Pub Date : 2025-11-19DOI: 10.1016/j.jaut.2025.103500
Alen Zabotti , Lucia Novelli , Michele Maria Luchetti Gentiloni , Giuliana Guggino , Ana Biljan , Ennio Lubrano , Dennis McGonagle
Interleukin-23 (IL-23) plays a pivotal role in the intricate interplay between the skin, gut, and joints, contributing significantly to the pathogenesis of various inflammatory diseases including psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease (IBD) and Behcet's disease. In recent years, several IL-23 inhibitors have been granted approval for the treatment of psoriasis, PsA and IBD. As up to one-third of patients diagnosed with psoriasis may go on to develop PsA and given the strong immunogenetic pathway incrimination of the IL-23 pathway in both psoriasis and PsA, dermatological lead therapy for psoriasis may therefore delay the development of PsA. Furthermore, patients with psoriasis or PsA are associated with increased risk of developing IBD. There is also evidence for psoriasis-directed therapy preventing IBD in keeping with the known pivotal role of IL-23 in both intestinal homeostasis and in the pathogenesis of IBD, including ulcerative colitis and Crohn's disease. This review discusses the multifaceted roles of IL-23 in regulating immune response and maintaining tissue homeostasis within the skin-gut-joint axis. In particular, the use of IL-23 inhibitors in trials in patients with psoriasis, IBD and PsA patients will also be discussed in relation to reverse translational immunology insights around inflammation in these domains.
{"title":"The pivotal role of Interleukin-23 in the skin-gut-joint axis","authors":"Alen Zabotti , Lucia Novelli , Michele Maria Luchetti Gentiloni , Giuliana Guggino , Ana Biljan , Ennio Lubrano , Dennis McGonagle","doi":"10.1016/j.jaut.2025.103500","DOIUrl":"10.1016/j.jaut.2025.103500","url":null,"abstract":"<div><div>Interleukin-23 (IL-23) plays a pivotal role in the intricate interplay between the skin, gut, and joints, contributing significantly to the pathogenesis of various inflammatory diseases including psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease (IBD) and Behcet's disease. In recent years, several IL-23 inhibitors have been granted approval for the treatment of psoriasis, PsA and IBD. As up to one-third of patients diagnosed with psoriasis may go on to develop PsA and given the strong immunogenetic pathway incrimination of the IL-23 pathway in both psoriasis and PsA, dermatological lead therapy for psoriasis may therefore delay the development of PsA. Furthermore, patients with psoriasis or PsA are associated with increased risk of developing IBD. There is also evidence for psoriasis-directed therapy preventing IBD in keeping with the known pivotal role of IL-23 in both intestinal homeostasis and in the pathogenesis of IBD, including ulcerative colitis and Crohn's disease. This review discusses the multifaceted roles of IL-23 in regulating immune response and maintaining tissue homeostasis within the skin-gut-joint axis. In particular, the use of IL-23 inhibitors in trials in patients with psoriasis, IBD and PsA patients will also be discussed in relation to reverse translational immunology insights around inflammation in these domains.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103500"},"PeriodicalIF":7.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563125","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 : 2025-11-15DOI: 10.1016/j.jaut.2025.103502
Signe Hässler , Julie Aste , Francis Berenbaum , Michelle Rosenzwajg , Jérémie Sellam , David Klatzmann , Milka Maravic
Background
Patients with immunological diseases exhibit distinct comorbidity patterns, categorized into low comorbidity, polyautoimmunity, and polyinflammation profiles. This retrospective cohort study aimed to validate these profiles in rheumatoid arthritis (RA) patients, examine their longitudinal trajectories, and assess their impact on treatment persistence.
Methods
RA patients, and their associated treatments, were identified from the French pharmacy-dispensing database LRx through an algorithm based on targeted therapies. Algorithms to identify 17 comorbidities were designed based on drug indications. Comorbidity clusters were assigned yearly using a multinomial regression model, and state sequence analysis with hierarchical clustering was used to define their temporal trajectories. DMARD retention across comorbidity trajectories was evaluated through Cox regression models.
Results
Among 15,189 RA patients (maximum follow-up: 10 years), initial comorbidity profiles included low comorbidity (61.9 %), polyautoimmunity (24.7 %), and polyinflammation (13.4 %). Four trajectory patterns emerged among 5223 patients with at least 8 years of follow-up: stable low comorbidity (50 %), dominant polyautoimmune (31 %), stable polyinflammatory (9 %), and low comorbidity switching to polyinflammation (polyinflammation switchers, 10 %). The prevalence of polyautoimmunity and polyinflammation increased with age by 2.5 % [0.9 %–4.1 %] and 3.8 % [3.6 %–4.7 %] per decade, respectively.
Comorbidity trajectories in RA are associated with DMARD persistence, reflecting distinct subgroups with potential theranostic relevance. These results should be confirmed through a prospective study on DMARD-initiating patients.
{"title":"Temporal trajectories and DMARD therapy retention of rheumatoid arthritis patients with different autoimmune and inflammatory comorbidity profiles: a retrospective analysis","authors":"Signe Hässler , Julie Aste , Francis Berenbaum , Michelle Rosenzwajg , Jérémie Sellam , David Klatzmann , Milka Maravic","doi":"10.1016/j.jaut.2025.103502","DOIUrl":"10.1016/j.jaut.2025.103502","url":null,"abstract":"<div><h3>Background</h3><div>Patients with immunological diseases exhibit distinct comorbidity patterns, categorized into low comorbidity, polyautoimmunity, and polyinflammation profiles. This retrospective cohort study aimed to validate these profiles in rheumatoid arthritis (RA) patients, examine their longitudinal trajectories, and assess their impact on treatment persistence.</div></div><div><h3>Methods</h3><div>RA patients, and their associated treatments, were identified from the French pharmacy-dispensing database LRx through an algorithm based on targeted therapies. Algorithms to identify 17 comorbidities were designed based on drug indications. Comorbidity clusters were assigned yearly using a multinomial regression model, and state sequence analysis with hierarchical clustering was used to define their temporal trajectories. DMARD retention across comorbidity trajectories was evaluated through Cox regression models.</div></div><div><h3>Results</h3><div>Among 15,189 RA patients (maximum follow-up: 10 years), initial comorbidity profiles included low comorbidity (61.9 %), polyautoimmunity (24.7 %), and polyinflammation (13.4 %). Four trajectory patterns emerged among 5223 patients with at least 8 years of follow-up: stable low comorbidity (50 %), dominant polyautoimmune (31 %), stable polyinflammatory (9 %), and low comorbidity switching to polyinflammation (polyinflammation switchers, 10 %). The prevalence of polyautoimmunity and polyinflammation increased with age by 2.5 % [0.9 %–4.1 %] and 3.8 % [3.6 %–4.7 %] per decade, respectively.</div><div>Patients with stable polyinflammation had the lowest conventional synthetic DMARD 18-month persistence (stable polyinflammation: 15.68 % [10.26 %; 23.96 %]; polyinflammation switchers: 40.34 % [32.72 %; 49.75 %]; HR: 1.79 [1.33–2.42]). Stable low comorbidity patients had the highest biological and targeted synthetic DMARD persistence (polyinflammation switchers: 58.68 % [53.53 %; 64.32 %]; stable low comorbidity [65.66 % [63.20 %; 68.22 %]; aHR: 1.32 [1.09–1.60]).</div></div><div><h3>Conclusions</h3><div>Comorbidity trajectories in RA are associated with DMARD persistence, reflecting distinct subgroups with potential theranostic relevance. These results should be confirmed through a prospective study on DMARD-initiating patients.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103502"},"PeriodicalIF":7.0,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534342","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 : 2025-11-14DOI: 10.1016/j.jaut.2025.103501
Antonio Tonutti , Francesca Motta , Gianluigi Bajocchi , Silvia Bellando-Randone , Cosimo Bruni , Martina Orlandi , Giovanni Zanframundo , Roberta Foti , Giovanna Cuomo , Alarico Ariani , Edoardo Rosato , Gemma Lepri , Francesco Girelli , Elisabetta Zanatta , Silvia Laura Bosello , Ilaria Cavazzana , Francesca Ingegnoli , Fabio Cacciapaglia , Giuseppe Murdaca , Giuseppina Abignano , Rossella De Angelis
Objective
Elderly-onset systemic sclerosis (SSc) is relatively uncommon, and its clinical phenotype and prognostic implications remain poorly characterized, with conflicting evidence regarding disease course and outcomes.
Methods
Within the Italian SPRING (Systemic Sclerosis PRogression INvestiGation) registry, we compared demographic and clinical characteristics of patients with elderly-onset SSc (≥70 years at the time of the first non-Raynaud's manifestation) to those with younger onset. Cross-sectional analyses, multivariable logistic regression, and unsupervised cluster analysis were conducted to identify features associated with elderly-onset SSc. Longitudinal analysis was performed to assess mortality risk within SSc patients and compared to the general Italian population.
Results
Elderly-onset accounted for 8.5 % (160/1893) SSc cases in SPRING. These patients exhibited fewer peripheral vascular complications (digital ulcers: 13 % vs. 23 %; p = 0.016), higher prevalence of anticentromere antibodies (60 % vs. 39 %; p = 0.007), a lower prevalence and likelihood of diffuse skin subset (OR 0.40; 95 % CI 0.19–0.83) but an increased risk of pulmonary arterial hypertension confirmed on right-heart catheterization (OR 14.1; 95 % CI 3.68–54.5) at multivariate analysis. As expected, patients with elderly onset SSc had an increased risk of death compared to younger-onset individuals. Compared with the age-, sex-, and calendar year-matched general Italian population, patients with SSc showed a fivefold increased mortality, with a trend toward a higher risk in young-onset (SMR 6.3; 95 %CI 4.1–9.1) compared with elderly-onset (SMR 4.5; 95 %CI 2.4–7.7) cases.
Conclusions
Elderly-onset identifies a distinct clinical subset of SSc, mainly characterized by mild cutaneous and peripheral vascular involvement, but showing a greater burden of pulmonary vascular disease and increased mortality compared to the age-matched general population.
目的：老年性系统性硬化症（SSc）相对罕见，其临床表型和预后特征仍然不明确，关于病程和结局的证据相互矛盾。方法：在意大利的系统性硬化症进展调查中，我们比较了老年发病的SSc患者（首次非雷诺症状时≥70岁）和年轻发病的SSc患者的人口学和临床特征。采用横断面分析、多变量逻辑回归和无监督聚类分析来确定与老年发病SSc相关的特征。进行纵向分析以评估SSc患者的死亡风险，并与意大利一般人群进行比较。结果春季SSc病例中，老年发病占8.5%（160/1893）。这些患者外周血管并发症较少（指部溃疡：13% vs. 23%; p = 0.016），抗着丝点抗体的患病率较高（60% vs. 39%; p = 0.007），弥漫性皮肤亚群的患病率和可能性较低（OR 0.40; 95% CI 0.19-0.83），但在多因素分析中，右心导管置入证实肺动脉高压的风险增加（OR 14.1; 95% CI 3.68-54.5）。正如预期的那样，与年轻发病的个体相比，老年发病的SSc患者的死亡风险增加。与年龄、性别和日历年匹配的意大利一般人群相比，SSc患者的死亡率增加了5倍，年轻发病（SMR为6.3；95% CI为4.1-9.1）的风险高于老年发病（SMR为4.5；95% CI为2.4-7.7）。结论：老年发病是SSc的一个独特的临床亚群，主要特征是轻度皮肤和周围血管受累，但与年龄匹配的普通人群相比，肺血管疾病负担更重，死亡率更高。
{"title":"Elderly-onset systemic sclerosis defines a distinct clinical subset: analysis from the SPRING registry of the Italian Society for Rheumatology","authors":"Antonio Tonutti , Francesca Motta , Gianluigi Bajocchi , Silvia Bellando-Randone , Cosimo Bruni , Martina Orlandi , Giovanni Zanframundo , Roberta Foti , Giovanna Cuomo , Alarico Ariani , Edoardo Rosato , Gemma Lepri , Francesco Girelli , Elisabetta Zanatta , Silvia Laura Bosello , Ilaria Cavazzana , Francesca Ingegnoli , Fabio Cacciapaglia , Giuseppe Murdaca , Giuseppina Abignano , Rossella De Angelis","doi":"10.1016/j.jaut.2025.103501","DOIUrl":"10.1016/j.jaut.2025.103501","url":null,"abstract":"<div><h3>Objective</h3><div>Elderly-onset systemic sclerosis (SSc) is relatively uncommon, and its clinical phenotype and prognostic implications remain poorly characterized, with conflicting evidence regarding disease course and outcomes.</div></div><div><h3>Methods</h3><div>Within the Italian SPRING (Systemic Sclerosis PRogression INvestiGation) registry, we compared demographic and clinical characteristics of patients with elderly-onset SSc (≥70 years at the time of the first non-Raynaud's manifestation) to those with younger onset. Cross-sectional analyses, multivariable logistic regression, and unsupervised cluster analysis were conducted to identify features associated with elderly-onset SSc. Longitudinal analysis was performed to assess mortality risk within SSc patients and compared to the general Italian population.</div></div><div><h3>Results</h3><div>Elderly-onset accounted for 8.5 % (160/1893) SSc cases in SPRING. These patients exhibited fewer peripheral vascular complications (digital ulcers: 13 % vs. 23 %; p = 0.016), higher prevalence of anticentromere antibodies (60 % vs. 39 %; p = 0.007), a lower prevalence and likelihood of diffuse skin subset (OR 0.40; 95 % CI 0.19–0.83) but an increased risk of pulmonary arterial hypertension confirmed on right-heart catheterization (OR 14.1; 95 % CI 3.68–54.5) at multivariate analysis. As expected, patients with elderly onset SSc had an increased risk of death compared to younger-onset individuals. Compared with the age-, sex-, and calendar year-matched general Italian population, patients with SSc showed a fivefold increased mortality, with a trend toward a higher risk in young-onset (SMR 6.3; 95 %CI 4.1–9.1) compared with elderly-onset (SMR 4.5; 95 %CI 2.4–7.7) cases.</div></div><div><h3>Conclusions</h3><div>Elderly-onset identifies a distinct clinical subset of SSc, mainly characterized by mild cutaneous and peripheral vascular involvement, but showing a greater burden of pulmonary vascular disease and increased mortality compared to the age-matched general population.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103501"},"PeriodicalIF":7.0,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516875","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 : 2025-11-11DOI: 10.1016/j.jaut.2025.103499
Wenfeng Xi, Yunlu Feng, Wen Shi, Jianing Li, Tao Guo, Xiaoyin Bai , Aiming Yang
Background
Type 1 autoimmune pancreatitis (AIP) is a rare, immune-mediated pancreatic disease prone to relapse. The influence of age on relapse risk remains unclear. This study aimed to determine whether age at diagnosis is associated with disease relapse.
Methods
We retrospectively analyzed 413 patients with type 1 AIP with over 2 years of follow-up. Patients were divided into two groups based on age at diagnosis: <60 years (n = 221) and ≥60 years (n = 192). Relapse rates were compared between groups. Logistic regression was used to assess the association between age group and relapse risk. Subgroup analyses by sex, diabetes, smoking, and heavy drinking were performed to test the stability of this association.
Results
The median age was 58.0 years, with 79.4 % male patients and a median follow-up of 4.6 years. The overall relapse rate was 41.9 %, being higher in the <60 years group (46.2 %) than in the ≥60 years group (37.0 %). Age <60 years was significantly associated with increased relapse risk (OR = 1.7; 95 % CI: 1.1–2.7, P = 0.022) in multivariate logistic analysis. This effect was consistent across all subgroups examined.
Conclusions
In type 1 AIP, age<60 years increases the risk of disease relapse. Age should be considered in long-term disease management.
{"title":"Association between age groups and relapse of type 1 autoimmune pancreatitis: a large-scale retrospective cohort study","authors":"Wenfeng Xi, Yunlu Feng, Wen Shi, Jianing Li, Tao Guo, Xiaoyin Bai , Aiming Yang","doi":"10.1016/j.jaut.2025.103499","DOIUrl":"10.1016/j.jaut.2025.103499","url":null,"abstract":"<div><h3>Background</h3><div>Type 1 autoimmune pancreatitis (AIP) is a rare, immune-mediated pancreatic disease prone to relapse. The influence of age on relapse risk remains unclear. This study aimed to determine whether age at diagnosis is associated with disease relapse.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed 413 patients with type 1 AIP with over 2 years of follow-up. Patients were divided into two groups based on age at diagnosis: <60 years (n = 221) and ≥60 years (n = 192). Relapse rates were compared between groups. Logistic regression was used to assess the association between age group and relapse risk. Subgroup analyses by sex, diabetes, smoking, and heavy drinking were performed to test the stability of this association.</div></div><div><h3>Results</h3><div>The median age was 58.0 years, with 79.4 % male patients and a median follow-up of 4.6 years. The overall relapse rate was 41.9 %, being higher in the <60 years group (46.2 %) than in the ≥60 years group (37.0 %). Age <60 years was significantly associated with increased relapse risk (OR = 1.7; 95 % CI: 1.1–2.7, <em>P</em> = 0.022) in multivariate logistic analysis. This effect was consistent across all subgroups examined.</div></div><div><h3>Conclusions</h3><div>In type 1 AIP, age<60 years increases the risk of disease relapse. Age should be considered in long-term disease management.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103499"},"PeriodicalIF":7.0,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145504531","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 : 2025-11-08DOI: 10.1016/j.jaut.2025.103496
Desiré Casares-Marfil , K. Bates Gribbons , Guher Saruhan-Direskeneli , Sema Kaymaz-Tahra , Kaitlin A. Quinn , Fatma Alibaz-Oner , Peter C. Grayson , Haner Direskeneli , Amr H. Sawalha , Peter A. Merkel
Background
Prior studies identified subsets of patients with Takayasu arteritis (TAK) based on angiographic patterns of disease in cohorts from India and North America. This study aimed to validate these patterns in a TAK cohort from Turkey and determine the role of genetics in arterial patterns.
Methods
421 Turkish patients with TAK underwent angiography of the aorta and branch vessels, with disease involvement characterized in 13 arterial territories. K-means cluster analysis identified angiographically-based subgroups. 282 patients with TAK from Turkey and 115 European-American patients from North America were genotyped. Approximately 6.5 million SNPs were evaluated in a meta-analysis of both cohorts. Logistic regressions identified genetic associations with angiographic clusters (threshold for association: p-value<1x10−5). Associated variants were functionally annotated.
Results
Three clusters were identified in Turkish patients, validating the previously-identified cluster pattern. Genome-wide meta-analyses revealed a locus in the solute carrier family gene SLC24A2 in Cluster One as the most significant association (rs2891138, OR = 3.34, p-value = 2.32x10−7). Several genetic loci were associated with Cluster Two, including in LGALSL (rs883021, OR = 0.43, p-value = 1.00X10−5), AK4P3 (rs1072778, OR = 0.39, p-value = 4.07X10−6), and TMEM132B (rs4765045, OR = 3.05, p-value = 6.18X10−6). The most significant locus associated with Cluster Three was in FRMD6 (rs55692665, OR = 2.79, p-value = 1.11X10−7). Genetic effects were consistent between the cohorts. Several loci were associated with levels of mRNA expression in arterial tissues. A Cluster Two-associated variant in APBB2 (rs2465578, OR = 0.35, p-value = 6.69x10−6) showed evidence for chromatin interaction with the NSUN7 promoter and increased aortic NSUN7 expression.
Conclusions
Genetic factors are associated with distinct subsets of TAK defined by angiographic pattern of disease.
背景：先前的研究在印度和北美的队列中根据疾病的血管造影模式确定了Takayasu动脉炎（TAK）患者亚群。本研究旨在在土耳其的TAK队列中验证这些模式，并确定遗传学在动脉模式中的作用。方法：421例土耳其TAK患者行主动脉和分支血管造影，疾病累及13个动脉区域。k均值聚类分析确定了基于血管造影的亚组。282例土耳其TAK患者和115例北美欧美患者进行基因分型。在两个队列的荟萃分析中评估了大约650万个snp。Logistic回归确定了与血管造影簇的遗传关联（关联阈值：p值5）。对相关的变体进行了功能注释。结果：在土耳其患者中发现了三个集群，验证了先前确定的集群模式。全基因组荟萃分析显示，集群1中溶质载体家族基因SLC24A2的一个位点是最显著的关联位点（rs2891138, OR = 3.34， p值= 2.32x10-7）。多个遗传位点与聚类2相关，包括LGALSL （rs883021, OR = 0.43， p值= 1.00X10-5）、AK4P3 （rs1072778, OR = 0.39， p值= 4.07X10-6）和TMEM132B （rs4765045, OR = 3.05， p值= 6.18X10-6）。与聚类3相关的最显著位点为FRMD6 （rs55692665, OR = 2.79， p值= 1.11X10-7）。遗传效应在队列之间是一致的。有几个位点与动脉组织中mRNA的表达水平相关。APBB2簇2相关变异（rs2465578, OR = 0.35， p值= 6.69x10-6）显示与NSUN7启动子的染色质相互作用和主动脉NSUN7表达增加。结论：遗传因素与不同的TAK亚群有关，这些亚群由疾病的血管造影模式定义。
{"title":"Genetic susceptibility and validation of angiographic patterns in Takayasu arteritis","authors":"Desiré Casares-Marfil , K. Bates Gribbons , Guher Saruhan-Direskeneli , Sema Kaymaz-Tahra , Kaitlin A. Quinn , Fatma Alibaz-Oner , Peter C. Grayson , Haner Direskeneli , Amr H. Sawalha , Peter A. Merkel","doi":"10.1016/j.jaut.2025.103496","DOIUrl":"10.1016/j.jaut.2025.103496","url":null,"abstract":"<div><h3>Background</h3><div>Prior studies identified subsets of patients with Takayasu arteritis (TAK) based on angiographic patterns of disease in cohorts from India and North America. This study aimed to validate these patterns in a TAK cohort from Turkey and determine the role of genetics in arterial patterns.</div></div><div><h3>Methods</h3><div>421 Turkish patients with TAK underwent angiography of the aorta and branch vessels, with disease involvement characterized in 13 arterial territories. K-means cluster analysis identified angiographically-based subgroups. 282 patients with TAK from Turkey and 115 European-American patients from North America were genotyped. Approximately 6.5 million SNPs were evaluated in a meta-analysis of both cohorts. Logistic regressions identified genetic associations with angiographic clusters (threshold for association: p-value<1x10<sup>−5</sup>). Associated variants were functionally annotated.</div></div><div><h3>Results</h3><div>Three clusters were identified in Turkish patients, validating the previously-identified cluster pattern. Genome-wide meta-analyses revealed a locus in the solute carrier family gene <em>SLC24A2</em> in Cluster One as the most significant association (rs2891138, OR = 3.34, p-value = 2.32x10<sup>−7</sup>). Several genetic loci were associated with Cluster Two, including in <em>LGALSL</em> (rs883021, OR = 0.43, p-value = 1.00X10<sup>−5</sup>), <em>AK4P3</em> (rs1072778, OR = 0.39, p-value = 4.07X10<sup>−6</sup>), and <em>TMEM132B</em> (rs4765045, OR = 3.05, p-value = 6.18X10<sup>−6</sup>). The most significant locus associated with Cluster Three was in <em>FRMD6</em> (rs55692665, OR = 2.79, p-value = 1.11X10<sup>−7</sup>). Genetic effects were consistent between the cohorts. Several loci were associated with levels of mRNA expression in arterial tissues. A Cluster Two-associated variant in <em>APBB2</em> (rs2465578, OR = 0.35, p-value = 6.69x10<sup>−6</sup>) showed evidence for chromatin interaction with the <em>NSUN7</em> promoter and increased aortic <em>NSUN7</em> expression.</div></div><div><h3>Conclusions</h3><div>Genetic factors are associated with distinct subsets of TAK defined by angiographic pattern of disease.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103496"},"PeriodicalIF":7.0,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145481841","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 : 2025-11-07DOI: 10.1016/j.jaut.2025.103498
Manuel Rojas , Luke S. Heuer , Weici Zhang , Nicolle Sweeney , Carolina Ramírez-Santana , Patrick S.C. Leung , Alvin Lam , Shraddha Kamat , Andrew R. Mendelsohn , Manley Huang , Bo Yu , Paulina Ackerman , Qisheng Wei , James W. Larrick , Yi-Guang Chen , William M. Ridgway
Human membrane-bound CD137 (mCD137) is a well-known costimulatory molecule; however, it is alternatively spliced into two transcripts (sCD137-1, 2) whose function is not yet known. Here, we show that sCD137 isoforms lack the CRD4 region and form unique structures compared to mCD137. Human activated Tregs produce both CD137 splice isoforms, which are rapidly upregulated after cell activation, and identify an activated Treg phenotype along with FOXP3, CTLA4, and sCTLA4. We engineered recombinant Fc-Hu-sCD137 variants, which are immunosuppressive, inhibiting IFN-γ secretion and proliferation in purified CD4+ and CD8+ T cells in an APC-independent manner. These effects are mediated by the downregulation of S6 and 4EBP1 of the mTOR complex 1 pathway. Human sCD137 variants, in contrast to the membrane-bound form, are immunosuppressive and may be a novel treatment for inflammation and autoimmunity.
{"title":"Alternate splicing converts human CD137 from costimulatory to immunosuppressive function","authors":"Manuel Rojas , Luke S. Heuer , Weici Zhang , Nicolle Sweeney , Carolina Ramírez-Santana , Patrick S.C. Leung , Alvin Lam , Shraddha Kamat , Andrew R. Mendelsohn , Manley Huang , Bo Yu , Paulina Ackerman , Qisheng Wei , James W. Larrick , Yi-Guang Chen , William M. Ridgway","doi":"10.1016/j.jaut.2025.103498","DOIUrl":"10.1016/j.jaut.2025.103498","url":null,"abstract":"<div><div>Human membrane-bound CD137 (mCD137) is a well-known costimulatory molecule; however, it is alternatively spliced into two transcripts (sCD137-1, 2) whose function is not yet known. Here, we show that sCD137 isoforms lack the CRD4 region and form unique structures compared to mCD137. Human activated Tregs produce both <em>CD137</em> splice isoforms, which are rapidly upregulated after cell activation, and identify an activated Treg phenotype along with <em>FOXP3</em>, <em>CTLA4</em>, and <em>sCTLA4</em>. We engineered recombinant Fc-Hu-sCD137 variants, which are immunosuppressive, inhibiting IFN-γ secretion and proliferation in purified CD4<sup>+</sup> and CD8<sup>+</sup> T cells in an APC-independent manner. These effects are mediated by the downregulation of S6 and 4EBP1 of the mTOR complex 1 pathway. Human sCD137 variants, in contrast to the membrane-bound form, are immunosuppressive and may be a novel treatment for inflammation and autoimmunity.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"157 ","pages":"Article 103498"},"PeriodicalIF":7.0,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145463046","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 : 2025-11-04DOI: 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}
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