Search Results (86)

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of autoimmune diseases with wide variation in pathogenesis, clinical presentation, and serological profiles, leading to substantial differences in diagnosis, classification, treatment response, and prognosis among patients. Although decades of progress have been made in understanding myositis-specific autoantibodies and molecular pathology, important gaps remain in elucidating disease mechanisms and identifying effective therapeutic targets. Therefore, animal models that recapitulate key characteristics of human IIMs provide an indispensable platform for addressing current limitations in mechanistic research and promoting translational studies. This review comprehensively discusses animal models related to the major clinical–serological subtypes of IIMs, including polymyositis-like T-cell-mediated models, dermatomyositis models, inclusion body myositis models, antisynthetase syndrome models, and immune-mediated necrotizing myopathy models. Particular attention is given to model construction, pathological phenotypes, dominant immune mechanisms, therapeutic applications, and translational limitations. By organizing current models according to subtype-related pathological and immunological features, this narrative review aims to provide a clearer framework for selecting appropriate experimental systems and to facilitate more precise, mechanism-driven myositis research. Full article

Autoimmune and immune-mediated inflammatory diseases (IMIDs) develop when genetically and environmentally susceptible hosts lose stable immune tolerance. The gut ecosystem is increasingly recognized as a biologically active interface in this process. Its bacterial, fungal, and viral components may shape mucosal and systemic immunity through antigenic stimulation, barrier regulation, and metabolite-dependent signaling, although the strength of evidence is uneven: bacteriome data are currently the most mature, whereas mycobiome, virome, and phageome findings remain more disease-specific and emerging. Dysbiosis may influence autoimmunity through overlapping routes, including epithelial barrier failure, altered short-chain fatty acid, bile acid, and tryptophan metabolism, molecular mimicry, and cross-kingdom microbial interactions. Nutrition is central to this network because dietary substrates determine microbial growth, metabolic output, epithelial integrity, and immune-cell differentiation. In this narrative review, we integrate evidence on disease-associated bacteriome, mycobiome, and virome patterns in systemic autoimmune diseases, with emphasis on rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, spondyloarthritis, vasculitides, and idiopathic inflammatory myopathies. COVID-19 is considered not as a proven causal driver of autoimmunity, but as an example of an environmental and infectious insult capable of perturbing microbiome–barrier–immune communication. Finally, we discuss diet-based and microbiome-targeted approaches, including probiotics, prebiotics, synbiotics, and postbiotics, as adjunctive strategies that may help restore microbial resilience and immune balance. A better understanding of the diet–microbiome–host immunity axis may support more personalized preventive and therapeutic concepts in autoimmune disease. Full article

Idiopathic inflammatory myopathies constitute a group of immune-mediated disorders primarily affecting skeletal muscle, but they may also lead to significant involvement of internal organs. These conditions are highly heterogeneous, encompassing diverse clinical manifestations and multiple underlying pathophysiological mechanisms. A unifying feature across this disease spectrum is an autoimmune response characterized by the production of highly specific autoantibodies, which are detected in the majority of patients. Genetic studies have identified the principal susceptibility background as the 8.1 ancestral haplotype within the HLA region on chromosome 6. However, genetic predisposition extends beyond HLA loci and includes numerous genes encoding key molecules involved in cytokine production, the regulation of immune signaling pathways, and metabolic processes. In this paper, we review the currently identified genetic loci associated with inflammatory myopathies, with particular emphasis on the HLA system, as well as non-HLA genes and newly identified candidates. Full article

Background: Idiopathic inflammatory myopathies (IIMs), characterized by muscle weakness and chronic inflammation, currently lack highly effective therapies. This study investigated the therapeutic potential and underlying mechanism of (5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative with reduced toxicity, using an experimental autoimmune myositis (EAM) mouse model and in vitro assays. Methods: Forty female BALB/c mice were randomly assigned to five groups: normal, vehicle, methylprednisolone (MP), LLDT-8 (0.0625 mg/kg), and LLDT-8 (0.125 mg/kg). EAM mice were treated with LLDT-8 (0.0625 or 0.125 mg/kg) or methylprednisolone as a positive control. Cellular experiments and molecular docking were performed to investigate potential mechanisms of LLDT-8. Results: LLDT-8 significantly attenuated clinicopathological features, including muscle weakness and pain sensitivity, while reducing serum levels of aspartate aminotransferase and lactate dehydrogenase. Histological analysis revealed that LLDT-8 reduced inflammatory cell infiltration and the presence of CD4⁺ and CD8⁺ T cells in muscle tissues. Mechanistically, LLDT-8 inhibited the expression of nucleotide-binding oligomerization domain receptor caspase recruitment domain 5 (NLRC5), a key transcriptional regulator of major histocompatibility complex-I (MHC-I). This suppression extended to downstream antigen presentation-related molecules, including the transporter associated with antigen processing and proteasome 20S subunit beta. Molecular docking further confirmed the high binding affinity of LLDT-8 to both NLRC5 and MHC-I. Conclusions: LLDT-8 alleviates inflammatory muscle injury by targeting the NLRC5/MHC-I signaling axis, suggesting it may be a promising therapeutic candidate for IIMs. Full article

Dermatomyositis (DM) is a rare, autoimmune inflammatory myopathy characterized by a heterogeneous clinical course and complex etiopathogenesis. Although classically defined by the coexistence of muscle inflammation and distinctive skin lesions, DM frequently presents as a systemic disease, and, in some patients, cutaneous manifestations may precede muscle involvement or represent the sole clinical feature. The spectrum of skin lesions in DM is broad and includes pathognomonic, characteristic, rare, or atypical manifestations, ranging from classic Gottron’s sign and heliotrope rash to uncommon subtypes such as vesiculobullous dermatomyositis, Wong-type dermatomyositis, or flagellate dermatitis. Particular cutaneous phenotypes often correlate with distinct clinical subtypes, autoantibody profiles, systemic involvement, and prognosis. The diversity of dermatological presentations and their resemblance to other dermatoses may delay accurate diagnosis, especially in amyopathic and hypomyopathic forms of the disease. The aim of this review is to comprehensively discuss the wide spectrum of cutaneous manifestations of dermatomyositis, emphasize less recognized and rare dermatological clinical presentations, and highlight their diagnostic and prognostic significance. However, histopathological examination may support the diagnostic process in challenging cases. Early identification of characteristic skin lesions remains crucial for prompt diagnosis, appropriate screening for systemic complications and malignancy, and optimal management. Close interdisciplinary cooperation among dermatologists, rheumatologists, and other specialists is essential to ensure accurate diagnosis and improve outcomes in patients with dermatomyositis. Full article

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disorder of the central nervous system, traditionally considered distinct from neuromuscular diseases, which primarily affect the peripheral nervous system, neuromuscular junction, or skeletal muscle. Growing clinical and experimental evidence, however, indicates that certain neuromuscular disorders may coexist with MS or shared overlapping pathophysiological, immunological, and metabolic mechanisms. This narrative review summarizes reported associations between MS and neuromuscular diseases, with particular focus on well-characterized overlaps such as Leber hereditary optic neuropathy (LHON)-associated MS (Harding’s disease), combined central and peripheral demyelination (CCPD), and myasthenia gravis (MG) co-occurring with MS. Additional associations with Charcot–Marie–Tooth disease, mitochondrial disorders with MS-like phenotypes, inherited and autoimmune myopathies, and rare syndromes such as Guillain–Barré syndrome are also discussed. This review highlights proposed mechanisms potentially linking these conditions, including immune dysregulation, T- and B-cell-mediated autoimmunity, antibody-driven demyelination, mitochondrial dysfunction, impaired neuromuscular transmission, and molecular mimicry. Limitations of the current literature are acknowledged, particularly the predominance of case reports for rare associations and the frequent lack of systematic screening for coexisting disorders. By integrating evidence from case series, cohort studies, and mechanistic research, this review provides a comprehensive overview of the biological and clinical intersections between MS and neuromuscular diseases. Enhanced understanding of these overlaps may improve diagnostic accuracy, guide individualized management strategies, and inform future research on shared neuroimmunological and neurodegenerative pathways. Full article

Idiopathic inflammatory myopathies (IIM) comprise a heterogeneous group of autoimmune disorders with variable systemic involvement. Among them, dermatomyositis (DM) is the subtype with the most extensive biomarker characterization due to its defined immunopathology and frequent association with interstitial lung disease (ILD). This narrative review summarizes studies retrieved from PubMed, Scopus, and Web of Science up to March 2025, focusing on non-autoantibody biomarkers in DM. Reported categories include soluble proteins, cytokines, chemokines, muscle-specific microRNAs, and transcriptomic signatures reflecting interferon activation, tissue injury, and fibrotic remodeling. Among the most validated molecules, interferon-stimulated genes, ferritin, KL-6, SP-D, and CXCL10 demonstrate diagnostic and prognostic value, particularly in anti-MDA5-positive DM, where they support early identification of patients at risk for rapidly progressive ILD. However, despite increasing evidence, most biomarkers lack disease specificity, standardized cutoffs, and multicenter validation, while molecular assays remain confined to specialized laboratories. Clinically accessible markers such as ferritin, KL-6, and CXCL10 currently offer the highest translational potential. Nevertheless, the heterogeneity of study designs and analytical methods continues to limit comparability and routine clinical integration. Future research should prioritize the validation of composite biomarker panels through standardized, multicentric studies to enhance diagnostic precision and enable precision medicine approaches in DM and related inflammatory myopathies. Full article

Background and Clinical Significance: Idiopathic inflammatory myopathies are a heterogeneous group of autoimmune disorders that may present as paraneoplastic syndromes. Although most frequently associated with solid-organ malignancies, hematological neoplasia, particularly lymphomas, is also likely linked. Case Presentation: We describe a sexagenarian female with progressive proximal muscle weakness, myalgias, and lymphadenopathy. Laboratory evaluation revealed markedly elevated creatine phosphokinase and myositis-specific antibodies: anti-Mi-2α and anti-EJ. Magnetic resonance imaging of the thighs confirmed active myositis. Lymph node biopsy reported follicular lymphoma. The patient was initiated on methotrexate and rituximab, with which she reported significant symptomatic relief. Conclusions: Inflammatory myopathy is an exceedingly rare presentation of follicular lymphoma. This case emphasizes that lymphomas can closely mimic other disease processes and present significant diagnostic challenges, and they should be included in the differential diagnosis of myopathies. Improved awareness and early diagnosis of lymphoproliferative neoplasia often yield better overall clinical outcomes. Full article

Connective tissue disease-associated interstitial lung disease (CTD-ILD) comprises a heterogeneous group of immune-mediated pulmonary disorders with significant morbidity and mortality. The pathogenesis involves complex interactions of autoimmunity, chronic inflammation, and fibrosis. B cells play a central role in these processes through antigen presentation, autoantibody production, cytokine secretion, and the formation of ectopic lymphoid tissue within the lung parenchyma. Rituximab (RTX)—a chimeric anti-CD20 monoclonal antibody—depletes B cells and has emerged as a promising therapeutic agent for CTD-ILD. This review comprehensively presents the immunopathogenic mechanisms underlying CTD-ILD, elaborating on the multifaceted mode of action of RTX and summarizing the evolving clinical evidence. Full article

Myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and idiopathic inflammatory myopathies are among the most widely recognized autoimmune neuromuscular disorders. Although they differ in clinical presentation, shared immunopathogenic mechanisms place them at a molecular crossroads. Evidence of overlapping pathways has led to the development of targeted strategies including complement inhibition, FcRn antagonism, B-cell depletion, and the CAR-T cell approach. In this review, we analyze current knowledge regarding pathogenic mechanisms and their link to immunotherapy, extensively outlining both similarities and distinctions. We further discuss existing challenges, including diagnostic limitations and refractory disease variants, how technological advances have already addressed some of these issues, and where further progress is still needed. Full article

Background: Chimeric Antigen Receptor T-cell (CAR-T) cell therapy has revolutionized cancer treatment and is now being explored as a novel approach to treat refractory autoimmune diseases by targeting autoreactive immune components, especially B cells. Objective: Our aim was to provide a narrative review of the current evidence, mechanisms, efficacy, safety, and future directions of CAR-T cell therapy in autoimmune diseases. Methods: A structured literature search was conducted in MEDLINE via PubMed using keywords such as “CAR-T”, “chimeric antigen receptor T-cell”, “autoimmune diseases”, “lupus”, “rheumatoid arthritis”, “multiple sclerosis”, and “vasculitis”. Studies on CAR-T mechanisms, efficacy, safety, and clinical outcomes were included. Results: CAR-T cell therapies, especially CD19-directed constructs, demonstrated sustained drug-free remission in all patients across early SLE case series (n = 5–7), with normalization of serological markers and improved renal outcomes. Emerging preclinical and early clinical data in rheumatoid arthritis, multiple sclerosis, ANCA-associated vasculitis, juvenile autoimmune diseases, and idiopathic inflammatory myopathies also report clinical improvement and biomarker normalization. Reported adverse events in autoimmune cohorts were limited to mild cytokine release syndrome in a minority of cases, with no severe neurotoxicity or life-threatening infections, suggesting a more favorable safety profile compared to oncology settings. In parallel, next-generation innovations—including dual-target CARs, CAR-Tregs, and molecular safety switches—are advancing toward clinical translation. Conclusions: CAR-T cell therapy is emerging as a transformative strategy for autoimmune disease management, especially in refractory cases. Although initial outcomes are promising, long-term safety, cost-effectiveness, and broader accessibility remain key challenges. Future research should focus on optimizing cell targets, minimizing off-target effects, and improving affordability. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by musculoskeletal manifestations such as myopathies, arthritis, and arthralgia. Physical activity may improve patients’ quality of life and overall wellbeing. This study aimed to evaluate physical activity levels in patients with SLE and identify how clinical, psychosocial, and sociodemographic factors influence these levels. Methods: A multicentre cross-sectional study was conducted including 64 patients with SLE. Clinical variables were obtained from medical records, and patient-reported outcomes were collected at the time of the survey. Physical activity was assessed using the International Physical Activity Questionnaire (IPAQ-SF). Independent variables included fatigue (FAS), quality of life (SF-36), sleep (PSQI), depression (BDI-II), anxiety (HARS), age, disease factors (activity, duration, damage), sex, smoking, and comorbidities. Results: Significant associations were found between physical activity levels and smoking status (χ² = 11.88; p = 0.003), sleep quality (χ² = 6.81; p = 0.03), and anxiety (χ² = 18.39; p = 0.001). In multivariable analyses, poor sleep (PSQI > 5) (OR = 14.40; 95% CI: 2.50–82.99), higher anxiety (HARS; per point OR = 1.12; 95% CI: 1.05–1.20), and higher SF-36 Physical Component Summary (PCS) scores (per point OR = 1.29; 95% CI: 1.15–1.45) were associated with being in a higher physical activity category. Given the counterintuitive direction for sleep and the limited model fit, these results should be interpreted cautiously. Conclusions: In patients with SLE, physical activity was associated with sleep disturbances, anxiety, and perceived physical health. These findings underscore the need to integrate psychosocial and behavioural factors into multidisciplinary strategies promoting physical activity in lupus care and provide a rationale for future longitudinal and interventional studies to validate and extend these associations. Full article

Background and Objectives: Idiopathic inflammatory myopathies (IIMs) are rare autoimmune diseases with extra-muscular manifestations. A firm association with malignancy, mainly observed in dermatomyositis (DM) is well established and several predictors of malignancy were previously published. However, given the low prevalence of IIMs, large population-based studies are scarce, hindering a comprehensive understanding of site-specific cancer patterns and risk factors. This study aimed to evaluate malignancy patterns and predictors, in a large, diverse cohort of patients with DM and PM. Materials and Methods: This retrospective cohort study used the Clalit Health Services electronic database, including 1557 DM patients and 528 PM patients diagnosed between 2002 and 2018, along with age-, sex-, and residence-matched controls at a 1:5 ratio. The incidence and risk of malignancies were assessed using Cox proportional hazards models, and predictors of solid and hematologic malignancies within the PM/DM cohort were analyzed using adjusted logistic regression. Results: In our cohort, DM was associated with an increased risk of both solid and hematologic malignancies (HR 1.89, 95%CI 1.47–2.41), whereas in PM the association was less pronounced and limited to solid malignancies (HR 1.50, 95%CI 1.06–2.11). In DM, higher risks were observed for breast cancer (HR 1.86) and chronic leukemia (HR 5.02). Across both subtypes, older age at diagnosis, the presence of specific autoantibodies were associated with increased malignancy risk. Significant markers included antiphospholipid antibodies (OR 2.28), lupus anticoagulant (OR 2.29), anti-Mi2 (OR 2.09), any of the antinuclear antibodies (OR 2.37), and individually anti-RNP/Sm (OR 1.70), anti-Ro/La (OR 1.79), anti-Scl-70 (OR 1.60), and anti-DNA (OR 1.97). Conclusions: Our study demonstrates an increased risk of malignancy in both DM and PM, with the relationship being stronger and broader in DM, involving both solid and hematologic cancers. Older age at diagnosis, and a distinct serological profile, particularly antiphospholipid antibodies and various antinuclear antibodies, identify patients at highest risk, warranting heightened clinical vigilance. Full article

Background and Clinical Significance: Idiopathic pulmonary arterial hypertension is a rare disorder, often linked to genetic predisposition. Canonical pulmonary arterial hypertension genes such as BMPR2, KCNK3, and TBX4 are well described, but novel associations continue to emerge. Glomulin (GLMN) encodes a protein essential for vascular smooth-muscle biology, classically implicated in glomuvenous malformations, yet not previously associated with pulmonary arterial hypertension. Case Presentation: We present a 49-year-old woman with progressive dyspnea, edema, and persistent hypercapnic respiratory failure. Right-heart catheterization confirmed precapillary pulmonary hypertension. Comprehensive evaluation, including ventilation/perfusion scanning, autoimmune panel, polysomnography, and high-resolution computed tomography, excluded secondary causes. Respiratory assessment revealed diaphragmatic weakness and reduced respiratory muscle pressures, consistent with primary myopathy and explaining the unusual hypercapnic profile. Whole-genome sequencing identified a heterozygous pathogenic GLMN nonsense variant, while canonical pulmonary arterial hypertension genes were negative. No cutaneous or mucosal glomuvenous malformations were found. The patient was treated with oxygen therapy, diuretics, non-invasive ventilation, and dual oral pulmonary arterial hypertension therapy (ambrisentan and tadalafil), with stabilization but persistent hypercapnia. Conclusions: To our knowledge, this is the first reported co-occurrence of idiopathic pulmonary arterial hypertension and a pathogenic GLMN variant. While causality cannot be inferred, glomulin’s role in vascular smooth-muscle maturation provides a plausible link to pulmonary vascular remodeling. This case underscores the importance of assessing respiratory muscle function in idiopathic pulmonary arterial hypertension patients with hypercapnia and highlights the potential relevance of extended genetic testing in rare pulmonary vascular disease. Full article

Skeletal muscle pathologies, including sarcopenia, inflammatory myopathies, and various muscular dystrophies, are strongly influenced by chronic low-grade inflammation and impaired proteostasis. Immunoproteasomes (IMPs), inducible proteolytic complexes activated by pro-inflammatory cytokines, are emerging as regulators linking immune signaling to protein quality control. Evidence suggests that IMPs have paradoxical, context-dependent roles in skeletal muscle. On one hand, they can support proteostasis and muscle regeneration under stress; on the other, persistent activation may sustain cytokine production, antigen presentation, and maladaptive immune–muscle interactions, promoting chronic inflammation and muscle wasting. Selective IMP inhibitors, such as ONX 0914 and KZR-616, display potent anti-inflammatory effects in preclinical models of autoimmune myositis and muscle atrophy. Yet, their use in skeletal muscle pathologies is controversial; while inhibition may dampen harmful immune activation, it could also impair muscle repair and proteostasis. This review summarizes current findings, highlights key contradictions, and explores unresolved questions about the role of IMPs in skeletal muscle pathologies. We emphasize the need for a deeper understanding of IMP-mediated mechanisms in skeletal muscle pathology and strategies combining selective inhibitors to enhance therapeutic efficacy while minimizing adverse effects. IMPs thus represent both a promising and potentially risky therapeutic target, with outcomes highly dependent on disease context. Full article