Search Results (2,714)

Interactions between the gut microbiota, immune system, and brain seem to be involved in the pathogenesis and disease activity of multiple sclerosis (MS). Some MS disease-modifying therapies (DMTs) have been shown to alter the microbiota, but whether this is related to their specific mode of action or indirectly related to their immune-modulatory effect is unknown. In this longitudinal study, we characterized the effects of two DMTs on the microbiota under similar conditions and populations: the injectable, moderate-efficacy DMT interferon beta-1a (INFβ-1a) and the oral, high-efficacy DMT cladribine tablets (CladT). Taxonomic differences were identified following 6 months of therapy for each DMT, and both were associated with the elevation of short-chain fatty acid (SCFA) producers from the Lachnospiraceae, Lactobacillaceae, and Ruminococcaceae families (Firmicutes), while members of Bacteroidetes and Proteobacteria were reduced. Moreover, a higher abundance of Alphaproteobacteria and Betaproteobacteria at baseline was associated with disease activity within 1–2 years of follow-up, while a higher abundance of Lachnospiraceae, Ruminococcaceae, Bifidobacteriaceae, and Streptococcaceae microbes, among others, was associated with no evidence of disease activity (NEDA). Our results provide supporting evidence that alteration of the microbiota by DMTs is part of their beneficial effect, and while some modifications seem to be DMT-specific, MS-DMTs in general promote SCFA-producing microbes, which positively correlate with a favorable clinical outcome. Future therapeutic strategies for PwMS may benefit from microbiome modulation, contingent upon additional mechanistic and interventional studies. Full article

Objective: The objective of this study was to characterize real-world distributions of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) across major rheumatic diagnoses and to quantify concordance/discordance patterns and combined CRP-ESR inflammatory phenotypes. Methods: We retrospectively extracted all CRP and ESR tests performed in a tertiary university rheumatology hospital (January 2018–December 2023), including ICD-10-coded diagnoses. Analyses were conducted at the measurement level and patient level (medians across repeated tests). CRP and ESR were expressed as raw values and multiples of ULN and categorized into severity strata. CRP and ESR datasets were merged by patient identifier and calendar date to define same-day pairs; paired analyses used Spearman correlations and ULN-based phenotype classes. Sensitivity analyses tested alternative pairing windows, first-pair-only analyses, phenotype persistence rules, and tertile/quartile discordance definitions. Results: Among 16,921 patients with ≥1 CRP and 17,126 with ≥1 ESR, CRP was more disease-discriminative and only negligibly age-related, whereas ESR increased modestly with age and showed marked sex shifts across severity categories. Inflammatory burden was highest in gout and rheumatoid arthritis, intermediate in psoriatic arthritis and ankylosing spondylitis, and lower in connective tissue diseases (systemic lupus erythematosus, mixed connective tissue disease, Sjogren’s disease, systemic sclerosis, and dermato/polymyositis) and osteoarthritis; CRP distributions were more strongly right-tailed than ESR. Merging yielded 44,427 same-day CRP-ESR pairs from 16,824 patients (99.1% match). CRP and ESR were moderately correlated at measurement and patient levels, yet discordance was common: 27.3% of pairs showed isolated elevation of a single marker. Conclusions: In routine rheumatology care, CRP and ESR provide complementary information. CRP-ESR dissociation is frequent, persists at the patient level, and follows diagnosis-dependent phenotype patterns. Full article

Multiple sclerosis (MS) reflects a dynamic interplay between peripheral immune activation and compartmentalized inflammation within the central nervous system (CNS). While current disease-modifying therapies effectively reduce relapse activity driven by transient peripheral immune infiltration, their impact on progressive disability remains limited, prompting interest in strategies targeting CNS-resident immune mechanisms. Bruton’s tyrosine kinase (BTK), expressed in B cells and myeloid-derived cells, including microglia, serves as a shared intracellular signaling node linking adaptive and innate immune pathways. Second-generation BTK inhibitors, including evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib, have advanced through Phase II-III development in MS. These agents differ in binding mode, selectivity, pharmacokinetics, CNS penetration, and safety profiles, distinctions that may influence stage-specific therapeutic performance. Recent trials across relapsing and progressive phenotypes have yielded heterogeneous outcomes. Divergent signals in primary and secondary progressive MS reflect underlying biological heterogeneity and suggest that therapeutic responsiveness may depend on residual inflammatory activity, lesion biology, and pharmacologic characteristics. Emerging biomarker frameworks further emphasize the importance of stratifying inflammatory activity and degenerative progression when interpreting trial data. This review integrates molecular pharmacology and the most recent clinical evidence available through 2026 to examine how pharmacologic properties translate into stage-dependent therapeutic positioning. We also consider safety constraints within a disease-stage-specific benefit-risk framework, aiming to clarify the evolving role of BTK inhibition in MS. Full article

Background: Pleuroparenchymal fibroelastosis (PPFE) is a rare fibroelastotic lung disease characterized histologically by dense pleural and subpleural fibrosis with upper-lobe predominance. In clinical practice, diagnosis often relies on characteristic radiologic findings, as surgical lung biopsy is rarely feasible. Unlike idiopathic pulmonary fibrosis, robust radiologic criteria validated against biopsy-proven cohorts remain limited, and the diagnostic performance of imaging alone is incompletely defined. Although initially described as idiopathic, PPFE is increasingly recognized in secondary settings, including connective tissue disease-associated interstitial lung disease (CTD-ILD), where it frequently overlaps with more common fibrotic patterns. Methods: We conducted a focused narrative review of the literature on PPFE in CTD-ILD, synthesizing evidence on morphology, epidemiology, clinical course, prognostic implications, and proposed pathobiological mechanisms, with emphasis on distinguishing true PPFE from PPFE-like lesions. Results: CTD-associated PPFE is associated with accelerated lung function decline, increased risk of pneumothorax, and poorer outcomes, particularly in systemic sclerosis and rheumatoid arthritis. However, distinguishing true PPFE from radiologic mimics remains challenging, and diagnostic approaches rely heavily on imaging without robust histopathologic validation. Proposed mechanisms include epithelial injury, immune dysregulation, and vascular or lymphatic abnormalities, although causal links remain unproven. Significant gaps persist regarding natural history and therapeutic responsiveness. Conclusions: Earlier identification of PPFE in CTD-ILD is important, as misclassification may delay risk stratification and management. Longitudinal imaging, multidisciplinary evaluation, and standardized diagnostic criteria are needed to improve clinical care and guide future research. Full article

Skin diseases frequently coexist with other disorders, such as metabolic syndrome, diabetes mellitus, depression, psoriatic arthritis, and cardiovascular disease. Altered levels of distinct chemokines, like CCL5/RANTES, CXCL12/SDF-1a, CCL7/MCP-3, CCL2/MCP-1, CXCL1/GROa, and the eotaxin family, contribute to the development and/or exacerbation of inflammation, which is a common feature of numerous skin diseases as well as metabolic syndrome. The pathological and molecular connections between chronic inflammatory skin diseases and metabolic syndrome are increasingly recognized as being driven by shared inflammatory pathways, oxidative stress, and adipokine dysregulation. While systemic inflammation acts as a common thread, the precise mechanisms for some conditions remain partially understood. Nevertheless, the exact pathological and molecular connections between skin diseases (i.e., psoriasis, atopic dermatitis, pemphigus vulgaris, acute and chronic spontaneous urticaria, bullous pemphigoid, squamous cell carcinoma, alopecia areata, systemic sclerosis, discoid lupus erythematosus, diffuse large B-cell lymphoma) and metabolic syndrome are not yet fully understood. This narrative review summarizes the robust association between various chronic inflammatory skin diseases and metabolic syndrome in the context of pro-inflammatory chemokines. Full article

Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is a major complication and leading cause of mortality in SSc. Transforming growth factor-β (TGF-β) has been implicated as a central mediator of fibrosis; however, while TGF-β1 has been extensively studied, the roles of TGF-β2 and TGF-β3 remain incompletely defined. Here, we systematically compared the effects of TGF-β1, TGF-β2, and TGF-β3 in dermal and lung fibroblasts, evaluating extracellular matrix synthesis and contraction, cytokine secretion, proliferation, and myofibroblast differentiation. TGF-β2 and TGF-β3 induced greater profibrotic cytokine release of Interleukin (IL)-6 and IL-11 and increased collagen-I and fibronectin synthesis compared with TGF-β1 in dermal and lung fibroblasts (all p < 0.05). TGF-β2 and TGF-β3 stimulated greater collagen-I contraction in dermal fibroblasts (p < 0.05), but greater myofibroblast differentiation in lung fibroblasts (p < 0.05). The TGF-β isoforms did not affect proliferation. All TGF-β isoforms activated SMAD2/3 signalling; however, TGF-β2 and TGF-β3 reduced expression of TGF-β Receptor II and the inhibitory regulator, SMAD7. In summary, TGF-β2 and TGF-β3 have a more pronounced profibrotic effect than TGF-β1 on dermal and lung fibroblast functions, making them potential targets for treatment for skin and lung fibrosis in diseases such as SSc. Full article

Background: Vestibular symptoms and objective vestibular dysfunction have been reported in patients with autoimmune and rheumatologic diseases, but available evidence remains fragmented and methodologically heterogeneous. Previous studies have often addressed audiovestibular involvement as a combined entity, limiting disease-specific interpretation of vestibular outcomes. Methods: A PRISMA 2020-based systematic review was conducted using predefined eligibility criteria targeting vestibular outcomes in autoimmune and systemic rheumatologic diseases. Observational studies reporting vestibular symptoms and/or objective vestibular test results were included. Vestibular data were extracted even when studies reported combined audiovestibular outcomes. Certainty of evidence was assessed using the GRADE approach. Results: Twenty-seven studies were included in the qualitative synthesis, comprising 14 primary observational studies and 13 reviews. Vestibular involvement was reported across multiple diseases, including systemic sclerosis, giant cell arteritis, ankylosing spondylitis, psoriatic arthritis, Behçet disease, primary Sjögren syndrome, rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, and vasculitic disorders. Objective vestibular abnormalities were most frequently identified using caloric testing, balance integration measures, videonystagmography, and video head impulse testing. Systemic sclerosis and giant cell arteritis showed more consistently reported vestibular findings, although heterogeneity in assessment methods precluded quantitative synthesis. Conclusions: Vestibular involvement occurs across autoimmune and systemic inflammatory diseases, but overall certainty of evidence remains limited. Standardized vestibular assessment and longitudinal studies are needed to better define disease-specific vestibular phenotypes. Full article

Ferroptosis is an iron-dependent cell death driven by lipid peroxidation and failure of cellular antioxidant defenses. It is triggered by oxidative stress and can be aggravated by aging, inflammation, and dysregulation of iron homeostasis. In the central nervous system, iron dyshomeostasis, mitochondrial dysfunction, and membrane lipid remodeling can amplify oxidative injury and increase susceptibility to ferroptotic damage, particularly in vulnerable neurons. There is growing evidence that ferroptosis-related processes are linked to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis. This review addresses novel approaches to track ferroptosis in vivo, such as imaging and biomarker techniques, and important molecular mechanisms linking iron metabolism, reactive oxygen species, and PUFA-driven lipid peroxidation to neuronal damage. We also explore upstream transcriptional control via NRF2, iron chelation and iron-handling modulation, inhibition of lipid peroxidation, and reinforcement of the System Xc-GSH-GPX4 and CoQ10-linked defense pathways. Subsequently, we highlight translational issues that need attention to further progress ferroptosis-targeted therapies for neurodegenerative disease. Full article

Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood–brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases. Full article

Immune-mediated inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, impose a severe and growing global health burden, where current therapies are limited by poor specificity and significant side effects. The peptidylarginine deiminase (PAD)/citrullination axis, in which protein citrullination catalyzed by PADs drives autoantigen generation and sustains inflammation, has emerged as a critical therapeutic target. This review outlines a comprehensive strategy for targeting this axis using natural products. We first detail the established role of natural compounds as direct PAD inhibitors, covering their chemical diversity, inhibitory mechanisms, and therapeutic applications in disease models. Subsequently, the discussion extends to their broader, indirect modulatory functions, highlighting how these compounds can suppress pathogenic citrullination by regulating upstream processes like NETosis and inflammatory signaling. Furthermore, the review introduces the innovative substrate-centric intervention strategy, which represents a paradigm shift toward shielding key arginine residues on autoantigens, thereby preventing the formation of immunogenic neoepitopes. The translational challenges and future directions for each of these avenues are outlined, addressing persistent obstacles including achieving isoform selectivity and biomarker validation. By integrating these multifaceted strategies, from direct inhibition and indirect modulation to substrate protection, this work provides a strategic roadmap for advancing the next generation of more precise, effective, and safe anti-citrullination therapies, ultimately moving beyond conventional enzyme inhibition toward targeted immunomodulation in immune-mediated inflammatory diseases. Full article

Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is an important but under-recognised complication in neuromuscular diseases. In adults, emerging epidemiological data suggests increased VTE occurrence in conditions such as Amyotrophic Lateral Sclerosis, myotonic dystrophy, myasthenia gravis, inflammatory neuropathies, inflammatory myopathies, and POEMS syndrome. This heightened risk reflects not only disease-related immobility but also disorder-specific biological mechanisms, including inflammation, endothelial dysfunction and cardiomyopathy-related stasis. Therapies such as corticosteroids, IVIG-related hyperviscosity, long-term central venous access, perioperative immobility, critical illness, and complex orthopaedic procedures have prothrombotic effects. Despite this multifactorial risk profile, disease-specific guidance for thromboprophylaxis is lacking, and current practice relies heavily on extrapolation from general medical and surgical recommendations rather than data derived from neuromuscular cohorts. In children and adolescents, the VTE burden is less well-characterised, but events have been reported in Duchenne and Becker muscular dystrophy, congenital myopathies, and spinal muscular atrophy particularly with advanced motor impairment, severe cardiomyopathy, ventilatory insufficiency, and prolonged hospitalisation. Beyond venous events, selected neuromuscular disorders also exhibit increased arterial thrombosis risk. Myotonic dystrophy and dystrophinopathies are associated with cardiomyopathy and arrhythmia that predispose to systemic embolism and stroke, while inflammatory myopathies may demonstrate arterial events related to vasculitic or endothelial processes, although overall evidence remains limited. This review summarises available empirical and epidemiological evidence on venous and arterial thrombosis across adult and paediatric neuromuscular disorders, outlines disease-specific mechanistic pathways, examines treatment-related contributors, and highlights key evidence gaps that must be addressed to guide rational and targeted prophylaxis strategies in this complex, heterogeneous population. Full article

Neuroinflammation is a hallmark of multiple sclerosis (MS). MS is marked by glial cell activation, autoreactive T cells, and the release of pro-inflammatory cytokines and free radicals. Current therapeutic strategies aim to modulate the immune response using disease-modifying therapies, to slow disease progression. The specific aims of this study were: (a) to investigate the effect of cannabinoid acids on the release of glial neuroinflammatory mediators, (b) to examine the effect of intraperitoneally administered cannabinoid acids on symptoms of MS, and (c) to evaluate their effects on microglial and astrocyte activation and CD4⁺ T cell infiltration into the spinal cords of MS mice. Exposure of BV2 microglia to cannabinoid acids attenuated lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase by 40–90% it also reduced the release of nitric oxide and interleukin-17A. Among the cannabinoid acids tested, cannabidiolic acid (CBDA) significantly increased tumor necrosis factor alpha (TNFα) secretion by up to 40% in LPS-stimulated BV2 cells. Intraperitoneal administration of CBDA also resulted in a twofold increase in TNFα secretion in splenocytes isolated from MS mice, compared to untreated MS controls. This study provides evidence that CBDA significantly reduces neurological scores, while both cannabinoid acids attenuate microgliosis, astrogliosis, and CD4+ T cell migration in lumbar spinal cord sections of MS mice. These compounds cross the blood–brain barrier (BBB) and act directly within the central nervous system. The consistent elevation of TNFα in the presence of CBDA across three experimental models suggests a distinctive immunomodulatory role for CBDA, with potential therapeutic implications in MS. Full article

Cyclodextrins (CDs) have gained increasing attention as versatile platforms for enhancing drug delivery to the central nervous system, particularly in overcoming the restrictive properties of the blood–brain barrier (BBB). Owing to their unique cyclic oligosaccharide structure, CDs are capable of forming inclusion complexes with a wide range of therapeutic agents, thereby improving their solubility, stability, and bioavailability. In addition to their role as excipients, growing evidence indicates that CDs can actively modulate biological processes, including membrane fluidity and cholesterol homeostasis, which are critical factors in neurological disorders. This review explores the application of CDs in facilitating drug transport across the BBB through multiple mechanisms, including carrier-mediated transport, receptor-mediated transcytosis, and nanoparticle-based delivery systems. Special emphasis is placed on their use in the treatment of neurodegenerative and neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Niemann–Pick type C disease, and other central nervous system disorders. In these contexts, CD-based formulations have demonstrated the ability to enhance brain targeting, reduce pathological protein aggregation, and improve therapeutic outcomes in preclinical models. This review uniquely integrates cyclodextrin’s physicochemical properties with specific blood–brain barrier transport mechanisms, proposing a structure–transport–therapy framework that enables a more predictive understanding of brain-targeted drug delivery. Full article

Neurodegenerative diseases (NDs), including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies—such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications—aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms. Full article

Elevated levels of platelet-derived growth factor (PDGF) isoforms in fibrosis are implicated in driving a dysfunctional profibrotic fibroblast phenotype. This study investigated the differential effects of the five PDGF isoforms (AA, AB, BB, CC, and DD) in inducing neonatal dermal and fetal lung fibroblast contraction, proliferation, cytokine production, myofibroblast differentiation, and extracellular matrix (ECM) deposition. All PDGF isoforms, except PDGF-AA, increased contraction of 3-dimensional collagen I gels by dermal (p < 0.01) and lung fibroblasts (p < 0.05) compared to media control. PDGF-AB, BB, and CC enhanced proliferation only in dermal fibroblasts (p < 0.05). PDGF-BB induced profibrotic IL-11 cytokine release in dermal and lung fibroblasts (p < 0.0001) and IL-6 cytokine release in dermal fibroblasts (p < 0.05) compared to media control. None of the PDGF isoforms affected ECM synthesis or myofibroblast differentiation. Dermal fibroblasts exhibited elevated PDGF Receptor-β (PDGFRβ) expression (p < 0.01) and increased basal ERK1/2 phosphorylation (p < 0.05) compared to lung fibroblasts. In summary, PDGF modulates fibroblast functions in a tissue-specific manner, with PDGF-BB driving profibrotic processes in dermal fibroblasts through high PDGFRβ expression and ERK1/2 signalling. Further research is needed to explore the benefit of tissue and isoform-specific PDGF inhibition strategies in skin and lung fibrosis. Full article