Kristina Lend, Jon Lampa, Leonid Padyukov, Merete Lund Hetland, Marte Schrumpf Heiberg, Dan C Nordström, Michael T Nurmohamed, Anna Rudin, Mikkel Østergaard, Espen A Haavardsholm, Kim Hørslev-Petersen, Till Uhlig, Tuulikki Sokka-Isler, Bjorn Gudbjornsson, Gerdur Grondal, Giulia Frazzei, Jeroen Christiaans, Gertjan Wolbink, Theo Rispens, Jos W R Twisk, Ronald F van Vollenhoven
Objectives: To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT).
Methods: Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking.
Results: In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks.
Conclusions: Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice.
{"title":"Association of rheumatoid factor, anti-citrullinated protein antibodies and shared epitope with clinical response to initial treatment in patients with early rheumatoid arthritis: data from a randomised controlled trial.","authors":"Kristina Lend, Jon Lampa, Leonid Padyukov, Merete Lund Hetland, Marte Schrumpf Heiberg, Dan C Nordström, Michael T Nurmohamed, Anna Rudin, Mikkel Østergaard, Espen A Haavardsholm, Kim Hørslev-Petersen, Till Uhlig, Tuulikki Sokka-Isler, Bjorn Gudbjornsson, Gerdur Grondal, Giulia Frazzei, Jeroen Christiaans, Gertjan Wolbink, Theo Rispens, Jos W R Twisk, Ronald F van Vollenhoven","doi":"10.1136/ard-2024-226024","DOIUrl":"10.1136/ard-2024-226024","url":null,"abstract":"<p><strong>Objectives: </strong>To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT).</p><p><strong>Methods: </strong>Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking.</p><p><strong>Results: </strong>In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks.</p><p><strong>Conclusions: </strong>Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice.</p><p><strong>Trial registration number: </strong>EudraCT 2011-004720-35; ClinicalTrials.gov NCT01491815.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1657-1665"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fanlei Hu, Xin Li, Kai Liu, Yanpeng Li, Yang Xie, Chaonan Wei, Shuyan Liu, Jing Song, Ping Wang, Lianjie Shi, Chun Li, Jing Li, Liling Xu, Jimeng Xue, Xi Zheng, Mingxin Bai, Xiangyu Fang, Xu Jin, Lulu Cao, Pei Hao, Jing He, Jun Wang, Chiyu Zhang, Zhanguo Li
Objectives: Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis.
Methods: Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and β diversity of the virome and the virome-bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4+ T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied.
Results: The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular Prevotella phage and Oscillibacter phage could provoke the autoimmune responses in CD4+ T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip.
Conclusions: This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.
目的:病毒一直被认为是类风湿性关节炎(RA)发病的重要参与者。然而,肠道病毒组的概况及其在 RA 中的作用仍然难以捉摸。本研究旨在调查类风湿关节炎发病机制中病毒组的图谱和参与情况:方法:收集 30 对 RA 和健康兄弟姐妹的粪便样本进行元基因组测序,以尽量减少遗传干扰。分析了病毒组的α和β多样性以及病毒组与细菌组之间的相互作用。鉴定了不同的噬菌体,并分析了它们与 RA 临床和免疫学特征的相关性。通过辅助代谢基因注释和分子模拟研究,进一步研究了这些差异噬菌体在RA发病机制中的潜在参与。系统研究了CD4+ T细胞和B细胞对来自差异噬菌体的模拟物的反应:结果:肠道噬菌体组的组成在RA中发生了扭曲。结果:RA患者肠道噬菌体组的组成发生了扭曲,不同的噬菌体与RA的免疫学特征相关,包括抗CCP自身抗体和HLA-DR共享表位。耐人寻味的是,RA噬菌体中的甘油脂和嘌呤代谢基因高度活跃。此外,富含RA的噬菌体,特别是普雷沃特氏菌噬菌体和奥希氏菌噬菌体的肽可通过分子模拟疾病相关的自身抗原表位,尤其是Bip的表位,激发CD4+ T细胞和浆细胞的自身免疫反应:这项研究为了解肠道噬菌体在 RA 发病过程中的作用提供了新的视角。结论:这项研究为了解肠道噬菌体组在 RA 发病过程中的作用提供了新的视角,尤其是噬菌体的异常表现出了诱发自身免疫的潜力,这将促进疾病的发生。
{"title":"Rheumatoid arthritis patients harbour aberrant enteric bacteriophages with autoimmunity-provoking potential: a paired sibling study.","authors":"Fanlei Hu, Xin Li, Kai Liu, Yanpeng Li, Yang Xie, Chaonan Wei, Shuyan Liu, Jing Song, Ping Wang, Lianjie Shi, Chun Li, Jing Li, Liling Xu, Jimeng Xue, Xi Zheng, Mingxin Bai, Xiangyu Fang, Xu Jin, Lulu Cao, Pei Hao, Jing He, Jun Wang, Chiyu Zhang, Zhanguo Li","doi":"10.1136/ard-2024-225564","DOIUrl":"10.1136/ard-2024-225564","url":null,"abstract":"<p><strong>Objectives: </strong>Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis.</p><p><strong>Methods: </strong>Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and β diversity of the virome and the virome-bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4<sup>+</sup> T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied.</p><p><strong>Results: </strong>The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular <i>Prevotella</i> phage and <i>Oscillibacter</i> phage could provoke the autoimmune responses in CD4<sup>+</sup> T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip.</p><p><strong>Conclusions: </strong>This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1677-1690"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: Helicobacter pylori infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of H. pylori infection in the progression of RA.
Methods: The Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared between H. pylori-negative and H. pylori-positive patients with RA. MH7A cells were stimulated with polyclonal ACPA purified from the peripheral blood of patients with RA. The citrullination levels were assessed by western blot in GES-1 cells and sera. ChIP, luciferase reporter assays, mass spectrometry and ELISA were applied to explore the molecular mechanism of H. pylori infection in RA progression.
Results: The DAS-28 and ACPA levels of patients with RA in the H. pylori-positive group were significantly higher than those in the H. pylori-negative group. Polyclonal ACPA derived from H. pylori-positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found that H. pylori infection induces cellular protein citrullination by upregulating protein arginine deiminase type 4 (PAD4). Furthermore, we confirmed a direct functional binding of hypoxia-inducible factor 1α on the PADI4 gene promoter. We demonstrated that PAD4 interacts with and citrullinates keratin 1 (K1), and serum and synovial fluid levels of anti-Cit-K1 antibody were markedly increased in H. pylori-infected patients with RA.
Conclusion: Our findings reveal a novel mechanism by which H. pylori infection contributes to RA progression. Therapeutic interventions targeting H. pylori may be a viable strategy for the management of RA.
目的:有报道称幽门螺杆菌感染会加重类风湿性关节炎(RA),但相关机制仍不清楚。本研究旨在探讨幽门螺杆菌感染导致 RA 病变进展的潜在致病机制:方法:比较幽门螺杆菌阴性和幽门螺杆菌阳性 RA 患者的疾病活动评分(DAS-28)和血清抗瓜氨酸蛋白抗体(ACPA)水平。用从 RA 患者外周血中纯化的多克隆 ACPA 刺激 MH7A 细胞。在 GES-1 细胞和血清中通过 Western 印迹评估瓜氨酸化水平。应用 ChIP、荧光素酶报告实验、质谱法和 ELISA 等方法探讨幽门螺杆菌感染导致 RA 病变的分子机制:结果:幽门螺杆菌阳性组RA患者的DAS-28和ACPA水平明显高于幽门螺杆菌阴性组。来自幽门螺杆菌阳性患者的多克隆ACPA能促进细胞增殖并诱导IL-6和IL-8的分泌。我们首次发现幽门螺杆菌感染会通过上调精氨酸脱氨酶 4 型(PAD4)诱导细胞蛋白瓜氨酸化。此外,我们还证实了低氧诱导因子 1α 与 PADI4 基因启动子的直接功能性结合。我们证明了 PAD4 与角蛋白 1(K1)相互作用并使其瓜氨酸化,幽门螺杆菌感染的 RA 患者血清和滑膜液中抗 Cit-K1 抗体水平明显升高:我们的研究结果揭示了幽门螺杆菌感染导致RA进展的新机制。针对幽门螺杆菌的治疗干预可能是治疗 RA 的可行策略。
{"title":"<i>Helicobacter pylori</i> upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis.","authors":"Hui Wu, Hanmei Yuan, Jin Zhang, Taojun He, Yilin Deng, Ying Chen, Yunqi Zhang, Weisan Chen, Chao Wu","doi":"10.1136/ard-2023-225306","DOIUrl":"10.1136/ard-2023-225306","url":null,"abstract":"<p><strong>Objective: </strong><i>Helicobacter pylori</i> infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of <i>H. pylori</i> infection in the progression of RA.</p><p><strong>Methods: </strong>The Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared between <i>H. pylori</i>-negative and <i>H. pylori</i>-positive patients with RA. MH7A cells were stimulated with polyclonal ACPA purified from the peripheral blood of patients with RA. The citrullination levels were assessed by western blot in GES-1 cells and sera. ChIP, luciferase reporter assays, mass spectrometry and ELISA were applied to explore the molecular mechanism of <i>H. pylori</i> infection in RA progression.</p><p><strong>Results: </strong>The DAS-28 and ACPA levels of patients with RA in the <i>H. pylori</i>-positive group were significantly higher than those in the <i>H. pylori</i>-negative group. Polyclonal ACPA derived from <i>H. pylori</i>-positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found that <i>H. pylori</i> infection induces cellular protein citrullination by upregulating protein arginine deiminase type 4 (PAD4). Furthermore, we confirmed a direct functional binding of hypoxia-inducible factor 1α on the <i>PADI4</i> gene promoter. We demonstrated that PAD4 interacts with and citrullinates keratin 1 (K1), and serum and synovial fluid levels of anti-Cit-K1 antibody were markedly increased in <i>H. pylori</i>-infected patients with RA.</p><p><strong>Conclusion: </strong>Our findings reveal a novel mechanism by which <i>H. pylori</i> infection contributes to RA progression. Therapeutic interventions targeting <i>H. pylori</i> may be a viable strategy for the management of RA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1666-1676"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ann-Kathrin Eiers, Sabine Vettorazzi, Jan P Tuckermann
For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis.
{"title":"Journey through discovery of 75 years glucocorticoids: evolution of our knowledge of glucocorticoid receptor mechanisms in rheumatic diseases.","authors":"Ann-Kathrin Eiers, Sabine Vettorazzi, Jan P Tuckermann","doi":"10.1136/ard-2023-225371","DOIUrl":"10.1136/ard-2023-225371","url":null,"abstract":"<p><p>For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1603-1613"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara Bindoli, Arianna De Matteis, Stéphane Mitrovic, Bruno Fautrel, Loreto Carmona, Fabrizio De Benedetti
Objectives: To analyse the efficacy and safety of treatments for Still's disease and macrophage activation syndrome (MAS).
Methods: Medline, Embase and Cochrane Library were searched for clinical trials (randomised, randomised controlled trial (RCT), controlled and clinical controlled trial (CCT)), observational studies (retrospective, longitudinal observational retrospective (LOR), prospective and longitudinal observational prospective (LOP)) and systematic reviews (SRs), in which the populations studied were patients with Still's disease and MAS. The intervention was any pharmacological treatment (approved or under evaluation) versus any comparator drug or placebo, and as outcomes, any relevant efficacy and safety event. The risk of bias (RoB) was assessed with the Cochrane RoB and AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews-2, version 2) for SRs.
Results: 128 full texts were included: 25 RCTs, 1 CCT, 11 SRs published after 2013 and 91 LOP/LOR studies. In Still's disease, interleukin (IL)-1 inhibitors (IL-1i) and IL-6R inhibitors (IL-6i) were the most studied drugs. Two meta-analyses on RCTs showed an OR, to achieve an ARC50 response rate, of 6.02 (95% CI 2.24 to 21.36) and 8.08 (95% CI 1.89 to 34.57) for IL-1i and IL-6Ri, respectively. Retrospective studies showed that early initiation of IL-1i or IL-6i was associated with high rates of clinically inactive disease. In MAS, GCs were employed in all patients, often associated with ciclosporin and/or anakinra. Rates of complete response were reported, with a range from 53% to 100%. Emapalumab was the only drug tested in a CCT, with a complete response of 93%.
Conclusion: IL-1i and IL-6Ri show the highest level of efficacy in the treatment of Still's disease. For MAS, IL-1 and interferon-γ inhibition appear to be effective on a background of high-dose glucocorticoids.
目的:分析治疗斯蒂尔病和巨噬细胞活化综合征(MAS)的疗效和安全性:分析治疗斯蒂尔病和巨噬细胞活化综合征(MAS)的有效性和安全性:在 Medline、Embase 和 Cochrane 图书馆检索了临床试验(随机试验、随机对照试验 (RCT)、对照试验和临床对照试验 (CCT))、观察性研究(回顾性研究、纵向观察性回顾性研究 (LOR)、前瞻性研究和纵向观察性前瞻性研究 (LOP))和系统综述 (SR),研究人群为斯蒂尔病和巨噬细胞活化综合征患者。干预措施为任何药物治疗(已获批准或正在评估中)与任何对比药物或安慰剂的比较,结果为任何相关的疗效和安全性事件。偏倚风险(RoB)采用 Cochrane RoB 和 AMSTAR-2(Assessing the Methodological Quality of Systematic Reviews-2, version 2)进行评估:结果:共纳入 128 篇全文:结果:共纳入 128 篇全文:25 篇 RCT、1 篇 CCT、11 篇 2013 年后发表的 SR 和 91 篇 LOP/LOR 研究。在斯蒂尔病中,白细胞介素(IL)-1抑制剂(IL-1i)和IL-6R抑制剂(IL-6i)是研究最多的药物。两项 RCT 的荟萃分析表明,IL-1i 和 IL-6Ri 达到 ARC50 反应率的 OR 分别为 6.02(95% CI 2.24 至 21.36)和 8.08(95% CI 1.89 至 34.57)。回顾性研究显示,早期开始使用IL-1i或IL-6i与临床非活动性疾病的高发病率有关。在 MAS 中,所有患者都使用了 GCs,通常与环孢素和/或 Anakinra 联用。完全应答率从53%到100%不等。Emapalumab是唯一一种在CCT中进行测试的药物,完全应答率为93%:结论:IL-1i 和 IL-6Ri 在治疗斯蒂尔病方面显示出最高水平的疗效。对于 MAS,在大剂量糖皮质激素的背景下,抑制 IL-1 和干扰素-γ 似乎是有效的。
{"title":"Efficacy and safety of therapies for Still's disease and macrophage activation syndrome (MAS): a systematic review informing the EULAR/PReS guidelines for the management of Still's disease.","authors":"Sara Bindoli, Arianna De Matteis, Stéphane Mitrovic, Bruno Fautrel, Loreto Carmona, Fabrizio De Benedetti","doi":"10.1136/ard-2024-225854","DOIUrl":"10.1136/ard-2024-225854","url":null,"abstract":"<p><strong>Objectives: </strong>To analyse the efficacy and safety of treatments for Still's disease and macrophage activation syndrome (MAS).</p><p><strong>Methods: </strong>Medline, Embase and Cochrane Library were searched for clinical trials (randomised, randomised controlled trial (RCT), controlled and clinical controlled trial (CCT)), observational studies (retrospective, longitudinal observational retrospective (LOR), prospective and longitudinal observational prospective (LOP)) and systematic reviews (SRs), in which the populations studied were patients with Still's disease and MAS. The intervention was any pharmacological treatment (approved or under evaluation) versus any comparator drug or placebo, and as outcomes, any relevant efficacy and safety event. The risk of bias (RoB) was assessed with the Cochrane RoB and AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews-2, version 2) for SRs.</p><p><strong>Results: </strong>128 full texts were included: 25 RCTs, 1 CCT, 11 SRs published after 2013 and 91 LOP/LOR studies. In Still's disease, interleukin (IL)-1 inhibitors (IL-1i) and IL-6R inhibitors (IL-6i) were the most studied drugs. Two meta-analyses on RCTs showed an OR, to achieve an ARC50 response rate, of 6.02 (95% CI 2.24 to 21.36) and 8.08 (95% CI 1.89 to 34.57) for IL-1i and IL-6Ri, respectively. Retrospective studies showed that early initiation of IL-1i or IL-6i was associated with high rates of clinically inactive disease. In MAS, GCs were employed in all patients, often associated with ciclosporin and/or anakinra. Rates of complete response were reported, with a range from 53% to 100%. Emapalumab was the only drug tested in a CCT, with a complete response of 93%.</p><p><strong>Conclusion: </strong>IL-1i and IL-6Ri show the highest level of efficacy in the treatment of Still's disease. For MAS, IL-1 and interferon-γ inhibition appear to be effective on a background of high-dose glucocorticoids.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1731-1747"},"PeriodicalIF":3.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guy Katz, Cory Perugino, Zachary S Wallace, Bohang Jiang, Thomas Guy, Grace A McMahon, Isha Jha, Yuqing Zhang, Hang Liu, Ana D Fernandes, Shiv S Pillai, John Patterson Atkinson, Alfred Hyoungju Kim, John H Stone
Objectives: Hypocomplementaemia is common in patients with IgG4-related disease (IgG4-RD). We aimed to determine the IgG4-RD features associated with hypocomplementaemia and investigate mechanisms of complement activation in this disease.
Methods: We performed a single-centre cross-sectional study of 279 patients who fulfilled the IgG4-RD classification criteria, using unadjusted and multivariable-adjusted logistic regression to identify factors associated with hypocomplementaemia.
Results: Hypocomplementaemia was observed in 90 (32%) patients. In the unadjusted model, the number of organs involved (OR 1.42, 95% CI 1.23 to 1.63) and involvement of the lymph nodes (OR 3.87, 95% CI 2.19 to 6.86), lungs (OR 3.81, 95% CI 2.10 to 6.89), pancreas (OR 1.66, 95% CI 1.001 to 2.76), liver (OR 2.73, 95% CI 1.17 to 6.36) and kidneys (OR 2.48, 95% CI 1.47 to 4.18) were each associated with hypocomplementaemia. After adjusting for age, sex and number of organs involved, only lymph node (OR 2.59, 95% CI 1.36 to 4.91) and lung (OR 2.56, 95% CI 1.35 to 4.89) involvement remained associated with hypocomplementaemia while the association with renal involvement was attenuated (OR 1.6, 95% CI 0.92 to 2.98). Fibrotic disease manifestations (OR 0.43, 95% CI 0.21 to 0.87) and lacrimal gland involvement (OR 0.53, 95% CI 0.28 to 0.999) were inversely associated with hypocomplementaemia in the adjusted analysis. Hypocomplementaemia was associated with higher concentrations of all IgG subclasses and IgE (all p<0.05). After adjusting for serum IgG1 and IgG3, only IgG1 but not IgG4 remained strongly associated with hypocomplementaemia.
Conclusions: Hypocomplementaemia in IgG4-RD is not unique to patients with renal involvement and may reflect the extent of disease. IgG1 independently correlates with hypocomplementaemia in IgG4-RD, but IgG4 does not. Complement activation is likely involved in IgG4-RD pathophysiology.
目的:低补体血症常见于 IgG4 相关疾病(IgG4-RD)患者。我们旨在确定与低补体血症相关的 IgG4-RD 特征,并研究这种疾病的补体激活机制:我们对符合IgG4-RD分类标准的279名患者进行了单中心横断面研究,使用未调整和多变量调整的逻辑回归来确定与低补体血症相关的因素:结果:90 例(32%)患者出现低补体血症。在未调整模型中,受累器官的数量(OR 1.42,95% CI 1.23 至 1.63)和受累淋巴结(OR 3.87,95% CI 2.19 至 6.86)、肺(OR 3.81,95% CI 2.10至6.89)、胰腺(OR 1.66,95% CI 1.001至2.76)、肝脏(OR 2.73,95% CI 1.17至6.36)和肾脏(OR 2.48,95% CI 1.47至4.18)分别与低补体血症相关。在对年龄、性别和受累器官数量进行调整后,只有淋巴结(OR 2.59,95% CI 1.36 至 4.91)和肺(OR 2.56,95% CI 1.35 至 4.89)受累仍与低补体血症相关,而肾脏受累的相关性减弱(OR 1.6,95% CI 0.92 至 2.98)。在调整分析中,纤维化疾病表现(OR 0.43,95% CI 0.21 至 0.87)和泪腺受累(OR 0.53,95% CI 0.28 至 0.999)与低补体血症呈反比关系。低补体血症与较高的所有 IgG 亚类和 IgE 浓度有关(所有 p 结论:IgG4-RD 中的低补体血症并非肾脏受累患者所独有,它可能反映了疾病的程度。IgG1 与 IgG4-RD 中的低补体血症有独立的相关性,但 IgG4 则没有。补体激活可能与 IgG4-RD 的病理生理学有关。
{"title":"Multiorgan involvement and circulating IgG1 predict hypocomplementaemia in IgG4-related disease.","authors":"Guy Katz, Cory Perugino, Zachary S Wallace, Bohang Jiang, Thomas Guy, Grace A McMahon, Isha Jha, Yuqing Zhang, Hang Liu, Ana D Fernandes, Shiv S Pillai, John Patterson Atkinson, Alfred Hyoungju Kim, John H Stone","doi":"10.1136/ard-2024-225846","DOIUrl":"10.1136/ard-2024-225846","url":null,"abstract":"<p><strong>Objectives: </strong>Hypocomplementaemia is common in patients with IgG4-related disease (IgG4-RD). We aimed to determine the IgG4-RD features associated with hypocomplementaemia and investigate mechanisms of complement activation in this disease.</p><p><strong>Methods: </strong>We performed a single-centre cross-sectional study of 279 patients who fulfilled the IgG4-RD classification criteria, using unadjusted and multivariable-adjusted logistic regression to identify factors associated with hypocomplementaemia.</p><p><strong>Results: </strong>Hypocomplementaemia was observed in 90 (32%) patients. In the unadjusted model, the number of organs involved (OR 1.42, 95% CI 1.23 to 1.63) and involvement of the lymph nodes (OR 3.87, 95% CI 2.19 to 6.86), lungs (OR 3.81, 95% CI 2.10 to 6.89), pancreas (OR 1.66, 95% CI 1.001 to 2.76), liver (OR 2.73, 95% CI 1.17 to 6.36) and kidneys (OR 2.48, 95% CI 1.47 to 4.18) were each associated with hypocomplementaemia. After adjusting for age, sex and number of organs involved, only lymph node (OR 2.59, 95% CI 1.36 to 4.91) and lung (OR 2.56, 95% CI 1.35 to 4.89) involvement remained associated with hypocomplementaemia while the association with renal involvement was attenuated (OR 1.6, 95% CI 0.92 to 2.98). Fibrotic disease manifestations (OR 0.43, 95% CI 0.21 to 0.87) and lacrimal gland involvement (OR 0.53, 95% CI 0.28 to 0.999) were inversely associated with hypocomplementaemia in the adjusted analysis. Hypocomplementaemia was associated with higher concentrations of all IgG subclasses and IgE (all p<0.05). After adjusting for serum IgG1 and IgG3, only IgG1 but not IgG4 remained strongly associated with hypocomplementaemia.</p><p><strong>Conclusions: </strong>Hypocomplementaemia in IgG4-RD is not unique to patients with renal involvement and may reflect the extent of disease. IgG1 independently correlates with hypocomplementaemia in IgG4-RD, but IgG4 does not. Complement activation is likely involved in IgG4-RD pathophysiology.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1773-1780"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11563845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frederick W Miller, John J O'Shea, Daniel L Kastner
{"title":"Paul Hunter Plotz (1937-2024): renaissance rheumatologist, human rights advocate and mensch.","authors":"Frederick W Miller, John J O'Shea, Daniel L Kastner","doi":"10.1136/ard-2024-226596","DOIUrl":"10.1136/ard-2024-226596","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1644-1646"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elise van Mulligen, Maureen Rutten-van Mölken, Annette van der Helm-van Mil
Objective: Early diagnosis and treatment-start is key for rheumatoid arthritis (RA), but the economic effect of an early versus a later diagnosis has never been investigated. We aimed to investigate whether early diagnosis of RA is associated with lower treatment-related costs compared with later diagnosis.
Methods: Patients with RA consecutively included in the Leiden Early Arthritis Clinic between 2011 and 2017 were studied (n=431). Symptom duration was defined as the time between symptom onset and first presentation at the outpatient clinic; early treatment start was defined as symptom duration <12 weeks. Information on disease-modifying anti-rheumatic drug use per patient over 5 years was obtained from prescription data from patient records. Prices were used from 2022 and 2012 (proxy of time of prescription) to study the impact of changes in drug costs. Autoantibody-positive and autoantibody-negative RA were studied separately because differences in disease severity may influence costs.
Results: Within autoantibody-negative RA, costs were 316% higher in the late compared with the early group (β=4.16 (95% CI 1.57 to 11.1); €4856 vs €1159). When using 2012 prices, results were similar. For autoantibody-positive RA, costs were 19% higher in the late group (€9418 vs €7934, β=1.19, 0.57 to 2.47). This effect was present but smaller when using 2012 prices. Within patients with autoantibody-positive RA using biologicals, late treatment start was associated with 46% higher costs (β=1.46 (0.91 to 2.33)); higher costs were also seen when using 2012 prices.
Conclusion: When RA is detected within 12 weeks after symptom onset, treatment-related costs were lower in both autoantibody-negative and autoantibody-positive RA. This study is the first to report how early diagnosis and treatment start impact treatment-related costs.
目的:早期诊断和开始治疗是类风湿关节炎(RA)的关键所在,但对于早期诊断与晚期诊断的经济效益却从未进行过调查。我们的目的是研究与晚期诊断相比,早期诊断 RA 是否会降低治疗相关费用:研究对象为 2011 年至 2017 年间连续纳入莱顿早期关节炎诊所的 RA 患者(431 人)。症状持续时间定义为从症状出现到首次到门诊就诊的时间;早期治疗开始时间定义为症状持续时间:在自身抗体阴性的RA患者中,晚期治疗组的费用比早期治疗组高316%(β=4.16(95% CI 1.57至11.1);4856欧元对1159欧元)。如果采用2012年的价格,结果类似。对于自身抗体阳性的RA患者,晚期组的费用高出19%(9418欧元对7934欧元,β=1.19,0.57对2.47)。如果采用2012年的价格,这一影响依然存在,但幅度较小。在使用生物制剂的自身抗体阳性的RA患者中,治疗开始晚与46%的高成本相关(β=1.46(0.91至2.33));如果使用2012年的价格,成本也会更高:结论:如果在症状出现后12周内发现RA,自身抗体阴性和自身抗体阳性RA的治疗相关费用均较低。这项研究首次报告了早期诊断和治疗对治疗相关费用的影响。
{"title":"Early identification of rheumatoid arthritis: does it induce treatment-related cost savings?","authors":"Elise van Mulligen, Maureen Rutten-van Mölken, Annette van der Helm-van Mil","doi":"10.1136/ard-2024-225746","DOIUrl":"10.1136/ard-2024-225746","url":null,"abstract":"<p><strong>Objective: </strong>Early diagnosis and treatment-start is key for rheumatoid arthritis (RA), but the economic effect of an early versus a later diagnosis has never been investigated. We aimed to investigate whether early diagnosis of RA is associated with lower treatment-related costs compared with later diagnosis.</p><p><strong>Methods: </strong>Patients with RA consecutively included in the Leiden Early Arthritis Clinic between 2011 and 2017 were studied (n=431). Symptom duration was defined as the time between symptom onset and first presentation at the outpatient clinic; early treatment start was defined as symptom duration <12 weeks. Information on disease-modifying anti-rheumatic drug use per patient over 5 years was obtained from prescription data from patient records. Prices were used from 2022 and 2012 (proxy of time of prescription) to study the impact of changes in drug costs. Autoantibody-positive and autoantibody-negative RA were studied separately because differences in disease severity may influence costs.</p><p><strong>Results: </strong>Within autoantibody-negative RA, costs were 316% higher in the late compared with the early group (β=4.16 (95% CI 1.57 to 11.1); €4856 vs €1159). When using 2012 prices, results were similar. For autoantibody-positive RA, costs were 19% higher in the late group (€9418 vs €7934, β=1.19, 0.57 to 2.47). This effect was present but smaller when using 2012 prices. Within patients with autoantibody-positive RA using biologicals, late treatment start was associated with 46% higher costs (β=1.46 (0.91 to 2.33)); higher costs were also seen when using 2012 prices.</p><p><strong>Conclusion: </strong>When RA is detected within 12 weeks after symptom onset, treatment-related costs were lower in both autoantibody-negative and autoantibody-positive RA. This study is the first to report how early diagnosis and treatment start impact treatment-related costs.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1647-1656"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"News from EULAR.","authors":"","doi":"10.1136/ard-2023-225125","DOIUrl":"10.1136/ard-2023-225125","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":"83 12","pages":"1800"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Augustin Latourte, Sarah Jaulerry, Alice Combier, Chahrazad Cherifi, Yohan Jouan, Thierry Grange, Julien Daligault, Hang-Korng Ea, Martine Cohen-Solal, Eric Hay, Pascal Richette
Objectives: Inflammatory mediators such as interleukin 6 (IL-6) are known to activate catabolic responses in chondrocytes during osteoarthritis (OA). This study aimed to investigate the role of a downstream target gene of IL-6, the serine protease inhibitor SerpinA3N, in the development of cartilage damage in OA.
Methods: RNA sequencing was performed in murine primary chondrocytes treated with IL-6, and identified target genes were confirmed in human and murine OA cartilage samples. Male cartilage-specific Serpina3n-deficient mice and control mice underwent meniscectomy (MNX) or sham surgery at 10 weeks of age. Intra-articular injections of SerpinA3N or sivelestat (an inhibitor of leucocyte elastase (LE), a substrate for SerpinA3N) were performed in wild-type mice after MNX. Joint damage was assessed 3-9 weeks after surgery by histology and micro-CT. The effect of sivelestat was assessed in cartilage explants exposed to macrophage-derived conditioned media.
Results: RNA sequencing revealed that SerpinA3N is a major target gene of IL-6 in chondrocytes. The expression of SerpinA3N is increased in OA cartilage. Conditional loss of SerpinA3N in chondrocytes aggravated OA in mice, while intra-articular injection of SerpinA3N limited joint damage. Chondrocytes did not produce serine proteases targeted by SerpinA3N. By contrast, macrophages produced LE on IL-6 stimulation. Sivelestat limited the cartilage catabolism induced by conditioned media derived from IL-6-stimulated macrophages. Additionally, an intra-articular injection of sivelestat is protected against OA in the MNX model.
Conclusions: SerpinA3N protects cartilage against catabolic factors produced by macrophages, including LE. SerpinA3N and LE represent new therapeutic targets to dampen cartilage damage in OA.
{"title":"SerpinA3N limits cartilage destruction in osteoarthritis by inhibiting macrophage-derived leucocyte elastase.","authors":"Augustin Latourte, Sarah Jaulerry, Alice Combier, Chahrazad Cherifi, Yohan Jouan, Thierry Grange, Julien Daligault, Hang-Korng Ea, Martine Cohen-Solal, Eric Hay, Pascal Richette","doi":"10.1136/ard-2024-225645","DOIUrl":"10.1136/ard-2024-225645","url":null,"abstract":"<p><strong>Objectives: </strong>Inflammatory mediators such as interleukin 6 (IL-6) are known to activate catabolic responses in chondrocytes during osteoarthritis (OA). This study aimed to investigate the role of a downstream target gene of IL-6, the serine protease inhibitor SerpinA3N, in the development of cartilage damage in OA.</p><p><strong>Methods: </strong>RNA sequencing was performed in murine primary chondrocytes treated with IL-6, and identified target genes were confirmed in human and murine OA cartilage samples. Male cartilage-specific <i>Serpina3n</i>-deficient mice and control mice underwent meniscectomy (MNX) or sham surgery at 10 weeks of age. Intra-articular injections of SerpinA3N or sivelestat (an inhibitor of leucocyte elastase (LE), a substrate for SerpinA3N) were performed in wild-type mice after MNX. Joint damage was assessed 3-9 weeks after surgery by histology and micro-CT. The effect of sivelestat was assessed in cartilage explants exposed to macrophage-derived conditioned media.</p><p><strong>Results: </strong>RNA sequencing revealed that SerpinA3N is a major target gene of IL-6 in chondrocytes. The expression of SerpinA3N is increased in OA cartilage. Conditional loss of SerpinA3N in chondrocytes aggravated OA in mice, while intra-articular injection of SerpinA3N limited joint damage. Chondrocytes did not produce serine proteases targeted by SerpinA3N. By contrast, macrophages produced LE on IL-6 stimulation. Sivelestat limited the cartilage catabolism induced by conditioned media derived from IL-6-stimulated macrophages. Additionally, an intra-articular injection of sivelestat is protected against OA in the MNX model.</p><p><strong>Conclusions: </strong>SerpinA3N protects cartilage against catabolic factors produced by macrophages, including LE. SerpinA3N and LE represent new therapeutic targets to dampen cartilage damage in OA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1781-1790"},"PeriodicalIF":20.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}