Pub Date : 2025-11-04DOI: 10.1016/j.jaut.2025.103497
Zhenguo Liang , Hui Xie , Mengyun Mao , Bing Hou , James Cheng-Chung Wei , Dongze Wu
Immune-mediated inflammatory diseases (IMIDs, distinct from IMiDs, immunomodulatory drugs) pose major therapeutic challenges due to complex pathophysiology, limited treatment durability, and associated adverse effects. T cell engagers (TCEs) and antibody-drug conjugates (ADCs) offer innovative approaches that leverage antibody specificity to precisely target pathogenic immune cells. TCEs redirect T cell cytotoxicity to eliminate autoreactive B cells and plasma cells, showing efficacy in diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. In contrast, ADCs deliver immunomodulatory payloads to disease-relevant cells, with agents like ABBV-154 and brentuximab vedotin showing promise in rheumatoid arthritis and systemic sclerosis. However, challenges such as cytokine release syndrome with TCEs and off- and on-target toxicities with ADCs highlight the need for optimal target selection and innovative design. This review provides a comprehensive comparison of the mechanisms, current evidence, and future directions of TCEs and ADCs in IMIDs, highlighting their potential to address unmet needs in disease management.
{"title":"Immune mediated inflammatory disease: T cell engager versus antibody drug conjugate","authors":"Zhenguo Liang , Hui Xie , Mengyun Mao , Bing Hou , James Cheng-Chung Wei , Dongze Wu","doi":"10.1016/j.jaut.2025.103497","DOIUrl":"10.1016/j.jaut.2025.103497","url":null,"abstract":"<div><div>Immune-mediated inflammatory diseases (IMIDs, distinct from IMiDs, immunomodulatory drugs) pose major therapeutic challenges due to complex pathophysiology, limited treatment durability, and associated adverse effects. T cell engagers (TCEs) and antibody-drug conjugates (ADCs) offer innovative approaches that leverage antibody specificity to precisely target pathogenic immune cells. TCEs redirect T cell cytotoxicity to eliminate autoreactive B cells and plasma cells, showing efficacy in diseases such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. In contrast, ADCs deliver immunomodulatory payloads to disease-relevant cells, with agents like ABBV-154 and brentuximab vedotin showing promise in rheumatoid arthritis and systemic sclerosis. However, challenges such as cytokine release syndrome with TCEs and off- and on-target toxicities with ADCs highlight the need for optimal target selection and innovative design. This review provides a comprehensive comparison of the mechanisms, current evidence, and future directions of TCEs and ADCs in IMIDs, highlighting their potential to address unmet needs in disease management.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103497"},"PeriodicalIF":7.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145451974","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}
The concept of severity in psoriatic arthritis (PsA) remains inconsistently defined, often conflated with disease activity. This scoping review aimed to explore how severity has been defined in the PsA literature and to identify criteria used to characterize severe disease.
Methods
A scoping review was conducted in April 2025 following PRISMA-ScR guidelines. PubMed was searched for English-language articles from the last 25 years, alongside abstracts from major rheumatology conferences. Eligible studies had to explicitly define or discuss PsA severity. Articles focusing solely on activity, isolated disease manifestations, or other conditions were excluded. Data were extracted on the type of article, definitions of severity, and criteria used.
Results
Of 4,014 records screened, 32 studies met inclusion criteria. Definitions of severity varied widely and were categorized into imaging (e.g., erosions), clinical (e.g., dactylitis, joint counts), and functional (e.g., HAQ-DI scores) criteria. The most commonly used indicators were structural damage, polyarticular involvement, dactylitis, arthritis mutilans, and validated composite indices such as CPDAI. Only a few studies incorporated functional impairment or patient-reported outcomes. While some guidelines, including GRAPPA and ACR/NPF, proposed multidomain frameworks, a standardized definition remains lacking.
Conclusion
The concept of PsA severity has evolved beyond mere disease activity to encompass long-term outcomes, radiographic damage and overall disease burden. However, considerable heterogeneity persists across studies, reflecting the complexity of PsA. A standardized, multidimensional definition of severity, distinct from disease activity, would enhance patient stratification, guide treatment decisions, and support clinical research.
{"title":"The concept of severity in psoriatic arthritis: a scoping review of the literature","authors":"Ennio Lubrano , Mauro Fatica , Rubén Queiro , Fabio Massimo Perrotta","doi":"10.1016/j.jaut.2025.103494","DOIUrl":"10.1016/j.jaut.2025.103494","url":null,"abstract":"<div><h3>Objective</h3><div>The concept of severity in psoriatic arthritis (PsA) remains inconsistently defined, often conflated with disease activity. This scoping review aimed to explore how severity has been defined in the PsA literature and to identify criteria used to characterize severe disease.</div></div><div><h3>Methods</h3><div>A scoping review was conducted in April 2025 following PRISMA-ScR guidelines. PubMed was searched for English-language articles from the last 25 years, alongside abstracts from major rheumatology conferences. Eligible studies had to explicitly define or discuss PsA severity. Articles focusing solely on activity, isolated disease manifestations, or other conditions were excluded. Data were extracted on the type of article, definitions of severity, and criteria used.</div></div><div><h3>Results</h3><div>Of 4,014 records screened, 32 studies met inclusion criteria. Definitions of severity varied widely and were categorized into imaging (e.g., erosions), clinical (e.g., dactylitis, joint counts), and functional (e.g., HAQ-DI scores) criteria. The most commonly used indicators were structural damage, polyarticular involvement, dactylitis, arthritis mutilans, and validated composite indices such as CPDAI. Only a few studies incorporated functional impairment or patient-reported outcomes. While some guidelines, including GRAPPA and ACR/NPF, proposed multidomain frameworks, a standardized definition remains lacking.</div></div><div><h3>Conclusion</h3><div>The concept of PsA severity has evolved beyond mere disease activity to encompass long-term outcomes, radiographic damage and overall disease burden. However, considerable heterogeneity persists across studies, reflecting the complexity of PsA. A standardized, multidimensional definition of severity, distinct from disease activity, would enhance patient stratification, guide treatment decisions, and support clinical research.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103494"},"PeriodicalIF":7.0,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358096","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 : 2025-10-24DOI: 10.1016/j.jaut.2025.103495
Xueting An , Xiaoyu Huang
Chimeric antigen receptor-T (CAR-T) cells are genetically engineered T cells that has demonstrated significant success in treating hematologic tumors. The therapeutic landscape of CAR-T cell therapy is undergoing paradigm-shifting expansion into autoimmune disease management. Emerging clinical evidence demonstrates that engineered CAR-T cells can achieve unprecedented disease remission in the treatment of autoimmune diseases by efficiently depleting autoreactive B cells, thereby resetting the immune system, while maintaining favorable safety profiles. These encouraging results have motivated in-depth exploration into expanding the application of CAR-T cells to a broader spectrum of autoimmune diseases, as well as the development of advanced cell products with better efficacy and safety. This review systematically explores fundamental research and clinical applications of CAR-T cell therapy in autoimmune diseases, critically examines existing limitations, and proposes potential future directions. Significantly, the study elucidates structural characteristics of disease-associated autoantigens in autoimmune diseases, offering novel perspectives and technical frameworks for developing next-generation chimeric autoantibody receptor-T (CAAR-T) therapeutics with enhanced precision.
嵌合抗原受体T （CAR-T）细胞是一种基因工程T细胞，在治疗血液病肿瘤方面已经取得了显著的成功。CAR-T细胞疗法的治疗前景正在经历范式转移扩展到自身免疫性疾病管理。新出现的临床证据表明，工程化CAR-T细胞可以通过有效地消耗自身反应性B细胞，从而重置免疫系统，同时保持良好的安全性，从而在自身免疫性疾病的治疗中实现前所未有的疾病缓解。这些令人鼓舞的结果促使深入探索将CAR-T细胞应用于更广泛的自身免疫性疾病，以及开发具有更好疗效和安全性的先进细胞产品。本综述系统地探讨了CAR-T细胞治疗自身免疫性疾病的基础研究和临床应用，批判性地检查了现有的局限性，并提出了潜在的未来方向。值得注意的是，该研究阐明了自身免疫性疾病中疾病相关自身抗原的结构特征，为开发下一代嵌合自身抗体受体- t （car - t）疗法提供了新的视角和技术框架，具有更高的精度。
{"title":"Chimeric antigen receptor T cell therapy: a new frontier therapeutic landscape in autoimmune diseases","authors":"Xueting An , Xiaoyu Huang","doi":"10.1016/j.jaut.2025.103495","DOIUrl":"10.1016/j.jaut.2025.103495","url":null,"abstract":"<div><div>Chimeric antigen receptor-T (CAR-T) cells are genetically engineered T cells that has demonstrated significant success in treating hematologic tumors. The therapeutic landscape of CAR-T cell therapy is undergoing paradigm-shifting expansion into autoimmune disease management. Emerging clinical evidence demonstrates that engineered CAR-T cells can achieve unprecedented disease remission in the treatment of autoimmune diseases by efficiently depleting autoreactive B cells, thereby resetting the immune system, while maintaining favorable safety profiles. These encouraging results have motivated in-depth exploration into expanding the application of CAR-T cells to a broader spectrum of autoimmune diseases, as well as the development of advanced cell products with better efficacy and safety. This review systematically explores fundamental research and clinical applications of CAR-T cell therapy in autoimmune diseases, critically examines existing limitations, and proposes potential future directions. Significantly, the study elucidates structural characteristics of disease-associated autoantigens in autoimmune diseases, offering novel perspectives and technical frameworks for developing next-generation chimeric autoantibody receptor-T (CAAR-T) therapeutics with enhanced precision.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103495"},"PeriodicalIF":7.0,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358097","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 : 2025-10-18DOI: 10.1016/j.jaut.2025.103493
Fu-Shun Yen , Shiow-Ing Wang , Chii-Min Hwu , Chien-Wei Haung , Renin Chang , Chih-Cheng Hsu , James Cheng-Chung Wei
Introduction
Rheumatoid arthritis (RA) causes disability, chronic pain, and reduced quality of life. Preclinical studies suggest glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may reduce inflammation and protect joint tissues. This study compared GLP-1 RAs with non-GLP-1 RAs on the risk of RA in patients with type 2 diabetes mellitus (T2DM).
Methods
Using the TriNetX network (2016–2023), we identified 2,688,327 patients with T2DM. Propensity score matching yielded 89,938, 111,074, and 88,054 pairs of GLP-1 RA users versus dipeptidyl peptidase-4 inhibitors (DPP-4i), basal insulin, and sodium-glucose cotransporter-2 inhibitors (SGLT2i), respectively. Analyses followed an as-treated approach. Relative hazards of RA were estimated with Kaplan–Meier methods. Subgroup analyses were performed, and a sensitivity analysis used the intention-to-treat approach.
Results
In matched cohorts, GLP-1 RAs showed no significant difference in 7-year RA risk versus DPP-4i (HR 1.06, 95 % CI 0.98–1.15) or basal insulin (HR 0.98, 95 % CI 0.89–1.08). By contrast, SGLT2i use was associated with lower RA risk compared with GLP-1 RAs (HR 0.88, 95 % CI 0.80–0.96). Kaplan–Meier curves confirmed a significantly lower cumulative incidence of RA in SGLT2i users (log-rank p = 0.007).
Conclusions
In this multicenter cohort study of patients with T2DM, GLP-1 RAs did not significantly alter RA risk compared with DPP-4i or basal insulin. In contrast, SGLT2i was associated with a significantly reduced risk of new-onset RA, suggesting potential anti-inflammatory benefits.
类风湿性关节炎（RA）会导致残疾、慢性疼痛和生活质量下降。临床前研究表明胰高血糖素样肽-1受体激动剂（GLP-1 RAs）可以减轻炎症并保护关节组织。本研究比较了GLP-1 RAs与非GLP-1 RAs对2型糖尿病（T2DM）患者RA发病风险的影响。方法使用TriNetX网络（2016-2023），我们确定了2,688,327例T2DM患者。倾向评分匹配分别产生89,938对、111,074对和88,054对GLP-1 RA使用者与二肽基肽酶-4抑制剂（DPP-4i）、基础胰岛素和钠-葡萄糖共转运蛋白-2抑制剂（SGLT2i）。分析采用已处理方法。用Kaplan-Meier法估计RA的相对危险度。进行亚组分析，并采用意向治疗方法进行敏感性分析。结果在匹配的队列中，GLP-1 RAs与DPP-4i （HR 1.06, 95% CI 0.98 - 1.15）或基础胰岛素（HR 0.98, 95% CI 0.89-1.08）相比，7年RA风险无显著差异。相比之下，与GLP-1 RAs相比，使用SGLT2i与较低的RA风险相关（HR 0.88, 95% CI 0.80-0.96）。Kaplan-Meier曲线证实SGLT2i使用者的RA累积发病率显著降低（log-rank p = 0.007）。结论在这项T2DM患者的多中心队列研究中，与DPP-4i或基础胰岛素相比，GLP-1 RAs没有显著改变RA的风险。相反，SGLT2i与新发RA的风险显著降低相关，提示潜在的抗炎益处。
{"title":"Comparative risk of rheumatoid arthritis between glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors in type 2 diabetes","authors":"Fu-Shun Yen , Shiow-Ing Wang , Chii-Min Hwu , Chien-Wei Haung , Renin Chang , Chih-Cheng Hsu , James Cheng-Chung Wei","doi":"10.1016/j.jaut.2025.103493","DOIUrl":"10.1016/j.jaut.2025.103493","url":null,"abstract":"<div><h3>Introduction</h3><div>Rheumatoid arthritis (RA) causes disability, chronic pain, and reduced quality of life. Preclinical studies suggest glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may reduce inflammation and protect joint tissues. This study compared GLP-1 RAs with non-GLP-1 RAs on the risk of RA in patients with type 2 diabetes mellitus (T2DM).</div></div><div><h3>Methods</h3><div>Using the TriNetX network (2016–2023), we identified 2,688,327 patients with T2DM. Propensity score matching yielded 89,938, 111,074, and 88,054 pairs of GLP-1 RA users versus dipeptidyl peptidase-4 inhibitors (DPP-4i), basal insulin, and sodium-glucose cotransporter-2 inhibitors (SGLT2i), respectively. Analyses followed an as-treated approach. Relative hazards of RA were estimated with Kaplan–Meier methods. Subgroup analyses were performed, and a sensitivity analysis used the intention-to-treat approach.</div></div><div><h3>Results</h3><div>In matched cohorts, GLP-1 RAs showed no significant difference in 7-year RA risk versus DPP-4i (HR 1.06, 95 % CI 0.98–1.15) or basal insulin (HR 0.98, 95 % CI 0.89–1.08). By contrast, SGLT2i use was associated with lower RA risk compared with GLP-1 RAs (HR 0.88, 95 % CI 0.80–0.96). Kaplan–Meier curves confirmed a significantly lower cumulative incidence of RA in SGLT2i users (log-rank p = 0.007).</div></div><div><h3>Conclusions</h3><div>In this multicenter cohort study of patients with T2DM, GLP-1 RAs did not significantly alter RA risk compared with DPP-4i or basal insulin. In contrast, SGLT2i was associated with a significantly reduced risk of new-onset RA, suggesting potential anti-inflammatory benefits.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103493"},"PeriodicalIF":7.0,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324703","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 : 2025-10-15DOI: 10.1016/j.jaut.2025.103492
François Barde , Kevin Chevalier , Paul Decker , Matéo Merin , Amélie Nicolas , Alain Lescoat , Alban Deroux , Vincent Koether , Emmanuel Chatelus , Cyrille Coustal , Alexandre Maria , Martin Michaud , Grégory Pugnet , Anne Murarasu , Sébastien Riviere , Pierre Charles , Claire de Moreuil , Juliette Lodovichetti , François Maillet , Arthur Renaud , Benjamin Chaigne
Objectives
Mycophenolate mofetil (MMF) and rituximab (RTX) are recommended as first-line therapies for skin and interstitial lung disease (ILD) involvement in systemic sclerosis (SSc). However, data on their combined use remain limited. This study evaluated the efficacy and safety of MMF/RTX combination therapy compared to each drug alone.
Methods
We conducted a retrospective multicenter French study including SSc patients treated with MMF, RTX, or MMF/RTX combination for ≥12-months. Primary outcomes were changes in modified Rodnan skin score (mRSS) and predicted forced vital capacity (FVC) at 12 months. Secondary outcomes included factors associated with improvement in skin or ILD and adverse events.
Results
Forty-seven patients received MMF/RTX combination, 30 received RTX, and 50 received MMF. At 12 months, intra-group analyses showed significant mRSS improvement with MMF/RTX combination and MMF (p = 0.002 and p = 0.04, respectively). FVC increased significantly only with combination group (p = 0.003). In multivariate inter-group analysis, MMF/RTX combination was independently associated with greater mRSS improvement versus RTX (OR 0.07, 95 % CI [0.007–0.67], p = 0.02) and greater skin and/or lung improvement compared to RTX (OR 0.27 [0.08–0.89], p = 0.03) or MMF (OR 0.24 [0.07–0.81], p = 0.02). Adverse events were not significantly increased with MMF/RTX combination. In subgroup analyses restricted to MMF/RTX combination group, patients with upfront initiation significantly improved their FVC compared to patients with sequential introduction. Upfront initiation of MMF/RTX was associated with ILD improvement in multivariate analysis.
Conclusion
In SSc, MMF/RTX combination is well-tolerated and improves skin and ILD involvement, particularly when MMF and RTX are introduced simultaneously.
目的：霉酚酸酯（MMF）和利妥昔单抗（RTX）被推荐作为皮肤和间质性肺疾病（ILD）累及系统性硬化症（SSc）的一线治疗药物。然而，关于它们联合使用的数据仍然有限。本研究评估了MMF/RTX联合治疗与单独用药相比的有效性和安全性。方法：我们在法国进行了一项回顾性多中心研究，纳入了MMF、RTX或MMF/RTX联合治疗≥12个月的SSc患者。主要结局是12个月时改良罗德曼皮肤评分（mRSS）和预测用力肺活量（FVC）的变化。次要结局包括与皮肤或ILD改善和不良事件相关的因素。结果：MMF/RTX联合治疗47例，RTX治疗30例，MMF治疗50例。在12个月时，组内分析显示MMF/RTX联合治疗和MMF显著改善mRSS （p = 0.002和p = 0.04分别）。FVC只有联合组显著升高（p = 0.003）。在多变量组间分析中，与RTX相比，MMF/RTX联合治疗与更大的mRSS改善（OR 0.07, 95% CI [0.007-0.67], p = 0.02）以及与RTX （OR 0.27 [0.08-0.89], p = 0.03）或MMF （OR 0.24 [0.07-0.81], p = 0.02）相比，更大的皮肤和/或肺改善独立相关。MMF/RTX联合治疗的不良事件没有显著增加。在仅限于MMF/RTX联合组的亚组分析中，与顺序引入患者相比，预先引入患者的FVC显著改善。在多变量分析中，MMF/RTX的前期治疗与ILD的改善相关。结论：在SSc中，MMF/RTX联合使用耐受性良好，可改善皮肤和ILD受损伤，特别是当MMF和RTX同时使用时。
{"title":"Evaluation of the mycophenolate mofetil–rituximab combination in systemic sclerosis: a French retrospective multicenter study (MycRiSSc)","authors":"François Barde , Kevin Chevalier , Paul Decker , Matéo Merin , Amélie Nicolas , Alain Lescoat , Alban Deroux , Vincent Koether , Emmanuel Chatelus , Cyrille Coustal , Alexandre Maria , Martin Michaud , Grégory Pugnet , Anne Murarasu , Sébastien Riviere , Pierre Charles , Claire de Moreuil , Juliette Lodovichetti , François Maillet , Arthur Renaud , Benjamin Chaigne","doi":"10.1016/j.jaut.2025.103492","DOIUrl":"10.1016/j.jaut.2025.103492","url":null,"abstract":"<div><h3>Objectives</h3><div>Mycophenolate mofetil (MMF) and rituximab (RTX) are recommended as first-line therapies for skin and interstitial lung disease (ILD) involvement in systemic sclerosis (SSc). However, data on their combined use remain limited. This study evaluated the efficacy and safety of MMF/RTX combination therapy compared to each drug alone.</div></div><div><h3>Methods</h3><div>We conducted a retrospective multicenter French study including SSc patients treated with MMF, RTX, or MMF/RTX combination for ≥12-months. Primary outcomes were changes in modified Rodnan skin score (mRSS) and predicted forced vital capacity (FVC) at 12 months. Secondary outcomes included factors associated with improvement in skin or ILD and adverse events.</div></div><div><h3>Results</h3><div>Forty-seven patients received MMF/RTX combination, 30 received RTX, and 50 received MMF. At 12 months, intra-group analyses showed significant mRSS improvement with MMF/RTX combination and MMF (p = 0.002 and p = 0.04, respectively). FVC increased significantly only with combination group (p = 0.003). In multivariate inter-group analysis, MMF/RTX combination was independently associated with greater mRSS improvement versus RTX (OR 0.07, 95 % CI [0.007–0.67], p = 0.02) and greater skin and/or lung improvement compared to RTX (OR 0.27 [0.08–0.89], p = 0.03) or MMF (OR 0.24 [0.07–0.81], p = 0.02). Adverse events were not significantly increased with MMF/RTX combination. In subgroup analyses restricted to MMF/RTX combination group, patients with upfront initiation significantly improved their FVC compared to patients with sequential introduction. Upfront initiation of MMF/RTX was associated with ILD improvement in multivariate analysis.</div></div><div><h3>Conclusion</h3><div>In SSc, MMF/RTX combination is well-tolerated and improves skin and ILD involvement, particularly when MMF and RTX are introduced simultaneously.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103492"},"PeriodicalIF":7.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308154","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 : 2025-10-10DOI: 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}
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