Objective Dysregulated type I interferon (IFN) signaling contributes to autoimmune myositis pathogenesis. We investigated the therapeutic effects of JAK inhibitors in two mouse models. We also examined how type I IFNs affect muscle vasculature. Methods Myositis was induced in MHC class I transgenic (HT) female mice at day 21. Mice were randomized into four groups (n=10‐11/group): baricitinib (10 mg/kg), tofacitinib (20 mg/kg), vehicle, and healthy controls. Outcomes included survival, weight, muscle strength, histopathology, and IFN stimulated gene expression. To model IFNβ overexpression, C57BL/6 mice received AAV9‐tMCK‐IFNβ and were treated with vehicle or tofacitinib (40 mg/kg/day) for 10 weeks (n=8‐13/group). Results Tofacitinib—but not baricitinib—significantly reduced IFN scores in severe myositis mice (p<0.05). Survival differed across groups (overall log‐rank p<0.01), with untreated‐ and baricitinib‐treated HT mice showing shorter survival than BL/6 controls, while tofacitinib‐treated mice did not differ from controls. IFNβ overexpression induced muscle inflammation (p<0.01), reduced grip strength (p<0.0001), and increased the IFN score (p<0.0001) and H2Kb (p<0.0001) expression. Conclusion Tofacitinib reduced the IFN signature, and survival in this group did not differ significantly from healthy controls, whereas untreated‐ and baricitinib‐treated HT mice showed shorter survival; functional improvement was not observed. Our results also show that type I IFN signaling contributes to muscle inflammation and weakness, making it a key driver of muscle damage and thereby reinforcing its potential as a therapeutic target. image
{"title":"Investigating the role of Type I Interferon Signaling on Muscle Disease using mouse models","authors":"Rita Spathis, Sabrina Narvesen, Deeva Robles Kuriplach, Karen Huang, Teja Sundar, Elizabeth Bagley, Joanna E Parkes, Xinyu Jia, Nandhana Sudhan, Alfredo Guzman, Kanneboyina Nagaraju, Melissa Morales","doi":"10.1002/art.70096","DOIUrl":"https://doi.org/10.1002/art.70096","url":null,"abstract":"Objective Dysregulated type I interferon (IFN) signaling contributes to autoimmune myositis pathogenesis. We investigated the therapeutic effects of JAK inhibitors in two mouse models. We also examined how type I IFNs affect muscle vasculature. Methods Myositis was induced in MHC class I transgenic (HT) female mice at day 21. Mice were randomized into four groups (n=10‐11/group): baricitinib (10 mg/kg), tofacitinib (20 mg/kg), vehicle, and healthy controls. Outcomes included survival, weight, muscle strength, histopathology, and IFN stimulated gene expression. To model IFNβ overexpression, C57BL/6 mice received AAV9‐tMCK‐IFNβ and were treated with vehicle or tofacitinib (40 mg/kg/day) for 10 weeks (n=8‐13/group). Results Tofacitinib—but not baricitinib—significantly reduced IFN scores in severe myositis mice (p<0.05). Survival differed across groups (overall log‐rank p<0.01), with untreated‐ and baricitinib‐treated HT mice showing shorter survival than BL/6 controls, while tofacitinib‐treated mice did not differ from controls. IFNβ overexpression induced muscle inflammation (p<0.01), reduced grip strength (p<0.0001), and increased the IFN score (p<0.0001) and H2Kb (p<0.0001) expression. Conclusion Tofacitinib reduced the IFN signature, and survival in this group did not differ significantly from healthy controls, whereas untreated‐ and baricitinib‐treated HT mice showed shorter survival; functional improvement was not observed. Our results also show that type I IFN signaling contributes to muscle inflammation and weakness, making it a key driver of muscle damage and thereby reinforcing its potential as a therapeutic target. <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/art70096-toc-0001-m.png\"> <jats:alt-text>image</jats:alt-text> </jats:graphic> </jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"33 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215624","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}
Wenyan Sun, Lingfang Xu, Haibing Chen, Mingshu Sun, Zhiqiang Li, Rui Li, Lidan Ma, Hui Zhang, Aichang Ji, Yuwei He, Na Wu, Le Yan, Robert Terkeltaub, Changgui Li
Objective This study investigated that serum metabolomics, prior to ULT initiation, could serve as a biomarker for responsiveness to colchicine prophylaxis in patients with gout commencing treat‐to‐target ULT. Methods We studied a multicenter prospective cohort (n=409) initiating treat‐to‐target ULT plus colchicine prophylaxis. Untargeted metabolomics were measured at enrollment. We defined putative colchicine‐response or colchicine non‐response as no‐flare, or > 1 flare, respectively, during 6 months after first colchicine dose. Cox regression and machine learning models defined the metabolomic signatures associated with reported flare activity on colchicine prophylaxis in the cohort. Results In our cohort, 36.9% participants experienced at least one flare. Many inflammation‐related metabolites were differentially abundant in the recurrent flare group and correlated with recurrent flare risk. A significant association was found between a four‐metabolite risk score and gout flare activity (adjusted hazard ratio 3.21, 95% CI 2.24‐4.59), independent of the adjusted clinical factors. The machine learning model, which incorporated the top‐ranked metabolites selected by MUVR along with traditional clinical factors, reached an area under the receiver operating characteristic of 0.771 (95% CI 0.713‐0.828) and 0.724 (95% CI 0.611‐0.837) for predicting flare risk in the discovery and validation cohort, respectively. Conclusions Metabolomic profile‐defined inflammation status was associated with gout flare outcomes in ULT initiators receiving colchicine prophylaxis. Identification of these novel metabolomic predictive signatures prior to ULT could potentially help optimize clinical decision‐making for flare prophylaxis colchicine dosing and duration in the first 6 months after initiation of treat‐to‐target ULT in gout. image
目的：本研究探讨了ULT开始前的血清代谢组学可以作为痛风患者对秋水仙碱预防反应性的生物标志物。方法：我们研究了一项多中心前瞻性队列研究（n=409），开始治疗-目标ULT加秋水仙碱预防。在入组时测量非靶向代谢组学。我们将假定的秋水仙碱反应或秋水仙碱无反应分别定义为在首次服用秋水仙碱后6个月内无耀斑或1耀斑。Cox回归和机器学习模型定义了代谢组学特征与报道的秋水仙碱预防的耀斑活性相关。结果在我们的队列中，36.9%的参与者至少经历过一次耀斑。许多炎症相关代谢物在复发性耀斑组中差异丰富，并与复发性耀斑风险相关。发现四种代谢物风险评分与痛风发作活动之间存在显著关联（校正风险比3.21,95% CI 2.24‐4.59），独立于校正临床因素。机器学习模型将MUVR选择的最高代谢物与传统临床因素结合在一起，在预测发现和验证队列中，受试者工作特征下的区域分别达到0.771 （95% CI 0.713‐0.828）和0.724 （95% CI 0.611‐0.837）。结论：代谢组学特征定义的炎症状态与接受秋水仙碱预防的ULT启动者的痛风爆发结果相关。在ULT治疗前识别这些新的代谢组学预测特征，可能有助于优化痛风治疗开始后6个月内秋水仙碱剂量和持续时间的临床决策。图像
{"title":"A Metabolomic Signature Predicts Gout Flare Clinical Outcome Associated with Colchicine Prophylaxis","authors":"Wenyan Sun, Lingfang Xu, Haibing Chen, Mingshu Sun, Zhiqiang Li, Rui Li, Lidan Ma, Hui Zhang, Aichang Ji, Yuwei He, Na Wu, Le Yan, Robert Terkeltaub, Changgui Li","doi":"10.1002/art.70094","DOIUrl":"https://doi.org/10.1002/art.70094","url":null,"abstract":"Objective This study investigated that serum metabolomics, prior to ULT initiation, could serve as a biomarker for responsiveness to colchicine prophylaxis in patients with gout commencing treat‐to‐target ULT. Methods We studied a multicenter prospective cohort (n=409) initiating treat‐to‐target ULT plus colchicine prophylaxis. Untargeted metabolomics were measured at enrollment. We defined putative colchicine‐response or colchicine non‐response as no‐flare, or <jats:styled-content>></jats:styled-content> 1 flare, respectively, during 6 months after first colchicine dose. Cox regression and machine learning models defined the metabolomic signatures associated with reported flare activity on colchicine prophylaxis in the cohort. Results In our cohort, 36.9% participants experienced at least one flare. Many inflammation‐related metabolites were differentially abundant in the recurrent flare group and correlated with recurrent flare risk. A significant association was found between a four‐metabolite risk score and gout flare activity (adjusted hazard ratio 3.21, 95% CI 2.24‐4.59), independent of the adjusted clinical factors. The machine learning model, which incorporated the top‐ranked metabolites selected by MUVR along with traditional clinical factors, reached an area under the receiver operating characteristic of 0.771 (95% CI 0.713‐0.828) and 0.724 (95% CI 0.611‐0.837) for predicting flare risk in the discovery and validation cohort, respectively. Conclusions Metabolomic profile‐defined inflammation status was associated with gout flare outcomes in ULT initiators receiving colchicine prophylaxis. Identification of these novel metabolomic predictive signatures prior to ULT could potentially help optimize clinical decision‐making for flare prophylaxis colchicine dosing and duration in the first 6 months after initiation of treat‐to‐target ULT in gout. <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/art70094-toc-0001-m.png\"> <jats:alt-text>image</jats:alt-text> </jats:graphic> </jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"7 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146215626","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}
Javad Rahimikollu, Priyamvada Guha Roy, Akash Kishore, Danica Morgan Lee, Lauren A Vanderlinden, Kiran Nazarali, Fan Zhang, Dana P Ascherman, Daniella M Schwartz, Larry Moreland, Jishnu Das
Summary Background Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease characterized by clinical and molecular heterogeneity, notably in the presence of anti‐cyclic citrullinated peptide antibodies (CCP). CCP‐positive (CCP+) RA patients exhibit more severe disease progression and distinct treatment responses compared to CCP‐negative (CCP‐) patients. Although previous studies have investigated cellular and molecular differences between these subtypes, their genetic differences are understudied. Methods We leveraged the RACER (Rheumatoid Arthritis Comparative Effectiveness Research) cohort, comprising 555 CCP+/RF+ and 384 CCP‐/RF+ RA patients. Using a novel framework, we integrated a network‐based genome‐wide association study (GWAS) with multi‐omic data to uncover corresponding genetic and molecular differences. Findings We uncovered a significant heritability difference between these disease groups. Network‐based GWAS uncovered 14 putative gene modules, including many genes outside the HLA loci, that explained genetic differences between CCP+/RF+ and CCP‐/RF+ RA. Heritability partitioning and multivariate expression analyses validated 4 modules, highlighting novel genetic loci underlying phenotypic differences. Module functional significance was established using multiple orthogonal cohorts, underscoring their biological relevance. Interpretation Our findings demonstrate the utility of network‐based approaches in revealing differential genetic risk factors underlying CCP+/RF+ and CCP‐/RF+ RA. Disease‐associated gene modules detected in synovial tissue were also observed in peripheral blood, indicating joint‐specific molecular programs are reflected systemically. This cross‐tissue concordance highlights the potential for blood‐based assays to capture pathogenic mechanisms active in the joints, enabling practical patient stratification. Our findings highlight why CCP+/RF+ and CCP‐/RF+ RA patients exhibit distinct clinical courses and therapeutic responses, supporting precision‐guided treatment strategy development in RA.
{"title":"Multi‐modal integration of protein interactomes with genomic and molecular data discovers distinct RA endotypes","authors":"Javad Rahimikollu, Priyamvada Guha Roy, Akash Kishore, Danica Morgan Lee, Lauren A Vanderlinden, Kiran Nazarali, Fan Zhang, Dana P Ascherman, Daniella M Schwartz, Larry Moreland, Jishnu Das","doi":"10.1002/art.70091","DOIUrl":"https://doi.org/10.1002/art.70091","url":null,"abstract":"Summary Background Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease characterized by clinical and molecular heterogeneity, notably in the presence of anti‐cyclic citrullinated peptide antibodies (CCP). CCP‐positive (CCP+) RA patients exhibit more severe disease progression and distinct treatment responses compared to CCP‐negative (CCP‐) patients. Although previous studies have investigated cellular and molecular differences between these subtypes, their genetic differences are understudied. Methods We leveraged the RACER (Rheumatoid Arthritis Comparative Effectiveness Research) cohort, comprising 555 CCP+/RF+ and 384 CCP‐/RF+ RA patients. Using a novel framework, we integrated a network‐based genome‐wide association study (GWAS) with multi‐omic data to uncover corresponding genetic and molecular differences. Findings We uncovered a significant heritability difference between these disease groups. Network‐based GWAS uncovered 14 putative gene modules, including many genes outside the HLA loci, that explained genetic differences between CCP+/RF+ and CCP‐/RF+ RA. Heritability partitioning and multivariate expression analyses validated 4 modules, highlighting novel genetic loci underlying phenotypic differences. Module functional significance was established using multiple orthogonal cohorts, underscoring their biological relevance. Interpretation Our findings demonstrate the utility of network‐based approaches in revealing differential genetic risk factors underlying CCP+/RF+ and CCP‐/RF+ RA. Disease‐associated gene modules detected in synovial tissue were also observed in peripheral blood, indicating joint‐specific molecular programs are reflected systemically. This cross‐tissue concordance highlights the potential for blood‐based assays to capture pathogenic mechanisms active in the joints, enabling practical patient stratification. Our findings highlight why CCP+/RF+ and CCP‐/RF+ RA patients exhibit distinct clinical courses and therapeutic responses, supporting precision‐guided treatment strategy development in RA.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"32 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153672","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}
Qinglian Jiang, Mingxia Wang, Ming Wang, Jiajun Zhou, Kaijun Zheng, Ling Ding, Ming Hong
Objective Dual‐target CAR–T cell therapy targeting BCMA and CD19 is an emerging and promising treatment for systemic lupus erythematosus (SLE). However, its effects on fertility and neonatal safety are largely unknown. This report describes the outcomes of two successful pregnancies and deliveries in a patient with SLE treated with BCMA/CD19 CAR–T cell therapy. Methods A 24‐year‐old woman with class IV lupus nephritis received BCMA/CD19 CAR–T cell therapy. The patient achieved sustained molecular remission of SLE and became pregnant spontaneously at 6‐months and 21‐months postinfusion. We monitored for CAR–T cell presence in maternal and neonatal samples and assessed the health of the infants. Results Lupus activity remained minimal without flares throughout both pregnancies. The patient had two term vaginal deliveries of healthy female infants. Serial digital polymerase chain reaction analysis of the patient's blood, breast milk, and placenta, as well as the infants’ blood at birth and during follow‐up, were all uniformly negative for CAR–T cell DNA. Both infants showed normal growth, neurodevelopment, and immune function at follow‐up, with no evidence of CAR–T cell transmission. The patient's self‐reported quality of life also improved significantly after the therapy. Conclusion This case suggests that BCMA/CD19 CAR–T cell therapy may induce sustained remission (over 30 months) in SLE, preserve fertility, and result in healthy pregnancies and neonates. This finding highlights the need for evidence‐based guidelines for patients considering pregnancy after CAR–T cell therapy. image
{"title":"Successful Spontaneous Pregnancies and Healthy Neonates After Dual‐Target CAR –T Cell Therapy in Systemic Lupus Erythematosus","authors":"Qinglian Jiang, Mingxia Wang, Ming Wang, Jiajun Zhou, Kaijun Zheng, Ling Ding, Ming Hong","doi":"10.1002/art.70070","DOIUrl":"https://doi.org/10.1002/art.70070","url":null,"abstract":"Objective Dual‐target CAR–T cell therapy targeting BCMA and CD19 is an emerging and promising treatment for systemic lupus erythematosus (SLE). However, its effects on fertility and neonatal safety are largely unknown. This report describes the outcomes of two successful pregnancies and deliveries in a patient with SLE treated with BCMA/CD19 CAR–T cell therapy. Methods A 24‐year‐old woman with class IV lupus nephritis received BCMA/CD19 CAR–T cell therapy. The patient achieved sustained molecular remission of SLE and became pregnant spontaneously at 6‐months and 21‐months postinfusion. We monitored for CAR–T cell presence in maternal and neonatal samples and assessed the health of the infants. Results Lupus activity remained minimal without flares throughout both pregnancies. The patient had two term vaginal deliveries of healthy female infants. Serial digital polymerase chain reaction analysis of the patient's blood, breast milk, and placenta, as well as the infants’ blood at birth and during follow‐up, were all uniformly negative for CAR–T cell DNA. Both infants showed normal growth, neurodevelopment, and immune function at follow‐up, with no evidence of CAR–T cell transmission. The patient's self‐reported quality of life also improved significantly after the therapy. Conclusion This case suggests that BCMA/CD19 CAR–T cell therapy may induce sustained remission (over 30 months) in SLE, preserve fertility, and result in healthy pregnancies and neonates. This finding highlights the need for evidence‐based guidelines for patients considering pregnancy after CAR–T cell therapy. <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/art70070-gra-0001-m.png\"> <jats:alt-text>image</jats:alt-text> </jats:graphic> </jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"59 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153565","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}
Mariana Correia Marques, Zuoming Deng, Navid Chowdhury, Elizabeth Schmitz, Alana Platukus, Emily D. Rosenbaum, Shajia Lu, Stephen Brooks, Massimo Gadina, Hanna Kim, Carol Lake, Ly‐Lan Bergeron, Michelle Millwood, Michael J. Ombrello
Objectives To evaluate the relationship between type I interferon (IFN‐I) stimulated gene (ISG) expression, Still's disease, and the development of lung disease (LD) and drug‐associated immune reactions (DAIR) to IL‐1/IL‐6 inhibitors. Methods Whole blood ISG expression was quantified by NanoString array. ISG‐28 scores were calculated in consecutive patients with Still's or Still's‐like disease. Exome sequencing with family‐based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. Results Among 57 patients (32 children, 25 adults), 16 had elevated ISG‐28 scores. This group exhibited higher prevalence of LD (0.44 vs. 0.1, p=0.007) and DAIR (0.63 vs. 0.17, p=0.003), and lower IL‐6 inhibitor use (0 vs. 0.25, p=0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL‐18, or current IL‐1 inhibition. The combination of HLA‐DRB1*15 with high ISG‐28 scores associated with LD and DAIR with high specificity, while absence of both biomarkers had high negative predictive value. Candidate genes from high ISG‐28 individuals were enriched in interferon‐related pathways, including autophagy, IFN‐I production, toll‐like receptor signaling, macrophage activation, cytoskeletal organization and responses to stress. Conclusion High IFN‐I expression correlates with LD and DAIR in Still's disease, linked to rare genetic variation in immune pathways. Combining high ISG‐28 with HLA‐DRB1*15 significantly improves post‐hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN‐I directed treatments in Still's disease with IFN‐I signature.
目的探讨I型干扰素（IFN‐I）刺激基因（ISG）表达与斯蒂尔斯病、肺部疾病（LD）发展和IL‐1/IL‐6抑制剂药物相关免疫反应（DAIR）之间的关系。方法采用NanoString阵列法测定全血ISG的表达。对患有Still's或Still's样疾病的连续患者计算ISG - 28评分。外显子组测序与基于家族的变异优先级确定候选基因包含罕见的候选致病变异。候选基因列表进行功能富集分析。结果在57例患者中（32例儿童，25例成人），16例ISG‐28评分升高。与其他组相比，该组的LD患病率（0.44 vs. 0.1, p=0.007）和DAIR患病率（0.63 vs. 0.17, p=0.003）较高，IL - 6抑制剂的使用率较低（0 vs. 0.25, p=0.048）。在巨噬细胞激活综合征、活动性疾病、IL - 18升高或当前IL - 1抑制率方面没有发现显著差异。HLA - DRB1*15联合高ISG - 28评分与LD和DAIR相关，具有高特异性，而缺乏这两种生物标志物具有高阴性预测价值。来自高ISG - 28个体的候选基因在干扰素相关通路中富集，包括自噬、IFN - I产生、toll样受体信号传导、巨噬细胞激活、细胞骨架组织和应激反应。结论在Still病中，IFN‐I的高表达与LD和DAIR相关，与免疫途径中罕见的遗传变异有关。高ISG - 28与HLA - DRB1*15结合可显著改善这些并发症患者的事后分层。如果前瞻性验证，这些发现可能指导分子风险评估和靶向治疗，包括IFN‐I靶向治疗Still病。
{"title":"Type I interferon signature associates with lung disease, drug‐associated immune reactions, and genetic variation in interferon‐linked pathways in Still's disease","authors":"Mariana Correia Marques, Zuoming Deng, Navid Chowdhury, Elizabeth Schmitz, Alana Platukus, Emily D. Rosenbaum, Shajia Lu, Stephen Brooks, Massimo Gadina, Hanna Kim, Carol Lake, Ly‐Lan Bergeron, Michelle Millwood, Michael J. Ombrello","doi":"10.1002/art.70079","DOIUrl":"https://doi.org/10.1002/art.70079","url":null,"abstract":"Objectives To evaluate the relationship between type I interferon (IFN‐I) stimulated gene (ISG) expression, Still's disease, and the development of lung disease (LD) and drug‐associated immune reactions (DAIR) to IL‐1/IL‐6 inhibitors. Methods Whole blood ISG expression was quantified by NanoString array. ISG‐28 scores were calculated in consecutive patients with Still's or Still's‐like disease. Exome sequencing with family‐based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. Results Among 57 patients (32 children, 25 adults), 16 had elevated ISG‐28 scores. This group exhibited higher prevalence of LD (0.44 vs. 0.1, p=0.007) and DAIR (0.63 vs. 0.17, p=0.003), and lower IL‐6 inhibitor use (0 vs. 0.25, p=0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL‐18, or current IL‐1 inhibition. The combination of HLA‐DRB1*15 with high ISG‐28 scores associated with LD and DAIR with high specificity, while absence of both biomarkers had high negative predictive value. Candidate genes from high ISG‐28 individuals were enriched in interferon‐related pathways, including autophagy, IFN‐I production, toll‐like receptor signaling, macrophage activation, cytoskeletal organization and responses to stress. Conclusion High IFN‐I expression correlates with LD and DAIR in Still's disease, linked to rare genetic variation in immune pathways. Combining high ISG‐28 with HLA‐DRB1*15 significantly improves post‐hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN‐I directed treatments in Still's disease with IFN‐I signature.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"97 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153628","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}
Helen Twohig, David Jenkinson, James Bailey, Samantha Hider, Ian C Scott, Sara Muller
Objectives Polymyalgia rheumatica (PMR) is a common indication for long‐term glucocorticoid (GC) treatment. Bone‐ and gastro‐protective medications are recommended for those at high‐risk of adverse events from GCs but no trials have evaluated their effectiveness in PMR. We describe bone‐/gastro‐protective medicine prescribing in people with PMR and evaluate its impact on adverse GC outcomes using a target trial approach. Methods A sample of >40,000 individuals aged ≥50 years, with a coded PMR diagnosis from January 2010‐March 2022, prescribed GCs within 21 days of first PMR diagnosis code, was constructed in CPRD Aurum. Prescriptions were defined as prevalent (pre‐PMR diagnosis), incident (at diagnosis), or late (post‐diagnosis, still GC‐treated), reported stratified by age/gender/deprivation. A target‐trial approach assessed the effect of: a) bisphosphonates on fragility fractures and b) proton‐pump inhibitors/H2‐receptor antagonists (PPIs/H2RAs) on gastrointestinal (GI) ulceration/bleeding. Treatment effect, adjusted for confounders, was modelled using targeted maximum likelihood estimation. Results 67.2% were co‐prescribed bisphosphonates and 78.6% PPIs/H2RAs. Males and those in more deprived areas were less likely to receive bisphosphonates. 1.40% (95%CI 1.10%,1.70%) of those prescribed vs 2.32% (2.12%,2.52%) of those not prescribed bisphosphonates for 12 months experienced a fracture (risk difference 0.92% points [0.56%,1.27%], NNT 109). Prescribing gastro‐protective medications was not associated with serious GI events. Conclusion Rates of prescribing to mitigate GC harms are higher than previously reported. Bisphosphonates are associated with approximately one less fragility fracture per year for every 100 people treated. Gastro‐prophylaxis is not associated with reduced risk of GI ulceration/bleeding, suggesting potential to reduce prescribing for this indication.
{"title":"Prescribing of medication to prevent glucocorticoid harms in patients with Polymyalgia Rheumatica: a cross‐sectional study and two emulated target trials in the Clinical Practice Research Datalink Aurum","authors":"Helen Twohig, David Jenkinson, James Bailey, Samantha Hider, Ian C Scott, Sara Muller","doi":"10.1002/art.70087","DOIUrl":"https://doi.org/10.1002/art.70087","url":null,"abstract":"Objectives Polymyalgia rheumatica (PMR) is a common indication for long‐term glucocorticoid (GC) treatment. Bone‐ and gastro‐protective medications are recommended for those at high‐risk of adverse events from GCs but no trials have evaluated their effectiveness in PMR. We describe bone‐/gastro‐protective medicine prescribing in people with PMR and evaluate its impact on adverse GC outcomes using a target trial approach. Methods A sample of >40,000 individuals aged ≥50 years, with a coded PMR diagnosis from January 2010‐March 2022, prescribed GCs within 21 days of first PMR diagnosis code, was constructed in CPRD Aurum. Prescriptions were defined as prevalent (pre‐PMR diagnosis), incident (at diagnosis), or late (post‐diagnosis, still GC‐treated), reported stratified by age/gender/deprivation. A target‐trial approach assessed the effect of: a) bisphosphonates on fragility fractures and b) proton‐pump inhibitors/H2‐receptor antagonists (PPIs/H2RAs) on gastrointestinal (GI) ulceration/bleeding. Treatment effect, adjusted for confounders, was modelled using targeted maximum likelihood estimation. Results 67.2% were co‐prescribed bisphosphonates and 78.6% PPIs/H2RAs. Males and those in more deprived areas were less likely to receive bisphosphonates. 1.40% (95%CI 1.10%,1.70%) of those prescribed vs 2.32% (2.12%,2.52%) of those not prescribed bisphosphonates for 12 months experienced a fracture (risk difference 0.92% points [0.56%,1.27%], NNT 109). Prescribing gastro‐protective medications was not associated with serious GI events. Conclusion Rates of prescribing to mitigate GC harms are higher than previously reported. Bisphosphonates are associated with approximately one less fragility fracture per year for every 100 people treated. Gastro‐prophylaxis is not associated with reduced risk of GI ulceration/bleeding, suggesting potential to reduce prescribing for this indication.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"35 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153671","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}
Alexis Ogdie, Joseph F Merola, Philip J Mease, Christopher T Ritchlin, Jose U Scher, Kimberly Parnell Lafferty, Daphne Chan, Soumya D Chakravarty, Wayne Langholff, Yanli Wang, Jie Shao, Yevgeniy Krol, Alice B Gottlieb
Objective Evaluate the efficacy and safety of guselkumab, an interleukin‐23p19‐subunit inhibitor, in participants with active psoriatic arthritis (PsA) and inadequate response (inadequate efficacy and/or intolerance) to one prior tumor necrosis factor inhibitor (TNFi‐IR). Methods In SOLSTICE (phase 3b, randomized, multicenter, double‐blind, placebo‐controlled study), enrolled adults with active PsA (≥3 swollen joints;≥3 tender joints; C‐reactive protein ≥0.3 mg/dL) and inadequate response to one prior TNFi were randomized to guselkumab 100mg every 4 weeks (Q4W); guselkumab 100mg at Weeks 0 and 4, then Q8W; or placebo➔guselkumab Q4W at Week24. The primary endpoint was ≥20% improvement in American College of Rheumatology criteria (ACR20) at Week24. Secondary endpoints included ACR50; ACR70; Investigator's Global Assessment of psoriasis (IGA) of 0/1 with ≥2‐grade improvement; ≥90% improvement in Psoriasis Area and Severity Index (PASI 90); and minimal disease activity (MDA) at Week24 and were analyzed by intention‐to‐treat. Results Analyses included 451 randomized participants (Q4W N=150; Q8W N=151; placebo N=150). At Week24, significantly greater proportions of guselkumab Q4W/Q8W‐treated vs placebo‐treated participants, respectively, achieved ACR20 (primary endpoint: 58.6%/62.2% vs 34.8%), ACR50 (31.4%/32.1% vs 12.2%), ACR70 (17.5%/17.3% vs 2.0%), IGA 0/1 response (50.0%/57.3% vs 17.4%, PASI 90 (49.4%/45.5% vs 12.0%), and MDA (18.8%/23.9% vs 5.4%) (all p<0.001). Through Week24, 46.7%, 53.6%, and 48.3% of participants receiving Q4W, Q8W, and placebo, respectively, had ≥1 adverse event. One death occurred (myocardial infarction). Conclusion Comparable efficacy was observed with both guselkumab regimens in TNFi‐IR participants with active PsA; safety findings were consistent with the known profile of guselkumab in patients with psoriatic disease.
{"title":"Efficacy and Safety of Guselkumab in Participants with Active Psoriatic Arthritis After Inadequate Response to One Prior Tumor Necrosis Factor Inhibitor: Week‐24 Results of the Phase 3, Randomized, Placebo‐Controlled SOLSTICE Study","authors":"Alexis Ogdie, Joseph F Merola, Philip J Mease, Christopher T Ritchlin, Jose U Scher, Kimberly Parnell Lafferty, Daphne Chan, Soumya D Chakravarty, Wayne Langholff, Yanli Wang, Jie Shao, Yevgeniy Krol, Alice B Gottlieb","doi":"10.1002/art.70092","DOIUrl":"https://doi.org/10.1002/art.70092","url":null,"abstract":"Objective Evaluate the efficacy and safety of guselkumab, an interleukin‐23p19‐subunit inhibitor, in participants with active psoriatic arthritis (PsA) and inadequate response (inadequate efficacy and/or intolerance) to one prior tumor necrosis factor inhibitor (TNFi‐IR). Methods In SOLSTICE (phase 3b, randomized, multicenter, double‐blind, placebo‐controlled study), enrolled adults with active PsA (≥3 swollen joints;≥3 tender joints; C‐reactive protein ≥0.3 mg/dL) and inadequate response to one prior TNFi were randomized to guselkumab 100mg every 4 weeks (Q4W); guselkumab 100mg at Weeks 0 and 4, then Q8W; or placebo➔guselkumab Q4W at Week24. The primary endpoint was ≥20% improvement in American College of Rheumatology criteria (ACR20) at Week24. Secondary endpoints included ACR50; ACR70; Investigator's Global Assessment of psoriasis (IGA) of 0/1 with ≥2‐grade improvement; ≥90% improvement in Psoriasis Area and Severity Index (PASI 90); and minimal disease activity (MDA) at Week24 and were analyzed by intention‐to‐treat. Results Analyses included 451 randomized participants (Q4W N=150; Q8W N=151; placebo N=150). At Week24, significantly greater proportions of guselkumab Q4W/Q8W‐treated vs placebo‐treated participants, respectively, achieved ACR20 (primary endpoint: 58.6%/62.2% vs 34.8%), ACR50 (31.4%/32.1% vs 12.2%), ACR70 (17.5%/17.3% vs 2.0%), IGA 0/1 response (50.0%/57.3% vs 17.4%, PASI 90 (49.4%/45.5% vs 12.0%), and MDA (18.8%/23.9% vs 5.4%) (all p<0.001). Through Week24, 46.7%, 53.6%, and 48.3% of participants receiving Q4W, Q8W, and placebo, respectively, had ≥1 adverse event. One death occurred (myocardial infarction). Conclusion Comparable efficacy was observed with both guselkumab regimens in TNFi‐IR participants with active PsA; safety findings were consistent with the known profile of guselkumab in patients with psoriatic disease.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"10 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153627","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}
Ilaria Maccora, Catherine Guly, Cinzia de Libero, Giulia Carreras, Athimalaipet V Ramanan, Gabriele Simonini
Objective: Treatment of childhood chronic idiopathic uveitis (cCIU) is predominantly based on studies in juvenile idiopathic arthritis-associated uveitis and expert opinion. Our aim was to report the treatment outcomes of our cohort of cCIU.
Methods: Retrospective multicenter study involving the rheumatology and ophthalmology units at Florence, Italy, and Bristol, United Kingdom. We included children with cCIU, who received at least one systemic treatment. Ocular inflammation and treatment response were assessed according to the standardized uveitis nomenclature.
Results: A total of 116 patients with cCIU received at least one systemic treatment (93 methotrexate, 22 adalimumab, and 1 mycophenolate), whereas 60 of them received an additional second-line treatment (45 adalimumab, 14 mycophenolate, and 1 tocilizumab). Children treated with adalimumab (plus or minus methotrexate) as a first-line therapy were more likely to achieve remission than methotrexate alone (χ2 = 31.35; P < 0.001); furthermore, children treated with methotrexate as a first-line therapy relapsed earlier (χ2 = 4.35; P = 0.043). Children receiving adalimumab were more likely to stop treatment for remission than methotrexate (χ2 = 25.9; P < 0.001). Regarding second-line therapy, children who started adalimumab (plus or minus methotrexate) were more likely to achieve remission than mycophenolate (χ2 = 14.66; P = 0.005). Children with nonanterior uveitis, conversely to the others, were more likely to achieve remission with adalimumab as a first-line therapy than methotrexate (χ2 = 32.3; P < 0.001). Children with nonanterior uveitis, but not children with anterior uveitis, were more likely to stop the first-line treatment when receiving adalimumab than methotrexate (χ2 = 18.56; P = 0.001) due to persistent remission.
Conclusion: Adalimumab shows promise as a potential first-line therapy for cCIU, particularly for posterior segment uveitis. Although effective in anterior uveitis, methotrexate leads children to relapse earlier than adalimumab.
{"title":"Treatment of a Large Cohort of Childhood Chronic Noninfectious Uveitis in a Multicentric Large Study: Adalimumab Versus Methotrexate as First-Line Therapy.","authors":"Ilaria Maccora, Catherine Guly, Cinzia de Libero, Giulia Carreras, Athimalaipet V Ramanan, Gabriele Simonini","doi":"10.1002/art.70090","DOIUrl":"10.1002/art.70090","url":null,"abstract":"<p><strong>Objective: </strong>Treatment of childhood chronic idiopathic uveitis (cCIU) is predominantly based on studies in juvenile idiopathic arthritis-associated uveitis and expert opinion. Our aim was to report the treatment outcomes of our cohort of cCIU.</p><p><strong>Methods: </strong>Retrospective multicenter study involving the rheumatology and ophthalmology units at Florence, Italy, and Bristol, United Kingdom. We included children with cCIU, who received at least one systemic treatment. Ocular inflammation and treatment response were assessed according to the standardized uveitis nomenclature.</p><p><strong>Results: </strong>A total of 116 patients with cCIU received at least one systemic treatment (93 methotrexate, 22 adalimumab, and 1 mycophenolate), whereas 60 of them received an additional second-line treatment (45 adalimumab, 14 mycophenolate, and 1 tocilizumab). Children treated with adalimumab (plus or minus methotrexate) as a first-line therapy were more likely to achieve remission than methotrexate alone (χ<sup>2</sup> = 31.35; P < 0.001); furthermore, children treated with methotrexate as a first-line therapy relapsed earlier (χ<sup>2</sup> = 4.35; P = 0.043). Children receiving adalimumab were more likely to stop treatment for remission than methotrexate (χ<sup>2</sup> = 25.9; P < 0.001). Regarding second-line therapy, children who started adalimumab (plus or minus methotrexate) were more likely to achieve remission than mycophenolate (χ<sup>2</sup> = 14.66; P = 0.005). Children with nonanterior uveitis, conversely to the others, were more likely to achieve remission with adalimumab as a first-line therapy than methotrexate (χ<sup>2</sup> = 32.3; P < 0.001). Children with nonanterior uveitis, but not children with anterior uveitis, were more likely to stop the first-line treatment when receiving adalimumab than methotrexate (χ<sup>2</sup> = 18.56; P = 0.001) due to persistent remission.</p><p><strong>Conclusion: </strong>Adalimumab shows promise as a potential first-line therapy for cCIU, particularly for posterior segment uveitis. Although effective in anterior uveitis, methotrexate leads children to relapse earlier than adalimumab.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148498","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":"Associations and diagnostic accuracy of ultrasound features in knee osteoarthritis: cross-sectional results from a large community-based cohort. Comment on the article by Yates et al.","authors":"Haojie Guan, Haidong Zhou, Hongyu Xu, Hejing Pan","doi":"10.1002/art.70086","DOIUrl":"10.1002/art.70086","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140397","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":"ACR Presidential Address: The American College of Rheumatology in 2025 - The Strength, Resilience, and Importance of Our Rheumatology Community.","authors":"Carol A Langford","doi":"10.1002/art.70064","DOIUrl":"https://doi.org/10.1002/art.70064","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":10.9,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146148544","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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