297
Views
0
CrossRef citations to date
0
Altmetric
Review

Drug development and novel therapeutics to ensure a personalized approach in the treatment of systemic sclerosis

ORCID Icon, ORCID Icon, , ORCID Icon, , , & show all
Pages 1131-1142 | Received 24 Mar 2023, Accepted 23 Jun 2023, Published online: 29 Jun 2023

References

  • Farina N, Benanti G, de Luca G, et al. The role of the multidisciplinary health care team in the management of patients with systemic sclerosis. J Multidiscip Healthc. 2022;15:815–824. doi: 10.2147/JMDH.S295478
  • Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390(10103):1685–1699. doi: 10.1016/S0140-6736(17)30933-9
  • Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380:2518–2528. doi: 10.1056/NEJMoa1903076
  • Ebata S, Yoshizaki A, Oba K, et al. Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blind, investigator-initiated, randomised, placebo-controlled trial. Lancet Rheumatol. 2021;3(7):e489–e497. doi: 10.1016/S2665-9913(21)00107-7
  • 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 - ACR meeting abstracts.
  • Spiera RF, Gordon JK, Mersten JN, et al. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis. 2011;70(6):1003–1009. doi: 10.1136/ard.2010.143974
  • Gordon J, Udeh U, Doobay K, et al. Imatinib mesylate (Gleevec?) in the treatment of diffuse cutaneous systemic sclerosis: results of a 24-month open label, extension phase, single-centre trial. Clin Exp Rheumatol. 2014;32:S–189–93.
  • Khanna D, Saggar R, Mayes MD, et al. A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease. Arthritis Rheum. 2011;63(11):3540–3546. doi: 10.1002/art.30548
  • Prey S, Ezzedine K, Doussau A, et al. Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. Br J Dermatol. 2012;167(5):1138–1144. doi: 10.1111/j.1365-2133.2012.11186.x
  • Gordon JK, Martyanov V, Magro C, et al. Nilotinib (Tasigna™) in the treaTMent of early diffuse systemic sclerosis: an open-label, pilot clinical trial. Arthritis Res Ther. 2015;17:17. doi: 10.1186/s13075-015-0721-3
  • 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 & Rheumat. 2018;70(2):308–316. doi: 10.1002/art.40358
  • 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;205:674–684. doi: 10.1164/rccm.202103-0714OC
  • Roofeh D, Lin CJF, Goldin J, et al. Tocilizumab prevents progression of early systemic sclerosis-associated interstitial lung disease. Arthritis & Rheumat 2021;73:1301–1310. doi: 10.1002/art.41668
  • Fukasawa T, Yoshizaki A, Ebata S, et al. Pharmacokinetics, safety, and efficacy of subcutaneous brodalumab for systemic sclerosis with moderate-to-severe skin thickening: a single-arm, open-label, multi-dose, phase 1 Trial - ACR meeting abstracts [Internet]. [cited 2023 Feb 28]. Available from: https://acrabstracts.org/abstract/pharmacokinetics-safety-and-efficacy-of-subcutaneous-brodalumab-for-systemic-sclerosis-with-moderate-to-severe-skin-thickening-a-single-arm-open-label-multi-dose-phase-1-trial/
  • 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.
  • Spiera R, Hummers L, Chung L, et al. Safety and Efficacy of Lenabasum in a Phase II, Randomized, Placebo-Controlled Trial in Adults with Systemic Sclerosis. Arthritis & Rheumat. 2020;72(8):1350–1360. doi: 10.1002/art.41294
  • Behr J, Prasse A, Kreuter M, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. 2021;9(5):476–486. doi: 10.1016/S2213-2600(20)30554-3
  • 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(9):1672–1679. doi: 10.3899/jrheum.151322
  • 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(12):e743–e753–. doi: 10.1016/S2665-9913(20)30237-X
  • 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 & rheumat. 2020;72(1):125–136. doi: 10.1002/art.41055
  • O’Shea JJ, Kontzias A, Yamaoka K, et al. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis. 2013;72(suppl 2):ii111–ii115. doi: 10.1136/annrheumdis-2012-202576
  • Campochiaro C, Allanore Y. An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years. Arthritis Res Ther. 2021;23(1):23. doi: 10.1186/s13075-021-02536-5
  • Pendergrass SA, Hayes E, Farina G, et al. Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS One. 2010;5(8):e12106. doi: 10.1371/journal.pone.0012106
  • 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. doi: 10.1177/2397198319865367
  • Rubbert-Roth A, Enejosa J, Pangan AL, et al. Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis. N Engl J Med. 2020;383(16):1511–1521. doi: 10.1056/NEJMoa2008250
  • Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017;376(7):652–662. doi: 10.1056/NEJMoa1608345
  • Combe B, Kivitz A, Tanaka Y, et al. Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial. Ann Rheum Dis. 2021;80(7):848–858. doi: 10.1136/annrheumdis-2020-219214
  • Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316–326. doi: 10.1056/NEJMoa2109927
  • Fujita Y, Nawata M, Nagayasu A, et al. Fifty-Two-Week Results of Clinical and Imaging Assessments of a Patient with Rheumatoid Arthritis Complicated by Systemic Sclerosis with Interstitial Pneumonia and Type 1 Diabetes despite Multiple Disease-Modifying Antirheumatic Drug Therapy That Was Successfully Treated with Baricitinib: a Novel Case Report. Case Rep Rheumatol. 2019;2019:1–5.
  • Boleto G, Cren J-B, Avouac J, et al. Successful treatment with baricitinib of refractory arthritis in a patient with severe diffuse cutaneous systemic sclerosis-rheumatoid arthritis overlap syndrome. Clin Exp Rheumatol. 2021;39(131):163–164. doi: 10.55563/clinexprheumatol/gu1ac8
  • Hudowenz O, Klemm P, Lange U, et al. Widespread soft tissue calcification in systemic sclerosis, polymyositis, and polyarthritis. Lancet. 2021;397(10272):409. doi: 10.1016/S0140-6736(21)00134-3
  • Kitanaga Y, Imamura E, Nakahara Y, et al. In vitro pharmacological effects of peficitinib on lymphocyte activation: a potential treatment for systemic sclerosis with JAK inhibitors. Rheumatology (Oxford). 2020;59(8):1957–1968. doi: 10.1093/rheumatology/kez526
  • Etra AM, Capellini A, Alousi AM, et al. Effective treatment of low-risk acute GVHD with itacitinib monotherapy. Blood. 2023;141(5):481–489. doi: 10.1182/blood.2022017442
  • Knipe RS, Tager AM, Liao JK, et al. The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev. 2015;67(1):103–117. doi: 10.1124/pr.114.009381
  • Ali F, Ilyas A. Belumosudil with ROCK-2 inhibition: chemical and therapeutic development to FDA approval for the treatment of chronic graft-versus-host disease. Curr Res Transl Med. 2022;70:103343. doi: 10.1016/j.retram.2022.103343
  • 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(8):2553–2564. doi: 10.1002/art.23677
  • 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(1):44–55. doi: 10.3109/01902148.2016.1141263
  • Zhou Y, Huang X, Hecker L, et al. Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest. 2013;123(3):1096–1108. doi: 10.1172/JCI66700
  • Brown M, O’Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin Exp Immunol. 2019;195(3):310–321. doi: 10.1111/cei.13238
  • Dees C, Pötter S, Zhang Y, et al. TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. J Clin Invest. 2020;130:2347–2363. doi: 10.1172/JCI122462
  • Lomelí-Nieto JA, Muñoz-Valle JF, Baños-Hernández CJ, et al. Transforming growth factor beta isoforms and TGF-βR1 and TGF-βR2 expression in systemic sclerosis patients. Clin Exp Med. 2022;23(2):471–481. doi: 10.1007/s10238-022-00841-0
  • Trojanowska M. Role of PDGF in fibrotic diseases and systemic sclerosis. Rheumatology (Oxford). 2008;47(5):v2–v4. doi: 10.1093/rheumatology/ken265
  • Svegliati Baroni S, Santillo M, Bevilacqua F, et al. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med. 2006;354(25):2667–2676. doi: 10.1056/NEJMoa052955
  • Papadopoulos N, Lennartsson J. The PDGF/PDGFR pathway as a drug target. Mol Aspects Med. 2018;62:75–88. doi: 10.1016/j.mam.2017.11.007
  • 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. doi: 10.1002/art.22289
  • Karimizadeh E, Motamed N, Mahmoudi M, et al. Attenuation of fibrosis with selective inhibition of c-Abl by siRNA in systemic sclerosis dermal fibroblasts. Arch Dermatol Res. 2015;307(2):135–142. doi: 10.1007/s00403-014-1532-0
  • Karimizadeh E, Gharibdoost F, Motamed N, et al. C-Abl silencing reduced the inhibitory effects of TGF-β1 on apoptosis in systemic sclerosis dermal fibroblasts. Mol Cell Biochem. 2015;405(1–2):169–176. doi: 10.1007/s11010-015-2408-0
  • Waller CF. Imatinib Mesylate. Recent Results Cancer Res. 2018;212:1–27.
  • Nagar B. C-Abl tyrosine kinase and inhibition by the cancer drug imatinib (Gleevec/STI-571). J Nutr. 2007;137(6):1518S–1523S. doi: 10.1093/jn/137.6.1518S
  • Hinchcliff M, Huang CC, Ishida W, et al. Imatinib Mesylate Causes Genome-wide Transcriptional Changes in Systemic Sclerosis Fibroblasts in vitro. Clin Exp Rheumatol. 2012;30:S86.
  • Bournia VK, Evangelou K, Sfikakis PP. Therapeutic inhibition of tyrosine kinases in systemic sclerosis: a review of published experience on the first 108 patients treated with imatinib. Semin Arthritis Rheum. 2013;42(4):377–390. doi: 10.1016/j.semarthrit.2012.06.001
  • Liakouli V, Ciaffi J, Ursini F, et al. Efficacy and safety of imatinib mesylate in systemic sclerosis. A systematic review and meta-analysis. Expert Rev Clin Immunol. 2020;16(9):931–942. doi: 10.1080/1744666X.2020.1813569
  • Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110:3540–3546. doi: 10.1182/blood-2007-03-080689
  • Manley PW, Drueckes P, Fendrich G, et al. Extended kinase profile and properties of the protein kinase inhibitor nilotinib. Biochim Biophys Acta. 2010;1804(3):445–453. doi: 10.1016/j.bbapap.2009.11.008
  • Akhmetshina A, Dees C, Pileckyte M, et al. Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. Faseb J. 2008;22(7):2214–2222. doi: 10.1096/fj.07-105627
  • Xue M, Cao X, Zhong Y, et al. Insulin-like growth factor-1 receptor (IGF-1R) kinase inhibitors in cancer therapy: advances and perspectives. Curr Pharm Des. 2012;18(20):2901–2913. doi: 10.2174/138161212800672723
  • Hamaguchi Y, Fujimoto M, Matsushita T, et al. Elevated serum insulin-like growth factor (IGF-1) and IGF binding protein-3 levels in patients with systemic sclerosis: possible role in development of fibrosis. J Rheumatol. 2008;35(12):2363–2371. doi: 10.3899/jrheum.080340
  • Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the Treatment of Active Thyroid Eye Disease. N Engl J Med. 2020 [[cited 2023 Feb 5]];382:341–352. InternetAvailable from https://pubmed.ncbi.nlm.nih.gov/31971679/
  • Yap DYH, Chan TM. B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis—Role in Pathogenesis and Effect of Immunosuppressive Treatments. Int J Mol Sci. 2019;20:20. doi: 10.3390/ijms20246231
  • Liem SIE, Neppelenbroek S, Fehres CM, et al. Autoreactive B cell responses targeting nuclear antigens in systemic sclerosis: implications for disease pathogenesis. Semin Arthritis Rheum. 2023;58:152136. doi: 10.1016/j.semarthrit.2022.152136
  • Morgan K, Woollard C, Beinart D, et al. Rituximab treatment for systemic sclerosis-associated interstitial lung disease: a case series of 13 patients. Intern Med J. 2022. doi:10.1111/imj.15832.
  • 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. 2023 [[cited 2023 Feb 28]];11:45–54. InternetAvailable from https://pubmed.ncbi.nlm.nih.gov/36375479/
  • 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;18(1): doi: 10.1186/s13075-016-1021-2
  • 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 & Rheumat. 2018;70(12):2087–2095. doi: 10.1002/art.40656
  • Malysz J, Erdman P, Klapper J, et al. Clinical Implications of CD30 Expression in Aggressive B-Cell Lymphomas. Clin Lymphoma Myeloma Leuk. 2016;16(8):429–433. doi: 10.1016/j.clml.2016.04.011
  • Giacomelli R, Cipriani P, Lattanzio R, et al. Circulating levels of soluble CD30 are increased in patients with systemic sclerosis (SSc) and correlate with serological and clinical features of the disease. Clin Exp Immunol. 2003;108(1):42–46. doi: 10.1046/j.1365-2249.1997.d01-991.x
  • Furie R, Rovin BH, Houssiau F, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med. 2020;383(12):1117–1128. doi: 10.1056/NEJMoa2001180
  • Shipa M, Embleton-Thirsk A, Parvaz M, et al. Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus: a Randomized Controlled Trial. Ann Intern Med. 2021;174(12):1647–1657. doi: 10.7326/M21-2078
  • de Luca G, Cavalli G, Campochiaro C, et al. Interleukin-1 and Systemic Sclerosis: getting to the Heart of Cardiac Involvement. Front Immunol. 2021;12:12. doi: 10.3389/fimmu.2021.653950
  • O’Reilly S, Cant R, Ciechomska M, et al. Interleukin-6: a new therapeutic target in systemic sclerosis? Clin Transl Immunology. 2013;2(4):e4. doi: 10.1038/cti.2013.2
  • 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. doi: 10.1016/S0140-6736(16)00232-4
  • FDA. Highlights of prescribing information of Actemra.
  • Rafael-Vidal C, Pérez N, Altabás I, et al. Blocking IL-17: a Promising Strategy in the Treatment of Systemic Rheumatic Diseases. Int J Mol Sci. 2020;21:1–14. doi: 10.3390/ijms21197100
  • Lei L, Zhao C, Qin F, et al. Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis. Clin Exp Rheumatol. 2016;34(100):14–22.
  • Wei L, Abraham D, Ong V. The Yin and Yang of IL-17 in Systemic Sclerosis. Front Immunol. 2022;13: doi: 10.3389/fimmu.2022.885609
  • Lebwohl M, Strober B, Menter A, et al. Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis. N Engl J Med. 2015;373(14):1318–1328. doi: 10.1056/NEJMoa1503824
  • Dinarello CA. The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol. 2019;15(10):612–632. doi: 10.1038/s41584-019-0277-8
  • De Luca G, Cavalli G, Campochiaro C, et al. Myocarditis: an Interleukin-1-Mediated Disease? Front Immunol. 2018;9:1335. doi: 10.3389/fimmu.2018.01335
  • Dinarello CA. Immunological and Inflammatory Functions of the Interleukin-1 Family. Annu Rev Immunol. 2009;27(1):519–550. doi: 10.1146/annurev.immunol.021908.132612
  • Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117(14):3720–3732. doi: 10.1182/blood-2010-07-273417
  • Xu D, Mu R, Wei X. The Roles of IL-1 Family Cytokines in the Pathogenesis of Systemic Sclerosis. Front Immunol. 2019;10: doi: 10.3389/fimmu.2019.02025
  • Higgins GC, Wu Y, Postlethwaite AE. Intracellular IL-1 receptor antagonist is elevated in human dermal fibroblasts that overexpress intracellular precursor IL-1α. J Immunol. 1999;163(7):3969–3975. doi: 10.4049/jimmunol.163.7.3969
  • Hussein MR, Hassan HI, Hofny ERM, et al. Alterations of mononuclear inflammatory cells, CD4/CD8+ T cells, interleukin 1β, and tumour necrosis factor α in the bronchoalveolar lavage fluid, peripheral blood, and skin of patients with systemic sclerosis. J Clin Pathol. 2005;58:178–184. doi: 10.1136/jcp.2004.019224
  • Martínez-Godínez MA, Del P C-DM, Jara LJ, et al. Expression of NLRP3 inflammasome, cytokines and vascular mediators in the skin of systemic sclerosis patients. Isr Med Assoc J. 2015;17(1):5–10.
  • Gottlieb A, Natsis NE, Kerdel F, et al. A Phase II Open-Label Study of Bermekimab in Patients with Hidradenitis Suppurativa Shows Resolution of Inflammatory Lesions and Pain. J Invest Dermatol. 2020 [[cited 2023 Feb 5]];140:1538–1545.e2. InternetAvailable from https://pubmed.ncbi.nlm.nih.gov/32004568/
  • Komura K, Fujimoto M, Hasegawa M, et al. Increased Serum Interleukin 23 in Patients with Systemic Sclerosis. J Rheumatol. 2008;35:2359–2362. doi: 10.3899/jrheum.080120
  • Senoo S, Taniguchi A, Itano J, et al. Essential role of IL-23 in the development of acute exacerbation of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2021;321(5):L925–L940. doi: 10.1152/ajplung.00582.2020
  • Deodhar A, Helliwell PS, Boehncke WH, et al. Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10230):1115–1125. doi: 10.1016/S0140-6736(20)30265-8
  • Kuzumi A, Yoshizaki A, Matsuda KM, et al. Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis. Nat Commun. 2021;12(1):12. doi: 10.1038/s41467-021-26099-w
  • Ständer S, Yosipovitch G, Legat FJ, et al. Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis. N Engl J Med. 2020;382(8):706–716. doi: 10.1056/NEJMoa1908316
  • SJ K. Nemolizumab: first Approval. Drugs. 2022;82:1143–1150. doi: 10.1007/s40265-022-01741-z
  • Lünemann JD, Nimmerjahn F, Dalakas MC. Intravenous immunoglobulin in neurology–mode of action and clinical efficacy. Nat Rev Neurol. 2015;11:80–89. doi: 10.1038/nrneurol.2014.253
  • Hoffmann JHO, Enk AH. High-Dose Intravenous Immunoglobulin in Skin Autoimmune Disease. Front Immunol. 2019;10:10. doi: 10.3389/fimmu.2019.01090
  • Aggarwal R, Charles-Schoeman C, Schessl J, et al. Trial of Intravenous Immune Globulin in Dermatomyositis. N Engl J Med. 2022;387(14):1264–1278. doi: 10.1056/NEJMoa2117912
  • Molina V, Haj-Yahia S, Solodeev I, et al. Immunomodulation of experimental pulmonary fibrosis by intravenous immunoglobulin (IVIG). Autoimmunity. 2006;39(8):711–717. doi: 10.1080/08916930601061272
  • Blank M, Levy Y, Amital H, et al. The role of intravenous immunoglobulin therapy in mediating skin fibrosis in tight skin mice. Arthritis Rheum. 2002;46(6):1689–1690. doi: 10.1002/art.10363
  • Levy Y, Sherer Y, Langevitz P, et al. Skin score decrease in systemic sclerosis patients treated with intravenous immunoglobulin–a preliminary report. Clin Rheumatol. 2000;19:207–211. doi: 10.1007/s100670050158
  • Agostini E, de Luca G, Bruni C, et al. Intravenous immunoglobulins reduce skin thickness in systemic sclerosis: evidence from Systematic Literature Review and from real life experience. Autoimmun Rev. 2021;20(12):20. doi: 10.1016/j.autrev.2021.102981
  • Clark KEN, Etomi O, Denton CP, et al. Intravenous immunoglobulin therapy for severe gastrointestinal involvement in systemic sclerosis. Clin Exp Rheumatol. 2015;33:168–170.
  • Mauhin W, Rivière S, Cabane J, et al. Improvement in lung fibrosis using intravenous immunoglobulin in systemic sclerosis with myositis. Scand J Rheumatol. 2014;43(2):170–171. doi: 10.3109/03009742.2013.868510
  • Garcia-Gonzalez E, Selvi E, Balistreri E, et al. Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts. Rheumatology (Oxford). 2009;48(9):1050–1056. doi: 10.1093/rheumatology/kep189
  • García-Martín A, Garrido-Rodríguez M, Navarrete C, et al. EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, alleviates bleomycin-induced skin and lung fibrosis. Biochem Pharmacol. 2018;157:304–313. doi: 10.1016/j.bcp.2018.07.047
  • Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760–1769. doi: 10.1016/S0140-6736(11)60405-4
  • Xiao H, Zhang GF, Liao XP, et al. Anti-fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis-associated interstitial lung disease. Int J Rheum Dis. 2018;21(2):477–486. doi: 10.1111/1756-185X.13247
  • Khanna D, Spino C, Bernstein E, et al. Combination Therapy of Mycophenolate Mofetil and Pirfenidone vs. Mycophenolate Alone: results from the Scleroderma Lung Study III - ACR Meeting Abstracts [Internet].
  • Varricchio L, Iancu-Rubin C, Upadhyaya B, et al. TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis. JCI Insight. 2021;6(18):6. doi: 10.1172/jci.insight.145651
  • Xie S, Li S, Tian J, et al. Iguratimod as a New Drug for Rheumatoid Arthritis: current Landscape. Front Pharmacol. 2020;11:11. doi: 10.3389/fphar.2020.00073
  • Mu R, Li C, Li X, et al. Effectiveness and safety of iguratimod treatment in patients with active rheumatoid arthritis in Chinese: a nationwide, prospective real-world study. Lancet Reg Health West Pac. 2021;10:100128.
  • Shu P, Shao SQ, Cai XN, et al. Iguratimod attenuates general disease activity and improves lung function in rheumatoid arthritis-associated interstitial lung disease patients. Eur Rev Med Pharmacol Sci. 2021;25(14):4687–4692. doi: 10.26355/eurrev_202107_26379
  • Lin H, Wu C, Zhu F, et al. Anti-fibrotic effect of iguratimod on pulmonary fibrosis by inhibiting the fibroblast-to-myofibroblast transition. Adv Med Sci. 2020;65:338–347. doi: 10.1016/j.advms.2020.05.006
  • Zhao L, Mu B, Zhou R, et al. Iguratimod ameliorates bleomycin-induced alveolar inflammation and pulmonary fibrosis in mice by suppressing expression of matrix metalloproteinase-9. Int J Rheum Dis. 2019;22(4):686–694. doi: 10.1111/1756-185X.13463
  • Xie X, Gan H, Tian J, et al. Iguratimod inhibits skin fibrosis by regulating TGF-β1/Smad signalling pathway in systemic sclerosis. Eur J Clin Invest. 2022;52(8): doi: 10.1111/eci.13791
  • Wang W, Guo DY, Lin YJ, et al. Melanocortin Regulation of Inflammation. Front Endocrinol. 2019;10:683.
  • Wolf Horrell EM, Boulanger MC, D’Orazio JA. Melanocortin 1 Receptor: structure, Function, and Regulation. Front Genet. 2016;7: doi: 10.3389/fgene.2016.00095
  • 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. doi: 10.1002/art.24228
  • Kondo M, Suzuki T, Kawano Y, et al. Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis. Arthritis Res Ther. 2022;24(1):24. doi: 10.1186/s13075-022-02899-3
  • Xu WD, Li R, Huang AF. Role of TL1A in Inflammatory Autoimmune Diseases: a Comprehensive Review. Front Immunol. 2022;13: doi: 10.3389/fimmu.2022.891328
  • Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: a Phase 2a Single-Arm Study. Clin Gastroenterol Hepatol. 2021;19(11):2324–2332.e6. doi: 10.1016/j.cgh.2021.06.011
  • Herro R, Miki H, Sethi GS, et al. TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling. J Immunol. 2020;205(9):2414–2422. doi: 10.4049/jimmunol.2000665
  • 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;36(6):1317–1324. doi: 10.1007/s10067-017-3612-y
  • Tsou PS, Talia NN, Pinney AJ, et al. Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts. Arthritis Rheum. 2012;64(6):1978–1989. doi: 10.1002/art.34336
  • Morrow JD. The isoprostanes: their quantification as an index of oxidant stress status in vivo. Drug Metab Rev. 2000;32:377–385. doi: 10.1081/DMR-100102340
  • Tsou PS, Amin MA, Campbell PL, et al. Activation of the Thromboxane A2 Receptor by 8-Isoprostane Inhibits the Pro-Angiogenic Effect of Vascular Endothelial Growth Factor in Scleroderma. J Invest Dermatol. 2015;135(12):3153–3162. doi: 10.1038/jid.2015.323
  • Katz SD, Radin M, Graves T, et al. Effect of aspirin and ifetroban on skeletal muscle blood flow in patients with congestive heart failure treated with enalapril. J Am Coll Cardiol. 1999;34(1):170–176. doi: 10.1016/S0735-1097(99)00180-1
  • Suzuki T, Kropski JA, Chen J, et al. Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis. Am J Respir Crit Care Med. 2022;206:596–607. doi: 10.1164/rccm.202106-1503OC
  • Coux O, Tanaka K, Goldberg AL. Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem. 1996;65(1):801–847. doi: 10.1146/annurev.bi.65.070196.004101
  • Krüger E, Kloetzel PM. Immunoproteasomes at the interface of innate and adaptive immune responses: two faces of one enzyme. Curr Opin Immunol. 2012;24(1):77–83. doi: 10.1016/j.coi.2012.01.005
  • Limanaqi F, Biagioni F, Gaglione A, et al. A Sentinel in the Crosstalk Between the Nervous and Immune System: the (Immuno)-Proteasome. Front Immunol. 2019;10:10. doi: 10.3389/fimmu.2019.00628
  • Verbrugge EE, Scheper RJ, Lems WF, et al. Proteasome inhibitors as experimental therapeutics of autoimmune diseases. Arthritis Res Ther. 2015;17:17. doi: 10.1186/s13075-015-0529-1
  • Yoon B, Yun Y, Kim KB, et al. Inhibition of immunoproteasome attenuates NLRP3 inflammasome formation in tumor necrosis factor α-stimulated intestinal epithelial cell. Biochem Biophys Res Commun. 2022;624:157–163. doi: 10.1016/j.bbrc.2022.07.120
  • Del Rio Oliva M, Mellett M, Basler M. Immunoproteasome inhibition attenuates experimental psoriasis. Front Immunol. 2022;13: doi: 10.3389/fimmu.2022.1075615
  • Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;374(17):1621–1634. doi: 10.1056/NEJMoa1516282
  • Fernández-Díaz C, Castañeda S, Melero-González RB, et al. Abatacept in interstitial lung disease associated with rheumatoid arthritis: national multicenter study of 263 patients. Rheumatology (Oxford). 2020;59(12):3906–3916. doi: 10.1093/rheumatology/keaa621
  • Kalogerou A, Gelou E, Mountantonakis S, et al. Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis. 2005;64:1233–1235. doi: 10.1136/ard.2004.027094
  • 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(12):2142–2149. doi: 10.1136/annrheumdis-2015-208213
  • 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):17. doi: 10.1186/s13075-015-0669-3

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.