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Comparison of cognitive performance measures in individuals with systemic lupus erythematosus 系统性红斑狼疮患者的认知能力测量比较

IF 3.9 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-04-01 DOI: 10.1136/lupus-2024-001151

Laura Plantinga, Jinoos Yazdany, C Barrett Bowling, Charmayne Dunlop-Thomas, Courtney Hoge, Brad D Pearce, S Sam Lim, Patricia Katz

Objective Cognitive impairment is a common complaint in SLE, but approaches to measuring cognitive performance objectively vary. Leveraging data collected in a population-based cohort of individuals with validated SLE, we compared performance and potential impairment across multiple measures of cognition. Methods During a single study visit (October 2019–May 2022), times to complete the Trail Making Test B (TMTB; N=423) were recorded; potential impairment was defined as an age-corrected and education-corrected T-score <35 (>1.5 SD longer than the normative time). A clock drawing assessment (CLOX; N=435) with two parts (free clock draw (CLOX1) and copy (CLOX2)) was also performed (score range: 0–15; higher scores=better performance); potential impairment was defined as CLOX1 <10 or CLOX2 <12. Fluid cognition (N=199; in-person visits only) was measured via the National Institutes of Health (NIH) Toolbox Fluid Cognition Battery and expressed as age-corrected standard scores; potential impairment was defined by a score <77.5 (>1.5 SD lower the normative score). Results Participants (mean age 46 years; 92% female; 82% black) had a median (IQR) TMTB time of 96 (76–130) s; median (IQR) CLOX1 and CLOX2 scores of 12 (10–13) and 14 (13–15); and a mean (SD) fluid cognition standard score of 87.2 (15.6). TMTB time and fluid cognition score (ρ=−0.53, p<0.001) were the most highly intercorrelated measures. Overall, 65%, 55% and 28% were potentially impaired by the TMTB test, CLOX task and NIH Toolbox Fluid Cognition Battery, respectively. While there was overlap in potential impairment between TMTB and CLOX, more than half (58%) had impairment by only one of these assessments. Few (2%) had impairment in fluid cognition only. Conclusion The TMTB, CLOX and NIH Fluid Cognition Battery each provided unique and potentially important information about cognitive performance in our SLE cohort. Future studies are needed to validate these measures in SLE and explore interventions that maintain or improve cognitive performance in this population. Data are available upon reasonable request. De-identified data will be made available per NIH requirements when funding is complete.

客观认知障碍是系统性红斑狼疮患者的常见症状，但客观测量认知能力的方法各不相同。我们利用在基于人群的系统性红斑狼疮患者队列中收集到的数据，比较了多种认知测量指标的表现和潜在损伤。方法在单次研究访问期间（2019 年 10 月至 2022 年 5 月），记录完成路径制作测试 B（TMTB；N=423）的时间；潜在损伤定义为经年龄校正和教育校正后的 T 分数比常模时间长 1.5 SD）。此外，还进行了时钟绘制评估（CLOX；N=435），包括两个部分（自由绘制时钟（CLOX1）和复制时钟（CLOX2））（评分范围：0-15；分数越高=表现越好）；潜在障碍定义为 CLOX1 比常模分数低 1.5 SD）。结果参与者（平均年龄 46 岁；92% 为女性；82% 为黑人）的 TMTB 时间中位数（IQR）为 96（76-130）秒；CLOX1 和 CLOX2 的得分中位数（IQR）分别为 12（10-13）分和 14（13-15）分；流体认知标准分数的平均值（SD）为 87.2（15.6）分。TMTB 时间和流体认知得分（ρ=-0.53，p<0.001）是相互关联度最高的测量指标。总体而言，在 TMTB 测试、CLOX 任务和 NIH 工具箱流体认知测试中，分别有 65%、55% 和 28% 的人存在潜在障碍。虽然 TMTB 和 CLOX 之间的潜在障碍存在重叠，但超过半数（58%）的人只在其中一项评估中存在障碍。只有极少数人（2%）仅在流体认知方面存在障碍。结论 TMTB、CLOX 和 NIH 流体认知电池都提供了有关系统性红斑狼疮队列认知表现的独特且潜在的重要信息。未来的研究需要验证这些测量方法在系统性红斑狼疮中的有效性，并探索在这一人群中保持或改善认知能力的干预措施。如有合理要求，可提供相关数据。根据美国国立卫生研究院（NIH）的要求，在资助完成后将提供去身份化的数据。

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引用次数: 0

Enhancing lupus outcomes by means of biology beyond overt clinical features, exemplified in an in-depth investigation of the effects of circadian rhythm disruption 深入研究昼夜节律紊乱的影响，超越明显的临床特征，通过生物学手段提高狼疮的治疗效果

IF 3.9 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-04-01 DOI: 10.1136/lupus-2024-001215

Ioannis Parodis

SLE is a complex autoimmune disease, characterised by a prominent clinical heterogeneity,1 with lupus nephritis (LN) standing as one of its most severe manifestations.2 Despite significant advances in understanding SLE pathogenesis, the precise role of circadian rhythm disruption (CRD) in SLE and particularly its link to LN has remained elusive. In this issue of Lupus Science and Medicine , we are presented with a thought-provoking study by Shen et al , shedding new light on the intricate interplay between circadian rhythms and SLE severity.3 What sets this study apart is its comprehensive exploration of the impact of circadian rhythms on immune function and inflammation in the context of SLE. The authors embarked on a retrospective analysis, delving into clinical characteristics and transcriptional profiles of a large number of samples using advanced bioinformatics and machine learning methodologies. Through meticulous analysis, they uncovered compelling evidence of abnormalities within the circadian pathway in patients with SLE, indicating a potential link with the disease or disease states. Notably, the authors’ findings unveil an association between CRD and lupus flares, potentially implicating a role for CRD in disease evolution. Central to the authors’ investigation is the introduction of a Flare Risk Score (FRS), a tool designed to predict overall disease progression in patients with SLE. The FRS, developed through a rigorous analytical pipeline, exhibited good ability to forecast disease severity, offering a novel approach …

系统性红斑狼疮是一种复杂的自身免疫性疾病，临床表现具有明显的异质性1 ，其中狼疮性肾炎（LN）是其最严重的表现之一2 。尽管在了解系统性红斑狼疮发病机制方面取得了重大进展，但昼夜节律紊乱（CRD）在系统性红斑狼疮中的确切作用，尤其是它与 LN 的联系，却仍然难以捉摸。在本期的《狼疮科学与医学》（Lupus Science and Medicine）杂志上，Shen 等人发表了一项发人深省的研究，为我们揭示昼夜节律与系统性红斑狼疮严重程度之间错综复杂的相互作用提供了新的思路。作者利用先进的生物信息学和机器学习方法，对大量样本的临床特征和转录特征进行了回顾性分析。通过细致的分析，他们发现了系统性红斑狼疮患者昼夜节律通路异常的有力证据，这表明昼夜节律通路与疾病或疾病状态存在潜在联系。值得注意的是，作者的研究结果揭示了昼夜节律变化与狼疮发作之间的联系，这可能意味着昼夜节律变化在疾病演变中的作用。作者研究的核心内容是引入了复发风险评分（FRS），这是一种用于预测系统性红斑狼疮患者总体疾病进展的工具。通过严格的分析流程开发出的FRS表现出了预测疾病严重程度的良好能力，提供了一种新颖的方法...

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引用次数: 0

Association of phenotypic frailty and hand grip strength with telomere length in SLE. 系统性红斑狼疮患者的表型虚弱和手部握力与端粒长度的关系。

IF 3.9 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-03-22 DOI: 10.1136/lupus-2023-001008

Sarah B Lieber, Robyn A Lipschultz, Shahrez Syed, Mangala Rajan, Sara Venkatraman, Myriam Lin, M Carrington Reid, Neal F Lue, Lisa A Mandl

Objective: Frailty and objective hand grip strength (one of the components of the frailty phenotype) are both risk factors for worse health outcomes in SLE. Whether telomere length, an established cellular senescence marker, is a biologic correlate of the frailty phenotype and hand grip strength in patients with SLE is not clear. First, we aimed to evaluate differences in telomere length between frail and non-frail women with SLE and then assessed whether frailty or hand grip strength is differentially associated with telomere length after adjusting for relevant confounders.

Methods: Women ≥18 years of age with validated SLE enrolled at a single medical centre. Fried frailty status (which includes hand grip strength), clinical characteristics and telomere length were assessed cross-sectionally. Differences between frail and non-frail participants were evaluated using Fisher's exact or Wilcoxon rank-sum tests. The associations between frailty and hand grip strength and telomere length were determined using linear regression.

Results: Of the 150 enrolled participants, 131 had sufficient data for determination of frailty classification; 26% were frail with a median age of 45 years. There was a non-significant trend towards shorter telomere length in frail versus non-frail participants (p=0.07). Hand grip strength was significantly associated with telomere length (beta coefficient 0.02, 95% CI 0.004, 0.04), including after adjustment for age, SLE disease activity and organ damage, and comorbidity (beta coefficient 0.02, 95% CI 0.002, 0.04).

Conclusions: Decreased hand grip strength, but not frailty, was independently associated with shortened telomere length in a cohort of non-elderly women with SLE. Frailty in this middle-aged cohort may be multifactorial rather than strictly a manifestation of accelerated ageing.

目的：虚弱和客观手部握力（虚弱表型的组成部分之一）都是系统性红斑狼疮患者健康状况恶化的风险因素。端粒长度是一种公认的细胞衰老标志物，它是否与系统性红斑狼疮患者的虚弱表型和手部握力存在生物学相关性尚不清楚。首先，我们旨在评估患有系统性红斑狼疮的虚弱女性和非虚弱女性之间端粒长度的差异，然后评估在调整相关混杂因素后，虚弱或手部握力是否与端粒长度有不同程度的关联：方法：在一个单一的医疗中心招募年龄≥18岁、经证实患有系统性红斑狼疮的女性。横断面评估弗里德虚弱状态（包括手部握力）、临床特征和端粒长度。采用费雪精确检验或 Wilcoxon 秩和检验来评估虚弱和非虚弱参与者之间的差异。采用线性回归法确定体弱与手部握力和端粒长度之间的关系：在 150 名注册参与者中，131 人有足够的数据用于确定虚弱程度分类；26% 的参与者体弱多病，中位年龄为 45 岁。体弱者端粒长度比非体弱者端粒长度短的趋势并不明显（P=0.07）。手部握力与端粒长度有明显相关性（β系数0.02，95% CI 0.004，0.04），包括在调整年龄、系统性红斑狼疮疾病活动性和器官损伤以及合并症（β系数0.02，95% CI 0.002，0.04）之后：结论：在一群非老年系统性红斑狼疮女性患者中，手部握力下降与端粒长度缩短有独立关联，但与体弱无关。该中年队列中的体弱现象可能是多因素造成的，而非严格意义上的加速衰老表现。

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引用次数: 0

Cardiovascular risk factors and complications in patients with systemic lupus erythematosus with and without nephritis: a systematic review and meta-analysis. 伴有或不伴有肾炎的系统性红斑狼疮患者的心血管风险因素和并发症：系统回顾和荟萃分析。

IF 3.7 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-03-21 DOI: 10.1136/lupus-2024-001152

Cheuk Yin Wong, Becky M Y Ma, Danting Zhang, Wynn Cheung, Tak Mao Chan, Desmond Y H Yap

Introduction: It remains unclear how the presence of renal involvement will affect the cardiovascular (CV) risk factors and complications in patients with SLE.

Methods: We conducted a systematic review and meta-analysis using PubMed, EMBASE, MEDLINE and Scopus to identify studies published between 1947 and 2022 that evaluate the CV risk factors and complications in patients with SLE with or without lupus nephritis (LN).

Results: 58 studies were evaluated, with 22 two-arm studies (n=8675) included in two-arm meta-analysis and 45 studies (n=385 315) included in proportional meta-analysis. Patients with SLE with LN showed significantly higher risk of hypertension (HT) (OR=4.93, 95% CI=3.17 to 7.65, p<0.00001, I²=56%), hyperlipidaemia (OR=11.03, 95% CI=4.20 to 28.95, p<0.00001, I²=0%) and diabetes mellitus (DM) (OR=1.88, 95% CI=1.09 to 3.25, p=0.02, I²=32%) compared with those without LN. Patients with LN showed numerically higher prevalence of myocardial infarction (OR=1.35, 95% CI=0.53 to 3.45, p=0.52, I²=78%) and cerebrovascular accident (OR=1.64, 95% CI=0.79 to 3.39, p=0.27, I²=23%) than general patients with SLE. The incidence rates of CV mortality are also increased in patients with SLE with LN compared with those without LN (11.7/1000 patient-years vs 3.6/1000 patient-years).

Conclusion: Patients with SLE with LN show increased risk of CV risk factors including DM, HT and hyperlipidaemia. Early identification and optimal control of these CV risk factors may reduce the risk of CV disease and other non-CV complications.

Prospero registration number: CRD42022314682.

简介：肾脏受累会如何影响系统性红斑狼疮患者的心血管风险因素和并发症？目前仍不清楚肾脏受累会如何影响系统性红斑狼疮患者的心血管（CV）风险因素和并发症：我们使用PubMed、EMBASE、MEDLINE和Scopus进行了一项系统回顾和荟萃分析，以确定1947年至2022年间发表的、评估伴有或不伴有狼疮性肾炎（LN）的系统性红斑狼疮患者心血管风险因素和并发症的研究：共评估了58项研究，其中22项双臂研究（n=8675）纳入双臂荟萃分析，45项研究（n=385 315）纳入比例荟萃分析。与无LN的患者相比，伴有LN的系统性红斑狼疮患者患高血压（HT）（OR=4.93，95% CI=3.17至7.65，P2=56%）、高脂血症（OR=11.03，95% CI=4.20至28.95，P2=0%）和糖尿病（DM）（OR=1.88，95% CI=1.09至3.25，P=0.02，I2=32%）的风险明显更高。与一般系统性红斑狼疮患者相比，LN患者的心肌梗死（OR=1.35，95% CI=0.53至3.45，P=0.52，I2=78%）和脑血管意外（OR=1.64，95% CI=0.79至3.39，P=0.27，I2=23%）发病率更高。与无LN的系统性红斑狼疮患者相比，伴有LN的系统性红斑狼疮患者的心血管疾病死亡率也有所上升（11.7/1000患者年 vs 3.6/1000患者年）：结论：伴有LN的系统性红斑狼疮患者出现心血管疾病风险因素（包括糖尿病、高血压和高脂血症）的风险增加。早期识别和优化控制这些心血管风险因素可降低心血管疾病和其他非心血管并发症的风险：CRD42022314682。

{"title":"Cardiovascular risk factors and complications in patients with systemic lupus erythematosus with and without nephritis: a systematic review and meta-analysis.","authors":"Cheuk Yin Wong, Becky M Y Ma, Danting Zhang, Wynn Cheung, Tak Mao Chan, Desmond Y H Yap","doi":"10.1136/lupus-2024-001152","DOIUrl":"10.1136/lupus-2024-001152","url":null,"abstract":"Introduction: It remains unclear how the presence of renal involvement will affect the cardiovascular (CV) risk factors and complications in patients with SLE.Methods: We conducted a systematic review and meta-analysis using PubMed, EMBASE, MEDLINE and Scopus to identify studies published between 1947 and 2022 that evaluate the CV risk factors and complications in patients with SLE with or without lupus nephritis (LN).Results: 58 studies were evaluated, with 22 two-arm studies (n=8675) included in two-arm meta-analysis and 45 studies (n=385 315) included in proportional meta-analysis. Patients with SLE with LN showed significantly higher risk of hypertension (HT) (OR=4.93, 95% CI=3.17 to 7.65, p<0.00001, I2=56%), hyperlipidaemia (OR=11.03, 95% CI=4.20 to 28.95, p<0.00001, I2=0%) and diabetes mellitus (DM) (OR=1.88, 95% CI=1.09 to 3.25, p=0.02, I2=32%) compared with those without LN. Patients with LN showed numerically higher prevalence of myocardial infarction (OR=1.35, 95% CI=0.53 to 3.45, p=0.52, I2=78%) and cerebrovascular accident (OR=1.64, 95% CI=0.79 to 3.39, p=0.27, I2=23%) than general patients with SLE. The incidence rates of CV mortality are also increased in patients with SLE with LN compared with those without LN (11.7/1000 patient-years vs 3.6/1000 patient-years).Conclusion: Patients with SLE with LN show increased risk of CV risk factors including DM, HT and hyperlipidaemia. Early identification and optimal control of these CV risk factors may reduce the risk of CV disease and other non-CV complications.Prospero registration number: CRD42022314682.","PeriodicalId":18126,"journal":{"name":"Lupus Science & Medicine","volume":"11 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10961538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140189869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Concentrations of subcutaneously administered belimumab in human breast milk of a woman with systemic lupus erythematosus: a case report. 一名患有系统性红斑狼疮的妇女的母乳中皮下注射的贝利木单抗的浓度：病例报告。

IF 3.9 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-03-18 DOI: 10.1136/lupus-2024-001167

Birgit S Blomjous, Marjon A de Boer, Mirjam M van Weissenbruch, Koen C J Laan, Theo Rispens, Alexandre E Voskuyl, Irene E M Bultink

引用次数: 0

Association of genetic variation on X chromosome with systemic lupus erythematosus in both Thai and Chinese populations. 泰国和中国人群中 X 染色体遗传变异与系统性红斑狼疮的关系

IF 3.9 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-03-08 DOI: 10.1136/lupus-2023-001061

Pattarin Tangtanatakul, Yao Lei, Krisana Jaiwan, Wanling Yang, Manon Boonbangyang, Punna Kunhapan, Pimpayao Sodsai, Surakameth Mahasirimongkol, Prapaporn Pisitkun, Yi Yang, Jakris Eu-Ahsunthornwattana, Wichai Aekplakorn, Natini Jinawath, Nareemarn Neelapaichit, Nattiya Hirankarn, Yong-Fei Wang

Objectives: X chromosome has been considered as a risk factor for SLE, which is a prototype of autoimmune diseases with a significant sex difference (female:male ratio is around 9:1). Our study aimed at exploring the association of genetic variants in X chromosome and investigating the influence of trisomy X in the development of SLE.

Methods: X chromosome-wide association studies were conducted using data from both Thai (835 patients with SLE and 2995 controls) and Chinese populations (1604 patients with SLE and 3324 controls). Association analyses were performed separately in females and males, followed by a meta-analysis of the sex-specific results. In addition, the dosage of X chromosome in females with SLE were also examined.

Results: Our analyses replicated the association of TMEM187-IRAK1-MECP2, TLR7, PRPS2 and GPR173 loci with SLE. We also identified two loci suggestively associated with SLE. In addition, making use of the difference in linkage disequilibrium between Thai and Chinese populations, a synonymous variant in TMEM187 was prioritised as a likely causal variant. This variant located in an active enhancer of immune-related cells, with the risk allele associated with decreased expression level of TMEM187. More importantly, we identified trisomy X (47,XXX) in 5 of 2231 (0.22%) females with SLE. The frequency is significantly higher than that found in the female controls (0.08%; two-sided exact binomial test P=0.002).

Conclusion: Our study confirmed previous SLE associations in X chromosome, and identified two loci suggestively associated with SLE. More importantly, our study indicated a higher risk of SLE for females with trisomy X.

研究目的系统性红斑狼疮是一种自身免疫性疾病的原型，具有显著的性别差异（男女比例约为9:1）。我们的研究旨在探索 X 染色体遗传变异的相关性，并研究 X 三体综合征对系统性红斑狼疮发病的影响：我们使用泰国（835 名系统性红斑狼疮患者和 2995 名对照组）和中国（1604 名系统性红斑狼疮患者和 3324 名对照组）人群的数据进行了 X 染色体全范围关联研究。对女性和男性分别进行了关联分析，然后对性别特异性结果进行了荟萃分析。此外，还研究了系统性红斑狼疮女性患者的 X 染色体剂量：结果：我们的分析重复了 TMEM187-IRAK1-MECP2、TLR7、PRPS2 和 GPR173 位点与系统性红斑狼疮的相关性。我们还发现了两个与系统性红斑狼疮相关的基因位点。此外，我们还利用泰国人和中国人之间的连锁不平衡差异，将 TMEM187 中的一个同义变异列为可能的致病变异。该变异位于免疫相关细胞的活性增强子中，风险等位基因与 TMEM187 的表达水平下降有关。更重要的是，我们在2231名系统性红斑狼疮女性患者中的5人（0.22%）中发现了X三体综合征（47,XXX）。该频率明显高于女性对照组（0.08%；双侧精确二项式检验 P=0.002）：我们的研究证实了之前在 X 染色体中发现的系统性红斑狼疮相关性，并确定了两个与系统性红斑狼疮有提示性关联的位点。更重要的是，我们的研究表明，患有 X 三体综合征的女性患系统性红斑狼疮的风险更高。

{"title":"Association of genetic variation on X chromosome with systemic lupus erythematosus in both Thai and Chinese populations.","authors":"Pattarin Tangtanatakul, Yao Lei, Krisana Jaiwan, Wanling Yang, Manon Boonbangyang, Punna Kunhapan, Pimpayao Sodsai, Surakameth Mahasirimongkol, Prapaporn Pisitkun, Yi Yang, Jakris Eu-Ahsunthornwattana, Wichai Aekplakorn, Natini Jinawath, Nareemarn Neelapaichit, Nattiya Hirankarn, Yong-Fei Wang","doi":"10.1136/lupus-2023-001061","DOIUrl":"10.1136/lupus-2023-001061","url":null,"abstract":"Objectives: X chromosome has been considered as a risk factor for SLE, which is a prototype of autoimmune diseases with a significant sex difference (female:male ratio is around 9:1). Our study aimed at exploring the association of genetic variants in X chromosome and investigating the influence of trisomy X in the development of SLE.Methods: X chromosome-wide association studies were conducted using data from both Thai (835 patients with SLE and 2995 controls) and Chinese populations (1604 patients with SLE and 3324 controls). Association analyses were performed separately in females and males, followed by a meta-analysis of the sex-specific results. In addition, the dosage of X chromosome in females with SLE were also examined.Results: Our analyses replicated the association of TMEM187-IRAK1-MECP2, TLR7, PRPS2 and GPR173 loci with SLE. We also identified two loci suggestively associated with SLE. In addition, making use of the difference in linkage disequilibrium between Thai and Chinese populations, a synonymous variant in TMEM187 was prioritised as a likely causal variant. This variant located in an active enhancer of immune-related cells, with the risk allele associated with decreased expression level of TMEM187. More importantly, we identified trisomy X (47,XXX) in 5 of 2231 (0.22%) females with SLE. The frequency is significantly higher than that found in the female controls (0.08%; two-sided exact binomial test P=0.002).Conclusion: Our study confirmed previous SLE associations in X chromosome, and identified two loci suggestively associated with SLE. More importantly, our study indicated a higher risk of SLE for females with trisomy X.","PeriodicalId":18126,"journal":{"name":"Lupus Science & Medicine","volume":"11 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10928741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Celastrol ameliorates lupus by promoting apoptosis of autoimmune T cells and preventing autoimmune response in MRL/lpr mice Celastrol 通过促进自身免疫 T 细胞凋亡和预防 MRL/lpr 小鼠的自身免疫反应来改善狼疮症状

IF 3.9 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-03-01 DOI: 10.1136/lupus-2023-001057

Tianhong Xie, Hongliang Rui, Huiqiang Liu, Xin Liu, Xiang Liu, Ping Li

Objective Celastrol is a bioactive constituent extracted from Tripterygium wilfordii (thunder god vine). It has been demonstrated to have a therapeutic effect on experimental disease models for chronic inflammatory and immune disorders. In the present study, we investigated whether and how celastrol exerts a regulatory effect on the autoimmune response in MRL/lpr mice. Methods We performed an in vivo study to determine the therapeutic effects of celastrol in MRL/lpr mice and then further investigated the underlying mechanism of celastrol in the regulation of the autoimmune response in MRL/lpr mice. Results Celastrol showed a therapeutic effect in MRL/lpr mice by preventing the enlargement of the spleen and lymph nodes, alleviating renal injury, and reducing the levels of ANA and anti-double-stranded DNA antibodies. Furthermore, celastrol suppressed the in vivo inflammatory response in MRL/lpr mice by reducing the serum levels of multiple cytokines, including interleukin (IL)-6, tumour necrosis factor (TNF) and interferon (IFN)-γ, and the production of multiple antibody subsets, including total IgG, IgG1 and IgG2b. In vitro, celastrol reduced anti-CD3 antibody stimulation-induced T helper 1 and TNF-producing cells in CD4+ T cells of MRL/lpr mice. In addition, celastrol significantly affected B cell differentiation and prevented the generation of plasma cells from B cells in MRL/lpr mice by reducing the frequency of activated and germinal centre B cells. Celastrol treatment also affected T cell differentiation and significantly reduced central memory T cell frequencies in MRL/lpr mice. Importantly, celastrol treatment specifically promoted apoptosis of CD138+ but not CD138− T cells to suppress autoimmune T cell accumulation in MRL/lpr mice. Conclusions Celastrol exerted therapeutic effects on lupus by specifically promoting apoptosis of autoimmune T cells and preventing the progression of autoimmune response. Data are available upon reasonable request.

目的 Celastrol 是一种从雷公藤（Tripterygium wilfordii）中提取的生物活性成分。实验证明，它对慢性炎症和免疫性疾病的实验模型有治疗作用。在本研究中，我们探讨了青蒿素是否以及如何对 MRL/lpr 小鼠的自身免疫反应产生调节作用。方法我们进行了一项体内研究，以确定青霉烯醇对 MRL/lpr 小鼠的治疗效果，然后进一步研究青霉烯醇调节 MRL/lpr 小鼠自身免疫反应的内在机制。结果车前子醇对MRL/lpr小鼠有治疗作用，可防止脾脏和淋巴结肿大，减轻肾损伤，降低ANA和抗双链DNA抗体水平。此外，通过降低多种细胞因子（包括白细胞介素 (IL)-6、肿瘤坏死因子 (TNF) 和干扰素 (IFN)-γ）的血清水平以及多种抗体亚群（包括总 IgG、IgG1 和 IgG2b）的产生，青蒿素抑制了 MRL/lpr 小鼠体内的炎症反应。在体外，西司替醇减少了抗 CD3 抗体刺激诱导的 T 辅助细胞 1 和 MRL/lpr 小鼠 CD4+ T 细胞中的 TNF 生成细胞。此外，西司他洛尔还通过降低活化和生殖中心B细胞的频率，明显影响了MRL/lpr小鼠的B细胞分化，并阻止了B细胞生成浆细胞。西司他醇治疗也会影响T细胞分化，并显著降低MRL/lpr小鼠的中心记忆T细胞频率。重要的是，塞拉司醇治疗可特异性地促进 CD138+ T 细胞而非 CD138- T 细胞的凋亡，从而抑制 MRL/lpr 小鼠自身免疫 T 细胞的积累。结论西司他醇通过特异性促进自身免疫T细胞凋亡和阻止自身免疫反应的进展，对狼疮产生治疗效果。如有合理要求，可提供相关数据。

{"title":"Celastrol ameliorates lupus by promoting apoptosis of autoimmune T cells and preventing autoimmune response in MRL/lpr mice","authors":"Tianhong Xie, Hongliang Rui, Huiqiang Liu, Xin Liu, Xiang Liu, Ping Li","doi":"10.1136/lupus-2023-001057","DOIUrl":"https://doi.org/10.1136/lupus-2023-001057","url":null,"abstract":"Objective Celastrol is a bioactive constituent extracted from Tripterygium wilfordii (thunder god vine). It has been demonstrated to have a therapeutic effect on experimental disease models for chronic inflammatory and immune disorders. In the present study, we investigated whether and how celastrol exerts a regulatory effect on the autoimmune response in MRL/lpr mice. Methods We performed an in vivo study to determine the therapeutic effects of celastrol in MRL/lpr mice and then further investigated the underlying mechanism of celastrol in the regulation of the autoimmune response in MRL/lpr mice. Results Celastrol showed a therapeutic effect in MRL/lpr mice by preventing the enlargement of the spleen and lymph nodes, alleviating renal injury, and reducing the levels of ANA and anti-double-stranded DNA antibodies. Furthermore, celastrol suppressed the in vivo inflammatory response in MRL/lpr mice by reducing the serum levels of multiple cytokines, including interleukin (IL)-6, tumour necrosis factor (TNF) and interferon (IFN)-γ, and the production of multiple antibody subsets, including total IgG, IgG1 and IgG2b. In vitro, celastrol reduced anti-CD3 antibody stimulation-induced T helper 1 and TNF-producing cells in CD4+ T cells of MRL/lpr mice. In addition, celastrol significantly affected B cell differentiation and prevented the generation of plasma cells from B cells in MRL/lpr mice by reducing the frequency of activated and germinal centre B cells. Celastrol treatment also affected T cell differentiation and significantly reduced central memory T cell frequencies in MRL/lpr mice. Importantly, celastrol treatment specifically promoted apoptosis of CD138+ but not CD138− T cells to suppress autoimmune T cell accumulation in MRL/lpr mice. Conclusions Celastrol exerted therapeutic effects on lupus by specifically promoting apoptosis of autoimmune T cells and preventing the progression of autoimmune response. Data are available upon reasonable request.","PeriodicalId":18126,"journal":{"name":"Lupus Science & Medicine","volume":"42 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140107757","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

Enhanced medullary and extramedullary granulopoiesis sustain the inflammatory response in lupus nephritis 增强的髓质和髓外粒细胞生成维持狼疮肾炎的炎症反应

IF 3.9 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-03-01 DOI: 10.1136/lupus-2023-001110

Eleni Zervopoulou, Maria Grigoriou, Stavros A Doumas, Danae Yiannakou, Pavlos Pavlidis, Gilles Gasparoni, Jörn Walter, Anastasia Filia, Harikleia Gakiopoulou, Aggelos Banos, Ioannis Mitroulis, Dimitrios T Boumpas

Objectives In SLE, deregulation of haematopoiesis is characterised by inflammatory priming and myeloid skewing of haematopoietic stem and progenitor cells (HSPCs). We sought to investigate the role of extramedullary haematopoiesis (EMH) as a key player for tissue injury in systemic autoimmune disorders. Methods Transcriptomic analysis of bone marrow (BM)-derived HSPCs from patients with SLE and NZBW/F1 lupus-prone mice was performed in combination with DNA methylation profile. Trained immunity (TI) was induced through β-glucan administration to the NZBW/F1 lupus-prone model. Disease activity was assessed through lupus nephritis (LN) histological grading. Colony-forming unit assay and adoptive cell transfer were used to assess HSPCs functionalities. Results Transcriptomic analysis shows that splenic HSPCs carry a higher inflammatory potential compared with their BM counterparts. Further induction of TI, through β-glucan administration, exacerbates splenic EMH, accentuates myeloid skewing and worsens LN. Methylomic analysis of BM-derived HSPCs demonstrates myeloid skewing which is in part driven by epigenetic tinkering. Importantly, transcriptomic analysis of human SLE BM-derived HSPCs demonstrates similar findings to those observed in diseased mice. Conclusions These data support a key role of granulocytes derived from primed HSPCs both at medullary and extramedullary sites in the pathogenesis of LN. EMH and TI contribute to SLE by sustaining the systemic inflammatory response and increasing the risk for flare. Data are available on reasonable request. Murine RNA sequencing (RNA-seq) and methylation data have been deposited to GEO under accession number (GSE218780). Human RNA-seq data have been deposited to the EGA database under study EGAS00001003679; dataset EGAD00001009744. Any additional information required to reanalyse the data reported in this paper is available from the corresponding authors on reasonable request.

目的在系统性红斑狼疮中，造血功能的失调表现为炎症引诱和造血干细胞和祖细胞（HSPCs）的髓样化。我们试图研究髓外造血（EMH）在全身性自身免疫性疾病的组织损伤中的关键作用。我们结合 DNA 甲基化图谱对系统性红斑狼疮患者和 NZBW/F1 狼疮易感小鼠骨髓（BM）衍生的 HSPCs 进行了转录组分析。通过给 NZBW/F1 红斑狼疮易感小鼠注射β-葡聚糖诱导训练免疫（TI）。疾病活动性通过狼疮肾炎（LN）组织学分级进行评估。集落形成单位检测和收养性细胞转移用于评估 HSPCs 的功能。结果转录组分析表明，脾脏的 HSPCs 与它们的 BM 细胞相比，具有更高的炎症潜能。通过服用β-葡聚糖进一步诱导TI会加剧脾脏EMH，加重骨髓偏斜并恶化LN。对来源于骨髓的 HSPCs 的甲基组分析表明，骨髓偏斜部分是由表观遗传修饰驱动的。重要的是，对人类系统性红斑狼疮血浆来源的 HSPCs 进行的转录组分析显示了与患病小鼠类似的结果。结论这些数据支持髓质和髓外部位由原始 HSPCs 衍生的粒细胞在 LN 发病机制中的关键作用。EMH和TI通过维持系统性炎症反应和增加复发风险，对系统性红斑狼疮起到促进作用。如有合理要求，可提供相关数据。小鼠 RNA 测序（RNA-seq）和甲基化数据已存入 GEO，登录号为 (GSE218780)。人类 RNA-seq 数据已存入 EGA 数据库，研究号为 EGAS00001003679；数据集为 EGAD00001009744。如需重新分析本文所报道的数据，可向相应作者索取所需的任何其他信息。

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引用次数: 0

Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease 美扎吉单抗在系统性红斑狼疮中的应用：在自身免疫性疾病中抑制 CD38 的临床和机理研究结果

IF 3.9 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-03-01 DOI: 10.1136/lupus-2023-001112

Scott R P McDonnell, Van Anh Nguyen, Noah M Walton, Carsten Merkwirth, Feng Hong, Deborah Berg, Elena Tomaselli Muensterman, Richard A Furie

Objective To evaluate safety and mechanism of action of mezagitamab (TAK-079), an anti-CD38 monoclonal antibody, in patients with moderate to severe systemic lupus erythematosus (SLE). Methods A phase 1b double-blind, placebo-controlled, multicentre study was conducted in patients with SLE receiving standard background therapy. Eligible patients were adults who met the 2012 SLICC or ACR criteria for diagnosis, had a baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 and were positive for anti-double-stranded DNA antibodies and/or anti-extractable nuclear antigens antibodies. Patients received 45 mg, 90 mg or 135 mg of mezagitamab or placebo every 3 weeks over 12 weeks. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and pharmacodynamics. Exploratory assessments included disease activity scales, deep immune profiling and interferon pathway analysis. Results 22 patients received at least one dose of either mezagitamab or placebo. In patients exposed to mezagitamab (n=17), drug was well tolerated. Adverse event (AEs) were balanced across treatment groups, with no treatment emergent AEs exceeding grade 2. Responder analyses for Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and SLEDAI-2K did not reveal any observable differences across treatment groups. However, there was a trend for more profound skin responses among patients with higher CLASI scores (>10) at baseline. Pharmacodynamic analysis showed median CD38 receptor occupancy up to 88.4% on CD38+ natural killer cells with concurrent depletion of these cells up to 90% in the 135 mg group. Mean reductions in IgG and autoantibodies were less than 20% in all dose groups. Cytometry by time of flight and type 1 interferon gene analysis revealed unique fingerprints that are indicative of a broad immune landscape shift following CD38 targeting. Conclusions Mezagitamab had a favourable safety profile in patients with moderate to severe SLE and elicited a pharmacodynamic effect consistent with CD38+ cell depletion. These findings reveal novel insights into the drug’s mechanism of action and support the continued investigation of mezagitamab in autoimmune diseases. Data are available upon reasonable request. The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results reported in this article, will be made available within three months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymisation.

目的评估抗CD38单克隆抗体mezagitamab（TAK-079）在中重度系统性红斑狼疮（SLE）患者中的安全性和作用机制。方法在接受标准背景疗法的系统性红斑狼疮患者中开展了一项1b期双盲、安慰剂对照多中心研究。符合条件的患者均为符合2012 SLICC或ACR诊断标准、系统性红斑狼疮疾病活动指数2000（SLEDAI-2K）基线评分≥6分、抗双链DNA抗体和/或抗可提取核抗原抗体阳性的成年患者。患者每3周接受45毫克、90毫克或135毫克的mezagitamab或安慰剂治疗，共12周。主要终点是安全性和耐受性。次要终点包括药代动力学和药效学。探索性评估包括疾病活动量表、深度免疫分析和干扰素通路分析。结果 22名患者至少接受了一次麦扎吉单抗或安慰剂治疗。接受麦扎吉单抗治疗的患者（17人）耐受性良好。各治疗组的不良事件（AEs）分布均衡，没有出现超过2级的治疗突发AEs。皮肤红斑狼疮疾病面积和严重程度指数（CLASI）和SLEDAI-2K的应答者分析显示，各治疗组之间没有任何明显差异。不过，基线时CLASI评分较高（大于10分）的患者的皮肤反应有加深的趋势。药效学分析表明，CD38+ 自然杀伤细胞的 CD38 受体占用率中位数高达 88.4%，135 毫克组中这些细胞的同时耗竭率高达 90%。在所有剂量组中，IgG 和自身抗体的平均降低率均低于 20%。通过飞行时间和 1 型干扰素基因分析进行的细胞测定显示出独特的指纹，表明 CD38 靶向后免疫格局发生了广泛的变化。结论 Mezagitamab 对中重度系统性红斑狼疮患者具有良好的安全性，并产生了与 CD38+ 细胞耗竭一致的药效学效应。这些发现揭示了药物作用机制的新见解，支持继续研究美扎吉单抗在自身免疫性疾病中的作用。如有合理要求，可提供数据。数据集（包括经编辑的研究方案、经编辑的统计分析计划以及支持本文所报道结果的参与者个人数据）将在首次申请后三个月内提供给提出合理方法建议的研究人员。这些数据将根据适用的隐私法、数据保护以及同意和匿名化要求进行去标识化处理后提供。

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引用次数: 0

Systemic lupus in the era of machine learning medicine 机器学习医学时代的系统性狼疮

IF 3.9 2区医学 Q1 RHEUMATOLOGY

Lupus Science & Medicine

Pub Date : 2024-03-01 DOI: 10.1136/lupus-2023-001140

Kevin Zhan, Katherine A Buhler, Irene Y Chen, Marvin J Fritzler, May Y Choi

Artificial intelligence and machine learning applications are emerging as transformative technologies in medicine. With greater access to a diverse range of big datasets, researchers are turning to these powerful techniques for data analysis. Machine learning can reveal patterns and interactions between variables in large and complex datasets more accurately and efficiently than traditional statistical methods. Machine learning approaches open new possibilities for studying SLE, a multifactorial, highly heterogeneous and complex disease. Here, we discuss how machine learning methods are rapidly being integrated into the field of SLE research. Recent reports have focused on building prediction models and/or identifying novel biomarkers using both supervised and unsupervised techniques for understanding disease pathogenesis, early diagnosis and prognosis of disease. In this review, we will provide an overview of machine learning techniques to discuss current gaps, challenges and opportunities for SLE studies. External validation of most prediction models is still needed before clinical adoption. Utilisation of deep learning models, access to alternative sources of health data and increased awareness of the ethics, governance and regulations surrounding the use of artificial intelligence in medicine will help propel this exciting field forward.

人工智能和机器学习应用正在成为医学领域的变革性技术。随着对各种大数据集的访问越来越多，研究人员正在转向使用这些强大的技术进行数据分析。与传统统计方法相比，机器学习能更准确、更高效地揭示大型复杂数据集中变量之间的模式和相互作用。机器学习方法为研究系统性红斑狼疮这种多因素、高度异质性的复杂疾病提供了新的可能性。在此，我们将讨论机器学习方法如何迅速融入系统性红斑狼疮研究领域。最近的报道主要集中在利用监督和非监督技术建立预测模型和/或识别新型生物标志物，以了解疾病的发病机制、早期诊断和预后。在本综述中，我们将概述机器学习技术，讨论系统性红斑狼疮研究目前存在的差距、挑战和机遇。在临床应用之前，大多数预测模型仍需要外部验证。利用深度学习模型、获取其他健康数据源以及提高对医学中使用人工智能的伦理、管理和法规的认识，将有助于推动这一令人兴奋的领域向前发展。

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引用次数: 0