{"title":"Longitudinal Autoantibody and Proteomic Profiles Uncover Biomarkers and Mechanisms of Disease Progression in Systemic Sclerosis","authors":"Muyao Guo, Sijia Liu, Jing Huang, Ying Long, Yu Wei, Quanzhen Li, Hui Luo, Honglin Zhu","doi":"10.1002/art.43354","DOIUrl":"https://doi.org/10.1002/art.43354","url":null,"abstract":"ObjectiveTo evaluate dynamic changes in autoantibody and proteomic profiles in treatment‐naïve systemic sclerosis (SSc) patients and identify biomarkers and mechanisms associated with disease progression.MethodsSerum samples from 30 baseline and 49 follow‐up SSc patients, along with 38 controls, were analyzed. Autoantibody profiles were assessed using an autoantigen microarray targeting 120 autoantibodies, while proteomic analysis was conducted via liquid chromatography–mass spectrometry in data‐independent acquisition mode. Cox proportional hazards models were used to assess associations with disease progression, and Spearman's correlation was applied to analyze antibody‐protein interactions.ResultsBaseline autoantibody profiling identified two patient subgroups: high‐expression (SSc_high) and low‐expression (SSc_low), though their clinical characteristics were similar. Longitudinal analysis revealed that 88.9% of patients with rising autoantibody titers experienced disease progression, while 60% of those with decreasing titers showed clinical improvement. Notably, increased CENP‐B titers (HR = 5.036) were strongly linked to disease progression. Proteomic analysis identified 112 proteins involved in tissue repair and immune modulation in patients with declining titers and clinical improvement, whereas 46 proteins linked to lipid metabolism and oxidative stress were enriched in those with rising titers and disease progression. SERPINA10 emerged as the strongest risk factor for progression, while ENTPD5 was most protective. Antibody‐protein correlations highlighted key molecular interactions, including SERPINE1 and muscarinic receptor antibodies, were identified.ConclusionDynamic changes in autoantibody titers, rather than baseline levels, were more strongly associated with SSc trajectory. Proteomic signatures suggest lipid metabolism and oxidative stress as potential drivers, highlighting novel biomarkers and therapeutic targets for personalized SSc management.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"48 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850949","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":"Chitinase 3-Like 1 Promotes Endothelial-to-Mesenchymal Transition in Systemic Sclerosis via mTORC1 Signaling Pathway.","authors":"Xiuyuan Wang,Xue Han,Jia Yu,Feifei Hu,Chengjie Huang,Cheng Chen,Liuting Huang,Ying Jiang,Xinzhi Xu,Manna Lin,Junxia Huang,Tianbao Ye,Ji Yang","doi":"10.1002/art.43356","DOIUrl":"https://doi.org/10.1002/art.43356","url":null,"abstract":"OBJECTIVESystemic sclerosis (SSc) is a complicated autoimmune connective tissue disorder. Endothelial-to-mesenchymal transition (EndoMT) contributes to vasculopathy and fibrosis in SSc, yet its underlying mechanism remains to be elucidated. Here, we determined the role and mechanism of chitinase 3-Like 1 (CHI3L1) in SSc EndoMT.METHODSSkin sections were immunostained for detecting the EndoMT and the expression pattern of CHI3L1 in patients with SSc. Human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant CHI3L1 and anti-CHI3L1 antibody (CHI3L1 Ab) to explore the effects of CHI3L1 on endothelial cells (ECs) in vitro. In vivo, the bleomycin (BLM) induced SSc mice were treated with CHI3L1 Ab to investigate the improvement of vasculopathy and fibrosis. Furthermore, proteomics was conducted to explore the specific mechanism by which CHI3L1 induces EndoMT in ECs.RESULTSImmunofluorescence staining of skin sections confirmed EndoMT and the co-localization of CHI3L1 and ECs in patients with SSc. Subsequently, CHI3L1 was demonstrated to facilitate EndoMT in HUVECs. Furthermore, treatment with CHI3L1 Ab in BLM-SSc mice showed alleviation in SSc vasculopathy and fibrosis. Mechanistically, CHI3L1 mediated EndoMT primarily by binding to the CD44 receptor on ECs, then activating the downstream AKT/mTOR complex 1 (mTORC1)/S6K signaling pathway, thereby regulating the EndoMT trigger transcription factors Snail and Slug. Finally, administration of rapamycin, a mTORC1 inhibitor, has been shown to inhibit the CHI3L1 mediated EndoMT process.CONCLUSIONThis research reveals a new function of CHI3L1 in facilitating EndoMT in SSc and highlight CHI3L1 as a promising therapeutic target for SSc.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"36 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825235","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}
Arsene M Mekinian,Sophie Georgin-Lavaille,Marcela A Ferrada,Sinisa Savic,Matthew J Koster,Olivier Kosmider,Thibault Comont,Mael Heilblig,Juan I Arostegui,Annmarie Bosco,Rim Bourguiba,Katherine R Calvo,Catherine Cargo,Chiara Cattaneo,François Chasset,Henrique Coelho,Corrado Campochiaro,Francesca Crisafulli,Stephanie Ducharme-Benard,Raquel Faria,Franco Franceschini,Micol Frassi,Emma M Groarke,Carmelo Gurnari,Yervand Hakobyan,Yvan Jamilloux,Ciprian Jurcut,Yohei Kirino,Austin Kulasekararaj,Hiroyoshi Kunimoto,Lauren M Madigan,Heřman F Mann,Chiara Marvisi,Marcin Milchert,Sara Morais,Katja Sockel,Francesco Muratore,Hideaki Nakajima,Mrinal M Patnaik,Luísa Regadas,Marie Robin,Abraham Rutgers,Carlo Salvarani,Anthony M Sammel,Joerg Seebach,Pierre Sujobert,Alessandro Tomelleri,Geoffrey Urbanski,Frédéric Vandergheynst,Romana Vieira,David S Viswanatha,Ewa Więsik-Szewczyk,Elisa Diral,Benjamin Terrier,Bhavisha A Patel,Pierre Fenaux,Peter C Grayson,David B Beck,
{"title":"American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.","authors":"Arsene M Mekinian,Sophie Georgin-Lavaille,Marcela A Ferrada,Sinisa Savic,Matthew J Koster,Olivier Kosmider,Thibault Comont,Mael Heilblig,Juan I Arostegui,Annmarie Bosco,Rim Bourguiba,Katherine R Calvo,Catherine Cargo,Chiara Cattaneo,François Chasset,Henrique Coelho,Corrado Campochiaro,Francesca Crisafulli,Stephanie Ducharme-Benard,Raquel Faria,Franco Franceschini,Micol Frassi,Emma M Groarke,Carmelo Gurnari,Yervand Hakobyan,Yvan Jamilloux,Ciprian Jurcut,Yohei Kirino,Austin Kulasekararaj,Hiroyoshi Kunimoto,Lauren M Madigan,Heřman F Mann,Chiara Marvisi,Marcin Milchert,Sara Morais,Katja Sockel,Francesco Muratore,Hideaki Nakajima,Mrinal M Patnaik,Luísa Regadas,Marie Robin,Abraham Rutgers,Carlo Salvarani,Anthony M Sammel,Joerg Seebach,Pierre Sujobert,Alessandro Tomelleri,Geoffrey Urbanski,Frédéric Vandergheynst,Romana Vieira,David S Viswanatha,Ewa Więsik-Szewczyk,Elisa Diral,Benjamin Terrier,Bhavisha A Patel,Pierre Fenaux,Peter C Grayson,David B Beck, ","doi":"10.1002/art.43287","DOIUrl":"https://doi.org/10.1002/art.43287","url":null,"abstract":"OBJECTIVEVacuoles E1 enzyme X-linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality.METHODSGiven the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS. To address this gap, we formed an international multidisciplinary panel of VEXAS experts.RESULTSThrough formalized meetings and a voting process, the group developed consensus clinical guidance considerations for the management of VEXAS. These considerations offer practical advice on several key topics: (1) clinical features of VEXAS, (2) UBA1 screening methods, (3) the diagnosis of myelodysplastic syndromes (MDSs) in patients with VEXAS, and (4) prognosis and management. The aim is to provide expert guidance on which patients to test, how to test for VEXAS, how to approach MDS in the context of VEXAS, and considerations for management.CONCLUSIONThis work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"11 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813067","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":"Serum cytokine profiling differentiates underlying diseases in cytokine storm syndrome.","authors":"Shuya Kaneko,Maho Hatano,Asami Shimbo,Futaba Miyaoka,Hitoshi Irabu,Yuko Akutsu,Yuko Hayashi,Mao Mizuta,Yasuo Nakagishi,Keiji Akamine,Naomi Iwata,Kenji Furuno,Takayuki Tanaka,Kazuyuki Ueno,Shuhei Fujita,Koji Yokoyama,Toshinori Minato,Kazushi Izawa,Takahiro Yasumi,Tadashi Matsubayashi,Tadashi Hosoya,Hiroki Nishikawa,Junya Fujimura,Ryoko Asano,Yuko Sugita,Kenichi Watanabe,Anna Kobayashi,Takuya Endo,Katsuhide Eguchi,Ryuta Nishikomori,Ryuhei Yasuoka,Takaki Asano,Miyako Kanno,Kazuya Hamada,Yuji Fujita,Daisuke Hayashi,Shojiro Watanabe,Takeshi Shiba,Shinsuke Yasuda,Masaaki Mori,Hirokazu Kanegane,Masatoshi Takagi,Masaki Shimizu","doi":"10.1002/art.43349","DOIUrl":"https://doi.org/10.1002/art.43349","url":null,"abstract":"OBJECTIVECytokine storm syndrome (CSS), commonly associated with hemophagocytic lymphohistiocytosis (HLH), is a fatal hyperinflammatory syndrome. Differentiating the underlying diseases responsible for CSS is essential for timely therapeutic decisions. This study explored the clinical usefulness of serum cytokine profiling in distinguishing underlying diseases in patients with CSS.METHODSSerum samples were collected from 143 adult and pediatric patients with CSS and 22 healthy controls. The cohort included patients with various diagnoses of primary and secondary HLH, and Kawasaki disease (KD)-like hyperinflammatory syndromes. Serum levels of 48 cytokines were analyzed in 97 patients using a bead-based multiplex immunoassay (Luminex assay). Serum levels of IFN-α, IL-18, IL-6, CXCL9, and sTNF-RII were measured in 165 participants using enzyme-linked immunosorbent assay (ELISA).RESULTSLuminex assay categorized patients with CSS into five clusters based on serum cytokine patterns. ELISA revealed distinct cytokine patterns, wherein patients with histiocytic necrotizing lymphadenitis-associated HLH and systemic lupus erythematosus-associated-MAS showed elevated IFN-α; systemic juvenile idiopathic arthritis- and adult-onset Still's disease-associated MAS, XIAP deficiency with HLH, and NLRC4-associated autoinflammatory disorder exhibited higher IL-18 levels. Additionally, KD shock syndrome had higher IL-6 levels than the other groups. CXCL9 was significantly elevated in patients with virus-associated HLH, familial HLH, malignant lymphoma-associated HLH, and KD-MAS. Multisystem inflammatory syndrome in children and toxic shock syndrome also showed moderate elevations of CXCL9 and IL-6 levels.CONCLUSIONSerum cytokine profiling effectively differentiates CSS subtypes, facilitating better diagnosis and personalized treatment strategies based on specific disease backgrounds.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"156 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144796796","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}
Benjamin Klein,Deborah J Colesa,Yiqing Gao,Patrick A O'Brien,Lin Zhang,Lori Lowe,Kelsey E McNeely,Nguyen Thi Kim Nguyen,Svenja Henning,Mehrnaz Gharaee-Kermani,Jeffrey B Hodgin,Jacob W S Martens,Johann E Gudjonsson,Celine C Berthier,J Michelle Kahlenberg
{"title":"Epidermal Interferon kappa drives cutaneous lupus-like lesions, photosensitivity and systemic autoimmunity in vivo.","authors":"Benjamin Klein,Deborah J Colesa,Yiqing Gao,Patrick A O'Brien,Lin Zhang,Lori Lowe,Kelsey E McNeely,Nguyen Thi Kim Nguyen,Svenja Henning,Mehrnaz Gharaee-Kermani,Jeffrey B Hodgin,Jacob W S Martens,Johann E Gudjonsson,Celine C Berthier,J Michelle Kahlenberg","doi":"10.1002/art.43350","DOIUrl":"https://doi.org/10.1002/art.43350","url":null,"abstract":"OBJECTIVEKeratinocyte-derived interferon kappa (IFN-κ) is chronically overexpressed in human non-lesional systemic lupus erythematosus (SLE) skin. Recent evidence suggests that epidermal signals instruct the immune system in SLE, but whether epidermal IFN-κ alone is sufficient to drive lupus phenotypes has not been investigated. This study aimed to identify whether epidermal-specific overexpression of Interferon kappa (Ifnk) results in lupus-like cutaneous and systemic inflammation.METHODSWe compared three month (young) and twelve month (aged) old Balb/c mice that overexpress Ifnk in the epidermis under the keratin 14 promoter (transgenic, TG) with age-matched Balb/c wild type mice (WT) and assessed local and systemic immune responses at baseline and after UV exposure. Skin lesions were assessed by histopathology, bulk RNA sequencing and immunohistochemistry and subsequently compared to human cutaneous lupus erythematosus (CLE). Flow cytometry on lymph nodes and splenocytes at baseline and after UV exposure was performed to phenotype immune cell compositions.RESULTSIfnk TG mice spontaneously develop CLE-like lesions and systemic immune dysregulation. Lesions show facial predominance, lymphocytic infiltration, immune complex deposition and a transcriptional signature reflective of human CLE. Ifnk TG mice exhibit increased immune cell activation and spontaneous signs of systemic autoimmunity with higher anti-dsDNA-antibodies, lymphadenopathy and splenomegaly, but lack signs of renal inflammation. UV exposure enhanced cutaneous inflammation and splenic T cell activation in Ifnk TG mice.CONCLUSIONTogether, we describe a new CLE mouse model that recapitulates features of human CLE and substantiates the role of epidermal IFN-κ as a driver of CLE, photosensitivity and systemic inflammation.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"17 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144796797","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":"When less is more, none can be even better: Rethinking routine follow-up of chronic disease exemplified with rheumatoid arthritis.","authors":"Alen Brkic,Glenn Haugeberg","doi":"10.1002/art.43346","DOIUrl":"https://doi.org/10.1002/art.43346","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"1 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769785","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}
Hiroyuki Nakamura,Tsutomu Tanaka,Masayuki Noguchi,Tatsuya Atsumi,Blake M Warner,John A Chiorini
{"title":"Investigation of Lysosome-Associated Membrane Protein 3 Highlights the Role of Lysosome in Pathophysiology and Treatment of Sjögren's Disease.","authors":"Hiroyuki Nakamura,Tsutomu Tanaka,Masayuki Noguchi,Tatsuya Atsumi,Blake M Warner,John A Chiorini","doi":"10.1002/art.43347","DOIUrl":"https://doi.org/10.1002/art.43347","url":null,"abstract":"Lysosome-associated membrane protein 3 (LAMP3) is a unique lysosomal membrane protein specifically expressed in mature dendritic cells and type II pneumocytes. Its ectopic expression in salivary gland epithelial cells (SGECs) is induced by type I interferon (IFN) signaling and further amplified through Toll-like receptor 7 (TLR7) activation, which is implicated in the pathogenesis of Sjögren's disease (SjD). This aberrant upregulation disrupts glandular function by promoting endolysosomal degradation of aquaporin 5 (AQP5) and Na-K-Cl cotransporter-1, leading to impaired fluid secretion and associated clinical sequelae (e.g., dry mouth). Additionally, LAMP3-mediated lysosomal exocytosis of damage-associated molecular patterns enhances monocytic bone morphogenetic protein 6 (BMP6) production, which in turn suppresses AQP5 transcription. Moreover, LAMP3 drives the extracellular vesicle-mediated release of autoantigens, which further amplifies autoimmunity, and lysosome-dependent cell death in SGECs contributes to tissue damage. These findings establish LAMP3 as a pivotal regulatory hinge in SjD pathogenesis, linking IFN-TLR7 signaling, lysosomal dysfunction, and glandular hypofunction. Its central role makes it a compelling therapeutic target, with strategies including IFN and TLR7 pathway inhibitors to limit its induction, restoration of lysosomal function, BMP6 inhibition to preserve AQP5 expression, and aquaporin gene therapy to improve fluid secretion.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"15 1","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769781","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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