Advances in biological and targeted therapies for systemic sclerosis

References

• Rubio-Rivas M, Royo C, Simeon CP, et al. Mortality and survival in systemic sclerosis: systematic review and meta-analysis. Semin Arthritis Rheum. 2014 Oct;44(2):208–219.
   PubMed Web of Science ®Google Scholar
• Ingegnoli F, Ughi N, Mihai C. Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis. Best Pract Res Clin Rheumatol. 2018 Apr;32(2):223–240.
   PubMed Web of Science ®Google Scholar
• van den Hoogen F, Khanna D, Fransen J, et al. Classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum. 2013 Nov;65(11):2737–2747.
   PubMed Web of Science ®Google Scholar
• Tsou PS, Varga J, O’reilly S. Advances in epigenetics in systemic sclerosis: molecular mechanisms and therapeutic potential. Nat Rev Rheumatol. 2021 Oct;17(10):596–607.
   PubMed Web of Science ®Google Scholar
• Zanin-Silva DC, Santana-Goncalves M, Kawashima-Vasconcelos MY, et al. Management of endothelial dysfunction in systemic sclerosis: current and developing strategies. Front Med. 2021;8:788250.
   PubMed Web of Science ®Google Scholar
• Gasparini G, Cozzani E, Parodi A. Interleukin-4 and interleukin-13 as possible therapeutic targets in systemic sclerosis. Cytokine. 2020 Jan;125:154799.
   PubMed Web of Science ®Google Scholar
• Liu M, Wu W, Sun X, et al. New insights into CD4(+) T cell abnormalities in systemic sclerosis. Cytokine Growth Factor Rev. 2016 Apr;28:31–36.
   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 Jun;27(6):645–653.
   PubMedGoogle Scholar
• Furue M, Mitoma C, Mitoma H, et al. Pathogenesis of systemic sclerosis-current concept and emerging treatments. Immunol Res. 2017 Aug;65(4):790–797.
   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 1;130(5):2451–2464.
   PubMed Web of Science ®Google Scholar
• Allanore Y, Simms R, Distler O, et al. Systemic sclerosis. Nat Rev Dis Primers. 2015 Apr 23;1:15002.
   PubMed Web of Science ®Google Scholar
• Lescoat A, Lecureur V, Varga J. Contribution of monocytes and macrophages to the pathogenesis of systemic sclerosis: recent insights and therapeutic implications. Curr Opin Rheumatol. 2021 Nov 1;33(6):463–470.
   PubMed Web of Science ®Google Scholar
• Sakkas LI, Bogdanos DP. Systemic sclerosis: new evidence re-enforces the role of B cells. Autoimmun Rev. 2016 Feb;15(2):155–161.
   PubMed Web of Science ®Google Scholar
• Matsushita T, Hasegawa M, Yanaba K, et al. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 2006 Jan;54(1):192–201.
   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 Jun 13;17(1):159.
   PubMedGoogle 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 Oct;8(10):963–974.
   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 Jun 25;387(10038):2630–2640.
   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 Jul;73(7):1301–1310. 10.1002/art.41668.
   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 Jul 1;125(7):2795–2807.
   PubMed Web of Science ®Google Scholar
• Fukasawa T, Yoshizaki A, Kageybayashi H, et al. POS0857 Pharmacokinetics, safety, and efficicay of subcutaneous brodalumab for systemic sclerosis with moderate-to-severe skin thickening: a single-arm, open-label, multi-dose, phase 1 trial. Ann Rheum Dis. 2022;81:722–723.
   Web of Science ®Google Scholar
• Fukasawa T, Yoshizaki A, Kageybayashi H. POS0881 Efficacy and safety of subcutaneous brodalumab, a fully human anti-IL-17RA monoclonal antibody, for systemic sclerosis with moderate-to-severe skint hickening: a multcicenter, randomized, placebo-controlled, double-blind phase 3 study. Ann Rheum Dis. 2022;81:736.
   Web of Science ®Google Scholar
• Khanna D, Denton C, Furst D. A 24-Week, Phase IIa, Randomized, Double-blind, Placebo-controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis (NOVESA). Arthritis Rheumatol. 2023. In Press. doi:10.1002/art.42477
   Google Scholar
• Khanna D, Lin CJF, Furst DE, et al. Long-term safety and efficacy of tocilizumab in early systemic sclerosis-interstitial lung disease: open-label extension of a phase 3 randomized controlled trial. Am J Respir Crit Care Med. 2022 Mar 15;205(6):674–684. doi:10.1164/rccm.202103-0714OC.
   PubMed Web of Science ®Google Scholar
• Ebata S, Yoshizaki A, Koji O, et al. Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blien, investigator-initiated, randomised, placebo-controlled trial. Lancet Rheumatol. 2021;3(7):E489–97. DOI:10.1016/S2665-9913(21)00107-7
   Google Scholar
• 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 1;57(12):2106–2113.
   PubMed Web of Science ®Google Scholar
• Maher TM, Tudor VA, Saunders P, et al. Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial. Lancet Respir Med. 2022 Nov11;11(1):45–54.
   PubMedGoogle 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 multicenter, double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2021 Jul 15;204(2):209–221.
   PubMed Web of Science ®Google 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 Feb;70(2):308–316.
   PubMed Web of Science ®Google Scholar
• Schiopu E, Chatterjee S, Hsu V, et al. Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study. Arthritis Res Ther. 2016 Jun 7;18(1):131.
   PubMedGoogle Scholar
• US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov.
   Google Scholar
• Lafyatis R, Spiera R, Domsic R, 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;79:394–395.
   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 Feb;42(2):299–305.
   PubMedGoogle Scholar
• Chizzolini C, Boin F. The role of the acquired immune response in systemic sclerosis. Semin Immunopathol. 2015 Sep;37(5):519–528.
   PubMed Web of Science ®Google Scholar
• Milano A, Pendergrass SA, Sargent JL, et al. Molecular subsets in the gene expression signatures of scleroderma skin. PLoS ONE. 2008 Jul 16;3(7):e2696.
   PubMed Web of Science ®Google Scholar
• Hinchcliff M, Huang CC, Wood TA, et al. Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis. J Invest Dermatol. 2013 Aug;133(8):1979–1989.
   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 Jan;72(1):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 Dec;2(12):e743–53.
   PubMedGoogle Scholar
• Mehta BK, Espinoza ME, Franks JM, et al. Machine-learning classification identifies early systemic sclerosis patients that improve with abatacept treatment by modulating CD28-pathways. JCI Insight. 2022 Nov 10;7. DOI:10.1172/jci.insight.155282
   Web of Science ®Google Scholar
• Domsic RT, Medsger TA, Gao S, et al. A data-driven approach finds RNA polymerase III antibody and tendon friction rubs as enrichment tools for early diffuse scleroderma trials. Rheumatology (Oxford). 2022 Aug 29. DOI:10.1093/rheumatology/keac501.
   PubMed Web of Science ®Google Scholar
• Raja J, Denton CP. Cytokines in the immunopathology of systemic sclerosis. Semin Immunopathol. 2015 Sep;37(5):543–557.
   PubMed Web of Science ®Google Scholar
• O’reilly S, Cant R, Ciechomska M, et al. Interleukin-6: a new therapeutic target in systemic sclerosis? Clin Transl Immunology. 2013 Apr;2(4):e4.
   PubMedGoogle Scholar
• Needleman BW. Immunologic aspects of scleroderma. Curr Opin Rheumatol. 1992 Dec;4(6):862–868.
   PubMedGoogle Scholar
• Saito F, Tasaka S, Inoue K, et al. Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. Am J Respir Cell Mol Biol. 2008 May;38(5):566–571.
   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 Feb;77(2):212–220.
   PubMed Web of Science ®Google Scholar
• O’reilly S. Role of interleukin-13 in fibrosis, particularly systemic sclerosis. BioFactors. 2013 Nov;39(6):593–596.
   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 Jan;116(1):136–143.
   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 Dec;52(6):1801130.
   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 Dec;79(12):1600–1607.
   PubMed Web of Science ®Google Scholar
• Roberts AB, Sporn MB. Transforming growth factors. Cancer Surv. 1985;4(4):683–705.
   PubMedGoogle Scholar
• Roberts AB, Flanders KC, Heine UI, et al. Transforming growth factor-beta: multifunctional regulator of differentiation and development. Philos Trans R Soc Lond B Biol Sci. 1990 Mar 12;327(1239):145–154.
   PubMed Web of Science ®Google Scholar
• Derynck R, Budi EH. Specificity, versatility, and control of TGF-beta family signaling. Sci Signal. 2019 Feb 26;12(570). doi:10.1126/scisignal.aav5183.
   Web of Science ®Google Scholar
• Sun T, Huang Z, Liang WC, et al. Tgfbeta2 and TGFbeta3 isoforms drive fibrotic disease pathogenesis. Sci Transl Med. 2021 Aug 4;13(605). doi :10.1126/scitranslmed.abe0407.
   Google Scholar
• Barr T. A selective TGF-B1 and TGF-B3 trap demonstrates target engagement and anti-fibrotic efficacy in mouse and translational mdoels of systemic sclerosis-associated intersitial lung disease. 7th Systemic Sclerosis World Congress; 2022 March 10-12; Virtual; 2022.
   Google Scholar
• Farina G, Lafyatis D, Lemaire R, et al. A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2010 Feb;62(2):580–588.
   PubMed Web of Science ®Google Scholar
• Shi N, Wang Z, Zhu H, et al. Research progress on drugs targeting the TGF-beta signaling pathway in fibrotic diseases. Immunol Res. 2022 Jun;70(3):276–288.
   PubMed Web of Science ®Google Scholar
• Martin CJ, Datta A, Littlefield C, et al. Selective inhibition of TGFbeta1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci Transl Med. 2020 Mar 25;12(536). doi :10.1126/scitranslmed.aay8456.
   Web of Science ®Google Scholar
• Rapoza ML, Fu D, Sendak RA. Development of an in vitro potency assay for therapeutic TGFbeta antagonists: the A549 cell bioassay. J Immunol Methods. 2006 Oct 20;316(1–2):18–26.
   PubMed Web of Science ®Google Scholar
• Nakashima T, Jinnin M, Yamane K, et al. Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J Immunol. 2012 Apr 15;188(8):3573–3583.
   PubMed Web of Science ®Google Scholar
• Corrado A, Rotondo C, Sanpaolo ER, et al. 1,25OH-Vitamin D3 and IL-17 inhibition modulate pro-fibrotic cytokines production in peripheral blood mononuclear cells of patients with systemic sclerosis. Int J Med Sci. 2022;19(5):867–877. DOI:10.7150/ijms.70984
   PubMed Web of Science ®Google Scholar
• Wu M, Assassi S. Dysregulation of type 1 interferon signaling in systemic sclerosis: a promising therapeutic target? Curr Treatm Opt Rheumatol. 2021 Dec;7(4):349–360.
   PubMedGoogle Scholar
• Ototake Y, Yamaguchi Y, Asami M, et al. Downregulated IRF8 in monocytes and macrophages of patients with systemic sclerosis may aggravate the fibrotic phenotype. J Invest Dermatol. 2021 Aug;141(8):1954–1963.
   PubMed Web of Science ®Google Scholar
• Kakkar V, Assassi S, Allanore Y, et al. Type 1 interferon activation in systemic sclerosis: a biomarker, a target or the culprit. Curr Opin Rheumatol. 2022 Nov 1;34(6):357–364.
   PubMed Web of Science ®Google Scholar
• Goldberg A, Geppert T, Schiopu E, et al. Dose-escalation of human anti-interferon-alpha receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study. Arthritis Res Ther. 2014 Feb 24;16(1):R57.
   PubMed Web of Science ®Google Scholar
• Guo X, Higgs BW, Bay-Jensen AC, et al. Suppression of T cell activation and collagen accumulation by an anti-ifnar1 mab, anifrolumab, in adult patients with systemic sclerosis. J Invest Dermatol. 2015 Oct;135(10):2402–2409.
   PubMed Web of Science ®Google Scholar
• Bohdziewicz A, Pawlik KK, Maciejewska M, et al. Future treatment options in systemic sclerosis—potential targets and ongoing clinical trials. J Clin Med. 2022 Feb 27;11(5):1310.
   PubMed Web of Science ®Google Scholar
• Segal Salto M, Mor A, Del Galdo F. CCL24 Serum concentration correlates with disease activity and worse prognosis in diffuse cutaneous SSc: a promising biological target to prevent disease progression. Ann Rheum Dis. 2022;81:499.
   Web of Science ®Google Scholar
• Mor A, Segal Salto M, Katav A, et al. Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis. Ann Rheum Dis. 2019 Sep;78(9):1260–1268.
   PubMed Web of Science ®Google Scholar
• Ferdinand JR, Richard AC, Meylan F, et al. Cleavage of TL1A differentially regulates its effects on innate and adaptive immune cells. J Immunol. 2018 Feb 15;200(4):1360–1369.
   PubMed Web of Science ®Google Scholar
• Prehn JL, Thomas LS, Landers CJ, et al. The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells. J Immunol. 2007 Apr 1;178(7):4033–4038.
   PubMed Web of Science ®Google Scholar
• Valatas V, Kolios G, Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): a co-stimulatory system of cytokines with diverse functions in gut mucosal immunity. Front Immunol. 2019;10:583.
   PubMed Web of Science ®Google Scholar
• Jacob N, Kumagai K, Abraham JP, et al. Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo. Sci Rep. 2020 Oct 23;10(1):18189.
   PubMed Web of Science ®Google Scholar
• Xu W, Su L, Qing P, et al. Elevated levels of TL1A are associated with disease activity in patients with systemic sclerosis. Clin Rheumatol. 2017 Jun;36(6):1317–1324.
   PubMed Web of Science ®Google Scholar
• Herro R, Miki H, Gs S, et al. TL1A promotes lung tissue fibrosis and airway remodeling. J Immunol. 2020 Nov 1;205(9):2414–2422.
   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 Dec;68(12):2964–2974.
   PubMed Web of Science ®Google Scholar
• Taneja A, Desrivot J, Diderichsen PM, et al. Population pharmacokinetic and pharmacodynamic analysis of GLPG1690, an autotaxin inhibitor, in healthy volunteers and patients with idiopathic pulmonary fibrosis. Clin Pharmacokinet. 2019 Sep;58(9):1175–1191.
   PubMed Web of Science ®Google Scholar
• Castelino FV, Seiders J, Bain G, et al. Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheum. 2011 May;63(5):1405–1415.
   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 Oct;70(10):1634–1643.
   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 Feb;5(1):40–50.
   PubMed Web of Science ®Google Scholar
• Hodge JA, Kawabata TT, Krishnaswami S, et al. The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016 Mar;34(2):318–328.
   PubMed Web of Science ®Google Scholar
• Migita K, Izumi Y, Torigoshi T, et al. Inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds. Clin Exp Immunol. 2013 Dec;174(3):356–363.
   PubMed Web of Science ®Google Scholar
• Khanna D, Padilla C, Tsoi LC, et al. Tofacitinib blocks IFN-regulated biomarker genes in skin fibroblasts and keratinocytes in a systemic sclerosis trial. JCI Insight. 2022 Sep 8;7(17). doi :10.1172/jci.insight.159566.
   Web of Science ®Google Scholar
• Moriana C, Moulinet T, Jaussaud R, et al. JAK inhibitors and systemic sclerosis: a systematic review of the literature. Autoimmun Rev. 2022 Oct;21(10):103168.
   PubMed Web of Science ®Google Scholar
• Actemra (tocilizumab) for intravenous or subcutaneous use [package insert]. South San Francisco CA: Genentech Inc.; 2021.
   Google Scholar
• Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009 Feb;60(2):578–583.
   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 Sep;56(9):3167–3168.
   PubMed Web of Science ®Google Scholar
• Whitfield ML, Finlay DR, Murray JI, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12319–12324.
   PubMed Web of Science ®Google 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 Jul;78(7):979–987.
   PubMed Web of Science ®Google Scholar
• Streicher K, Sridhar S, Kuziora M, et al. Baseline plasma cell gene signature predicts improvement in systemic sclerosis skin scores following treatment with inebilizumab (MEDI-551) and correlates with disease activity in systemic lupus erythematosus and chronic obstructive pulmonary disease. Arthritis Rheumatol. 2018 Dec;70(12):2087–2095.
   PubMed Web of Science ®Google Scholar
• Dorner T, Jacobi AM, Lipsky PE. B cells in autoimmunity. Arthritis Res Ther. 2009;11(5):247.
   PubMed Web of Science ®Google Scholar
• Bowman SJ, Fox R, Dorner T, et al. Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjogren’s syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. Lancet. 2022 Jan 8;399(10320):161–171.
   PubMed Web of Science ®Google Scholar
• Kraaij T, Huizinga TW, Rabelink TJ, et al. Belimumab after rituximab as maintenance therapy in lupus nephritis. Rheumatology (Oxford). 2014 Nov;53(11):2122–2124.
   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 Mar;79(3):379–386.
   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 Jan;11(1):e1004005.
   PubMed Web of Science ®Google Scholar
• Taroni JN, Mahoney JM, Whitfield ML. The mechanistic implications of gene expression studies in SSc: insights from systems biology. Curr Treatm Opt Rheumatol. 2017 Sep;3(3):181–192.
   PubMedGoogle Scholar
• Franks JM, Toledo DM, Martyanov V, et al. A genomic meta-analysis of clinical variables and their association with intrinsic molecular subsets in systemic sclerosis. Rheumatology (Oxford). 2022 Dec 23;62(1):19–28.
   PubMed Web of Science ®Google Scholar
• Yang M, Goh V, Lee J, et al. Clinical phenotypes of patients with systemic sclerosis with distinct molecular signatures in skin. Arthritis Care Res (Hoboken). 2022 Aug 23. DOI:10.1002/acr.24998.
   Web of Science ®Google Scholar
• Franks JM, Martyanov V, Wang Y, et al. Machine learning predicts stem cell transplant response in severe scleroderma. Ann Rheum Dis. 2020 Dec;79(12):1608–1615.
   PubMed Web of Science ®Google Scholar
• Shand L, Lunt M, Nihtyanova S, et al. Relationship between change in skin score and disease outcome in diffuse cutaneous systemic sclerosis: application of a latent linear trajectory model. Arthritis Rheum. 2007 Jul;56(7):2422–2431.
   PubMed Web of Science ®Google Scholar
• Ramahi A, Lescoat A, Roofeh D, et al. Risk factors for lung function decline in systemic sclerosis-associated interstitial lung disease in a large single-center cohort. Rheumatology (Oxford). 2022 Nov 15. DOI:10.1093/rheumatology/keac639.
   PubMedGoogle Scholar
• Isomura Y, Shirai Y, Kuwana M. Clinical worsening following discontinuation of tocilizumab in diffuse cutaneous systemic sclerosis: a single-centre experience in Japan. Rheumatology (Oxford). 2022 Nov 2;61(11):4491–4496.
   PubMed Web of Science ®Google Scholar