Pub Date : 2025-12-18Epub Date: 2025-09-02DOI: 10.1016/j.autrev.2025.103925
Inbar Michaeli , Simon Lassman , Gilad Halpert , Giris Jacob , Howard Amital
The medical use of cannabis is expanding across many countries, with some legalizing its use outright and others implementing medical licensure systems to approve treatment for eligible patients.
Despite this growing interest and utilization, there remains a lack of solid scientific evidence supporting its medical use, even though cannabis has been used therapeutically for thousands of years.
The goal of the following communication is to present updated data on the potential roles of cannabis-based treatments in various autoimmune and rheumatic conditions. The information highlights that incorporating cannabis into the therapeutic armamentarium may offer benefits. However, in many cases, despite encouraging perspectives and outcomes, the supporting evidence remains insufficient and requires further validation.
Due to social and legal barriers, the conduct of such rigorous clinical trials has been hindered, limiting the availability of high-quality evidence to guide medical practice.
{"title":"Exploring therapeutic potential of Cannabis based therapy in autoimmune and rheumatic disorders","authors":"Inbar Michaeli , Simon Lassman , Gilad Halpert , Giris Jacob , Howard Amital","doi":"10.1016/j.autrev.2025.103925","DOIUrl":"10.1016/j.autrev.2025.103925","url":null,"abstract":"<div><div>The medical use of cannabis is expanding across many countries, with some legalizing its use outright and others implementing medical licensure systems to approve treatment for eligible patients.</div><div>Despite this growing interest and utilization, there remains a lack of solid scientific evidence supporting its medical use, even though cannabis has been used therapeutically for thousands of years.</div><div>The goal of the following communication is to present updated data on the potential roles of cannabis-based treatments in various autoimmune and rheumatic conditions. The information highlights that incorporating cannabis into the therapeutic armamentarium may offer benefits. However, in many cases, despite encouraging perspectives and outcomes, the supporting evidence remains insufficient and requires further validation.</div><div>Due to social and legal barriers, the conduct of such rigorous clinical trials has been hindered, limiting the availability of high-quality evidence to guide medical practice.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"24 12","pages":"Article 103925"},"PeriodicalIF":8.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999505","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 : 2025-12-18Epub Date: 2025-08-16DOI: 10.1016/j.autrev.2025.103912
Xiang-Yu Qi , Meng-Xia Liu , Xiao-Jing Jiang , Tian Gao , Guo-Qiang Xu , He-Yi Zhang , Qin-Yi Su , Yi Du , Jing Luo , Sheng-Xiao Zhang
Rheumatoid arthritis (RA) is a systemic autoimmune disease shaped by complex interactions between genetics and environmental factors, among which gut microbiota has emerged as a critical modulator. Recent advances have implicated gut microbiota dysbiosis in RA pathophysiology, with evidence spanning mechanistic, diagnostic, and therapeutic dimensions. This review summarizes current knowledge of the gut-joint axis and outlines microbiota-based strategies for RA management. Numerous studies have demonstrated consistent alterations in gut microbial communities in patients with RA, with enrichment of Prevotella copri observed in 75% of patients with new-onset RA compared to 21.4% of healthy controls, suggesting a potential association with disease initiation. Mechanistically, we detail how microbial dysbiosis, including that of bacteria, fungi, and viruses, disrupts intestinal barrier integrity, skews T helper 17/T regulatory and T follicular helper/T follicular regulatory immune axes, induces molecular mimicry, and alters the profiles of microbial metabolites such as short-chain fatty acids. Diagnostically, microbial taxa and metabolites serve as promising biomarkers. Machine learning models based on microbiota profiles have achieved area under the curve (AUC) values exceeding 0.88, with discriminatory taxa such as Ruminococcus gnavus and Fusicatenibacter. Therapeutically, we reviewed microbiota-targeted interventions, such as probiotics, prebiotics, antibiotics, fecal microbiota transplantation, diet, and herbal medicines, highlighting the emerging field of pharmacomicrobiomics. Gut microbial signatures have shown promise in predicting treatment responses, including methotrexate efficacy via the enterotype-based gut microbial human index model (AUC = 0.945). This review proposes an integrated framework linking microbial alterations with RA onset and progression and presents gut microbiota as a promising frontier for biomarker discovery, personalized intervention, and precision medicine.
{"title":"Gut microbiota in rheumatoid arthritis: Mechanistic insights, clinical biomarkers, and translational perspectives","authors":"Xiang-Yu Qi , Meng-Xia Liu , Xiao-Jing Jiang , Tian Gao , Guo-Qiang Xu , He-Yi Zhang , Qin-Yi Su , Yi Du , Jing Luo , Sheng-Xiao Zhang","doi":"10.1016/j.autrev.2025.103912","DOIUrl":"10.1016/j.autrev.2025.103912","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a systemic autoimmune disease shaped by complex interactions between genetics and environmental factors, among which gut microbiota has emerged as a critical modulator. Recent advances have implicated gut microbiota dysbiosis in RA pathophysiology, with evidence spanning mechanistic, diagnostic, and therapeutic dimensions. This review summarizes current knowledge of the gut-joint axis and outlines microbiota-based strategies for RA management. Numerous studies have demonstrated consistent alterations in gut microbial communities in patients with RA, with enrichment of <em>Prevotella copri</em> observed in 75% of patients with new-onset RA compared to 21.4% of healthy controls, suggesting a potential association with disease initiation. Mechanistically, we detail how microbial dysbiosis, including that of bacteria, fungi, and viruses, disrupts intestinal barrier integrity, skews T helper 17/T regulatory and T follicular helper/T follicular regulatory immune axes, induces molecular mimicry, and alters the profiles of microbial metabolites such as short-chain fatty acids. Diagnostically, microbial taxa and metabolites serve as promising biomarkers. Machine learning models based on microbiota profiles have achieved area under the curve (AUC) values exceeding 0.88, with discriminatory taxa such as <em>Ruminococcus gnavus</em> and <em>Fusicatenibacter</em>. Therapeutically, we reviewed microbiota-targeted interventions, such as probiotics, prebiotics, antibiotics, fecal microbiota transplantation, diet, and herbal medicines, highlighting the emerging field of pharmacomicrobiomics. Gut microbial signatures have shown promise in predicting treatment responses, including methotrexate efficacy via the enterotype-based gut microbial human index model (AUC = 0.945). This review proposes an integrated framework linking microbial alterations with RA onset and progression and presents gut microbiota as a promising frontier for biomarker discovery, personalized intervention, and precision medicine.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"24 12","pages":"Article 103912"},"PeriodicalIF":8.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871178","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 : 2025-12-18Epub Date: 2025-08-20DOI: 10.1016/j.autrev.2025.103914
Athanasia Dara, Nikolaos I. Vlachogiannis, George E. Fragoulis, Maria G. Tektonidou, Petros P. Sfikakis
Prompt initiation of effective drug treatment is crucial for controlling inflammation and preventing disease progression in rheumatoid arthritis, the most prevalent systemic rheumatic disease. The growing range of drug therapies over the past three decades and the fact that only a minority of patients achieve sustained long-term remission with any given therapy, make imperative the need for biomarkers predicting responses to specific drugs. Moreover, promising therapeutic approaches under development, namely cellular therapies, could be promptly applicable at earlier disease stages in about 10-15 % of RA patients who will be refractory to all approved drugs. In this scoping review of original articles published until 25th of July 2025, we present a critical overview of the literature pertaining to the prognostic value of blood immunophenotyping, circulating proteins and blood proteomics, transcriptomics, metabolomics and lipidomics, as well as of endogenous cortisol production and synovial histopathology. We also discuss the emerging use of artificial intelligence-based approaches for developing response prediction models that integrate clinical features with molecular profiling. We conclude that current knowledge does not allow to discern future responders to methotrexate and/or to different biologic agents from non-responders because established biomarkers to identify those patients who will benefit the most from each therapeutic option are lacking. We also emphasize the lack of standardized research approaches to discover biomarkers predicting drug treatment responses and try to identify the relevant pitfalls and describe the lessons learned over the years. Finally, we propose a roadmap and the application of advanced analytical and machine learning techniques for future research in this area.
{"title":"In search of biomarkers for prediction of drug treatment responses in rheumatoid arthritis: Lessons learned and future perspectives","authors":"Athanasia Dara, Nikolaos I. Vlachogiannis, George E. Fragoulis, Maria G. Tektonidou, Petros P. Sfikakis","doi":"10.1016/j.autrev.2025.103914","DOIUrl":"10.1016/j.autrev.2025.103914","url":null,"abstract":"<div><div>Prompt initiation of effective drug treatment is crucial for controlling inflammation and preventing disease progression in rheumatoid arthritis, the most prevalent systemic rheumatic disease. The growing range of drug therapies over the past three decades and the fact that only a minority of patients achieve sustained long-term remission with any given therapy, make imperative the need for biomarkers predicting responses to specific drugs. Moreover, promising therapeutic approaches under development, namely cellular therapies, could be promptly applicable at earlier disease stages in about 10-15 % of RA patients who will be refractory to all approved drugs. In this scoping review of original articles published until 25th of July 2025, we present a critical overview of the literature pertaining to the prognostic value of blood immunophenotyping, circulating proteins and blood proteomics, transcriptomics, metabolomics and lipidomics, as well as of endogenous cortisol production and synovial histopathology. We also discuss the emerging use of artificial intelligence-based approaches for developing response prediction models that integrate clinical features with molecular profiling. We conclude that current knowledge does not allow to discern future responders to methotrexate and/or to different biologic agents from non-responders because established biomarkers to identify those patients who will benefit the most from each therapeutic option are lacking. We also emphasize the lack of standardized research approaches to discover biomarkers predicting drug treatment responses and try to identify the relevant pitfalls and describe the lessons learned over the years. Finally, we propose a roadmap and the application of advanced analytical and machine learning techniques for future research in this area.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"24 12","pages":"Article 103914"},"PeriodicalIF":8.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908576","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 : 2025-12-18Epub Date: 2025-08-28DOI: 10.1016/j.autrev.2025.103923
Thuy Duong Nguyen , Hugo Abreu , Nicoletta Tommasi , Luigi Azzarone , Rita Maria Concetta Di Martino , Beatrice Riva , Davide Raineri , Tracey Pirali , Annalisa Chiocchetti , Giuseppe Cappellano
Rheumatoid arthritis and osteoarthritis are among the most prevalent chronic diseases worldwide, imposing a significant burden on both patients and healthcare systems. Despite their distinct etiology and progression, emerging evidence suggests that calcium signaling plays a pivotal role in the pathogenesis of both diseases by influencing a variety of cellular processes within joint tissues. Calcium is essential for regulating key cellular functions, including gene expression, muscle contraction, cell cycle progression, proliferation, apoptosis, excitation-contraction coupling, synaptic transmission, and embryonic development. Particularly, in the context of arthritic diseases, an imbalance in calcium homeostasis has significant consequences, since the osteogenic and chondrogenic processes, as well as extracellular matrix formation, are highly influenced by calcium levels. Given these insights, a deeper understanding of the mechanisms governing calcium uptake, release, and metabolism could enhance our comprehension of disease pathogenesis and facilitate the development of novel therapeutic strategies. This review provides an overview of calcium signaling mechanisms, particularly in the most affected cells and tissues in rheumatoid arthritis and osteoarthritis, and summarizes the emerging therapies targeting calcium metabolism that may improve current treatment options.
{"title":"Calcium signaling dysregulation in rheumatoid arthritis: a comparative perspective with osteoarthritis","authors":"Thuy Duong Nguyen , Hugo Abreu , Nicoletta Tommasi , Luigi Azzarone , Rita Maria Concetta Di Martino , Beatrice Riva , Davide Raineri , Tracey Pirali , Annalisa Chiocchetti , Giuseppe Cappellano","doi":"10.1016/j.autrev.2025.103923","DOIUrl":"10.1016/j.autrev.2025.103923","url":null,"abstract":"<div><div>Rheumatoid arthritis and osteoarthritis are among the most prevalent chronic diseases worldwide, imposing a significant burden on both patients and healthcare systems. Despite their distinct etiology and progression, emerging evidence suggests that calcium signaling plays a pivotal role in the pathogenesis of both diseases by influencing a variety of cellular processes within joint tissues. Calcium is essential for regulating key cellular functions, including gene expression, muscle contraction, cell cycle progression, proliferation, apoptosis, excitation-contraction coupling, synaptic transmission, and embryonic development. Particularly, in the context of arthritic diseases, an imbalance in calcium homeostasis has significant consequences, since the osteogenic and chondrogenic processes, as well as extracellular matrix formation, are highly influenced by calcium levels. Given these insights, a deeper understanding of the mechanisms governing calcium uptake, release, and metabolism could enhance our comprehension of disease pathogenesis and facilitate the development of novel therapeutic strategies. This review provides an overview of calcium signaling mechanisms, particularly in the most affected cells and tissues in rheumatoid arthritis and osteoarthritis, and summarizes the emerging therapies targeting calcium metabolism that may improve current treatment options.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"24 12","pages":"Article 103923"},"PeriodicalIF":8.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916341","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}
Systemic lupus erythematosus (SLE) often progresses to critical illness requiring intensive care unit (ICU) admission, yet contemporary data on outcomes, prognostic factors, and therapeutic approaches are scattered.
Objective
To synthesize recent evidence on causes of ICU admission, mortality predictors, and management strategies in adult SLE.
Methods
A PRISMA-compliant search of PubMed, Web of Science and Cochrane Library (inception–31 December 2024) retrieved studies enrolling adults (≥18 years) with confirmed SLE treated in ICUs. Two reviewers independently selected articles and extracted data; methodological heterogeneity precluded meta-analysis, so results were narratively synthesized.
Results
Thirty-nine studies met the criteria. Infection (40 %), pulmonary involvement (17 %) and renal flares (13 %) were the most common admission triggers. Reported ICU mortality ranged from 20 % to 82 % but rose sharply when baseline Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) exceeded 16, approximating 80 % mortality (sensitivity 84 %, specificity 90 %) and outperforming Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) in discriminating survivors. Additional independent predictors were APACHE II > 16, need for mechanical ventilation, renal replacement therapy and vasopressor support. Mechanical ventilation (59 %) and vasoactive agents (39 %) were the predominant ICU interventions. Immunomodulatory management was heterogeneous: high-dose corticosteroids and cyclophosphamide were ubiquitous, whereas mycophenolate, antimalarials, intravenous immunoglobulin, plasmapheresis, and extracorporeal membrane oxygenation were reserved for selected scenarios.
Conclusions
Early recognition of poor prognostic factors and prompt ICU admission are essential to improving outcomes in SLE.
{"title":"Systemic lupus erythematosus in critical care: A systematic review of ICU outcomes and management","authors":"Edith Ramírez-Lara , Claudia Mendoza-Pinto , Pamela Munguía-Realpozo , Miguel Ángel Saavedra-Salinas , Ivet Etchegaray-Morales , Jorge Ayón-Aguilar , Álvaro José Montiel-Jarquín , Socorro Martínez-Méndez","doi":"10.1016/j.autrev.2025.103911","DOIUrl":"10.1016/j.autrev.2025.103911","url":null,"abstract":"<div><h3>Background</h3><div>Systemic lupus erythematosus (SLE) often progresses to critical illness requiring intensive care unit (ICU) admission, yet contemporary data on outcomes, prognostic factors, and therapeutic approaches are scattered.</div></div><div><h3>Objective</h3><div>To synthesize recent evidence on causes of ICU admission, mortality predictors, and management strategies in adult SLE.</div></div><div><h3>Methods</h3><div>A PRISMA-compliant search of PubMed, Web of Science and Cochrane Library (inception–31 December 2024) retrieved studies enrolling adults (≥18 years) with confirmed SLE treated in ICUs. Two reviewers independently selected articles and extracted data; methodological heterogeneity precluded meta-analysis, so results were narratively synthesized.</div></div><div><h3>Results</h3><div>Thirty-nine studies met the criteria. Infection (40 %), pulmonary involvement (17 %) and renal flares (13 %) were the most common admission triggers. Reported ICU mortality ranged from 20 % to 82 % but rose sharply when baseline Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) exceeded 16, approximating 80 % mortality (sensitivity 84 %, specificity 90 %) and outperforming Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) in discriminating survivors. Additional independent predictors were APACHE II > 16, need for mechanical ventilation, renal replacement therapy and vasopressor support. Mechanical ventilation (59 %) and vasoactive agents (39 %) were the predominant ICU interventions. Immunomodulatory management was heterogeneous: high-dose corticosteroids and cyclophosphamide were ubiquitous, whereas mycophenolate, antimalarials, intravenous immunoglobulin, plasmapheresis, and extracorporeal membrane oxygenation were reserved for selected scenarios.</div></div><div><h3>Conclusions</h3><div>Early recognition of poor prognostic factors and prompt ICU admission are essential to improving outcomes in SLE<strong>.</strong></div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"24 12","pages":"Article 103911"},"PeriodicalIF":8.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881968","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 : 2025-12-18Epub Date: 2025-08-26DOI: 10.1016/j.autrev.2025.103920
Xiaoqing Wang , Ying Luo , Qiang Zhou , Jie Ma
The S100 protein family, the largest group of calcium-binding proteins, functions as key molecular regulators both intracellularly and extracellularly. Among these, S100A8/A9 and S100A12 have gained particular attention for their roles in the pathogenesis of autoimmune diseases (AID). These proteins interact with pivotal receptors, including G-protein-coupled receptors (GPCRs), toll-like receptor-4 (TLR4), and receptor for advanced glycation end-products (RAGE), driving innate immune activation, amplifying inflammatory responses, and modulating immune cell function. Dysregulation of S100A8/A9 and S100A12 is closely associated with disease progression across multiple autoimmune conditions. Their elevated expression correlates with disease severity, making them valuable biomarkers for monitoring disease activity, predicting therapeutic responses, and assessing disease progression. This review provides an in-depth synthesis of current evidence on the mechanistic roles of S100A8/A9 and S100A12 in AID, emphasizing their biomarker potential and therapeutic value. We further discuss emerging therapeutic strategies that target S100 proteins, their receptors, downstream signaling pathways using small-molecule inhibitors, RNA-based approaches, and monoclonal antibodies. These insights highlight the dual promise of S100A8/A9 and S100A12 as both disease indicators and intervention points, offering novel avenues for the management of AID.
{"title":"The roles of S100A8/A9 and S100A12 in autoimmune diseases: Mechanisms, biomarkers, and therapeutic potential","authors":"Xiaoqing Wang , Ying Luo , Qiang Zhou , Jie Ma","doi":"10.1016/j.autrev.2025.103920","DOIUrl":"10.1016/j.autrev.2025.103920","url":null,"abstract":"<div><div>The S100 protein family, the largest group of calcium-binding proteins, functions as key molecular regulators both intracellularly and extracellularly. Among these, S100A8/A9 and S100A12 have gained particular attention for their roles in the pathogenesis of autoimmune diseases (AID). These proteins interact with pivotal receptors, including G-protein-coupled receptors (GPCRs), toll-like receptor-4 (TLR4), and receptor for advanced glycation end-products (RAGE), driving innate immune activation, amplifying inflammatory responses, and modulating immune cell function. Dysregulation of S100A8/A9 and S100A12 is closely associated with disease progression across multiple autoimmune conditions. Their elevated expression correlates with disease severity, making them valuable biomarkers for monitoring disease activity, predicting therapeutic responses, and assessing disease progression. This review provides an in-depth synthesis of current evidence on the mechanistic roles of S100A8/A9 and S100A12 in AID, emphasizing their biomarker potential and therapeutic value. We further discuss emerging therapeutic strategies that target S100 proteins, their receptors, downstream signaling pathways using small-molecule inhibitors, RNA-based approaches, and monoclonal antibodies. These insights highlight the dual promise of S100A8/A9 and S100A12 as both disease indicators and intervention points, offering novel avenues for the management of AID.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"24 12","pages":"Article 103920"},"PeriodicalIF":8.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908590","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 : 2025-12-18Epub Date: 2025-08-25DOI: 10.1016/j.autrev.2025.103919
Ziyi Tang , Hang Yang , Xiuping Liang , Jiehao Chen , Qi He , Dezhi Zhu , Yi Liu
Interstitial lung disease (ILD) significantly contributes to connective tissue disease (CTD) mortality. Although guidelines for managing CTD-associated ILD (CTD-ILD) exist, many patients respond poorly to treatment owing to two key factors: (1) incomplete understanding of subtype-specific pathogenic mechanisms, and (2) reliance on therapies adapted from systemic sclerosis or nonpulmonary rheumatic diseases, which fail to address the unique pathophysiology of distinct CTD-ILD subtypes. This hinders personalized treatment and underscores the need for robust preclinical models that accurately replicate disease-specific mechanisms. However, challenges remain: (1) the lack of models that fully capture the heterogeneity of these disorders and (2) the absence of systematic structured reviews to guide model selection, despite recent advancements in experimental methodologies. These issues often result in mismatches between research goals and model utility.
This review summarizes current CTD-ILD animal models, focusing on their construction, characteristics, and limitations, and highlighting differences between each model and the corresponding human disease. We summarize these disparities and propose emerging technologies, including CRISPR/Cas9-mediated genome editing, humanized mice, and lung organoids/lung-on-a-chip systems, that may facilitate the development of next-generation models. By integrating established and emerging strategies, we aim to provide guidance for model selection and development, promote precision modeling, accelerate targeted therapy discovery, and ultimately improve clinical outcomes. We emphasize the importance of developing subtype-specific models to avoid a “one-model-fits-all” approach.
{"title":"Animal models for connective tissue disease-associated interstitial lung disease: Current status and future directions","authors":"Ziyi Tang , Hang Yang , Xiuping Liang , Jiehao Chen , Qi He , Dezhi Zhu , Yi Liu","doi":"10.1016/j.autrev.2025.103919","DOIUrl":"10.1016/j.autrev.2025.103919","url":null,"abstract":"<div><div>Interstitial lung disease (ILD) significantly contributes to connective tissue disease (CTD) mortality. Although guidelines for managing CTD-associated ILD (CTD-ILD) exist, many patients respond poorly to treatment owing to two key factors: (1) incomplete understanding of subtype-specific pathogenic mechanisms, and (2) reliance on therapies adapted from systemic sclerosis or nonpulmonary rheumatic diseases, which fail to address the unique pathophysiology of distinct CTD-ILD subtypes. This hinders personalized treatment and underscores the need for robust preclinical models that accurately replicate disease-specific mechanisms. However, challenges remain: (1) the lack of models that fully capture the heterogeneity of these disorders and (2) the absence of systematic structured reviews to guide model selection, despite recent advancements in experimental methodologies. These issues often result in mismatches between research goals and model utility.</div><div>This review summarizes current CTD-ILD animal models, focusing on their construction, characteristics, and limitations, and highlighting differences between each model and the corresponding human disease. We summarize these disparities and propose emerging technologies, including CRISPR/Cas9<strong>-</strong>mediated genome editing, humanized mice, and lung organoids/lung-on-a-chip systems, that may facilitate the development of next-generation models. By integrating established and emerging strategies, we aim to provide guidance for model selection and development, promote precision modeling, accelerate targeted therapy discovery, and ultimately improve clinical outcomes. We emphasize the importance of developing subtype-specific models to avoid a “one-model-fits-all” approach.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"24 12","pages":"Article 103919"},"PeriodicalIF":8.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913490","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 : 2025-12-18Epub Date: 2025-09-10DOI: 10.1016/j.autrev.2025.103934
Dimitrios Nikolakis , Christoph Teichert , Joep Grootjans , Marleen G.H. van de Sande , Geert R. D’Haens
Background
Sphingosine-1-phosphate receptor (S1PR) modulators are approved as a treatment for several autoimmune diseases. While their role on total leukocyte populations is well-studied, their effects on specific leukocyte subsets remain unclear. This systematic review describes the impact of various S1PR modulators on human leukocyte subpopulations.
Methods
We conducted a systematic literature search through the databases PubMed, Medline, Embase, and Cochrane, up to the 25th of July 2024. Studies were included if they involved patients treated with S1PR modulators and provided data on leukocyte subsets. Among the exclusion criteria, were non-English articles, animal studies, and in vitro studies. Data extraction focused on changes in leukocyte subsets post-treatment.
Results
Out of 1658 articles identified, 63 met the inclusion criteria. Fingolimod was the most frequently studied agent and displayed significant reductions in total T-cell counts. More specifically, CD4+ T-cells, including naïve and central memory populations were reduced. CD8+ T-cells also decreased, although the alterations of effector memory subsets were inconsistent. B-lymphocytes were generally attenuated. Innate immune cells showed variable responses, with most studies indicating a reduction or no change. Data on other S1PR modulators suggested similar trends.
Conclusion
S1PR modulators primarily reduce T- and B-cell subpopulations, which are known to play a prominent role in immune-mediated inflammatory disorders. Further research is needed to fully elucidate the differential effects among drugs targeting specific isoforms of the S1PR, focusing on the lymph nodes or inflammatory tissue sites (e.g. intestinal mucosa and cerebrospinal fluid), to explore the exact clinical implications of these pharmacodynamic findings.
{"title":"The effect of Sphingosine-1-phosphate receptor modulator treatment on leukocyte subsets across different clinical indications: A systematic review","authors":"Dimitrios Nikolakis , Christoph Teichert , Joep Grootjans , Marleen G.H. van de Sande , Geert R. D’Haens","doi":"10.1016/j.autrev.2025.103934","DOIUrl":"10.1016/j.autrev.2025.103934","url":null,"abstract":"<div><h3>Background</h3><div>Sphingosine-1-phosphate receptor (S1PR) modulators are approved as a treatment for several autoimmune diseases. While their role on total leukocyte populations is well-studied, their effects on specific leukocyte subsets remain unclear. This systematic review describes the impact of various S1PR modulators on human leukocyte subpopulations.</div></div><div><h3>Methods</h3><div>We conducted a systematic literature search through the databases PubMed, Medline, Embase, and Cochrane, up to the 25th of July 2024. Studies were included if they involved patients treated with S1PR modulators and provided data on leukocyte subsets. Among the exclusion criteria, were non-English articles, animal studies, and in vitro studies. Data extraction focused on changes in leukocyte subsets post-treatment.</div></div><div><h3>Results</h3><div>Out of 1658 articles identified, 63 met the inclusion criteria. Fingolimod was the most frequently studied agent and displayed significant reductions in total T-cell counts. More specifically, CD4+ T-cells, including naïve and central memory populations were reduced. CD8+ T-cells also decreased, although the alterations of effector memory subsets were inconsistent. B-lymphocytes were generally attenuated. Innate immune cells showed variable responses, with most studies indicating a reduction or no change. Data on other S1PR modulators suggested similar trends.</div></div><div><h3>Conclusion</h3><div>S1PR modulators primarily reduce T- and B-cell subpopulations, which are known to play a prominent role in immune-mediated inflammatory disorders. Further research is needed to fully elucidate the differential effects among drugs targeting specific isoforms of the S1PR, focusing on the lymph nodes or inflammatory tissue sites (e.g. intestinal mucosa and cerebrospinal fluid), to explore the exact clinical implications of these pharmacodynamic findings.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"24 12","pages":"Article 103934"},"PeriodicalIF":8.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051547","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 : 2025-11-28Epub Date: 2025-08-06DOI: 10.1016/j.autrev.2025.103902
Susanna Cordone, Valentina Alfonsi, Luigi De Gennaro
Multiple Sclerosis (MS) is an autoimmunity-related disorder that mainly affects young adults. The high prevalence of the disease and its impact on patients' quality of life led researchers to investigate the etiopathogenesis of the disease to identify possible modifiable factors and consequent effective intervention strategies. Recent hypotheses suggest that the etiopathogenesis of MS is multifactorial and includes factors related to the immune system, neuroinflammation and neurodegeneration. In this scenario, sleep seems to have a close indirect relationship with MS, through its relationship with each of those factors and given the high incidence of sleep disorders in the MS population. Furthermore, given the growing interest of research in the mechanisms underlying MS and therapies able to alleviate MS-related symptoms at all stages of the disease, a more in-depth study of the role of sleep and its loss and disturbances and the factors intrinsically related to sleep and MS could be useful both to investigate the etiopathogenetic factors of MS and to develop non-invasive intervention strategies for MS treatment.
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