Pub Date : 2025-10-10DOI: 10.1016/j.jaut.2025.103491
Yindi Liu , Joris A.J. Osinga , Ulla Feldt-Rasmussen , Tanja G.M. Vrijkotte , Peter N. Taylor , Ashraf Aminorroaya , Ghalia Ashoor , Sofie Bliddal , Liang-Miao Chen , Bijay Vaidya , Glenn E. Palomaki , Farkhanda Ghafoor , Abel López-Bermejo , Victor J.M. Pop , Sachiko Itoh , Fang-biao Tao , Lorena Mosso , Tuija Männistö , Kris G. Poppe , Elizabeth N. Pearce , Tim I.M. Korevaar
<div><h3>Background</h3><div>Thyroid peroxidase antibody (TPOAb) positivity is the most important risk factor for hypothyroidism and determines thyroid function follow-up during pregnancy. TPOAb positivity is usually defined by manufacturer cut-offs which typically derived from non-pregnant populations. However, as a state of immune tolerance, pregnancy can affect TPOAb concentrations. To improve the understanding of clinical relevance of TPOAb concentrations during pregnancy, we investigated the association of TPOAbs with maternal thyroid function.</div></div><div><h3>Methods</h3><div>We performed an individual participant data meta-analysis embedded in the Consortium on Thyroid and Pregnancy. Participants with multiple gestations, pre-existing thyroid disease, thyroid (interfering) medication usage, or conception by in vitro fertilization were excluded. We used mixed effects regression models to assess the association of TPOAb percentiles calculated in each cohort with maternal thyroid function.</div></div><div><h3>Results</h3><div>The study population comprised 62,634 pregnant women from 24 cohorts. As compared to TPOAb percentiles ≤80, there were progressively higher mean thyroid stimulating hormone (TSH) concentrations across TPOAb percentiles ≥89, with corresponding mean differences ranging from +0.11 SD (95 % confidence interval [CI] +0.04 SD, +0.19 SD) at the 89th percentile to +1.04 SD (95 % CI + 0.96 SD, 1.11 SD) at the 100th percentile. Higher TPOAb percentiles were associated with progressively lower mean free thyroxine (FT4) concentrations across TPOAb percentiles ≥91, with corresponding mean differences ranging from −0.08 SD (95 % CI -0.16 SD, −0.01 SD) at the 91st percentile to −0.48 SD (95 % CI -0.56 SD, −0.4 SD) at the 100th percentile. From the 89th TPOAb percentile upwards, there were progressively higher risks of TSH >4.0 mU/L, with absolute risks of 2.4 %, 4.0 %, and 28.1 % in cases of ≤80th, 89th, and 100th TPOAb percentiles, respectively. Higher TPOAb percentiles were also associated with lower thyroidal response to human chorionic gonadotropin stimulation and higher risks of overt and subclinical hypothyroidism. In 19 of the included cohorts, there were 0.4–6.3 % of pregnant women with TPOAb concentrations lower than the positivity cut-offs but larger than or equal to the 89th-percentile concentrations. The associations of TPOAbs with TSH and with FT4 were most apparent during early pregnancy (<em>P</em> for interaction <0.001 for both TSH and FT4).</div></div><div><h3>Conclusions</h3><div>During pregnancy, TPOAbs were dose-dependently associated with TSH, FT4, and the risk of abnormal thyroid function. With concentrations below currently used positivity cut-offs, TPOAbs could be associated with lower maternal thyroid function, which indicates clinically relevant thyroid autoimmunity. These findings implicates that high normal TPOAb concentrations upon first assessment in pregnancy may warrant active follow-up.</div>
{"title":"Interpretation of the association between thyroid peroxidase antibodies and thyroid function during pregnancy: An individual participant data meta-analysis","authors":"Yindi Liu , Joris A.J. Osinga , Ulla Feldt-Rasmussen , Tanja G.M. Vrijkotte , Peter N. Taylor , Ashraf Aminorroaya , Ghalia Ashoor , Sofie Bliddal , Liang-Miao Chen , Bijay Vaidya , Glenn E. Palomaki , Farkhanda Ghafoor , Abel López-Bermejo , Victor J.M. Pop , Sachiko Itoh , Fang-biao Tao , Lorena Mosso , Tuija Männistö , Kris G. Poppe , Elizabeth N. Pearce , Tim I.M. Korevaar","doi":"10.1016/j.jaut.2025.103491","DOIUrl":"10.1016/j.jaut.2025.103491","url":null,"abstract":"<div><h3>Background</h3><div>Thyroid peroxidase antibody (TPOAb) positivity is the most important risk factor for hypothyroidism and determines thyroid function follow-up during pregnancy. TPOAb positivity is usually defined by manufacturer cut-offs which typically derived from non-pregnant populations. However, as a state of immune tolerance, pregnancy can affect TPOAb concentrations. To improve the understanding of clinical relevance of TPOAb concentrations during pregnancy, we investigated the association of TPOAbs with maternal thyroid function.</div></div><div><h3>Methods</h3><div>We performed an individual participant data meta-analysis embedded in the Consortium on Thyroid and Pregnancy. Participants with multiple gestations, pre-existing thyroid disease, thyroid (interfering) medication usage, or conception by in vitro fertilization were excluded. We used mixed effects regression models to assess the association of TPOAb percentiles calculated in each cohort with maternal thyroid function.</div></div><div><h3>Results</h3><div>The study population comprised 62,634 pregnant women from 24 cohorts. As compared to TPOAb percentiles ≤80, there were progressively higher mean thyroid stimulating hormone (TSH) concentrations across TPOAb percentiles ≥89, with corresponding mean differences ranging from +0.11 SD (95 % confidence interval [CI] +0.04 SD, +0.19 SD) at the 89th percentile to +1.04 SD (95 % CI + 0.96 SD, 1.11 SD) at the 100th percentile. Higher TPOAb percentiles were associated with progressively lower mean free thyroxine (FT4) concentrations across TPOAb percentiles ≥91, with corresponding mean differences ranging from −0.08 SD (95 % CI -0.16 SD, −0.01 SD) at the 91st percentile to −0.48 SD (95 % CI -0.56 SD, −0.4 SD) at the 100th percentile. From the 89th TPOAb percentile upwards, there were progressively higher risks of TSH >4.0 mU/L, with absolute risks of 2.4 %, 4.0 %, and 28.1 % in cases of ≤80th, 89th, and 100th TPOAb percentiles, respectively. Higher TPOAb percentiles were also associated with lower thyroidal response to human chorionic gonadotropin stimulation and higher risks of overt and subclinical hypothyroidism. In 19 of the included cohorts, there were 0.4–6.3 % of pregnant women with TPOAb concentrations lower than the positivity cut-offs but larger than or equal to the 89th-percentile concentrations. The associations of TPOAbs with TSH and with FT4 were most apparent during early pregnancy (<em>P</em> for interaction <0.001 for both TSH and FT4).</div></div><div><h3>Conclusions</h3><div>During pregnancy, TPOAbs were dose-dependently associated with TSH, FT4, and the risk of abnormal thyroid function. With concentrations below currently used positivity cut-offs, TPOAbs could be associated with lower maternal thyroid function, which indicates clinically relevant thyroid autoimmunity. These findings implicates that high normal TPOAb concentrations upon first assessment in pregnancy may warrant active follow-up.</div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103491"},"PeriodicalIF":7.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145268017","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}
Pub Date : 2025-10-01DOI: 10.1016/j.jaut.2025.103489
Yiyang Wang , Shaoying Yang , Ye Yu , Peng Xia , Cuiwei Xie , Chunyan Zhang , Liangjing Lu
Background
Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative treatment in autoimmune diseases. Relmacabtagene autoleucel (relma‐cel) is an autologous, CD19-directed CAR-T cell product developed with a commercial-ready process in China. This study evaluates the safety and efficacy of relma‐cel in patients with moderately to severely active systemic lupus erythematosus (SLE).
Methods
In this phase I, single-arm, dose escalation study, 8 female patients with moderately to severely active SLE were enrolled. All patients received a single infusion of relma‐cel at escalating doses (50 × 106, 75 × 106, or 100 × 106 CAR-T cells) after preconditioning with fludarabine and cyclophosphamide. The primary endpoints included the incidence of dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs). Secondary endpoints comprised pharmacokinetics, pharmacodynamics, and efficacy, which was evaluated by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), SLE Responder Index (SRI)-4, Lupus Low Disease Activity State (LLDAS), and Definition of Remission in SLE (DORIS) remission criteria.
Results
No dose-limiting toxicities were reported. Adverse events were manageable, with cytokine release syndrome (CRS) occurred in 7 patients and immune effector cell-associated neurotoxicity syndrome (ICANS) in 1 patient. The mean SLEDAI-2K score of patients decreased from 12.625 at baseline to 3.25 at follow-up. All patients achieved an SRI-4 response at 6 months, with 6 patients meeting LLDAS criteria and 5 achieving DORIS remission. Improvements in renal function and complement levels were also noted.
Conclusions
Relma-cel demonstrates a manageable safety profile and promising efficacy in patients with moderately to severely active SLE. A dose of 100 × 106 CAR-T cells was identified as the recommended phase II dose based on clinical response and tolerability.
{"title":"Preliminary safety and efficacy of relmacabtagene autoleucel (relma-cel) in adults with moderately to severely active systemic lupus erythematosus: a phase I dose-escalation study","authors":"Yiyang Wang , Shaoying Yang , Ye Yu , Peng Xia , Cuiwei Xie , Chunyan Zhang , Liangjing Lu","doi":"10.1016/j.jaut.2025.103489","DOIUrl":"10.1016/j.jaut.2025.103489","url":null,"abstract":"<div><h3>Background</h3><div>Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative treatment in autoimmune diseases. Relmacabtagene autoleucel (relma‐cel) is an autologous, CD19-directed CAR-T cell product developed with a commercial-ready process in China. This study evaluates the safety and efficacy of relma‐cel in patients with moderately to severely active systemic lupus erythematosus (SLE).</div></div><div><h3>Methods</h3><div>In this phase I, single-arm, dose escalation study, 8 female patients with moderately to severely active SLE were enrolled. All patients received a single infusion of relma‐cel at escalating doses (50 × 10<sup>6</sup>, 75 × 10<sup>6</sup>, or 100 × 10<sup>6</sup> CAR-T cells) after preconditioning with fludarabine and cyclophosphamide. The primary endpoints included the incidence of dose-limiting toxicities (DLTs), adverse events (AEs), and serious adverse events (SAEs). Secondary endpoints comprised pharmacokinetics, pharmacodynamics, and efficacy, which was evaluated by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), SLE Responder Index (SRI)-4, Lupus Low Disease Activity State (LLDAS), and Definition of Remission in SLE (DORIS) remission criteria.</div></div><div><h3>Results</h3><div>No dose-limiting toxicities were reported. Adverse events were manageable, with cytokine release syndrome (CRS) occurred in 7 patients and immune effector cell-associated neurotoxicity syndrome (ICANS) in 1 patient. The mean SLEDAI-2K score of patients decreased from 12.625 at baseline to 3.25 at follow-up. All patients achieved an SRI-4 response at 6 months, with 6 patients meeting LLDAS criteria and 5 achieving DORIS remission. Improvements in renal function and complement levels were also noted.</div></div><div><h3>Conclusions</h3><div>Relma-cel demonstrates a manageable safety profile and promising efficacy in patients with moderately to severely active SLE. A dose of 100 × 10<sup>6</sup> CAR-T cells was identified as the recommended phase II dose based on clinical response and tolerability.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103489"},"PeriodicalIF":7.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212819","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}
Despite treatment advances, some rheumatoid arthritis (RA) patients fail to achieve remission with biological/targeted synthetic DMARDs. We prospectively evaluated 200 patients to determine if interferon profiles and autoantibodies predict treatment outcomes. A significant positive correlation between rheumatoid factor and IFN-γ levels was observed. Patients with high IFN-γ/low IFN-α2 profiles achieved significantly higher remission rates and demonstrated elevated B cell-stimulating cytokines with distinct immunological clustering patterns. This group showed superior responses to IL-6 inhibitors. Anti-carbamylated protein IgM antibodies differed significantly between groups. Interferon profiling offers a practical screening approach for personalized therapy selection in RA.
{"title":"Treatment outcomes stratified by interferon profile and autoantibodies in rheumatoid arthritis","authors":"Shoichi Fukui , Tohru Michitsuji , Yushiro Endo , Ayako Nishino , Kaori Furukawa , Toshimasa Shimizu , Masataka Umeda , Remi Sumiyoshi , Tomohiro Koga , Naoki Iwamoto , Mami Tamai , Tomoki Origuchi , K.A. van Schie , Yukitaka Ueki , Nobutaka Eiraku , Tamami Yoshitama , Naoki Matsuoka , Takahisa Suzuki , Akitomo Okada , Hiroaki Hamada , Shin-ya Kawashiri","doi":"10.1016/j.jaut.2025.103490","DOIUrl":"10.1016/j.jaut.2025.103490","url":null,"abstract":"<div><div>Despite treatment advances, some rheumatoid arthritis (RA) patients fail to achieve remission with biological/targeted synthetic DMARDs. We prospectively evaluated 200 patients to determine if interferon profiles and autoantibodies predict treatment outcomes. A significant positive correlation between rheumatoid factor and IFN-γ levels was observed. Patients with high IFN-γ/low IFN-α2 profiles achieved significantly higher remission rates and demonstrated elevated B cell-stimulating cytokines with distinct immunological clustering patterns. This group showed superior responses to IL-6 inhibitors. Anti-carbamylated protein IgM antibodies differed significantly between groups. Interferon profiling offers a practical screening approach for personalized therapy selection in RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103490"},"PeriodicalIF":7.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199594","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}
Pub Date : 2025-09-19DOI: 10.1016/j.jaut.2025.103487
Francesco Peyronel , Alessandra Palmisano , Federica Maritati , Federico Alberici , Maria L. Urban , Davide Gianfreda , Giovanni M. Rossi , Paride Fenaroli , Alessandra Bettiol , Gabriella Moroni , Augusto Vaglio
Objectives
To test the efficacy and safety of methotrexate plus low-dose prednisone in patients with idiopathic retroperitoneal fibrosis.
Methods
We conducted an open-label, randomised, active-controlled, non-inferiority phase III trial. Sixty (out of 78 screened) adults with newly diagnosed idiopathic retroperitoneal fibrosis and an estimated glomerular filtration rate >30 mL/min/1.73 m2 were enrolled at outpatient clinics of two Italian centres (Nephrology units of Parma University Hospital and Milano Policlinico Hospital). Patients were randomly assigned (1:1) to receive low-dose prednisone plus methotrexate (MTX + LowPred) or standard-dose prednisone alone (standPred) for nine months. The primary endpoint was remission at month 9. Remission was defined as absence of symptoms and ureteral obstruction (free of stents or nephrostomies), and normal acute-phase reactants; secondary endpoints included reduction in RPF thickness, relapses and treatment-related toxicity.
Results
29 patients received MTX + LowPred and 31 standPred. Twenty-six patients (89.7 %) receiving MTX + LowPred and 25 (80.6 %) receiving standPred achieved and maintained remission until month 9. The difference between remission rates was 9.1 % (95 %CI -9.9 %–27.3 %), meeting the criterion for non-inferiority. Time-to-remission was similar (log-rank test p = 0.549). The two groups showed comparable RPF thickness reduction and relapse rates. The median cumulative prednisone dose was significantly higher in the standPred group (p < 0.001). No significant differences in adverse events were observed.
Conclusions
A low-dose prednisone plus methotrexate regimen is non-inferior to standard-dose prednisone in achieving remission in idiopathic retroperitoneal fibrosis, allowing significant reduction in glucocorticoid exposure.
{"title":"Methotrexate and low-dose prednisone in idiopathic retroperitoneal fibrosis: a randomised clinical trial","authors":"Francesco Peyronel , Alessandra Palmisano , Federica Maritati , Federico Alberici , Maria L. Urban , Davide Gianfreda , Giovanni M. Rossi , Paride Fenaroli , Alessandra Bettiol , Gabriella Moroni , Augusto Vaglio","doi":"10.1016/j.jaut.2025.103487","DOIUrl":"10.1016/j.jaut.2025.103487","url":null,"abstract":"<div><h3>Objectives</h3><div>To test the efficacy and safety of methotrexate plus low-dose prednisone in patients with idiopathic retroperitoneal fibrosis.</div></div><div><h3>Methods</h3><div>We conducted an open-label, randomised, active-controlled, non-inferiority phase III trial. Sixty (out of 78 screened) adults with newly diagnosed idiopathic retroperitoneal fibrosis and an estimated glomerular filtration rate >30 mL/min/1.73 m<sup>2</sup> were enrolled at outpatient clinics of two Italian centres (Nephrology units of Parma University Hospital and Milano Policlinico Hospital). Patients were randomly assigned (1:1) to receive low-dose prednisone plus methotrexate (MTX + LowPred) or standard-dose prednisone alone (standPred) for nine months. The primary endpoint was remission at month 9. Remission was defined as absence of symptoms and ureteral obstruction (free of stents or nephrostomies), and normal acute-phase reactants; secondary endpoints included reduction in RPF thickness, relapses and treatment-related toxicity.</div></div><div><h3>Results</h3><div>29 patients received MTX + LowPred and 31 standPred. Twenty-six patients (89.7 %) receiving MTX + LowPred and 25 (80.6 %) receiving standPred achieved and maintained remission until month 9. The difference between remission rates was 9.1 % (95 %CI -9.9 %–27.3 %), meeting the criterion for non-inferiority. Time-to-remission was similar (log-rank test p = 0.549). The two groups showed comparable RPF thickness reduction and relapse rates. The median cumulative prednisone dose was significantly higher in the standPred group (p < 0.001). No significant differences in adverse events were observed.</div></div><div><h3>Conclusions</h3><div>A low-dose prednisone plus methotrexate regimen is non-inferior to standard-dose prednisone in achieving remission in idiopathic retroperitoneal fibrosis, allowing significant reduction in glucocorticoid exposure.</div></div><div><h3>Trial registration</h3><div>ClinicalTrials.gov: NCT01240850.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103487"},"PeriodicalIF":7.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145099521","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}
Pub Date : 2025-09-18DOI: 10.1016/j.jaut.2025.103488
Xinxin Liu, Chao Wang, Xiuru Guan
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, and its course is often accompanied by multiple organ damage. The mortality rate of SLE exhibits a “bimodal pattern”, namely the early death peak is primarily attributed to infection and lupus activity, while the late death peak lists cardiovascular diseases (CVD) caused by atherosclerosis (AS) as the leading cause of death. Mitochondria, as the hub of energy metabolism and the multi-dimensional regulatory center of cellular functions, play a key role in the occurrence and development of AS plaques under the pathological background of SLE. This review systematically sorted out the mitochondrial dysfunction mechanisms of different immune cells and endothelial cells in SLE, and deeply expounded their influence pathways on the pathological process of AS. Furthermore, this article explores the current clinical treatment strategies for SLE and analyzes the therapeutic potential of mitochondrial-targeted intervention measures.
{"title":"Mitochondrial dysfunction is a potential key mechanism for atherosclerosis predisposition in patients with systemic lupus erythematosus","authors":"Xinxin Liu, Chao Wang, Xiuru Guan","doi":"10.1016/j.jaut.2025.103488","DOIUrl":"10.1016/j.jaut.2025.103488","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, and its course is often accompanied by multiple organ damage. The mortality rate of SLE exhibits a “bimodal pattern”, namely the early death peak is primarily attributed to infection and lupus activity, while the late death peak lists cardiovascular diseases (CVD) caused by atherosclerosis (AS) as the leading cause of death. Mitochondria, as the hub of energy metabolism and the multi-dimensional regulatory center of cellular functions, play a key role in the occurrence and development of AS plaques under the pathological background of SLE. This review systematically sorted out the mitochondrial dysfunction mechanisms of different immune cells and endothelial cells in SLE, and deeply expounded their influence pathways on the pathological process of AS. Furthermore, this article explores the current clinical treatment strategies for SLE and analyzes the therapeutic potential of mitochondrial-targeted intervention measures.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103488"},"PeriodicalIF":7.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086318","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}
Pub Date : 2025-09-17DOI: 10.1016/j.jaut.2025.103484
Xiao Guan , Zhiyi Huang , Jingrong Chen , Xiaoli Fan , Song Guo Zheng
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease with an unclear etiology, in which abnormal copper homeostasis has been shown in the blood and synovial fluid of the joints of patients. As an essential trace element in the human body, copper plays a critical role in various biological processes, including antioxidant defense, angiogenesis, and bone maintenance. However, the accumulation of excessive copper ions has been shown to be positively correlated with disease activity and the degree of inflammation in RA. While copper-bound ceruloplasmin may exert anti-inflammatory effects, excess "free" copper acts as a potent pro-oxidant, driving oxidative stress, cartilage and bone destruction, inflammatory responses, as well as pannus formation. The recently discovered copper-dependent cell death pathway, named cuproptosis, further adds to the complexity of its role in RA. This review integrates current research advances on the double-edged role of copper in the pathogenesis of RA, systematically examines copper-related therapeutic strategies, and finally analyzes their potential applications and challenges. The aim is to harness the physiological functions of copper while mitigating its pathological effects, thereby opening new avenues for the diagnosis and precision treatment of RA.
{"title":"The double-edged sword role of copper in rheumatoid arthritis: Mechanisms, therapeutics, and challenges","authors":"Xiao Guan , Zhiyi Huang , Jingrong Chen , Xiaoli Fan , Song Guo Zheng","doi":"10.1016/j.jaut.2025.103484","DOIUrl":"10.1016/j.jaut.2025.103484","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease with an unclear etiology, in which abnormal copper homeostasis has been shown in the blood and synovial fluid of the joints of patients. As an essential trace element in the human body, copper plays a critical role in various biological processes, including antioxidant defense, angiogenesis, and bone maintenance. However, the accumulation of excessive copper ions has been shown to be positively correlated with disease activity and the degree of inflammation in RA. While copper-bound ceruloplasmin may exert anti-inflammatory effects, excess \"free\" copper acts as a potent pro-oxidant, driving oxidative stress, cartilage and bone destruction, inflammatory responses, as well as pannus formation. The recently discovered copper-dependent cell death pathway, named cuproptosis, further adds to the complexity of its role in RA. This review integrates current research advances on the double-edged role of copper in the pathogenesis of RA, systematically examines copper-related therapeutic strategies, and finally analyzes their potential applications and challenges. The aim is to harness the physiological functions of copper while mitigating its pathological effects, thereby opening new avenues for the diagnosis and precision treatment of RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103484"},"PeriodicalIF":7.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086284","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}
Pub Date : 2025-09-09DOI: 10.1016/j.jaut.2025.103476
Frauke Stascheit , Daniel Schulze , Sophie Lehnerer , Lea Gerischer , Maike Stein , Paolo Doksani , Meret Herdick , Carla Dusemund , Philipp Mergenthaler , Paul Triller , Jan D. Lünemann , Sarah Hoffmann , Andreas Meisel
Objective
New therapeutic options have recently emerged for patients with highly active, acetylcholine receptor antibody–positive (AChR-Ab+) generalized myasthenia gravis (gMG), including fast-acting, endplate-protective agents such as complement C5 inhibitors (C5-I) and neonatal Fc receptor inhibitors (FcRn-I). However, objective biomarkers beyond clinical scoring systems are lacking to guide individualized treatment decisions.
Methods
In this exploratory, prospective real-world study, we assessed serum calprotectin (sCLP) and serum neurofilament light chain (sNfL) levels in a total of 22 AChR-Ab+ gMG patients, who were treatment-naïve for either C5-I or FcRn-I. Changes in biomarker levels were correlated with clinical response, as measured by the Myasthenia Gravis–Activities of Daily Living (MG-ADL) score.
Results
We observed a correlation of changes in sCLP and sNfl with clinical treatment response to C5-I and FcRn-I therapies. Specifically, rising levels of sNfL and sCLP were associated with a poor treatment response, as measured by the MG-ADL score.
Conclusion
Our preliminary findings suggest that markers of systemic inflammation (such as sCLP) and local destruction of the neuromuscular junction (such as sNfL) may assist in treatment decision-making for gMG patients. Larger, multicenter studies are warranted to validate these results and define their clinical utility.
{"title":"Calprotectin and neurofilament serum levels correlate with treatment response in myasthenia gravis under intensified therapy–A pilot study","authors":"Frauke Stascheit , Daniel Schulze , Sophie Lehnerer , Lea Gerischer , Maike Stein , Paolo Doksani , Meret Herdick , Carla Dusemund , Philipp Mergenthaler , Paul Triller , Jan D. Lünemann , Sarah Hoffmann , Andreas Meisel","doi":"10.1016/j.jaut.2025.103476","DOIUrl":"10.1016/j.jaut.2025.103476","url":null,"abstract":"<div><h3>Objective</h3><div>New therapeutic options have recently emerged for patients with highly active, acetylcholine receptor antibody–positive (AChR-Ab<sup>+</sup>) generalized myasthenia gravis (gMG), including fast-acting, endplate-protective agents such as complement C5 inhibitors (C5-I) and neonatal Fc receptor inhibitors (FcRn-I). However, objective biomarkers beyond clinical scoring systems are lacking to guide individualized treatment decisions.</div></div><div><h3>Methods</h3><div>In this exploratory, prospective <em>real-world</em> study, we assessed serum calprotectin (sCLP) and serum neurofilament light chain (sNfL) levels in a total of 22 AChR-Ab<sup>+</sup> gMG patients, who were treatment-naïve for either C5-I or FcRn-I. Changes in biomarker levels were correlated with clinical response, as measured by the Myasthenia Gravis–Activities of Daily Living (MG-ADL) score.</div></div><div><h3>Results</h3><div>We observed a correlation of changes in sCLP and sNfl with clinical treatment response to C5-I and FcRn-I therapies. Specifically, rising levels of sNfL and sCLP were associated with a poor treatment response, as measured by the MG-ADL score.</div></div><div><h3>Conclusion</h3><div>Our preliminary findings suggest that markers of systemic inflammation (such as sCLP) and local destruction of the neuromuscular junction (such as sNfL) may assist in treatment decision-making for gMG patients. Larger, multicenter studies are warranted to validate these results and define their clinical utility.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103476"},"PeriodicalIF":7.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020299","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}
Pub Date : 2025-09-06DOI: 10.1016/j.jaut.2025.103474
Shane Kelly , Mandeep Singh , Amanda Russell , Katherine J.L. Jackson , Timothy J. Peters , Andrew Carr , Anthony D. Kelleher , Matt Field , Matthew Silsby , Dan Suan , Christopher C. Goodnow
Background
In autoimmune disease it is not understood how self-reactive B cells escape immune tolerance checkpoints to produce pathogenic autoantibodies.
Objective
In patients with demyelinating polyneuropathy caused by IgM autoantibodies against myelin associated glycoprotein (MAG) and the sulphated trisaccharide CD57, we aimed to test the hypothesis that B cells making the autoantibody escaped tolerance by acquiring lymphoma driver somatic mutations.
Methods
Deep single-cell RNA, DNA, flow cytometric and antibody specificity analysis of blood from three patients with MAG neuropathy.
Results
MAG autoantibody-producing B cell clones exhibited extensive intraclonal immunoglobulin V(D)J hypermutation. In many of the sub-clonal branches, the replacement:silent ratio of V-region mutations was not different from that expected for unselected mutations, although in some branches the mutations either increased or eliminated binding to MAG and CD57 autoantigens. Prior to intraclonal V(D)J diversification, each clone had acquired a gain-of-function MYD88p.L265P mutation, and some branches had acquired additional somatic mutations in CXCR4, IGLL5 and BTG2. Whilst all MAG-binding clones harboured the MYD88p.L265P mutation, the same mutation was also found in some control, polyclonal B cells. Deep sequencing of different blood cell subsets indicated MYD88p.L265P was confined to B cells.
Conclusion
In three MAG neuropathy patients we find evidence that the self-reactive B cells responsible for their disease acquired a classical lymphoma driver somatic mutation early in their clonal expansion.
{"title":"Lymphoma driver mutations at the root of somatic evolution of nerve-damaging autoantibodies in myelin associated glycoprotein neuropathy","authors":"Shane Kelly , Mandeep Singh , Amanda Russell , Katherine J.L. Jackson , Timothy J. Peters , Andrew Carr , Anthony D. Kelleher , Matt Field , Matthew Silsby , Dan Suan , Christopher C. Goodnow","doi":"10.1016/j.jaut.2025.103474","DOIUrl":"10.1016/j.jaut.2025.103474","url":null,"abstract":"<div><h3>Background</h3><div>In autoimmune disease it is not understood how self-reactive B cells escape immune tolerance checkpoints to produce pathogenic autoantibodies.</div></div><div><h3>Objective</h3><div>In patients with demyelinating polyneuropathy caused by IgM autoantibodies against myelin associated glycoprotein (MAG) and the sulphated trisaccharide CD57, we aimed to test the hypothesis that B cells making the autoantibody escaped tolerance by acquiring lymphoma driver somatic mutations.</div></div><div><h3>Methods</h3><div>Deep single-cell RNA, DNA, flow cytometric and antibody specificity analysis of blood from three patients with MAG neuropathy.</div></div><div><h3>Results</h3><div>MAG autoantibody-producing B cell clones exhibited extensive intraclonal immunoglobulin V(D)J hypermutation. In many of the sub-clonal branches, the replacement:silent ratio of V-region mutations was not different from that expected for unselected mutations, although in some branches the mutations either increased or eliminated binding to MAG and CD57 autoantigens. Prior to intraclonal V(D)J diversification, each clone had acquired a gain-of-function <em>MYD88</em><sup><em>p.L265P</em></sup> mutation, and some branches had acquired additional somatic mutations in <em>CXCR4, IGLL5</em> and <em>BTG2</em>. Whilst all MAG-binding clones harboured the <em>MYD88</em><sup><em>p.L265P</em></sup> mutation, the same mutation was also found in some control, polyclonal B cells. Deep sequencing of different blood cell subsets indicated <em>MYD88</em><sup><em>p.L265P</em></sup> was confined to B cells.</div></div><div><h3>Conclusion</h3><div>In three MAG neuropathy patients we find evidence that the self-reactive B cells responsible for their disease acquired a classical lymphoma driver somatic mutation early in their clonal expansion.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103474"},"PeriodicalIF":7.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005150","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}
Pub Date : 2025-09-01Epub Date: 2025-08-08DOI: 10.1016/j.jaut.2025.103469
Xiaoyan Yi, Priscila L Zimath, Eugenia Martin-Vazquez, Junior Garcia Oliveira, Sayro Jawurek, Alexandra C Title, Burcak Yesildag, Nizar I Mourad, Antoine Buemi, François Pattou, Julie Kerr-Conte, Sabine Costagliola, Mírian Romitti, Decio L Eizirik
Autoimmune diseases, such as type 1 diabetes (T1D) and Hashimoto's thyroiditis (HT), are often studied from an immune perspective with less focus on the target tissue responses. Target tissues, however, are key to disease and engage in a harmful crosstalk with the immune system contributing to their own destruction. We presently integrated transcriptomic data from the target tissues of six autoimmune/inflammatory diseases affecting β-cells (T1D and type 2 diabetes), thyroid (HT), brain (multiple sclerosis and Alzheimer's disease) or the joints (rheumatoid arthritis), using both bulk and single-cell/nucleus RNA-sequencing (sc/snRNA-seq) approaches. Common upregulated pathways were associated with innate/adaptive immunity, antigen presentation and interferon (IFN) signaling. The role of IFNs was confirmed by RNA-seq in human insulin-producing EndoC-βH1 cells and stem cell-derived thyroid follicle cells exposed to IFNα or IFNγ. Commonly upregulated inflammatory gene signatures were explored, and fibroblast growth factor receptor (FGFR) inhibitors emerged as a potential strategy to counteract these inflammatory transcriptional signatures. The effects of the FGFR1 inhibitor PD173074 on IFN-induced immune related genes were evaluated in EndoC-βH1 cells, stem cell-derived islets and adult human islets. We validated the FGFR inhibitor PD173074 as a promising drug for preserving expression of β-cell protective genes (PDL1 and HLA-E) while reducing HLA class I expression and β-cell recognition by diabetogenic pre-proinsulin-specific CD8+ T-cells. In conclusion, we integrated transcriptomic data from the target tissues of autoimmune and inflammatory/degenerative diseases and departing from these data identified the potential beneficial effects of FGFR inhibitors in T1D.
{"title":"Transcriptomics of autoimmune diseases identifies FGFR1 as a target for pancreatic β-cell protection.","authors":"Xiaoyan Yi, Priscila L Zimath, Eugenia Martin-Vazquez, Junior Garcia Oliveira, Sayro Jawurek, Alexandra C Title, Burcak Yesildag, Nizar I Mourad, Antoine Buemi, François Pattou, Julie Kerr-Conte, Sabine Costagliola, Mírian Romitti, Decio L Eizirik","doi":"10.1016/j.jaut.2025.103469","DOIUrl":"10.1016/j.jaut.2025.103469","url":null,"abstract":"<p><p>Autoimmune diseases, such as type 1 diabetes (T1D) and Hashimoto's thyroiditis (HT), are often studied from an immune perspective with less focus on the target tissue responses. Target tissues, however, are key to disease and engage in a harmful crosstalk with the immune system contributing to their own destruction. We presently integrated transcriptomic data from the target tissues of six autoimmune/inflammatory diseases affecting β-cells (T1D and type 2 diabetes), thyroid (HT), brain (multiple sclerosis and Alzheimer's disease) or the joints (rheumatoid arthritis), using both bulk and single-cell/nucleus RNA-sequencing (sc/snRNA-seq) approaches. Common upregulated pathways were associated with innate/adaptive immunity, antigen presentation and interferon (IFN) signaling. The role of IFNs was confirmed by RNA-seq in human insulin-producing EndoC-βH1 cells and stem cell-derived thyroid follicle cells exposed to IFNα or IFNγ. Commonly upregulated inflammatory gene signatures were explored, and fibroblast growth factor receptor (FGFR) inhibitors emerged as a potential strategy to counteract these inflammatory transcriptional signatures. The effects of the FGFR1 inhibitor PD173074 on IFN-induced immune related genes were evaluated in EndoC-βH1 cells, stem cell-derived islets and adult human islets. We validated the FGFR inhibitor PD173074 as a promising drug for preserving expression of β-cell protective genes (PDL1 and HLA-E) while reducing HLA class I expression and β-cell recognition by diabetogenic pre-proinsulin-specific CD8<sup>+</sup> T-cells. In conclusion, we integrated transcriptomic data from the target tissues of autoimmune and inflammatory/degenerative diseases and departing from these data identified the potential beneficial effects of FGFR inhibitors in T1D.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"103469"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812075","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}
Autoimmune diseases pose significant challenges due to the high risks associated with abnormal immune responses to self-antigens and the limitations of broad-spectrum immunosuppressants. Current therapeutic approaches primarily rely on immunosuppressive drugs, yet their non-specificity and side effects urge researchers to explore novel targets and the advancement of precision medicine. Recent advances in targeted protein degradation (TPD) technologies, including PROTAC, MGD and LYTAC, offer therapeutic potential by precisely eliminating pathogenic proteins. By leveraging cellular degradation machinery such as ubiquitin-proteasome an endolysosomal systems to overcome the undruggable targets, these TPD technologies offer promising therapeutic strategies for precise immune regulation. Preclinical studies demonstrate PROTAC-mediated degradation of IRAK4 reduce inflammatory cytokines. RIPK2 degraders are expected to become a new approach for treating inflammatory diseases. While BTK degraders L18I surpass inhibitors in blocking autoantibodies. There are still challenges to overcome, such as delivery barriers, off-target effects and limited E3 ligase diversity. Emerging solutions such as AI-driven design and modular platforms may improve the specificity and efficacy. This review summarizes the underlying mechanisms, therapeutic breakthroughs, and translational hurdles of TPD technologies, and explores how integrating AI can optimize the technologies. TPD strategies have the potential to revolutionize the treatment of autoimmune diseases by providing more targeted and personalized therapies.
{"title":"Targeted protein degradation in autoimmune diseases: from mechanisms to therapeutic breakthroughs","authors":"Yuxin Song, Boyang Zhou, Jiangang Long, Yunhua Peng","doi":"10.1016/j.jaut.2025.103475","DOIUrl":"10.1016/j.jaut.2025.103475","url":null,"abstract":"<div><div>Autoimmune diseases pose significant challenges due to the high risks associated with abnormal immune responses to self-antigens and the limitations of broad-spectrum immunosuppressants. Current therapeutic approaches primarily rely on immunosuppressive drugs, yet their non-specificity and side effects urge researchers to explore novel targets and the advancement of precision medicine. Recent advances in targeted protein degradation (TPD) technologies, including PROTAC, MGD and LYTAC, offer therapeutic potential by precisely eliminating pathogenic proteins. By leveraging cellular degradation machinery such as ubiquitin-proteasome an endolysosomal systems to overcome the undruggable targets, these TPD technologies offer promising therapeutic strategies for precise immune regulation. Preclinical studies demonstrate PROTAC-mediated degradation of IRAK4 reduce inflammatory cytokines. RIPK2 degraders are expected to become a new approach for treating inflammatory diseases. While BTK degraders L18I surpass inhibitors in blocking autoantibodies. There are still challenges to overcome, such as delivery barriers, off-target effects and limited E3 ligase diversity. Emerging solutions such as AI-driven design and modular platforms may improve the specificity and efficacy. This review summarizes the underlying mechanisms, therapeutic breakthroughs, and translational hurdles of TPD technologies, and explores how integrating AI can optimize the technologies. TPD strategies have the potential to revolutionize the treatment of autoimmune diseases by providing more targeted and personalized therapies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103475"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932341","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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