Chen Fangfang, Ye Wenjing, Wang Qian, Zhao Li, Liang Minrui, Zheng Shucong, Zhao Tianyi, Xuan Dandan, Zhu Zaihua, Yu Yiyun, Kong Ning, Jiang Li, Yang Xue, Zhu Xiaoxia, Wan Weiguo, Zou Hejian, Xue Yu
Department of Rheumatology, Huashan Hospital, Institute of Rheumatology, Immunology and Allergy, Fudan University, No. 12, Middle Urumqi Road, Jing'an District, Shanghai, 200000, China.
Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
Clin Rheumatol. 2025 May 17. doi: 10.1007/s10067-025-07433-9.
Despite advances in approaches to treatment for patients with systemic sclerosis (SSc), the effects have been modest at best. This investigator-initiated study aimed to evaluate the therapeutic benefit, safety and the genetic characteristics related to effect of baricitinib in SSc.
In this 24-week study, eligible SSc patients were randomised to baricitinib 4 mg, 2 mg or control group. The primary outcome was the change in modified Rodnan skin score (mRSS) from baseline to week 12. Secondary outcomes included changes in the American College of Rheumatology Combined Response Index in Systemic Sclerosis (ACR-CRISS) score, forced vital capacity (FVC), Systemic Sclerosis Score, tender and swollen joint counts, digital ulcers, EQ5D (EuroQol five-dimensions) and safety at week 12 and 24. Transcriptome differences in blood samples from patients before and after baricitinib treatment were compared. Gene Ontology enrichment analysis was performed to identify potential biological functions and canonical pathways.
Between April 2021 to January 2022, 48 patients were randomly assigned to three groups. Mean change in mRSS score from baseline to week 12 was - 8.9 in 4 mg group, - 3.8 in 2 mg group, and - 3.6 in control group (P = 0.019). At week 12, the ACR-CRISS scores were 0.5 and 0.3 in baricitinib 4 mg and 2 mg group, as compared with 0.2 among those in control group (P = 0.171). FVC (%), digital ulcers and EQ5D in 4 mg baricitinib group showed favorable responses over 24 weeks. There were no significant differences in adverse events among groups. The differentially expressed genes (DEGs) identified in our analysis were significantly enriched in gene ontology (GO) terms related to the positive regulation of cytokine production, immune response-activating signaling pathway, and activation of immune response pathway. Interleukin- 1 Receptor Like 1 (IL- 1RL1 or ST2) and synaptotagmin- 17 (SYT17) were downregulated and upregulated respectively, after baricitinib treatment.
The therapy with baricitinib 4 mg appeared to improve mRSS of SSc patients, probably by influencing mechanisms of immune inflammation, and had an acceptable safety profile. This study paves the way for further investigations into Janus kinase (JAK) 1/2 inhibition with baricitinib as a prospective treatment for SSc. Key Points • The baricitinib 4 mg seems to improve clinical outcomes of SSc patients with safety profiles. • The mechanism of JAK inhibitors has been confirmed to be related to anti-inflammatory pathways and molecules in clinical samples.
尽管系统性硬化症（SSc）患者的治疗方法有所进展，但效果充其量也只是一般。这项由研究者发起的研究旨在评估巴瑞替尼治疗SSc的疗效、安全性以及与疗效相关的基因特征。
在这项为期24周的研究中，符合条件的SSc患者被随机分为巴瑞替尼4毫克组、2毫克组或对照组。主要结局是从基线到第12周改良罗德南皮肤评分（mRSS）的变化。次要结局包括第12周和第24周时系统性硬化症美国风湿病学会综合反应指数（ACR-CRISS）评分、用力肺活量（FVC）、系统性硬化症评分、压痛和肿胀关节计数、指端溃疡、EQ5D（欧洲五维健康量表）以及安全性的变化。比较了巴瑞替尼治疗前后患者血液样本中的转录组差异。进行基因本体富集分析以确定潜在的生物学功能和经典途径。
在2021年4月至2022年1月期间，48名患者被随机分配到三组。从基线到第12周，4毫克组mRSS评分的平均变化为-8.9，2毫克组为-3.8，对照组为-3.6（P = 0.019）。在第12周时，巴瑞替尼4毫克组和2毫克组的ACR-CRISS评分分别为0.5和0.3，而对照组为0.2（P = 0.171）。在24周内，4毫克巴瑞替尼组的FVC（%）、指端溃疡和EQ5D显示出良好的反应。各组间不良事件无显著差异。我们分析中鉴定出的差异表达基因（DEG）在与细胞因子产生的正调控、免疫反应激活信号通路和免疫反应途径激活相关的基因本体（GO）术语中显著富集。巴瑞替尼治疗后，白细胞介素-1受体样1（IL-1RL1或ST2）下调，突触结合蛋白-17（SYT17）上调。
4毫克巴瑞替尼治疗似乎可改善SSc患者的mRSS，可能是通过影响免疫炎症机制实现的，并且具有可接受的安全性。这项研究为进一步研究将巴瑞替尼作为SSc的前瞻性治疗抑制Janus激酶（JAK）1/2铺平了道路。要点 • 4毫克巴瑞替尼似乎可改善SSc患者的临床结局且安全性良好。 • JAK抑制剂的机制已在临床样本中被证实与抗炎途径和分子有关。
