{"title":"Gout Flares As Vascular Red Flags","authors":"Mariano Andrés","doi":"10.1002/art.43015","DOIUrl":"https://doi.org/10.1002/art.43015","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276895","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}
Anna Eberhard, Daniela Di Giuseppe, Johan Askling, Stefan Bergman, Hannah Bower, Katerina Chatzidionysiou, Helena Forsblad‐d'Elia, Alf Kastbom, Tor Olofsson, Thomas Frisell, Carl Turesson
ObjectiveTo compare the effectiveness of Janus kinase inhibitors (JAKis) and biologic disease‐modifying anti‐rheumatic drugs (bDMARDs) on pain in patients with rheumatoid arthritis (RA).MethodsIn this retrospective study, we investigated patients with a diagnosis of RA, starting treatment with a JAKi (n=1827), TNF inhibitor (TNFi, n=6422), IL‐6 inhibitor (n=887), abatacept (n=1102) or rituximab (n=1149) in 2017‐2019, using data from several linked Swedish national registers. Differences in change in pain, assessed with a visual analogue scale (VAS; 0‐100 mm), from baseline to 3 months, as well as proportions of patients remaining on initial treatment with low pain (VAS pain <20) at 12 months, were compared between treatments. Comparisons of treatment responses between JAKis and bDMARDs were evaluated using multivariable linear regression, adjusted for patient characteristics, comorbidities, current co‐medication and previous treatment.ResultsJAKi treatment was associated with a greater decrease in pain at 3 months compared with TNFi treatment (adjusted mean additional decrease: 4.0 mm; 95% confidence interval (CI) 1.6, 6.3), with similar trends in comparisons with non‐TNFi bDMARDs. More patients achieved low pain at 12 months on JAKis compared with TNFis, in particular among those previously treated with ≥2 bDMARDs (adjusted change contrast: 5.3 percentage points; 95% CI 1.0, 9.6).ConclusionJAKis had a slightly better effect on pain outcomes at 3 and 12 months compared with TNFis, with significantly greater differences in patients previously treated with ≥2 bDMARDs. The effect of JAKis on pain reduction was at least similar to that of non‐TNFi bDMARDs.
{"title":"Effectiveness of janus kinase inhibitors compared with biologic disease modifying anti‐rheumatic drugs on pain reduction in rheumatoid arthritis","authors":"Anna Eberhard, Daniela Di Giuseppe, Johan Askling, Stefan Bergman, Hannah Bower, Katerina Chatzidionysiou, Helena Forsblad‐d'Elia, Alf Kastbom, Tor Olofsson, Thomas Frisell, Carl Turesson","doi":"10.1002/art.43014","DOIUrl":"https://doi.org/10.1002/art.43014","url":null,"abstract":"ObjectiveTo compare the effectiveness of Janus kinase inhibitors (JAKis) and biologic disease‐modifying anti‐rheumatic drugs (bDMARDs) on pain in patients with rheumatoid arthritis (RA).MethodsIn this retrospective study, we investigated patients with a diagnosis of RA, starting treatment with a JAKi (n=1827), TNF inhibitor (TNFi, n=6422), IL‐6 inhibitor (n=887), abatacept (n=1102) or rituximab (n=1149) in 2017‐2019, using data from several linked Swedish national registers. Differences in change in pain, assessed with a visual analogue scale (VAS; 0‐100 mm), from baseline to 3 months, as well as proportions of patients remaining on initial treatment with low pain (VAS pain <20) at 12 months, were compared between treatments. Comparisons of treatment responses between JAKis and bDMARDs were evaluated using multivariable linear regression, adjusted for patient characteristics, comorbidities, current co‐medication and previous treatment.ResultsJAKi treatment was associated with a greater decrease in pain at 3 months compared with TNFi treatment (adjusted mean additional decrease: 4.0 mm; 95% confidence interval (CI) 1.6, 6.3), with similar trends in comparisons with non‐TNFi bDMARDs. More patients achieved low pain at 12 months on JAKis compared with TNFis, in particular among those previously treated with ≥2 bDMARDs (adjusted change contrast: 5.3 percentage points; 95% CI 1.0, 9.6).ConclusionJAKis had a slightly better effect on pain outcomes at 3 and 12 months compared with TNFis, with significantly greater differences in patients previously treated with ≥2 bDMARDs. The effect of JAKis on pain reduction was at least similar to that of non‐TNFi bDMARDs.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276796","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":"Clinical Images: Erdheim-Chester disease presenting with palpitations and spondylopathy.","authors":"Xiang Li, Chun Wang","doi":"10.1002/art.43016","DOIUrl":"10.1002/art.43016","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306744","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":"Strength Training Associates with Less Symptom and Structure Outcomes for Knee Osteoarthritis.","authors":"Grace H Lo,Jeffrey B Driban","doi":"10.1002/art.42994","DOIUrl":"https://doi.org/10.1002/art.42994","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273532","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}
OBJECTIVETo assess the efficacy and safety of intravenous (IV) secukinumab for the treatment of adults with active axial spondyloarthritis (axSpA) in INVIGORATE-1.METHODSINVIGORATE-1 (NCT04156620) was a randomized, double-blind, parallel-group, phase III trial in patients with active axSpA (either radiographic or non-radiographic). Patients were randomized 1:1 to receive IV secukinumab (6 mg/kg at baseline followed by 3 mg/kg every 4 weeks) or IV placebo for 16 weeks. After Week 16, patients randomized to placebo were switched to IV secukinumab (3 mg/kg every 4 weeks), while patients randomized to secukinumab continued treatment through Week 52. The primary endpoint was Assessment of SpondyloArthritis international Society (ASAS40) response at Week 16. Safety was evaluated through Week 60.RESULTSAmong patients initially randomized to IV secukinumab (n = 264) or placebo (n = 262), 86.0% and 88.9% completed the entire 60-week study period, respectively. A higher proportion of patients receiving secukinumab vs placebo met the primary endpoint (ASAS40 response) at Week 16 (40.9% vs 22.9%; P<.0001). By Week 24, patients who switched from placebo to secukinumab at Week 16 achieved ASAS40 response rates comparable to those in patients originally randomized to secukinumab. All secondary efficacy endpoints were met at Week 16, and responses were sustained through Week 52. No new or unexpected safety signals were observed with IV secukinumab.CONCLUSIONIV secukinumab was effective for the treatment of adults with active axSpA over 52 weeks. The safety profile was consistent with that in previous reports on subcutaneous secukinumab.
目的评估INVIGORATE-1中静脉注射（IV）secukinumab治疗活动性轴性脊椎关节炎（axSpA）成人患者的疗效和安全性。方法INVIGORATE-1（NCT04156620）是一项随机、双盲、平行分组的III期试验，对象是活动性axSpA（放射性或非放射性）患者。患者按1:1的比例随机接受静脉注射secukinumab（基线剂量为6毫克/千克，之后每4周3毫克/千克）或静脉注射安慰剂，疗程为16周。第16周后，随机接受安慰剂治疗的患者转为静脉注射secukinumab（3毫克/千克，每4周一次），而随机接受secukinumab治疗的患者则继续治疗至第52周。主要终点是第16周时国际脊柱炎协会（ASAS40）的反应评估。结果在最初随机接受静脉注射secukinumab（264人）或安慰剂（262人）治疗的患者中，分别有86.0%和88.9%的患者完成了整个60周的研究。与安慰剂相比，接受secukinumab治疗的患者在第16周达到主要终点（ASAS40反应）的比例更高（40.9% vs 22.9%; P<.0001）。到第24周时，在第16周从安慰剂转用secukinumab的患者的ASAS40应答率与最初随机使用secukinumab的患者相当。所有次要疗效终点均在第16周达到，反应持续到第52周。静脉注射secukinumab没有观察到新的或意外的安全信号。其安全性与之前关于皮下注射secukinumab的报告一致。
{"title":"Efficacy and Safety of Intravenous Secukinumab in Patients With Active Axial Spondyloarthritis: Results From the Randomized, Placebo-Controlled, Phase III INVIGORATE-1 Study.","authors":"Atul Deodhar,Jerzy Supronik,Alan Kivitz,Guillermo Valenzuela,Karen Kapur,Susanne Rohrer,Eva Dokoupilova,Hanno B Richards,Karel Pavelka","doi":"10.1002/art.42993","DOIUrl":"https://doi.org/10.1002/art.42993","url":null,"abstract":"OBJECTIVETo assess the efficacy and safety of intravenous (IV) secukinumab for the treatment of adults with active axial spondyloarthritis (axSpA) in INVIGORATE-1.METHODSINVIGORATE-1 (NCT04156620) was a randomized, double-blind, parallel-group, phase III trial in patients with active axSpA (either radiographic or non-radiographic). Patients were randomized 1:1 to receive IV secukinumab (6 mg/kg at baseline followed by 3 mg/kg every 4 weeks) or IV placebo for 16 weeks. After Week 16, patients randomized to placebo were switched to IV secukinumab (3 mg/kg every 4 weeks), while patients randomized to secukinumab continued treatment through Week 52. The primary endpoint was Assessment of SpondyloArthritis international Society (ASAS40) response at Week 16. Safety was evaluated through Week 60.RESULTSAmong patients initially randomized to IV secukinumab (n = 264) or placebo (n = 262), 86.0% and 88.9% completed the entire 60-week study period, respectively. A higher proportion of patients receiving secukinumab vs placebo met the primary endpoint (ASAS40 response) at Week 16 (40.9% vs 22.9%; P<.0001). By Week 24, patients who switched from placebo to secukinumab at Week 16 achieved ASAS40 response rates comparable to those in patients originally randomized to secukinumab. All secondary efficacy endpoints were met at Week 16, and responses were sustained through Week 52. No new or unexpected safety signals were observed with IV secukinumab.CONCLUSIONIV secukinumab was effective for the treatment of adults with active axSpA over 52 weeks. The safety profile was consistent with that in previous reports on subcutaneous secukinumab.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273538","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}
OBJECTIVETo evaluate the efficacy and safety of intravenous (IV) secukinumab in patients with active psoriatic arthritis (PsA).METHODSINVIGORATE-2 (NCT04209205) is a randomized, placebo-controlled, phase III trial. Patients with active PsA were randomized 1:1 to receive IV secukinumab (6 mg/kg at baseline followed by 3 mg/kg every 4 weeks [q4w]) or placebo. At Week 16, patients randomized to placebo were switched to IV secukinumab (3 mg/kg q4w), and patients receiving IV secukinumab continued treatment through Week 52. The primary efficacy endpoint was achievement of American College of Rheumatology (ACR) 50 response at Week 16. Efficacy and safety were evaluated through Weeks 52 and 60, respectively.RESULTSAmong 191 patients randomized to IV secukinumab and 190 to placebo/IV secukinumab, 177 (92.7%) and 170 (89.5%) completed the entire study period, respectively. A significantly higher proportion of patients receiving IV secukinumab vs placebo achieved ACR50 at Week 16 (31.4% vs 6.3%; adjusted P<.0001). All secondary efficacy endpoints were met at Week 16 (all adjusted P<.05 using the predefined hypothesis-testing hierarchy). Patients who switched from placebo to secukinumab at Week 16 showed rapid improvements in ACR50 response rates; by Week 52, both treatment arms experienced similar improvements in efficacy outcomes. No new or unexpected safety signals were observed with IV secukinumab. One death was reported in the placebo group prior to Week 16.CONCLUSIONIV secukinumab led to rapid and sustained improvements in clinical measures of PsA, and the safety profile was consistent with that of secukinumab administered subcutaneously.
目的评估活动性银屑病关节炎（PsA）患者静脉注射（IV）secukinumab的疗效和安全性。方法INVIGORATE-2（NCT04209205）是一项随机、安慰剂对照的III期试验。活动性PsA患者按1:1比例随机接受静脉注射secukinumab（基线剂量为6毫克/千克，之后每4周[q4w]剂量为3毫克/千克）或安慰剂。在第16周，随机接受安慰剂治疗的患者转为静脉注射secukinumab（3 mg/kg q4w），接受静脉注射secukinumab的患者继续治疗至第52周。主要疗效终点是在第16周时达到美国风湿病学会（ACR）50的应答水平。结果在191名随机接受静脉注射secukinumab治疗的患者和190名随机接受安慰剂/静脉注射secukinumab治疗的患者中，分别有177人（92.7%）和170人（89.5%）完成了整个研究。与安慰剂相比，接受IV secukinumab治疗的患者在第16周达到ACR50的比例明显更高（31.4% vs 6.3%；调整后P<.0001）。所有次要疗效终点均在第16周达到（采用预定义的假设检验层次，调整后P<.05）。在第16周从安慰剂转用secukinumab的患者的ACR50反应率迅速改善；到第52周时，两种治疗方案的疗效改善情况相似。静脉注射secukinumab未发现新的或意外的安全信号。结论静脉注射secukinumab能快速、持续地改善PsA的临床症状，其安全性与皮下注射secukinumab一致。
{"title":"Efficacy and Safety of Intravenous Secukinumab for the Treatment of Active Psoriatic Arthritis: Results From the Randomized, Placebo-Controlled Phase III INVIGORATE-2 Study.","authors":"Alan Kivitz,Liliana Sedova,Melvin Churchill,Roshan Kotha,Atul Singhal,Alexander Torres,Guillermo Valenzuela,Sarah Whelan,Thomas Dumortier,Xuan Zhu,Ruvie Martin,Luminita Pricop","doi":"10.1002/art.42997","DOIUrl":"https://doi.org/10.1002/art.42997","url":null,"abstract":"OBJECTIVETo evaluate the efficacy and safety of intravenous (IV) secukinumab in patients with active psoriatic arthritis (PsA).METHODSINVIGORATE-2 (NCT04209205) is a randomized, placebo-controlled, phase III trial. Patients with active PsA were randomized 1:1 to receive IV secukinumab (6 mg/kg at baseline followed by 3 mg/kg every 4 weeks [q4w]) or placebo. At Week 16, patients randomized to placebo were switched to IV secukinumab (3 mg/kg q4w), and patients receiving IV secukinumab continued treatment through Week 52. The primary efficacy endpoint was achievement of American College of Rheumatology (ACR) 50 response at Week 16. Efficacy and safety were evaluated through Weeks 52 and 60, respectively.RESULTSAmong 191 patients randomized to IV secukinumab and 190 to placebo/IV secukinumab, 177 (92.7%) and 170 (89.5%) completed the entire study period, respectively. A significantly higher proportion of patients receiving IV secukinumab vs placebo achieved ACR50 at Week 16 (31.4% vs 6.3%; adjusted P<.0001). All secondary efficacy endpoints were met at Week 16 (all adjusted P<.05 using the predefined hypothesis-testing hierarchy). Patients who switched from placebo to secukinumab at Week 16 showed rapid improvements in ACR50 response rates; by Week 52, both treatment arms experienced similar improvements in efficacy outcomes. No new or unexpected safety signals were observed with IV secukinumab. One death was reported in the placebo group prior to Week 16.CONCLUSIONIV secukinumab led to rapid and sustained improvements in clinical measures of PsA, and the safety profile was consistent with that of secukinumab administered subcutaneously.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273533","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":"Strength Training Is Associated With Less Knee Osteoarthritis: Data From the Osteoarthritis Initiative: comment on the article by Lo et al.","authors":"Yuncheng Bai,Yang Wu,Ge Wang","doi":"10.1002/art.42995","DOIUrl":"https://doi.org/10.1002/art.42995","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273535","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}
Jie Wei,Yilun Wang,Nicola Dalbeth,Junqing Xie,Jing Wu,Chao Zeng,Guanghua Lei,Yuqing Zhang
OBJECTIVESWeight loss is conditionally recommended for gout management; however, its impact on incident gout and recurrent gout flares among overweight and obese individuals remains unknown. We aimed to investigate the relationship between weight loss rate following the initiation of anti-obesity medications and the risk of incident gout and recurrent gout flares among overweight/obese individuals.METHODSUsing data from The Health Improvement Network, we selected individuals aged 18 and older who were overweight or obese and started anti-obesity medication. We emulated a target trial to examine the association of different weight loss rates, slow (2-5%), moderate (5-10%), or fast (≥10%), within the first year of treatment with incident gout and recurrent gout flares during a 5-year follow-up period.RESULTSAmong 131,000 participants without gout starting orlistat, the 5-year risk of incident gout was 1.6% for those with weight gain/stable, compared with 1.5%, 1.3%, and 1.2% for those with slow, moderate, and fast weight loss, respectively. Compared with the weight gain/stable arm, the hazard ratios were 0.91 (95% confidence interval [CI]: 0.81 to 1.01), 0.82 (95%CI: 0.72 to 0.92), and 0.73 (95%CI: 0.62 to 0.86) for slow, moderate and fast rate of weight loss arms, respectively. Similar results were observed for the recurrent gout flares among 3,847 overweight or obese individuals with gout starting orlistat.CONCLUSIONSA higher rate of weight loss after initiating orlistat within 1-year was associated with lower risks of incident gout and lower rates of recurrent gout flares among overweight or obese people.
{"title":"Weight loss after initiating anti-obesity medications and gout among overweight and obesity individuals: a population-based cohort study.","authors":"Jie Wei,Yilun Wang,Nicola Dalbeth,Junqing Xie,Jing Wu,Chao Zeng,Guanghua Lei,Yuqing Zhang","doi":"10.1002/art.42996","DOIUrl":"https://doi.org/10.1002/art.42996","url":null,"abstract":"OBJECTIVESWeight loss is conditionally recommended for gout management; however, its impact on incident gout and recurrent gout flares among overweight and obese individuals remains unknown. We aimed to investigate the relationship between weight loss rate following the initiation of anti-obesity medications and the risk of incident gout and recurrent gout flares among overweight/obese individuals.METHODSUsing data from The Health Improvement Network, we selected individuals aged 18 and older who were overweight or obese and started anti-obesity medication. We emulated a target trial to examine the association of different weight loss rates, slow (2-5%), moderate (5-10%), or fast (≥10%), within the first year of treatment with incident gout and recurrent gout flares during a 5-year follow-up period.RESULTSAmong 131,000 participants without gout starting orlistat, the 5-year risk of incident gout was 1.6% for those with weight gain/stable, compared with 1.5%, 1.3%, and 1.2% for those with slow, moderate, and fast weight loss, respectively. Compared with the weight gain/stable arm, the hazard ratios were 0.91 (95% confidence interval [CI]: 0.81 to 1.01), 0.82 (95%CI: 0.72 to 0.92), and 0.73 (95%CI: 0.62 to 0.86) for slow, moderate and fast rate of weight loss arms, respectively. Similar results were observed for the recurrent gout flares among 3,847 overweight or obese individuals with gout starting orlistat.CONCLUSIONSA higher rate of weight loss after initiating orlistat within 1-year was associated with lower risks of incident gout and lower rates of recurrent gout flares among overweight or obese people.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273534","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}
Matteo Bianchi, Sergey V. Kozyrev, Antonella Notarnicola, Johanna K. Sandling, Mats Pettersson, Dag Leonard, Christopher Sjöwall, Iva Gunnarsson, Solbritt Rantapää‐Dahlqvist, Anders A. Bengtsson, Andreas Jönsen, Elisabet Svenungsson, Helena Enocsson, Marika Kvarnström, Helena Forsblad‐d'Elia, Sara Magnusson Bucher, Katrine B. Norheim, Eva Baecklund, Roland Jonsson, Daniel Hammenfors, Per Eriksson, Thomas Mandl, Roald Omdal, Leonid Padyukov, Helena Andersson, Øyvind Molberg, Louise Pyndt Diederichsen, Ann‐Christine Syvänen, Marie Wahren‐Herlenius, Gunnel Nordmark, Ingrid E. Lundberg, Lars Rönnblom, Kerstin Lindblad‐Toh
OBJECTIVESSystemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study aimed at elucidating the genetics underlying these common features.METHODSWe performed targeted DNA sequencing of coding and regulatory regions from ~1,900 immune‐related genes in a large SIAD cohort of 2,292 well‐characterized Scandinavian patients with SLE, pSS and myositis, as well as 1,252 controls. A gene‐based functionally‐weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in‐silico functional analyses and in‐vitro reporter experiments.RESULTSCase‐control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case‐case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by ANA and anti‐dsDNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that DUSP1 protective genetic variants lead to increased gene expression and potentially to anti‐inflammatory effects on the SIAD‐associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported downregulation of the MAPK signaling‐related gene DUSP1 in other skin disorders.CONCLUSIONTogether, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.
目的系统性红斑狼疮（SLE）、原发性斯约格伦综合征（pSS）和特发性炎症性肌病（肌炎）等系统性炎症性自身免疫病（SIADs）是一种复杂的疾病，其特点是具有共同的循环自身抗体和临床表现，包括皮疹等。本研究旨在阐明这些共同特征的遗传学基础。方法 我们在一个由 2292 名特征明确的斯堪的纳维亚系统性红斑狼疮、特发性炎症性肌病和肌炎患者以及 1252 名对照者组成的大型 SIAD 队列中，对约 1900 个免疫相关基因的编码区和调控区进行了有针对性的 DNA 测序。结果病例对照关联分析发现了已知和潜在的新基因位点，这与之前与 SIAD 自身免疫背景相关的基因和转录组学发现一致。耐人寻味的是，对有和无特异性自身抗体的患者亚组进行病例比较后发现，由ANA和抗dsDNA抗体定义的亚组具有独特的遗传特征，反映了其异质性。在关注临床特征时，我们总体上表明，DUSP1 保护性遗传变异会导致基因表达增加，并可能对 SIAD 相关皮肤表型产生抗炎作用。这与最近关于湿疹的基因研究结果以及之前报道的其他皮肤疾病中 MAPK 信号相关基因 DUSP1 的下调结果一致。结论：这一研究结果表明，在不同疾病的重叠临床表现背后可能存在共同的分子机制，并为临床异质性提供了信息，这些信息可用于改善疾病诊断和治疗，也可用于更广泛的疾病框架中。
{"title":"Unraveling The Genetics of Shared Clinical and Serological Manifestations in Systemic Inflammatory Autoimmune Diseases","authors":"Matteo Bianchi, Sergey V. Kozyrev, Antonella Notarnicola, Johanna K. Sandling, Mats Pettersson, Dag Leonard, Christopher Sjöwall, Iva Gunnarsson, Solbritt Rantapää‐Dahlqvist, Anders A. Bengtsson, Andreas Jönsen, Elisabet Svenungsson, Helena Enocsson, Marika Kvarnström, Helena Forsblad‐d'Elia, Sara Magnusson Bucher, Katrine B. Norheim, Eva Baecklund, Roland Jonsson, Daniel Hammenfors, Per Eriksson, Thomas Mandl, Roald Omdal, Leonid Padyukov, Helena Andersson, Øyvind Molberg, Louise Pyndt Diederichsen, Ann‐Christine Syvänen, Marie Wahren‐Herlenius, Gunnel Nordmark, Ingrid E. Lundberg, Lars Rönnblom, Kerstin Lindblad‐Toh","doi":"10.1002/art.42988","DOIUrl":"https://doi.org/10.1002/art.42988","url":null,"abstract":"OBJECTIVESSystemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS) and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study aimed at elucidating the genetics underlying these common features.METHODSWe performed targeted DNA sequencing of coding and regulatory regions from ~1,900 immune‐related genes in a large SIAD cohort of 2,292 well‐characterized Scandinavian patients with SLE, pSS and myositis, as well as 1,252 controls. A gene‐based functionally‐weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by <jats:italic>in‐silico</jats:italic> functional analyses and <jats:italic>in‐vitro</jats:italic> reporter experiments.RESULTSCase‐control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case‐case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by ANA and anti‐dsDNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that <jats:italic>DUSP1</jats:italic> protective genetic variants lead to increased gene expression and potentially to anti‐inflammatory effects on the SIAD‐associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported downregulation of the MAPK signaling‐related gene <jats:italic>DUSP1</jats:italic> in other skin disorders.CONCLUSIONTogether, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236431","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}
Yin Wu, Aditee Deshpande, Nicholas Geraci, Petra Budde, Vera Sellers, Phanindra Velisetty, Chia‐Chi Sun, Fatima Strand, Carmina Bhavsar, Timothy B. Niewold, Mark A. Jensen, Irina Kalatskaya, Kavita Y. Sarin, David Fiorentino, Andrew T. Bender
ObjectiveActivation of endosomal toll‐like receptors (TLRs) is one possible driver of inflammation in idiopathic inflammatory myopathies (IIM). We investigated the potential contribution of TLR7 and TLR8 to IIM pathogenesis.MethodsActivation of TLR7/8 in healthy donor peripheral blood mononuclear cells (PBMCs) by immune complexes from patients with IIM and lupus was tested. Autoantibody profiling of patient IgG samples was performed using a 1581‐antigen array. TLR7 and/or TLR8 activation by RNA molecules associated with autoantibodies was assessed. Gene expression in human myoblasts and satellite cells following treatment with supernatants from TLR7/8‐activated PBMCs was evaluated by NanoString. C57BL/6 mice were dosed intramuscularly with the TLR7/8 agonist R848 and single‐cell RNA‐sequencing was performed on the muscle to ascertain the cell types responding to TLR7/8 activation and the downstream effects.ResultsOverall, 69 patients with IIM were included with representation of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) subsets. Immune complexes from patients with IIM, as well as autoantibody‐associated RNAs His‐tRNA, Y1, Y4 and U1, activated PBMCs to produce IFN‐α and IL‐6 via TLR7/8. Several canonical (Ro60, Ro52, HIST1H4A) and novel (IL‐36RN) autoreactivities correlated highly with TLR7/8 activation. Supernatants from TLR7/8‐activated PBMCs had a negative impact on human myoblasts and satellite cells. Endothelial cells were activated by R848 in mouse muscle in vivo, in addition to immune cells such as monocytes and macrophages.ConclusionOur results suggest that patients with IIM have autoantibodies in their blood causing TLR7/8 activation, which leads to inflammation in muscles with potential deleterious effects.image
{"title":"TLR7/8 Activation in Immune Cells and Muscle by RNA‐Containing Immune Complexes: Role in Inflammation and the Pathogenesis of Myositis","authors":"Yin Wu, Aditee Deshpande, Nicholas Geraci, Petra Budde, Vera Sellers, Phanindra Velisetty, Chia‐Chi Sun, Fatima Strand, Carmina Bhavsar, Timothy B. Niewold, Mark A. Jensen, Irina Kalatskaya, Kavita Y. Sarin, David Fiorentino, Andrew T. Bender","doi":"10.1002/art.42989","DOIUrl":"https://doi.org/10.1002/art.42989","url":null,"abstract":"ObjectiveActivation of endosomal toll‐like receptors (TLRs) is one possible driver of inflammation in idiopathic inflammatory myopathies (IIM). We investigated the potential contribution of TLR7 and TLR8 to IIM pathogenesis.MethodsActivation of TLR7/8 in healthy donor peripheral blood mononuclear cells (PBMCs) by immune complexes from patients with IIM and lupus was tested. Autoantibody profiling of patient IgG samples was performed using a 1581‐antigen array. TLR7 and/or TLR8 activation by RNA molecules associated with autoantibodies was assessed. Gene expression in human myoblasts and satellite cells following treatment with supernatants from TLR7/8‐activated PBMCs was evaluated by NanoString. C57BL/6 mice were dosed intramuscularly with the TLR7/8 agonist R848 and single‐cell RNA‐sequencing was performed on the muscle to ascertain the cell types responding to TLR7/8 activation and the downstream effects.ResultsOverall, 69 patients with IIM were included with representation of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) subsets. Immune complexes from patients with IIM, as well as autoantibody‐associated RNAs His‐tRNA, Y1, Y4 and U1, activated PBMCs to produce IFN‐α and IL‐6 via TLR7/8. Several canonical (Ro60, Ro52, HIST1H4A) and novel (IL‐36RN) autoreactivities correlated highly with TLR7/8 activation. Supernatants from TLR7/8‐activated PBMCs had a negative impact on human myoblasts and satellite cells. Endothelial cells were activated by R848 in mouse muscle <jats:italic>in vivo</jats:italic>, in addition to immune cells such as monocytes and macrophages.ConclusionOur results suggest that patients with IIM have autoantibodies in their blood causing TLR7/8 activation, which leads to inflammation in muscles with potential deleterious effects.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" mimetype=\"image/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic/art42989-toc-0001-m.png\"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236432","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}
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