背景:风湿性多肌痛(PMR)是老年人常见的炎症性疾病,其发病机制尚未阐明。糖皮质激素是主要的一线治疗方法,但会导致许多副作用。因此,有必要探索致病因素并确定可能的糖皮质激素保护剂.我们旨在研究该疾病的发病特征,并评估Janus酪氨酸激酶(JAK)抑制剂托法替尼在PMR患者中的疗效和安全性。
结果:我们从第一附属医院招募了未经治疗的PMR患者,浙江大学医学院,2020年9月至2022年9月。在第一个队列中,我们发现11例患者(10例女性,1男,年龄68.0±8.3)的新诊断PMR与20名健康对照(17名女性,3男,年龄63.7±9.8)通过RNA测序。炎症反应和细胞因子-细胞因子受体相互作用是受影响最显著的途径。我们观察到IL6R的表达显著增加,IL1B,IL1R1、JAK2、TLR2、TLR4、TLR8、CCR1、CR1、S100A8、S100A12和IL17RA,这可能会触发JAK信号。此外,托法替尼在体外抑制PMR患者CD4+T细胞的IL-6R和JAK2表达.在第二个队列中,PMR患者被随机分组,接受托法替尼或糖皮质激素(1/1)治疗24周.所有PMR患者在第0、4、8、12、16、20和24周接受临床和实验室检查,计算PMR活动性疾病评分(PMR-AS)。主要终点是12周和24周时PMR-AS≤10的患者比例。次要终点:PMR-AS评分,C反应蛋白(CRP),和红细胞沉降率(ESR)在第12周和第24周。39例新诊断的PMR患者接受了托法替尼,37例患者接受糖皮质激素治疗。35名患者(29名女性,6男,年龄64.4±8.4)和32名患者(23名女性,9男,年龄65.3±8.7)患者完成了24周的干预,分别。主要或次要结局无统计学差异。在第12周和第24周,两组患者的PMR-AS均<10。PMR-AS,CRP,两组的ESR均显著降低。两组均未发生严重不良事件。研究局限性包括单中心研究设计,观察时间短。
结论:我们发现JAK信号参与了PMR的发病机制。Tofacitinib与糖皮质激素一样有效治疗PMR患者,单中心,开放标签,对照试验(ChiCTR2000038253)。
背景:这项由研究者发起的临床试验(IIT)已在网站上注册(http://www.chictr.org.cn/,ChiCTR2000038253)。
BACKGROUND: Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly persons whose mechanism of pathogenesis has not been elucidated. Glucocorticoids are the main first-line treatments but result in numerous side effects. Therefore, there is a need to explore pathogenetic factors and identify possible glucocorticoid-sparing agents. We aimed to study the pathogenetic features of the disease and assess the efficacy and safety of Janus tyrosine kinase (JAK)-inhibitor tofacitinib in patients with PMR.
RESULTS: We recruited treatment-naïve PMR patients from the First Affiliated Hospital, Zhejiang University School of Medicine, between September 2020 and September 2022. In the first cohort, we found that the gene expression patterns of peripheral blood mononuclear cells (PBMCs) in 11 patients (10 female, 1 male, age 68.0 ± 8.3) with newly diagnosed PMR were significantly different from 20 healthy controls (17 female, 3 male, age 63.7 ± 9.8) by RNA sequencing. Inflammatory response and cytokine-cytokine receptor interaction were the most notable pathways affected. We observed marked increases in expression of IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA, which could trigger JAK signaling. Furthermore, tofacitinib suppressed the IL-6R and JAK2 expression of CD4+T cells from patients with PMR in vitro. In the second cohort, patients with PMR were randomized and treated with tofacitinib or glucocorticoids (1/1) for 24 weeks. All PMR patients underwent clinical and laboratory examinations at 0, 4, 8, 12, 16, 20, and 24 weeks, and PMR activity disease scores (PMR-AS) were calculated. The primary endpoint was the proportion of patients with PMR-AS ≤10 at weeks 12 and 24. Secondary endpoints: PMR-AS score, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) at weeks 12 and 24. Thirty-nine patients with newly diagnosed PMR received tofacitinib, and 37 patients received glucocorticoid. Thirty-five patients (29 female, 6 male, age 64.4 ± 8.4) and 32 patients (23 female, 9 male, age 65.3 ± 8.7) patients completed the 24-week intervention, respectively. There were no statistically significant differences in primary or secondary outcomes. At weeks 12 and 24, all patients in both groups had PMR-AS <10. PMR-AS, CRP, and ESR were all significantly decreased in both groups. No severe adverse events were observed in either group. Study limitations included the single-center study design with a short observation period.
CONCLUSIONS: We found that JAK signaling was involved in the pathogenesis of PMR. Tofacitinib effectively treated patients with PMR as glucocorticoid does in this randomized, monocenter, open-label, controlled trial (ChiCTR2000038253).
BACKGROUND: This investigator-initiated clinical trial (IIT) had been registered on the website (http://www.chictr.org.cn/, ChiCTR2000038253).