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Exploration of the combined role of immune checkpoints and immune cells in the diagnosis and treatment of ankylosing spondylitis: a preliminary study immune checkpoints in ankylosing spondylitis 探讨免疫检查点和免疫细胞在诊断和治疗强直性脊柱炎中的联合作用:一项初步研究 强直性脊柱炎中的免疫检查点
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-06-04 DOI: 10.1186/s13075-024-03341-6
Feihong Huang, Zhiping Su, Yibin Huang, Yuxiang Huang, Chengyu Zhou, Sitan Feng, Xiong Qin, Xi Xie, Chong Liu, Chaojie Yu
Immune checkpoints have emerged as promising therapeutic targets for autoimmune diseases. However, the specific roles of immune checkpoints in the pathophysiology of ankylosing spondylitis (AS) remain unclear. Hip ligament samples were obtained from two patient groups: those with AS and femoral head deformity, and those with femoral head necrosis but without AS, undergoing hip arthroplasty. Label-Free Quantification (LFQ) Protein Park Analysis was used to identify the protein composition of the ligaments. Peripheral blood samples of 104 AS patients from public database were used to validate the expression of key proteins. KEGG, GO, and GSVA were employed to explore potential pathways regulated by immune checkpoints in AS progression. xCell was used to calculate cell infiltration levels, LASSO regression was applied to select key cells, and the correlation between immune checkpoints and immune cells was analyzed. Drug sensitivity analysis was conducted to identify potential therapeutic drugs targeting immune checkpoints in AS. The expression of key genes was validated through immunohistochemistry (IHC). HLA-DMB and HLA-DPA1 were downregulated in the ligaments of AS and this has been validated through peripheral blood datasets and IHC. Significant differences in expression were observed in CD8 + Tcm, CD8 + T cells, CD8 + Tem, osteoblasts, Th1 cells, and CD8 + naive T cells in AS. The infiltration levels of CD8 + Tcm and CD8 + naive T cells were significantly positively correlated with the expression levels of HLA-DMB and HLA-DPA1. Immune cell selection using LASSO regression showed good predictive ability for AS, with AUC values of 0.98, 0.81, and 0.75 for the three prediction models, respectively. Furthermore, this study found that HLA-DMB and HLA-DPA1 are involved in Th17 cell differentiation, and both Th17 cell differentiation and the NF-kappa B signaling pathway are activated in the AS group. Drug sensitivity analysis showed that AS patients are more sensitive to drugs such as doramapimod and GSK269962A. Immune checkpoints and immune cells could serve as avenues for exploring diagnostic and therapeutic strategies for AS.
免疫检查点已成为治疗自身免疫性疾病的有望靶点。然而,免疫检查点在强直性脊柱炎(AS)病理生理学中的具体作用仍不清楚。研究人员从两组接受髋关节置换术的患者中采集了髋关节韧带样本:一组是患有强直性脊柱炎和股骨头畸形的患者,另一组是患有股骨头坏死但没有强直性脊柱炎的患者。采用无标记定量(LFQ)蛋白质公园分析法确定韧带的蛋白质组成。公共数据库中 104 例 AS 患者的外周血样本被用来验证关键蛋白的表达。利用KEGG、GO和GSVA探索免疫检查点在强直性脊柱炎进展中调控的潜在通路。利用xCell计算细胞浸润水平,应用LASSO回归选择关键细胞,并分析免疫检查点与免疫细胞之间的相关性。进行了药物敏感性分析,以确定针对强直性脊柱炎免疫检查点的潜在治疗药物。通过免疫组织化学(IHC)验证了关键基因的表达。HLA-DMB和HLA-DPA1在强直性脊柱炎韧带中下调,这一点已通过外周血数据集和IHC得到验证。在强直性脊柱炎患者的 CD8 + Tcm、CD8 + T 细胞、CD8 + Tem、成骨细胞、Th1 细胞和 CD8 + 天真 T 细胞中观察到明显的表达差异。CD8 + Tcm和CD8 +幼稚T细胞的浸润水平与HLA-DMB和HLA-DPA1的表达水平呈显著正相关。使用 LASSO 回归法进行的免疫细胞选择对强直性脊柱炎显示出良好的预测能力,三个预测模型的 AUC 值分别为 0.98、0.81 和 0.75。此外,该研究还发现,HLA-DMB和HLA-DPA1参与了Th17细胞的分化,而在AS组中,Th17细胞分化和NF-kappa B信号通路均被激活。药物敏感性分析表明,强直性脊柱炎患者对多拉帕莫德和GSK269962A等药物更敏感。免疫检查点和免疫细胞可作为探索强直性脊柱炎诊断和治疗策略的途径。
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引用次数: 0
Malignancy is increased in patients with antineutrophil cytoplasmic antibody-associated vasculitis in China 中国抗中性粒细胞胞浆抗体相关性血管炎患者恶性肿瘤发病率升高
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-05-31 DOI: 10.1186/s13075-024-03345-2
Xiang-Yu Han, Zhi-Ying Li, Ming-Hui Zhao, Mark A. Little, Min Chen
It has been reported that in western countries malignancy risk was higher in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with that in the general population. In the current study, we investigated the incidence, spectrum and risk factors of malignancy in Chinese AAV patients. AAV patients diagnosed from 1995 to 2021 in Peking University First Hospital with a follow-up more than 12 months were recruited. Standardized incidence ratios (SIR) were calculated to describe the risk of malignancy, adjusted for sex, age and follow-up time. A total of 552 AAV patients were recruited, among which 23 patients had malignancies either preceding or concurrent with AAV diagnosis, and 43 of the remaining 529 patients developed malignancies within 4.3 ± 4.2 years post AAV diagnosis (SIR: 2.24; 95% CI: 1.68–2.99; p < 0.001). Among these 66 patients, twenty different sites of malignancy were observed, lung cancer being most frequent. To get exactly expected malignancies for the calculation of SIR, 529 patients without preceding or concurrent malignancies were included in the following analysis. Lung cancer was still the leading malignancy diagnosis (SIR: 5.01; 95% CI: 3.29–7.62), followed by malignancies in the kidney, bladder, ureter and prostate. Male gender (HR:2.84; 95%CI:1.36–5.96; p = 0.006) and older age (per year, HR:1.04; 95%CI:1.00-1.07; p = 0.038) were significantly associated with increased risk of malignancy. For patients with malignancy developed beyond 5 years after the diagnosis of AAV, a significantly higher malignancy risk was observed in those with a cumulative cyclophosphamide dose over 20.0 g (SIR: 11.54; 95% CI: 4.77–27.93; p < 0.001). Within the first 2 years after the diagnosis of AAV, the risk of malignancy was still significantly higher than that in the general population, but the cumulative cyclophosphamide dose was not significantly associated with malignancy occurrence in this subgroup of patients. Malignancy risk is higher in Chinese AAV patients than that in the general population, with a different malignancy spectrum from western countries. Both the use of cyclophosphamide and AAV per se might be associated with higher incidence of malignancy occurrence.
据报道,在西方国家,与普通人群相比,抗中性粒细胞胞浆抗体(ANCA)相关性血管炎(AAV)患者的恶性肿瘤风险更高。在本研究中,我们调查了中国 AAV 患者恶性肿瘤的发病率、发病谱和风险因素。研究招募了 1995 年至 2021 年期间在北京大学第一医院确诊并随访 12 个月以上的 AAV 患者。经性别、年龄和随访时间调整后,计算了恶性肿瘤的标准化发病率(SIR),以描述恶性肿瘤的风险。共招募了 552 例 AAV 患者,其中 23 例患者在确诊 AAV 之前或同时患有恶性肿瘤,其余 529 例患者中有 43 例在确诊 AAV 后 4.3 ± 4.2 年内发生恶性肿瘤(SIR:2.24;95% CI:1.68-2.99;P < 0.001)。在这 66 名患者中,发现了 20 种不同部位的恶性肿瘤,其中以肺癌最为常见。为了准确计算预期恶性肿瘤的 SIR,以下分析中纳入了 529 例无先发或并发恶性肿瘤的患者。肺癌仍然是最主要的恶性肿瘤诊断(SIR:5.01;95% CI:3.29-7.62),其次是肾脏、膀胱、输尿管和前列腺恶性肿瘤。男性性别(HR:2.84;95%CI:1.36-5.96;p = 0.006)和年龄(每年,HR:1.04;95%CI:1.00-1.07;p = 0.038)与恶性肿瘤风险的增加显著相关。对于在确诊AAV后5年后发生恶性肿瘤的患者,观察到累积环磷酰胺剂量超过20.0克的患者发生恶性肿瘤的风险明显更高(SIR:11.54;95% CI:4.77-27.93;p < 0.001)。在AAV确诊后的头两年内,恶性肿瘤的风险仍明显高于普通人群,但在这一亚组患者中,环磷酰胺的累积剂量与恶性肿瘤的发生并无明显关联。中国 AAV 患者的恶性肿瘤风险高于普通人群,其恶性肿瘤谱与西方国家不同。使用环磷酰胺和AAV本身都可能与恶性肿瘤发生率较高有关。
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引用次数: 0
Predictive models of radiographic progression and pain progression in patients with knee osteoarthritis: data from the FNIH OA biomarkers consortium project 膝关节骨性关节炎患者放射学进展和疼痛进展的预测模型:来自 FNIH OA 生物标记物联盟项目的数据
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-05-30 DOI: 10.1186/s13075-024-03346-1
Xiaoyu Li, Chunpu Li, Peng Zhang
The progression of knee osteoarthritis (OA) can be defined as either radiographic progression or pain progression. This study aimed to construct models to predict radiographic progression and pain progression in patients with knee OA. We retrieved data from the FNIH OA Biomarkers Consortium project, a nested case-control study. A total of 600 subjects with mild to moderate OA (Kellgren-Lawrence grade of 1, 2, or 3) in one target knee were enrolled. The patients were classified as radiographic progressors (n = 297), non-radiographic progressors (n = 303), pain progressors (n = 297), or non-pain progressors (n = 303) according to the change in the minimum joint space width of the medial compartment and the WOMAC pain score during the follow-up period of 24–48 months. Initially, 376 variables concerning demographics, clinical questionnaires, imaging measurements, and biochemical markers were included. We developed predictive models based on multivariate logistic regression analysis and visualized the models with nomograms. We also tested whether adding changes in predictors from baseline to 24 months would improve the predictive efficacy of the models. The predictive models of radiographic progression and pain progression consisted of 8 and 10 variables, respectively, with area under curve (AUC) values of 0.77 and 0.76, respectively. Incorporating the change in the WOMAC pain score from baseline to 24 months into the pain progression predictive model significantly improved the predictive effectiveness (AUC = 0.86). We identified risk factors for imaging progression and pain progression in patients with knee OA over a 2- to 4-year period, and provided effective predictive models, which could help identify patients at high risk of progression.
膝关节骨性关节炎(OA)的进展可定义为影像学进展或疼痛进展。本研究旨在构建膝关节OA患者的放射学进展和疼痛进展预测模型。我们从 FNIH OA 生物标志物联盟项目(一项巢式病例对照研究)中获取了数据。我们共招募了600名患有轻度至中度膝关节OA(Kellgren-Lawrence分级为1、2或3级)的受试者。根据随访24-48个月期间内侧室最小关节间隙宽度和WOMAC疼痛评分的变化,将患者分为影像学进展者(n = 297)、非影像学进展者(n = 303)、疼痛进展者(n = 297)或非疼痛进展者(n = 303)。最初,我们纳入了有关人口统计学、临床问卷调查、影像学测量和生化指标的 376 个变量。我们根据多变量逻辑回归分析建立了预测模型,并用提名图直观显示了模型。我们还测试了添加从基线到 24 个月的预测因子变化是否会提高模型的预测效果。放射学进展和疼痛进展的预测模型分别由 8 个和 10 个变量组成,其曲线下面积 (AUC) 值分别为 0.77 和 0.76。将 WOMAC 疼痛评分从基线到 24 个月的变化纳入疼痛进展预测模型可显著提高预测效果(AUC = 0.86)。我们确定了膝关节OA患者在2至4年期间影像学进展和疼痛进展的风险因素,并提供了有效的预测模型,有助于识别高风险进展患者。
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引用次数: 0
MiR-653-5p drives osteoarthritis pathogenesis by modulating chondrocyte senescence MiR-653-5p 通过调节软骨细胞衰老驱动骨关节炎发病机制
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-05-29 DOI: 10.1186/s13075-024-03334-5
Yucheng Lin, Lu Zhang, Mingliang Ji, Sinuo Shen, Yuzhi Chen, Shichao Wu, Xiaotao Wu, Nancy Q. Liu, Jun Lu
Due to the unclear pathogenesis of osteoarthritis (OA), effective treatment for this ailment is presently unavailable. Accumulating evidence points to chondrocyte senescence as a key driver in OA development. This study aims to identify OA-specific microRNAs (miRNAs) targeting chondrocyte senescence to alleviate OA progression. We screened and identified miRNAs differentially expressed in OA and normal cartilage, then confirmed the impact of miR-653-5p on chondrocyte functions and senescence phenotypes through in vitro experiments with overexpression/silencing. We identified interleukin 6 (IL-6) as the target gene of miR-653-5p and confirmed the regulatory influence of miR-653-5p on the IL-6/JAK/STAT3 signaling pathway through gain/loss-of-function studies. Finally, we assessed the therapeutic efficacy of miR-653-5p on OA using a mouse model with destabilization of the medial meniscus. MiR-653-5p was significantly downregulated in cartilage tissues and chondrocytes from OA patients. Overexpression of miR-653-5p promoted chondrocyte matrix synthesis and proliferation while inhibiting chondrocyte senescence. Furthermore, bioinformatics target prediction and the luciferase reporter assays identified IL-6 as a target of miR-653-5p. Western blot assays demonstrated that miR-653-5p overexpression inhibited the protein expression of IL-6, the phosphorylation of JAK1 and STAT3, and the expression of chondrocyte senescence phenotypes by regulating the IL-6/JAK/STAT3 signaling pathway. More importantly, the cartilage destruction was significantly alleviated and chondrocyte senescence phenotypes were remarkably decreased in the OA mouse model treated by agomiR-653-5p compared to the control mice. MiR-653-5p showed a significant decrease in cartilage tissues of individuals with OA, leading to an upregulation of chondrocyte senescence phenotypes in the articular cartilage. AgomiR-653-5p emerges as a potential treatment approach for OA. These findings provide further insight into the role of miR-653-5p in chondrocyte senescence and the pathogenesis of OA.
由于骨关节炎(OA)的发病机理尚不清楚,目前还没有有效的治疗方法。越来越多的证据表明,软骨细胞衰老是导致 OA 发生的关键因素。本研究旨在鉴定针对软骨细胞衰老的 OA 特异性微 RNA(miRNA),以缓解 OA 的进展。我们筛选并鉴定了在 OA 和正常软骨中差异表达的 miRNA,然后通过过表达/沉默的体外实验证实了 miR-653-5p 对软骨细胞功能和衰老表型的影响。我们确定了白细胞介素 6(IL-6)是 miR-653-5p 的靶基因,并通过功能增益/功能缺失研究证实了 miR-653-5p 对 IL-6/JAK/STAT3 信号通路的调控作用。最后,我们利用内侧半月板失稳的小鼠模型评估了 miR-653-5p 对 OA 的疗效。在 OA 患者的软骨组织和软骨细胞中,miR-653-5p 明显下调。过表达 miR-653-5p 能促进软骨细胞基质的合成和增殖,同时抑制软骨细胞的衰老。此外,生物信息学靶点预测和荧光素酶报告实验确定了 IL-6 是 miR-653-5p 的靶点。Western 印迹分析表明,miR-653-5p 的过表达通过调节 IL-6/JAK/STAT3 信号通路,抑制了 IL-6 蛋白表达、JAK1 和 STAT3 磷酸化以及软骨细胞衰老表型的表达。更重要的是,与对照组相比,用agomiR-653-5p治疗的OA小鼠软骨破坏明显减轻,软骨细胞衰老表型明显减少。MiR-653-5p在OA患者的软骨组织中明显减少,导致关节软骨中软骨细胞衰老表型的上调。AgomiR-653-5p成为治疗OA的一种潜在方法。这些发现进一步揭示了 miR-653-5p 在软骨细胞衰老和 OA 发病机制中的作用。
{"title":"MiR-653-5p drives osteoarthritis pathogenesis by modulating chondrocyte senescence","authors":"Yucheng Lin, Lu Zhang, Mingliang Ji, Sinuo Shen, Yuzhi Chen, Shichao Wu, Xiaotao Wu, Nancy Q. Liu, Jun Lu","doi":"10.1186/s13075-024-03334-5","DOIUrl":"https://doi.org/10.1186/s13075-024-03334-5","url":null,"abstract":"Due to the unclear pathogenesis of osteoarthritis (OA), effective treatment for this ailment is presently unavailable. Accumulating evidence points to chondrocyte senescence as a key driver in OA development. This study aims to identify OA-specific microRNAs (miRNAs) targeting chondrocyte senescence to alleviate OA progression. We screened and identified miRNAs differentially expressed in OA and normal cartilage, then confirmed the impact of miR-653-5p on chondrocyte functions and senescence phenotypes through in vitro experiments with overexpression/silencing. We identified interleukin 6 (IL-6) as the target gene of miR-653-5p and confirmed the regulatory influence of miR-653-5p on the IL-6/JAK/STAT3 signaling pathway through gain/loss-of-function studies. Finally, we assessed the therapeutic efficacy of miR-653-5p on OA using a mouse model with destabilization of the medial meniscus. MiR-653-5p was significantly downregulated in cartilage tissues and chondrocytes from OA patients. Overexpression of miR-653-5p promoted chondrocyte matrix synthesis and proliferation while inhibiting chondrocyte senescence. Furthermore, bioinformatics target prediction and the luciferase reporter assays identified IL-6 as a target of miR-653-5p. Western blot assays demonstrated that miR-653-5p overexpression inhibited the protein expression of IL-6, the phosphorylation of JAK1 and STAT3, and the expression of chondrocyte senescence phenotypes by regulating the IL-6/JAK/STAT3 signaling pathway. More importantly, the cartilage destruction was significantly alleviated and chondrocyte senescence phenotypes were remarkably decreased in the OA mouse model treated by agomiR-653-5p compared to the control mice. MiR-653-5p showed a significant decrease in cartilage tissues of individuals with OA, leading to an upregulation of chondrocyte senescence phenotypes in the articular cartilage. AgomiR-653-5p emerges as a potential treatment approach for OA. These findings provide further insight into the role of miR-653-5p in chondrocyte senescence and the pathogenesis of OA.","PeriodicalId":8419,"journal":{"name":"Arthritis Research & Therapy","volume":"17 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165242","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
Microstructural changes of the white matter in systemic lupus erythematosus patients without neuropsychiatric symptoms: a multi-shell diffusion imaging study. 无神经精神症状的系统性红斑狼疮患者白质的微结构变化:多壳弥散成像研究。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-05-28 DOI: 10.1186/s13075-024-03344-3
Wenjun Hu, Ziru Qiu, Qin Huang, Yuhao Lin, Jiaying Mo, Linhui Wang, Jingyi Wang, Kan Deng, Yanqiu Feng, Xinyuan Zhang, Xiangliang Tan

Background: Diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) provide more comprehensive and informative perspective on microstructural alterations of cerebral white matter (WM) than single-shell diffusion tensor imaging (DTI), especially in the detection of crossing fiber. However, studies on systemic lupus erythematosus patients without neuropsychiatric symptoms (non-NPSLE patients) using multi-shell diffusion imaging remain scarce.

Methods: Totally 49 non-NPSLE patients and 41 age-, sex-, and education-matched healthy controls underwent multi-shell diffusion magnetic resonance imaging. Totally 10 diffusion metrics based on DKI (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, mean kurtosis, axial kurtosis and radial kurtosis) and NODDI (neurite density index, orientation dispersion index and volume fraction of the isotropic diffusion compartment) were evaluated. Tract-based spatial statistics (TBSS) and atlas-based region-of-interest (ROI) analyses were performed to determine group differences in brain WM microstructure. The associations of multi-shell diffusion metrics with clinical indicators were determined for further investigation.

Results: TBSS analysis revealed reduced FA, AD and RK and increased ODI in the WM of non-NPSLE patients (P < 0.05, family-wise error corrected), and ODI showed the best discriminative ability. Atlas-based ROI analysis found increased ODI values in anterior thalamic radiation (ATR), inferior frontal-occipital fasciculus (IFOF), forceps major (F_major), forceps minor (F_minor) and uncinate fasciculus (UF) in non-NPSLE patients, and the right ATR showed the best discriminative ability. ODI in the F_major was positively correlated to C3.

Conclusion: This study suggested that DKI and NODDI metrics can complementarily detect WM abnormalities in non-NPSLE patients and revealed ODI as a more sensitive and specific biomarker than DKI, guiding further understanding of the pathophysiological mechanism of normal-appearing WM injury in SLE.

背景:与单壳弥散张量成像(DTI)相比,弥散峰度成像(DKI)和神经元定向弥散和密度成像(NODDI)能更全面、更翔实地透视脑白质(WM)的微观结构改变,尤其是在检测交叉纤维方面。然而,针对无神经精神症状的系统性红斑狼疮患者(非 NPSLE 患者)使用多壳弥散成像的研究仍然很少:方法:49 名非非系统性红斑狼疮患者和 41 名年龄、性别和教育程度相匹配的健康对照者接受了多壳弥散磁共振成像。共评估了 10 项基于 DKI(分数各向异性、平均扩散率、轴向扩散率、径向扩散率、平均峰度、轴向峰度和径向峰度)和 NODDI(神经元密度指数、定向弥散指数和各向同性扩散区的体积分数)的扩散指标。为确定脑WM微观结构的组间差异,还进行了基于肽段的空间统计(TBSS)和基于图谱的感兴趣区(ROI)分析。多壳扩散指标与临床指标的关系有待进一步研究:结果:TBSS分析表明,非NPSLE患者的WM中FA、AD和RK减少,ODI增加(P 结论:该研究表明,DKI和NPSLE患者的WM微观结构存在差异:这项研究表明,DKI 和 NODDI 指标可以互补地检测非 NPSLE 患者的 WM 异常,并揭示了 ODI 是比 DKI 更敏感、更特异的生物标志物,这将有助于进一步了解系统性红斑狼疮正常表现 WM 损伤的病理生理机制。
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引用次数: 0
Investigating protease-mediated peptides of inflammation and tissue remodeling as biomarkers associated with flares in psoriatic arthritis 将蛋白酶介导的炎症和组织重塑肽作为与银屑病关节炎复发相关的生物标记物的研究
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-05-27 DOI: 10.1186/s13075-024-03332-7
Solveig Skovlund Groen, Signe Holm Nielsen, Anne Christine Bay-Jensen, Mozhgan Rasti, Darshini Ganatra, Katerina Oikonomopoulou, Vinod Chandran
Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. PsA disease involves flares, which are associated with increased joint inflammation and tissue remodeling. There is a need for identifying biomarkers related to PsA disease activity and flares to improve the management of PsA patients and decrease flares. The tissue turnover imbalance that occurs during the inflammatory and fibro-proliferative processes during flares leads to an increased degradation and/or reorganization of the extracellular matrix (ECM), where increased proteolysis plays a key role. Hence, protease-mediated fragments of inflammatory and tissue-remodeling components could be used as markers reflecting flares in PsA patients. A broad panel of protease-mediated biomarkers reflecting inflammation and tissue remodeling was measured in serum and synovial fluid (SF) obtained from PsA patients experiencing flares (acutely swollen joint[s], PsA-flare). In serum, biomarker levels assessed in PsA-flare patients were compared to controls and in early-diagnosed PsA patients not experiencing flares (referred to as PsA without flare). Furthermore, the biomarker levels assessed in SF from PsA-flare patients were compared to the levels in SF of osteoarthritis (OA) patients. In serum, levels of the PRO-C3 and C3M, reflecting formation and degradation of the interstitial matrix, were found significantly elevated in PsA-flare compared to controls and PsA without flare. The remodeling marker of the basement membrane, PRO-C4, was significantly elevated in PsA-flare compared to PsA without flare. The inflammation and immune cell activity related markers, CRPM, VICM, and CPa9-HNE were significantly elevated in PsA-flare patients compared to controls and PsA without flare. In addition, VICM (AUC = 0.71), CPa9-HNE (AUC = 0.89), CRPM (AUC = 0.76), and PRO-C3 (AUC = 0.86) showed good discriminatory performance for separating PsA-flare from PsA without flare. In SF, the macrophage activity marker, VICM, was significantly elevated whereas the type II collagen formation marker, PRO-C2, was significantly reduced in the PsA-flare compared to OA. The combination of five serum markers reflecting type III and IV collagen degradation (C3M and C4M, respectively), type III and VI collagen formation (PRO-C3 and PRO-C6, respectively), and neutrophil activity (CPa9-HNE) showed an excellent discriminatory performance (AUC = 0.98) for separating PsA-flare from PsA without flares. The serum biomarker panel of C3M, C4M, PRO-C3, PRO-C6, and CPa9-HNE reflecting synovitis, enthesitis, and neutrophil activity may serve as novel tool for quantitatively monitoring flares in PsA patients.
银屑病关节炎(PsA)是一种与银屑病相关的炎症性关节炎。PsA 疾病会复发,这与关节炎症加重和组织重塑有关。目前需要确定与 PsA 疾病活动和复发有关的生物标志物,以改善对 PsA 患者的管理并减少复发。炎症和纤维增生过程中出现的组织更替失衡会导致细胞外基质(ECM)降解和/或重组增加,其中蛋白水解增加起着关键作用。因此,蛋白酶介导的炎症和组织重塑成分片段可用作反映 PsA 患者病情发作的标志物。研究人员测量了PsA复发(急性关节肿胀,PsA-复发)患者血清和滑液(SF)中反映炎症和组织重塑的一系列蛋白酶介导的生物标记物。在血清中,PsA 病发患者的生物标记物水平评估结果与对照组和未发生病发的早期诊断 PsA 患者(称为未发生病发的 PsA 患者)的生物标记物水平进行了比较。此外,还将 PsA 复发患者自体组织中评估的生物标志物水平与骨关节炎(OA)患者自体组织中的水平进行了比较。在血清中,PRO-C3和C3M的水平反映了间质基质的形成和降解,与对照组和未发作的PsA相比,PsA发作期患者的PRO-C3和C3M水平明显升高。与未发作的 PsA 相比,发作期 PsA 的基底膜重塑标志物 PRO-C4 明显升高。与对照组和未发作的 PsA 相比,发作期 PsA 患者的炎症和免疫细胞活性相关标记物 CRPM、VICM 和 CPa9-HNE 明显升高。此外,VICM(AUC = 0.71)、CPa9-HNE(AUC = 0.89)、CRPM(AUC = 0.76)和PRO-C3(AUC = 0.86)在区分PsA发作和非发作PsA方面表现出良好的鉴别性能。在 SF 中,与 OA 相比,PsA-发作期的巨噬细胞活性标记物 VICM 明显升高,而 II 型胶原形成标记物 PRO-C2 则明显降低。反映Ⅲ型和Ⅳ型胶原降解(分别为C3M和C4M)、Ⅲ型和Ⅵ型胶原形成(分别为PRO-C3和PRO-C6)以及中性粒细胞活性(CPa9-HNE)的五种血清标记物组合在区分PsA-flare和PsA-flare方面表现出极佳的鉴别性能(AUC = 0.98)。由 C3M、C4M、PRO-C3、PRO-C6 和 CPa9-HNE 组成的反映滑膜炎、粘膜炎和中性粒细胞活性的血清生物标记物面板可作为定量监测 PsA 患者复发的新型工具。
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引用次数: 0
The prognosis and management of reclassified systemic lupus erythematosus associated pulmonary arterial hypertension according to 2022 ESC/ERS guidelines 根据 2022 年 ESC/ERS 指南重新分类的系统性红斑狼疮相关肺动脉高压的预后与管理
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-05-27 DOI: 10.1186/s13075-024-03338-1
Yutong Li, Junyan Qian, Xingbei Dong, Jiuliang Zhao, Qian Wang, Yanhong Wang, Xiaofeng Zeng, Zhuang Tian, Mengtao Li
The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guideline has recently revised the hemodynamic definition of pulmonary arterial hypertension. However, there is currently limited research on the prognosis and treatment of system lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH) patients that have been reclassified by the new hemodynamic definition. This study aims to analyze the prognosis of newly reclassified SLE-PAH patients and provide recommendations for the management strategy. This retrospective study analyzed records of 236 SLE-PAH patients who visited Peking Union Medical College Hospital (PUMCH) from 2011 to 2023, among whom 22 patients were reclassified into mild SLE-PAH (mean pulmonary arterial pressure (mPAP) of 21–24 mmHg, pulmonary vascular resistance (PVR) of 2–3 WU, and PAWP ≤ 15 mmHg) according to the guidelines and 14 were defined as unclassified SLE-PAH patients (mPAP 21–24 mmHg and PVR ≤ 2 WU). The prognosis was compared among mild SLE-PAH, unclassified SLE-PH, and conventional SLE-PAH patients (mPAP ≥ 25 mmHg and PVR > 3WU). Besides, the effectiveness of pulmonary arterial hypertension (PAH)-specific therapy was evaluated in mild SLE-PAH patients. Those mild SLE-PAH patients had significantly longer progression-free time than the conventional SLE-PAH patients. Among the mild SLE-PAH patients, 4 did not receive PAH-specific therapy and had a similar prognosis as patients not receiving specific therapy. This study supports the revised hemodynamic definition of SLE-PAH in the 2022 ESC/ERS guideline. Those mild and unclassified SLE-PH patients had a better prognosis, demonstrating the possibility and significance of early diagnosis and intervention for SLE-PAH. This study also proposed a hypothesis that IIT against SLE might be sufficient for those reclassified SLE-PAH patients.
2022 年欧洲心脏病学会/欧洲呼吸学会(ESC/ERS)指南最近修订了肺动脉高压的血液动力学定义。然而,目前有关系统性红斑狼疮相关性肺动脉高压(SLE-PAH)患者的预后和治疗的研究还很有限。本研究旨在分析新近被重新分类的系统性红斑狼疮相关性肺动脉高压患者的预后,并为治疗策略提供建议。这项回顾性研究分析了2011年至2023年期间在北京协和医院就诊的236名SLE-PAH患者的病历,其中22名患者被重新分类为轻度SLE-PAH(平均肺动脉压(mPAP)为21-24 mmHg、肺血管阻力(PVR)为 2-3 WU,PAWP ≤ 15 mmHg),14 名患者被定义为未分类的 SLE-PAH 患者(mPAP 为 21-24 mmHg,PVR ≤ 2 WU)。对轻度 SLE-PAH、未分类 SLE-PAH 和常规 SLE-PAH 患者(mPAP ≥ 25 mmHg 和 PVR > 3 WU)的预后进行了比较。此外,还对轻度系统性红斑狼疮-PAH 患者的肺动脉高压(PAH)特异性治疗效果进行了评估。与传统的系统性红斑狼疮-PAH患者相比,轻度系统性红斑狼疮-PAH患者的无进展时间明显更长。在轻度系统性红斑狼疮-PAH患者中,有4人未接受PAH特异性治疗,其预后与未接受特异性治疗的患者相似。这项研究支持2022年ESC/ERS指南中修订后的SLE-PAH血液动力学定义。那些轻度和未分类的系统性红斑狼疮-PAH 患者预后较好,这说明了早期诊断和干预系统性红斑狼疮-PAH 的可能性和意义。这项研究还提出了一个假设,即对于那些重新分类的系统性红斑狼疮-PAH 患者,针对系统性红斑狼疮的 IIT 可能就足够了。
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引用次数: 0
Epidemiological trends in psoriatic arthritis: a comprehensive population-based study 银屑病关节炎的流行病学趋势:一项基于人群的综合研究
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-05-27 DOI: 10.1186/s13075-024-03339-0
Amir Haddad, Perach Chen Elkayam, Nili Stein, Ilan Feldhamer, Arnon Dov Cohen, Walid Saliba, Devy Zisman
Psoriatic arthritis (PsA) is a chronic, potentially debilitating inflammatory arthritis often associated with psoriasis. Understanding the epidemiology of PsA across diverse populations can provide valuable insights into its global burden and the role of genetic and environmental factors. This study aimed to estimate PsA’s temporal trends, prevalence, and incidence, while assessing variations in age, gender, and ethnicity in Israel from 2016 to 2022. Data were sourced from the Clalit Health Services (CHS) database, covering over half of the Israeli population. Algorithm-based definitions for PsA and psoriasis cases were used. Demographic factors, including age, gender, socioeconomic status (SES), ethnicity, urban/rural residence, BMI, and smoking status, were analyzed. Standardized prevalence and incidence rates were calculated. Logistic regression analyses examined associations of sociodemographic variables with PsA. In 2022, the prevalence of PsA was 0.221%, with an incidence rate of 13.54 per 100,000 population. This prevalence has tripled since 2006, reflecting a rising trend in PsA over time. Females exhibited a higher prevalence (1.15; 95%CI 1.09–1.21), and PsA was more common in Jewish individuals (1.58; 95%CI 1.45–1.71) those with higher SES (1.4; 95% CI 1.31, 1.5), and those with obesity (2.17; 95%CI 2.04–2.31). This comprehensive population-based study pointed to an increase prevalence of PsA, emphasizing the rising healthcare demands and economic burden faced by this patient population. Further research is essential to delve into the factors driving these trends.
银屑病关节炎(PsA)是一种慢性、可能使人衰弱的炎症性关节炎,通常与银屑病有关。了解 PsA 在不同人群中的流行病学可为了解其全球负担以及遗传和环境因素的作用提供有价值的见解。本研究旨在估算 PsA 的时间趋势、患病率和发病率,同时评估 2016 年至 2022 年以色列的年龄、性别和种族差异。数据来源于Clalit健康服务(CHS)数据库,该数据库覆盖了以色列一半以上的人口。采用基于算法的 PsA 和银屑病病例定义。分析了人口统计学因素,包括年龄、性别、社会经济地位 (SES)、种族、城市/农村居住地、体重指数和吸烟状况。计算了标准化患病率和发病率。逻辑回归分析检验了社会人口学变量与 PsA 的关联。2022 年,PsA 患病率为 0.221%,发病率为每 10 万人 13.54 例。这一患病率自2006年以来增加了两倍,反映出PsA随着时间的推移呈上升趋势。女性发病率更高(1.15;95%CI 1.09-1.21),PsA 在犹太人(1.58;95%CI 1.45-1.71)、社会经济地位较高者(1.4;95%CI 1.31,1.5)和肥胖者(2.17;95%CI 2.04-2.31)中更为常见。这项以人群为基础的综合研究表明,PsA 的患病率正在上升,强调了这一患者群体所面临的日益增长的医疗保健需求和经济负担。进一步的研究对于深入探讨推动这些趋势的因素至关重要。
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引用次数: 0
Two-year post-distraction cartilage-related structural improvement is accompanied by increased serum full-length SIRT1. 牵引两年后,与软骨相关的结构改善伴随着血清全长 SIRT1 的增加。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-05-24 DOI: 10.1186/s13075-024-03342-5
Miya Marco, Mylène Jansen, Goran van der Weiden, Eli Reich, Yonathan H Maatuf, Simon C Mastbergen, Mona Dvir-Ginzberg

Background: Previously, fragments from Sirtuin 1 (SIRT1) were identified in preclinical and clinical samples to display an increase in serum levels for N-terminal (NT) SIRT1 vs. C-terminal (CT) SIRT1, indicative of early signs of OA. Here we tested NT/CT SIRT1 levels as well as a novel formulated sandwich assay to simultaneously detect both domains of SIRT1 in a manner that may inform us about the levels of full-length SIRT1 in the circulation (flSIRT1) of clinical cohorts undergoing knee joint distraction (KJD).

Methods: We employed an indirect ELISA assay to test NT- and CT-SIRT1 levels and calculated their ratio. Further, to test flSIRT1 we utilized novel antibodies (Ab), which were validated for site specificity and used in a sandwich ELISA method, wherein the CT-reactive served as capture Ab, and its NT-reactive served as primary detection Ab. This method was employed in human serum samples derived from a two-year longitudinal study of KJD patients. Two-year clinical and structural outcomes were correlated with serum levels of flSIRT1 compared to baseline.

Results: Assessing the cohort, exhibited a significant increase of NT/CT SIRT1 serum levels with increased osteophytes and PIIANP/CTX-II at baseline, while a contradictory increase in NT/CT SIRT1 was associated with less denuded bone, post-KJD. On the other hand, flSIRT1 exhibited an upward trend in serum level, accompanied by reduced denuded bone for 2-year adjusted values. Moreover, 2 year-adjusted flSIRT1 levels displayed a steeper linear regression for cartilage and bone-related structural improvement than those observed for NT/CT SIRT1.

Conclusions: Our data support that increased flSIRT1 serum levels are a potential molecular endotype for cartilage-related structural improvement post-KJD, while NT/CT SIRT1 appears to correlate with osteophyte and PIIANP/CTX-II reduction at baseline, to potentially indicate baseline OA severity.

背景:以前,在临床前和临床样本中发现 Sirtuin 1 (SIRT1) 片段显示 N 端 (NT) SIRT1 相对于 C 端 (CT) SIRT1 的血清水平升高,这表明 OA 的早期症状。在这里,我们测试了NT/CT SIRT1的水平,以及一种新型配方夹心检测法,该方法可同时检测SIRT1的两个结构域,从而让我们了解接受膝关节牵张术(KJD)的临床人群循环中全长SIRT1(flSIRT1)的水平:我们采用间接酶联免疫吸附试验检测了NT-和CT-SIRT1的水平,并计算了它们的比值。此外,为了检测 flSIRT1,我们使用了新型抗体(Ab),这些抗体经过了位点特异性验证,并用于夹心 ELISA 方法,其中 CT 反应型抗体作为捕获抗体,NT 反应型抗体作为主要检测抗体。这种方法被用于对 KJD 患者进行为期两年的纵向研究,并在人类血清样本中进行了应用。与基线相比,两年的临床和结构结果与血清中的 flSIRT1 水平相关:结果:在对队列进行评估后发现,基线时,NT/CT SIRT1血清水平的显著增加与骨质增生和PIIANP/CTX-II的增加有关,而NT/CT SIRT1的增加与KJD后较少的骨质变性有关。另一方面,flSIRT1 的血清水平呈上升趋势,2 年调整后的值与骨质疏松减少有关。此外,与 NT/CT SIRT1 相比,2 年调整后的 flSIRT1 水平对软骨和骨相关结构改善的线性回归更为陡峭:我们的数据表明,flSIRT1血清水平的升高是KJD术后软骨相关结构改善的潜在分子内型,而NT/CT SIRT1似乎与基线时骨质增生和PIIANP/CTX-II的减少相关,可能表明基线OA的严重程度。
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引用次数: 0
Time to improvement of pain, morning stiffness, fatigue, and disease activity in patients with ankylosing spondylitis treated with tofacitinib: a post hoc analysis. 强直性脊柱炎患者接受托法替尼治疗后疼痛、晨僵、疲劳和疾病活动的改善时间:一项事后分析。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2024-05-24 DOI: 10.1186/s13075-024-03313-w
Victoria Navarro-Compán, Atul Deodhar, Rachid Bahiri, Andrew G Bushmakin, Joseph C Cappelleri, Jihane Rammaoui

Background: Tofacitinib is an oral Janus kinase inhibitor for treatment of ankylosing spondylitis (AS). Time to improvement in core domains of AS was estimated in tofacitinib-treated patients with AS.

Methods: This post hoc analysis used phase 3 trial data from patients with AS receiving tofacitinib 5 mg twice daily or placebo to week (W)16; all patients received open-label tofacitinib W16-48.

Outcomes: nocturnal pain; total back pain; fatigue, spinal pain, peripheral joint pain/swelling, enthesitis, and morning stiffness (Bath AS Disease Activity Index [BASDAI] questions 1-6); BASDAI total score; AS Disease Activity Score (ASDAS). Median time to improvement events was estimated using non-parametric Kaplan-Meier models. Improvement events were defined as initial (first post-baseline observation) and continued (sustained for 2 consecutive visits) ≥ 30% and ≥ 50% improvement in back/nocturnal pain or BASDAI questions/total scores, or ASDAS improvement ≥ 1.1 and ≥ 2.0 points.

Results: 269 patients (tofacitinib: n = 133; placebo-to-tofacitinib: n = 136) were assessed. Median time to improvement was shorter, and more patients experienced improvements with tofacitinib vs. placebo-to-tofacitinib; differences observed from W2 (first post-baseline assessment). Median time to initial (continued) ≥ 30% pain improvement was 4 (4-8) weeks for tofacitinib vs. 24 (24) weeks for placebo-to-tofacitinib (8 [8] weeks post-switch). Median time to initial (continued) ≥ 50% improvement of pain, peripheral joint pain/swelling and enthesitis, morning stiffness, BASDAI total score, and fatigue was 8-24 (12-40) weeks with tofacitinib vs. 24-32 weeks (32 weeks-not estimable [NE]) with placebo-to-tofacitinib. Median time to initial (continued) ASDAS improvement ≥ 1.1 points was 4 (8) weeks for tofacitinib vs. 24 (24) weeks for placebo-to-tofacitinib, and NE for improvement ≥ 2.0 points with either treatment.

Conclusions: Improvements in AS core domains occurred more rapidly with tofacitinib vs. placebo-to-tofacitinib. Half of tofacitinib-treated patients with AS will likely experience improvements ≥ 30% in pain and ≥ 1.1 points in ASDAS during month (M)1, ≥ 50% improvement in nocturnal pain and enthesitis by M2, and in morning stiffness by M3. Results show that initiating tofacitinib as soon as possible is associated with quicker improvements in AS core domains vs. delaying treatment.

Trial registration: ClinicalTrials.gov, NCT03502616, 11 April 2018.

背景托法替尼是一种口服Janus激酶抑制剂,用于治疗强直性脊柱炎(AS)。对接受托法替尼治疗的强直性脊柱炎患者的强直性脊柱炎核心指标改善时间进行了估算:结果:夜间疼痛、全背痛、疲劳、脊柱疼痛、外周关节疼痛/肿胀、粘连炎和晨僵(巴斯强直性脊柱炎疾病活动指数[BASDAI]问题1-6);BASDAI总分;强直性脊柱炎疾病活动评分(ASDAS)。采用非参数 Kaplan-Meier 模型估算病情改善事件的中位时间。改善事件定义为背部/夜间疼痛或BASDAI问题/总分的初始(基线后首次观察)和持续(连续2次就诊持续)改善≥30%和≥50%,或ASDAS改善≥1.1和≥2.0分。与安慰剂对托法替尼相比,托法替尼的中位改善时间更短,更多患者的病情有所改善;从W2(基线后首次评估)起观察到了差异。首次(持续)疼痛改善≥30%的中位时间为:托法替尼4(4-8)周,安慰剂对托法替尼24(24)周(切换后8 [8]周)。疼痛、外周关节疼痛/肿胀和肌腱炎、晨僵、BASDAI总分和疲劳首次(持续)改善≥50%的中位时间:托法替尼为8-24(12-40)周,安慰剂-托法替尼为24-32周(32周-无法估计[NE])。托法替尼初始(持续)ASDAS改善≥1.1分的中位时间为4(8)周,安慰剂对托法替尼为24(24)周,两种治疗方法改善≥2.0分的中位时间均为NE:结论:与安慰剂对托法替尼相比,托法替尼对强直性脊柱炎核心领域的改善更快。半数接受托法替尼治疗的强直性脊柱炎患者的疼痛可能会在第1个月(M)改善≥30%,ASDAS改善≥1.1分;到第2个月,夜间疼痛和腱鞘炎改善≥50%;到第3个月,晨僵改善≥50%。结果表明,与推迟治疗相比,尽快开始服用托法替尼能更快地改善强直性脊柱炎的核心症状:试验注册:ClinicalTrials.gov,NCT03502616,2018年4月11日。
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Arthritis Research & Therapy
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