
  • Medsger TA Jr. Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being. Rheum Dis Clin North Am. 2003 May;29(2):255–73, vi.
  • Sultan N, Pope JE, Clements PJ. Scleroderma trials study G. The health assessment questionnaire (HAQ) is strongly predictive of good outcome in early diffuse scleroderma: results from an analysis of two randomized controlled trials in early diffuse scleroderma. Rheumatology (Oxford). 2004 Apr;43(4):472–478.
  • Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun 22;354(25):2655–2666.
  • Khanna D, Furst DE, Clements PJ, et al. Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. J Scleroderma Relat Disord. 2017 Jan-Apr;2(1):11–18.
  • Tashkin DP, Roth MD, Clements PJ, et al. 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 Sep 4;4(9):708–719.
  • Namas R, Tashkin DP, Furst DE, et al. Efficacy of mycophenolate mofetil and oral cyclophosphamide on skin thickness: post hoc analyses from two randomized placebo-controlled trials. Arthritis Care Res (Hoboken). 2018 Mar;70(3):439–444.
  • Volkmann ER, Tashkin DP, Li N, 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 Jul;69(7):1451–1460.
  • Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017 Aug;76(8):1327–1339.
  • 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 Jun 25;311(24):2490–2498.
  • Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018 Jan 4;378(1):35–47.
  • Khanna D, Denton CP, Lin CJF, 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 Feb;77(2):212–220.
  • Khanna D, Spino C, Johnson S, et al. Abatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial. Arthritis Rheumatol. 2020 Jan;72(1):125–136.
  • Gonzalez EG, Selvi E, Balistreri E, et al. Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis. Ann Rheum Dis. 2012 Sep;71(9):1545–1551. .
  • Spiera R, Hummers L, Chung L, et al. Safety and efficacy of lenabasum (JBT-101) in diffuse cutaneous systemic sclerosis subjects treated for one year in an open-label extension of trial JBT101-SSC-001. EULAR Annual Meeting (Amsterdam, Netherlands); 2018.
  • Khanna D, Berrocal VJ, Giannini EH, et al. The American college of rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 2016 Feb;68(2):299–311.
  • R Dn S, Bloom B, White B, et al. Baseline subject demographics and disease characteristics in a phase 3 study of safety and efficacy of lenabasum in diffuse cutaneous systemic sclerosis. Atlanta GA: ACR Annual Meeting; 2019.
  • Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: the LOTUSS trial. J Rheumatol. 2016 Sep;43(9):1672–1679.
  • Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019 Jun 27;380(26):2518–2528.
  • Sircar G, Goswami RP, Sircar D, et al. Intravenous cyclophosphamide vs rituximab for the treatment of early diffuse scleroderma lung disease: open label, randomized, controlled trial. Rheumatology (Oxford). 2018 Dec;57(12):2106–2113.
  • Daoussis D, Melissaropoulos K, Sakellaropoulos G, 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 Apr;46(5):625–631. .
  • 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 Jan;69(1):193–197.
  • 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 Jun;74(6):1188–1194.
  • Fraticelli P, Fischetti C, Salaffi F, et al. Combination therapy with rituximab and mycophenolate mofetil in systemic sclerosis. A single-centre case series study. Clin Exp Rheumatol. 2018 Jul-Aug;36(Suppl 113(4)):142–145.
  • Steele R, Hudson M, Lo E, et al. Clinical decision rule to predict the presence of interstitial lung disease in systemic sclerosis. Arthritis Care Res (Hoboken). 2012 Apr;64(4):519–524.
  • Sanchez-Cano D, Ortego-Centeno N, Callejas JL, et al. Interstitial lung disease in systemic sclerosis: data from the spanish scleroderma study group. Rheumatol Int. 2018 Mar;38(3):363–374.
  • Steen VD, Conte C, Owens GR, et al. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. 1994 Sep;37(9):1283–1289.
  • Tyndall AJ, Bannert B, Vonk M, 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):1809–1815. .
  • Volkmann ER, Tashkin DP, Kuwana M, et al. Progression of Interstitial Lung Disease in Systemic Sclerosis: the Importance of Pneumoproteins Krebs von den Lungen 6 and CCL18. Arthritis Rheumatol. 2019 Dec;71(12):2059–2067. .
  • Fischer A, Strek ME, Cottin V, et al. Proceedings of the American College of Rheumatology/Association of Physicians of Great Britain and Ireland connective tissue disease-associated interstitial lung disease summit: a multidisciplinary approach to address challenges and opportunities. Arthritis Rheumatol. 2019 Feb;71(2):182–195. .
  • Goldin JG, Kim GHJ, Tseng CH, et al. Longitudinal changes in quantitative interstitial lung disease on computed tomography after immunosuppression in the scleroderma lung study II. Ann Am Thorac Soc. 2018 Nov;15(11):1286–1295.
  • Khanna D, Yan X, Tashkin DP, et al. Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lung disease: results from the scleroderma lung study. Arthritis Rheum. 2007 May;56(5):1676–1684.
  • Tashkin DP, Elashoff R, Clements PJ, et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med. 2007 Nov 15;176(10):1026–1034.
  • Volkmann ER, Tashkin DP, Sim M, et al. Cyclophosphamide for systemic sclerosis-related interstitial lung disease: a comparison of scleroderma lung study I and II. J Rheumatol. 2019 Oct;46(10):1316–1325.
  • VolkmannER, TashkinD. Roth M, LeClair H, et al. Mycophenolate mofetil and cyclophosphamide improve health-related quality of life in patients with systemic sclerosis who participated in SLS II. Arthritis Rheumatol. 2019;71(suppl 10).
  • 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 Jun 25;387(10038):2630–2640.
  • D Lc K, Kuwana M, Allanore Y, et al. Efficacy and safety of tocilizumab for the treatment of systemic sclerosis: results from a phase 3 randomized controlled trial. Arthritis Rheumatol. 2018;70(suppl 10).
  • 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 Feb;49(2):271–280.
  • Saunders P, Tsipouri V, Keir GJ, et al. Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial. Trials. 2017 Jun 15;18(1):275.
  • Wigley FM, Flavahan NA. Raynaud’s Phenomenon. N Engl J Med. 2016 Aug 11;375(6):556–565.
  • Nihtyanova SI, Brough GM, Black CM, et al. Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2008 Jan;67(1):120–123.
  • Roustit M, Giai J, Gaget O, et al. On-demand sildenafil as a treatment for Raynaud phenomenon: a series of n-of-1 trials. Ann Intern Med. 2018 Nov;169(10):694–703.
  • Roustit M, Blaise S, Allanore Y, et al. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: systematic review and meta-analysis of randomised trials. Ann Rheum Dis. 2013 Oct;72(10):1696–1699.
  • Andrigueti FV, Ebbing PCC, Arismendi MI, et al. Evaluation of the effect of sildenafil on the microvascular blood flow in patients with systemic sclerosis: a randomised, double-blind, placebo-controlled study. Clin Exp Rheumatol. 2017 Sep-Oct;35(Suppl 106(4)):151–158.
  • Hachulla E, Hatron PY, Carpentier P, et al. Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study. Ann Rheum Dis. 2016 Jun;75(6):1009–1015.
  • Schiopu E, Hsu VM, Impens AJ, et al. Randomized placebo-controlled crossover trial of tadalafil in Raynaud’s phenomenon secondary to systemic sclerosis. J Rheumatol. 2009 Oct;36(10):2264–2268.
  • Shenoy PD, Kumar S, Jha LK, et al. Efficacy of tadalafil in secondary Raynaud’s phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial. Rheumatology (Oxford). 2010 Dec;49(12):2420–2428.
  • Wigley FM, Seibold JR, Wise RA, et al. Intravenous iloprost treatment of Raynaud’s phenomenon and ischemic ulcers secondary to systemic sclerosis. J Rheumatol. 1992 Sep;19(9):1407–1414.
  • Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med. 1994 Feb 1;120(3):199–206.
  • McHugh NJ, Csuka M, Watson H, et al. Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud’s phenomenon in systemic sclerosis. Ann Rheum Dis. 1988 Jan;47(1):43–47.
  • Milio G, Corrado E, Genova C, et al. Iloprost treatment in patients with Raynaud’s phenomenon secondary to systemic sclerosis and the quality of life: a new therapeutic protocol. Rheumatology (Oxford). 2006 Aug;45(8):999–1004.
  • Shah AA, Schiopu E, Hummers LK, et al. Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion. Arthritis Res Ther. 2013 Apr;15(2):R54.
  • Shah AA, Schiopu E, Chatterjee S, et al. The recurrence of digital ulcers in patients with systemic sclerosis after discontinuation of oral treprostinil. J Rheumatol. 2016 Sep;43(9):1665–1671.
  • Mecoli CA, Perin J, Van Eyk JE, et al. Vascular biomarkers and digital ulcerations in systemic sclerosis: results from a randomized controlled trial of oral treprostinil (DISTOL-1). Clin Rheumatol. 2020 Apr;39(4):1199–1205.
  • Gaillard-Bigot F, Roustit M, Blaise S, et al. Treprostinil iontophoresis improves digital blood flow during local cooling in systemic sclerosis. Microcirculation. 2016 Apr;23(3):266–270.
  • Guigui A, Mazet R, Blaise S, et al. Treprostinil hydrogel iontophoresis in systemic sclerosis-related digital skin ulcers: a safety study. J Clin Pharmacol. 2020 Feb;60:758–767.
  • Matucci-Cerinic M, Denton CP, Furst DE, 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. 2011 Jan;70(1):32–38.
  • Khanna D, Denton CP, Merkel PA, et al. Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: DUAL-1 and DUAL-2 randomized clinical trials. JAMA. 2016 May 10;315(18):1975–1988.
  • Curtiss P, Schwager Z, Cobos G, et al. A systematic review and meta-analysis of the effects of topical nitrates in the treatment of primary and secondary Raynaud’s phenomenon. J Am Acad Dermatol. 2018 Jun;78(6):1110–18 e3.
  • Segreto F, Marangi GF, Cerbone V, et al. The role of botulinum toxin a in the treatment of Raynaud phenomenon. Ann Plast Surg. 2016 Sep;77(3):318–323.
  • Bello RJ, Cooney CM, Melamed E, et al. The therapeutic efficacy of botulinum toxin in treating scleroderma-associated Raynaud’s phenomenon: a randomized, double-blind, placebo-controlled clinical trial. Arthritis Rheumatol. 2017 Aug;69(8):1661–1669.
  • Nagaraja V, Spino C, Bush E, et al. A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers. Arthritis Res Ther. 2019 Sep;21(1):202.
  • R Lm D, Goundappa B, Medsger T, et al. The effect of atorvastatin on microvascular endothelial function and Raynaud phenomenon in early diffuse scleroderma: results of the “tamer”‘ study. Arthritis Rheumatol. 2019;71(suppl 10).
  • Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis. 2003 Nov;62(11):1088–1093.
  • Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 19722002. Ann Rheum Dis. 2007 Jul;66(7):940–944.
  • Chung L, Farber HW, Benza R, et al. Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest. 2014 Dec;146(6):1494–1504.
  • Fisher MR, Mathai SC, Champion HC, et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum. 2006 Sep;54(9):3043–3050.
  • Mullin CJ, Mathai SC. New insights into the recognition, classification and management of systemic sclerosis-associated pulmonary hypertension. Curr Opin Rheumatol. 2017 Nov;29(6):561–567.
  • Lammi MR, Mathai SC, Saketkoo LA, et al. Association between initial oral therapy and outcomes in systemic sclerosis-related pulmonary arterial hypertension. Arthritis Rheumatol. 2016 Mar;68(3):740–748. .
  • Hassoun PM, Zamanian RT, Damico R, et al. Ambrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015 Nov 1;192(9):1102–1110.
  • Dwivedi PSS, Dhir V, Rohit MK, et al. A randomized double blind placebo controlled trial to compare the efficacy of initial combination therapy vs monotherapy for pulmonary arterial hypertension in systemic sclerosis. Ann Rheum Dis. 2018;77:1531.
  • Herve P, Lau EM, Sitbon O, et al. Criteria for diagnosis of exercise pulmonary hypertension. Eur Respir J. 2015 Sep;46(3):728–737.
  • Stamm A, Saxer S, Lichtblau M, et al. Exercise pulmonary haemodynamics predict outcome in patients with systemic sclerosis. Eur Respir J. 2016 Dec;48(6):1658–1667.
  • Yang S, Wu J, Lei S, et al. Abnormal pulmonary artery systolic pressure response after exercise in systemic sclerosis patients: A PRISMA-compliant meta-analysis. Medicine (Baltimore). 2019 Feb;98(6):e14342.
  • Saggar R, Khanna D, Shapiro S, et al. Brief report: effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: a prospective single-center, open-label pilot study. Arthritis Rheum. 2012 Dec;64(12):4072–4077.
  • Humbert M, Coghlan JG, Ghofrani HA, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017 Feb;76(2):422–426.
  • Gaine S, Chin K, Coghlan G, et al. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. Eur Respir J. 2017 Aug;50:2.
  • Catania MV, Sortino MA, Rampello L, et al. Adenosine deaminase increases release of excitatory amino acids through a mechanism independent of adenosine depletion. Neuropharmacology. 1991 Feb;30(2):153–159.
  • Frech TM, Khanna D, Maranian P, et al. Probiotics for the treatment of systemic sclerosis-associated gastrointestinal bloating/distention. Clin Exp Rheumatol. 2011 Mar-Apr;29(2 Suppl 65):S22–5.
  • Marighela TF, Arismendi MI, Marvulle V, et al. Effect of probiotics on gastrointestinal symptoms and immune parameters in systemic sclerosis: a randomized placebo-controlled trial. Rheumatology (Oxford). 2019 Nov 1;58(11):1985–1990.
  • Garcia-Collinot G, Madrigal-Santillan EO, Martinez-Bencomo MA, et al. Effectiveness of saccharomyces boulardii and metronidazole for small intestinal bacterial overgrowth in systemic sclerosis. Dig Dis Sci. 2020 Apr;65(4):1134–1143.
  • Karamanolis GP, Panopoulos S, Denaxas K, et al. The 5-HT1A receptor agonist buspirone improves esophageal motor function and symptoms in systemic sclerosis: a 4-week, open-label trial. Arthritis Res Ther. 2016 Sep 1;18:195.
  • Bharadwaj S, Tandon P, Gohel T, et al. Gastrointestinal manifestations, malnutrition, and role of enteral and parenteral nutrition in patients with scleroderma. J Clin Gastroenterol. 2015 Aug;49(7):559–564.
  • Baron M, Bernier P, Côté LF, et al. Screening and therapy for malnutrition and related gastro-intestinal disorders in systemic sclerosis: recommendations of a North American expert panel. Clin Exp Rheumatol. 2010 Mar-Apr;28(2 Suppl 58):S42–6.
  • Stratton RJ, Hackston A, Longmore D, et al. Malnutrition in hospital outpatients and inpatients: prevalence, concurrent validity and ease of use of the ‘malnutrition universal screening tool’ (‘MUST’) for adults. Br J Nutr. 2004 Nov;92(5):799–808.

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