Department of Dermatology, College of Medicine, University of Florida, Gainesville, Florida, USA.
Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA.
Dermatol Ther. 2022 Jun;35(6):e15437. doi: 10.1111/dth.15437. Epub 2022 Mar 22.
Morphea and systemic sclerosis (SSc) are rare disorders of connective tissue characterized by increased skin thickness and fibrosis, with current treatment options having variable efficacies, many with limited therapeutic benefit. Janus kinase (JAK) inhibitors have been shown in preclinical studies to inhibit the fibrotic pathway in murine models of systemic sclerosis, by blocking TGF-beta mediated pathway of STAT protein activation. Additionally, case reports of the treatment of morphea and SSc with tofacitinib, a JAK 1/3 inhibitor, have shown improvement in skin sclerosis. Several JAK inhibitors have been developed and utilized in dermatologic and rheumatologic diseases. To date, tofacitinib has been by far the most commonly trialed JAK inhibitor in patients with SSc and morphea. Herein we review the preclinical studies reported in the literature supporting the use and efficacy of JAK inhibitors for the treatment of morphea and the cutaneous manifestations of SSc, as well as discuss the clinical cases published to date illustrating the benefits of JAK inhibitors in disease management. The pathogenesis and mechanism of action will be reviewed as it relates to the process of skin fibrosis in morphea and SSc, along with the murine models illustrating efficacy of JAK inhibitors in fibrotic disease. Based on available preclinical and clinical data as well as consideration of the mechanism of action of JAK inhibitors on the pathway for cutaneous fibrosis, there is promising evidence to support the use and further study of JAK inhibitors in the management of morphea and cutaneous fibrosis in SSc.
硬皮病和系统性硬化症（SSc）是罕见的结缔组织疾病，其特征为皮肤增厚和纤维化，目前的治疗选择疗效各异，许多治疗方法的疗效有限。临床前研究表明，Janus 激酶（JAK）抑制剂通过阻断 TGF-β介导的 STAT 蛋白激活途径，抑制系统性硬化症小鼠模型中的纤维化途径。此外，有报道称使用 JAK1/3 抑制剂托法替尼治疗硬斑病和 SSc，可改善皮肤硬化。已经开发和用于皮肤科和风湿病学疾病的几种 JAK 抑制剂。迄今为止，托法替尼是 SSc 和硬斑病患者中最常试用的 JAK 抑制剂。本文综述了文献中报道的支持 JAK 抑制剂治疗硬斑病和 SSc 皮肤表现的临床前研究，并讨论了迄今为止发表的说明 JAK 抑制剂在疾病管理中益处的临床病例。将综述发病机制和作用机制，因为它与硬斑病和 SSc 中的皮肤纤维化过程有关，以及说明 JAK 抑制剂在纤维化疾病中的疗效的小鼠模型。基于现有临床前和临床数据以及对 JAK 抑制剂在皮肤纤维化途径上的作用机制的考虑，有令人鼓舞的证据支持在硬斑病和 SSc 的皮肤纤维化管理中使用和进一步研究 JAK 抑制剂。
