Abraham David J, Black Carol M, Denton Christopher P, Distler Jörg H W, Domsic Robyn, Feghali-Bostwick Carol, Gourh Pravitt, Hinchcliff Monique, Kolling Fred, Kuwana Masataka, Lafyatis Robert, Landegren Ulf, Mahoney J Matthew, Martin Javier, Matucci-Cerinic Marco, McMahan Zsuzsanna H, Mora Ana L, Mouthon Luc, Rabinovitch Marlene, Rojas Mauricio, Rubin Kristofer, Trojanowska Maria, Varga John, Whitfield Michael L, Gabrielli Armando, Krieg Thomas
Department of Inflammation and Rare Diseases, UCL Centre for Rheumatology, UCL Division of Medicine, Royal Free Hospital Campus, London, UK.
Department of Rheumatology, University Hospital Düsseldorf, Medical Faculty of the Heinrich-Heine University, Düsseldorf, Germany.
Nat Rev Rheumatol. 2025 Mar;21(3):174-187. doi: 10.1038/s41584-024-01217-2. Epub 2025 Feb 14.
Systemic sclerosis (SSc) remains a challenging and enigmatic systemic autoimmune disease, owing to its complex pathogenesis, clinical and molecular heterogeneity, and the lack of effective disease-modifying treatments. Despite a century of research in SSc, the interconnections among microvascular dysfunction, autoimmune phenomena and tissue fibrosis in SSc remain unclear. The absence of validated biomarkers and reliable animal models complicates diagnosis and treatment, contributing to high morbidity and mortality. Advances in the past 5 years, such as single-cell RNA sequencing, next-generation sequencing, spatial biology, transcriptomics, genomics, proteomics, metabolomics, microbiome profiling and artificial intelligence, offer new avenues for identifying the early pathogenetic events that, once treated, could change the clinical history of SSc. Collaborative global efforts to integrate these approaches are crucial to developing a comprehensive, mechanistic understanding and enabling personalized therapies. Challenges include disease classification, clinical heterogeneity and the establishment of robust biomarkers for disease activity and progression. Innovative clinical trial designs and patient-centred approaches are essential for developing effective treatments. Emerging therapies, including cell-based and fibroblast-targeting treatments, show promise. Global cooperation, standardized protocols and interdisciplinary research are vital for advancing SSc research and improving patient outcomes. The integration of advanced research techniques holds the potential for important breakthroughs in the diagnosis, treatment and care of individuals with SSc.
系统性硬化症（SSc）仍然是一种具有挑战性且神秘的系统性自身免疫性疾病，这归因于其复杂的发病机制、临床和分子异质性，以及缺乏有效的疾病改善治疗方法。尽管对SSc进行了长达一个世纪的研究，但SSc中微血管功能障碍、自身免疫现象和组织纤维化之间的相互联系仍不清楚。缺乏经过验证的生物标志物和可靠的动物模型使诊断和治疗变得复杂，导致高发病率和死亡率。过去5年的进展，如单细胞RNA测序、下一代测序、空间生物学、转录组学、基因组学、蛋白质组学、代谢组学、微生物组分析和人工智能，为识别早期致病事件提供了新途径，一旦对这些事件进行治疗，可能会改变SSc的临床进程。全球共同努力整合这些方法对于形成全面的、基于机制的理解并实现个性化治疗至关重要。挑战包括疾病分类、临床异质性以及建立用于疾病活动和进展的可靠生物标志物。创新的临床试验设计和以患者为中心的方法对于开发有效治疗方法至关重要。包括基于细胞和靶向成纤维细胞的治疗在内的新兴疗法显示出前景。全球合作、标准化方案和跨学科研究对于推进SSc研究和改善患者预后至关重要。整合先进研究技术有可能在SSc患者的诊断、治疗和护理方面取得重要突破。
