Pub Date : 2026-01-01DOI: 10.1016/j.autrev.2025.103939
Ting Sun , Yuxian Wu , Lingyun Kong , Jingtong Wang , Feng Zhang , Yang Liu , Jie Gao , Yaoyang Liu
The methylenetetrahydrofolate reductase (MTHFR) gene encodes a crucial enzyme in folate metabolism, serving as a central regulator of homocysteine homeostasis and one‑carbon metabolic pathways. This review synthesizes current evidence on the mechanistic and clinical implications of two common MTHFR polymorphisms, C677T and A1298C, in autoimmune pathogenesis. We critically examine their contributions to inflammatory responses, endothelial dysfunction, immune imbalance, and epigenetic modifications. Furthermore, we analyze population-specific associations between these variants and susceptibility to eight autoimmune disorders, genotype-phenotype correlations related to clinical manifestations and comorbidities, as well as pharmacogenomic interactions influencing response to methotrexate therapy. By integrating genetic, molecular, and clinical insights, this review highlights the translational potential of MTHFR genotyping for improving risk stratification and personalized treatment strategies in autoimmune and immune-mediated inflammatory conditions.
{"title":"MTHFR polymorphisms in autoimmune diseases: Mechanistic and clinical perspectives","authors":"Ting Sun , Yuxian Wu , Lingyun Kong , Jingtong Wang , Feng Zhang , Yang Liu , Jie Gao , Yaoyang Liu","doi":"10.1016/j.autrev.2025.103939","DOIUrl":"10.1016/j.autrev.2025.103939","url":null,"abstract":"<div><div>The methylenetetrahydrofolate reductase (<em>MTHFR</em>) gene encodes a crucial enzyme in folate metabolism, serving as a central regulator of homocysteine homeostasis and one‑carbon metabolic pathways. This review synthesizes current evidence on the mechanistic and clinical implications of two common <em>MTHFR</em> polymorphisms, C677T and A1298C, in autoimmune pathogenesis. We critically examine their contributions to inflammatory responses, endothelial dysfunction, immune imbalance, and epigenetic modifications. Furthermore, we analyze population-specific associations between these variants and susceptibility to eight autoimmune disorders, genotype-phenotype correlations related to clinical manifestations and comorbidities, as well as pharmacogenomic interactions influencing response to methotrexate therapy. By integrating genetic, molecular, and clinical insights, this review highlights the translational potential of <em>MTHFR</em> genotyping for improving risk stratification and personalized treatment strategies in autoimmune and immune-mediated inflammatory conditions.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 1","pages":"Article 103939"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285537","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 : 2026-01-01DOI: 10.1016/j.autrev.2025.103943
Iliopoulos Georgios , Sideridou Fani , Bogdanos Dmitrios , Liew David , Daoussis Dimitrios
Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of oncology but are frequently accompanied by immune-related adverse events (irAEs). Among these, ICI-induced inflammatory arthritis (ICI-IA) has emerged as the most common musculoskeletal toxicity, often mimicking rheumatoid arthritis (RA) in its clinical and imaging features. This narrative review synthesizes current evidence comparing ICI-IA with RA across epidemiology, pathophysiology, clinical presentation, imaging, treatment, and prognosis. While both entities share overlapping manifestations such as polyarthritis, synovitis, and joint erosions, ICI-IA is typically seronegative, arises subacutely after ICI initiation, and exhibits distinct immunopathologic signatures, including cytotoxic CD8+ T-cell predominance and unique B-cell alterations. ICI-IA may persist after ICI cessation, with chronic disease linked to improved oncologic outcomes. Therapeutic strategies require balancing arthritis control and preservation of anti-tumor immunity. Glucocorticoids and conventional disease modifying anti-rheumatic drugs (cDMARDs) are key players with proven safety and efficacy, whereas biologic therapies remain reserved for severe or refractory cases mainly due to cancer progression concerns. Furthermore, early rheumatology referral improves patient outcomes and reduces glucocorticoid exposure. Understanding the differences between ICI-IA and RA is essential for optimizing diagnosis, guiding individualized approach and applying precision medicine at the crossroads of oncology and rheumatology.
{"title":"Immune checkpoint inhibitor-induced inflammatory arthritis vs rheumatoid arthritis: A comparative review","authors":"Iliopoulos Georgios , Sideridou Fani , Bogdanos Dmitrios , Liew David , Daoussis Dimitrios","doi":"10.1016/j.autrev.2025.103943","DOIUrl":"10.1016/j.autrev.2025.103943","url":null,"abstract":"<div><div>Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of oncology but are frequently accompanied by immune-related adverse events (irAEs). Among these, ICI-induced inflammatory arthritis (ICI-IA) has emerged as the most common musculoskeletal toxicity, often mimicking rheumatoid arthritis (RA) in its clinical and imaging features. This narrative review synthesizes current evidence comparing ICI-IA with RA across epidemiology, pathophysiology, clinical presentation, imaging, treatment, and prognosis. While both entities share overlapping manifestations such as polyarthritis, synovitis, and joint erosions, ICI-IA is typically seronegative, arises subacutely after ICI initiation, and exhibits distinct immunopathologic signatures, including cytotoxic CD8+ T-cell predominance and unique B-cell alterations. ICI-IA may persist after ICI cessation, with chronic disease linked to improved oncologic outcomes. Therapeutic strategies require balancing arthritis control and preservation of anti-tumor immunity. Glucocorticoids and conventional disease modifying anti-rheumatic drugs (cDMARDs) are key players with proven safety and efficacy, whereas biologic therapies remain reserved for severe or refractory cases mainly due to cancer progression concerns. Furthermore, early rheumatology referral improves patient outcomes and reduces glucocorticoid exposure. Understanding the differences between ICI-IA and RA is essential for optimizing diagnosis, guiding individualized approach and applying precision medicine at the crossroads of oncology and rheumatology.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 1","pages":"Article 103943"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336269","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 : 2026-01-01DOI: 10.1016/j.autrev.2025.103942
Julie Better , Sylvie Leroy , Maarten K. Ninaber , Georgia Trakada , Bilge Kesikburun , Stephan Rosenkranz , Ralph Ewert , Dirk Habedank , Daniel Dumitrescu , Yanis Kouchit , Nihal Martis
Context
Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in patients with systemic sclerosis (SSc). Cardiopulmonary exercise testing (CPET) has been studied to detect SSc-associated PAH.
Objectives
To evaluate the diagnostic value of the ventilatory equivalent for CO2 at anaerobic or ventilatory threshold [VE/VCO2(VeT)] and peak oxygen uptake (peak VO2) for SSc-associated PAH obtained by CPET.
Methods
A systematic database search from 1993 to 2024 and meta-analyses were performed according to PRISMA guidelines to include original studies relating to SSc and CPET reporting VE/VCO2(VeT) and peak VO2. The random-effects model was chosen for the meta-analyses studying VE/VCO2(VeT), indexed and predicted percentage (%pred.) peak VO2, respectively. Meta-regression was only performed for VE/VCO2(VeT) with covariates defined as the percentage of limited cutaneous disease, percentage of interstitial lung disease, and %pred. of peak VO2.
Results
Out of 206 studies, 941 SSc patients from 15 studies were included. VE/VCO2(VeT) (11 studies, n = 850) was statistically lower in patients without PAH (32.68 ± 5.42 vs. 39.81 ± 9.32) with a mean effect size of −1.182 (95 %CI, −1.691 to −0.672; p < 0.001) (I2 = 86 %). The mean effect size for weight-indexed peak VO2 (11 studies, n = 848) was 0.713 (95 %CI, 0.371 to 1.054; p < 0.001) with higher values in patients without PAH (16.47 ± 4.62 vs. 13.61 ± 4.16 mL/kg/mn) (I2 = 70 %). Similarly, the mean effect size for %pred. Peak VO2 (12 studies, n = 850) was 0.659 (95 %CI, 0.425 to 0.894; p < 0.001) reflecting higher values in patients without PAH (74.00 ± 17.50 vs. 54.84 ± 18.14 %pred.) (I2 = 37 %). Meta-regression analysis of data from 7 studies did not yield significant p values for the covariates.
Conclusions
The effect size of each meta-analysis indicates that higher VE/VCO2(VeT) and lower peak VO2 may be considered as independent CPET markers of PAH in patients with SSc. CPET is a non-invasive and safe procedure for exploring dyspnoea in patients with SSc and, in association with conventional imaging techniques, may provide a reliable assessment of the presence of PAH.
{"title":"VE/VCO2 at ventilatory threshold and peak VO2 in CPET studies of patients with scleroderma-associated PAH: A systematic review and meta-analyses","authors":"Julie Better , Sylvie Leroy , Maarten K. Ninaber , Georgia Trakada , Bilge Kesikburun , Stephan Rosenkranz , Ralph Ewert , Dirk Habedank , Daniel Dumitrescu , Yanis Kouchit , Nihal Martis","doi":"10.1016/j.autrev.2025.103942","DOIUrl":"10.1016/j.autrev.2025.103942","url":null,"abstract":"<div><h3>Context</h3><div>Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in patients with systemic sclerosis (SSc). Cardiopulmonary exercise testing (CPET) has been studied to detect SSc-associated PAH.</div></div><div><h3>Objectives</h3><div>To evaluate the diagnostic value of the ventilatory equivalent for CO<sub>2</sub> at anaerobic or ventilatory threshold [VE/VCO<sub>2</sub>(VeT)] and peak oxygen uptake (peak VO<sub>2</sub>) for SSc-associated PAH obtained by CPET.</div></div><div><h3>Methods</h3><div>A systematic database search from 1993 to 2024 and meta-analyses were performed according to PRISMA guidelines to include original studies relating to SSc and CPET reporting VE/VCO<sub>2</sub>(VeT) and peak VO<sub>2</sub>. The random-effects model was chosen for the meta-analyses studying VE/VCO<sub>2</sub>(VeT), indexed and predicted percentage (%pred.) peak VO<sub>2</sub>, respectively. Meta-regression was only performed for VE/VCO<sub>2</sub>(VeT) with covariates defined as the percentage of limited cutaneous disease, percentage of interstitial lung disease, and %pred. of peak VO<sub>2</sub>.</div></div><div><h3>Results</h3><div>Out of 206 studies, 941 SSc patients from 15 studies were included. VE/VCO<sub>2</sub>(VeT) (11 studies, <em>n</em> = 850) was statistically lower in patients without PAH (32.68 ± 5.42 vs. 39.81 ± 9.32) with a mean effect size of −1.182 (95 %CI, −1.691 to −0.672; <em>p</em> < 0.001) (I<sup>2</sup> = 86 %). The mean effect size for weight-indexed peak VO<sub>2</sub> (11 studies, <em>n</em> = 848) was 0.713 (95 %CI, 0.371 to 1.054; <em>p</em> < 0.001) with higher values in patients without PAH (16.47 ± 4.62 vs. 13.61 ± 4.16 mL/kg/mn) (I<sup>2</sup> = 70 %). Similarly, the mean effect size for %pred. Peak VO<sub>2</sub> (12 studies, <em>n</em> = 850) was 0.659 (95 %CI, 0.425 to 0.894; p < 0.001) reflecting higher values in patients without PAH (74.00 ± 17.50 vs. 54.84 ± 18.14 %pred.) (I<sup>2</sup> = 37 %). Meta-regression analysis of data from 7 studies did not yield significant <em>p</em> values for the covariates.</div></div><div><h3>Conclusions</h3><div>The effect size of each meta-analysis indicates that higher VE/VCO<sub>2</sub>(VeT) and lower peak VO<sub>2</sub> may be considered as independent CPET markers of PAH in patients with SSc. CPET is a non-invasive and safe procedure for exploring dyspnoea in patients with SSc and, in association with conventional imaging techniques, may provide a reliable assessment of the presence of PAH.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 1","pages":"Article 103942"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353381","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 : 2026-01-01DOI: 10.1016/j.autrev.2025.103955
Geir Bjørklund , David R. Wallace , Kimiya Kangarlou , Fahimida Hossain , Massimiliano Peana
Environmental toxins, including toxic metal(oid)s such as mercury, lead, cadmium, and arsenic, as well as endocrine-disrupting chemicals like bisphenol A and phthalates, play a critical role in the onset and progression of autoimmune diseases. These substances accumulate in biological tissues and disrupt immune homeostasis through oxidative stress, molecular mimicry, and epigenetic modifications, mechanisms that contribute to autoantibody production and chronic inflammation, hallmarks of autoimmunity. Women are disproportionately affected by autoimmune diseases due to inherent differences in immune function, hormonal regulation, and genetic susceptibility. Estrogen, a key immunomodulatory hormone, can amplify immune responses and promote autoantibody generation. Its interaction with environmental toxins further exacerbates immune dysregulation, increasing female vulnerability to conditions such as systemic lupus erythematosus, rheumatoid arthritis, and autoimmune thyroid disorders. Hormonal fluctuations during puberty, pregnancy, and menopause additionally influence toxin metabolism and detoxification efficiency, compounding the risk of immune imbalance and disease onset in women. This review synthesizes current evidence on the mechanisms through which environmental toxicants contribute to autoimmune pathogenesis, with particular focus on sex-specific vulnerabilities. It explores the role of hormonal-immune-environment interactions across the female lifespan and highlights emerging research on epigenetic inheritance, gut dysbiosis, and biomarker development. By integrating mechanistic, epidemiological, and clinical findings, this review aims to inform targeted strategies for prevention, early detection, and risk reduction of environmentally driven autoimmune diseases.
{"title":"Environmental toxins and toxic metals in autoimmune diseases: Sex differences, hormonal influences, and immune dysregulation","authors":"Geir Bjørklund , David R. Wallace , Kimiya Kangarlou , Fahimida Hossain , Massimiliano Peana","doi":"10.1016/j.autrev.2025.103955","DOIUrl":"10.1016/j.autrev.2025.103955","url":null,"abstract":"<div><div>Environmental toxins, including toxic metal(<em>oid</em>)s such as mercury, lead, cadmium, and arsenic, as well as endocrine-disrupting chemicals like bisphenol A and phthalates, play a critical role in the onset and progression of autoimmune diseases. These substances accumulate in biological tissues and disrupt immune homeostasis through oxidative stress, molecular mimicry, and epigenetic modifications, mechanisms that contribute to autoantibody production and chronic inflammation, hallmarks of autoimmunity. Women are disproportionately affected by autoimmune diseases due to inherent differences in immune function, hormonal regulation, and genetic susceptibility. Estrogen, a key immunomodulatory hormone, can amplify immune responses and promote autoantibody generation. Its interaction with environmental toxins further exacerbates immune dysregulation, increasing female vulnerability to conditions such as systemic lupus erythematosus, rheumatoid arthritis, and autoimmune thyroid disorders. Hormonal fluctuations during puberty, pregnancy, and menopause additionally influence toxin metabolism and detoxification efficiency, compounding the risk of immune imbalance and disease onset in women. This review synthesizes current evidence on the mechanisms through which environmental toxicants contribute to autoimmune pathogenesis, with particular focus on sex-specific vulnerabilities. It explores the role of hormonal-immune-environment interactions across the female lifespan and highlights emerging research on epigenetic inheritance, gut dysbiosis, and biomarker development. By integrating mechanistic, epidemiological, and clinical findings, this review aims to inform targeted strategies for prevention, early detection, and risk reduction of environmentally driven autoimmune diseases.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 1","pages":"Article 103955"},"PeriodicalIF":8.3,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421205","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 : 2025-12-24DOI: 10.1016/j.autrev.2025.103977
Liang Li , Yumin Xia , Yale Liu
Tissue-resident memory T (Trm) cells, once heralded as gatekeepers of localized immune protection, have emerged as central players in the pathogenesis of chronic inflammation and autoimmunity at epithelial barriers. At the heart of this immunological paradox lies the dynamic interplay between Trm and regulatory T (Treg) cells—a tissue-encoded checkpoint that calibrates immune defense against the need for tolerance and repair. Disruption of this axis unleashes the latent pathogenicity of Trm cells, fueling persistent inflammation, epithelial dysfunction, and disease relapse. Here, we propose that the Trm-Treg interaction acts as a molecular rheostat that tunes immune homeostasis at barrier sites. We dissect the tissue-specific mechanisms that sustain this alliance, highlight its failure in diseases such as inflammatory bowel disease (IBD), psoriasis, and chronic obstructive pulmonary disease (COPD), and explore emerging therapeutic strategies aimed at recalibrating this immune checkpoint to restore durable epithelial tolerance.
{"title":"The Trm-Treg Axis as a tissue-encoded immune checkpoint in chronic inflammation and autoimmunity","authors":"Liang Li , Yumin Xia , Yale Liu","doi":"10.1016/j.autrev.2025.103977","DOIUrl":"10.1016/j.autrev.2025.103977","url":null,"abstract":"<div><div>Tissue-resident memory T (Trm) cells, once heralded as gatekeepers of localized immune protection, have emerged as central players in the pathogenesis of chronic inflammation and autoimmunity at epithelial barriers. At the heart of this immunological paradox lies the dynamic interplay between Trm and regulatory T (Treg) cells—a tissue-encoded checkpoint that calibrates immune defense against the need for tolerance and repair. Disruption of this axis unleashes the latent pathogenicity of Trm cells, fueling persistent inflammation, epithelial dysfunction, and disease relapse. Here, we propose that the Trm-Treg interaction acts as a molecular rheostat that tunes immune homeostasis at barrier sites. We dissect the tissue-specific mechanisms that sustain this alliance, highlight its failure in diseases such as inflammatory bowel disease (IBD), psoriasis, and chronic obstructive pulmonary disease (COPD), and explore emerging therapeutic strategies aimed at recalibrating this immune checkpoint to restore durable epithelial tolerance.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 2","pages":"Article 103977"},"PeriodicalIF":8.3,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839645","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.
{"title":"The role of sleep in multiple sclerosis.","authors":"Susanna Cordone, Valentina Alfonsi, Luigi De Gennaro","doi":"10.1016/j.autrev.2025.103902","DOIUrl":"10.1016/j.autrev.2025.103902","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":" ","pages":"103902"},"PeriodicalIF":8.3,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-10DOI: 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":"2025-09-10","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 : 2025-09-02DOI: 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":"2025-09-02","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 : 2025-08-28DOI: 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":"2025-08-28","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}
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