New promising drugs for the treatment of systemic sclerosis: pathogenic considerations, enhanced classifications, and personalized medicine

References

• Allanore Y, Simms R, Distler O, et al. Systemic sclerosis. Nat Rev Dis Primers. 2015;1:15002.
   PubMed Web of Science ®Google Scholar
• Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557–567.
   PubMed Web of Science ®Google Scholar
• Hughes M, Allanore Y, Chung L, et al. Raynaud phenomenon and digital ulcers in systemic sclerosis. Nat Rev Rheumatol. 2020;16:208–221.
   PubMed Web of Science ®Google Scholar
• Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390:1685–1699.
   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;380:2518–2528.
   PubMed Web of Science ®Google Scholar
• Wollin L, Distler JH, Denton CP, et al. Rationale for the evaluation of nintedanib as a treatment for systemic sclerosis–associated interstitial lung disease. J Scleroderma Relat Disord. 2019;4:212–218.
   Web of Science ®Google Scholar
• Kuwana M, Distler O. Recent progress and missing gaps to achieve goal in the care of systemic sclerosis–associated interstitial lung disease. J Scleroderma Relat Disord. 2020;5:3–5.
   Web of Science ®Google Scholar
• Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65:1953–1962.
   PubMed Web of Science ®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. 2020;79:379–386.
   PubMed Web of Science ®Google 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;8:1130.
   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;130:2451–2464.
   PubMed Web of Science ®Google Scholar
• Fox DA, Lundy SK, Whitfield ML, et al. Lymphocyte subset abnormalities in early diffuse cutaneous systemic sclerosis. Arthritis Res Ther. 2021;23:10.
   PubMed Web of Science ®Google Scholar
• Stifano G, Christmann RB. Macrophage involvement in systemic sclerosis: do we need more evidence? Curr Rheumatol Rep. 2016;18:2.
   PubMed Web of Science ®Google Scholar
• Murray PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.
   PubMed Web of Science ®Google Scholar
• Lescoat A, Ballerie A, Jouneau S, et al. M1/M2 polarisation state of M-CSF blood-derived macrophages in systemic sclerosis. Ann Rheum Dis. 2019;78:e127.
   PubMedGoogle Scholar
• Lescoat A, Jégo P, Lecureur V. M-CSF and GM-CSF monocyte-derived macrophages in systemic sclerosis: the two sides of the same coin? Ann Rheum Dis. 2019;78:e19.
   PubMed Web of Science ®Google Scholar
• Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–969.
   PubMed Web of Science ®Google Scholar
• Mauer J, Chaurasia B, Goldau J, et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol. 2014;15:423–430.
   PubMed Web of Science ®Google Scholar
• Christmann RB, Sampaio-Barros P, Stifano G, et al. Association of Interferon- and transforming growth factor β-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol (Hoboken). 2014;66:714–725.
   PubMed Web of Science ®Google Scholar
• Jun J-I, Lau LF. Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov. 2011;10:945–963.
   PubMed Web of Science ®Google Scholar
• Tam AYY, Horwell AL, Trinder SL, et al. Selective deletion of connective tissue growth factor attenuates experimentally -induced pulmonary fibrosis and pulmonary arterial hypertension. Int J Biochem Cell Biol. 2021;134:105961.
   PubMed Web of Science ®Google Scholar
• Murphy-Marshman H, Quensel K, Shi-Wen X, et al. Antioxidants and NOX1/NOX4 inhibition blocks TGFβ1-induced CCN2 and α-SMA expression in dermal and gingival fibroblasts. PLoS One. 2017;12:e0186740.
   PubMed Web of Science ®Google Scholar
• Walraven M, Hinz B. Therapeutic approaches to control tissue repair and fibrosis: extracellular matrix as a game changer. Matrix Biol. 2018;71–72:205–224.
   PubMed Web of Science ®Google Scholar
• Shaw TJ, Rognoni E. Dissecting fibroblast heterogeneity in health and fibrotic disease. Curr Rheumatol Rep. 2020;22:33.
   PubMed Web of Science ®Google Scholar
• Hinz B, Phan SH, Thannickal VJ, et al. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170:1807–1816.
   PubMed Web of Science ®Google Scholar
• Lafyatis R. Transforming growth factor β–at the centre of systemic sclerosis. Nat Rev Rheumatol. 2014;10:706–719.
   PubMed Web of Science ®Google Scholar
• Parapuram SK, Shi-wen X, Elliott C, et al. Loss of PTEN expression by dermal fibroblasts causes skin fibrosis. J Invest Dermatol. 2011;131:1996–2003.
   PubMed Web of Science ®Google Scholar
• Liu S, Shi-wen X, Abraham DJ, et al. CCN2 is required for bleomycin-induced skin fibrosis in mice. Arthritis Rheum. 2011;63:239–246.
   PubMed Web of Science ®Google Scholar
• Toyama T, Looney AP, Baker BM, et al. Therapeutic Targeting of TAZ and YAP by dimethyl fumarate in systemic sclerosis fibrosis. J Invest Dermatol. 2018;138:78–88.
   PubMed Web of Science ®Google Scholar
• Shi-Wen X, Racanelli M, Ali A, et al. Verteporfin inhibits the persistent fibrotic phenotype of lesional scleroderma dermal fibroblasts. J Cell Commun Signal. 2021;15:71–80.
   PubMed Web of Science ®Google Scholar
• Zhao X, Psarianos P, Ghoraie LS, et al. Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis. Nat Metab. 2019;1:147–157.
   PubMedGoogle Scholar
• Shi B, Wang W, Korman B, et al. Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis. iScience. 2021;24:101902.
   PubMed Web of Science ®Google Scholar
• Lerbs T, Cui L, King ME, et al. CD47 prevents the elimination of diseased fibroblasts in scleroderma. JCI Insight. 2020;5.
   PubMed Web of Science ®Google Scholar
• Nihtyanova SI, Denton CP. Pathogenesis of systemic sclerosis associated interstitial lung disease. J Scleroderma Relat Disord. 2020;5(16):e140458.
   Web of Science ®Google Scholar
• Bhattacharyya S, Wang W, Morales-Nebreda L, et al. Tenascin-C drives persistence of organ fibrosis. Nat Commun. 2016;7:11703.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Huang X, Hecker L, et al. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest. 2013;123:1096–1108.
   PubMed Web of Science ®Google Scholar
• Lagares D, Busnadiego O, García-Fernández RA, et al. Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation. Arthritis Rheum. 2012;64:1653–1664.
   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 (Oxford). 2012;51:2146–2154.
   PubMed Web of Science ®Google Scholar
• Lagares D, Santos A, Grasberger PE, et al. Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Sci Transl Med. 2017;9(420):eaal3765.
   Web of Science ®Google Scholar
• Apostolidis SA, Stifano G, Tabib T, et al. Single cell RNA sequencing identifies HSPG2 and APLNR as markers of endothelial cell injury in systemic sclerosis skin. Front Immunol. 2018;9:2191.
   PubMed Web of Science ®Google Scholar
• Valenzi E, Bulik M, Tabib T, et al. Single-cell analysis reveals fibroblast heterogeneity and myofibroblasts in systemic sclerosis-associated interstitial lung disease. Ann Rheum Dis. 2019;78:1379–1387.
   PubMed Web of Science ®Google Scholar
• Ledoult E, Launay D, Béhal H, et al. Early trajectories of skin thickening are associated with severity and mortality in systemic sclerosis. Arthritis Res Ther. 2020;22:30.
   PubMed Web of Science ®Google Scholar
• Nihtyanova SI, Sari A, Harvey JC, et al. Using autoantibodies and cutaneous subset to develop outcome‐based disease classification in systemic sclerosis. Arthritis Rheumatol. 2020;72:465–476.
   PubMed Web of Science ®Google Scholar
• Sobanski V, Lescoat A, Launay D. Novel classifications for systemic sclerosis: challenging historical subsets to unlock new doors. Curr Opin Rheumatol. 2020;32:463–471.
   PubMed Web of Science ®Google Scholar
• Hinchcliff M, Mahoney JM. Towards a new classification of systemic sclerosis. Nat Rev Rheumatol. 2019;34:1–2.
   Google Scholar
• Dobrota R, Maurer B, Graf N, et al. Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis. Ann Rheum Dis. 2016;75:1743–1748.
   PubMed Web of Science ®Google Scholar
• Khanna D, Lin CJF, Furst DE, et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2020:8(10):963-974.
   PubMedGoogle Scholar
• Volkmann ER, Tashkin DP, LeClair H, et al. Treatment with mycophenolate and cyclophosphamide leads to clinically meaningful improvements in patient-reported outcomes in scleroderma lung disease: results of scleroderma lung study II. ACR Open Rheumatol. 2020;2:362–370.
   PubMedGoogle Scholar
• Roofeh D, Lescoat A, Khanna D. Emerging drugs for the treatment of scleroderma: a review of recent phase 2 and 3 trials. Expert Opin Emerg Drugs. 2020;25(4):455-466.
   PubMedGoogle Scholar
• Roofeh D, Khanna D. Management of systemic sclerosis: the first five years. Curr Opin Rheumatol. 2020;32:228–237.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Distler JH. Therapeutic molecular targets of SSc-ILD. J Scleroderma Relat Disord. 2020;5:17–30.
   PubMed 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;387:2630–2640.
   PubMed Web of Science ®Google Scholar
• 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;72:125–136.
   PubMed Web of Science ®Google Scholar
• Chung L, Spino C, McLain R, et al. Safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis (ASSET): open-label extension of a phase 2, double-blind randomised trial. Lancet Rheumatol. 2020;2:e743–e753.
   PubMedGoogle Scholar
• Chung MP, Chung L. Drugs in phase I and phase II clinical trials for systemic sclerosis. Expert Opin Investig Drugs. 2020;29:349–362.
   PubMed Web of Science ®Google Scholar
• Black CM, Silman AJ, Herrick AI, et al. Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1999;42:299–305.
   PubMed Web of Science ®Google Scholar
• Skaug B, Assassi S. Type I interferon dysregulation in systemic sclerosis. Cytokine. 2020;132:154635.
   PubMed Web of Science ®Google 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;125:2795–2807.
   PubMed Web of Science ®Google Scholar
• Zhang C, Zhang Y, Zhang C, et al. Pioglitazone increases VEGFR3 expression and promotes activation of M2 macrophages via the peroxisome proliferator‑activated receptor γ. Mol Med Rep. 2019;19:2740–2748.
   PubMed Web of Science ®Google Scholar
• Roofeh D, Lin CJF, Goldin J, et al. Tocilizumab prevents progression of early systemic sclerosis associated interstitial lung disease. Arthritis Rheumatol. 2021.DOI: 10.1002/art.41668.
   PubMed Web of Science ®Google Scholar
• Varga J, Rosenbloom J, Jimenez SA. Transforming growth factor beta (TGF beta) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts. Biochem J. 1987;247:597–604.
   PubMed Web of Science ®Google Scholar
• Schultz-Cherry S, Chen H, Mosher DF, et al. Regulation of transforming growth factor-beta activation by discrete sequences of thrombospondin 1. J Biol Chem. 1995;270:7304–7310.
   PubMed Web of Science ®Google Scholar
• Morin F, Kavian N, Batteux F. Animal models of systemic sclerosis. Curr Pharm Des. 2015;21:2365–2379.
   PubMed Web of Science ®Google Scholar
• Roberts AB, Sporn MB, Assoian RK, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986;83:4167–4171.
   PubMed Web of Science ®Google Scholar
• Sfikakis PP, McCune BK, Tsokos M, et al. Immunohistological demonstration of transforming growth factor-beta isoforms in the skin of patients with systemic sclerosis. Clin Immunol Immunopathol. 1993;69:199–204.
   PubMedGoogle Scholar
• Higley H, Persichitte K, Chu S, et al. Immunocytochemical localization and serologic detection of transforming growth factor beta 1. Association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud’s phenomenon. Arthritis Rheum. 1994;37:278–288.
   PubMedGoogle Scholar
• Ozbilgin MK, Inan S. The roles of transforming growth factor type beta3 (TGF-beta3) and mast cells in the pathogenesis of scleroderma. Clin Rheumatol. 2003;22:189–195.
   PubMed Web of Science ®Google Scholar
• Hasegawa M, Sato S, Takehara K. Augmented production of transforming growth factor-beta by cultured peripheral blood mononuclear cells from patients with systemic sclerosis. Arch Dermatol Res. 2004;296:89–93.
   PubMed Web of Science ®Google Scholar
• King TE, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–2092.
   PubMed Web of Science ®Google Scholar
• Hall CL, Wells AR, Leung KP. Pirfenidone reduces profibrotic responses in human dermal myofibroblasts, in vitro. Lab Invest. 2018;98:640–655.
   PubMed Web of Science ®Google Scholar
• 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;43:1672–1679.
   PubMed Web of Science ®Google Scholar
• Acharya N, Sharma SK, Mishra D, et al. Efficacy and safety of pirfenidone in systemic sclerosis-related interstitial lung disease-a randomised controlled trial. Rheumatol Int. 2020;40:703–710.
   PubMed Web of Science ®Google Scholar
• Denton CP, Merkel PA, Furst DE, et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 2007;56:323–333.
   PubMed Web of Science ®Google Scholar
• Lafyatis R, Spiera R, Domsic R, et al. Thu0329 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;79:394–395.
   Web of Science ®Google Scholar
• Khanna D, Tashkin DP, Wells AU, et al. STRATUS: a phase II study of Abituzumab in patients with systemic sclerosis–associated interstitial lung disease. J Rheumatol. 2021. DOI: 10.3899/jrheum.191365.
   PubMedGoogle Scholar
• Da Q, Yan Z, Li Z, et al. TAK1 is involved in sodium L-lactate-stimulated p38 signaling and promotes apoptosis. Mol Cell Biochem. 2021;476(2):873-882.
   PubMed Web of Science ®Google Scholar
• Chen Y, Shi-wen X, Eastwood M, et al. Contribution of activin receptor-like kinase 5 (transforming growth factor beta receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts. Arthritis Rheum. 2006;54:1309–1316.
   PubMed Web of Science ®Google Scholar
• Thannickal VJ, Lee DY, White ES, et al. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem. 2003;278:12384–12389.
   PubMed Web of Science ®Google Scholar
• Kahl DJ, Hutchings KM, Lisabeth EM, et al. 5-Aryl-1,3,4-oxadiazol-2-ylthioalkanoic acids: a highly potent new class of inhibitors of Rho/Myocardin-Related Transcription Factor (MRTF)/Serum Response Factor (SRF)-mediated gene transcription as potential antifibrotic agents for scleroderma. J Med Chem. 2019;62:4350–4369.
   PubMed Web of Science ®Google Scholar
• Gilles G, McCulloch AD, Brakebusch CH, et al. Maintaining resting cardiac fibroblasts in vitro by disrupting mechanotransduction. PLoS One. 2020;15:e0241390.
   PubMed Web of Science ®Google Scholar
• Akhmetshina A, Dees C, Pileckyte M, et al. Rho-associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts. Arthritis Rheum. 2008;58:2553–2564.
   PubMedGoogle Scholar
• Oh RS, Haak AJ, Smith KMJ, et al. RNAi screening identifies a mechanosensitive ROCK-JAK2-STAT3 network central to myofibroblast activation. J Cell Sci. 2018;131(10):jcs209932.
   Web of Science ®Google Scholar
• Lescoat A, Ballerie A, Lelong M, et al. Crystalline silica impairs efferocytosis abilities of human and mouse macrophages: implication for silica-associated systemic sclerosis. Front Immunol. 2020;11:219.
   PubMed Web of Science ®Google Scholar
• Pehlivan Y, Yolbas S, Cetin GY, et al. Investigation of the association between Rho/Rho-kinase gene polymorphisms and systemic sclerosis. Rheumatol Int. 2016;36:421–427.
   PubMed Web of Science ®Google Scholar
• Xie Y, Zhao D, Dong P, et al. Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization. Biosci Rep. 2018. DOI: 10.1042/BSR20171734.
   Google Scholar
• Novelli D, Fumagalli F, Staszewsky L, et al. Monocrotaline-induced pulmonary arterial hypertension: time-course of injury and comparative evaluation of macitentan and Y-27632, a Rho kinase inhibitor. Eur J Pharmacol. 2019;865:172777.
   PubMed Web of Science ®Google Scholar
• Bei Y, Hua-Huy T, Nicco C, et al. RhoA/Rho-kinase activation promotes lung fibrosis in an animal model of systemic sclerosis. Exp Lung Res. 2016;42:44–55.
   PubMed Web of Science ®Google Scholar
• Flynn R, Paz K, Du J, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127:2144–2154.
   PubMed Web of Science ®Google Scholar
• Fava A, Wung PK, Wigley FM, et al. Efficacy of Rho kinase inhibitor fasudil in secondary Raynaud’s phenomenon. Arthritis Care Res (Hoboken). 2012;64:925–929.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Wu S. Effects of fasudil on pulmonary hypertension in clinical practice. Pulm Pharmacol Ther. 2017;46:54–63.
   PubMed Web of Science ®Google Scholar
• De Silva TM, Kinzenbaw DA, Modrick ML, et al. Heterogeneous impact of ROCK2 on carotid and cerebrovascular function. Hypertension. 2016;68:809–817.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Natarajan V. Lysophosphatidic acid (LPA) and its receptors: role in airway inflammation and remodeling. Biochim Biophys Acta. 2013;1831:86–92.
   PubMed Web of Science ®Google Scholar
• Kihara Y, Maceyka M, Spiegel S, et al. Lysophospholipid receptor nomenclature review: IUPHAR review 8. Br J Pharmacol. 2014;171:3575–3594.
   PubMed Web of Science ®Google Scholar
• Ledein L, Léger B, Dees C, et al. Translational engagement of lysophosphatidic acid receptor 1 in skin fibrosis: from dermal fibroblasts of patients with scleroderma to tight skin 1 mouse. Br J Pharmacol. 2020;177:4296–4309.
   PubMed Web of Science ®Google Scholar
• Sato M, Shegogue D, Hatamochi A, et al. Lysophosphatidic acid inhibits TGF-beta-mediated stimulation of type I collagen mRNA stability via an ERK-dependent pathway in dermal fibroblasts. Matrix Biol. 2004;23:353–361.
   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 (Hoboken). 2016;68:2964–2974.
   PubMed Web of Science ®Google Scholar
• Tokumura A, Carbone LD, Yoshioka Y, et al. Elevated serum levels of arachidonoyl-lysophosphatidic acid and sphingosine 1-phosphate in systemic sclerosis. Int J Med Sci. 2009;6:168–176.
   PubMed Web of Science ®Google Scholar
• Ninou I, Kaffe E, Müller S, et al. Pharmacologic targeting of the ATX/LPA axis attenuates bleomycin-induced pulmonary fibrosis. Pulm Pharmacol Ther. 2018;52:32–40.
   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;70:1634–1643.
   PubMed Web of Science ®Google Scholar
• Khanna D, Denton C, Furst D, et al. A phase 2a randomized, double-blind, Placebo-controlled study of Ziritaxestat in early diffuse cutaneous systemic sclerosis (NOVESA). Arthritis Rheumatol. 2020;72(suppl 10). [cited 2021 May 3]. Available from: https://acrabstracts.org/abstract/a-phase-2a-randomized-double-blind-placebo-controlled-study-of-ziritaxestat-in-early-diffuse-cutaneous-systemic-sclerosis-novesa/
   Google Scholar
• Zhang Y, Liang R, Chen C-W, et al. JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment. Ann Rheum Dis. 2017;76:1467–1475.
   PubMed Web of Science ®Google Scholar
• Talotta R. The rationale for targeting the JAK/STAT pathway in scleroderma-associated interstitial lung disease. Immunotherapy. 2020;13:241–256.
   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.
   PubMed Web of Science ®Google 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;5:40–50.
   PubMed Web of Science ®Google Scholar
• Aung WW, Wang C, Xibei J, et al. Immunomodulating role of the JAKs inhibitor tofacitinib in a mouse model of bleomycin-induced scleroderma. J Dermatol Sci. 2021;101(3):174-184.
   PubMed Web of Science ®Google Scholar
• Khanna D, Nagaraja V, Koenig A, et al. Tofacitinib in early diffuse cutaneous systemic sclerosis— results of Phase I/II investigator-initiated, double-blind randomized Placebo-controlled trial. ACR Meeting Abstracts. [cited 2020 Aug 17]. Available from: https://acrabstracts.org/abstract/tofacitinib-in-early-diffuse-cutaneous-systemic-sclerosis-results-of-phase-i-ii-investigator-initiated-double-blind-randomized-placebo-controlled-trial/.
   Google Scholar
• Komai T, Shoda H, Hanata N, et al. Tofacitinib rapidly ameliorated polyarthropathy in a patient with systemic sclerosis. Scand J Rheumatol. 2018;47:505–506.
   PubMed Web of Science ®Google Scholar
• Damsky W, Patel D, Garelli CJ, et al. Jak inhibition prevents Bleomycin-induced fibrosis in mice and is effective in patients with Morphea. J Invest Dermatol. 2020;140:1446–1449.e4.
   PubMed Web of Science ®Google Scholar
• Zeiser R. Bubnoff N von, Butler J, Mohty M, Niederwieser D, Or R, et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020;382:1800–1810.
   PubMed Web of Science ®Google Scholar
• Saidu NEB, Bonini C, Dickinson A, et al. New approaches for the treatment of Chronic Graft-Versus-Host Disease: current status and future directions. Front Immunol. 2020;11:578314.
   PubMed Web of Science ®Google Scholar
• Goll GL, Kvien TK. New-generation JAK inhibitors: how selective can they be? Lancet. 2018;391:2477–2478.
   PubMed Web of Science ®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;5:61–71.
   PubMed Web of Science ®Google Scholar
• Raghu G, Richeldi L, Crestani B, et al. SAR156597 in idiopathic pulmonary fibrosis: a phase 2 placebo-controlled study (DRI11772). Eur Respir J. 2018;52(6):1801130..
   Web of Science ®Google Scholar
• Hasegawa M, Fujimoto M, Kikuchi K, et al. Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J Rheumatol. 1997;24:328–332.
   PubMed Web of Science ®Google Scholar
• Nguyen JK, Austin E, Huang A, et al. The IL-4/IL-13 axis in skin fibrosis and scarring: mechanistic concepts and therapeutic targets. Arch Dermatol Res. 2020;312:81–92.
   PubMed Web of Science ®Google Scholar
• McGaha T, Saito S, Phelps RG, et al. Lack of skin fibrosis in tight skin (TSK) mice with targeted mutation in the interleukin-4R alpha and transforming growth factor-beta genes. J Invest Dermatol. 2001;116:136–143.
   PubMed Web of Science ®Google Scholar
• Jakubzick C, Choi ES, Joshi BH, et al. Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4- and IL-13-responsive cells. J Immunol. 2003;171:2684–2693.
   PubMed Web of Science ®Google 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;79:1600–1607.
   PubMed Web of Science ®Google Scholar
• Mountjoy KG, Robbins LS, Mortrud MT, et al. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992;257:1248–1251.
   PubMed Web of Science ®Google Scholar
• Böhm M, Raghunath M, Sunderkötter C, et al. Collagen metabolism is a novel target of the neuropeptide alpha-melanocyte-stimulating hormone. J Biol Chem. 2004;279:6959–6966.
   PubMed Web of Science ®Google Scholar
• Kokot A, Sindrilaru A, Schiller M, et al. alpha-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;60:592–603.
   PubMed Web of Science ®Google Scholar
• Taherzadeh S, Sharma S, Chhajlani V, et al. Alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages. Am J Physiol. 1999;276:R1289–1294.
   PubMed Web of Science ®Google Scholar
• Delgado R, Carlin A, Airaghi L, et al. Melanocortin peptides inhibit production of proinflammatory cytokines and nitric oxide by activated microglia. J Leukoc Biol. 1998;63:740–745.
   PubMed Web of Science ®Google Scholar
• Dinparastisaleh R, Mirsaeidi M. Antifibrotic and anti-inflammatory actions of α-Melanocytic hormone: new roles for an old player. Pharmaceuticals (Basel). 2021;14(1):45.
   Google Scholar
• Hanayama R, Tanaka M, Miyasaka K, et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science. 2004;304:1147–1150.
   PubMed Web of Science ®Google Scholar
• Montero-Melendez T, Patel HB, Seed M, et al. The melanocortin agonist AP214 exerts anti-inflammatory and proresolving properties. Am J Pathol. 2011;179:259–269.
   PubMed Web of Science ®Google Scholar
• Miao Y-L, Deng X-M, Li J-B, et al. Effect of alpha-melanocyte stimulating hormone on the apoptosis of the vascular endothelial cell of the lung in two-hit acute respiratory distress syndrome in rat. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2004;16:596–598.
   PubMedGoogle Scholar
• Colombo G, Gatti S, Sordi A, et al. Production and effects of alpha-melanocyte-stimulating hormone during acute lung injury. Shock. 2007;27:326–333.
   PubMed Web of Science ®Google Scholar
• Leroy V, Henrot P, Barnetche T, et al. Association of skin hyperpigmentation disorders with digital ulcers in systemic sclerosis: analysis of a cohort of 239 patients. J Am Acad Dermatol. 2019;80:478–484.
   PubMed Web of Science ®Google Scholar
• Raschi E, Chighizola CB, Cesana L, et al. Immune complexes containing scleroderma-specific autoantibodies induce a profibrotic and proinflammatory phenotype in skin fibroblasts. Arthritis Res Ther. 2018;20:187.
   PubMed Web of Science ®Google Scholar
• Gao X, Jia G, Guttman A, et al. Osteopontin links myeloid activation and disease progression in systemic sclerosis. Cell Rep Med. 2020;1:100140.
   PubMedGoogle Scholar
• Sato S, Fujimoto M, Hasegawa M, et al. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 2004;50:1918–1927.
   PubMed Web of Science ®Google Scholar
• Matsushita T, Kobayashi T, Mizumaki K, et al. BAFF inhibition attenuates fibrosis in scleroderma by modulating the regulatory and effector B cell balance. Sci Adv. 2018;4:eaas9944.
   PubMed Web of Science ®Google Scholar
• Lafyatis R, O’Hara C, Feghali-Bostwick CA, et al. B cell infiltration in systemic sclerosis-associated interstitial lung disease. Arthritis Rheum. 2007;56:3167–3168.
   PubMed Web of Science ®Google Scholar
• Hasegawa M, Hamaguchi Y, Yanaba K, et al. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol. 2006;169:954–966.
   PubMed Web of Science ®Google Scholar
• Yoshizaki A, Iwata Y, Komura K, et al. CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma. Am J Pathol. 2008;172:1650–1663.
   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
• Einhaus J, Pecher A-C, Asteriti E, et al. Inhibition of effector B cells by ibrutinib in systemic sclerosis. Arthritis Res Ther. 2020;22:66.
   PubMed Web of Science ®Google Scholar
• Goswami RP, Ray A, Chatterjee M, et al. Rituximab in the treatment of systemic sclerosis-related interstitial lung disease: a systematic review and meta-analysis. Rheumatology (Oxford). 2021;60(2):557-567.
   PubMedGoogle Scholar
• Elhai M, Boubaya M, Distler O, et al. Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study. Ann Rheum Dis. 2019;78:979–987.
   PubMed Web of Science ®Google Scholar
• Zamanian RT, Badesch D, Chung L, et al. Safety and efficacy of B-cell depletion with Rituximab for the treatment of systemic sclerosis associated pulmonary arterial hypertension: a multi-center, double-blind, randomized, Placebo-controlled trial. Am J Respir Crit Care Med. 2021. Accessed 2021 Mar 13. Available from: http://www.atsjournals.org/doi/10.1164/rccm.202009-3481OC
   PubMedGoogle Scholar
• Gordon JK, Martyanov V, Franks JM, et al. Belimumab for the treatment of early diffuse systemic sclerosis: results of a randomized, double-blind, Placebo-controlled, pilot trial. Arthritis Rheumatol. 2018;70:308–316.
   PubMed Web of Science ®Google Scholar
• Waller EK, Miklos D, Cutler C, et al. Ibrutinib for Chronic Graft-versus-Host disease after failure of prior therapy: 1-year update of a phase 1b/2 study. Biol Blood Marrow Transplant. 2019;25:2002–2007.
   PubMed Web of Science ®Google Scholar
• Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system? Nat Rev Immunol. 2013;13:176–189.
   PubMed Web of Science ®Google Scholar
• Raschi E, Privitera D, Bodio C, et al. Scleroderma-specific autoantibodies embedded in immune complexes mediate endothelial damage: an early event in the pathogenesis of systemic sclerosis. Arthritis Res Ther. 2020;22:265.
   PubMed Web of Science ®Google Scholar
• Domínguez-Soto Á, Simón-Fuentes M, De Las Casas-engel M, et al. IVIg promote cross-tolerance against inflammatory stimuli in vitro and in vivo. J Immunol. 2018;201:41–52.
   PubMed Web of Science ®Google Scholar
• Kozicky LK, Zhao ZY, Menzies SC, et al. Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state. J Leukoc Biol. 2015;98:983–994.
   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;163:235–241.
   PubMed Web of Science ®Google Scholar
• Nacci F, Righi A, Conforti ML, et al. Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study. Ann Rheum Dis. 2007;66:977–979.
   PubMed Web of Science ®Google Scholar
• Raja J, Nihtyanova SI, Murray CD, et al. Sustained benefit from intravenous immunoglobulin therapy for gastrointestinal involvement in systemic sclerosis. Rheumatol (Oxford). 2016;55:115–119.
   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;16:377–384.
   PubMed Web of Science ®Google Scholar
• Chaigne B, Rodeia S, Benmostefa N, et al. Corticosteroid-sparing benefit of intravenous immunoglobulin in systemic sclerosis-associated myopathy: a comparative study in 52 patients. Autoimmun Rev. 2020;19:102431.
   PubMed Web of Science ®Google Scholar
• 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;31:151–156.
   PubMed Web of Science ®Google Scholar
• Bellando Randone S, George J, Mazzotta C, et al. Angiostatic and angiogenic chemokines in systemic sclerosis: an overview. J Scleroderma Relat Disord. 2017;2:1–10.
   Web of Science ®Google Scholar
• Mathes AL, Christmann RB, Stifano G, et al. Global chemokine expression in systemic sclerosis (SSc): CCL19 expression correlates with vascular inflammation in SSc skin. Ann Rheum Dis. 2014;73:1864–1872.
   PubMed Web of Science ®Google Scholar
• Forssmann U, Uguccioni M, Loetscher P, et al. Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes. J Exp Med. 1997;185:2171–2176.
   PubMed Web of Science ®Google Scholar
• Mor A, Salto MS, Katav A, et al. Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis. Ann Rheum Dis. 2019;78:1260–1268.
   PubMed Web of Science ®Google Scholar
• Makino K, Makino T, Stawski L, et al. Anti-connective tissue growth factor (CTGF/CCN2) monoclonal antibody attenuates skin fibrosis in mice models of systemic sclerosis. Arthritis Res Ther. 2017;19:134.
   PubMed Web of Science ®Google Scholar
• Nouno T, Okamoto M, Ohnishi K, et al. Elevation of pulmonary CD163+ and CD204+ macrophages is associated with the clinical course of idiopathic pulmonary fibrosis patients. J Thorac Dis. 2019;11:4005–4017.
   PubMed Web of Science ®Google Scholar
• Cox N, Pilling D, Gomer RH. Serum amyloid P: a systemic regulator of the innate immune response. J Leukoc Biol. 2014;96:739–743.
   PubMed Web of Science ®Google Scholar
• Pilling D, Gomer RH. Persistent lung inflammation and fibrosis in serum amyloid P component (APCs-/-) knockout mice. PLoS One. 2014;9:e93730.
   PubMed Web of Science ®Google Scholar
• Tennent GA, Dziadzio M, Triantafillidou E, et al. Normal circulating serum amyloid P component concentration in systemic sclerosis. Arthritis Rheum. 2007;56:2013–2017.
   PubMedGoogle Scholar
• Pilling D, Buckley CD, Salmon M, et al. Serum amyloid P and fibrosis in systemic sclerosis: comment on the article by Tennent et al. Arthritis Rheum. 2007;56:4229. author reply 4229-4230.
   PubMedGoogle Scholar
• Dosoki H, Stegemann A, Taha M, et al. Targeting of NADPH oxidase in vitro and in vivo suppresses fibroblast activation and experimental skin fibrosis. Exp Dermatol. 2017;26:73–81.
   PubMed Web of Science ®Google Scholar
• Hinchcliff M, 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;133:1979–1989.
   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;17:1–14.
   PubMed Web of Science ®Google Scholar
• Volkmann ER, Varga J. Emerging targets of disease-modifying therapy for systemic sclerosis. Nat Rev Rheumatol. 2019;15:208–224.
   PubMed Web of Science ®Google Scholar
• Kanemaru R, Takahashi F, Kato M, et al. Dasatinib suppresses TGFβ-mediated epithelial-mesenchymal transition in alveolar epithelial cells and inhibits pulmonary fibrosis. Lung. 2018;196:531–541.
   PubMed Web of Science ®Google Scholar
• Martyanov V, Whitfield ML, Varga J. Senescence signature in skin biopsies from systemic sclerosis patients treated with senolytic therapy: potential predictor of clinical response? Arthritis Rheumatol. 2019;71:1766–1767.
   PubMed Web of Science ®Google Scholar
• Kubo S, Nakayamada S, Miyazaki Y, et al. Distinctive association of peripheral immune cell phenotypes with capillaroscopic microvascular patterns in systemic sclerosis. Rheumatol (Oxford). 2019;58:2273–2283.
   PubMed Web of Science ®Google Scholar
• Scott MKD, Quinn K, Li Q, et al. Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: a retrospective, multicentre cohort study. Lancet Respir Med. 2019;7:497–508.
   PubMed Web of Science ®Google Scholar
• Wohlfahrt T, Rauber S, Uebe S, et al. PU.1 controls fibroblast polarization and tissue fibrosis. Nature. 2019;566:344–349.
   PubMed Web of Science ®Google Scholar
• Park J-S, Oh Y, Park YJ, et al. Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma. Nat Commun. 2019;10:1128.
   PubMed Web of Science ®Google Scholar
• Galván-Peña S, O’Neill LAJ. Metabolic reprogramming in macrophage polarization. Front Immunol. 2014 [Accessed 2020 Sept 20];5. Available at https://www.frontiersin.org/articles/10.3389/fimmu.2014.00420/full
   PubMed Web of Science ®Google Scholar
• Tian F, Wang Z, He J, et al. 4-Octyl itaconate protects against renal fibrosis via inhibiting TGF-β/Smad pathway, autophagy and reducing generation of reactive oxygen species. Eur J Pharmacol. 2020;873:172989.
   PubMed Web of Science ®Google Scholar
• Ogger PP, Albers GJ, Hewitt RJ, et al. Itaconate controls the severity of pulmonary fibrosis. Sci Immunol. 2020;5(52):eabc1884.
   Web of Science ®Google Scholar
• Sobanski V, Giovannelli J, Allanore Y, et al. Phenotypes determined by cluster analysis and their survival in the prospective European scleroderma trials and research Cohort of patients with systemic sclerosis. Arthritis Rheumatol. 2019;71:1553–1570.
   PubMed Web of Science ®Google Scholar
• Wirz EG, Jaeger VK, Allanore Y, et al. Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database. Ann Rheum Dis. 2016;75:1285–1292.
   PubMed Web of Science ®Google Scholar
• Herrick AL, Peytrignet S, Lunt M, et al. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European scleroderma observational study. Ann Rheum Dis. 2018;77:563–570.
   PubMed Web of Science ®Google Scholar
• Allanore Y, Distler O, Matucci-Cerinic M, et al. Review: defining a unified vascular phenotype in systemic sclerosis. Arthritis Rheumatol (Hoboken). 2018;70:162–170.
   PubMed Web of Science ®Google Scholar
• Lescoat A, Ballerie A, Belhomme N, Carlan de M, Droitcourt C, et al. Synovial involvement assessed by power Doppler ultra-sonography in systemic sclerosis: results of a cross-sectional study. Rheumatology (Oxford). 2018;57:2012–2021.
   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. JAMA. 2014;311:2490–2498.
   PubMed Web of Science ®Google Scholar
• Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378:35–47.
   PubMed Web of Science ®Google Scholar
• Frantz C, Huscher D, Avouac J, et al. Outcomes of limited cutaneous systemic sclerosis patients: results on more than 12,000 patients from the EUSTAR database. Autoimmun Rev. 2020;19:102452.
   PubMed Web of Science ®Google Scholar
• Allanore Y. Limited cutaneous systemic sclerosis: the unfairly neglected subset. J Scleroderma Relat Disord. 2016;1:241–246.
   Web of Science ®Google Scholar
• Lescoat A, Murphy SL, Roofeh D, et al. Considerations for a combined index for limited cutaneous systemic sclerosis to support drug development and improve outcomes. J Scleroderma Relat Disord. 2020:2397198320961967.
   Web of Science ®Google Scholar