Pub Date : 2025-04-22DOI: 10.1016/j.jaut.2025.103423
Yalong Qi , Hewei Ge , Xiaoying Sun , Yuhan Wei , Jingtong Zhai , Haili Qian , Hongnan Mo , Fei Ma
Background
Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for cancer. However, frequent and sometimes life-threatening immune-related adverse events (irAEs) are associated with ICI treatment. Therefore, it is imperative to establish a model for predicting the risk of irAEs to identify high-risk groups, enable more accurate clinical risk‒benefit analysis for ICI treatment and decrease the incidence of irAEs. However, no ideal model for predicting irAEs has been applied in clinical practice. The aim of this study was to analyze the systemic immune characteristics of patients with irAEs and establish a model for predicting the risk of irAEs.
Methods
We conducted a study to monitor irAEs in patients with advanced breast cancer undergoing immunotherapy during and following the treatment course. Peripheral blood mononuclear cells (PBMCs) were collected before and after two cycles of therapy. Mass cytometry time-of-flight (CyTOF) was employed to identify baseline and posttreatment immune cell subpopulations, and the relationships between the proportions of cells in these subpopulations and the occurrence of irAEs were explored. Additionally, we conducted subgroup analyses stratified by the anatomic location and time of onset of irAEs. Furthermore, we developed a logistic regression model to predict the risk of irAEs and validated this model using two independent validation cohorts from the Gene Expression Omnibus (GEO) database (accession numbers GSE189125 and GSE186143).
Results
By analyzing 106 blood samples and samples from two independent validation cohorts (n = 16 and 60 patients), we found that high proportions of CXCR3+CCR6+CD4+ T cells and CD38+CD86+CXCR3+CCR6+CD8+ T cells and a low proportion of CXCR3lowCD56dim natural killer (NK) cells at baseline were significantly correlated with the incidence of irAEs (P = 0.0029, P < 0.001, and P = 0.0017, respectively). In the subgroup analysis, we observed consistent results in patients with immune-related pneumonitis (ir-pneumonitis) and immune-related thyroiditis (ir-thyroiditis). In the early irAE group, the baseline proportion of CXCR3+CCR6+CD4+ T cells was greater than that in the late irAE group (P = 0.011). An analysis of PBMCs before and after ICI treatment revealed thatthe dynamic changes in the proportions of naïve CD4+ T cells and CXCR3lowCD56dim NK cells were closely related to irAE occurrence. Finally, we ultimately developed a model for predicting the risk of irAEs, which yielded an area under the receiver operating characteristic curve (AUROC) of 0.79 in the training cohort and an AUROC of 0.75 in the single-cell validation cohort (GSE189125).
Concl
免疫检查点抑制剂（ICIs）是最有希望的癌症治疗方案之一。然而，与ICI治疗相关的频繁且有时危及生命的免疫相关不良事件（irAEs）。因此，建立irAEs的风险预测模型，识别高危人群，更准确地进行ICI治疗的临床风险-收益分析，降低irAEs的发生率势在必行。然而，目前尚无理想的irae预测模型应用于临床实践。本研究的目的是分析irAEs患者的全身免疫特征，建立预测irAEs风险的模型。方法对接受免疫治疗的晚期乳腺癌患者在治疗过程中和治疗后的irae进行监测。治疗前后采集外周血单个核细胞（PBMCs）。采用细胞计数飞行时间（CyTOF）鉴定基线和治疗后免疫细胞亚群，并探讨这些亚群中细胞比例与irae发生之间的关系。此外，我们根据irae的解剖位置和发病时间进行了亚组分析。此外，我们建立了一个逻辑回归模型来预测irae的风险，并使用来自基因表达综合数据库（GEO）的两个独立验证队列（登录号为GSE189125和GSE186143）对该模型进行了验证。结果通过分析106份血液样本和来自两个独立验证队列（n = 16和60例患者）的样本，我们发现在基线时CXCR3+CCR6+CD4+ T细胞和CD38+CD86+CXCR3+CCR6+CD8+ T细胞的高比例和CXCR3lowCD56dim自然杀伤（NK）细胞的低比例与irAEs的发生率显著相关(P = 0.0029, P <；0.001, P = 0.0017)。在亚组分析中，我们观察到免疫相关性肺炎（ir-pneumonitis）和免疫相关性甲状腺炎（ir-thyroiditis）患者的结果一致。在irAE早期组，CXCR3+CCR6+CD4+ T细胞的基线比例大于irAE晚期组（P = 0.011）。通过对ICI治疗前后PBMCs的分析发现，naïve CD4+ T细胞和CXCR3lowCD56dim NK细胞比例的动态变化与irAE的发生密切相关。最后，我们最终建立了一个预测irae风险的模型，训练队列的受试者工作特征曲线下面积（AUROC）为0.79，单细胞验证队列（GSE189125）的AUROC为0.75。结论这些发现表明，不同的免疫细胞群体与不同的irae相关，这些细胞的特征可能用作预测特定毒性风险的生物标志物。这将有助管理辐照事件，并可能减少辐照事件的发生。
{"title":"Systemic immune characteristics predicting toxicity to immune checkpoint inhibitors in patients with advanced breast cancer","authors":"Yalong Qi , Hewei Ge , Xiaoying Sun , Yuhan Wei , Jingtong Zhai , Haili Qian , Hongnan Mo , Fei Ma","doi":"10.1016/j.jaut.2025.103423","DOIUrl":"10.1016/j.jaut.2025.103423","url":null,"abstract":"<div><h3>Background</h3><div>Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for cancer. However, frequent and sometimes life-threatening immune-related adverse events (irAEs) are associated with ICI treatment. Therefore, it is imperative to establish a model for predicting the risk of irAEs to identify high-risk groups, enable more accurate clinical risk‒benefit analysis for ICI treatment and decrease the incidence of irAEs. However, no ideal model for predicting irAEs has been applied in clinical practice. The aim of this study was to analyze the systemic immune characteristics of patients with irAEs and establish a model for predicting the risk of irAEs.</div></div><div><h3>Methods</h3><div>We conducted a study to monitor irAEs in patients with advanced breast cancer undergoing immunotherapy during and following the treatment course. Peripheral blood mononuclear cells (PBMCs) were collected before and after two cycles of therapy. Mass cytometry time-of-flight (CyTOF) was employed to identify baseline and posttreatment immune cell subpopulations, and the relationships between the proportions of cells in these subpopulations and the occurrence of irAEs were explored. Additionally, we conducted subgroup analyses stratified by the anatomic location and time of onset of irAEs. Furthermore, we developed a logistic regression model to predict the risk of irAEs and validated this model using two independent validation cohorts from the Gene Expression Omnibus (GEO) database (accession numbers GSE189125 and GSE186143).</div></div><div><h3>Results</h3><div>By analyzing 106 blood samples and samples from two independent validation cohorts (n = 16 and 60 patients), we found that high proportions of CXCR3<sup>+</sup>CCR6<sup>+</sup>CD4<sup>+</sup> T cells and CD38<sup>+</sup>CD86<sup>+</sup>CXCR3<sup>+</sup>CCR6<sup>+</sup>CD8<sup>+</sup> T cells and a low proportion of CXCR3<sup>low</sup>CD56<sup>dim</sup> natural killer (NK) cells at baseline were significantly correlated with the incidence of irAEs (<em>P</em> = 0.0029, <em>P</em> < 0.001, and <em>P</em> = 0.0017, respectively). In the subgroup analysis, we observed consistent results in patients with immune-related pneumonitis (ir-pneumonitis) and immune-related thyroiditis (ir-thyroiditis). In the early irAE group, the baseline proportion of CXCR3<sup>+</sup>CCR6<sup>+</sup>CD4<sup>+</sup> T cells was greater than that in the late irAE group (<em>P</em> = 0.011). An analysis of PBMCs before and after ICI treatment revealed thatthe dynamic changes in the proportions of naïve CD4<sup>+</sup> T cells and CXCR3<sup>low</sup>CD56<sup>dim</sup> NK cells were closely related to irAE occurrence. Finally, we ultimately developed a model for predicting the risk of irAEs, which yielded an area under the receiver operating characteristic curve (AUROC) of 0.79 in the training cohort and an AUROC of 0.75 in the single-cell validation cohort (GSE189125).</div></div><div><h3>Concl","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103423"},"PeriodicalIF":7.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860273","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 : 2025-04-21DOI: 10.1016/j.jaut.2025.103418
Konstantinos N. Panagiotopoulos , Nikos Tsiknakis , Dimitrios I. Zaridis , Clio P. Mavragani , Athanasios G. Tzioufas , Dimitrios I. Fotiadis , Andreas V. Goules
Background
Sjögren's Disease (SjD) is histopathologically characterized by focal sialadenitis in minor labial salivary gland biopsies (mLSGB), which is evaluated by utilizing the focus score (FS). Focus score ≥1 identification is a critical step of the diagnostic approach and SjD classification. Nonetheless, during mLSGB analysis, FS reporting is neglected in a staggering 17 %, and a degree of inter-observer variability is introduced, even among specialized university centers. As the unmet need for reliable FS reporting is displayed, leveraging artificial intelligence in mLSGB evaluation shows encouraging potential and mandates to be investigated.
Methods
Minor LSGBs stained only with hematoxylin and eosin (H&E) during evaluation of individuals with a clinical suspicion of SjD, were randomly chosen from our archive. All mLSGBs were scanned digitally as whole slide images (WSI) and the final dataset was partitioned into a training (70 %) and a test set (30 %). An attention-based deep learning binary classification model was employed for evaluation of mLSGBs positivity (FS ≥ 1 or FS < 1).
Results
The final dataset consisted of 271 mLSGBs, with 153 (56 %) having FS < 1 and 118 (44 %) FS ≥ 1. In the FS ≥ 1 subset, 74 (63 %) were in the FS = 1–2 range, and the remaining biopsies had FS > 2, following the expected FS distribution among the typical SjD population. Our model resulted in: AUC = 0.932 (0.881–0.984), sensitivity 87 % (0.733–0.944), specificity 84 % (0.71–0.915) and accuracy 85.2 % (0.763–0.912), achieving better performance from previous works.
Conclusion
Artificial intelligence models may overcome the intra-observer biases and inter-observer variability in FS evaluation, reinforcing the diagnosis and biomarker discovery in SjD.
{"title":"Evaluation of minor labial salivary gland focus score in Sjögren's disease using deep learning: a tool for more efficient diagnosis and future tissue biomarker discovery","authors":"Konstantinos N. Panagiotopoulos , Nikos Tsiknakis , Dimitrios I. Zaridis , Clio P. Mavragani , Athanasios G. Tzioufas , Dimitrios I. Fotiadis , Andreas V. Goules","doi":"10.1016/j.jaut.2025.103418","DOIUrl":"10.1016/j.jaut.2025.103418","url":null,"abstract":"<div><h3>Background</h3><div>Sjögren's Disease (SjD) is histopathologically characterized by focal sialadenitis in minor labial salivary gland biopsies (mLSGB), which is evaluated by utilizing the focus score (FS). Focus score ≥1 identification is a critical step of the diagnostic approach and SjD classification. Nonetheless, during mLSGB analysis, FS reporting is neglected in a staggering 17 %, and a degree of inter-observer variability is introduced, even among specialized university centers. As the unmet need for reliable FS reporting is displayed, leveraging artificial intelligence in mLSGB evaluation shows encouraging potential and mandates to be investigated.</div></div><div><h3>Methods</h3><div>Minor LSGBs stained only with hematoxylin and eosin (H&E) during evaluation of individuals with a clinical suspicion of SjD, were randomly chosen from our archive. All mLSGBs were scanned digitally as whole slide images (WSI) and the final dataset was partitioned into a training (70 %) and a test set (30 %). An attention-based deep learning binary classification model was employed for evaluation of mLSGBs positivity (FS ≥ 1 or FS < 1).</div></div><div><h3>Results</h3><div>The final dataset consisted of 271 mLSGBs, with 153 (56 %) having FS < 1 and 118 (44 %) FS ≥ 1. In the FS ≥ 1 subset, 74 (63 %) were in the FS = 1–2 range, and the remaining biopsies had FS > 2, following the expected FS distribution among the typical SjD population. Our model resulted in: AUC = 0.932 (0.881–0.984), sensitivity 87 % (0.733–0.944), specificity 84 % (0.71–0.915) and accuracy 85.2 % (0.763–0.912), achieving better performance from previous works.</div></div><div><h3>Conclusion</h3><div>Artificial intelligence models may overcome the intra-observer biases and inter-observer variability in FS evaluation, reinforcing the diagnosis and biomarker discovery in SjD.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103418"},"PeriodicalIF":7.9,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855064","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 : 2025-04-18DOI: 10.1016/j.jaut.2025.103421
Marta Bustaffa , Saverio La Bella , Yagmur Bayindir , Gayane Amaryan , Romina Gallizzi , Efimia Papadopoulou-Alataki , Giovanna Fabio , Naiera Assalia , Gil Amarilyo , Sevcan Bakkaloglu , Milos Jesenak , Luciana Breda , Jordi Anton , Elizabeth Legger , Maria Alessio , Gabriele Simonini , Donato Rigante , Laura Obici , Jasmin Kuemmerle-Deschner , Ozgur Kasapcopur , Seza Ozen
Introduction
The majority of currently available data on familial Mediterranean fever (FMF) come from retrospective national or international studies.
Methods
An observational study collected data on the Eurofever international FMF cohort. Patients fulfilling genetic and clinical Eurofever criteria were considered as FMF+. Patients not fulfilling clinical and/or genetic (one VUS or benign variants or negative for MEFV variants) criteria were considered as FMF-. Data on compliance to treatment and quality of life were also recorded.
Results
Since November 2024, 876 FMF patients (466 M, 410 F) were enrolled, with a mean follow-up of 2.9 ± 3.1 years. 730 (84 %) patients were classified as FMF+, 146 (16 %) as FMF-, with significant differences in the prevalence of clinical manifestations and treatment response between the two groups. At the last follow-up, 433 patients (50.6 %) still had some disease activity. At the last follow-up 749 (85.5 %) patients received colchicine with a relative under dosage of the drug. Anti-IL-1 treatment was reported in 133 patients (15.2 %), mostly canakinumab (117, 13.4 %). Treatment compliance was generally satisfactory, and adverse events were generally mild.
Conclusions
Patients with an FMF-like phenotype who lack genetic confirmation display significant differences in clinical features and duration of attacks and show a less response to treatment during their disease course in respect, and thus, should be considered as FMF-mimics and investigated for other causes. Longitudinal data provides a more detailed comprehension of the long-term burden of FMF and the impact of treatment on disease activity and patients' quality of life.
{"title":"Long-term efficacy and safety of colchicine and anti-IL-1 blockers in FMF: results from the Eurofever multicenter observational study","authors":"Marta Bustaffa , Saverio La Bella , Yagmur Bayindir , Gayane Amaryan , Romina Gallizzi , Efimia Papadopoulou-Alataki , Giovanna Fabio , Naiera Assalia , Gil Amarilyo , Sevcan Bakkaloglu , Milos Jesenak , Luciana Breda , Jordi Anton , Elizabeth Legger , Maria Alessio , Gabriele Simonini , Donato Rigante , Laura Obici , Jasmin Kuemmerle-Deschner , Ozgur Kasapcopur , Seza Ozen","doi":"10.1016/j.jaut.2025.103421","DOIUrl":"10.1016/j.jaut.2025.103421","url":null,"abstract":"<div><h3>Introduction</h3><div>The majority of currently available data on familial Mediterranean fever (FMF) come from retrospective national or international studies.</div></div><div><h3>Methods</h3><div>An observational study collected data on the Eurofever international FMF cohort. Patients fulfilling genetic and clinical Eurofever criteria were considered as FMF+. Patients not fulfilling clinical and/or genetic (one VUS or benign variants or negative for <em>MEFV</em> variants) criteria were considered as FMF-. Data on compliance to treatment and quality of life were also recorded.</div></div><div><h3>Results</h3><div>Since November 2024, 876 FMF patients (466 M, 410 F) were enrolled, with a mean follow-up of 2.9 ± 3.1 years. 730 (84 %) patients were classified as FMF+, 146 (16 %) as FMF-, with significant differences in the prevalence of clinical manifestations and treatment response between the two groups. At the last follow-up, 433 patients (50.6 %) still had some disease activity. At the last follow-up 749 (85.5 %) patients received colchicine with a relative under dosage of the drug. Anti-IL-1 treatment was reported in 133 patients (15.2 %), mostly canakinumab (117, 13.4 %). Treatment compliance was generally satisfactory, and adverse events were generally mild.</div></div><div><h3>Conclusions</h3><div>Patients with an FMF-like phenotype who lack genetic confirmation display significant differences in clinical features and duration of attacks and show a less response to treatment during their disease course in respect, and thus, should be considered as FMF-mimics and investigated for other causes. Longitudinal data provides a more detailed comprehension of the long-term burden of FMF and the impact of treatment on disease activity and patients' quality of life.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103421"},"PeriodicalIF":7.9,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844553","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 : 2025-04-17DOI: 10.1016/j.jaut.2025.103415
Luman Wang , Maria-Ioanna Christodoulou , Zheng Jin , Yanmei Ma , Munnaf Hossen , Yuan Ji , Wenjun Wang , Xueqi Wang , Eryi Wang , Rongfei Wei , Xiaojun Xiao , Xiaoyu Liu , Ping-Chang Yang , Shaojun Xing , Bingni Chen , Kaifan Wang , Jim Yi Huang , Aysin Tulunay-Virlan , Iain B. McInnes , Jing Li , Damo Xu
Regulatory B cells (Bregs) are crucial for maintaining homeostasis and controlling inflammation. Although interleukin (IL)-10 has been traditionally suggested as the primary suppressive mechanism of Bregs in both mice and humans, the key functional differences between Bregs in these two species, particularly in the context of disease, is still largely unresolved. IL-37, the latest described immunosuppressive cytokine, is produced in humans but not in mice. Herein we identified the characteristics and functions of IL-37-producing Bregs, that naturally exist in human and can be induced by recombinant IL-37 (rIL-37) and/or Toll-like receptor 9 agonist CpG via different mechanisms. rIL-37 alone is sufficient to prompt IL-37, but not IL-10, production and proliferation of Bregs, whereas CpG elicits IL-37 expression in Bregs independently of IL-10, but dependent on HIF-1α which binds on the enhancer/promoter of the IL-37 gene. Functionally, IL-37+ Bregs exhibit superior anti-inflammatory efficacy than IL-37- Bregs in vitro, as well as in psoriasis and colitis models. However, the frequency of IL-37+ Bregs is reduced in patients with psoriasis. Thus, IL-37+ Bregs hold significant therapeutic potential for treating various inflammatory disorders, including psoriasis and colitis.
{"title":"Human regulatory B cells suppress autoimmune disease primarily via interleukin-37","authors":"Luman Wang , Maria-Ioanna Christodoulou , Zheng Jin , Yanmei Ma , Munnaf Hossen , Yuan Ji , Wenjun Wang , Xueqi Wang , Eryi Wang , Rongfei Wei , Xiaojun Xiao , Xiaoyu Liu , Ping-Chang Yang , Shaojun Xing , Bingni Chen , Kaifan Wang , Jim Yi Huang , Aysin Tulunay-Virlan , Iain B. McInnes , Jing Li , Damo Xu","doi":"10.1016/j.jaut.2025.103415","DOIUrl":"10.1016/j.jaut.2025.103415","url":null,"abstract":"<div><div>Regulatory B cells (Bregs) are crucial for maintaining homeostasis and controlling inflammation. Although interleukin (IL)-10 has been traditionally suggested as the primary suppressive mechanism of Bregs in both mice and humans, the key functional differences between Bregs in these two species, particularly in the context of disease, is still largely unresolved. IL-37, the latest described immunosuppressive cytokine, is produced in humans but not in mice. Herein we identified the characteristics and functions of IL-37-producing Bregs, that naturally exist in human and can be induced by recombinant IL-37 (rIL-37) and/or Toll-like receptor 9 agonist CpG via different mechanisms. rIL-37 alone is sufficient to prompt IL-37, but not IL-10, production and proliferation of Bregs, whereas CpG elicits IL-37 expression in Bregs independently of IL-10, but dependent on HIF-1α which binds on the enhancer/promoter of the IL-37 gene. Functionally, IL-37<sup>+</sup> Bregs exhibit superior anti-inflammatory efficacy than IL-37<sup>-</sup> Bregs in vitro, as well as in psoriasis and colitis models. However, the frequency of IL-37<sup>+</sup> Bregs is reduced in patients with psoriasis. Thus, IL-37<sup>+</sup> Bregs hold significant therapeutic potential for treating various inflammatory disorders, including psoriasis and colitis.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103415"},"PeriodicalIF":7.9,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838557","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 : 2025-04-16DOI: 10.1016/j.jaut.2025.103420
Kevin Chevalier , Benjamin Thoreau , Marc Michel , Bertrand Godeau , Christian Agard , Thomas Papo , Karim Sacre , Raphaèle Seror , Xavier Mariette , Patrice Cacoub , Ygal Benhamou , Hervé Levesque , Cécile Goujard , Olivier Lambotte , Bernard Bonnotte , Maxime Samson , Félix Ackermann , Jean Schmidt , Pierre Duhaut , Kahn Jean-Emmanuel , Luc Mouthon
Introduction
Mixed connective tissue disease (MCTD) is a rare systemic disorder that belongs to connective tissue diseases (CTD). Few studies are available on MCTD treatment.
Methods
We conducted an observational study within the French MCTD cohort. Data were collected at diagnosis, during follow-up, and at the last follow-up (LFU). We studied three treatment groups i) no treatment, ii) hydroxychloroquine (HCQ) and/or glucocorticoids (GC) and iii) disease-modifying antirheumatic drugs (DMARDs)/immunosuppressant (IS).
Results
Three hundred and fifteen patients were included and followed for 96 [40–156] months. At MCTD diagnosis, 52 (16.5 %) patients were treatment-free, while 224 (71.1 %) received GC and/or HCQ and 39 (12.4 %) received DMARDs and/or IS. During follow-up, 10 (3.2 %) patients remained treatment-free, and 77 (24.4 %) were GC-free. Most patients (n = 271; 85.8 %) received HCQ, and 161 (51.1 %) were treated with DMARDs and/or IS. DMARDs and/or IS, including anti-B cell therapeutics, were more frequently prescribed in patients with musculoskeletal involvement (p < 0.0001), interstitial lung disease (ILD, p < 0.0001) and/or pulmonary arterial hypertension (PAH, p < 0.01). Patients in clinical remission and those who did not evolve to a differentiated CTD (MCTD-dCTD) received significantly less frequently DMARDs and/or IS (including anti-B cell therapeutics; p < 0.0001 for both). Patients who received HCQ at MCTD diagnosis appeared to develop less frequently ILD or PAH (p < 0.05).
Conclusion
HCQ and GC were the cornerstones of MCTD treatment and were sufficient to control disease manifestations in nearly half of the patients, reflecting the good prognosis of this disease. DMARDs and IS were used for musculoskeletal involvement, PAH/ILD, and in MCTD-dCTD patients.
混合性结缔组织病（MCTD）是一种属于结缔组织病（CTD）的罕见全身性疾病。很少有关于MCTD治疗的研究。方法我们在法国MCTD队列中进行了一项观察性研究。在诊断时、随访期间和最后一次随访（LFU）时收集数据。我们研究了三个治疗组：i)不治疗，ii)羟氯喹（HCQ）和/或糖皮质激素（GC）和iii)改善疾病的抗风湿药物(DMARDs)/免疫抑制剂（IS）。结果共纳入315例患者，随访96个月[40-156]。在MCTD诊断时，52例（16.5%）患者未接受治疗，224例（71.1%）接受GC和/或HCQ治疗，39例（12.4%）接受DMARDs和/或IS治疗。随访期间，10例（3.2%）患者无治疗，77例（24.4%）患者无gc。大多数患者(n = 271；85.8%的患者接受了HCQ治疗，161例（51.1%）接受了DMARDs和/或IS治疗。DMARDs和/或IS，包括抗b细胞治疗，更常用于肌肉骨骼受累的患者(p <；0.0001)，间质性肺疾病(ILD, p <；0.0001)和/或肺动脉高压(PAH, p <；0.01)。临床缓解的患者和未发展为分化型CTD （MCTD-dCTD）的患者接受dmard和/或IS(包括抗b细胞治疗；p & lt;两者均为0.0001)。在MCTD诊断时接受HCQ的患者似乎较少发生ILD或PAH (p <；0.05)。结论hcq和GC是MCTD治疗的基础，足以控制近一半患者的疾病表现，反映了该病预后良好。DMARDs和IS用于肌肉骨骼受累、PAH/ILD和MCTD-dCTD患者。
{"title":"Treatment of mixed connective tissue disease: A multicenter retrospective study","authors":"Kevin Chevalier , Benjamin Thoreau , Marc Michel , Bertrand Godeau , Christian Agard , Thomas Papo , Karim Sacre , Raphaèle Seror , Xavier Mariette , Patrice Cacoub , Ygal Benhamou , Hervé Levesque , Cécile Goujard , Olivier Lambotte , Bernard Bonnotte , Maxime Samson , Félix Ackermann , Jean Schmidt , Pierre Duhaut , Kahn Jean-Emmanuel , Luc Mouthon","doi":"10.1016/j.jaut.2025.103420","DOIUrl":"10.1016/j.jaut.2025.103420","url":null,"abstract":"<div><h3>Introduction</h3><div>Mixed connective tissue disease (MCTD) is a rare systemic disorder that belongs to connective tissue diseases (CTD). Few studies are available on MCTD treatment.</div></div><div><h3>Methods</h3><div>We conducted an observational study within the French MCTD cohort. Data were collected at diagnosis, during follow-up, and at the last follow-up (LFU). We studied three treatment groups i) no treatment, ii) hydroxychloroquine (HCQ) and/or glucocorticoids (GC) and iii) disease-modifying antirheumatic drugs (DMARDs)/immunosuppressant (IS).</div></div><div><h3>Results</h3><div>Three hundred and fifteen patients were included and followed for 96 [40–156] months. At MCTD diagnosis, 52 (16.5 %) patients were treatment-free, while 224 (71.1 %) received GC and/or HCQ and 39 (12.4 %) received DMARDs and/or IS. During follow-up, 10 (3.2 %) patients remained treatment-free, and 77 (24.4 %) were GC-free. Most patients (n = 271; 85.8 %) received HCQ, and 161 (51.1 %) were treated with DMARDs and/or IS. DMARDs and/or IS, including anti-B cell therapeutics, were more frequently prescribed in patients with musculoskeletal involvement (p < 0.0001), interstitial lung disease (ILD, p < 0.0001) and/or pulmonary arterial hypertension (PAH, p < 0.01). Patients in clinical remission and those who did not evolve to a differentiated CTD (MCTD-dCTD) received significantly less frequently DMARDs and/or IS (including anti-B cell therapeutics; p < 0.0001 for both). Patients who received HCQ at MCTD diagnosis appeared to develop less frequently ILD or PAH (p < 0.05).</div></div><div><h3>Conclusion</h3><div>HCQ and GC were the cornerstones of MCTD treatment and were sufficient to control disease manifestations in nearly half of the patients, reflecting the good prognosis of this disease. DMARDs and IS were used for musculoskeletal involvement, PAH/ILD, and in MCTD-dCTD patients.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103420"},"PeriodicalIF":7.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834430","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 : 2025-04-15DOI: 10.1016/j.jaut.2025.103417
Shintaro Shirahama , Yoko Okunuki , May Y. Lee , Margarete M. Karg , Nasrin Refaian , Drenushe Krasniqi , Kip M. Connor , Meredith S. Gregory-Ksander , Bruce R. Ksander
Autoimmune uveitis is a major cause of blindness and experimental autoimmune uveitis (EAU) is mediated by interphotoreceptor retinoid-binding protein specific effector CD4+ T cells that infiltrate the retina. At least two MHC Class II (MHC II) antigen-presenting cell (APC) events are required for uveitis to develop. The first occurs in the secondary lymphoid organs when dendritic cells (DCs) activate and expand effector CD4+ T cells that enter the circulation and migrate systemically. The second APC event occurs when DC-primed effector CD4+ T cells infiltrate the retina and are restimulated by the relevant autoantigen. Importantly, if this second restimulation does not occur, then uveitis does not develop. However, it is still unclear which cell type(s) function as APCs within the retina. There are two candidate MHC II+ cell types-resident microglia and infiltrating DCs. We used the inducible Cre-lox approach to develop mouse strains in which MHC II was knocked out specifically on microglia using either the P2ry12 or Tmem119 gene to drive recombination. We also used Itgax (CD11c encoding gene) to drive recombination in DCs. Using this approach, we uncovered that the second APC event was mediated by MHC II+ microglia and not infiltrating MHC II+ DCs. Therefore, microglia are an important therapeutic target that can prevent and/or diminish uveitis even in the presence of circulating retinal autoantigen-specific effector CD4+ T cells.
{"title":"Preventing the antigen-presenting function of retinal microglia blocks autoimmune neuroinflammation by dendritic cell-primed CD4+ T cells","authors":"Shintaro Shirahama , Yoko Okunuki , May Y. Lee , Margarete M. Karg , Nasrin Refaian , Drenushe Krasniqi , Kip M. Connor , Meredith S. Gregory-Ksander , Bruce R. Ksander","doi":"10.1016/j.jaut.2025.103417","DOIUrl":"10.1016/j.jaut.2025.103417","url":null,"abstract":"<div><div>Autoimmune uveitis is a major cause of blindness and experimental autoimmune uveitis (EAU) is mediated by interphotoreceptor retinoid-binding protein specific effector CD4<sup>+</sup> T cells that infiltrate the retina. At least two MHC Class II (MHC II) antigen-presenting cell (APC) events are required for uveitis to develop. The first occurs in the secondary lymphoid organs when dendritic cells (DCs) activate and expand effector CD4<sup>+</sup> T cells that enter the circulation and migrate systemically. The second APC event occurs when DC-primed effector CD4<sup>+</sup> T cells infiltrate the retina and are restimulated by the relevant autoantigen. Importantly, if this second restimulation does not occur, then uveitis does not develop. However, it is still unclear which cell type(s) function as APCs within the retina. There are two candidate MHC II<sup>+</sup> cell types-resident microglia and infiltrating DCs. We used the inducible Cre-lox approach to develop mouse strains in which MHC II was knocked out specifically on microglia using either the <em>P2ry12</em> or <em>Tmem119</em> gene to drive recombination. We also used <em>Itgax</em> (CD11c encoding gene) to drive recombination in DCs. Using this approach, we uncovered that the second APC event was mediated by MHC II<sup>+</sup> microglia and not infiltrating MHC II<sup>+</sup> DCs. Therefore, microglia are an important therapeutic target that can prevent and/or diminish uveitis even in the presence of circulating retinal autoantigen-specific effector CD4<sup>+</sup> T cells.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103417"},"PeriodicalIF":7.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834429","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 : 2025-04-08DOI: 10.1016/j.jaut.2025.103416
Annalisa Marino , Irene Genovali , Luca Navarini , Elena Pontarini , Marta Vomero , Damiano Currado , Andrea Pilato , Letizia Pia Di Corcia , Michele Bombardieri , Roberto Giacomelli , Onorina Berardicurti
Sjögren's disease is a systemic autoimmune disease that primarily affects the exocrine glands, causing the main symptoms of xerostomia and xerophthalmia. In about half of the patients, it also causes systemic symptoms, which can potentially involve any organ or system. To date, the management of these patients is particularly complex due to the lack of recognized and approved therapies for the disease, except for medications used as symptomatic treatment for dryness. Due to the limited evidence available, therapeutic decisions in daily practice are frequently based on a combination of expert opinions and personal experience, which can vary significantly between clinicians. On these bases, we performed as systematic literature review critically analyzing the results of the previous trials, unpacking the single domains of ESSDAI, to evaluate if there are treatments significantly effective in some manifestations of the disease.
{"title":"Clinical targeted treatment in Sjogren's disease: A systematic literature review for an evidence-based medicine approach","authors":"Annalisa Marino , Irene Genovali , Luca Navarini , Elena Pontarini , Marta Vomero , Damiano Currado , Andrea Pilato , Letizia Pia Di Corcia , Michele Bombardieri , Roberto Giacomelli , Onorina Berardicurti","doi":"10.1016/j.jaut.2025.103416","DOIUrl":"10.1016/j.jaut.2025.103416","url":null,"abstract":"<div><div>Sjögren's disease is a systemic autoimmune disease that primarily affects the exocrine glands, causing the main symptoms of xerostomia and xerophthalmia. In about half of the patients, it also causes systemic symptoms, which can potentially involve any organ or system. To date, the management of these patients is particularly complex due to the lack of recognized and approved therapies for the disease, except for medications used as symptomatic treatment for dryness. Due to the limited evidence available, therapeutic decisions in daily practice are frequently based on a combination of expert opinions and personal experience, which can vary significantly between clinicians. On these bases, we performed as systematic literature review critically analyzing the results of the previous trials, unpacking the single domains of ESSDAI, to evaluate if there are treatments significantly effective in some manifestations of the disease.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103416"},"PeriodicalIF":7.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792079","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 : 2025-04-03DOI: 10.1016/j.jaut.2025.103411
Haoyue Hu , You Peng , Chi Chiu Wang , Jun Chen , Xiao Yu , Xiaoyan Chen , Haotong Ouyang , Qin Huang , Jing Ma , Qian Yin , Lien Ma , Ziling Ding , Minyi Zhang , Hao Ren , Jiaman Zheng , Wenqian Chen , Zixin Tao , Ruiyan Liu , Lu Chen , Xuefei Wang , Mei Zhong
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder primarily affecting women during the reproductive years, often complicating pregnancy outcomes with elevated levels of neutrophil extracellular traps (NETs) infiltration. However, potential impacts of NETs on placental trophoblasts in SLE and the underlying molecular mechanisms remain unclear. To address this, transcriptome sequencing was conducted on placentas collected from seven pregnant women with SLE and six healthy pregnant controls to identify SLE-specific placental features. The effects of NETs were further assessed in MRL/lpr lupus-prone mice and pristane-induced lupus (PIL) mice, focusing on pregnancy outcomes and placental pathology. In vitro, trophoblasts were stimulated with NETs derived from patients with SLE, followed by molecular analyses such as transcriptomic, cellular energy metabolism assays and liquid chromatography-tandem mass spectrometry to explore the effects and mechanisms of NETs. Results showed elevated NETs were observed in the placentas of both patients with SLE and lupus mouse models, accompanied by activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Treatment with DNase I significantly improved pregnancy outcomes in MRL/lpr mice, while the use of peptidyl arginine deiminase 4 (PAD4)-deficient mice was beneficial on the pregnancy outcomes of PIL mice. Furthermore, SLE-derived NETs activated pyroptosis in trophoblasts by promoting glycolysis and subsequent lactylation of NLRP3. These findings highlight that NETs contribute to placental damage in SLE by inducing the lactylation of the NLRP3 inflammasome in trophoblasts, demonstrating the therapeutic potential of inhibiting NETs to improve placental function.
{"title":"Neutrophil extracellular traps induce trophoblasts pyroptosis via enhancing NLRP3 lactylation in SLE pregnancies","authors":"Haoyue Hu , You Peng , Chi Chiu Wang , Jun Chen , Xiao Yu , Xiaoyan Chen , Haotong Ouyang , Qin Huang , Jing Ma , Qian Yin , Lien Ma , Ziling Ding , Minyi Zhang , Hao Ren , Jiaman Zheng , Wenqian Chen , Zixin Tao , Ruiyan Liu , Lu Chen , Xuefei Wang , Mei Zhong","doi":"10.1016/j.jaut.2025.103411","DOIUrl":"10.1016/j.jaut.2025.103411","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder primarily affecting women during the reproductive years, often complicating pregnancy outcomes with elevated levels of neutrophil extracellular traps (NETs) infiltration. However, potential impacts of NETs on placental trophoblasts in SLE and the underlying molecular mechanisms remain unclear. To address this, transcriptome sequencing was conducted on placentas collected from seven pregnant women with SLE and six healthy pregnant controls to identify SLE-specific placental features. The effects of NETs were further assessed in MRL/lpr lupus-prone mice and pristane-induced lupus (PIL) mice, focusing on pregnancy outcomes and placental pathology. <em>In vitro,</em> trophoblasts were stimulated with NETs derived from patients with SLE, followed by molecular analyses such as transcriptomic, cellular energy metabolism assays and liquid chromatography-tandem mass spectrometry to explore the effects and mechanisms of NETs. Results showed elevated NETs were observed in the placentas of both patients with SLE and lupus mouse models, accompanied by activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. Treatment with DNase I significantly improved pregnancy outcomes in MRL/lpr mice, while the use of peptidyl arginine deiminase 4 (PAD4)-deficient mice was beneficial on the pregnancy outcomes of PIL mice. Furthermore, SLE-derived NETs activated pyroptosis in trophoblasts by promoting glycolysis and subsequent lactylation of NLRP3. These findings highlight that NETs contribute to placental damage in SLE by inducing the lactylation of the NLRP3 inflammasome in trophoblasts, demonstrating the therapeutic potential of inhibiting NETs to improve placental function.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103411"},"PeriodicalIF":7.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759447","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}
Labial salivary glands (LSG) from Sjögren's disease (SjD) patients are characterized by increased levels of pro-inflammatory cytokines, such as type I interferons (IFN-I). These LSG also show activation of the integrated stress response (ISR) with overexpression of protein kinase R (PKR), a known IFN-stimulated gene. In vitro, IFN-I stimulation reproduces the downregulation of hsa-miR-145-5p, which is associated with TLR4 overexpression observed in LSG of SjD patients. MicroRNA levels depend on its biogenesis, which is a multi-step process involving several protein complexes. It is not known whether altered miRNA biogenesis is associated with the activation of the ISR induced by IFN-I in LSG from SjD. The aim of this study was to characterize the expression and localization of components of the miRNA biogenesis machinery in LSG of SjD patients, to assess the effect of pro-inflammatory cytokines on these components, and to test whether inhibition of the IFN-β-induced ISR restores the levels of hsa-miR-145-5p. In LSG from 12 SjD patients and 11 non-SjD sicca controls, we determined mRNA fold changes, relative protein levels, and the localization of the ISR and miRNA biogenesis machinery components by RT-qPCR, Western blot, and immunofluorescence, respectively. Pro-inflammatory cytokines, the ISR inhibitor ISRIB, and the PKR inhibitor C16 were used for in vitro assays. In LSG from SjD patients, PKR and its activator PACT colocalized in the cytoplasm, whereas the PKR inhibitor TRBP was observed in the nuclei. IFN-β activates PKR, increases p-eIF2α and ATF4 levels, and increases PACT and AGO2 detection in stress granules. C16 inhibits PKR phosphorylation but increases ATF4 by activating GCN2. ISRIB restores levels of hsa-miR-145-5p and its target TLR4 mRNA upon IFN-β stimulation. These findings suggest an association between inflammation, cellular stress, and miRNA biogenesis, where modulation of the ISR emerges as a potential strategy to restore cellular homeostasis in LSG from SjD patients.
{"title":"Integrated stress response inhibition restores hsa-miR-145-5p levels after IFN-β stimulation in salivary gland epithelial cells. Association between cellular stress and miRNA biogenesis in Sjögren's disease","authors":"Isabel Castro , Patricia Carvajal , Sergio Aguilera , María-José Barrera , Soledad Matus , Sergio González , Claudio Molina , María-Julieta González","doi":"10.1016/j.jaut.2025.103412","DOIUrl":"10.1016/j.jaut.2025.103412","url":null,"abstract":"<div><div>Labial salivary glands (LSG) from Sjögren's disease (SjD) patients are characterized by increased levels of pro-inflammatory cytokines, such as type I interferons (IFN-I). These LSG also show activation of the integrated stress response (ISR) with overexpression of protein kinase R (PKR), a known IFN-stimulated gene. <em>In vitro</em>, IFN-I stimulation reproduces the downregulation of hsa-miR-145-5p, which is associated with TLR4 overexpression observed in LSG of SjD patients. MicroRNA levels depend on its biogenesis, which is a multi-step process involving several protein complexes. It is not known whether altered miRNA biogenesis is associated with the activation of the ISR induced by IFN-I in LSG from SjD. The aim of this study was to characterize the expression and localization of components of the miRNA biogenesis machinery in LSG of SjD patients, to assess the effect of pro-inflammatory cytokines on these components, and to test whether inhibition of the IFN-β-induced ISR restores the levels of hsa-miR-145-5p. In LSG from 12 SjD patients and 11 non-SjD sicca controls, we determined mRNA fold changes, relative protein levels, and the localization of the ISR and miRNA biogenesis machinery components by RT-qPCR, Western blot, and immunofluorescence, respectively. Pro-inflammatory cytokines, the ISR inhibitor ISRIB, and the PKR inhibitor C16 were used for <em>in vitro</em> assays. In LSG from SjD patients, PKR and its activator PACT colocalized in the cytoplasm, whereas the PKR inhibitor TRBP was observed in the nuclei. IFN-β activates PKR, increases p-eIF2α and ATF4 levels, and increases PACT and AGO2 detection in stress granules. C16 inhibits PKR phosphorylation but increases ATF4 by activating GCN2. ISRIB restores levels of hsa-miR-145-5p and its target TLR4 mRNA upon IFN-β stimulation. These findings suggest an association between inflammation, cellular stress, and miRNA biogenesis, where modulation of the ISR emerges as a potential strategy to restore cellular homeostasis in LSG from SjD patients.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103412"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748148","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 : 2025-04-01DOI: 10.1016/j.jaut.2025.103414
Yuanyuan Yang , Wencong Liu , Zechang Zhang , Yujia zhang , Xuebin Wang , Jing Wang , Huaifang Cai , Yichan Liu , Ran Meng , Yuqi Fu , Hongmin Luo , Lei Yang , Wenxuan Liu
Background
Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging with therapeutic agents for the treatment of two of the most prevalent metabolic disorders: diabetes and obesity. However, the causal relationship between GLP-1R agonists and autoimmune diseases is still unclear.
Methods
The available cis-eQTLs for drug target genes (GLP-1Rs) were used as proxies for exposure to GLP-1R agonists. Obesity and type 2 diabetes mellitus (T2DM) were used as positive controls to ensure the reliability of the genetic instrument. Mendelian randomization (MR) was performed to reveal the causal association of genetic proxy GLP-1R agonists with 18 autoimmune diseases from the IEU OpenGwas database and FinnGen database. Finally, the results of the two databases were analyzed via meta-analysis.
Results
A total of 22 significant cis-eQTL single-nucleotide polymorphisms were included as genetic instruments. Positive control analysis revealed that GLP-1R agonists were significantly associated with obesity (OR = 0.826, p = 0.021) and T2DM (OR = 0.886, p < 0.001), which is consistent with the meta-analysis. MR analysis revealed that increased expression of the GLP-1R gene has a significant protective effect on type 1 diabetes mellitus (T1DM), hypothyroidism, primary biliary cholangitis (PBC) and rheumatoid arthritis (RA). However, the MR analysis suggested that increased expression of GLP-1R agonists may increase the risk of Graves' disease (GD), ulcerative colitis (UC) and psoriasis. Our findings were consistent with those of the meta-analysis.
Conclusions
This study provides new insights into potential adjuvant treatments for autoimmune diseases from the perspective of genetic variation and provides evidence for the safety of GLP-1R agonists.
胰高血糖素样肽-1受体（GLP-1R）激动剂正在作为治疗药物出现，用于治疗两种最常见的代谢紊乱：糖尿病和肥胖。然而，GLP-1R激动剂与自身免疫性疾病之间的因果关系尚不清楚。方法利用现有的药物靶基因（GLP-1Rs）顺式等位基因（cis- eqtl）作为GLP-1R激动剂暴露的指标。为确保遗传仪器的可靠性，以肥胖和2型糖尿病（T2DM）为阳性对照。采用孟德尔随机化（MR）来揭示遗传代理GLP-1R激动剂与来自IEU OpenGwas数据库和FinnGen数据库的18种自身免疫性疾病的因果关系。最后，对两个数据库的结果进行meta分析。结果共纳入22个显著的顺式eqtl单核苷酸多态性作为遗传工具。阳性对照分析显示，GLP-1R激动剂与肥胖（OR = 0.826, p = 0.021）和2型糖尿病(OR = 0.886, p <；0.001)，这与meta分析一致。MR分析显示，GLP-1R基因表达增加对1型糖尿病（T1DM）、甲状腺功能减退、原发性胆管炎（PBC）和类风湿性关节炎（RA）具有显著的保护作用。然而，MR分析表明，GLP-1R激动剂的表达增加可能增加Graves病（GD）、溃疡性结肠炎（UC）和牛皮癣的风险。我们的发现与meta分析的结果一致。结论本研究从遗传变异的角度为自身免疫性疾病的潜在辅助治疗提供了新的见解，为GLP-1R激动剂的安全性提供了证据。
{"title":"Exploring glucagon-like peptide-1 receptor agonists as potential disease-modifying agents in autoimmune diseases","authors":"Yuanyuan Yang , Wencong Liu , Zechang Zhang , Yujia zhang , Xuebin Wang , Jing Wang , Huaifang Cai , Yichan Liu , Ran Meng , Yuqi Fu , Hongmin Luo , Lei Yang , Wenxuan Liu","doi":"10.1016/j.jaut.2025.103414","DOIUrl":"10.1016/j.jaut.2025.103414","url":null,"abstract":"<div><h3>Background</h3><div>Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging with therapeutic agents for the treatment of two of the most prevalent metabolic disorders: diabetes and obesity. However, the causal relationship between GLP-1R agonists and autoimmune diseases is still unclear.</div></div><div><h3>Methods</h3><div>The available cis-eQTLs for drug target genes (GLP-1Rs) were used as proxies for exposure to GLP-1R agonists. Obesity and type 2 diabetes mellitus (T2DM) were used as positive controls to ensure the reliability of the genetic instrument. Mendelian randomization (MR) was performed to reveal the causal association of genetic proxy GLP-1R agonists with 18 autoimmune diseases from the IEU OpenGwas database and FinnGen database. Finally, the results of the two databases were analyzed via meta-analysis.</div></div><div><h3>Results</h3><div>A total of 22 significant cis-eQTL single-nucleotide polymorphisms were included as genetic instruments. Positive control analysis revealed that GLP-1R agonists were significantly associated with obesity (OR = 0.826, <em>p</em> = 0.021) and T2DM (OR = 0.886, <em>p</em> < 0.001), which is consistent with the meta-analysis. MR analysis revealed that increased expression of the GLP-1R gene has a significant protective effect on type 1 diabetes mellitus (T1DM), hypothyroidism, primary biliary cholangitis (PBC) and rheumatoid arthritis (RA). However, the MR analysis suggested that increased expression of GLP-1R agonists may increase the risk of Graves' disease (GD), ulcerative colitis (UC) and psoriasis. Our findings were consistent with those of the meta-analysis.</div></div><div><h3>Conclusions</h3><div>This study provides new insights into potential adjuvant treatments for autoimmune diseases from the perspective of genetic variation and provides evidence for the safety of GLP-1R agonists.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"153 ","pages":"Article 103414"},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739157","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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