Priyanka Yalamanchili, Lydia Y Lee, Greta Bushnell, Melissa L Mannion, Chintan V Dave, Daniel B Horton
Objective: The objective of this study is to describe recent trends in disease-modifying antirheumatic drug (DMARD) use for children with juvenile idiopathic arthritis (JIA) in the United States.
Methods: We used commercial claims data (2000-2022) to perform a serial cross-sectional utilization study of children aged 1 to 18 that were diagnosed with JIA. Initiations of conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), or targeted synthetic DMARDs (tsDMARDs) were identified after a ≥12-month baseline and expressed as a percentage of all new DMARD initiations per year, by category, class, and individual agent. Trends were evaluated using linear regression. We also examined the first bDMARDs and tsDMARDs initiated after csDMARD monotherapy.
Results: We identified 20,258 new DMARD use episodes among 13,696 individuals (median age 14 years, 67.5% female). csDMARDs, although most used overall, declined from 89.5% of new use episodes to 43.2% (2001-2022, P < 0.001 for trend). In contrast, bDMARD use increased (10.5-50.0%, P < 0.001). For tumor necrosis factor inhibitors (TNFi), etanercept peaked at 28.3% in 2006 and declined to 4.2% in 2022 (P = 0.002). Meanwhile, adalimumab use doubled (7.0-14.0%, 2007-2008) after JIA approval, increasing further following a less painful formulation release (20.5% in 2022, P < 0.001). However, overall TNFi use has declined with increasing use of other bDMARDs and tsDMARDs, particularly ustekinumab, secukinumab, and tofacitinib. By 2022, adalimumab was the most common b/tsDMARD initiated first after csDMARDs (77.8%).
Conclusion: Among commercially insured children with JIA in the United States, new b/tsDMARD use is rising and new csDMARD use is declining. For b/tsDMARDs, adalimumab is most used and is the predominant b/tsDMARD initiated first after csDMARDs. Patterns in DMARD use for JIA have evolved relative to multiple factors, including regulatory approvals and tolerability.
{"title":"Trends in New Use of Disease-Modifying Antirheumatic Drugs for Juvenile Idiopathic Arthritis Among Commercially Insured Children in the United States from 2001 to 2022.","authors":"Priyanka Yalamanchili, Lydia Y Lee, Greta Bushnell, Melissa L Mannion, Chintan V Dave, Daniel B Horton","doi":"10.1002/art.43041","DOIUrl":"10.1002/art.43041","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study is to describe recent trends in disease-modifying antirheumatic drug (DMARD) use for children with juvenile idiopathic arthritis (JIA) in the United States.</p><p><strong>Methods: </strong>We used commercial claims data (2000-2022) to perform a serial cross-sectional utilization study of children aged 1 to 18 that were diagnosed with JIA. Initiations of conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs), or targeted synthetic DMARDs (tsDMARDs) were identified after a ≥12-month baseline and expressed as a percentage of all new DMARD initiations per year, by category, class, and individual agent. Trends were evaluated using linear regression. We also examined the first bDMARDs and tsDMARDs initiated after csDMARD monotherapy.</p><p><strong>Results: </strong>We identified 20,258 new DMARD use episodes among 13,696 individuals (median age 14 years, 67.5% female). csDMARDs, although most used overall, declined from 89.5% of new use episodes to 43.2% (2001-2022, P < 0.001 for trend). In contrast, bDMARD use increased (10.5-50.0%, P < 0.001). For tumor necrosis factor inhibitors (TNFi), etanercept peaked at 28.3% in 2006 and declined to 4.2% in 2022 (P = 0.002). Meanwhile, adalimumab use doubled (7.0-14.0%, 2007-2008) after JIA approval, increasing further following a less painful formulation release (20.5% in 2022, P < 0.001). However, overall TNFi use has declined with increasing use of other bDMARDs and tsDMARDs, particularly ustekinumab, secukinumab, and tofacitinib. By 2022, adalimumab was the most common b/tsDMARD initiated first after csDMARDs (77.8%).</p><p><strong>Conclusion: </strong>Among commercially insured children with JIA in the United States, new b/tsDMARD use is rising and new csDMARD use is declining. For b/tsDMARDs, adalimumab is most used and is the predominant b/tsDMARD initiated first after csDMARDs. Patterns in DMARD use for JIA have evolved relative to multiple factors, including regulatory approvals and tolerability.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453973","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, Chao Zeng, Guanghua Lei, Yuqing Zhang
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{"title":"Reply to insights into “Weight loss after initiating anti-obesity medications and gout among overweight and obesity individuals”","authors":"Jie Wei, Yilun Wang, Chao Zeng, Guanghua Lei, Yuqing Zhang","doi":"10.1002/art.43043","DOIUrl":"https://doi.org/10.1002/art.43043","url":null,"abstract":"Click on the article title to read more.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"12 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451923","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}
Sigrid V. Hestetun, Hamid K. Rudsari, Piotr Jaholkowski, Alexey Shadrin, Kristine L. Haftorn, Svend Andersen, Marite Rygg, Ellen Nordal, Oleksandr Frei, Ole A. Andreassen, Anne M. Selvaag, Ketil Størdal, Helga Sanner
We aimed to investigate the incidence of juvenile idiopathic arthritis (JIA) in the three geographical regions of Norway, and whether potential regional incidence differences are explained by environmental or genetic factors across regions.
{"title":"Incidence and genetic risk of juvenile idiopathic arthritis in Norway by latitude","authors":"Sigrid V. Hestetun, Hamid K. Rudsari, Piotr Jaholkowski, Alexey Shadrin, Kristine L. Haftorn, Svend Andersen, Marite Rygg, Ellen Nordal, Oleksandr Frei, Ole A. Andreassen, Anne M. Selvaag, Ketil Størdal, Helga Sanner","doi":"10.1002/art.43040","DOIUrl":"https://doi.org/10.1002/art.43040","url":null,"abstract":"We aimed to investigate the incidence of juvenile idiopathic arthritis (JIA) in the three geographical regions of Norway, and whether potential regional incidence differences are explained by environmental or genetic factors across regions.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"40 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451924","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}
Kevin Sheng-Kai Ma, Jui-En Lo, Vasileios C. Kyttaris, George C. Tsokos, Karen H. Costenbader
Patients with systemic lupus erythematosus (SLE) were excluded from sodium-glucose co-transporter 2 inhibitors (SGLT2i) clinical trials. It is unknown whether the cardiorenal benefits of SGLT2i extend to patients with SLE and comorbid type 2 diabetes (T2D).
{"title":"Efficacy and Safety of Sodium-Glucose Co-Transporter 2 Inhibitors for the Primary Prevention of Cardiovascular, Renal Events and Safety Outcomes in Patients with Systemic Lupus Erythematosus and Comorbid Type 2 Diabetes: A Population-based Target Trial Emulation","authors":"Kevin Sheng-Kai Ma, Jui-En Lo, Vasileios C. Kyttaris, George C. Tsokos, Karen H. Costenbader","doi":"10.1002/art.43037","DOIUrl":"https://doi.org/10.1002/art.43037","url":null,"abstract":"Patients with systemic lupus erythematosus (SLE) were excluded from sodium-glucose co-transporter 2 inhibitors (SGLT2i) clinical trials. It is unknown whether the cardiorenal benefits of SGLT2i extend to patients with SLE and comorbid type 2 diabetes (T2D).","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"1 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451935","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, Stefania Vio, Marta Sbaraglia, Fabrizio Vianello, Roberta Ramonda
We are describing an unusual presentation of Erdheim-Chester Disease (ECD), a non -Langerhans histiocytosis provoked by abnormal aggregation of foamy histiocytes in several organs and systems. Our patient, already with osteoporosis, presented severe bilateral ankle pain with functional impairment, clinically mimicking “Complex Regional Pain Syndrome” (CRPS); the radiological images and subsequently the bone biopsy were fundamental for achieving the proper diagnosis. The diagnosis was challenging given the isolated bone localization which is uncommonly seen in ECD.
{"title":"A rare and misleading condition: isolated skeletal involvement of Erdheim-Chester Disease","authors":"Sara Bindoli, Stefania Vio, Marta Sbaraglia, Fabrizio Vianello, Roberta Ramonda","doi":"10.1002/art.43039","DOIUrl":"https://doi.org/10.1002/art.43039","url":null,"abstract":"We are describing an unusual presentation of Erdheim-Chester Disease (ECD), a non -Langerhans histiocytosis provoked by abnormal aggregation of foamy histiocytes in several organs and systems. Our patient, already with osteoporosis, presented severe bilateral ankle pain with functional impairment, clinically mimicking “Complex Regional Pain Syndrome” (CRPS); the radiological images and subsequently the bone biopsy were fundamental for achieving the proper diagnosis. The diagnosis was challenging given the isolated bone localization which is uncommonly seen in ECD.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"32 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451920","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}
Runa Kuley, Bhargavi Duvvuri, Sabeeha Hasnain, Ernst R. Dow, Alisa E. Koch, Richard E. Higgs, Venkatesh Krishnan, Christian Lood
Neutrophils play an important role in regulating immune and inflammatory responses in rheumatoid arthritis (RA). We assessed whether baricitinib, a JAK1/JAK2 inhibitor, could reduce neutrophil activation, and whether a neutrophil activation score could predict treatment response.
{"title":"Neutrophil activation markers can predict rheumatoid arthritis treatment response to the Janus Kinase 1/2 inhibitor baricitinib","authors":"Runa Kuley, Bhargavi Duvvuri, Sabeeha Hasnain, Ernst R. Dow, Alisa E. Koch, Richard E. Higgs, Venkatesh Krishnan, Christian Lood","doi":"10.1002/art.43042","DOIUrl":"https://doi.org/10.1002/art.43042","url":null,"abstract":"Neutrophils play an important role in regulating immune and inflammatory responses in rheumatoid arthritis (RA). We assessed whether baricitinib, a JAK1/JAK2 inhibitor, could reduce neutrophil activation, and whether a neutrophil activation score could predict treatment response.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"1 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451921","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}
Joshua F. Baker, George Reed, Ted R. Mikuls, Geoffrey M. Thiele, Dimitrios A. Pappas, Christina Charles‐Schoeman, Monica Guma, Leslie R. Harrold, Jeffrey R. Curtis, Joel M. Kremer
PurposeWe determined if metabolic syndrome, its components, and adipokines (adiponectin, leptin, Fibroblast Growth Factor‐21) were associated with response to advanced therapies among patients with rheumatoid arthritis (RA).MethodsThis study included participants with RA initiating either TNFi or non‐TNFi biologic therapies from the Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory Conditions (CERTAIN) cohort within the CorEvitas registry. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III definition. Adipokines were assessed on stored samples from a sub‐sample of responders and non‐responders (N=200). The primary outcome was the achievement of a change as large as the minimal clinically important difference (MCID) for the Clinical Disease Activity Index (CDAI) at 6 months.ResultsAmong 2,368 participants, 687 (29%) had metabolic syndrome. Metabolic syndrome was associated with lower odds of achieving CDAI MCID [OR (95% CI): 0.69 (0.56,0.86) p=0.001] with a dose‐dependent decrease in response rate according to the number of components present. Model fit was superior for metabolic syndrome compared to BMI. Associations between metabolic syndrome and MCID achievement were similar between patients receiving TNFi [OR (95% CI): 0.65 (0.49,0.87) p=0.003] v. non‐TNF therapies [OR (95% CI): 0.76 (0.55,1.04) p=0.08)] (p‐for‐interaction=0.49). Adipokines were not associated with MCID achievement.ConclusionsMetabolic syndrome is associated with lower response rates with the initiation of an advanced therapy in RA, with similar effects for both TNFi and non‐TNFi agents. Adipokines were strongly associated with metabolic syndrome but were not associated with clinical response.
{"title":"Metabolic Syndrome, Adipokines, and Response to Advanced Therapies in Rheumatoid Arthritis","authors":"Joshua F. Baker, George Reed, Ted R. Mikuls, Geoffrey M. Thiele, Dimitrios A. Pappas, Christina Charles‐Schoeman, Monica Guma, Leslie R. Harrold, Jeffrey R. Curtis, Joel M. Kremer","doi":"10.1002/art.43034","DOIUrl":"https://doi.org/10.1002/art.43034","url":null,"abstract":"PurposeWe determined if metabolic syndrome, its components, and adipokines (adiponectin, leptin, Fibroblast Growth Factor‐21) were associated with response to advanced therapies among patients with rheumatoid arthritis (RA).MethodsThis study included participants with RA initiating either TNFi or non‐TNFi biologic therapies from the <jats:italic>C</jats:italic>omparative <jats:italic>E</jats:italic>ffectiveness <jats:italic>R</jats:italic>egistry to study <jats:italic>T</jats:italic>herapies for <jats:italic>A</jats:italic>rthritis and <jats:italic>I</jats:italic>nflammatory Co<jats:italic>n</jats:italic>ditions (CERTAIN) cohort within the CorEvitas registry. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III definition. Adipokines were assessed on stored samples from a sub‐sample of responders and non‐responders (N=200). The primary outcome was the achievement of a change as large as the minimal clinically important difference (MCID) for the Clinical Disease Activity Index (CDAI) at 6 months.ResultsAmong 2,368 participants, 687 (29%) had metabolic syndrome. Metabolic syndrome was associated with lower odds of achieving CDAI MCID [OR (95% CI): 0.69 (0.56,0.86) p=0.001] with a dose‐dependent decrease in response rate according to the number of components present. Model fit was superior for metabolic syndrome compared to BMI. Associations between metabolic syndrome and MCID achievement were similar between patients receiving TNFi [OR (95% CI): 0.65 (0.49,0.87) p=0.003] v. non‐TNF therapies [OR (95% CI): 0.76 (0.55,1.04) p=0.08)] (p‐for‐interaction=0.49). Adipokines were not associated with MCID achievement.ConclusionsMetabolic syndrome is associated with lower response rates with the initiation of an advanced therapy in RA, with similar effects for both TNFi and non‐TNFi agents. Adipokines were strongly associated with metabolic syndrome but were not associated with clinical response.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"23 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448663","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}
Veerle F. A. M. Derksen, Klara Martinsson, Anouk G. van Mourik, Carlijn A. Wagenaar, René E. M. Toes, Wendy Walrabenstein, Daniel Sjöberg, Dirkjan van Schaardenburg, Tom W. J. Huizinga, Alf Kastbom, Anna Svärd, Diane van der Woude
ObjectiveAnti‐citrullinated protein antibodies (ACPA) have been detected in sputum and saliva, indicating that anti‐modified protein antibodies (AMPA) can be produced at mucosal sites in rheumatoid arthritis (RA) patients. However, the body's largest mucosal compartment, the gut, has not yet been examined. We therefore investigated the presence of several AMPA (antibodies against citrullinated (ACPA), carbamylated (anti‐CarP) and acetylated (AAPA) proteins) at different mucosal sites, including the intestinal tract.MethodsPaired fecal/ileal wash, saliva and serum samples of RA patients and healthy volunteers were collected in two independent cohorts. Data involving feces was replicated in a third cohort. In these secretions AMPA were analyzed using in‐house ELISA with unmodified peptides as control. In fecal samples total IgA and anti‐E. coli IgA were measured.ResultsACPA, anti‐CarP and AAPA IgA were measurable in saliva of seropositive RA patients (prevalence 9‐40%). No AMPA could be detected in feces. IgA was present since total IgA and anti‐E. coli IgA was detectable in feces of ACPA‐positive RA patients and healthy donors. Results were confirmed in another cohort using colonoscopically collected ileal wash samples.ConclusionOur study shows the presence of ACPA, anti‐CarP and AAPA IgA in saliva of ACPA‐seropositive RA patients. However, no AMPA could be detected in feces/ileal wash samples of these patients, although our assays were able to measure other antigen‐specific antibodies. These data suggest that mucosal autoantibody secretion may occur in the oral mucosa of RA patients, while no evidence could be found for this process in the lower gastro‐intestinal tract.
目的在痰液和唾液中检测到抗瓜氨酸蛋白抗体（ACPA），表明类风湿性关节炎（RA）患者的粘膜部位可能产生抗修饰蛋白抗体（AMPA）。然而，对人体最大的粘膜区--肠道--尚未进行研究。因此，我们研究了包括肠道在内的不同粘膜部位是否存在几种 AMPA（针对瓜氨酸化蛋白（ACPA）、氨甲酰化蛋白（抗 CarP）和乙酰化蛋白（AAPA）的抗体）。涉及粪便的数据在第三个队列中进行了重复。采用内部 ELISA 法分析这些分泌物中的 AMPA，并以未修饰的肽作为对照。在粪便样本中检测了总 IgA 和抗大肠杆菌 IgA。结果 在血清阳性 RA 患者的唾液中可检测到 AMPA、抗 CARP 和 AAPA IgA（发病率为 9-40%）。粪便中检测不到 AMPA。ACPA阳性RA患者和健康供体的粪便中可检测到总IgA和抗大肠杆菌IgA，因此存在IgA。结论：我们的研究表明，ACPA 血清阳性 RA 患者的唾液中存在 ACPA、抗 CarP 和 AAPA IgA。然而，在这些患者的粪便/回肠洗液样本中检测不到 AMPA，尽管我们的检测方法能够检测到其他抗原特异性抗体。这些数据表明，RA 患者的口腔黏膜可能会分泌黏膜自身抗体，而在下胃肠道却找不到这一过程的证据。
{"title":"Anti‐modified protein antibodies can be detected in saliva, but not in intestinal secretions of seropositive rheumatoid arthritis patients – evidence of site‐specific mucosal autoantibody secretion in RA","authors":"Veerle F. A. M. Derksen, Klara Martinsson, Anouk G. van Mourik, Carlijn A. Wagenaar, René E. M. Toes, Wendy Walrabenstein, Daniel Sjöberg, Dirkjan van Schaardenburg, Tom W. J. Huizinga, Alf Kastbom, Anna Svärd, Diane van der Woude","doi":"10.1002/art.43036","DOIUrl":"https://doi.org/10.1002/art.43036","url":null,"abstract":"ObjectiveAnti‐citrullinated protein antibodies (ACPA) have been detected in sputum and saliva, indicating that anti‐modified protein antibodies (AMPA) can be produced at mucosal sites in rheumatoid arthritis (RA) patients. However, the body's largest mucosal compartment, the gut, has not yet been examined. We therefore investigated the presence of several AMPA (antibodies against citrullinated (ACPA), carbamylated (anti‐CarP) and acetylated (AAPA) proteins) at different mucosal sites, including the intestinal tract.MethodsPaired fecal/ileal wash, saliva and serum samples of RA patients and healthy volunteers were collected in two independent cohorts. Data involving feces was replicated in a third cohort. In these secretions AMPA were analyzed using in‐house ELISA with unmodified peptides as control. In fecal samples total IgA and anti‐E. coli IgA were measured.ResultsACPA, anti‐CarP and AAPA IgA were measurable in saliva of seropositive RA patients (prevalence 9‐40%). No AMPA could be detected in feces. IgA was present since total IgA and anti‐E. coli IgA was detectable in feces of ACPA‐positive RA patients and healthy donors. Results were confirmed in another cohort using colonoscopically collected ileal wash samples.ConclusionOur study shows the presence of ACPA, anti‐CarP and AAPA IgA in saliva of ACPA‐seropositive RA patients. However, no AMPA could be detected in feces/ileal wash samples of these patients, although our assays were able to measure other antigen‐specific antibodies. These data suggest that mucosal autoantibody secretion may occur in the oral mucosa of RA patients, while no evidence could be found for this process in the lower gastro‐intestinal tract.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"7 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448671","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}
Mehmet Hocaoglu, Desiré Casares‐Marfil, Amr H. Sawalha
ObjectiveAntinuclear antibodies (ANA) are detected in up to 14% of the population, and the majority of individuals with ANA are asymptomatic. The literature on the genetic contribution to asymptomatic ANA positivity in the population is limited. In this study, we aimed to perform a genome‐wide association study (GWAS) of asymptomatic ANA positivity in multiple populations.MethodsAsymptomatic ANA positive and negative individuals from the All of Us Research Program were included in this study, selecting those with an ANA test by immunofluorescence and no evidence of autoimmune disease. Imputation was performed and a multi‐population meta‐analysis including approximately 6 million single‐nucleotide polymorphisms (SNPs) was conducted. Genome‐wide SNP based heritability was estimated using the GCTA software. A cumulative genetic risk score for lupus was constructed using previously reported genome‐wide significant loci.Results1,955 asymptomatic ANA positive and 3,634 asymptomatic ANA negative individuals were included across three genetic populations. The multi‐population meta‐analysis revealed SNPs with a suggestive association (p‐value < 1×10‐5) across 8 different loci, but no genome‐wide significant loci were identified. A gene variant upstream of HLA‐DQB1 (rs17211748, P = 1.4×10‐6, OR = 0.82, 95% CI 0.76‐0.89) showed the most significant association. The heritability of asymptomatic ANA positivity was estimated to be 24.9%. Asymptomatic ANA positive individuals did not exhibit increased cumulative genetic risk for lupus compared to ANA negative individuals.ConclusionANA production is not associated with significant genetic risk and is primarily determined by environmental factors.image
目的：多达 14% 的人群中可检测到抗核抗体 (ANA)，而大多数 ANA 患者是无症状的。有关人群中无症状 ANA 阳性的遗传贡献的文献十分有限。本研究旨在对多个人群中的无症状 ANA 阳性进行全基因组关联研究（GWAS）。研究方法纳入 "我们所有人研究计划 "中的无症状 ANA 阳性和阴性个体，选择那些通过免疫荧光法进行 ANA 检测且无自身免疫性疾病证据的个体。研究人员进行了估算，并进行了多人群荟萃分析，其中包括约 600 万个单核苷酸多态性 (SNP)。使用 GCTA 软件估算了基于 SNP 的全基因组遗传率。利用之前报告的全基因组重要基因位点，构建了狼疮累积遗传风险评分。多人群荟萃分析揭示了 8 个不同位点上具有提示性关联的 SNPs（p-value <1×10-5），但未发现具有全基因组意义的位点。HLA-DQB1上游的一个基因变异（rs17211748，P = 1.4×10-6，OR = 0.82，95% CI 0.76-0.89）显示了最显著的相关性。无症状 ANA 阳性的遗传率估计为 24.9%。与 ANA 阴性个体相比，无症状 ANA 阳性个体患红斑狼疮的累积遗传风险并没有增加。
{"title":"Genetic analysis of asymptomatic antinuclear antibody production","authors":"Mehmet Hocaoglu, Desiré Casares‐Marfil, Amr H. Sawalha","doi":"10.1002/art.43032","DOIUrl":"https://doi.org/10.1002/art.43032","url":null,"abstract":"ObjectiveAntinuclear antibodies (ANA) are detected in up to 14% of the population, and the majority of individuals with ANA are asymptomatic. The literature on the genetic contribution to asymptomatic ANA positivity in the population is limited. In this study, we aimed to perform a genome‐wide association study (GWAS) of asymptomatic ANA positivity in multiple populations.MethodsAsymptomatic ANA positive and negative individuals from the All of Us Research Program were included in this study, selecting those with an ANA test by immunofluorescence and no evidence of autoimmune disease. Imputation was performed and a multi‐population meta‐analysis including approximately 6 million single‐nucleotide polymorphisms (SNPs) was conducted. Genome‐wide SNP based heritability was estimated using the GCTA software. A cumulative genetic risk score for lupus was constructed using previously reported genome‐wide significant loci.Results1,955 asymptomatic ANA positive and 3,634 asymptomatic ANA negative individuals were included across three genetic populations. The multi‐population meta‐analysis revealed SNPs with a suggestive association (p‐value < 1×10<jats:sup>‐5</jats:sup>) across 8 different loci, but no genome‐wide significant loci were identified. A gene variant upstream of <jats:italic>HLA‐DQB1</jats:italic> (rs17211748, <jats:italic>P</jats:italic> = 1.4×10<jats:sup>‐6</jats:sup>, OR = 0.82, 95% CI 0.76‐0.89) showed the most significant association. The heritability of asymptomatic ANA positivity was estimated to be 24.9%. Asymptomatic ANA positive individuals did not exhibit increased cumulative genetic risk for lupus compared to ANA negative individuals.ConclusionANA production is not associated with significant genetic risk and is primarily determined by environmental factors.<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/art43032-toc-0001-m.png\"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"40 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449503","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}
Jessica Bryon, Christopher W Wasson, Katja Koeppen, Francesca Chandler, Leon F Willis, Stefano Di Donato, Elliott Klein, Elton Zeqiraj, Rebecca L Ross, Francesco Del Galdo
BackgroundActivation of Type I IFN response has been shown to correlates with disease activity in systemic sclerosis. It is currently unknown whether the tissue‐specific Type I IFN activation is a consequence of the response observed in blood or rather its source. Exosomes from SSc fibroblasts were recently shown to activate macrophages in vitro. Here, we aimed to determine the source of Type I IFN signature in SSc skin biopsies and the potential role of exosomes from SSc dermal fibroblasts in the process.MethodsSkin biopsies were obtained from healthy and SSc patients’ forearms and processed for dermal fibroblasts and keratinocytes. Exosomes were isolated from healthy and SSc dermal fibroblast supernatants by ultracentrifugation and added to human skin keratinocytes. Keratinocyte transcriptome was analysed by RNA‐seq analysis. TANK‐binding kinase (TBK) and JAK were inhibited using a small molecule inhibitor (GSK8612) and Tofacitinib, respectively.ResultsSSc skin biopsies showed highest levels of Type I IFN response in the epidermal layer. RNA‐seq analysis of keratinocytes transcriptome following exposure to dermal fibroblast exosomes showed strong upregulation of IFN signature genes induced by SSc exosomes compared to Healthy control. Inhibition of TBK or JAK activity suppressed the upregulation of the IFN signature induced by SSc exosomes.ConclusionIFN activation of SSc keratinocytes is dependent on their crosstalk with dermal fibroblasts and inducible by extracellular exosomes. Our data indicates that SSc fibroblasts exosomes contributes to theType I IFN activation in SSc skin through activation of pattern recognition receptors upstream of TBK.
背景I型IFN反应的激活已被证明与系统性硬化症的疾病活动有关。目前尚不清楚组织特异性 I 型 IFN 激活是血液中观察到的反应的结果还是其来源。最近有研究表明，来自 SSc 成纤维细胞的外泌体可在体外激活巨噬细胞。在此，我们旨在确定 SSc 皮肤活检组织中 I 型 IFN 特征的来源，以及 SSc 皮肤成纤维细胞的外泌体在这一过程中的潜在作用。通过超速离心从健康和 SSc 皮肤成纤维细胞上清液中分离出外泌体，并将其添加到人类皮肤角质细胞中。通过RNA-seq分析对角质细胞转录组进行了分析。分别使用小分子抑制剂（GSK8612）和托法替尼抑制 TANK 结合激酶（TBK）和 JAK。与健康对照组相比，暴露于真皮成纤维细胞外泌体后的角朊细胞转录组的RNA-seq分析表明，SSc外泌体诱导的IFN特征基因有很强的上调。结论IFN对SSc角质形成细胞的激活依赖于它们与真皮成纤维细胞的串联，并可由细胞外的外泌体诱导。我们的数据表明，SSc成纤维细胞外泌体通过激活TBK上游的模式识别受体，促进了SSc皮肤中I型IFN的激活。
{"title":"Systemic Sclerosis dermal fibroblast exosomes trigger a Type 1 interferon response in keratinocytes through the TBK/JAK/STAT signalling axis","authors":"Jessica Bryon, Christopher W Wasson, Katja Koeppen, Francesca Chandler, Leon F Willis, Stefano Di Donato, Elliott Klein, Elton Zeqiraj, Rebecca L Ross, Francesco Del Galdo","doi":"10.1002/art.43029","DOIUrl":"https://doi.org/10.1002/art.43029","url":null,"abstract":"BackgroundActivation of Type I IFN response has been shown to correlates with disease activity in systemic sclerosis. It is currently unknown whether the tissue‐specific Type I IFN activation is a consequence of the response observed in blood or rather its source. Exosomes from SSc fibroblasts were recently shown to activate macrophages <jats:italic>in vitro</jats:italic>. Here, we aimed to determine the source of Type I IFN signature in SSc skin biopsies and the potential role of exosomes from SSc dermal fibroblasts in the process.MethodsSkin biopsies were obtained from healthy and SSc patients’ forearms and processed for dermal fibroblasts and keratinocytes. Exosomes were isolated from healthy and SSc dermal fibroblast supernatants by ultracentrifugation and added to human skin keratinocytes. Keratinocyte transcriptome was analysed by RNA‐seq analysis. TANK‐binding kinase (TBK) and JAK were inhibited using a small molecule inhibitor (GSK8612) and Tofacitinib, respectively.ResultsSSc skin biopsies showed highest levels of Type I IFN response in the epidermal layer. RNA‐seq analysis of keratinocytes transcriptome following exposure to dermal fibroblast exosomes showed strong upregulation of IFN signature genes induced by SSc exosomes compared to Healthy control. Inhibition of TBK or JAK activity suppressed the upregulation of the IFN signature induced by SSc exosomes.ConclusionIFN activation of SSc keratinocytes is dependent on their crosstalk with dermal fibroblasts and inducible by extracellular exosomes. Our data indicates that SSc fibroblasts exosomes contributes to theType I IFN activation in SSc skin through activation of pattern recognition receptors upstream of TBK.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"13 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448674","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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