Rheumatology Unit, Department of Medicine, University of Padua, 35128 Pauda, Italy.
Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy.
Autoimmun Rev. 2023 Jun;22(6):103334. doi: 10.1016/j.autrev.2023.103334. Epub 2023 Apr 15.
Idiopathic inflammatory myopathies (IIM), even though sharing common clinical manifestations, are characterized by diversified molecular pathogenetic mechanisms which may account for the partial inefficacy of currently used immunomodulatory drugs. In the last decades, the role of interferon (IFN) in IIM has been extensively elucidated thanks to genomic and proteomic studies which have assessed the molecular signature at the level of affected tissues or in peripheral blood across distinct IIM subtypes. A predominant type I IFN response has been shown in dermatomyositis (DM), being especially enhanced in anti-melanoma differentiation-associated gene 5 (MDA5)+ DM, while a type 2 IFN profile characterizes anti-synthetase syndrome (ASyS) and inclusion body myositis (IBM); conversely, a less robust IFN footprint has been defined for immune-mediated necrotizing myopathy (IMNM). Intracellular IFN signaling is mediated by the janus kinase/signal transducer and activator of transcription (JAK/STAT) through dedicated transmembrane receptors and specific cytoplasmic molecular combinations. These results may have therapeutic implications and led to evaluating the efficacy of new targeted drugs such as the recently introduced janus kinase inhibitors (JAKi), currently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In this review we aim to summarize the most significant evidence of IFN role in IIM pathogenesis and to describe the current state of the art about the ongoing clinical trials on IFN-targeting drugs, with particular focus on JAKi.
特发性炎性肌病（IIM）尽管具有共同的临床表现，但具有多样化的分子发病机制，这可能是目前使用的免疫调节药物部分疗效不佳的原因。在过去的几十年中，由于基因组和蛋白质组学研究评估了不同 IIM 亚型受累组织或外周血中的分子特征，干扰素（IFN）在 IIM 中的作用得到了广泛阐明。在皮肌炎（DM）中已经显示出主要的 I 型 IFN 反应，尤其是在抗黑色素瘤分化相关基因 5（MDA5）+ DM 中增强，而 2 型 IFN 谱则特征性地存在于抗合成酶综合征（ASyS）和包涵体肌炎（IBM）中；相反，免疫介导的坏死性肌病（IMNM）中 IFN 的特征不明显。细胞内 IFN 信号通过特定的跨膜受体和特定的细胞质分子组合由 Janus 激酶/信号转导和转录激活因子（JAK/STAT）介导。这些结果可能具有治疗意义，并促使人们评估新的靶向药物的疗效，如最近引入的 Janus 激酶抑制剂（JAKi），目前已批准用于治疗类风湿关节炎、银屑病关节炎和强直性脊柱炎。在这篇综述中，我们旨在总结 IFN 在 IIM 发病机制中的作用的最显著证据，并描述目前正在进行的 IFN 靶向药物临床试验的最新进展，特别关注 JAKi。
