Immune checkpoint inhibitors (ICIs) have markedly improved the prognosis of previously fatal malignancies, as evidenced by substantial gains in overall and progression-free survival in multiple clinical trials. The mechanism of action of ICIs is based on altering the immune response while the reported side effects display clear autoimmune features. Designated as immune-related adverse events (irAEs) affect nearly every organ system, including the gastrointestinal tract, liver, and thyroid gland, and share features with autoimmune disorders of the same organs. The severity of irAEs ranges from mild to life-threatening reactions. Many cases require systemic corticosteroids, hospitalization, and in many instances the discontinuation of ICI therapy. In this review, we present the history of ICIs, their indications, and the reported irAEs in a systematic manner. We then focus on the autoimmune nature of these side effects, with particular attention to the epidemiology of autoimmune diseases, including their female preponderance in certain age groups. In the final sections, we discuss how irAEs may be altering the epidemiology of autoimmune disease and address the possible effect of COVID-19 as a potential trigger.
{"title":"Autoimmunity in the era of immune checkpoint inhibitors: the evolving epidemiology of autoimmune diseases and the possible impact of COVID-19","authors":"Naim Mahroum , Abdulrahman Elsalti , Mohamed Alsharif , Abdullah Jabri , Abderrahman Ouban","doi":"10.1016/j.autrev.2026.104002","DOIUrl":"10.1016/j.autrev.2026.104002","url":null,"abstract":"<div><div>Immune checkpoint inhibitors (ICIs) have markedly improved the prognosis of previously fatal malignancies, as evidenced by substantial gains in overall and progression-free survival in multiple clinical trials. The mechanism of action of ICIs is based on altering the immune response while the reported side effects display clear autoimmune features. Designated as immune-related adverse events (irAEs) affect nearly every organ system, including the gastrointestinal tract, liver, and thyroid gland, and share features with autoimmune disorders of the same organs. The severity of irAEs ranges from mild to life-threatening reactions. Many cases require systemic corticosteroids, hospitalization, and in many instances the discontinuation of ICI therapy. In this review, we present the history of ICIs, their indications, and the reported irAEs in a systematic manner. We then focus on the autoimmune nature of these side effects, with particular attention to the epidemiology of autoimmune diseases, including their female preponderance in certain age groups. In the final sections, we discuss how irAEs may be altering the epidemiology of autoimmune disease and address the possible effect of COVID-19 as a potential trigger.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 3","pages":"Article 104002"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146155756","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 : 2026-03-01Epub Date: 2026-02-05DOI: 10.1016/j.autrev.2026.104003
Nemat Ali , Ali M. Alaseem , Md. Meraj Ansari , Shambhu Kumar , Mohammad Suhail Akhter , Mohammad Fareed , Prawez Alam , Glowi Alasiri
Occupational and environmental exposure to heavy and trace metals is increasingly implicated in cellular dysfunction underlying the pathogenesis of rheumatoid arthritis (RA). While trace metals such as selenium (Se), zinc (Zn), and copper (Cu) are essential for the regulation of immune and inflammatory responses, excessive or imbalanced exposure can disrupt physiological homeostasis. In contrast, exposure to heavy metals including lead (Pb), mercury (Hg), cadmium (Cd), and nickel (Ni) poses significant risks to joint health and has been increasingly associated with progressive joint tissue deterioration. Accumulating evidence indicates that metal-induced toxicity disrupts cellular homeostasis by promoting reactive oxygen species (ROS)-mediated oxidative stress and impairing key cellular processes, including apoptosis, ferroptosis, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Moreover, heavy metals may interfere with the autophagy–lysosomal pathway, a critical mechanism for maintaining cellular integrity and immune balance. This review underscores the importance of understanding the complex interactions between heavy and trace metal exposure and their roles in cellular dysfunction and joint tissue degeneration. Elucidating the molecular mechanisms underlying metal-induced toxicity is essential for the development of targeted therapeutic strategies and effective preventive interventions aimed at mitigating RA progression.
{"title":"Heavy and trace metals toxicity implications in the breakdown of cellular homeostasis: A risk factor for rheumatoid arthritis pathogenesis","authors":"Nemat Ali , Ali M. Alaseem , Md. Meraj Ansari , Shambhu Kumar , Mohammad Suhail Akhter , Mohammad Fareed , Prawez Alam , Glowi Alasiri","doi":"10.1016/j.autrev.2026.104003","DOIUrl":"10.1016/j.autrev.2026.104003","url":null,"abstract":"<div><div>Occupational and environmental exposure to heavy and trace metals is increasingly implicated in cellular dysfunction underlying the pathogenesis of rheumatoid arthritis (RA). While trace metals such as selenium (Se), zinc (Zn), and copper (Cu) are essential for the regulation of immune and inflammatory responses, excessive or imbalanced exposure can disrupt physiological homeostasis. In contrast, exposure to heavy metals including lead (Pb), mercury (Hg), cadmium (Cd), and nickel (Ni) poses significant risks to joint health and has been increasingly associated with progressive joint tissue deterioration. Accumulating evidence indicates that metal-induced toxicity disrupts cellular homeostasis by promoting reactive oxygen species (ROS)-mediated oxidative stress and impairing key cellular processes, including apoptosis, ferroptosis, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Moreover, heavy metals may interfere with the autophagy–lysosomal pathway, a critical mechanism for maintaining cellular integrity and immune balance. This review underscores the importance of understanding the complex interactions between heavy and trace metal exposure and their roles in cellular dysfunction and joint tissue degeneration. Elucidating the molecular mechanisms underlying metal-induced toxicity is essential for the development of targeted therapeutic strategies and effective preventive interventions aimed at mitigating RA progression.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 3","pages":"Article 104003"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137055","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 : 2026-03-01Epub Date: 2026-02-16DOI: 10.1016/j.autrev.2026.104008
Yixiang Luo , Siqi Hua , Tongtong Song, Mingxin Cao, Shuangshuang Song, Shentong Fang, Bo Zhu
Background
Ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation (LPO), is implicated in the pathogenesis of autoimmune diseases (AIDs). However, comprehensive clinical evidence establishing the association between specific LPO biomarkers and AIDs is lacking.
Objective
To systematically evaluate the clinical evidence for elevated LPO in major AIDs through a meta-analysis, focusing on key biomarkers including malondialdehyde (MDA) and 8-iso-prostaglandin F2α (8-iso-PGF2α).
Methods
We searched four databases for studies reporting serum, plasma, or urinary LPO levels in patients with AIDs and healthy controls. Standardized mean differences (SMDs) were pooled using a random-effects model.
Results
Across 175 studies (8227 patients; 6866 controls), serum/plasma MDA levels were significantly elevated in all ten investigated AIDs: rheumatoid arthritis (RA) (SMD = 2.82), systemic sclerosis (SSc) (SMD = 2.08), Graves' disease (GD) (SMD = 1.92), Behçet's disease (BD) (SMD = 1.90), Crohn's disease (CD) (SMD = 1.71), multiple sclerosis (MS) (SMD = 1.52), psoriasis (PsO) (SMD = 1.44), ulcerative colitis (UC) (SMD = 1.32), systemic lupus erythematosus (SLE) (SMD = 1.20) and type 1 diabetes mellitus (T1DM) (SMD = 1.12). Disease-specific elevations were found for serum/plasma 8-iso-PGF2α and 4-hydroxynonenal in RA, urinary 8-iso-PGF2α in SSc and T1DM, and serum/plasma oxidized low-density lipoprotein in T1DM. MDA was higher in active or severe subgroups, with significant between-subgroup differences in GD and PsO.
Conclusion
This meta-analysis provides robust, large-scale clinical evidence that elevated lipid peroxidation is a common feature across diverse AIDs. These findings solidify the clinical relevance of ferroptosis, positioning LPO products as promising biomarkers and underscoring the therapeutic potential of targeting ferroptosis in autoimmune conditions.
{"title":"Elevated lipid peroxidation biomarkers in autoimmune diseases: A systematic review and meta-analysis","authors":"Yixiang Luo , Siqi Hua , Tongtong Song, Mingxin Cao, Shuangshuang Song, Shentong Fang, Bo Zhu","doi":"10.1016/j.autrev.2026.104008","DOIUrl":"10.1016/j.autrev.2026.104008","url":null,"abstract":"<div><h3>Background</h3><div>Ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation (LPO), is implicated in the pathogenesis of autoimmune diseases (AIDs). However, comprehensive clinical evidence establishing the association between specific LPO biomarkers and AIDs is lacking.</div></div><div><h3>Objective</h3><div>To systematically evaluate the clinical evidence for elevated LPO in major AIDs through a meta-analysis, focusing on key biomarkers including malondialdehyde (MDA) and 8-iso-prostaglandin F2α (8-iso-PGF2α).</div></div><div><h3>Methods</h3><div>We searched four databases for studies reporting serum, plasma, or urinary LPO levels in patients with AIDs and healthy controls. Standardized mean differences (SMDs) were pooled using a random-effects model.</div></div><div><h3>Results</h3><div>Across 175 studies (8227 patients; 6866 controls), serum/plasma MDA levels were significantly elevated in all ten investigated AIDs: rheumatoid arthritis (RA) (SMD = 2.82), systemic sclerosis (SSc) (SMD = 2.08), Graves' disease (GD) (SMD = 1.92), Behçet's disease (BD) (SMD = 1.90), Crohn's disease (CD) (SMD = 1.71), multiple sclerosis (MS) (SMD = 1.52), psoriasis (PsO) (SMD = 1.44), ulcerative colitis (UC) (SMD = 1.32), systemic lupus erythematosus (SLE) (SMD = 1.20) and type 1 diabetes mellitus (T1DM) (SMD = 1.12). Disease-specific elevations were found for serum/plasma 8-iso-PGF2α and 4-hydroxynonenal in RA, urinary 8-iso-PGF2α in SSc and T1DM, and serum/plasma oxidized low-density lipoprotein in T1DM. MDA was higher in active or severe subgroups, with significant between-subgroup differences in GD and PsO.</div></div><div><h3>Conclusion</h3><div>This meta-analysis provides robust, large-scale clinical evidence that elevated lipid peroxidation is a common feature across diverse AIDs. These findings solidify the clinical relevance of ferroptosis, positioning LPO products as promising biomarkers and underscoring the therapeutic potential of targeting ferroptosis in autoimmune conditions.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 3","pages":"Article 104008"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218436","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 : 2026-03-01Epub Date: 2026-02-04DOI: 10.1016/j.autrev.2026.103993
Jelle Miedema , Hilario Nunes , Virgil A.S.H. Dalm , Marc A. Judson , Paolo Spagnolo
Sarcoidosis is an inflammatory granulomatous disease that affects people worldwide and can involve virtually any organ but most commonly the lungs and thoracic lymph nodes. The cause of sarcoidosis remains unknown, but occupational and environmental exposures, genetic background, and ethnicity are likely contributors to disease development. Recent immunological studies, including single-cell RNA sequencing and spatial transcriptomics, have increased our understanding of disease pathogenesis. Diagnosing sarcoidosis is often challenging due to the lack of a diagnostic gold standard and the remarkable variability in clinical presentation. Accordingly, the diagnosis requires the presence of compatible clinical and radiological features along with histopathological evidence of noncaseating granulomas and exclusion of other granulomatous diseases. The differential diagnosis includes infection, drug-induced granulomatosis, inborn error of immunity, vasculitis and malignancies.
Sarcoidosis often resolves spontaneously, but it is not a benign disease. Up to one-third of patients develops chronic or progressive disease, which carries an increased risk of organ failure or death. Treatment is not always required, but is clearly indicated for progressive pulmonary disease, symptomatic cardiac or central nervous system involvement, and significantly impaired quality of life. Treatment aims to decrease symptom burden and preserve organ function. Corticosteroids have been considered first-line treatment for decades, but their long-term use is associated with substantial toxicity. Recently, methotrexate was found to be equally effective as prednisone as first-line treatment in pulmonary sarcoidosis. The identification of novel pathways involved in disease pathogenesis has suggested JAK inhibitors and mTOR inhibitors as potential therapies. More efficacious and better tolerated therapies are urgently needed; however, the rarity of the disease, its heterogeneous clinical course and the lack of prognostic biomarkers make it difficult to design and implement clinical trials of novel therapies.
{"title":"Sarcoidosis: Disease mechanisms, diagnostic pathway and treatment","authors":"Jelle Miedema , Hilario Nunes , Virgil A.S.H. Dalm , Marc A. Judson , Paolo Spagnolo","doi":"10.1016/j.autrev.2026.103993","DOIUrl":"10.1016/j.autrev.2026.103993","url":null,"abstract":"<div><div>Sarcoidosis is an inflammatory granulomatous disease that affects people worldwide and can involve virtually any organ but most commonly the lungs and thoracic lymph nodes. The cause of sarcoidosis remains unknown, but occupational and environmental exposures, genetic background, and ethnicity are likely contributors to disease development. Recent immunological studies, including single-cell RNA sequencing and spatial transcriptomics, have increased our understanding of disease pathogenesis. Diagnosing sarcoidosis is often challenging due to the lack of a diagnostic gold standard and the remarkable variability in clinical presentation. Accordingly, the diagnosis requires the presence of compatible clinical and radiological features along with histopathological evidence of noncaseating granulomas and exclusion of other granulomatous diseases. The differential diagnosis includes infection, drug-induced granulomatosis, inborn error of immunity, vasculitis and malignancies.</div><div>Sarcoidosis often resolves spontaneously, but it is not a benign disease. Up to one-third of patients develops chronic or progressive disease, which carries an increased risk of organ failure or death. Treatment is not always required, but is clearly indicated for progressive pulmonary disease, symptomatic cardiac or central nervous system involvement, and significantly impaired quality of life. Treatment aims to decrease symptom burden and preserve organ function. Corticosteroids have been considered first-line treatment for decades, but their long-term use is associated with substantial toxicity. Recently, methotrexate was found to be equally effective as prednisone as first-line treatment in pulmonary sarcoidosis. The identification of novel pathways involved in disease pathogenesis has suggested JAK inhibitors and mTOR inhibitors as potential therapies. More efficacious and better tolerated therapies are urgently needed; however, the rarity of the disease, its heterogeneous clinical course and the lack of prognostic biomarkers make it difficult to design and implement clinical trials of novel therapies.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 3","pages":"Article 103993"},"PeriodicalIF":8.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131189","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 : 2026-02-01Epub Date: 2026-01-20DOI: 10.1016/j.autrev.2026.103987
Zhibin Yu , Yuxiang Lin
Objectives
This study aimed to assess the risk of infections in the treatment of systemic lupus erythematosus (SLE) with various B-cell targeting agents.
Methods
We systematically searched PubMed, Web of Science, Cochrane Library, and Embase for randomized controlled trials (RCTs) of B-cell targeting agents for SLE as of March 1, 2025. The risk of bias was assessed using Cochrane and NIH tools. The main outcomes were total and serious infections. We performed traditional (TMA) and network meta-analyses (NMA). The risk ratios (RRs) with 95% confidence intervals (CIs) or credible intervals (CrIs) were calculated.
Results
A total of 26 studies with 16,338 patients were included, involving 12 B-cell targeting agents. Overall, B-cell targeting therapy did not significantly increase the risk of infections. Nonetheless, obinutuzumab was associated with a greater risk of infections in patients with lupus nephritis compared to placebo (RR [95% CrI] = 1.18 [1.03, 1.37]) and rituximab (RR [95% CrI] = 1.25 [1.04, 1.53]). It was also associated with an elevated risk of infections in the combined population compared to placebo (RR [95% CrI] = 1.18 [1.03, 1.36]), rituximab (RR [95% CrI] = 1.22 [1.04, 1.43]), and epratuzumab (RR [95% CrI] = 1.24 [1.06, 1.45]). BAFF/APRIL-targeting agents showed a higher risk of infections than anti-CD22 agents (only epratuzumab) (RR [95% CrI] = 1.16 [1.01, 1.34]). Low-dose therapy also showed a notably increased risk compared to placebo (RR [95% CrI] = 1.05 [1.00, 1.10]). No significant increase in the risk of serious infections was found.
Conclusions
Specific B-cell targeting therapies may modestly increase the risk of total infections.
{"title":"Risk of infection for different B-cell targeting agents in treating systemic lupus erythematosus: A systematic review and network meta-analysis","authors":"Zhibin Yu , Yuxiang Lin","doi":"10.1016/j.autrev.2026.103987","DOIUrl":"10.1016/j.autrev.2026.103987","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to assess the risk of infections in the treatment of systemic lupus erythematosus (SLE) with various B-cell targeting agents.</div></div><div><h3>Methods</h3><div>We systematically searched PubMed, Web of Science, Cochrane Library, and Embase for randomized controlled trials (RCTs) of B-cell targeting agents for SLE as of March 1, 2025. The risk of bias was assessed using Cochrane and NIH tools. The main outcomes were total and serious infections. We performed traditional (TMA) and network meta-analyses (NMA). The risk ratios (RRs) with 95% confidence intervals (CIs) or credible intervals (CrIs) were calculated.</div></div><div><h3>Results</h3><div>A total of 26 studies with 16,338 patients were included, involving 12 B-cell targeting agents. Overall, B-cell targeting therapy did not significantly increase the risk of infections. Nonetheless, obinutuzumab was associated with a greater risk of infections in patients with lupus nephritis compared to placebo (RR [95% CrI] = 1.18 [1.03, 1.37]) and rituximab (RR [95% CrI] = 1.25 [1.04, 1.53]). It was also associated with an elevated risk of infections in the combined population compared to placebo (RR [95% CrI] = 1.18 [1.03, 1.36]), rituximab (RR [95% CrI] = 1.22 [1.04, 1.43]), and epratuzumab (RR [95% CrI] = 1.24 [1.06, 1.45]). BAFF/APRIL-targeting agents showed a higher risk of infections than anti-CD22 agents (only epratuzumab) (RR [95% CrI] = 1.16 [1.01, 1.34]). Low-dose therapy also showed a notably increased risk compared to placebo (RR [95% CrI] = 1.05 [1.00, 1.10]). No significant increase in the risk of serious infections was found.</div></div><div><h3>Conclusions</h3><div>Specific B-cell targeting therapies may modestly increase the risk of total infections.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 2","pages":"Article 103987"},"PeriodicalIF":8.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028274","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 : 2026-02-01Epub Date: 2025-11-19DOI: 10.1016/j.autrev.2025.103960
Antonio Lauletta , Francesca Forcina , Gioia Merlonghi , Laura Fionda , Luca Leonardi , Rocco Costanzo , Laura Tufano , Elena Rossini , Demetrio Marando , Valentina Vera , Giovanni Antonini , Stefania Morino , Matteo Garibaldi
Sporadic Late-Onset Nemaline Myopathy (SLONM) is an acquired myopathy presenting in adulthood with progressive proximal and axial muscle weakness. A substantial proportion of cases are associated with monoclonal gammopathy of undetermined significance (MGUS), referred to as SLONM-MGUS, suggesting a potential immune-mediated pathogenesis. Although the presence of MGUS has clinical and therapeutic implications, its exact role in disease severity and progression remains unclear. We aimed to characterize clinical, pathological, and prognostic differences between SLONM-MGUS and SLONM without MGUS (SLONM-noMGUS).
We conducted a systematic review of SLONM case series published over the past 25 years, supplemented by a single-center case series of five additional patients from our institution (Sant'Andrea Hospital, Rome). Eligible subjects included adult patients diagnosed with SLONM based on clinical features and muscle biopsy demonstrating nemaline rods. Data on demographics, laboratory parameters, histopathological findings, treatments and outcomes were extracted and compared between SLONM-MGUS and SLONM-noMGUS cohorts.
Of the 144 patients analyzed, 47 % were classified as SLONM-MGUS. These patients exhibited more severe clinical manifestations, including increased respiratory involvement (p = 0.006). Histopathologically, SLONM-MGUS revealed more prominent nemaline rods (p = 0.032), often accompanied by cytoplasmic bodies and lobulated fibers, and frequently required repeat muscle biopsies for diagnosis (p = 0.0285). Inflammatory infiltrates were less frequent in SLONM-MGUS (p = 0.0176). Functional outcomes were significantly worse in this group, with reduced likelihood of full recovery (p = 0.013) and higher rates of non-ambulatory status (p = 0.01).
Patients receiving dual or more treatment regimens, particularly those including IVIg and/or autologous stem cell transplantation (ASCT), had more favorable outcomes.
These findings indicate that SLONM-MGUS represents a more severe phenotype of SLONM with distinct clinico-pathological features and poorer prognosis. Notably, combined treatment regimens, including IVIg and/or ASCT, were associated with improved outcomes, highlighting the importance of early recognition and aggressive therapeutic strategies in selected patients.
{"title":"Sporadic late-onset nemaline myopathy (SLONM): Data from a case series and literature review of 144 patients","authors":"Antonio Lauletta , Francesca Forcina , Gioia Merlonghi , Laura Fionda , Luca Leonardi , Rocco Costanzo , Laura Tufano , Elena Rossini , Demetrio Marando , Valentina Vera , Giovanni Antonini , Stefania Morino , Matteo Garibaldi","doi":"10.1016/j.autrev.2025.103960","DOIUrl":"10.1016/j.autrev.2025.103960","url":null,"abstract":"<div><div>Sporadic Late-Onset Nemaline Myopathy (SLONM) is an acquired myopathy presenting in adulthood with progressive proximal and axial muscle weakness. A substantial proportion of cases are associated with monoclonal gammopathy of undetermined significance (MGUS), referred to as SLONM-MGUS, suggesting a potential immune-mediated pathogenesis. Although the presence of MGUS has clinical and therapeutic implications, its exact role in disease severity and progression remains unclear. We aimed to characterize clinical, pathological, and prognostic differences between SLONM-MGUS and SLONM without MGUS (SLONM-noMGUS).</div><div>We conducted a systematic review of SLONM case series published over the past 25 years, supplemented by a single-center case series of five additional patients from our institution (Sant'Andrea Hospital, Rome). Eligible subjects included adult patients diagnosed with SLONM based on clinical features and muscle biopsy demonstrating nemaline rods. Data on demographics, laboratory parameters, histopathological findings, treatments and outcomes were extracted and compared between SLONM-MGUS and SLONM-noMGUS cohorts.</div><div>Of the 144 patients analyzed, 47 % were classified as SLONM-MGUS. These patients exhibited more severe clinical manifestations, including increased respiratory involvement (<em>p</em> = 0.006). Histopathologically, SLONM-MGUS revealed more prominent nemaline rods (<em>p</em> = 0.032), often accompanied by cytoplasmic bodies and lobulated fibers, and frequently required repeat muscle biopsies for diagnosis (<em>p</em> = 0.0285). Inflammatory infiltrates were less frequent in SLONM-MGUS (<em>p</em> = 0.0176). Functional outcomes were significantly worse in this group, with reduced likelihood of full recovery (<em>p</em> = 0.013) and higher rates of non-ambulatory status (<em>p</em> = 0.01).</div><div>Patients receiving dual or more treatment regimens, particularly those including IVIg and/or autologous stem cell transplantation (ASCT), had more favorable outcomes.</div><div>These findings indicate that SLONM-MGUS represents a more severe phenotype of SLONM with distinct clinico-pathological features and poorer prognosis. Notably, combined treatment regimens, including IVIg and/or ASCT, were associated with improved outcomes, highlighting the importance of early recognition and aggressive therapeutic strategies in selected patients.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 2","pages":"Article 103960"},"PeriodicalIF":8.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572848","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 : 2026-02-01Epub Date: 2025-11-25DOI: 10.1016/j.autrev.2025.103962
Raphael A. Kirou , Iago Pinal-Fernandez , Andrew L. Mammen
The inflammatory myopathies—including dermatomyositis, immune-mediated necrotizing myopathy, anti-synthetase syndrome, and overlap myositis—are systemic autoimmune diseases characterized by myositis-specific and myositis-associated autoantibodies targeting intracellular antigens. These diseases can be subclassified by autoantibody seropositivity, based on the understanding that each myositis autoantibody is associated with distinct clinical features. Traditionally, given the intracellular nature of their targets, myositis autoantibodies were thought to be non-pathogenic. However, this idea is now being challenged based on data from recent and older studies showing that autoantibodies reach their intracellular targets in vivo and exert functional pathogenic effects. In this review, we summarize experimental evidence supporting a model of pathogenic autoantibody internalization in the skeletal muscle of different inflammatory myopathies. We also address gaps in the evidence for this model, including the lack of a proven mechanism of autoantibody entry, while offering suggestions for future studies to fill these gaps. We discuss possible mechanisms of autoantibody entry, as well as the diagnostic, prognostic, and therapeutic implications of this model. Finally, we propose that autoantibodies targeting intracellular antigens in other autoimmune diseases—including certain autoimmune neurologic disorders, systemic sclerosis, systemic lupus erythematosus, and vasculitis—could potentially play a role in these conditions.
{"title":"Autoantibody internalization in myositis skeletal muscle: Emerging evidence, mechanistic insights, and therapeutic relevance","authors":"Raphael A. Kirou , Iago Pinal-Fernandez , Andrew L. Mammen","doi":"10.1016/j.autrev.2025.103962","DOIUrl":"10.1016/j.autrev.2025.103962","url":null,"abstract":"<div><div>The inflammatory myopathies—including dermatomyositis, immune-mediated necrotizing myopathy, anti-synthetase syndrome, and overlap myositis—are systemic autoimmune diseases characterized by myositis-specific and myositis-associated autoantibodies targeting intracellular antigens. These diseases can be subclassified by autoantibody seropositivity, based on the understanding that each myositis autoantibody is associated with distinct clinical features. Traditionally, given the intracellular nature of their targets, myositis autoantibodies were thought to be non-pathogenic. However, this idea is now being challenged based on data from recent and older studies showing that autoantibodies reach their intracellular targets <em>in vivo</em> and exert functional pathogenic effects. In this review, we summarize experimental evidence supporting a model of pathogenic autoantibody internalization in the skeletal muscle of different inflammatory myopathies. We also address gaps in the evidence for this model, including the lack of a proven mechanism of autoantibody entry, while offering suggestions for future studies to fill these gaps. We discuss possible mechanisms of autoantibody entry, as well as the diagnostic, prognostic, and therapeutic implications of this model. Finally, we propose that autoantibodies targeting intracellular antigens in other autoimmune diseases—including certain autoimmune neurologic disorders, systemic sclerosis, systemic lupus erythematosus, and vasculitis—could potentially play a role in these conditions.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 2","pages":"Article 103962"},"PeriodicalIF":8.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145628190","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 : 2026-02-01Epub Date: 2025-12-08DOI: 10.1016/j.autrev.2025.103974
Bo Zhu , Xinhua Cao , Xue Wang , Luyao Yu , Wenhao Zhou , Lihua Zhu , Qingling Yang , Ke Rui
Autoantibodies, hallmark mediators of autoimmune diseases, drive pathogenesis through Fc receptors (FcRs) engagement. Among human FcRs, FcγRIIa is the most abundantly expressed subtype and plays a pivotal role in regulating both innate and adaptive immune responses. Genetic polymorphisms and dysregulated FcγRIIa signaling are increasingly implicated in autoimmune pathogenesis. By governing immune cell activation, differentiation, and effector functions, FcγRIIa emerges as a central orchestrator of immune responses. Recent clinical studies have identified FcγRIIa as a promising therapeutic target in patients with autoimmune diseases, as well as in murine autoimmune models. This review outlines the structure and cellular expression profile of FcγRIIa and elucidates its role in immune regulation. Furthermore, we discuss its association with autoimmune pathogenesis and highlight FcγRIIa targeted therapeutics evaluated in past and ongoing clinical trials for autoimmune disease treatment.
{"title":"FcγRIIa in autoimmunity: Unraveling pathogenic mechanisms and therapeutic opportunities","authors":"Bo Zhu , Xinhua Cao , Xue Wang , Luyao Yu , Wenhao Zhou , Lihua Zhu , Qingling Yang , Ke Rui","doi":"10.1016/j.autrev.2025.103974","DOIUrl":"10.1016/j.autrev.2025.103974","url":null,"abstract":"<div><div>Autoantibodies, hallmark mediators of autoimmune diseases, drive pathogenesis through Fc receptors (FcRs) engagement. Among human FcRs, FcγRIIa is the most abundantly expressed subtype and plays a pivotal role in regulating both innate and adaptive immune responses. Genetic polymorphisms and dysregulated FcγRIIa signaling are increasingly implicated in autoimmune pathogenesis. By governing immune cell activation, differentiation, and effector functions, FcγRIIa emerges as a central orchestrator of immune responses. Recent clinical studies have identified FcγRIIa as a promising therapeutic target in patients with autoimmune diseases, as well as in murine autoimmune models. This review outlines the structure and cellular expression profile of FcγRIIa and elucidates its role in immune regulation. Furthermore, we discuss its association with autoimmune pathogenesis and highlight FcγRIIa targeted therapeutics evaluated in past and ongoing clinical trials for autoimmune disease treatment.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 2","pages":"Article 103974"},"PeriodicalIF":8.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720775","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 : 2026-02-01Epub Date: 2026-01-25DOI: 10.1016/j.autrev.2026.103994
Yan Liu , Xiyuan Bao , Xin Dai , Xue Liu , Danni Zhu , Jiejie Qiao , Haifeng Pan , Jing Wang
Autoimmune diseases, characterized by the immune system's erroneous attack on the body's own tissues, are highly challenging to treat. Recently discovered cuproptosis, triggered by excess copper ions, leads to the abnormal accumulation of acetylated proteins and mitochondrial dysfunction, and has become a research hotspot in this field. Recent studies have shown that cuproptosis-related genes (CRGs) play a potential role in various autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Primary Sjögren's syndrome (pSS), and ankylosing spondylitis (AS), and hold promise for diagnosis and regulation. This article systematically reviews the latest progress of cuproptosis in autoimmune diseases, explores the potential of CRGs as diagnostic biomarkers and immune modulators, evaluates the therapeutic potential of targeting CRGs, and looks forward to how nanotechnology can revolutionize treatment strategies. By elucidating the mechanisms of cuproptosis in autoimmune diseases, this article aims to pave new paths for future research and lay the foundation for innovative therapies.
{"title":"Recent advances in the mechanisms and treatment of cuproptosis in autoimmune diseases","authors":"Yan Liu , Xiyuan Bao , Xin Dai , Xue Liu , Danni Zhu , Jiejie Qiao , Haifeng Pan , Jing Wang","doi":"10.1016/j.autrev.2026.103994","DOIUrl":"10.1016/j.autrev.2026.103994","url":null,"abstract":"<div><div>Autoimmune diseases, characterized by the immune system's erroneous attack on the body's own tissues, are highly challenging to treat. Recently discovered cuproptosis, triggered by excess copper ions, leads to the abnormal accumulation of acetylated proteins and mitochondrial dysfunction, and has become a research hotspot in this field. Recent studies have shown that cuproptosis-related genes (CRGs) play a potential role in various autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Primary Sjögren's syndrome (pSS), and ankylosing spondylitis (AS), and hold promise for diagnosis and regulation. This article systematically reviews the latest progress of cuproptosis in autoimmune diseases, explores the potential of CRGs as diagnostic biomarkers and immune modulators, evaluates the therapeutic potential of targeting CRGs, and looks forward to how nanotechnology can revolutionize treatment strategies. By elucidating the mechanisms of cuproptosis in autoimmune diseases, this article aims to pave new paths for future research and lay the foundation for innovative therapies.</div></div>","PeriodicalId":8664,"journal":{"name":"Autoimmunity reviews","volume":"25 2","pages":"Article 103994"},"PeriodicalIF":8.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146059035","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 : 2026-02-01Epub 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":"2026-02-01","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}
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