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S100 proteins as potential predictive biomarkers of abatacept response in polyarticular juvenile idiopathic arthritis S100蛋白是多关节幼年特发性关节炎患者阿帕他赛反应的潜在预测性生物标记物
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-25 DOI: 10.1186/s13075-024-03347-0
Hermine I Brunner, Grant S Schulert, Alyssa Sproles, Sherry Thornton, Gabriel Vega Cornejo, Jordi Antón, Ruben Cuttica, Michael Henrickson, Ivan Foeldvari, Daniel J Kingsbury, Margarita Askelson, Jinqi Liu, Sumanta Mukherjee, Robert L Wong, Daniel J Lovell, Alberto Martini, Nicolino Ruperto, Alexei A Grom
Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25–5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48–9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03–8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02–5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57–5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23–5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46–9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76–7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07–3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10–4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15–8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.
幼年特发性关节炎(JIA)是一组可导致明显残疾和生活质量下降的异质性疾病。有关临床反应预测因素的数据不足以指导患者选择合适的生物制剂。本研究旨在探讨S100A8/9和S100A12作为阿帕赛普对多关节病程幼年特发性关节炎(pJIA)反应的预测性生物标志物的倾向性。这项探索性分析采用了皮下注射阿帕塞普治疗活动性pJIA患者(n = 219)的3期试验(NCT01844518)的数据。我们评估了基线生物标志物水平与JIA-美国风湿病学会(ACR)标准反应或基线疾病活动度(通过使用C反应蛋白[JADAS27-CRP]对27个关节的幼年关节炎疾病活动度评分)改善之间的关系。评估从基线到第 4 个月的生物标志物水平变化,以预测 21 个月后的疾病结果。基线时,158 名患者有可用的生物标志物样本。较低的基线 S100A8/9 水平(≤ 3295 ng/mL)与达到 JIA-ACR90 (几率比 [OR]:2.54 [95% 置信区间 (CI):1.25-5.18])、JIA-ACR100(OR:3.72 [95% CI:1.48-9.37])、第 4 个月时的 JIA-ACR 非活动性疾病(ID;OR:4.25 [95% CI:2.03-8.92])、第 4 个月时的 JADAS27-CRP ID(OR:2.34 [95% CI:1.02-5.39])和第 16 个月时的 JIA-ACR ID(OR:3.01 [95% CI:1.57-5.78])。较低的基线 S100A12 水平(≤ 176 ng/mL)与达到 JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]) 、JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28])、JIA-ACR ID(OR:3.66 [95% CI:1.76-7.61])、JIA-ACR90(OR:2.03 [95% CI:1.07-3.87])、JIA-ACR100(OR:2.14 [95% CI:1.10-4.17])和 JIA-ACR ID(OR:4.22 [95% CI:2.15-8.29])。从基线到第 4 个月,JIA-ACR90/100/ID 反应者中 S100A8/9 和 S100A12 的降幅普遍超过 50%。S100A8/9和S100A12蛋白的基线水平较低,预示着对阿帕他赛治疗的反应比水平较高者更好,可作为pJIA的早期预测生物标志物。这些生物标志物水平的降低也可预测pJIA患者对阿帕他赛治疗的长期反应。
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引用次数: 0
The impact of gastroesophageal reflux disease and its treatment on interstitial lung disease outcomes 胃食管反流病及其治疗对间质性肺病预后的影响
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-25 DOI: 10.1186/s13075-024-03355-0
A. Quinlivan, D. Neuen, D. Hansen, W. Stevens, L. Ross, N. Ferdowsi, S. M. Proudman, J. G. Walker, J. Sahhar, G-S. Ngian, D. Apostolopoulos, L. V. Host, G. Major, C. Basnayake, K. Morrisroe, M. Nikpour
To determine the relationship between gastroesophageal reflux disease (GORD) and its treatment and interstitial lung disease in patients with systemic sclerosis (SSc). SSc patients from the Australian Scleroderma Cohort Study (ASCS) were included. GORD was defined as self-reported GORD symptoms, therapy with a proton pump inhibitor (PPI) or histamine 2 receptor antagonist (H2RA) and/or the presence of reflux oesophagitis diagnosed endoscopically. The impact of GORD and its treatment on ILD features (including severity and time to ILD development) and survival was evaluated. GORD was a common manifestation affecting 1539/1632 (94%) of SSc patients. GORD affected 450/469 (96%) of those with SSc-ILD cohort. In SSc-ILD, there was no relationship between the presence of GORD or its treatment and time to ILD development or ILD severity. However, GORD treatment was associated with improved survival in those with ILD (p = 0.002). Combination therapy with both a PPI and a H2RA was associated with a greater survival benefit than single agent therapy with PPI alone (HR 0.3 vs 0.5 p < 0.050 respectively). GORD is a common SSc disease manifestation. While the presence or treatment of GORD does not influence the development or severity of ILD, aggressive GORD treatment, in particular with a combination of PPI and H2RA, is associated with improved survival in those with SSc-ILD.
目的:确定系统性硬化症(SSc)患者的胃食管反流病(GORD)及其治疗与间质性肺病之间的关系。研究对象包括澳大利亚硬皮病队列研究(ASCS)中的系统性硬化症患者。反流性食管炎的定义是自我报告的反流性食管炎症状、质子泵抑制剂(PPI)或组胺2受体拮抗剂(H2RA)治疗和/或内镜诊断的反流性食管炎。研究评估了胃食管反流及其治疗对 ILD 特征(包括严重程度和发生 ILD 的时间)和存活率的影响。胃食管反流是一种常见表现,影响了 1539/1632 例 SSc 患者(94%)。在SSc-ILD患者中,有450/469人(96%)患有GORD。在 SSc-ILD 患者中,GORD 的存在或治疗与 ILD 发病时间或 ILD 严重程度之间没有关系。但是,GORD 治疗与 ILD 患者生存率的提高有关(p = 0.002)。同时使用 PPI 和 H2RA 进行联合治疗比单独使用 PPI 进行单药治疗的生存率更高(HR 分别为 0.3 vs 0.5 p < 0.050)。胃食管反流是常见的 SSc 疾病表现。虽然GORD的存在或治疗并不影响ILD的发生或严重程度,但积极的GORD治疗,尤其是PPI和H2RA联合治疗,与SSc-ILD患者生存率的提高有关。
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引用次数: 0
Impact of RA treatment strategies on lipids and vascular inflammation in rheumatoid arthritis: a secondary analysis of the TARGET randomized active comparator trial 类风湿性关节炎治疗策略对血脂和血管炎症的影响:TARGET 随机积极比较试验的二次分析
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-24 DOI: 10.1186/s13075-024-03352-3
Katherine P. Liao, Pamela Rist, Jon Giles, Leah Santacroce, Margery A. Connelly, Robert J. Glynn, Paul Ridker, Ahmed Tawakol, Joan Bathon, Daniel H. Solomon
Treatments for rheumatoid arthritis (RA) are associated with complex changes in lipids and lipoproteins that may impact cardiovascular (CV) risk. The objective of this study was to examine lipid and lipoprotein changes associated with two common RA treatment strategies, triple therapy or tumor necrosis factor inhibitor (TNFi), and association with CV risk. In this secondary data analysis of the TARGET trial, methotrexate (MTX) inadequate responders with RA were randomized to either add sulfasalazine and hydroxychloroquine (triple therapy), or TNFi for 24-weeks. The primary trial outcome was the change in arterial inflammation measured in the carotid arteries or aorta by FDG-PET/CT at baseline and 24-weeks; this change was described as the target-to-background ratio (TBR) in the most diseased segment (MDS). Routine lipids and advanced lipoproteins were measured at baseline and 24-weeks; subjects on statin therapy at baseline were excluded. Comparisons between baseline and follow-up lipid measurements were performed within and across treatment arms, as well as change in lipids and change in MDS-TBR. We studied 122 participants, 61 in each treatment arm, with median age 57 years, 76% female, and 1.5 year median RA disease duration. When comparing treatment arms, triple therapy had on average a larger reduction in triglycerides (15.9 mg/dL, p = 0.01), total cholesterol to HDL-C ratio (0.29, p-value = 0.01), and LDL particle number (111.2, p = 0.02) compared to TNFi. TNFi had on average a larger increase in HDL particle number (1.6umol/L, p = 0.006). We observed no correlation between change in lipid measurements and change in MDS-TBR within and across treatment arms. Both treatment strategies were associated with improved lipid profiles via changes in different lipids and lipoproteins. These effects had no correlation with change in CV risk as measured by vascular inflammation by FDG-PET/CT. ClinicalTrials.gov ID NCT02374021.
类风湿性关节炎(RA)的治疗与血脂和脂蛋白的复杂变化有关,这些变化可能会影响心血管(CV)风险。本研究旨在探讨两种常见的 RA 治疗策略(三联疗法或肿瘤坏死因子抑制剂 (TNFi))引起的血脂和脂蛋白变化以及与心血管风险的关系。在这项TARGET试验的二次数据分析中,甲氨蝶呤(MTX)疗效不佳的RA患者被随机分配加入柳氮磺胺吡啶和羟氯喹(三联疗法)或TNFi治疗24周。主要试验结果是在基线和24周时通过FDG-PET/CT测量颈动脉或主动脉动脉炎症的变化;这种变化被描述为病变最严重区段(MDS)的目标-背景比值(TBR)。在基线和 24 周时测量常规血脂和高级脂蛋白;不包括基线时正在接受他汀类药物治疗的受试者。在治疗组内和不同治疗组之间对基线和随访血脂测量结果进行比较,并比较血脂变化和 MDS-TBR 变化。我们研究了 122 名参与者,每个治疗组 61 人,中位年龄为 57 岁,76% 为女性,中位 RA 病程为 1.5 年。在比较治疗组时,与 TNFi 相比,三联疗法平均降低甘油三酯(15.9 mg/dL,p = 0.01)、总胆固醇与高密度脂蛋白胆固醇比值(0.29,p 值 = 0.01)和低密度脂蛋白颗粒数(111.2,p = 0.02)的幅度更大。TNFi 的高密度脂蛋白颗粒数平均增加较多(1.6umol/L,p = 0.006)。我们观察到,在治疗组内和治疗组间,血脂测量值的变化与MDS-TBR的变化之间没有相关性。两种治疗策略都能通过改变不同的血脂和脂蛋白改善血脂状况。这些效果与通过 FDG-PET/CT 血管炎症测量的心血管风险变化无关。ClinicalTrials.gov ID NCT02374021。
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引用次数: 0
Rituximab in the treatment of progressive interstitial lung disease associated with the antisynthetase syndrome 利妥昔单抗治疗与抗合成酶综合征相关的进行性间质性肺病
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-18 DOI: 10.1186/s13075-024-03353-2
Javier Narváez, Elena Cañadillas, Iván Castellví, Juan José Alegre, Vanesa Vincens-Zygmunt, Guadalupe Bermudo, Paola Vidal-Montal, María Molina Molina, Joan Miquel Nolla
To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with antisynthetase syndrome and progressive interstitial lung disease (ASS-ILD). Multicentre observational retrospective longitudinal study of a cohort of patients with ASS-ILD that started treatment with RTX due to recurrent or ongoing progressive ILD despite therapy with glucocorticoids and immunosuppressants. Twenty-eight patients were analyzed. Examining the entire study population, before treatment with RTX the mean decline in %pFVC and %pDLCO from the ASS-ILD diagnosis to the initiation of RTX treatment (T0) was -6.44% and -14.85%, respectively. After six months of treatment, RTX reversed the decline in pulmonary function test (PFT) parameters: ∆%pFVC +6.29% (95% CI: -10.07 to 2.51; p=0.002 compared to T0) and ∆%pDLCO +6.15% (95% CI: -10.86 to -1.43; p=0.013). Twenty-four patients completed one year of therapy and 22 two years, maintaining the response in PFT: ∆%pFVC: +9.93% (95% CI: -15.61 to -4.25; p=0.002) and ∆%pDLCO: +7.66% (95% CI: -11.67 to -3.65; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 18% of cases. In 33% of patients who required oxygen therapy at the start of treatment, it could be discontinued. The frequency of adverse events reached 28.5% of cases. Based on our results, RTX appears to be effective as rescue therapy in most patients with recurrent or progressive ASS-ILD unresponsive to conventional treatment. The use of RTX was well tolerated in the majority of patients.
评估利妥昔单抗(RTX)作为抗异抗原酶综合征和进行性间质性肺病(ASS-ILD)患者的一种抢救疗法在真实世界中的长期疗效。这项多中心观察性回顾性纵向研究的对象是一组 ASS-ILD 患者,他们在接受糖皮质激素和免疫抑制剂治疗后,因反复发作或持续进展性间质性肺病而开始接受 RTX 治疗。共对 28 名患者进行了分析。从整个研究人群来看,在接受 RTX 治疗前,从确诊为 ASS-ILD 到开始接受 RTX 治疗(T0)期间,pFVC 和 %pDLCO 的平均降幅分别为 -6.44% 和 -14.85%。治疗六个月后,RTX 扭转了肺功能测试(PFT)参数的下降趋势:与 T0 相比,∆%pFVC +6.29%(95% CI:-10.07 至 2.51;p=0.002),∆%pDLCO +6.15%(95% CI:-10.86 至-1.43;p=0.013)。24 名患者完成了一年的治疗,22 名患者完成了两年的治疗,PFT 反应保持不变:∆%pFVC:+9.93%(95% CI:-15.61 至 -4.25;p=0.002),∆%pDLCO:+7.66%(95% CI:-11.67 至 -3.65;p<0.001)。此外,泼尼松的中位剂量也明显减少,18%的病例可以暂停使用泼尼松。在开始治疗时需要氧气治疗的患者中,有 33% 可以停止氧气治疗。不良反应发生率达到 28.5%。根据我们的研究结果,对于大多数对常规治疗无效的复发性或进展性 ASS-ILD 患者来说,RTX 似乎是一种有效的抢救疗法。大多数患者对 RTX 的耐受性良好。
{"title":"Rituximab in the treatment of progressive interstitial lung disease associated with the antisynthetase syndrome","authors":"Javier Narváez, Elena Cañadillas, Iván Castellví, Juan José Alegre, Vanesa Vincens-Zygmunt, Guadalupe Bermudo, Paola Vidal-Montal, María Molina Molina, Joan Miquel Nolla","doi":"10.1186/s13075-024-03353-2","DOIUrl":"https://doi.org/10.1186/s13075-024-03353-2","url":null,"abstract":"To assess the real-world, long-term effectiveness of rituximab (RTX) as a rescue therapy in patients with antisynthetase syndrome and progressive interstitial lung disease (ASS-ILD). Multicentre observational retrospective longitudinal study of a cohort of patients with ASS-ILD that started treatment with RTX due to recurrent or ongoing progressive ILD despite therapy with glucocorticoids and immunosuppressants. Twenty-eight patients were analyzed. Examining the entire study population, before treatment with RTX the mean decline in %pFVC and %pDLCO from the ASS-ILD diagnosis to the initiation of RTX treatment (T0) was -6.44% and -14.85%, respectively. After six months of treatment, RTX reversed the decline in pulmonary function test (PFT) parameters: ∆%pFVC +6.29% (95% CI: -10.07 to 2.51; p=0.002 compared to T0) and ∆%pDLCO +6.15% (95% CI: -10.86 to -1.43; p=0.013). Twenty-four patients completed one year of therapy and 22 two years, maintaining the response in PFT: ∆%pFVC: +9.93% (95% CI: -15.61 to -4.25; p=0.002) and ∆%pDLCO: +7.66% (95% CI: -11.67 to -3.65; p<0.001). In addition, there was a significant reduction in the median dose of prednisone, and it could be suspended in 18% of cases. In 33% of patients who required oxygen therapy at the start of treatment, it could be discontinued. The frequency of adverse events reached 28.5% of cases. Based on our results, RTX appears to be effective as rescue therapy in most patients with recurrent or progressive ASS-ILD unresponsive to conventional treatment. The use of RTX was well tolerated in the majority of patients.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"43 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons 巴利昔尼通过调节背根神经节神经元中的IL-6/JAK/STAT3通路和CSF-1表达,改善胶原抗体诱导的关节炎小鼠的炎症性疼痛和神经病理性疼痛
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-15 DOI: 10.1186/s13075-024-03354-1
Kenta Makabe, Hiroyuki Okada, Naohiro Tachibana, Hisatoshi Ishikura, Norihito Ito, Masaru Tanaka, Ryota Chijimatsu, Asuka Terashima, Fumiko Yano, Meiko Asaka, Dai Yanagihara, Shuji Taketomi, Takumi Matsumoto, Sakae Tanaka, Yasunori Omata, Taku Saito
Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis. We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells. Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1β and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia–astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells. Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.
巴利昔尼等Janus激酶(JAK)抑制剂被广泛用于治疗类风湿性关节炎(RA)。临床研究表明,巴利昔尼比其他同类药物更能有效减轻疼痛。在此,我们旨在利用关节炎小鼠模型阐明巴利昔尼缓解疼痛的分子机制。我们用巴利昔尼、塞来昔布或载体治疗胶原抗体诱导的关节炎(CAIA)模型小鼠,并评估了关节炎的严重程度、脊髓的组织学发现以及与疼痛相关的行为。我们还进行了 RNA 测序(RNA-seq),以确定巴利昔尼治疗后背根神经节(DRG)中基因表达的变化。最后,我们进行了体外实验,研究巴利替尼对神经元细胞的直接影响。巴利昔尼和塞来昔布都能显著降低CAIA并改善关节炎依赖性握力障碍,而只有巴利昔尼能明显抑制von Frey试验测定的残余触觉过敏。巴利昔尼或塞来昔布都能抑制 CAIA 对踝关节滑膜中炎症细胞因子(包括白细胞介素 (IL)-1β 和 IL-6)的诱导。相反,DRG的RNA-seq分析显示,巴利昔尼而非塞来昔布可将CAIA诱导的基因表达改变恢复到对照组状态。在CAIA和巴利昔尼治疗所改变的许多通路中,与塞来昔布组相比,巴利昔尼组的干扰素-α/γ、JAK-信号转导和激活转录3(STAT3)以及核因子卡巴B(NF-κB)通路明显减少。值得注意的是,只有巴利昔尼降低了集落刺激因子1(CSF-1)的表达,CSF-1是一种强效细胞因子,可通过激活脊髓中的小胶质细胞-胃细胞轴引起神经病理性疼痛。因此,巴利昔尼能阻止CAIA引起的小胶质细胞和星形胶质细胞的增加。巴利昔尼还抑制了JAK/STAT3通路的活性和培养神经元细胞中Csf1的表达。我们的研究结果表明,巴利昔尼对DRG具有改善炎症性疼痛和神经性疼痛的作用。
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引用次数: 0
Phosphoproteomic profiling of early rheumatoid arthritis synovium reveals active signalling pathways and differentiates inflammatory pathotypes 早期类风湿性关节炎滑膜的磷酸蛋白组图谱揭示了活跃的信号通路并区分了炎症病型
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-12 DOI: 10.1186/s13075-024-03351-4
Cankut Çubuk, Rachel Lau, Pedro Cutillas, Vinothini Rajeeve, Christopher R. John, Anna E. A. Surace, Rebecca Hands, Liliane Fossati-Jimack, Myles J. Lewis, Costantino Pitzalis
Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in rheumatoid arthritis (RA). Oral inhibitors of Janus Kinase family (JAKs) are widely used in RA, while inhibitors of other kinase families e.g. phosphoinositide 3-kinase (PI3K) are under development. Most current biomarker platforms quantify mRNA/protein levels, but give no direct information on whether proteins are active/inactive. Phosphoproteome analysis has the potential to measure specific enzyme activation status at tissue level. We validated the feasibility of phosphoproteome and total proteome analysis on 8 pre-treatment synovial biopsies from treatment-naive RA patients using label-free mass spectrometry, to identify active cell signalling pathways in synovial tissue which might explain failure to respond to RA therapeutics. Differential expression analysis and functional enrichment revealed clear separation of phosphoproteome and proteome profiles between lymphoid and myeloid RA pathotypes. Abundance of specific phosphosites was associated with the degree of inflammatory state. The lymphoid pathotype was enriched with lymphoproliferative signalling phosphosites, including Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted novel kinases not previously linked to RA, such as Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotype. Several phosphosites correlated with clinical features, such as Disease-Activity-Score (DAS)-28, suggesting that phosphosite analysis has potential for identifying novel biomarkers at tissue-level of disease severity and prognosis. Specific phosphoproteome/proteome signatures delineate RA pathotypes and may have clinical utility for stratifying patients for personalised medicine in RA.
激酶是细胞内的信号介质,是维持类风湿性关节炎(RA)炎症过程的关键。Janus 激酶家族(JAKs)的口服抑制剂被广泛用于治疗类风湿性关节炎,而其他激酶家族(如磷脂酰肌醇3-激酶(PI3K))的抑制剂也在开发之中。目前大多数生物标记物平台对mRNA/蛋白质水平进行量化,但不能直接提供蛋白质是否活跃/不活跃的信息。磷蛋白组分析有可能在组织水平上测量特定酶的激活状态。我们利用无标记质谱法验证了对8例未经治疗的RA患者治疗前滑膜活检组织进行磷酸蛋白组和总蛋白质组分析的可行性,以确定滑膜组织中可能导致RA治疗失败的活跃细胞信号通路。差异表达分析和功能富集显示,淋巴型和骨髓型RA病型的磷酸蛋白组和蛋白质组特征明显不同。特定磷酸位点的丰度与炎症状态的程度有关。淋巴样病理型富含淋巴增生信号磷酸位点,包括哺乳动物雷帕霉素靶标(MTOR)信号,而髓样病理型则与丝裂原活化蛋白激酶(MAPK)和CDK介导的信号有关。这项分析还突显了以前与RA无关的新型激酶,如骨髓病型中的DNA激活的蛋白激酶催化亚基(PRKDC)。一些磷酸化位点与疾病活动性评分(DAS)-28等临床特征相关,这表明磷酸化位点分析有可能在疾病严重程度和预后的组织水平上确定新的生物标记物。特定的磷酸化蛋白质组/蛋白质组特征可划分出RA的病理类型,并可用于对RA患者进行分层,进行个性化治疗。
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引用次数: 0
The integrin CD11b inhibits MSU-induced NLRP3 inflammasome activation in macrophages and protects mice against MSU-induced joint inflammation 整合素 CD11b 可抑制 MSU 诱导的巨噬细胞中 NLRP3 炎性体的激活,保护小鼠免受 MSU 诱导的关节炎症的影响
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-11 DOI: 10.1186/s13075-024-03350-5
Driss Ehirchiou, Ilaria Bernabei, Vishnuprabu Durairaj Pandian, Sonia Nasi, Veronique Chobaz, Mariela Castelblanco, Alexander So, Fabio Martinon, Xiaoyun Li, Hans Acha-Orbea, Thomas Hugle, Li Zhang, Nathalie Busso
In gout, monosodium urate crystals are taken up by macrophages, triggering the activation of the NLRP3 inflammasome and the maturation of IL-1β. This study aimed to investigate the role of integrin CD11b in inflammasome activation in macrophages stimulated by MSU. BMDM from WT and CD11b KO mice were stimulated in vitro with MSU crystals. Cellular supernatants were collected to assess the expression of the inflammatory cytokines by enzyme-linked immunosorbent assay and western blot methods. The role of integrin CD11b in MSU-induced gouty arthritis in vivo was investigated by intra-articular injection of MSU crystals. Real-time extracellular acidification rate and oxygen consumption rate of BMDMs were measured by Seahorse Extracellular Flux Analyzer. We demonstrate that CD11b-deficient mice developed exacerbated gouty arthritis with increased recruitment of leukocytes in the joint and higher IL-1β levels in the sera. In macrophages, genetic deletion of CD11b induced a shift of macrophage metabolism from oxidative phosphorylation to glycolysis, thus decreasing the overall generation of intracellular ATP. Upon MSU stimulation, CD11b-deficient macrophages showed an exacerbated secretion of IL-1β. Treating wild-type macrophages with a CD11b agonist, LA1, inhibited MSU-induced release of IL-1β in vitro and attenuated the severity of experimental gouty arthritis. Importantly, LA1, was also effective in human cells as it inhibited MSU-induced release of IL-1β by peripheral blood mononuclear cells from healthy donors. Our data identified the CD11b integrin as a principal cell membrane receptor that modulates NLRP3 inflammasome activation by MSU crystal in macrophages, which could be a potential therapeutic target to treat gouty arthritis in human patients.
在痛风中,单钠尿酸盐结晶被巨噬细胞吸收,引发NLRP3炎性体的激活和IL-1β的成熟。本研究旨在探讨整合素 CD11b 在受 MSU 刺激的巨噬细胞中激活炎性体的作用。用 MSU 晶体体外刺激 WT 和 CD11b KO 小鼠的 BMDM。收集细胞上清液,用酶联免疫吸附试验和免疫印迹法评估炎性细胞因子的表达。通过关节内注射 MSU 晶体,研究了整合素 CD11b 在 MSU 诱导的痛风性关节炎中的作用。海马细胞外通量分析仪实时测量了BMDMs的细胞外酸化率和耗氧量。我们的研究表明,CD11b缺陷小鼠患痛风性关节炎,关节中的白细胞募集增加,血清中的IL-1β水平升高。在巨噬细胞中,基因缺失 CD11b 会导致巨噬细胞的新陈代谢从氧化磷酸化转向糖酵解,从而减少细胞内 ATP 的总体生成。在受到 MSU 刺激时,CD11b 基因缺陷的巨噬细胞显示出 IL-1β 的加速分泌。用 CD11b 激动剂 LA1 处理野生型巨噬细胞可抑制 MSU 在体外诱导的 IL-1β 的释放,并减轻实验性痛风性关节炎的严重程度。重要的是,LA1 对人体细胞也有效,因为它能抑制健康捐献者的外周血单核细胞在 MSU 诱导下释放 IL-1β。我们的数据确定了 CD11b 整合素是调节巨噬细胞中 MSU 晶体激活 NLRP3 炎症小体的主要细胞膜受体,这可能是治疗人类痛风性关节炎的潜在治疗靶点。
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引用次数: 0
Development of primary osteoarthritis during aging in genetically diverse UM-HET3 mice 不同基因的 UM-HET3 小鼠在衰老过程中出现原发性骨关节炎
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-08 DOI: 10.1186/s13075-024-03349-y
Sher Bahadur Poudel, Ryan R. Ruff, Gozde Yildirim, Richard A. Miller, David E. Harrison, Randy Strong, Thorsten Kirsch, Shoshana Yakar
Primary osteoarthritis (OA) occurs without identifiable underlying causes such as previous injuries or specific medical conditions. Age is a major contributing factor to OA, and as one ages, various joint tissues undergo gradual change, including degeneration of the articular cartilage, alterations in subchondral bone (SCB) morphology, and inflammation of the synovium. We investigated the prevalence of primary OA in aged, genetically diverse UM-HET3 mice. Articular cartilage (AC) integrity and SCB morphology were assessed in 182 knee joints of 22-25 months old mice using the Osteoarthritis Research Society International (OARSI) scoring system and micro-CT, respectively. Additionally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging. Aged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13, inducible nitric oxide synthase, and the NLR family pyrin domain containing-3 inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance. Our study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes.
原发性骨关节炎(OA)的发生没有可识别的潜在原因,如以前受过伤或特定的医疗条件。年龄是导致 OA 的一个主要因素,随着年龄的增长,各种关节组织会逐渐发生变化,包括关节软骨的退化、软骨下骨(SCB)形态的改变以及滑膜的炎症。我们研究了老年、基因多样化的 UM-HET3 小鼠原发性 OA 的发病率。我们使用国际骨关节炎研究学会(OARSI)评分系统和显微 CT 分别评估了 182 只 22-25 个月大小鼠膝关节的关节软骨(AC)完整性和 SCB 形态。此外,我们还探讨了亚甲基蓝(MB)和线粒体醌(MitoQ)这两种影响线粒体功能的药物对衰老过程中 OA 发病率和进展的影响。衰老的 UM-HET3 小鼠在雌雄两性中都表现出较高的原发性 OA 患病率。研究发现,雌雄小鼠的累积关节活动度(cAC)评分与滑膜炎之间存在显著的正相关关系,而雌性小鼠的骨质增生则与滑膜炎之间存在显著的正相关关系。异位软骨形成与 cAC 评分无显著相关性。在雌雄小鼠中,AC评分与软骨细胞中的炎症标记物(包括基质金属蛋白酶-13、诱导型一氧化氮合酶和NLR家族含吡咯啉结构域的-3炎性体)之间存在显著的直接相关性,这表明OA的严重程度与炎症之间存在联系。此外,细胞周期停滞的标志物(如 p16 和 β-半乳糖苷酶)也与 AC 评分相关。在雄性小鼠中,SCB形态特征与cAC评分之间没有发现明显的相关性,而在雌性小鼠中,cAC评分与胫骨SCB板骨矿物质密度之间发现了明显的相关性。值得注意的是,MB 和 MitoQ 治疗以性别特异性的方式影响疾病的进展。MB 治疗能明显降低膝关节内侧的 cAC 分数,而 MitoQ 治疗则能降低 cAC 分数,但二者并不显著。我们的研究全面揭示了老年UM-HET3小鼠原发性OA的患病率和进展情况,突出了MB和MitoQ治疗对不同性别的影响。AC评分与各种病理因素之间的相关性强调了OA的多面性及其与炎症和软骨下骨变化的关联。
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引用次数: 0
A Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-dose escalation study to evaluate the safety and pharmacokinetics/pharmacodynamics of PF-06835375, a C-X-C chemokine receptor type 5 directed antibody, in patients with systemic lupus erythematosus or rheumatoid arthritis 一项 1 期随机、双盲、安慰剂对照、单剂量和多剂量递增研究,旨在评估 PF-06835375 (一种 C-X-C 趋化因子受体 5 型定向抗体)在系统性红斑狼疮或类风湿性关节炎患者中的安全性和药代动力学/药效学特性
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-06 DOI: 10.1186/s13075-024-03337-2
Stanley Cohen, Jean S. Beebe, Vishala Chindalore, Shunjie Guan, Mina Hassan-Zahraee, Madhurima Saxena, Li Xi, Craig Hyde, Sarita Koride, Robert Levin, Shannon Lubaczewski, Mikhail Salganik, Abigail Sloan, Erin Stevens, Elena Peeva, Michael S. Vincent, David A. Martin, Myron Chu
The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF‑06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18–70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03–6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3–10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant. In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4–121.4 h (SAD cohorts) and 162.0–234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3–99.3%/62.4–98.7% [SAD] and 91.1–99.6%/89.5–98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375. These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases. ClinicalTrials.gov identifier: NCT03334851.
PF-06835375是一种靶向C-X-C趋化因子受体5型(CXCR5)的强效选择性阿夫糖基免疫球蛋白G1抗体,可消耗系统性红斑狼疮(SLE)和类风湿性关节炎(RA)患者的B细胞、滤泡T辅助细胞(Tfh)和循环Tfh样细胞(cTfh)。这项首次进行的人体多中心、双盲、赞助商开放、安慰剂对照的 1 期研究招募了 18-70 岁的系统性红斑狼疮或类风湿关节炎患者。在 A 部分,患者在六个连续的单剂量递增(SAD)队列中接受单剂量静脉注射 PF-06835375(剂量范围:0.03-6 毫克)或安慰剂。在 B 部分中,患者在第 1 天和第 29 天重复接受皮下注射 PF-06835375(剂量范围:0.3-10 毫克)或安慰剂,共分为 5 个多剂量组。在第 4 天(Td 和 MenB)和第 8 周(仅 MenB)接种破伤风/白喉 (Td) 和脑膜炎球菌 B (MenB/Trumenba™) 疫苗,以评估 PF-06835375 的功能效应。终点包括治疗突发不良事件 (TEAE)、药代动力学参数、对 B 细胞和 cTfh 细胞的药效学效应、生物标记物计数、疫苗应答和探索性差异基因表达分析。对安全性、药代动力学和药效学终点进行了描述性总结。B细胞和Tfh细胞特异性基因随时间推移的基线变化采用预设的混合效应模型进行计算,假发现率<0.05被认为具有统计学意义。共有73名患者接受了治疗(SAD队列:SLE,n = 17;RA,n = 14;MAD队列:SLE,n = 22;RA,n = 20)。平均年龄为 53.3 岁。62名(84.9%)患者出现了TEAEs(安慰剂 n = 17;PF-06835375 n = 45);大多数为轻度或中度。3名(9.7%)患者出现严重不良事件。平均 t1/2 为 3.4-121.4 小时(SAD 组)和 162.0-234.0 小时(MAD 组,第 29 天)。各组的 B 细胞和 cTfh 细胞计数普遍呈剂量依赖性下降(平均最大消耗范围:67.3%-99.3%):分别为 67.3-99.3%/62.4-98.7% [SAD] 和 91.1-99.6%/89.5-98.1% [MAD])。在接受 PF-06835375 治疗的患者中,B 细胞相关基因和通路显著下调。这些数据支持进一步开发PF-06835375,以评估B细胞和Tfh细胞耗竭作为自身免疫性疾病治疗方法的临床潜力。ClinicalTrials.gov identifier:NCT03334851。
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引用次数: 0
Effectiveness of janus kinase inhibitors in relapsing giant cell arteritis in real-world clinical practice and review of the literature 破伤风激酶抑制剂在实际临床实践中对复发性巨细胞动脉炎的疗效及文献综述
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-05 DOI: 10.1186/s13075-024-03314-9
Javier Loricera, Toluwalase Tofade, Diana Prieto-Peña, Susana Romero-Yuste, Eugenio de Miguel, Anne Riveros-Frutos, Iván Ferraz-Amaro, Eztizen Labrador, Olga Maiz, Elena Becerra, Javier Narváez, Eva Galíndez-Agirregoikoa, Ismael González-Fernández, Ana Urruticoechea-Arana, Ángel Ramos-Calvo, Fernando López-Gutiérrez, Santos Castañeda, Sebastian Unizony, Ricardo Blanco
A substantial proportion of patients with giant cell arteritis (GCA) relapse despite standard therapy with glucocorticoids, methotrexate and tocilizumab. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is involved in the pathogenesis of GCA and JAK inhibitors (JAKi) could be a therapeutic alternative. We evaluated the effectiveness of JAKi in relapsing GCA patients in a real-world setting and reviewed available literature. Retrospective analysis of GCA patients treated with JAKi for relapsing disease at thirteen centers in Spain and one center in United States (01/2017-12/2022). Outcomes assessed included clinical remission, complete remission and safety. Clinical remission was defined as the absence of GCA signs and symptoms regardless of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values. Complete remission was defined as the absence of GCA signs and symptoms along with normal ESR and CRP values. A systematic literature search for other JAKi-treated GCA cases was conducted. Thirty-five patients (86% females, mean age 72.3) with relapsing GCA received JAKi therapy (baricitinib, n = 15; tofacitinib, n = 10; upadacitinib, n = 10). Before JAKi therapy, 22 (63%) patients had received conventional synthetic immunosuppressants (e.g., methotrexate), and 30 (86%) biologics (e.g., tocilizumab). After a median (IQR) follow-up of 11 (6-15.5) months, 20 (57%) patients achieved and maintained clinical remission, 16 (46%) patients achieved and maintained complete remission, and 15 (43%) patients discontinued the initial JAKi due to relapse (n = 11 [31%]) or serious adverse events (n = 4 [11%]). A literature search identified another 36 JAKi-treated GCA cases with clinical improvement reported for the majority of them. This real-world analysis and literature review suggest that JAKi could be effective in GCA, including in patients failing established glucocorticoid-sparing therapies such as tocilizumab and methotrexate. A phase III randomized controlled trial of upadacitinib is currently ongoing (ClinicalTrials.gov ID NCT03725202).
尽管使用了糖皮质激素、甲氨蝶呤和妥昔单抗等标准疗法,但仍有相当一部分巨细胞动脉炎(GCA)患者病情复发。Janus激酶/信号转导和转录激活因子(JAK/STAT)信号通路参与了GCA的发病机制,JAK抑制剂(JAKi)可能是一种治疗选择。我们评估了 JAKi 在现实世界中对复发性 GCA 患者的疗效,并回顾了现有文献。对西班牙十三家中心和美国一家中心使用JAKi治疗复发性GCA患者的情况进行了回顾性分析(01/2017-12/2022)。评估结果包括临床缓解、完全缓解和安全性。临床缓解的定义是,无论红细胞沉降率(ESR)和C反应蛋白(CRP)值如何,均无GCA体征和症状。完全缓解是指没有 GCA 体征和症状,同时血沉和 CRP 值正常。对其他接受过 JAKi 治疗的 GCA 病例进行了系统的文献检索。35名复发性GCA患者(86%为女性,平均年龄72.3岁)接受了JAKi治疗(巴利替尼,n = 15;托法替尼,n = 10;乌帕替尼,n = 10)。在接受JAKi治疗前,22名(63%)患者接受了传统合成免疫抑制剂(如甲氨蝶呤)治疗,30名(86%)患者接受了生物制剂(如托珠单抗)治疗。中位(IQR)随访11(6-15.5)个月后,20(57%)名患者获得并维持了临床缓解,16(46%)名患者获得并维持了完全缓解,15(43%)名患者因复发(11[31%])或严重不良事件(4[11%])而停止使用初始JAKi。文献检索发现了另外 36 例接受过 JAKi 治疗的 GCA 病例,其中大多数病例的临床症状都有所改善。这项真实世界分析和文献综述表明,JAKi对GCA可能有效,包括对托珠单抗和甲氨蝶呤等糖皮质激素保留疗法失败的患者。目前正在进行一项关于乌达替尼的III期随机对照试验(ClinicalTrials.gov ID NCT03725202)。
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Arthritis Research & Therapy
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