Emerging drugs for the treatment of scleroderma: a review of recent phase 2 and 3 trials

References

• Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24(2):165–170.
   PubMed Web of Science ®Google Scholar
• Mayes MD, Lacey JV, Beebe-Dimmer J, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48(8):2246–2255.
   PubMedGoogle Scholar
• Hoffmann-Vold AM, Midtvedt Ø, Molberg Ø, et al. Prevalence of systemic sclerosis in south-east Norway. Rheumatol (United Kingdom). 2012;51(9):1600–1605.
   PubMed Web of Science ®Google Scholar
• Nashid M, Khanna PP, Furst DE, et al. Gender and ethnicity differences in patients with diffuse systemic sclerosis-analysis from three large randomized clinical trials. Rheumatology. 2011;50(2):335–342.
   PubMed Web of Science ®Google Scholar
• Moore DF, Steen VD. Racial disparities in systemic sclerosis. Rheum Dis Clin North Am. 2020;46(4):705-712.
   PubMed Web of Science ®Google Scholar
• Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685–1699.
   PubMed Web of Science ®Google Scholar
• Allanore Y, Simms R, Distler O, et al. Systemic sclerosis. Nat Rev. 2015;1(April):1–21.
   Google Scholar
• LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–205.
   PubMed Web of Science ®Google Scholar
• Winthrop KL, Strand V, van der Heijde D, et al. The unmet need in rheumatology: reports from the targeted therapies meeting 2017. Clin Immunol. 2018;186:87–93.
   PubMed Web of Science ®Google Scholar
• Winthrop KL, Weinblatt ME, Crow MK, et al. Unmet need in rheumatology: reports from the targeted therapies meeting 2018. Ann Rheum Dis. 2019;78(7):872–878.
   PubMed Web of Science ®Google Scholar
• Winthrop KL, Weinblatt ME, Bathon J, et al. Unmet need in rheumatology: reports from the targeted therapies meeting 2019. Ann Rheum Dis. 2020;79(1):88–93.
   PubMed Web of Science ®Google Scholar
• Smith V, Scirè CA, Talarico R, et al. Systemic sclerosis: state of the art on clinical practice guidelines. RMD Open. 2018;4:1–9.
   Web of Science ®Google Scholar
• Garen T, Lerang K, Hoffmann-Vold AM, et al. Mortality and causes of death across the systemic connective tissue diseases and the primary systemic vasculitides. Rheumatol (United Kingdom). 2019;58(2):313–320.
   PubMed Web of Science ®Google Scholar
• Nagaraja V, Matucci-Cerinic M, Furst DE, et al. Current and future Outlook on disease modification and defining low disease activity in systemic sclerosis. Arthritis Rheumatol. 2020;72(7):1049–1058.
   PubMed Web of Science ®Google Scholar
• Bruni C, Praino E, Allanore Y, et al. Use of biologics and other novel therapies for the treatment of systemic sclerosis. Expert Rev Clin Immunol. 2017 May;13(5):469–482.
   PubMed Web of Science ®Google Scholar
• 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;70(1):32–38.
   PubMed Web of Science ®Google Scholar
• Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004;50(12):3985–3993.
   PubMed Web of Science ®Google Scholar
• 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;75(6):1009–1015.
   PubMed Web of Science ®Google Scholar
• Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834–844.
   PubMed Web of Science ®Google Scholar
• Coons JC, Pogue K, Kolodziej AR, et al. Pulmonary arterial hypertension: a pharmacotherapeutic update. Curr Cardiol Rep. 2019;21(11):141.
   PubMed Web of Science ®Google Scholar
• Nicolls M, Badesch D, Chung L, et al. Safety and E cacy of B-cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension in a multi-center NIH clinical trial. 2019;;71(suppl 10).
   Google Scholar
• Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis. 2007;66(7):940–944.
   PubMed Web of Science ®Google Scholar
• Denton CP. Challenges in systemic sclerosis trial design. Semin Arthritis Rheum. 2019;49(3):S3–7.
   PubMed Web of Science ®Google Scholar
• Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655–2666.
   PubMed Web of Science ®Google Scholar
• 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;4(9):708–719.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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. J Am Med Assoc. 2014;311(24):2490–2498.
   PubMed Web of Science ®Google Scholar
• Sullivan KM, Goldmuntz EA, Keyes-Elstein PA, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378(1):35–47.
   PubMed Web of Science ®Google Scholar
• Walker UA, Saketkoo LA, Distler O. Haematopoietic stem cell transplantation in systemic sclerosis. RMD Open. 2018;4(1):1–7.
   Web of Science ®Google Scholar
• 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;68(2):299–311.
   PubMed Web of Science ®Google Scholar
• Varga J, Abraham D. Systemic sclerosis: A prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117(3):557–567.
   PubMed Web of Science ®Google Scholar
• Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65(8):1953–1962.
   PubMed Web of Science ®Google Scholar
• Lescoat A, Lelong M, Jeljeli M, et al. Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages in vitro and in vivo: perspectives for scleroderma-associated interstitial lung disease. Biochem Pharmacol. 2020;178:114103.
   Web of Science ®Google Scholar
• Allanore Y, Simms R, Distler O, et al. Systemic sclerosis. Nat Rev Dis Prim. 2015;1(April):1–21.
   Google Scholar
• Skaug B, Khanna D, Swindell WR, et al. Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile. Ann Rheum Dis. 2019;79(3):379–386.
   PubMedGoogle Scholar
• Eckes B, Zweers MC, Zhang ZG, et al. Mechanical tension and integrin α2β1 regulate fibroblast functions. J Investig Dermatology Symp Proc. 2006;11(1):66–72.
   PubMedGoogle Scholar
• Shi-Wen X, Thompson K, Khan K, et al. Focal adhesion kinase and reactive oxygen species contribute to the persistent fibrotic phenotype of lesional scleroderma fibroblasts. Rheumatol (United Kingdom). 2012;51(12):2146–2154.
   PubMed Web of Science ®Google Scholar
• Van der Slot AJ, Zuurmond AM, Bardoel AFJ, et al. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J Biol Chem. 2003;278(42):40967–40972.
   PubMed Web of Science ®Google Scholar
• Spadoni T, Svegliati Baroni S, Amico D, et al. A reactive oxygen species-mediated loop maintains increased expression of NADPH oxidases 2 and 4 in skin fibroblasts from patients with systemic sclerosis. Arthritis Rheumatol. 2015;67(6):1611–1622.
   PubMed Web of Science ®Google Scholar
• Volkmann ER, Varga J. Emerging targets of disease-modifying therapy for systemic sclerosis. Nat Rev Rheumatol. 2019;15(4):208–224.
   PubMed Web of Science ®Google Scholar
• Chung MP, Chung L. Drugs in phase I and phase II clinical trials for systemic sclerosis. Expert Opin Investig Drugs. 2020;29(4):349–362.
   PubMed Web of Science ®Google Scholar
• Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–1727.
   PubMed Web of Science ®Google Scholar
• Prescott RJ, Freemont AJ, Jones CJ, et al. Sequential dermal micro- vascular and perivascular changes in the development of scleroderma. J Pathol. 1992;166:255–263.
   PubMed Web of Science ®Google Scholar
• Roumm AD, Whiteside TL, Medsger TA Jr, et al. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984;27:645–653.
   PubMed Web of Science ®Google Scholar
• Maehara T, Kaneko N, Perugino CA, et al. Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis. J Clin Invest. 2020 May;130(5):2451–2464.
   PubMed Web of Science ®Google Scholar
• Ponsoye M, Frantz C, Ruzehaji N, et al. Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation- driven fibrosis. Ann Rheum Dis. 2016;75:2142–2149.
   PubMed Web of Science ®Google Scholar
• Khanna D, Spino C, Johnson SR, 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. 2019;72(1):125–136.
   PubMed Web of Science ®Google Scholar
• Franks JM, Martyanov V, Cai G, et al. A machine learning classifier for assigning individual patients with systemic sclerosis to intrinsic molecular subsets. Arthritis Rheumatol. 2019;71(10):1701–1710.
   PubMed Web of Science ®Google Scholar
• Chakravarty EF, Martyanov V, Fiorentino D, et al. 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(1):159.
   PubMed Web of Science ®Google Scholar
• Hinchcliff ME, Huang -C-C, Wood TA, et al. Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis. J Invest Dermatol. 2013;133(8):1979–1989.
   PubMed Web of Science ®Google Scholar
• Boleto G, Allanore Y, Avouac J. Targeting costimulatory pathways in systemic sclerosis. Front Immunol. 2018;9(December):2998.
   PubMedGoogle Scholar
• Mehta B, Franks J, Yuan Y, et al. Machine-learning classi cation identi es a subset of patients that improve on abatacept via modulation of a CD28-related pathway. Arthritis Rheumatol. 2019;71(Suppl 10):1–3.
   Google Scholar
• Chung L, Spino C, McLain R, et al. Safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis: results from the open-label extension of a phase II investigator-initiated randomized controlled trial. Lancet Rheumatol. 2020. In Press.
   PubMedGoogle Scholar
• Pope JE. The future of treatment in systemic sclerosis: can we design better trials? Lancet Rheumatol. 2020;2(3):185.
   Google Scholar
• Matei AE, Beyer C, Györfi AH, et al. Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators. Ann Rheum Dis. 2018;77(3):459.
   PubMed Web of Science ®Google Scholar
• Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330–340.
   PubMed Web of Science ®Google Scholar
• Dees C, Beyer C, Distler A, et al. Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies. Ann Rheum Dis. 2015;74(8):1621–1625.
   PubMed Web of Science ®Google Scholar
• Beyer C, Zenzmaier C, Palumbo-Zerr K, et al. Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling. Ann Rheum Dis. 2015;74(7):1408–1416.
   PubMed Web of Science ®Google Scholar
• Beyer C, Reich N, Schindler SC, et al. Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Ann Rheum Dis. 2012;71(6):1019–1026.
   PubMed Web of Science ®Google Scholar
• Sandner P, Stasch JP. Anti-fibrotic effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence. Respir Med. 2017;122:S1–9.
   PubMed Web of Science ®Google Scholar
• Khanna D, Allanore Y, Denton CP, et al. Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial. Ann Rheum Dis. 2020;79(5):618–625.
   PubMed Web of Science ®Google Scholar
• Distler O, Kramer F, Höfler J, et al. Biomarker analysis from the RISE-SSc study of riociguat in early diffuse cutaneous systemic sclerosis (dcSSc). Ann Rheum Dis. 2020;79(1):886.
   Google Scholar
• Khanna D, Pope JE, Matucci-Cerinic M, et al. Long-term extension results of RISE-SSC, a randomized trial of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc). Ann Rheum Dis. 2020;79(1):156.
   Google Scholar
• Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76(8):1327–1339.
   PubMed Web of Science ®Google Scholar
• Huang J, Maier C, Zhang Y, et al. Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum Dis. 2017;76(11):1941–1948.
   PubMed Web of Science ®Google Scholar
• Wollin L, Distler JHW, Redente EF, et al. Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases. Eur Respir J. 2019;54(3):1900161.
   PubMed Web of Science ®Google Scholar
• Bournia VK, Mitsikostas D, Distler O, et al. The nocebo phenomenon partly accounts for diarrhea among participant sin the randomized placebo-controlled trial of nintedanib for interstitial lung disease associated with systemic sclerosis (SENSCIS). Ann Rheum Dis. 2020;79(1):1569.
   Google Scholar
• Distler O, Highland KB, Hoffmann-Vold A-M, et al. Correlation between progression of skin fibrosis and progression of interstitial lung disease (ILD) in patients with SSc-ILD: data from the SENSCIS trial. Ann Rheum Dis. 2020;79(1):1097.
   Google Scholar
• Allanore Y, Steen VD, Kuwana M, et al. Effects of nintedanib in patients with systemic sclerosis-associated ILD (SSc-ILD) and differing extents of skin fibrosis: further analyses of the SENSCIS trial. Ann Rheum Dis. 2020;79(1):391.
   Google Scholar
• Riemekasten G, Carreira P, Saketkoo LA, et al. Effects of nintedanib in patients with systemic sclerosis-associated ILD (SSc-ILD) and normal versus elevated C-reactive protein (CRP) at baseline: analyses from the SENSCIS trial. Ann Rheum Dis. 2020;79(1):409.
   Google Scholar
• Volkmann ER, Vettori S, Varga J, et al. Is there a difference between the sexes in the rate of progression of systemic sclerosis-associated ILD (SSc-ILD)? Date from the SENSCIS trial. Ann Rheum Dis. 2020;79(1):1114.
   Google Scholar
• Kafaja S, Clements PJ, Wilhalme H, et al. Reliability and minimal clinically important differences of forced vital capacity: results from the Scleroderma Lung Studies (SLS-I and SLS-II). Am J Respir Crit Care Med. 2018;197(5):PG-644–652):644–52.
   PubMed Web of Science ®Google Scholar
• Allanore Y, Khanna D, Volkmann E, et al. Improvement and stabilization of lung function in patients with SSc-ILD treated with nintedanib vs placebo in a randomized, placebo-controlled phase III Trial: proportions of patients with FVC changes using cutoffs previously proposed to define minimally. Arthritis Rheumatol. 2019;71(suppl 10):1–3.
   Google Scholar
• Roofeh D, Distler O, Allanore Y, et al. Treatment of systemic sclerosis– associated interstitial lung disease: lessons from clinical trials. J Scleroderma Relat Disord. 2020 Mar 5;5(2S):61–71.
   PubMedGoogle Scholar
• Desallais L, Avouac J, Fréchet M, et al. Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis. Arthritis Res Ther. 2014;16(4):1–12.
   Web of Science ®Google Scholar
• 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(10038):2630–2640.
   PubMed Web of Science ®Google Scholar
• 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;77(2):PG-212–220):212–20.
   Web of Science ®Google Scholar
• Denton CP, Ong VH, Xu S, et al. Therapeutic interleukin-6 blockade reverses transforming growth factor-beta pathway activation in dermal fibroblasts: insights from the faSScinate clinical trial in systemic sclerosis. Ann Rheum Dis. 2018;77(9):1362–1371.
   PubMed Web of Science ®Google Scholar
• Khanna D, Lin CJF, Furst DE, et al. A randomised placebo-controlled phase 3 trial of tocilizumab in systemic sclerosis. Lancet Respir Med. 2020;8(10):963-974.
   PubMedGoogle Scholar
• Hoyles RK, Ellis RW, Wellsbury J, 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(12PG–3962–70):3962–3970.
   PubMedGoogle Scholar
• Khanna D, Lin CJF, Spotswood H, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of the phase 3 focuSSced trial. Ann Rheum Dis. 2020;79(1):390.
   Google Scholar
• Lepri G, Hughes M, Bruni C, et al. Recent advances steer the future of systemic sclerosis toward precision medicine. Clin Rheumatol. 2020;39(1):1–4.
   PubMed Web of Science ®Google Scholar
• Skaug B, Assassi S. Biomarkers in systemic sclerosis. Curr Opin Rheumatol. 2019;31(6):595–602.
   PubMed Web of Science ®Google Scholar
• Wermuth PJ, Piera-Velazquez S, Rosenbloom J, et al. Existing and novel biomarkers for precision medicine in systemic sclerosis. Nat Rev Rheumatol. 2018;14(7):421–432.
   PubMed Web of Science ®Google Scholar
• Taroni JN, Greene CS, Martyanov V, et al. A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Med. 2017;9(1):1–24.
   PubMedGoogle Scholar
• Bhandari R, Ball MS, Martyanov V, et al. Profibrotic activation of human macrophages in systemic sclerosis. Arthritis Rheumatol. 2020;72(7):1160-1169.
   PubMed Web of Science ®Google Scholar
• Mahoney JM, Taroni J, Martyanov V, et al. Systems level analysis of systemic sclerosis shows a network of immune and profibrotic pathways connected with genetic polymorphisms. PLoS Comput Biol. 2015;11(1):e1004005.
   PubMed Web of Science ®Google Scholar
• Muraille E, Leo O, Moser M. Th1/Th2 paradigm extended: macrophage polarization as an unappreciated pathogen-driven escape mechanism? Front Immunol. 2014;5(NOV):1–12.
   PubMedGoogle Scholar
• Allanore Y, Wung P, Soubrane C, et al. A randomised, double- blind, placebo- controlled, 24- week, phase II, proof- of- concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2020; Epub ahead. DOI: 10.1136/annrheumdis-2020-218447.
   Google Scholar
• Lünemann JD, Nimmerjahn F, Dalakas MC. Intravenous immunoglobulin in neurology-mode of action and clinical efficacy. Nat Rev Neurol. 2015;11(2):80–89.
   PubMed Web of Science ®Google Scholar
• Kajii M, Suzuki C, Kashihara J, et al. Prevention of excessive collagen accumulation by human intravenous immunoglobulin treatment in a murine model of bleomycin-induced scleroderma. Clin Exp Immunol. 2011;163(2):235–241.
   PubMed Web of Science ®Google Scholar
• Sanges S, Rivière S, Mekinian A, et al. Intravenous immunoglobulins in systemic sclerosis: data from a French nationwide cohort of 46 patients and review of the literature. Autoimmun Rev. 2017;16(4):377–384.
   PubMed Web of Science ®Google Scholar
• Conte E, Gili E, Fagone E, et al. Effect of pirfenidone on proliferation, TGF-β-induced myofibroblast differentiation and fibrogenic activity of primary human lung fibroblasts. Eur J Pharm Sci. 2014;58(1):13–19.
   PubMedGoogle Scholar
• Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest. 2015;125(7):2795–2807.
   PubMed Web of Science ®Google Scholar
• Lafyatis RA, Spiera RF, Domsic RT, et al. Safety, target engagement, and initial efficacy of AVID200, a first-in-class potent and isoform-selective inhibitor of TGF-beta 1 and 3, in patients with diffuse cutaneous systemic sclerosis (dcSSc): a phase 1 dose escalation study. Ann Rheum Dis. 2020;79(1):390.
   Google Scholar
• Kokot A, Sindrilaru A, Schiller M, et al. α-melanocyte-stimulating hormone suppresses bleomycin-induced collagen synthesis and reduces tissue fibrosis in a mouse model of scleroderma: melanocortin peptides as a novel treatment strategy for scleroderma? Arthritis Rheum. 2009;60(2):592–603.
   PubMedGoogle Scholar
• Chakraborty D, Šumová B, Mallano T, et al. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nat Commun. 2017;8(1):1130.
   Google Scholar
• Pedroza M, Le TT, Lewis K, et al. STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. Faseb J. 2016;30(1):129–140.
   PubMed Web of Science ®Google Scholar
• Dees C, Tomcik M, Palumbo-Zerr K, et al. JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis. Arthritis Rheum. 2012;64(9):3006–3015.
   PubMedGoogle Scholar
• Wang W, Bhattacharyya S, Marangoni RG, et al. The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib. J Scleroderma Relat Disord. 2020;;5(1):40-50.
   Google Scholar
• Khanna D, Bush E, Nagaraja V, et al. Tofacitinib in early diffuse cutaneous systemic sclerosis— results of phase I/II investigator-initiated, double-blind randomized placebo-controlled trial [abstract]. Arthritis Rheumatol. 2019;71(suppl 10).
   Google Scholar
• Morimoto K, Janssen WJ, Fessler MB, et al. Lovastatin enhances clearance of apoptotic cells (Efferocytosis) with implications for chronic obstructive pulmonary disease. J Immunol. 2006;176(12):7657–7665.
   PubMed Web of Science ®Google Scholar
• Allanore Y, Distler O, Jagerschmidt A, et al. Lysophosphatidic acid receptor 1 antagonist SAR100842 for patients with diffuse cutaneous systemic sclerosis: a double-blind, randomized, eight-week placebo-controlled study followed by a sixteen-week open-label extension study. Arthritis Rheumatol. 2018;70(10):1634–1643.
   PubMed Web of Science ®Google Scholar
• Castelino FV, Bain G, Pace VA, et al. An autotaxin/lysophosphatidic acid/interleukin-6 amplification loop drives scleroderma fibrosis. Arthritis Rheumatol. 2016;68(12):2964–2974.
   PubMed Web of Science ®Google Scholar
• Bernstein EJ, Khanna D, Lederer DJ. Screening high-resolution Computed tomography of the chest to detect interstitial lung disease in systemic sclerosis: a global survey of rheumatologists. Arthritis Rheumatol. 2018;70(6):971–972.
   PubMed Web of Science ®Google Scholar