Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Emerging therapies for the treatment of systemic sclerosis

Nature Reviews Rheumatology volume 21, pages 612–625 (2025)Cite this article

Subjects

Abstract

Systemic sclerosis (SSc) is an autoimmune disease in which fibrotic, vascular, autoimmune and fibrotic mechanisms synergize to promote disease progression. SSc is associated with high morbidity and mortality, primarily owing to fibrotic tissue remodelling and subsequent organ failure. Despite progress with the approval of novel therapies, mortality remains high; approximately half of the people diagnosed with SSc will succumb to disease. This statistic highlights the considerable need for novel, effective therapies. Indeed, SSc has become a disease with very active drug development. Numerous drugs with different modes of actions are currently evaluated in or are about to enter clinical trials in SSc. These clinical trials provide hope for effectively slowing or even halting the progression of fibrosis and thereby further improving outcomes for patients with SSc.

Key points

  • Currently available drugs for systemic sclerosis (SSc) might slow down disease progression, but do not halt it, generating a great medical need for novel, more effective therapies.

  • These drug candidates have a broad-spectrum of distinct anti-inflammatory and/or anti-fibrotic modes of action relevant to the pathogenesis of SSc.

  • A large number of drug candidates and cellular therapies with different molecular modes of actions are currently under investigation or about to enter clinical trials in SSc.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Distler, J. H. W. et al. Shared and distinct mechanisms of fibrosis. Nat. Rev. Rheumatol. 15, 705–730 (2019).

    Article  CAS  PubMed  Google Scholar 

  2. Tyndall, A. J. et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR scleroderma trials and research (EUSTAR) database. Ann. Rheum. Dis. 69, 1809–1815 (2010).

    Article  PubMed  Google Scholar 

  3. Pope, J. E. et al. State-of-the-art evidence in the treatment of systemic sclerosis. Nat. Rev. Rheumatol. 19, 212–226 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Horn, A. et al. Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis. Ann. Rheum. Dis. 71, 785–789 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Lam, A. P. et al. Nuclear beta-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am. J. Respir. Cell Mol. Biol. 45, 915–922 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Horn, A. et al. Hedgehog signaling controls fibroblast activation and tissue fibrosis in systemic sclerosis. Arthritis Rheum. 64, 2724–2733 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Dees, C. et al. Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann. Rheum. Dis. 70, 1304–1310 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. He, W. et al. Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J. Am. Soc. Nephrol. 20, 765–776 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Konigshoff, M. et al. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J. Clin. Invest. 119, 772–787 (2009).

    PubMed  PubMed Central  Google Scholar 

  10. Guan, S. & Zhou, J. Frizzled-7 mediates TGF-β-induced pulmonary fibrosis by transmitting non-canonical Wnt signaling. Exp. Cell Res. 359, 226–234 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Saito, A. & Nagase, T. Hippo and TGF-β interplay in the lung field. Am. J. Physiol. Lung Cell Mol. Physiol. 309, L756–L767 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Burgy, O. & Konigshoff, M. The WNT signaling pathways in wound healing and fibrosis. Matrix Biol. 68–69, 67–80 (2018).

    Article  PubMed  Google Scholar 

  13. Beyer, C. & Distler, J. H. Morphogen pathways in systemic sclerosis. Curr. Rheumatol. Rep. 15, 299 (2013).

    Article  PubMed  Google Scholar 

  14. Bergmann, C. & Distler, J. H. Canonical Wnt signaling in systemic sclerosis. Lab. Invest. 96, 151–155 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Beyer, C. et al. Elevated serum levels of sonic hedgehog are associated with fibrotic and vascular manifestations in systemic sclerosis. Ann. Rheum. Dis. 77, 626–628 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Beyer, C. et al. Elevated serum levels of sonic hedgehog are associated with fibrotic and vascular manifestations in systemic sclerosis. Ann. Rheum. Dis. 77, 626–628 (2017).

    Article  PubMed  Google Scholar 

  17. Liang, R. et al. The transcription factor GLI2 as a downstream mediator of transforming growth factor-β-induced fibroblast activation in SSc. Ann. Rheum. Dis. 76, 756–764 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Hu, B. et al. Reemergence of hedgehog mediates epithelial-mesenchymal crosstalk in pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 52, 418–428 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ding, H. et al. Sonic hedgehog signaling mediates epithelial-mesenchymal communication and promotes renal fibrosis. J. Am. Soc. Nephrol. 23, 801–813 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. El-Agroudy, N. N., El-Naga, R. N., El-Razeq, R. A. & El-Demerdash, E. Forskolin, a hedgehog signalling inhibitor, attenuates carbon tetrachloride-induced liver fibrosis in rats. Br. J. Pharmacol. 173, 3248–3260 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dubey, A. K., Dubey, S., Handu, S. S. & Qazi, M. A. Vismodegib: the first drug approved for advanced and metastatic basal cell carcinoma. J. Postgrad. Med. 59, 48–50 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Maher, T. M. et al. American Thoracic Society International Conference. Am. J. Respir. Crit. Care Med. 209, A1056 (2024).

    Google Scholar 

  23. Song, Y. et al. Pharmacokinetics of fipaxalparant, a small-molecule selective negative allosteric modulator of lysophosphatidic acid receptor 1, and the effect of food in healthy volunteers. Clin. Pharmacol. Drug. Dev. 13, 819–827 (2024).

    Article  CAS  PubMed  Google Scholar 

  24. Tager, A. M. et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat. Med. 14, 45–54 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Corte, T. J. et al. Efficacy and safety of admilparant, an LPA(1) antagonist, in pulmonary fibrosis: a phase 2 randomized clinical trial. Am. J. Respir. Crit. Care Med. 211, 230–238 (2025).

    Article  CAS  PubMed  Google Scholar 

  26. Allanore, Y. 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. 70, 1634–1643 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Khanna, D. et al. A 24-week, phase IIa, randomized, double-blind, placebo-controlled study of ziritaxestat in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 75, 1434–1444 (2023).

    Article  CAS  PubMed  Google Scholar 

  28. Maher, T. M. et al. Ziritaxestat, a novel autotaxin inhibitor, and lung function in idiopathic pulmonary fibrosis: the ISABELA 1 and 2 randomized clinical trials. JAMA 329, 1567–1578 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Meng, X. M., Nikolic-Paterson, D. J. & Lan, H. Y. TGF-β: the master regulator of fibrosis. Nat. Rev. Nephrol. 12, 325–338 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Radaev, S. et al. Ternary complex of transforming growth factor-β1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily. J. Biol. Chem. 285, 14806–14814 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lodyga, M. & Hinz, B. TGF-β1 — a truly transforming growth factor in fibrosis and immunity. Semin. Cell Dev. Biol. 101, 123–139 (2020).

    Article  CAS  PubMed  Google Scholar 

  32. Gyorfi, A. H., Matei, A. E. & Distler, J. H. W. Targeting TGF-β signaling for the treatment of fibrosis. Matrix Biol. 68-69, 8–27 (2018).

    Article  PubMed  Google Scholar 

  33. Denton, C. P. et al. Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum. 56, 323–333 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Rice, L. M. et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J. Clin. Invest. 125, 2795–2807 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mascarenhas, J. et al. A phase Ib trial of AVID200, a TGFβ 1/3 trap, in patients with myelofibrosis. Clin. Cancer Res. 29, 3622–3632 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hoeper, M. M. et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N. Engl. J. Med. 388, 1478–1490 (2023).

    Article  CAS  PubMed  Google Scholar 

  37. Han, L. W. et al. A phase 1a study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, an anti-TGFβ3 antibody, in healthy volunteers. Rheumatol. Ther. 11, 755–771 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wu, L. et al. Transforming growth factor β3 (TGFβ3) accelerates wound healing without alteration of scar prominence. Histologic and competitive reverse-transcription-polymerase chain reaction studies. Arch. Surg. 132, 753–760 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Ren, H. L., Zhang, S. H. & Li, P. Y. The multifaceted role of phosphodiesterase 4 in tumor: from tumorigenesis to immunotherapy. Front. Immunol. 16, 1528932 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Aringer, M. et al. Rationale for phosphodiesterase-4 inhibition as a treatment strategy for interstitial lung diseases associated with rheumatic diseases. RMD Open. 10, e004704 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  41. McDonough, W. et al. PAN-selective inhibition of cAMP-phosphodiesterase 4 (PDE4) induces gastroparesis in mice. FASEB J. 34, 12533–12548 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Rogliani, P., Calzetta, L., Cazzola, M. & Matera, M. G. Drug safety evaluation of roflumilast for the treatment of COPD: a meta-analysis. Expert. Opin. Drug Saf. 15, 1133–1146 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Kolb, M., Crestani, B. & Maher, T. M. Phosphodiesterase 4B inhibition: a potential novel strategy for treating pulmonary fibrosis. Eur. Respir. Rev. 32, 220206 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Herrmann, F. E., Hesslinger, C., Wollin, L. & Nickolaus, P. BI 1015550 is a PDE4B inhibitor and a clinical drug candidate for the oral treatment of idiopathic pulmonary fibrosis. Front. Pharmacol. 13, 838449 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu, Y. et al. Nerandomilast improves bleomycin-induced systemic sclerosis-associated interstitial lung disease in mice by regulating the TGF-β1 pathway. Inflammation 48, 1760–1774 (2025).

    Article  PubMed  Google Scholar 

  46. Richeldi, L. et al. Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis. N. Engl. J. Med. 386, 2178–2187 (2022).

    Article  CAS  PubMed  Google Scholar 

  47. Maher, T. M. et al. Nerandomilast in patients with progressive pulmonary fibrosis. N. Engl. J. Med. 392, 2203–2214 (2025).

    Article  CAS  PubMed  Google Scholar 

  48. Khanna, D. et al. Design of CONQUEST, a novel, randomized, placebo-controlled, phase 2b platform clinical trial to investigate new treatments for patients with early active systemic sclerosis with interstitial lung disease. J. Scleroderma Relat. Disord. 23971983241278079 (2024).

  49. Jager, B. et al. The NLRP3-inflammasome-caspase-1 pathway is upregulated in idiopathic pulmonary fibrosis and acute exacerbations and is inducible by apoptotic A549 cells. Front. Immunol. 12, 642855 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Gronberg, C. et al. Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis. Ann. Rheum. Dis. 83, 1156–1168 (2024).

    Article  PubMed  Google Scholar 

  51. Garlanda, C., Dinarello, C. A. & Mantovani, A. The interleukin-1 family: back to the future. Immunity 39, 1003–1018 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kondo, M. et al. Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis. Arthritis Res. Ther. 24, 210 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, W., Guo, D. Y., Lin, Y. J. & Tao, Y. X. Melanocortin regulation of inflammation. Front. Endocrinol. 10, 683 (2019).

    Article  Google Scholar 

  54. Bohm, M. & Stegemann, A. Bleomycin-induced fibrosis in MC1 signalling-deficient C57BL/6J-Mc1r(e/e) mice further supports a modulating role for melanocortins in collagen synthesis of the skin. Exp. Dermatol. 23, 431–433 (2014).

    Article  PubMed  Google Scholar 

  55. Scholzen, T. E. et al. α-melanocyte stimulating hormone prevents lipopolysaccharide-induced vasculitis by down-regulating endothelial cell adhesion molecule expression. Endocrinology 144, 360–370 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Vecsernyes, M. et al. The administration of α-melanocyte-stimulating hormone protects the ischemic/reperfused myocardium. Eur. J. Pharmacol. 470, 177–183 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. US National Library of Medicine. Study to evaluate efficacy, safety, and tolerability of MT-7117 in subjects with diffuse cutaneous systemic sclerosis. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04440592 (2020).

  58. de Valliere, C. et al. pH-sensing G protein-coupled receptor OGR1 (GPR68) expression and activation increases in intestinal inflammation and fibrosis. Int. J. Mol. Sci. 23, 1419 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Li, J. et al. Ovarian cancer G protein coupled receptor 1 suppresses cell migration of MCF7 breast cancer cells via a Gα12/13-Rho-Rac1 pathway. J. Mol. Signal. 8, 6 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zhang, Y. et al. FT011, a new anti-fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy. Eur. J. Heart Fail. 14, 549–562 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Spiera, R. et al. Efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in a phase 3 randomized trial in diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 75, 1608–1618 (2023).

    Article  CAS  PubMed  Google Scholar 

  62. Roh, J. S. & Sohn, D. H. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 18, e27 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Strutz, F. et al. Identification and characterization of a fibroblast marker: FSP1. J. Cell Biol. 130, 393–405 (1995).

    Article  CAS  PubMed  Google Scholar 

  64. Tomcik, M. et al. S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis. Ann. Rheum. Dis. 74, 1748–1755 (2015).

    Article  CAS  PubMed  Google Scholar 

  65. Cerezo, L. A. et al. The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis. Rheumatology 53, 1520–1526 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Dahlmann, M. et al. RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis. Oncotarget 5, 3220–3233 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Svec, X. et al. S100A4-neutralizing monoclonal antibody 6B12 counteracts the established experimental skin fibrosis induced by bleomycin. Rheumatology 63, 817–825 (2024).

    Article  CAS  PubMed  Google Scholar 

  68. Denton, C. P. et al. Clinical and pathogenic significance of S100A4 overexpression in systemic sclerosis. Ann. Rheum. Dis. 82, 1205–1217 (2023).

    Article  CAS  PubMed  Google Scholar 

  69. Trinh-Minh, T. et al. Effect of anti-S100A4 monoclonal antibody treatment on experimental skin fibrosis and systemic sclerosis-specific transcriptional signatures in human skin. Arthritis Rheumatol. 76, 783–795 (2024).

    Article  CAS  PubMed  Google Scholar 

  70. Dees, C. et al. TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. J. Clin. Invest. 130, 2347–2363 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zehender, A. et al. The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis. Nat. Commun. 9, 3259 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Chakraborty, D. et al. Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nat. Commun. 8, 1130 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Zhang, Y. et al. JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment. Ann. Rheum. Dis. 76, 1467–1475 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Zhang, Y. et al. Inhibition of casein kinase II reduces TGFβ induced fibroblast activation and ameliorates experimental fibrosis. Ann. Rheum. Dis. 74, 936–943 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Dees, C. et al. JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis. Arthritis Rheum. 64, 3006–3015 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Avouac, J. et al. Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. Arthritis Rheum. 63, 800–809 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Rueda, B. et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum. Mol. Genet. 18, 2071–2077 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Sofen, H. et al. Efficacy and safety of vixarelimab, a human monoclonal oncostatin M receptor β antibody, in moderate-to-severe prurigo nodularis: a randomised, double-blind, placebo-controlled, phase 2a study. EClinicalMedicine 57, 101826 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kwatra, S. G. et al. Phase 3 trial of nemolizumab in patients with prurigo nodularis. N. Engl. J. Med. 389, 1579–1589 (2023).

    Article  CAS  PubMed  Google Scholar 

  80. Misery, L. et al. Basic mechanisms of itch. J. Allergy Clin. Immunol. 152, 11–23 (2023).

    Article  CAS  PubMed  Google Scholar 

  81. Yaseen, B. et al. Interleukin-31 promotes pathogenic mechanisms underlying skin and lung fibrosis in scleroderma. Rheumatology 59, 2625–2636 (2020).

    Article  CAS  PubMed  Google Scholar 

  82. Kuzumi, A. et al. Interleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis. Nat. Commun. 12, 5947 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hasegawa, M. et al. Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J. Rheumatol. 25, 308–313 (1998).

    CAS  PubMed  Google Scholar 

  84. de Almeida, A. R. et al. Increased levels of the soluble oncostatin M receptor (sOSMR) and glycoprotein 130 (sgp130) in systemic sclerosis patients and associations with clinical parameters. Immunobiology 225, 151964 (2020).

    Article  PubMed  Google Scholar 

  85. Denton, C. P. et al. Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis. Rheumatology 62, 234–242 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Marden, G. et al. The role of the oncostatin M/OSM receptor β axis in activating dermal microvascular endothelial cells in systemic sclerosis. Arthritis Res. Ther. 22, 179 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Roopenian, D. C. & Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715–725 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Chaudhury, C. et al. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J. Exp. Med. 197, 315–322 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Akilesh, S., Christianson, G. J., Roopenian, D. C. & Shaw, A. S. Neonatal FcR expression in bone marrow-derived cells functions to protect serum IgG from catabolism. J. Immunol. 179, 4580–4588 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Qiao, S. W. et al. Dependence of antibody-mediated presentation of antigen on FcRn. Proc. Natl Acad. Sci. USA 105, 9337–9342 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Montoyo, H. P. et al. Conditional deletion of the MHC class I-related receptor FcRn reveals the sites of IgG homeostasis in mice. Proc. Natl Acad. Sci. USA 106, 2788–2793 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ober, R. J., Martinez, C., Lai, X., Zhou, J. & Ward, E. S. Exocytosis of IgG as mediated by the receptor, FcRn: an analysis at the single-molecule level. Proc. Natl Acad. Sci. USA 101, 11076–11081 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Prabhat, P. et al. Elucidation of intracellular recycling pathways leading to exocytosis of the Fc receptor, FcRn, by using multifocal plane microscopy. Proc. Natl Acad. Sci. USA 104, 5889–5894 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kuo, T. T. et al. Neonatal Fc receptor: from immunity to therapeutics. J. Clin. Immunol. 30, 777–789 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ulrichts, P. et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J. Clin. Invest. 128, 4372–4386 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Francois, A. et al. B lymphocytes and B-cell activating factor promote collagen and profibrotic markers expression by dermal fibroblasts in systemic sclerosis. Arthritis Res. Ther. 15, R168 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Matsushita, T. et al. BAFF antagonist attenuates the development of skin fibrosis in tight-skin mice. J. Invest. Dermatol. 127, 2772–2780 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Francois, A. et al. B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis. J. Autoimmun. 56, 1–11 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Brkic, Z. et al. The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis. Ann. Rheum. Dis. 75, 1567–1573 (2016).

    Article  CAS  PubMed  Google Scholar 

  100. Dhillon, S. Telitacicept: first approval. Drugs 81, 1671–1675 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Arneth, B. M. Impact of B cells to the pathophysiology of multiple sclerosis. J. Neuroinflamm. 16, 128 (2019).

    Article  Google Scholar 

  102. Schett, G., Mackensen, A. & Mougiakakos, D. CAR T-cell therapy in autoimmune diseases. Lancet 402, 2034–2044 (2023).

    Article  CAS  PubMed  Google Scholar 

  103. Muller, F. et al. CD19 CAR T-cell therapy in autoimmune disease — a case series with follow-up. N. Engl. J. Med. 390, 687–700 (2024).

    Article  PubMed  Google Scholar 

  104. Schett, G. et al. Advancements and challenges in CAR T cell therapy in autoimmune diseases. Nat. Rev. Rheumatol. 20, 531–544 (2024).

    Article  PubMed  Google Scholar 

  105. Bergmann, C. et al. Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. Ann. Rheum. Dis. 82, 1117–1120 (2023).

    Article  PubMed  Google Scholar 

  106. Tur, C. et al. CD19-CAR T-cell therapy induces deep tissue depletion of B cells. Ann. Rheum. Dis. 84, 106–114 (2025).

    Article  CAS  PubMed  Google Scholar 

  107. Wang, X. et al. Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis. Cell 187, 4890–4904 e4899 (2024).

    Article  CAS  PubMed  Google Scholar 

  108. Muller, F. et al. BCMA CAR T cells in a patient with relapsing idiopathic inflammatory myositis after initial and repeat therapy with CD19 CAR T cells. Nat. Med. 31, 1793–1797 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Subklewe, M. et al. Application of blinatumomab, a bispecific anti-CD3/CD19 T-cell engager, in treating severe systemic sclerosis: a case study. Eur. J. Cancer 204, 114071 (2024).

    Article  CAS  PubMed  Google Scholar 

  110. Hagen, M. et al. BCMA-targeted T-cell-engager therapy for autoimmune disease. N. Engl. J. Med. 391, 867–869 (2024).

    Article  PubMed  Google Scholar 

  111. van de Donk, N. C. J. & Zweegman, S. T-cell-engaging bispecific antibodies in cancer. Lancet 402, 142–158 (2023).

    Article  PubMed  Google Scholar 

  112. Schiopu, E. 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. 18, 131 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Streicher, K. 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. 70, 2087–2095 (2018).

    Article  CAS  PubMed  Google Scholar 

  114. Fu, N., Xie, F., Sun, Z. & Wang, Q. The OX40/OX40L axis regulates T follicular helper cell differentiation: implications for autoimmune diseases. Front. Immunol. 12, 670637 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gourh, P. et al. Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis. Ann. Rheum. Dis. 69, 550–555 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Elhai, M. et al. OX40L blockade protects against inflammation-driven fibrosis. Proc. Natl Acad. Sci. USA 113, E3901–E3910 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Skaug, B. et al. Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile. Ann. Rheum. Dis. 79, 379–386 (2020).

    Article  CAS  PubMed  Google Scholar 

  118. Weidinger, S. et al. Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial. Br. J. Dermatol. 189, 531–539 (2023).

    Article  CAS  PubMed  Google Scholar 

  119. Herro, R. et al. TL1A promotes lung tissue fibrosis and airway remodeling. J. Immunol. 205, 2414–2422 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Llewellyn, H. et al. Expression of TL1A, inflammatory, and fibrotic pathways in patients with diffuse systemic sclerosis. Arthritis Rheumatol. 75, abstr. 0791 (2023).

    Google Scholar 

  121. Sands, B. E. et al. Phase 2 trial of anti-TL1A monoclonal antibody tulisokibart for ulcerative colitis. N. Engl. J. Med. 391, 1119–1129 (2024).

    Article  CAS  PubMed  Google Scholar 

  122. Stockinger, B. & Omenetti, S. The dichotomous nature of T helper 17 cells. Nat. Rev. Immunol. 17, 535–544 (2017).

    Article  CAS  PubMed  Google Scholar 

  123. Maddur, M. S., Miossec, P., Kaveri, S. V. & Bayry, J. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am. J. Pathol. 181, 8–18 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Ramani, K. & Biswas, P. S. Interleukin-17: friend or foe in organ fibrosis. Cytokine 120, 282–288 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bellando-Randone, S., Della-Torre, E. & Balanescu, A. The role of interleukin-17 in the pathogenesis of systemic sclerosis: pro-fibrotic or anti-fibrotic? J. Scleroderma Relat. Disord. 6, 227–235 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Ahmed, S., Misra, D. P. & Agarwal, V. Interleukin-17 pathways in systemic sclerosis-associated fibrosis. Rheumatol. Int. 39, 1135–1143 (2019).

    Article  CAS  PubMed  Google Scholar 

  127. Wei, L., Abraham, D. & Ong, V. The Yin and Yang of IL-17 in systemic sclerosis. Front. Immunol. 13, 885609 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ono, Y. et al. Interleukin-17A is a potential therapeutic target predicted by proteomics for systemic sclerosis patients at high risk of pulmonary arterial hypertension. Sci. Rep. 14, 29484 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Dufour, A. M. et al. IL-17A dissociates inflammation from fibrogenesis in systemic sclerosis. J. Invest. Dermatol. 140, 103–112.e8 (2020).

    Article  CAS  PubMed  Google Scholar 

  130. Fukayama, M. et al. Interleukin (IL)-17F and IL-17E are related to fibrosis and vasculopathy in systemic sclerosis. J. Dermatol. 47, 1287–1292 (2020).

    Article  CAS  PubMed  Google Scholar 

  131. Robak, E., Gerlicz-Kowalczuk, Z., Dziankowska-Bartkowiak, B., Wozniacka, A. & Bogaczewicz, J. Serum concentrations of IL-17A, IL-17B, IL-17E and IL-17F in patients with systemic sclerosis. Arch. Med. Sci. 15, 706–712 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Chizzolini, C., Dufour, A. M. & Brembilla, N. C. Is there a role for IL-17 in the pathogenesis of systemic sclerosis? Immunol. Lett. 195, 61–67 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Xing, X. et al. IL-17A induces endothelial inflammation in systemic sclerosis via the ERK signaling pathway. PLoS ONE 8, e85032 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Krueger, J. G. et al. IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy. Front. Immunol. 15, 1331217 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Benschop, R. J. et al. Development of tibulizumab, a tetravalent bispecific antibody targeting BAFF and IL-17A for the treatment of autoimmune disease. MAbs 11, 1175–1190 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Orvain, C., Assassi, S., Avouac, J. & Allanore, Y. Systemic sclerosis pathogenesis: contribution of recent advances in genetics. Curr. Opin. Rheumatol. 32, 505–514 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Assassi, S. et al. Systemic sclerosis and lupus: points in an interferon-mediated continuum. Arthritis Rheum. 62, 589–598 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Christmann, R. B. et al. Association of Interferon- and transforming growth factor beta-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol. 66, 714–725 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Liu, X. et al. Correlation of interferon-inducible chemokine plasma levels with disease severity in systemic sclerosis. Arthritis Rheum. 65, 226–235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Black, C. M. et al. Interferon-α does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 42, 299–305 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Granstein, R. D., Flotte, T. J. & Amento, E. P. Interferons and collagen production. J. Invest. Dermatol. 95, 75S–80S (1990).

    Article  CAS  PubMed  Google Scholar 

  142. Morand, E. F. et al. Trial of anifrolumab in active systemic lupus erythematosus. N. Engl. J. Med. 382, 211–221 (2020).

    Article  CAS  PubMed  Google Scholar 

  143. Goldberg, A. et al. Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study. Arthritis Res. Ther. 16, R57 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Guo, X. 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. 135, 2402–2409 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Rubio Gomez, M. A. & Ibba, M. Aminoacyl-tRNA synthetases. RNA 26, 910–936 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Baughman, R. P. et al. Efzofitimod: a novel anti-inflammatory agent for sarcoidosis. Sarcoidosis Vasc. Diffus. Lung Dis. 40, e2023011 (2023).

    Google Scholar 

  147. Cavagna, L. et al. Clinical spectrum time course in anti Jo-1 positive antisynthetase syndrome: results from an international retrospective multicenter study. Medicine 94, e1144 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Adams, R. A. et al. Serum-circulating His-tRNA synthetase inhibits organ-targeted immune responses. Cell Mol. Immunol. 18, 1463–1475 (2021).

    Article  CAS  PubMed  Google Scholar 

  149. Roy, S. et al. Multifaceted role of neuropilins in the immune system: potential targets for immunotherapy. Front. Immunol. 8, 1228 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Paz, S. et al. Neuropilin-2, the specific binding partner to ATYR1923, is expressed in sarcoid granulomas and key immune cells. Am. J. Respir. Crit. Care Med. 201, abstr. A3099 (2020).

    Google Scholar 

  151. US National Library of Medicine. Study to evaluate the efficacy, safety, and tolerability of efzofitimod in patients with systemic sclerosis (SSc)-related interstitial lung disease (ILD) (SSc-ILD). ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05892614 (2023).

  152. Manetti, M. et al. Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis. Ann. Rheum. Dis. 76, 924–934 (2017).

    Article  CAS  PubMed  Google Scholar 

  153. Di Benedetto, P. et al. Endothelial-to-mesenchymal transition in systemic sclerosis. Clin. Exp. Immunol. 205, 12–27 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Abraham, D. J., Krieg, T., Distler, J. & Distler, O. Overview of pathogenesis of systemic sclerosis. Rheumatology 48, iii3–iii7 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. Dees, C. et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J. Exp. Med. 208, 961–972 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Beyer, C. et al. Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Ann. Rheum. Dis. 71, 1019–1026 (2012).

    Article  CAS  PubMed  Google Scholar 

  157. Beyer, C. et al. Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling. Ann. Rheum. Dis. 74, 1408–1416 (2015).

    Article  CAS  PubMed  Google Scholar 

  158. Kaufman, J. et al. Avenciguat: a novel soluble guanylate cyclase activator that affects multiple cell types to inhibit IFN-1 signalling and fibrosis. Rheumatology 64, 4738–4743 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Matei, A. E. et al. Protein kinases G are essential downstream mediators of the antifibrotic effects of sGC stimulators. Ann. Rheum. Dis. 77, 459 (2018).

    Article  CAS  PubMed  Google Scholar 

  160. Dees, C. et al. Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies. Ann. Rheum. Dis. 74, 1621–1625 (2015).

    Article  CAS  PubMed  Google Scholar 

  161. Dou, C. et al. P300 acetyltransferase mediates stiffness-induced activation of hepatic stellate cells into tumor-promoting myofibroblasts. Gastroenterology 154, 2209–2221.e14 (2018).

    Article  CAS  PubMed  Google Scholar 

  162. Suzuki, T. et al. Thromboxane-prostanoid receptor signaling drives persistent fibroblast activation in pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 206, 596–607 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Mulvaney, E. P. et al. NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension. BMC Pulm. Med. 20, 85 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. West, J. D. et al. Antagonism of the thromboxane-prostanoid receptor is cardioprotective against right ventricular pressure overload. Pulm. Circ. 6, 211–223 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Gibson, F. et al. Epigenetic dysregulation in autoimmune and inflammatory skin diseases. Clin. Rev. Allergy Immunol. 63, 447–471 (2022).

    Article  CAS  PubMed  Google Scholar 

  166. Tsou, P. S., Varga, J. & O’Reilly, S. Advances in epigenetics in systemic sclerosis: molecular mechanisms and therapeutic potential. Nat. Rev. Rheumatol. 17, 596–607 (2021).

    Article  PubMed  Google Scholar 

  167. Papazoglou, A. et al. Epigenetic regulation of profibrotic macrophages in systemic sclerosis-associated interstitial lung disease. Arthritis Rheumatol. 74, 2003–2014 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bergmann, C. & Distler, J. H. Epigenetic factors as drivers of fibrosis in systemic sclerosis. Epigenomics 9, 463–477 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Malaab, M. et al. Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis. Ann. Rheum. Dis. 81, 268–277 (2022).

    Article  CAS  PubMed  Google Scholar 

  170. Wang, Z., Chang, C. & Lu, Q. Epigenetics of CD4+ T cells in autoimmune diseases. Curr. Opin. Rheumatol. 29, 361–368 (2017).

    Article  CAS  PubMed  Google Scholar 

  171. Shin, J. Y. et al. Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis. Sci. Transl. Med. 11, eaaw0790 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Ding, W. et al. Genome-wide DNA methylation analysis in systemic sclerosis reveals hypomethylation of IFN-associated genes in CD4+ and CD8+ T cells. J. Invest. Dermatol. 138, 1069–1077 (2018).

    Article  CAS  PubMed  Google Scholar 

  173. Dees, C. et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann. Rheum. Dis. 73, 1232–1239 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Noda, S. et al. Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis. Nat. Commun. 5, 5797 (2014).

    Article  CAS  PubMed  Google Scholar 

  175. Kramer, M. et al. Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Ann. Rheum. Dis. 72, 614–620 (2013).

    Article  PubMed  Google Scholar 

  176. Ghosh, A. K. et al. p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-β: epigenetic feed-forward amplification of fibrosis. J. Invest. Dermatol. 133, 1302–1310 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Huber, L. C. et al. Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin-induced skin fibrosis. Arthritis Rheum. 56, 2755–2764 (2007).

    Article  CAS  PubMed  Google Scholar 

  178. Zehender, A. et al. TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy. Nat. Commun. 12, 4404 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Bergmann, C. et al. The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis. Ann. Rheum. Dis. 77, 150–158 (2018).

    Article  CAS  PubMed  Google Scholar 

  180. O’Reilly, S., Tsou, P. S. & Varga, J. Senescence and tissue fibrosis: opportunities for therapeutic targeting. Trends Mol. Med. 30, 1113–1125 (2024).

    Article  PubMed  Google Scholar 

  181. Tsou, P. S., Shi, B. & Varga, J. Role of cellular senescence in the pathogenesis of systemic sclerosis. Curr. Opin. Rheumatol. 34, 343–350 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Zhu, H. et al. Fibroblast subpopulations in systemic sclerosis: functional implications of individual subpopulations and correlations with clinical features. J. Invest. Dermatol. 144, 1251–1261.e13 (2024).

    Article  CAS  PubMed  Google Scholar 

  183. Tabib, T. et al. Myofibroblast transcriptome indicates SFRP2(hi) fibroblast progenitors in systemic sclerosis skin. Nat. Commun. 12, 4384 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Distler, O. et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N. Engl. J. Med. 380, 2518–2528 (2019).

    Article  CAS  PubMed  Google Scholar 

  185. Flaherty, K. R. et al. Nintedanib in progressive fibrosing interstitial lung diseases. N. Engl. J. Med. 381, 1718–1727 (2019).

    Article  CAS  PubMed  Google Scholar 

  186. Khanna, D. et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 387, 2630–2640 (2016).

    Article  CAS  PubMed  Google Scholar 

  187. Khanna, D. et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir. Med. 8, 963–974 (2020).

    Article  CAS  PubMed  Google Scholar 

  188. Ebata, S. et al. Safety and efficacy of rituximab in systemic sclerosis (DESIRES): a double-blind, investigator-initiated, randomised, placebo-controlled trial. Lancet Rheumatol. 3, e489–e497 (2021).

    Article  CAS  PubMed  Google Scholar 

  189. Maher, T. M. 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. 11, 45–54 (2023).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Jörg H. W. Distler, Masataka Kuwana, Shervin Assassi, Christopher P. Denton.

Authors and Affiliations

  1. Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany

    Jörg H. W. Distler

  2. Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany

    Jörg H. W. Distler

  3. Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan

    Masataka Kuwana

  4. Department of Internal Medicine, Division of Rheumatology, UTHealth Houston, Houston, TX, USA

    Shervin Assassi

  5. Division of Medicine, Royal Free Campus, University College London, London, UK

    Christopher P. Denton

Authors
  1. Jörg H. W. Distler
    View author publications

    Search author on:PubMed Google Scholar

  2. Masataka Kuwana
    View author publications

    Search author on:PubMed Google Scholar

  3. Shervin Assassi
    View author publications

    Search author on:PubMed Google Scholar

  4. Christopher P. Denton
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Jörg H. W. Distler.

Ethics declarations

Competing interests

J.H.W.D. has consultancy relationships with Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Callidatas, Calluna, Galapagos, GSK, Johnson&Johnson, Kyverna, MSD, Novartis, Prolium, Quell Therapeutics and UCB, has research funding from Anamar, ARXX, BMS, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Exo Therapeutics, Galapagos, GSK, Incyte, Inventiva, Kiniksa, Kyverna, Lassen Therapeutics, Mestag, Sanofi-Aventis, SpicaTx, RedX, UCB and ZenasBio, and is CEO of 4D Science and scientific lead of FibroCure. M.K. has received consultancy fees, speaking fees, and research grants from AbbVie, Argenx, Asahi Kasei, AstraZeneca, Boehringer Ingelheim, Chugai, GlaxoSmithKline, Janssen, Kissei, MBL, Mitsubishi Tanabe, Mochida, Novartis and Ono Pharmaceuticals. S.A. reports grants paid to his institution from Boehringer Ingelheim, the Scleroderma Research Foundation, Janssen and aTyr, as well as consultancy fees from AbbVie, AstraZeneca, aTyr, Boehringer Ingelheim, CSL Behring, Merck, Mitsubishi Tanabe, Takeda, and TeneoFour. C.P.D. has consultancy relationships with GlaxoSmithKline, Johnson&Johnson, Bayer, Sanofi, Boehringer Ingelheim, Roche, CSL Behring, Corbus, Acceleron, Horizon, Arxx, Lilly, Novartis, Certa, Mitsubishi, Quell and research grant funding from AbbVie, Arxx, Horizon, GlaxoSmithKline, CSL Behring and Servier.

Peer review

Peer review information

Nature Reviews Rheumatology thanks Dilia Giuggioli, who co-reviewed with Amelia Spinella, Jeska de Vries-Bouwstra and Yoshihide Asano for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Distler, J.H.W., Kuwana, M., Assassi, S. et al. Emerging therapies for the treatment of systemic sclerosis. Nat Rev Rheumatol 21, 612–625 (2025). https://doi.org/10.1038/s41584-025-01294-x

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41584-025-01294-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research