Kevin D Deane, V Michael Holers, Paul Emery, Kulveer Mankia, Hani El Gabalawy, Jeffrey A Sparks, Karen H Costenbader, Georg Schett, Annette van der Helm-van Mil, Dirkjan van Schaardenburg, Ranjeny Thomas, Andrew P Cope
Multiple clinical trials for rheumatoid arthritis (RA) prevention have been completed. Here, we set out to report on the lessons learnt from these studies. Researchers who conducted RA prevention trials shared the background, rationale, approach and outcomes and evaluated the lessons learnt to inform the next generation of RA prevention trials. Individuals at risk of RA can be identified through population screening, referrals to musculoskeletal programmes and by recognition of arthralgia suspicious for RA. Clinical trials in individuals at risk for future clinical RA have demonstrated that limited courses of corticosteroids, atorvastatin and hydroxychloroquine do not alter incidence rates of clinical RA; however, rituximab delays clinical RA onset, and methotrexate has transient effects in individuals who are anticitrullinated protein antibody-positive with subclinical joint inflammation identified by imaging. Abatacept delays clinical RA onset but does not fully prevent onset of RA after treatment cessation. Additionally, subclinical joint inflammation and symptoms appear responsive to interventions such as methotrexate and abatacept. To advance prevention, next steps include building networks of individuals at risk for RA, to improve risk stratification for future RA and to understand the biological mechanisms of RA development, including potential endotypes of disease, which can be targeted for prevention, thus adopting a more precision-based approach. Future trials should focus on interceptions aimed at preventing clinical RA onset and which treat existing symptoms and imaging-defined subclinical inflammation. These trials may include advanced designs (eg, adaptive) and should be combined with mechanistic studies to further define pathophysiological drivers of disease development.
预防类风湿性关节炎(RA)的多项临床试验已经完成。在此,我们将报告这些研究的经验教训。进行类风湿性关节炎预防试验的研究人员分享了试验的背景、原理、方法和结果,并对经验教训进行了评估,以便为下一代类风湿性关节炎预防试验提供参考。可通过人群筛查、转诊至肌肉骨骼项目以及识别可疑的RA关节痛来识别RA高危人群。对未来可能出现临床 RA 的高危人群进行的临床试验表明,皮质类固醇、阿托伐他汀和羟氯喹的有限疗程不会改变临床 RA 的发病率;但利妥昔单抗可推迟临床 RA 的发病,而甲氨蝶呤对抗瓜氨酸蛋白抗体阳性且通过影像学检查发现有亚临床关节炎症的人群有短暂的疗效。阿帕他赛可延缓临床 RA 的发病,但不能完全防止停止治疗后 RA 的发病。此外,亚临床关节炎症和症状似乎对甲氨蝶呤和阿帕他赛等干预措施有反应。为推进预防工作,接下来的步骤包括建立 RA 高危人群网络,改善未来 RA 的风险分层,了解 RA 发病的生物机制,包括潜在的疾病内型,从而采取更精准的预防方法。未来的试验应侧重于旨在预防临床 RA 发病的拦截措施,这些措施可治疗现有症状和影像学定义的亚临床炎症。这些试验可能包括先进的设计(如适应性),并应与机理研究相结合,以进一步明确疾病发展的病理生理学驱动因素。
{"title":"Therapeutic interception in individuals at risk of rheumatoid arthritis to prevent clinically impactful disease.","authors":"Kevin D Deane, V Michael Holers, Paul Emery, Kulveer Mankia, Hani El Gabalawy, Jeffrey A Sparks, Karen H Costenbader, Georg Schett, Annette van der Helm-van Mil, Dirkjan van Schaardenburg, Ranjeny Thomas, Andrew P Cope","doi":"10.1136/ard-2023-224211","DOIUrl":"https://doi.org/10.1136/ard-2023-224211","url":null,"abstract":"<p><p>Multiple clinical trials for rheumatoid arthritis (RA) prevention have been completed. Here, we set out to report on the lessons learnt from these studies. Researchers who conducted RA prevention trials shared the background, rationale, approach and outcomes and evaluated the lessons learnt to inform the next generation of RA prevention trials. Individuals at risk of RA can be identified through population screening, referrals to musculoskeletal programmes and by recognition of arthralgia suspicious for RA. Clinical trials in individuals at risk for future clinical RA have demonstrated that limited courses of corticosteroids, atorvastatin and hydroxychloroquine do not alter incidence rates of clinical RA; however, rituximab delays clinical RA onset, and methotrexate has transient effects in individuals who are anticitrullinated protein antibody-positive with subclinical joint inflammation identified by imaging. Abatacept delays clinical RA onset but does not fully prevent onset of RA after treatment cessation. Additionally, subclinical joint inflammation and symptoms appear responsive to interventions such as methotrexate and abatacept. To advance prevention, next steps include building networks of individuals at risk for RA, to improve risk stratification for future RA and to understand the biological mechanisms of RA development, including potential endotypes of disease, which can be targeted for prevention, thus adopting a more precision-based approach. Future trials should focus on interceptions aimed at preventing clinical RA onset and which treat existing symptoms and imaging-defined subclinical inflammation. These trials may include advanced designs (eg, adaptive) and should be combined with mechanistic studies to further define pathophysiological drivers of disease development.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144898","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}
Jordan Elizabeth Roberts, Nayimisha Balmuri, Joyce C Chang, Jennifer Cooper, Onengiya Harry, Rebecca Hetrick, Jim Jarvis, Andrea M Knight, Laura B Lewandowski, Tamar B Rubinstein, Rebecca Sadun, William Daniel Soulsby, Scott Wenderfer, Jennifer M P Woo
{"title":"Correspondence on 'EULAR recommendations for the management of systemic lupus erythematosus: 2023 update' by Fanouriakis <i>et al</i>.","authors":"Jordan Elizabeth Roberts, Nayimisha Balmuri, Joyce C Chang, Jennifer Cooper, Onengiya Harry, Rebecca Hetrick, Jim Jarvis, Andrea M Knight, Laura B Lewandowski, Tamar B Rubinstein, Rebecca Sadun, William Daniel Soulsby, Scott Wenderfer, Jennifer M P Woo","doi":"10.1136/ard-2024-226392","DOIUrl":"https://doi.org/10.1136/ard-2024-226392","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139102","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}
Objectives: Dermatomyositis (DM) has been consistently linked to the type I interferon (IFN-I) pathway. However, the precise pathogenesis remains incompletely elucidated. We aimed to explore potential molecular mechanisms and identify promising therapeutic targets in DM.
Methods: We employed bioinformatics analysis to investigate molecular signatures, aiming to shed light on the pathogenesis of DM. The expression of protein kinase R (PKR) in DM muscle tissues was determined by real-time quantitative PCR, western blot and immunohistochemistry (IHC) analysis. We then assessed the sensitivity and specificity of sarcoplasmic PKR expression by IHC in a consecutive DM cohort and other diseases in this retrospective study. Furthermore, IFN-β was used to stimulate myoblasts and myotubes, and the relationship between PKR and IFN-β-induced pathogenic molecules was investigated in vitro.
Results: Bioinformatics analysis indicated two primary pathological processes: viral infection and the IFN-I signalling pathway. We subsequently verified that PKR was notably expressed in the cytoplasm of myofibers in DM patients. The sensitivity and specificity of sarcoplasmic PKR expression in DM were 84.6% and 97.6%, respectively. In vitro studies revealed that IFN-β upregulates the expression of PKR, along with several molecules associated with DM muscle damage. Conversely, inhibiting PKR has been shown to downregulate IFN-β-induced pathogenic molecules in both myoblasts and myotubes.
Conclusions: We observed that PKR exhibits specific expression in the cytoplasm of DM muscle and inhibiting PKR ameliorates IFN-β-induced muscle damage in vitro. These findings provide insights into the diagnostic and therapeutic roles of PKR in DM.
目的:皮肌炎(DM)一直与 I 型干扰素(IFN-I)通路有关。然而,确切的发病机制仍未完全阐明。我们旨在探索皮肌炎的潜在分子机制并确定有前景的治疗靶点:方法:我们采用生物信息学分析方法研究分子特征,旨在揭示DM的发病机制。通过实时定量 PCR、Western 印迹和免疫组织化学(IHC)分析确定了蛋白激酶 R(PKR)在 DM 肌肉组织中的表达。然后,我们在这项回顾性研究中通过 IHC 评估了连续 DM 队列和其他疾病中肌浆 PKR 表达的敏感性和特异性。此外,我们还用 IFN-β 刺激了成肌细胞和肌管,并在体外研究了 PKR 与 IFN-β 诱导的致病分子之间的关系:结果:生物信息学分析表明了两个主要病理过程:病毒感染和 IFN-I 信号通路。我们随后验证了 PKR 在 DM 患者肌纤维胞浆中的显著表达。DM患者肌浆中PKR表达的敏感性和特异性分别为84.6%和97.6%。体外研究显示,IFN-β能上调PKR以及与DM肌肉损伤相关的几种分子的表达。相反,抑制 PKR 则能下调 IFN-β 在成肌细胞和肌管中诱导的致病分子:我们观察到,PKR 在 DM 肌肉的细胞质中有特异性表达,抑制 PKR 可改善体外 IFN-β 诱导的肌肉损伤。这些发现为PKR在DM中的诊断和治疗作用提供了启示。
{"title":"Protein kinase R is highly expressed in dermatomyositis and promotes interferon-beta-induced muscle damage.","authors":"Guoyong Zhang, Lining Zhang, Dandan Zhao, Xiaoyu Liu, Wei Li, Chuanzhu Yan, Tingjun Dai","doi":"10.1136/ard-2024-226057","DOIUrl":"https://doi.org/10.1136/ard-2024-226057","url":null,"abstract":"<p><strong>Objectives: </strong>Dermatomyositis (DM) has been consistently linked to the type I interferon (IFN-I) pathway. However, the precise pathogenesis remains incompletely elucidated. We aimed to explore potential molecular mechanisms and identify promising therapeutic targets in DM.</p><p><strong>Methods: </strong>We employed bioinformatics analysis to investigate molecular signatures, aiming to shed light on the pathogenesis of DM. The expression of protein kinase R (PKR) in DM muscle tissues was determined by real-time quantitative PCR, western blot and immunohistochemistry (IHC) analysis. We then assessed the sensitivity and specificity of sarcoplasmic PKR expression by IHC in a consecutive DM cohort and other diseases in this retrospective study. Furthermore, IFN-β was used to stimulate myoblasts and myotubes, and the relationship between PKR and IFN-β-induced pathogenic molecules was investigated in vitro.</p><p><strong>Results: </strong>Bioinformatics analysis indicated two primary pathological processes: viral infection and the IFN-I signalling pathway. We subsequently verified that PKR was notably expressed in the cytoplasm of myofibers in DM patients. The sensitivity and specificity of sarcoplasmic PKR expression in DM were 84.6% and 97.6%, respectively. In vitro studies revealed that IFN-β upregulates the expression of PKR, along with several molecules associated with DM muscle damage. Conversely, inhibiting PKR has been shown to downregulate IFN-β-induced pathogenic molecules in both myoblasts and myotubes.</p><p><strong>Conclusions: </strong>We observed that PKR exhibits specific expression in the cytoplasm of DM muscle and inhibiting PKR ameliorates IFN-β-induced muscle damage in vitro. These findings provide insights into the diagnostic and therapeutic roles of PKR in DM.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139105","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}
Simone Castagno, Mark Birch, Mihaela van der Schaar, Andrew McCaskie
Objectives: To facilitate the stratification of patients with osteoarthritis (OA) for new treatment development and clinical trial recruitment, we created an automated machine learning (autoML) tool predicting the rapid progression of knee OA over a 2-year period.
Methods: We developed autoML models integrating clinical, biochemical, X-ray and MRI data. Using two data sets within the OA Initiative-the Foundation for the National Institutes of Health OA Biomarker Consortium for training and hold-out validation, and the Pivotal Osteoarthritis Initiative MRI Analyses study for external validation-we employed two distinct definitions of clinical outcomes: Multiclass (categorising OA progression into pain and/or radiographic) and binary. Key predictors of progression were identified through advanced interpretability techniques, and subgroup analyses were conducted by age, sex and ethnicity with a focus on early-stage disease.
Results: Although the most reliable models incorporated all available features, simpler models including only clinical variables achieved robust external validation performance, with area under the precision-recall curve (AUC-PRC) 0.727 (95% CI: 0.726 to 0.728) for multiclass predictions; and AUC-PRC 0.764 (95% CI: 0.762 to 0.766) for binary predictions. Multiclass models performed best in patients with early-stage OA (AUC-PRC 0.724-0.806) whereas binary models were more reliable in patients younger than 60 (AUC-PRC 0.617-0.693). Patient-reported outcomes and MRI features emerged as key predictors of progression, though subgroup differences were noted. Finally, we developed web-based applications to visualise our personalised predictions.
Conclusions: Our novel tool's transparency and reliability in predicting rapid knee OA progression distinguish it from conventional 'black-box' methods and are more likely to facilitate its acceptance by clinicians and patients, enabling effective implementation in clinical practice.
{"title":"Predicting rapid progression in knee osteoarthritis: a novel and interpretable automated machine learning approach, with specific focus on young patients and early disease.","authors":"Simone Castagno, Mark Birch, Mihaela van der Schaar, Andrew McCaskie","doi":"10.1136/ard-2024-225872","DOIUrl":"https://doi.org/10.1136/ard-2024-225872","url":null,"abstract":"<p><strong>Objectives: </strong>To facilitate the stratification of patients with osteoarthritis (OA) for new treatment development and clinical trial recruitment, we created an automated machine learning (autoML) tool predicting the rapid progression of knee OA over a 2-year period.</p><p><strong>Methods: </strong>We developed autoML models integrating clinical, biochemical, X-ray and MRI data. Using two data sets within the OA Initiative-the Foundation for the National Institutes of Health OA Biomarker Consortium for training and hold-out validation, and the Pivotal Osteoarthritis Initiative MRI Analyses study for external validation-we employed two distinct definitions of clinical outcomes: Multiclass (categorising OA progression into pain and/or radiographic) and binary. Key predictors of progression were identified through advanced interpretability techniques, and subgroup analyses were conducted by age, sex and ethnicity with a focus on early-stage disease.</p><p><strong>Results: </strong>Although the most reliable models incorporated all available features, simpler models including only clinical variables achieved robust external validation performance, with area under the precision-recall curve (AUC-PRC) 0.727 (95% CI: 0.726 to 0.728) for multiclass predictions; and AUC-PRC 0.764 (95% CI: 0.762 to 0.766) for binary predictions. Multiclass models performed best in patients with early-stage OA (AUC-PRC 0.724-0.806) whereas binary models were more reliable in patients younger than 60 (AUC-PRC 0.617-0.693). Patient-reported outcomes and MRI features emerged as key predictors of progression, though subgroup differences were noted. Finally, we developed web-based applications to visualise our personalised predictions.</p><p><strong>Conclusions: </strong>Our novel tool's transparency and reliability in predicting rapid knee OA progression distinguish it from conventional 'black-box' methods and are more likely to facilitate its acceptance by clinicians and patients, enabling effective implementation in clinical practice.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139104","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}
Objectives: Rheumatoid arthritis (RA) is an autoimmune disease characterised by aggressive fibroblast-like synoviocytes (FLSs). Very few RA patients-derived FLSs (RA-FLSs)-specific surface signatures have been identified, and there is currently no approved targeted therapy for RA-FLSs. This study aimed to screen therapeutic aptamers with cell-targeting and cytotoxic properties against RA-FLSs and to uncover the molecular targets and mechanism of action of the screened aptamers.
Methods: We developed a cell-specific and cytotoxic systematic evolution of ligands by exponential enrichment (CSCT-SELEX) method to screen the therapeutic aptamers without prior knowledge of the surface signatures of RA-FLSs. The molecular targets and mechanisms of action of the screened aptamers were determined by pull-down assays and RNA sequencing. The therapeutic efficacy of the screened aptamers was examined in arthritic mouse models.
Results: We obtained an aptamer SAPT8 that selectively recognised and killed RA-FLSs. The molecular target of SAPT8 was nucleolin (NCL), a shuttling protein overexpressed on the surface and involved in the tumor-like transformation of RA-FLSs. Mechanistically, SAPT8 interacted with the surface NCL and was internalised to achieve lysosomal degradation of NCL, leading to the upregulation of proapoptotic p53 and downregulation of antiapoptotic B-cell lymphoma 2 (Bcl-2) in RA-FLSs. When administrated systemically to arthritic mice, SAPT8 accumulated in the inflamed FLSs of joints. SAPT8 monotherapy or its combination with tumour necrosis factor (TNF)-targeted biologics was shown to relieve arthritis in mouse models.
Conclusions: CSCT-SELEX could be a promising strategy for developing cell-targeting and cytotoxic aptamers. SAPT8 aptamer selectively ablates RA-FLSs via modulating NCL-p53/Bcl-2 signalling, representing a potential alternative or complementary therapy for RA.
目的:类风湿性关节炎(RA)是一种以侵袭性成纤维细胞样滑膜细胞(FLSs)为特征的自身免疫性疾病。目前只发现了极少数 RA 患者衍生的 FLSs(RA-FLSs)特异性表面特征,而且目前还没有针对 RA-FLSs 的获批靶向疗法。本研究旨在筛选针对RA-FLSs具有细胞靶向性和细胞毒性的治疗性适配体,并揭示筛选出的适配体的分子靶点和作用机制:我们开发了一种细胞特异性和细胞毒性配体的指数富集系统进化(CSCT-SELEX)方法,在事先不了解RA-FLSs表面特征的情况下筛选治疗性适配体。筛选出的适配体的分子靶点和作用机制是通过下拉实验和RNA测序确定的。在关节炎小鼠模型中检验了筛选出的适配体的疗效:结果:我们获得了一种能选择性识别并杀死RA-FLS的适配体SAPT8。SAPT8的分子靶点是核仁蛋白(NCL),它是一种表面过度表达的穿梭蛋白,参与了RA-FLSs的肿瘤样转化。从机理上讲,SAPT8 与表面的 NCL 相互作用,并被内化以实现 NCL 的溶酶体降解,从而导致 RA-FLS 中促凋亡的 p53 上调和抗凋亡的 B 细胞淋巴瘤 2(Bcl-2)下调。给关节炎小鼠全身用药时,SAPT8会在关节发炎的FLS中积聚。在小鼠模型中,SAPT8单药治疗或与肿瘤坏死因子(TNF)靶向生物制剂联合治疗均可缓解关节炎:结论:CSCT-SELEX可能是开发细胞靶向和细胞毒性适配体的一种有前途的策略。SAPT8适配体通过调节NCL-p53/Bcl-2信号选择性地消减RA-FLS,是治疗RA的一种潜在替代或补充疗法。
{"title":"Generation of cytotoxic aptamers specifically targeting fibroblast-like synoviocytes by CSCT-SELEX for treatment of rheumatoid arthritis.","authors":"Fang Qiu, Duoli Xie, Hongzhen Chen, Zhuqian Wang, Jie Huang, Chunhao Cao, Yiying Liang, Xu Yang, Dong-Yi He, Xuekun Fu, Aiping Lu, Chao Liang","doi":"10.1136/ard-2024-225565","DOIUrl":"https://doi.org/10.1136/ard-2024-225565","url":null,"abstract":"<p><strong>Objectives: </strong>Rheumatoid arthritis (RA) is an autoimmune disease characterised by aggressive fibroblast-like synoviocytes (FLSs). Very few RA patients-derived FLSs (RA-FLSs)-specific surface signatures have been identified, and there is currently no approved targeted therapy for RA-FLSs. This study aimed to screen therapeutic aptamers with cell-targeting and cytotoxic properties against RA-FLSs and to uncover the molecular targets and mechanism of action of the screened aptamers.</p><p><strong>Methods: </strong>We developed a cell-specific and cytotoxic systematic evolution of ligands by exponential enrichment (CSCT-SELEX) method to screen the therapeutic aptamers without prior knowledge of the surface signatures of RA-FLSs. The molecular targets and mechanisms of action of the screened aptamers were determined by pull-down assays and RNA sequencing. The therapeutic efficacy of the screened aptamers was examined in arthritic mouse models.</p><p><strong>Results: </strong>We obtained an aptamer SAPT8 that selectively recognised and killed RA-FLSs. The molecular target of SAPT8 was nucleolin (NCL), a shuttling protein overexpressed on the surface and involved in the tumor-like transformation of RA-FLSs. Mechanistically, SAPT8 interacted with the surface NCL and was internalised to achieve lysosomal degradation of NCL, leading to the upregulation of proapoptotic p53 and downregulation of antiapoptotic B-cell lymphoma 2 (Bcl-2) in RA-FLSs. When administrated systemically to arthritic mice, SAPT8 accumulated in the inflamed FLSs of joints. SAPT8 monotherapy or its combination with tumour necrosis factor (TNF)-targeted biologics was shown to relieve arthritis in mouse models.</p><p><strong>Conclusions: </strong>CSCT-SELEX could be a promising strategy for developing cell-targeting and cytotoxic aptamers. SAPT8 aptamer selectively ablates RA-FLSs via modulating NCL-p53/Bcl-2 signalling, representing a potential alternative or complementary therapy for RA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139103","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 Siegert, Werner Stenzel, David Sinan Koca, Gerhard Krönke, Robert Biesen
{"title":"More than meets the eye.","authors":"Elise Siegert, Werner Stenzel, David Sinan Koca, Gerhard Krönke, Robert Biesen","doi":"10.1136/ard-2024-226168","DOIUrl":"https://doi.org/10.1136/ard-2024-226168","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103764","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":"Correspondence on 'Risk of cardiovascular disease with high-dose versus low-dose use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis' by Kim <i>et al</i>.","authors":"Robert B M Landewé, Maarten Boers","doi":"10.1136/ard-2024-226587","DOIUrl":"https://doi.org/10.1136/ard-2024-226587","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142091708","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}
Cecilia Leijding, Suchada Kaewin, Kristofer M Andreasson, Begum Horuluoglu, Angeles Shunashy Galindo-Feria, Eveline Van Gompel, Maryam Dastmalchi, Stefano Gastaldello, Helene Alexanderson, Ingrid E Lundberg, Daniel C Andersson
{"title":"Serum from patients with idiopathic inflammatory myopathy induces skeletal muscle weakness.","authors":"Cecilia Leijding, Suchada Kaewin, Kristofer M Andreasson, Begum Horuluoglu, Angeles Shunashy Galindo-Feria, Eveline Van Gompel, Maryam Dastmalchi, Stefano Gastaldello, Helene Alexanderson, Ingrid E Lundberg, Daniel C Andersson","doi":"10.1136/ard-2024-225912","DOIUrl":"https://doi.org/10.1136/ard-2024-225912","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142091709","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}
Gerd R Burmester, Jacques-Eric Gottenberg, Roberto Caporali, Kevin L Winthrop, Yoshiya Tanaka, Edmund V Ekoka Omoruyi, Vijay Rajendran, Paul Van Hoek, Katrien Van Beneden, Tsutomu Takeuchi, René Westhovens, Daniel Aletaha
Objectives: To update the long-term safety profile of filgotinib, a Janus kinase-1 preferential inhibitor, in patients with moderate-to-severe rheumatoid arthritis.
Methods: Data from seven trials were integrated (NCT01888874, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700 and NCT03025308). Patients received once-daily filgotinib 100 mg or 200 mg. Exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure (PYE) were calculated for treatment-emergent adverse events (TEAEs). Post hoc analyses assessed patients aged <65 and ≥65 years.
Results: Patients (N=3691) received filgotinib for a median (maximum) of 3.8 (8.3) years (12 541 PYE). Rates of TEAEs of interest: serious infections, malignancies, major adverse cardiovascular events (MACE) and venous thromboembolism were stable over time and comparable between doses. In the overall population, numerically lower EAIR (95% CI)/100 PYE of herpes zoster was observed for filgotinib 100 mg versus 200 mg (1.1 (0.8 to 1.5) vs 1.5 (1.2 to 1.8)). Incidence of serious infections, herpes zoster, MACE, malignancies and all-cause mortality was higher in patients aged ≥65 versus <65 years. In patients aged ≥65 years, EAIRs (95% CI)/100 PYE for non-melanoma skin cancer (NMSC) (0.4 (0.1 to 1.1) vs 1.4 (0.8 to 2.2)), malignancies excluding NMSC (1.0 (0.5 to 1.9) vs 2.0 (1.3 to 2.9)) and all-cause mortality (1.3 (0.7 to 2.2) vs 1.6 (1.0 to 2.5)) were numerically lower for filgotinib 100 mg versus 200 mg.
Conclusions: In the overall population, TEAEs of interest were stable over time and similar between filgotinib 100 mg and 200 mg dose groups, except for herpes zoster. A dose-dependent relationship between malignancies and all-cause mortality was suggested in patients ≥65 years old.
{"title":"Integrated safety analysis of filgotinib in patients with moderate-to-severe rheumatoid arthritis over a treatment duration of up to 8.3 years.","authors":"Gerd R Burmester, Jacques-Eric Gottenberg, Roberto Caporali, Kevin L Winthrop, Yoshiya Tanaka, Edmund V Ekoka Omoruyi, Vijay Rajendran, Paul Van Hoek, Katrien Van Beneden, Tsutomu Takeuchi, René Westhovens, Daniel Aletaha","doi":"10.1136/ard-2024-225759","DOIUrl":"10.1136/ard-2024-225759","url":null,"abstract":"<p><strong>Objectives: </strong>To update the long-term safety profile of filgotinib, a Janus kinase-1 preferential inhibitor, in patients with moderate-to-severe rheumatoid arthritis.</p><p><strong>Methods: </strong>Data from seven trials were integrated (NCT01888874, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700 and NCT03025308). Patients received once-daily filgotinib 100 mg or 200 mg. Exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure (PYE) were calculated for treatment-emergent adverse events (TEAEs). Post hoc analyses assessed patients aged <65 and ≥65 years.</p><p><strong>Results: </strong>Patients (N=3691) received filgotinib for a median (maximum) of 3.8 (8.3) years (12 541 PYE). Rates of TEAEs of interest: serious infections, malignancies, major adverse cardiovascular events (MACE) and venous thromboembolism were stable over time and comparable between doses. In the overall population, numerically lower EAIR (95% CI)/100 PYE of herpes zoster was observed for filgotinib 100 mg versus 200 mg (1.1 (0.8 to 1.5) vs 1.5 (1.2 to 1.8)). Incidence of serious infections, herpes zoster, MACE, malignancies and all-cause mortality was higher in patients aged ≥65 versus <65 years. In patients aged ≥65 years, EAIRs (95% CI)/100 PYE for non-melanoma skin cancer (NMSC) (0.4 (0.1 to 1.1) vs 1.4 (0.8 to 2.2)), malignancies excluding NMSC (1.0 (0.5 to 1.9) vs 2.0 (1.3 to 2.9)) and all-cause mortality (1.3 (0.7 to 2.2) vs 1.6 (1.0 to 2.5)) were numerically lower for filgotinib 100 mg versus 200 mg.</p><p><strong>Conclusions: </strong>In the overall population, TEAEs of interest were stable over time and similar between filgotinib 100 mg and 200 mg dose groups, except for herpes zoster. A dose-dependent relationship between malignancies and all-cause mortality was suggested in patients ≥65 years old.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086466","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}
Si Chen, Fengjing Liu, Jie Chen, Geng Gu, Haoyong Yu
{"title":"Clinical image: tophus in the sternoclavicular joint.","authors":"Si Chen, Fengjing Liu, Jie Chen, Geng Gu, Haoyong Yu","doi":"10.1136/ard-2024-225609","DOIUrl":"10.1136/ard-2024-225609","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":null,"pages":null},"PeriodicalIF":20.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118561","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}