Ngoc V. Nguyen, Anna Sandström, Annica Dominicus, Elisabet Svenungsson, Karin Hellgren, Julia F. Simard, Elizabeth V. Arkema
Objective This nationwide descriptive study examined temporal trends in adverse pregnancy outcomes (APOs) and treatments in systemic lupus erythematosus (SLE) pregnancies in Sweden over 2003‐2022. Methods Using nationwide Swedish registers, we identified 1,417 pregnancies of women with prevalent SLE and delivery dates in 2003‐2022, and matched them to 14,133 non‐SLE pregnancies from the general population on maternal age, delivery year, and parity. We assessed proportions of preeclampsia, preterm delivery, and small for gestational age (SGA) birth over time. Antimalarial, glucocorticoid, and low‐dose aspirin use were examined during 2007‐2022. Binomial generalized linear models with an identity link quantified mean annual absolute change (expressed in percentage point [pp]) in APO and treatment proportions. Results Overall, SLE pregnancies had 9.1% preeclampsia, 14.7% preterm delivery, and 6.9% SGA births (2003‐2022). These outcomes remained stable in the general population but decreased in SLE pregnancies (preeclampsia from 14.1% in 2003‐2004 to 9.6% in 2021‐2022, −0.11 pp/year; preterm delivery from 25.9% to 11.2%, −0.63 pp/year; SGA birth from 10.6% to 7.0%, −0.22 pp/year). Declines were more pronounced in nulliparous vs. parous SLE pregnancies. APOs modestly decreased over time in SLE pregnancies with antiphospholipid syndrome. Antimalarial use during pregnancy increased from 23.9% in 2007‐2008 to 76.5% in 2021‐2022 (+3.3 pp/year). Low‐dose aspirin use during pregnancy rose from 39.8% to 85.6% (+3.7 pp/year), while glucocorticoid use slightly decreased from 43.2% to 40.1% (−0.7 pp/year). Conclusion APOs in SLE pregnancies have decreased over the past two decades, potentially reflecting improved treatment strategies, particularly increased use of antimalarials and low‐dose aspirin.
{"title":"Nationwide temporal trends in adverse pregnancy outcomes and treatments in systemic lupus erythematosus pregnancy over two decades in Sweden","authors":"Ngoc V. Nguyen, Anna Sandström, Annica Dominicus, Elisabet Svenungsson, Karin Hellgren, Julia F. Simard, Elizabeth V. Arkema","doi":"10.1002/art.70018","DOIUrl":"https://doi.org/10.1002/art.70018","url":null,"abstract":"Objective This nationwide descriptive study examined temporal trends in adverse pregnancy outcomes (APOs) and treatments in systemic lupus erythematosus (SLE) pregnancies in Sweden over 2003‐2022. Methods Using nationwide Swedish registers, we identified 1,417 pregnancies of women with prevalent SLE and delivery dates in 2003‐2022, and matched them to 14,133 non‐SLE pregnancies from the general population on maternal age, delivery year, and parity. We assessed proportions of preeclampsia, preterm delivery, and small for gestational age (SGA) birth over time. Antimalarial, glucocorticoid, and low‐dose aspirin use were examined during 2007‐2022. Binomial generalized linear models with an identity link quantified mean annual absolute change (expressed in percentage point [pp]) in APO and treatment proportions. Results Overall, SLE pregnancies had 9.1% preeclampsia, 14.7% preterm delivery, and 6.9% SGA births (2003‐2022). These outcomes remained stable in the general population but decreased in SLE pregnancies (preeclampsia from 14.1% in 2003‐2004 to 9.6% in 2021‐2022, −0.11 pp/year; preterm delivery from 25.9% to 11.2%, −0.63 pp/year; SGA birth from 10.6% to 7.0%, −0.22 pp/year). Declines were more pronounced in nulliparous vs. parous SLE pregnancies. APOs modestly decreased over time in SLE pregnancies with antiphospholipid syndrome. Antimalarial use during pregnancy increased from 23.9% in 2007‐2008 to 76.5% in 2021‐2022 (+3.3 pp/year). Low‐dose aspirin use during pregnancy rose from 39.8% to 85.6% (+3.7 pp/year), while glucocorticoid use slightly decreased from 43.2% to 40.1% (−0.7 pp/year). Conclusion APOs in SLE pregnancies have decreased over the past two decades, potentially reflecting improved treatment strategies, particularly increased use of antimalarials and low‐dose aspirin.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"28 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807515","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}
Pengfei Xin, Wenzhen Li, Xinyu A, Jun Shen, Xiaohui Meng, Yanqin Bian, Haihui Han, Zheng Xiang, Lei Ran, Songtao Sun, Jun Xie, Tao Yue, Qi Zhu, Xiaoming Zhang, Lu Xie, Lianbo Xiao
Objective Bone destruction associated with active rheumatoid arthritis (RA) remains a major therapeutic challenge, with a lack of reliable molecular markers reflecting bone injury. This study aims to identify novel biomarkers linked to bone destruction in active RA through proteomic analysis, providing new strategies for precise monitoring and targeted therapy. Methods Data‐independent acquisition (DIA) mass spectrometry was used for proteomic quantification and bioinformatic analysis on plasma samples from 160 RA patients and 40 healthy controls. Key proteins associated with bone destruction were screened by integrating Sharp scores with synovial single‐cell RNA sequencing data, and subsequently validated in two independent cohorts (N₁ = 50, N₂ = 10) using ELISA and multiplex immunohistochemistry. Functional studies were conducted using fibroblast‐like synoviocytes (FLSs) in vitro and a collagen‐induced arthritis (CIA) mouse model in vivo. Results A total of 4,998 plasma proteins were identified, with 506 showing significant differential expression between active and remitted RA. TAOK3 levels were positively associated with Sharp scores and markedly elevated in active RA patients. Combining TAOK3 with CRP improved diagnostic accuracy for active RA (AUC = 0.915). High TAOK3 expression was also associated with increased relapse frequency. Functional studies showed that TAOK3 knockdown suppressed the tumor‐like phenotype of FLSs and downregulated MMP1/2/3 and CTSK, while TAOK3 overexpression promoted pannus cell–mediated bone erosion, mitigated by TAOK3‐targeted inhibitor. In vivo, its inhibition showed therapeutic effects in CIA mice. Conclusion TAOK3 serves as a potential biomarker for bone destruction in active RA and a therapeutic target for precision monitoring and intervention.
{"title":"Plasma Proteomics Identifies TAOK3 as a Potential Biomarker of Rheumatoid Arthritis Activity and a Novel Therapeutic Target","authors":"Pengfei Xin, Wenzhen Li, Xinyu A, Jun Shen, Xiaohui Meng, Yanqin Bian, Haihui Han, Zheng Xiang, Lei Ran, Songtao Sun, Jun Xie, Tao Yue, Qi Zhu, Xiaoming Zhang, Lu Xie, Lianbo Xiao","doi":"10.1002/art.70020","DOIUrl":"https://doi.org/10.1002/art.70020","url":null,"abstract":"Objective Bone destruction associated with active rheumatoid arthritis (RA) remains a major therapeutic challenge, with a lack of reliable molecular markers reflecting bone injury. This study aims to identify novel biomarkers linked to bone destruction in active RA through proteomic analysis, providing new strategies for precise monitoring and targeted therapy. Methods Data‐independent acquisition (DIA) mass spectrometry was used for proteomic quantification and bioinformatic analysis on plasma samples from 160 RA patients and 40 healthy controls. Key proteins associated with bone destruction were screened by integrating Sharp scores with synovial single‐cell RNA sequencing data, and subsequently validated in two independent cohorts (N₁ = 50, N₂ = 10) using ELISA and multiplex immunohistochemistry. Functional studies were conducted using fibroblast‐like synoviocytes (FLSs) in vitro and a collagen‐induced arthritis (CIA) mouse model in vivo. Results A total of 4,998 plasma proteins were identified, with 506 showing significant differential expression between active and remitted RA. TAOK3 levels were positively associated with Sharp scores and markedly elevated in active RA patients. Combining TAOK3 with CRP improved diagnostic accuracy for active RA (AUC = 0.915). High TAOK3 expression was also associated with increased relapse frequency. Functional studies showed that TAOK3 knockdown suppressed the tumor‐like phenotype of FLSs and downregulated MMP1/2/3 and CTSK, while TAOK3 overexpression promoted pannus cell–mediated bone erosion, mitigated by TAOK3‐targeted inhibitor. In vivo, its inhibition showed therapeutic effects in CIA mice. Conclusion TAOK3 serves as a potential biomarker for bone destruction in active RA and a therapeutic target for precision monitoring and intervention.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"185 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807678","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}
Jeffrey B. Driban, Lisa B. Rokoff, Bing Lu, Timothy E. McAlindon, Charles B. Eaton, Mary B. Roberts, Diana Mathes, Colleen Lestician, Zhijin Carrie Xu, Zhihua Tina Fan, Shawn P. O'Leary, Ida K. Haugen, Jérémie Sellam, Alice Courties, Abby F. Fleisch
Objective To explore whether biological levels of specific per‐ and polyfluoroalkyl substances (PFAS) and a mixture of PFAS – reflecting the overall effect and accounting for correlations among each PFAS – relate to incident hand osteoarthritis (HOA) and progression. Methods Among a case‐cohort sample from the Osteoarthritis Initiative (n=1,878), we examined associations of 8 PFAS in serum with odds of developing over the subsequent 4 years (1) symptomatic HOA and (2) an increased number of joints with radiographic osteoarthritis (Kellgren‐Lawrence≥2; yes/no). We used weighted logistic regression to assess single PFAS (continuous and quartiles) and quantile g‐computation to assess the PFAS‐mixture in relation to our primary outcomes. Results Participants were primarily female (58%) and on average 62 years of age and overweight (mean BMI=28.6 kg/m 2 ). Participants with higher perfluorodecanoic acid (PFDA) and perfluorononanoic acid (PFNA; continuous variables) had greater odds of incident symptomatic HOA [OR (95%CI) per interquartile‐range increment: PFDA 1.12 (1.05‐1.20); PFNA 1.07 (1.00‐1.13)], but associations were not monotonic when these PFAS were represented in quartiles. Participants with higher perfluorohexane sulfonoic acid (PFHxS) had lower odds of incident HOA [e.g., OR (95%CI): 0.94 (0.88‐1.00) per interquartile‐range increment]. We observed no other consistent associations between PFAS and either outcome. Conclusion We observed possible associations of PFDA and PFNA serum concentrations with symptomatic HOA incidence, but we otherwise found no consistent evidence that greater PFAS concentrations relate to a greater chance of developing HOA incidence or progression.
{"title":"Per‐ and polyfluoroalkyl substances and hand osteoarthritis: data from the Osteoarthritis Initiative","authors":"Jeffrey B. Driban, Lisa B. Rokoff, Bing Lu, Timothy E. McAlindon, Charles B. Eaton, Mary B. Roberts, Diana Mathes, Colleen Lestician, Zhijin Carrie Xu, Zhihua Tina Fan, Shawn P. O'Leary, Ida K. Haugen, Jérémie Sellam, Alice Courties, Abby F. Fleisch","doi":"10.1002/art.70026","DOIUrl":"https://doi.org/10.1002/art.70026","url":null,"abstract":"Objective To explore whether biological levels of specific per‐ and polyfluoroalkyl substances (PFAS) and a mixture of PFAS – reflecting the overall effect and accounting for correlations among each PFAS – relate to incident hand osteoarthritis (HOA) and progression. Methods Among a case‐cohort sample from the Osteoarthritis Initiative (n=1,878), we examined associations of 8 PFAS in serum with odds of developing over the subsequent 4 years (1) symptomatic HOA and (2) an increased number of joints with radiographic osteoarthritis (Kellgren‐Lawrence≥2; yes/no). We used weighted logistic regression to assess single PFAS (continuous and quartiles) and quantile g‐computation to assess the PFAS‐mixture in relation to our primary outcomes. Results Participants were primarily female (58%) and on average 62 years of age and overweight (mean BMI=28.6 kg/m <jats:sup>2</jats:sup> ). Participants with higher perfluorodecanoic acid (PFDA) and perfluorononanoic acid (PFNA; continuous variables) had greater odds of incident symptomatic HOA [OR (95%CI) per interquartile‐range increment: PFDA 1.12 (1.05‐1.20); PFNA 1.07 (1.00‐1.13)], but associations were not monotonic when these PFAS were represented in quartiles. Participants with higher perfluorohexane sulfonoic acid (PFHxS) had lower odds of incident HOA [e.g., OR (95%CI): 0.94 (0.88‐1.00) per interquartile‐range increment]. We observed no other consistent associations between PFAS and either outcome. Conclusion We observed possible associations of PFDA and PFNA serum concentrations with symptomatic HOA incidence, but we otherwise found no consistent evidence that greater PFAS concentrations relate to a greater chance of developing HOA incidence or progression.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"3 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807680","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}
Brian Meng‐Hsun Li, Jia‐Horung Hung, Po‐Cheng Yang, Swu‐Jane Lin, Edward Chia‐Cheng Lai, Meng‐Yu Weng
s Objective To weigh higher‐dose HCQ (>=400 mg/d) and lower‐dose HCQ (<400 mg/d) for effectiveness and safety among patients with systemic lupus erythematosus (SLE). Methods This nationwide study retrieved data from Taiwan's National Health Insurance Research Database, from 2010 to 2021. We included SLE patients aged over 10 years, initiating HCQ, with no other systemic autoimmune disease at baseline and no historical outcomes of interest. Patients were classified into higher‐dose (>=400 mg per day) or lower‐dose (<400 mg per day) treatment strategies based on the dosage of their first HCQ prescription. The outcomes were coronary artery disease (CAD), ischemic stroke, venous thromboembolism (VTE), end‐stage renal disease, malignancy, and HCQ retinopathy. Results 878 (3.77%) patients on higher‐dose HCQ and 22,405 (96.22%) on lower‐dose HCQ were included. After inverse probability weighting, higher‐dose HCQ was associated with lower risks of CAD (HR 0.86, 95% CI 0.80‐0.93) and VTE (HR 0.40, 95% CI 0.33‐0.49). We found no dose‐related difference in the risk of ischemic stroke, ESRD, malignancy and HCQ retinopathy through a mean follow‐up of 6 years, except for the HCQ retinopathy among SLE patients aged over 45 years (HR 1.87, 95% CI 1.45‐2.42). Conclusion For SLE patients, higher‐dose HCQ improves effectiveness with reduced risks of CAD and VTE. There was no dose‐related difference in the risk of HCQ retinopathy, for SLE patients aged younger than 45 years. Our study emphasizes the need for weighing the benefits and risks of optimal HCQ dosage in managing SLE. image
目的比较高剂量HCQ （>=400 mg/d）和低剂量HCQ （<400 mg/d）对系统性红斑狼疮（SLE）患者的有效性和安全性。方法本研究从2010年至2021年的台湾全民健康保险研究数据库中检索数据。我们纳入了年龄在10岁以上的SLE患者，首发HCQ，基线时没有其他系统性自身免疫性疾病，也没有感兴趣的历史结局。根据患者第一次HCQ处方的剂量，将患者分为高剂量（每天400毫克）或低剂量（每天400毫克）治疗策略。结果是冠状动脉疾病（CAD）、缺血性中风、静脉血栓栓塞（VTE）、终末期肾病、恶性肿瘤和HCQ视网膜病变。结果878例（3.77%）高剂量HCQ患者和22405例（96.22%）低剂量HCQ患者被纳入研究。在逆概率加权后，高剂量的HCQ与较低的CAD （HR 0.86, 95% CI 0.80‐0.93）和VTE （HR 0.40, 95% CI 0.33‐0.49）风险相关。通过平均6年的随访，我们发现除了45岁以上SLE患者的HCQ视网膜病变外，缺血性卒中、ESRD、恶性肿瘤和HCQ视网膜病变的风险没有剂量相关的差异（HR 1.87, 95% CI 1.45‐2.42）。结论：对于SLE患者，高剂量的HCQ可以提高疗效，降低冠心病和静脉血栓栓塞的风险。对于年龄小于45岁的SLE患者，HCQ视网膜病变的风险没有剂量相关的差异。我们的研究强调需要权衡最佳HCQ剂量在SLE治疗中的益处和风险。图像
{"title":"Weighing dose‐related benefits and risks of hydroxychloroquine treatment in systemic lupus erythematosus patients","authors":"Brian Meng‐Hsun Li, Jia‐Horung Hung, Po‐Cheng Yang, Swu‐Jane Lin, Edward Chia‐Cheng Lai, Meng‐Yu Weng","doi":"10.1002/art.70022","DOIUrl":"https://doi.org/10.1002/art.70022","url":null,"abstract":"s Objective To weigh higher‐dose HCQ (>=400 mg/d) and lower‐dose HCQ (<400 mg/d) for effectiveness and safety among patients with systemic lupus erythematosus (SLE). Methods This nationwide study retrieved data from Taiwan's National Health Insurance Research Database, from 2010 to 2021. We included SLE patients aged over 10 years, initiating HCQ, with no other systemic autoimmune disease at baseline and no historical outcomes of interest. Patients were classified into higher‐dose (>=400 mg per day) or lower‐dose (<400 mg per day) treatment strategies based on the dosage of their first HCQ prescription. The outcomes were coronary artery disease (CAD), ischemic stroke, venous thromboembolism (VTE), end‐stage renal disease, malignancy, and HCQ retinopathy. Results 878 (3.77%) patients on higher‐dose HCQ and 22,405 (96.22%) on lower‐dose HCQ were included. After inverse probability weighting, higher‐dose HCQ was associated with lower risks of CAD (HR 0.86, 95% CI 0.80‐0.93) and VTE (HR 0.40, 95% CI 0.33‐0.49). We found no dose‐related difference in the risk of ischemic stroke, ESRD, malignancy and HCQ retinopathy through a mean follow‐up of 6 years, except for the HCQ retinopathy among SLE patients aged over 45 years (HR 1.87, 95% CI 1.45‐2.42). Conclusion For SLE patients, higher‐dose HCQ improves effectiveness with reduced risks of CAD and VTE. There was no dose‐related difference in the risk of HCQ retinopathy, for SLE patients aged younger than 45 years. Our study emphasizes the need for weighing the benefits and risks of optimal HCQ dosage in managing SLE. <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/art70022-toc-0001-m.png\"> <jats:alt-text>image</jats:alt-text> </jats:graphic> </jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"12 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801132","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 develop evidence-based criteria to classify SURF patients.METHODS112 SURF patients followed in a single tertiary referral center were analyzed. Patients with genetically confirmed hereditary recurrent fever (HRF) or with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome already analyzed for the Eurofever classification criteria were used as disease controls. A decision tree approach was tested randomly splitting the available data in a training set and in an internal test set. An alternative model using a classical regression model was also analyzed. An external validation for both approaches was performed on 123 patients recruited from other four centers.RESULTSThe decision tree model integrating clinical and genetic data identified 91% of SURF patients. A decision tree model based solely on clinical variables identified up to 88% of SURF patients. The logistic regression model including genetic tests exhibited an overall accuracy of 89.2% (95% CI: 81.1-94.7). In contrast, the logistic regression model exclusively based on clinical manifestations displayed an overall accuracy of 66.7% (95% CI: 56.1-76.1). When the classification criteria including genetic tests were applied to the external validation cohort, the model demonstrated a strong discriminative power, with an AUC of 96.3% using the decision tree model and 88.0% with the logistic regression model.CONCLUSIONSThe study shows the possibility to achieve evidence-based criteria able to classify SURF at least in respect to the main HRF and PFAPA syndrome and may be considered as a preliminary tool for the enrolment of more homogeneous cohort of patients in future studies.
{"title":"Decision tree analysis as a preliminary evidence-based tool for identifying the syndrome of undifferentiated recurrent fever in children compared with hereditary recurrent fevers and periodic fever, aphthosis, pharyngitis and adenitis syndrome.","authors":"Riccardo Papa,Francesca Bovis,Silvia Federici,Serena Palmeri,Marta Bustaffa,Giada Recchi,Roberta Bertelli,Roberta Caorsi,Stefano Volpi,Sabrina Fuehner,Veysel Cam,Anna Kozáková,Šárka Horáčková Fingerhutová,Antonella Insalaco,Dirk Foell,Seza Ozen,Isabella Ceccherini,Marco Gattorno, ","doi":"10.1002/art.70019","DOIUrl":"https://doi.org/10.1002/art.70019","url":null,"abstract":"OBJECTIVETo develop evidence-based criteria to classify SURF patients.METHODS112 SURF patients followed in a single tertiary referral center were analyzed. Patients with genetically confirmed hereditary recurrent fever (HRF) or with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome already analyzed for the Eurofever classification criteria were used as disease controls. A decision tree approach was tested randomly splitting the available data in a training set and in an internal test set. An alternative model using a classical regression model was also analyzed. An external validation for both approaches was performed on 123 patients recruited from other four centers.RESULTSThe decision tree model integrating clinical and genetic data identified 91% of SURF patients. A decision tree model based solely on clinical variables identified up to 88% of SURF patients. The logistic regression model including genetic tests exhibited an overall accuracy of 89.2% (95% CI: 81.1-94.7). In contrast, the logistic regression model exclusively based on clinical manifestations displayed an overall accuracy of 66.7% (95% CI: 56.1-76.1). When the classification criteria including genetic tests were applied to the external validation cohort, the model demonstrated a strong discriminative power, with an AUC of 96.3% using the decision tree model and 88.0% with the logistic regression model.CONCLUSIONSThe study shows the possibility to achieve evidence-based criteria able to classify SURF at least in respect to the main HRF and PFAPA syndrome and may be considered as a preliminary tool for the enrolment of more homogeneous cohort of patients in future studies.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"11 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801302","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}
Stavros Giaglis,André N Tiaden,Simone Häner-Massimi,Diego Kyburz,Cedric André,Anton Glück,Enrico Ferrero,Stuart Hawtin,Tobias Junt,Ulrich A Walker
OBJECTIVEMitochondria are organelles with a hypomethylated circular genome. Mitochondrial DNA (mtDNA) in the systemic circulation has been implicated in inflammation. This study investigates the role of circulating DNA in systemic sclerosis (SSc) and the cellular mechanisms governing its release.METHODSTotal DNA was isolated from plasma of healthy individuals and SSc patients. Copy numbers were analyzed for mtDNA (ATP-6) and GAPDH abundance by qPCR. mtDNA was isolated from HC and SSc patients. Neutrophils and platelets were incubated with SSc patients' plasma and mtDNA, and NET formation was assessed by SytoxGreen and immunostainings. Platelets were tested for mtDNA release propensity. DNA oxidation was evaluated by MitoSOX Red staining in vitro and 8-OHdG ELISA of patient plasma. Plasma IFN type 1 and CXCL4 were measured by ELISA. IFN signaling activation capacity was evaluated utilizing THP1 reporter cells and confirmed by a whole blood bulk RNA transcriptomic analysis.RESULTSMedian plasma mtDNA levels were 152-fold higher in SSc patients compared to healthy controls (HC), while nDNA levels were similar. mtDNA from SSc plasma was highly oxidized. SSc-derived mtDNA efficiently promoted its own release by NETosis, most potently in SSc patient neutrophils, and by platelet activation. Oxidized mtDNA from SSc platelets in complex with CXCL4 further stimulated mtDNA release in both neutrophils and platelets. mtDNA plasma concentrations correlated with type I IFN concentrations in SSc patient blood, and SSc blood exhibited elevated interferon-stimulated gene (ISG) expression. SSc plasma-derived mtDNA induced IFN signaling and NET formation via endosomal TLR, cGAS/STING and the JAK/STAT pathway. The type I IFN pathway further promoted NETosis and mtDNA release since IFN receptor (IFNAR) and Janus kinase (JAK) inhibition antagonized the proNETotic effects of IFN.CONCLUSIONSSc plasma is characterized by highly abundant mtDNA, which drives feedback loops amplifying its own release from both neutrophils and platelets. Thus, mtDNA contributes to inflammation and tissue damage in SSc.
{"title":"A cooperative release of mitochondrial DNA from platelets and neutrophils drives an interferon signature in systemic sclerosis.","authors":"Stavros Giaglis,André N Tiaden,Simone Häner-Massimi,Diego Kyburz,Cedric André,Anton Glück,Enrico Ferrero,Stuart Hawtin,Tobias Junt,Ulrich A Walker","doi":"10.1002/art.70027","DOIUrl":"https://doi.org/10.1002/art.70027","url":null,"abstract":"OBJECTIVEMitochondria are organelles with a hypomethylated circular genome. Mitochondrial DNA (mtDNA) in the systemic circulation has been implicated in inflammation. This study investigates the role of circulating DNA in systemic sclerosis (SSc) and the cellular mechanisms governing its release.METHODSTotal DNA was isolated from plasma of healthy individuals and SSc patients. Copy numbers were analyzed for mtDNA (ATP-6) and GAPDH abundance by qPCR. mtDNA was isolated from HC and SSc patients. Neutrophils and platelets were incubated with SSc patients' plasma and mtDNA, and NET formation was assessed by SytoxGreen and immunostainings. Platelets were tested for mtDNA release propensity. DNA oxidation was evaluated by MitoSOX Red staining in vitro and 8-OHdG ELISA of patient plasma. Plasma IFN type 1 and CXCL4 were measured by ELISA. IFN signaling activation capacity was evaluated utilizing THP1 reporter cells and confirmed by a whole blood bulk RNA transcriptomic analysis.RESULTSMedian plasma mtDNA levels were 152-fold higher in SSc patients compared to healthy controls (HC), while nDNA levels were similar. mtDNA from SSc plasma was highly oxidized. SSc-derived mtDNA efficiently promoted its own release by NETosis, most potently in SSc patient neutrophils, and by platelet activation. Oxidized mtDNA from SSc platelets in complex with CXCL4 further stimulated mtDNA release in both neutrophils and platelets. mtDNA plasma concentrations correlated with type I IFN concentrations in SSc patient blood, and SSc blood exhibited elevated interferon-stimulated gene (ISG) expression. SSc plasma-derived mtDNA induced IFN signaling and NET formation via endosomal TLR, cGAS/STING and the JAK/STAT pathway. The type I IFN pathway further promoted NETosis and mtDNA release since IFN receptor (IFNAR) and Janus kinase (JAK) inhibition antagonized the proNETotic effects of IFN.CONCLUSIONSSc plasma is characterized by highly abundant mtDNA, which drives feedback loops amplifying its own release from both neutrophils and platelets. Thus, mtDNA contributes to inflammation and tissue damage in SSc.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"20 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777488","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}
Yonatan Lean,Carrie Richardson,Anthony Esposito,Katy Bedjeti,George E Georges
OBJECTIVEHigh intensity conditioning autologous hematopoietic stem cell transplantation (AHSCT) is standard of care for patients with advanced SSc. The role of reduced intensity conditioning (RIC) prior to AHSCT in this population remains unclear. We conducted this study to determine the long-term outcomes of RIC AHSCT in SSc patients with cardiac involvement.METHODSWe evaluated 42 participants who sequentially underwent RIC AHSCT five years after the last participant was treated. Progression was defined as reinitiation of DMARDs or worsening end-organ failure. We determined overall survival (OS) and progression-free survival (PFS) by the Kaplan-Meier method and identified pre-transplant characteristics associated with OS or PFS by multivariable Cox regression.RESULTSAll participants had evidence of SSc with cardiac involvement. 95% of participants had interstitial lung disease. The median percent predicted forced vital capacity and diffusing capacity of the lungs for carbon monoxide was 62% and 45%, respectively. The five-year OS was 75% (95% confidence interval [CI]: 63-90%), and five-year PFS was 59% (95% CI: 46-76%). Pre-transplant supplemental oxygen use (HR: 7.88, p<.01) and elevated B-type natriuretic peptide (BNP [HR: 1.005 per pg/mL, p<.01]) was associated with mortality. Anti-Scl-70 antibody positivity (HR: 3.03, p=.02) was associated with progression. 24 participants (57%) who did not use supplemental oxygen and had BNP < 100 pg/mL pre-transplant had a five-year OS of 91% (95% CI: 80-100%).CONCLUSIONRIC AHSCT is safe for patients with severe manifestations from SSc. Supplemental oxygen use, elevated BNP, and anti-Scl-70 antibody positivity were risk factors for worse outcomes after RIC AHSCT.
{"title":"Long-Term Outcomes of Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation for Systemic Sclerosis Patients with Impaired Cardiac Function.","authors":"Yonatan Lean,Carrie Richardson,Anthony Esposito,Katy Bedjeti,George E Georges","doi":"10.1002/art.70031","DOIUrl":"https://doi.org/10.1002/art.70031","url":null,"abstract":"OBJECTIVEHigh intensity conditioning autologous hematopoietic stem cell transplantation (AHSCT) is standard of care for patients with advanced SSc. The role of reduced intensity conditioning (RIC) prior to AHSCT in this population remains unclear. We conducted this study to determine the long-term outcomes of RIC AHSCT in SSc patients with cardiac involvement.METHODSWe evaluated 42 participants who sequentially underwent RIC AHSCT five years after the last participant was treated. Progression was defined as reinitiation of DMARDs or worsening end-organ failure. We determined overall survival (OS) and progression-free survival (PFS) by the Kaplan-Meier method and identified pre-transplant characteristics associated with OS or PFS by multivariable Cox regression.RESULTSAll participants had evidence of SSc with cardiac involvement. 95% of participants had interstitial lung disease. The median percent predicted forced vital capacity and diffusing capacity of the lungs for carbon monoxide was 62% and 45%, respectively. The five-year OS was 75% (95% confidence interval [CI]: 63-90%), and five-year PFS was 59% (95% CI: 46-76%). Pre-transplant supplemental oxygen use (HR: 7.88, p<.01) and elevated B-type natriuretic peptide (BNP [HR: 1.005 per pg/mL, p<.01]) was associated with mortality. Anti-Scl-70 antibody positivity (HR: 3.03, p=.02) was associated with progression. 24 participants (57%) who did not use supplemental oxygen and had BNP < 100 pg/mL pre-transplant had a five-year OS of 91% (95% CI: 80-100%).CONCLUSIONRIC AHSCT is safe for patients with severe manifestations from SSc. Supplemental oxygen use, elevated BNP, and anti-Scl-70 antibody positivity were risk factors for worse outcomes after RIC AHSCT.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"93 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777486","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}
Ellen Romich,Joshua F Baker,Thomas R Riley,Ian Green,Rennie L Rhee,Carol A McAlear,Ulrich Specks,Rona M Smith,David R Jayne,Peter A Merkel,
OBJECTIVETo determine risk factors for relapse of ANCA-associated vasculitis (AAV) after re-induction of remission with rituximab and discontinuation of maintenance therapy.METHODSThis is a post-hoc analysis of the RITAZAREM clinical trial. Patients 15 years or older with AAV and a positive test for anti-proteinase-3 (PR3-) or anti-myeloperoxidase (MPO)-ANCA who achieved remission after re-induction with rituximab and glucocorticoids were randomized at month 4 to receive continued rituximab or azathioprine for a maintenance period up to 24 months, followed by observation until relapse or up to 48 months. Generalized estimating equations logistic regression identified baseline and time-varying risk factors for relapse by the next visit for the two study phases: maintenance (months 4-24) and off-treatment (months 24-48).RESULTSAmong 170 patients (median (IQR) age 59 (48-68) years, disease duration 5 (2-10) years), 99 relapses occurred (46 during maintenance). During maintenance, musculoskeletal involvement (odds ratio (OR) [95% confidence interval (CI)]: 2.8 [1.1, 7.2], p=0.03) and higher patient global assessment (OR [95% CI]: 1.1 [1.0, 1.2], p=0.04) were associated with relapse. During the off-treatment phase, presence of CD19+ B-cells (OR [95% CI]: 2.5 [1.2, 5.1], p=0.01) and reappearance of ANCA (OR [95% CI]: 3.2 [1.3, 7.7], p=0.01) were each associated with higher relapse risk. Multivariable analysis identified markers of inflammation (changes in platelets, white blood cells, and immunoglobulin A) associated with relapse.CONCLUSIONSRisk factors for relapse in AAV vary by treatment phase. Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal.
{"title":"Risk factors for relapse in ANCA-associated vasculitis among patients with relapse after induction of remission with rituximab.","authors":"Ellen Romich,Joshua F Baker,Thomas R Riley,Ian Green,Rennie L Rhee,Carol A McAlear,Ulrich Specks,Rona M Smith,David R Jayne,Peter A Merkel, ","doi":"10.1002/art.70025","DOIUrl":"https://doi.org/10.1002/art.70025","url":null,"abstract":"OBJECTIVETo determine risk factors for relapse of ANCA-associated vasculitis (AAV) after re-induction of remission with rituximab and discontinuation of maintenance therapy.METHODSThis is a post-hoc analysis of the RITAZAREM clinical trial. Patients 15 years or older with AAV and a positive test for anti-proteinase-3 (PR3-) or anti-myeloperoxidase (MPO)-ANCA who achieved remission after re-induction with rituximab and glucocorticoids were randomized at month 4 to receive continued rituximab or azathioprine for a maintenance period up to 24 months, followed by observation until relapse or up to 48 months. Generalized estimating equations logistic regression identified baseline and time-varying risk factors for relapse by the next visit for the two study phases: maintenance (months 4-24) and off-treatment (months 24-48).RESULTSAmong 170 patients (median (IQR) age 59 (48-68) years, disease duration 5 (2-10) years), 99 relapses occurred (46 during maintenance). During maintenance, musculoskeletal involvement (odds ratio (OR) [95% confidence interval (CI)]: 2.8 [1.1, 7.2], p=0.03) and higher patient global assessment (OR [95% CI]: 1.1 [1.0, 1.2], p=0.04) were associated with relapse. During the off-treatment phase, presence of CD19+ B-cells (OR [95% CI]: 2.5 [1.2, 5.1], p=0.01) and reappearance of ANCA (OR [95% CI]: 3.2 [1.3, 7.7], p=0.01) were each associated with higher relapse risk. Multivariable analysis identified markers of inflammation (changes in platelets, white blood cells, and immunoglobulin A) associated with relapse.CONCLUSIONSRisk factors for relapse in AAV vary by treatment phase. Monitoring markers of inflammation and immune reconstitution may identify patients at risk for relapse, particularly after treatment withdrawal.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"1 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777487","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 Trevisan, Manuela Pardeo, Ivan Caiello, Claudia Bracaglia, Arianna de Matteis, Valentina Matteo, Elena Loricchio, Fabrizio De Benedetti, Giusi Prencipe
Objective To evaluate the prognostic utility of circulating Interleukin‐18 (IL‐18) levels in predicting disease activity, macrophage activation syndrome (MAS), and disease course in Still's disease (SD) patients receiving first‐line IL‐1 inhibitors (IL‐1i). Methods We retrospectively analyzed 66 biologic‐naïve SD patients who received first‐line treatment with IL‐1i. Plasma IL‐18 levels were measured at baseline and at 3, 6, and 12 months after IL‐1i initiation. Associations between IL‐18 levels and clinical outcomes were assessed using mixed‐effects models, receiver operating characteristic (ROC) curve analysis, and multivariate logistic regression. Results Median baseline IL‐18 levels were 61,425 pg/ml (IQR 16,194‐235,746) and declined significantly after IL‐1 blockade (p<0.0001). Higher IL‐18 levels persisted in patients with active disease (p<0.0001). Baseline IL‐18 >45,000 pg/ml predicted active disease at 12 months (AUC 0.82, p=0.0002), MAS development within 24 months (AUC 0.78, p=0.01), and a chronic‐persistent course (AUC 0.73, p=0.007). In multivariate models, elevated baseline IL‐18 and delayed IL‐1i initiation >3 months independently predicted adverse outcomes. Strikingly, at 3 months, IL‐18 >15,000 pg/ml was a stronger predictor of chronic‐persistent course (AUC 0.92, p<0.0001), independent of clinical disease activity (OR 25.6; p=0.01), with the multivariate model explaining 67% of variance (AUC 0.95). Conclusions In biologic‐naïve SD patients, IL‐18 levels, especially reassessed 3 months after IL‐1i initiation, robustly predict long‐term disease activity, MAS risk, and chronic‐persistent trajectory. Early measurement and dynamic monitoring of IL‐18 may enable risk stratification and guide timely therapeutic escalation or treatment adjustment to improve outcomes. image
{"title":"Interleukin‐18 levels are associated with disease course in patients with Still's disease treated with IL ‐1 inhibitors","authors":"Matteo Trevisan, Manuela Pardeo, Ivan Caiello, Claudia Bracaglia, Arianna de Matteis, Valentina Matteo, Elena Loricchio, Fabrizio De Benedetti, Giusi Prencipe","doi":"10.1002/art.70024","DOIUrl":"https://doi.org/10.1002/art.70024","url":null,"abstract":"Objective To evaluate the prognostic utility of circulating Interleukin‐18 (IL‐18) levels in predicting disease activity, macrophage activation syndrome (MAS), and disease course in Still's disease (SD) patients receiving first‐line IL‐1 inhibitors (IL‐1i). Methods We retrospectively analyzed 66 biologic‐naïve SD patients who received first‐line treatment with IL‐1i. Plasma IL‐18 levels were measured at baseline and at 3, 6, and 12 months after IL‐1i initiation. Associations between IL‐18 levels and clinical outcomes were assessed using mixed‐effects models, receiver operating characteristic (ROC) curve analysis, and multivariate logistic regression. Results Median baseline IL‐18 levels were 61,425 pg/ml (IQR 16,194‐235,746) and declined significantly after IL‐1 blockade (p<0.0001). Higher IL‐18 levels persisted in patients with active disease (p<0.0001). Baseline IL‐18 >45,000 pg/ml predicted active disease at 12 months (AUC 0.82, p=0.0002), MAS development within 24 months (AUC 0.78, p=0.01), and a chronic‐persistent course (AUC 0.73, p=0.007). In multivariate models, elevated baseline IL‐18 and delayed IL‐1i initiation >3 months independently predicted adverse outcomes. Strikingly, at 3 months, IL‐18 >15,000 pg/ml was a stronger predictor of chronic‐persistent course (AUC 0.92, p<0.0001), independent of clinical disease activity (OR 25.6; p=0.01), with the multivariate model explaining 67% of variance (AUC 0.95). Conclusions In biologic‐naïve SD patients, IL‐18 levels, especially reassessed 3 months after IL‐1i initiation, robustly predict long‐term disease activity, MAS risk, and chronic‐persistent trajectory. Early measurement and dynamic monitoring of IL‐18 may enable risk stratification and guide timely therapeutic escalation or treatment adjustment to improve outcomes. <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/art70024-toc-0001-m.png\"> <jats:alt-text>image</jats:alt-text> </jats:graphic> </jats:boxed-text>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"13 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759789","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}
Amala Ambati, Feiyang Ma, Katarina Kmetova, Sherwin Navaz, Claire K. Hoy, Cyrus Sarosh, Ajay Tambralli, Erika Navarro‐Mendoza, Johann E. Gudjonsson, J. Michelle Kahlenberg, Jacqueline A. Madison, Alí Duarte‐García, Jason S. Knight, Yu Zuo
Objective Antiphospholipid syndrome ( APS ) is a thrombo‐inflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody ( aPL )‐positive patients using whole‐blood transcriptomics. Methods Whole‐blood RNA sequencing was performed on 174 aPL‐positive patients, including those with primary APS (n=102), secondary APS (n=29), and aPL‐positivity without classifiable APS (n=43). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes. Results Four transcriptionally distinct clusters were identified. At one end of the spectrum, Cluster 1 showed upregulation of ribosomal and metabolic pathways and downregulation of mTOR, NETosis, and Hippo/IL‐6 signaling. In contrast, Cluster 4 exhibited the opposite pattern, with strong upregulation of mTOR, NETosis, and Hippo/IL‐6 signaling. Cluster 2 demonstrated modest enrichment in mRNA processing and amino acid metabolism, and Cluster 3 showed biosynthetic suppression with mild Hippo/IL‐6 activation. Clinically, Cluster 4 stood out with higher aCL and aβ2GPI IgG positivity, elevated neutrophil counts, and increased urine protein‐to‐creatinine ratios. Immune deconvolution revealed distinct cell‐type profiles: Cluster 1 was lymphoid‐predominant; Cluster 2 had a balanced composition; Cluster 3 was enriched in regulatory T cells, NK cells, macrophages, mast cells, and memory B cells; and Cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features including white matter lesions, seizures, and cardiac valve disease. Conclusion This study reveals four endotypes of aPL‐positive patients, a step toward personalized medicine for APS through pathway‐informed stratification and therapy.
{"title":"Molecular stratification of antiphospholipid syndrome through integrative analysis of the whole‐blood RNA transcriptome","authors":"Amala Ambati, Feiyang Ma, Katarina Kmetova, Sherwin Navaz, Claire K. Hoy, Cyrus Sarosh, Ajay Tambralli, Erika Navarro‐Mendoza, Johann E. Gudjonsson, J. Michelle Kahlenberg, Jacqueline A. Madison, Alí Duarte‐García, Jason S. Knight, Yu Zuo","doi":"10.1002/art.70021","DOIUrl":"https://doi.org/10.1002/art.70021","url":null,"abstract":"Objective Antiphospholipid syndrome ( APS ) is a thrombo‐inflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody ( aPL )‐positive patients using whole‐blood transcriptomics. Methods Whole‐blood RNA sequencing was performed on 174 aPL‐positive patients, including those with primary APS (n=102), secondary APS (n=29), and aPL‐positivity without classifiable APS (n=43). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes. Results Four transcriptionally distinct clusters were identified. At one end of the spectrum, Cluster 1 showed upregulation of ribosomal and metabolic pathways and downregulation of mTOR, NETosis, and Hippo/IL‐6 signaling. In contrast, Cluster 4 exhibited the opposite pattern, with strong upregulation of mTOR, NETosis, and Hippo/IL‐6 signaling. Cluster 2 demonstrated modest enrichment in mRNA processing and amino acid metabolism, and Cluster 3 showed biosynthetic suppression with mild Hippo/IL‐6 activation. Clinically, Cluster 4 stood out with higher aCL and aβ2GPI IgG positivity, elevated neutrophil counts, and increased urine protein‐to‐creatinine ratios. Immune deconvolution revealed distinct cell‐type profiles: Cluster 1 was lymphoid‐predominant; Cluster 2 had a balanced composition; Cluster 3 was enriched in regulatory T cells, NK cells, macrophages, mast cells, and memory B cells; and Cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features including white matter lesions, seizures, and cardiac valve disease. Conclusion This study reveals four endotypes of aPL‐positive patients, a step toward personalized medicine for APS through pathway‐informed stratification and therapy.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"1 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759790","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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