Rheumatoid arthritis: pathogenesis and therapeutic advances

MedComm, Год журнала: 2024, Номер 5(3)

Опубликована: Март 1, 2024

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the unresolved synovial inflammation for tissues‐destructive consequence, which remains one of significant causes disability and labor loss, affecting about 0.2–1% global population. Although treatments with disease‐modifying antirheumatic drugs (DMARDs) are effective to control decrease bone destruction, overall remission rates RA still stay at low level. Therefore, uncovering pathogenesis expediting clinical transformation imminently in need. Here, we summarize immunological basis, inflammatory pathways, genetic epigenetic alterations, metabolic disorders RA, highlights on abnormality immune cells atlas, epigenetics, immunometabolism. Besides an overview first‐line medications including conventional DMARDs, biologics, small molecule agents, discuss depth promising targeted therapies under or preclinical trials, especially regulators. Additionally, prospects precision medicine based biopsy RNA‐sequencing cell mesenchymal stem chimeric antigen receptor T‐cell also looked forward. The advancements innovations accelerates progress treatments.

Язык: Английский

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Basic helix–loop–helix ARNT like 1 regulates the function of immune cells and participates in the development of immune-related diseases

Burns & Trauma, Год журнала: 2025, Номер 13

Опубликована: Янв. 1, 2025

The circadian clock is an internal timekeeper system that regulates biological processes through a central and peripheral clocks controlling various genes. Basic helix-loop-helix ARNT-like 1 (BMAL1), also known as aryl hydrocarbon receptor nuclear translocator-like protein (ARNTL1), key component of the clock. deletion BMAL1 alone can abolish rhythms human body. plays critical role in immune cell function. Dysregulation linked to immune-related diseases such autoimmune diseases, infectious cancer, vice versa. This review highlights significant governing cells, including their development, differentiation, migration, homing, metabolism, effector functions. study explores how dysregulation have far-reaching implications potentially contribute onset sepsis, trauma. Furthermore, this discusses treatments for target disorders. Understanding impact on function provide insights into pathogenesis help development more effective treatment strategies. Targeting has been demonstrated achieve good efficacy indicating its promising potential targetable therapeutic these diseases.

Язык: Английский

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Ivarmacitinib, a selective Janus kinase 1 inhibitor, in patients with moderate-to-severe active rheumatoid arthritis and inadequate response to conventional synthetic DMARDs: results from a phase III randomised clinical trial

Annals of the Rheumatic Diseases, Год журнала: 2025, Номер 84(2), С. 188 - 200

Опубликована: Фев. 1, 2025

To assess the efficacy/safety of ivarmacitinib, a selective Janus kinase (JAK) 1 inhibitor, in patients with moderate-to-severe active rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Patients were randomised (1:1:1) receive either placebo (n=188), ivarmacitinib 4 mg (n=189) or 8 once daily, background csDMARDs allowed. After 24 weeks, on switched for additional 28 while those continued their initial dosage. The primary endpoint was proportion achieving 20% improvement American College Rheumatology criteria (ACR20) at week 24. At 24, ACR20 rates significantly higher (70.4%) and (75.1%) groups compared group (40.4%; both p<0.0001). Both doses achieved numerically Disease Activity Score 28-joint count C reactive protein <2.6/≤3.2 placebo. Improvements efficacy patient-reported outcomes sustained through 52 weeks noted from after During placebo-controlled period, treatment-emergent adverse events (TEAEs) occurred 81.5% 90.5% groups, versus 79.3% group. Infection-related TEAEs slightly groups. Ivarmacitinib may offer potential therapeutic option RA have csDMARDs, safety profile that generally manageable over year treatment similar other JAK inhibitors. NCT04333771.

Язык: Английский

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A reconfigurable integrated smart device for real-time monitoring and synergistic treatment of rheumatoid arthritis

Science Advances, Год журнала: 2024, Номер 10(18)

Опубликована: Май 1, 2024

Rheumatoid arthritis (RA) is a global autoimmune disease that requires long-term management. Ambulatory monitoring and treatment of RA favors remission rehabilitation. Here, we developed wearable reconfigurable integrated smart device (ISD) for real-time inflammatory synergistic therapy RA. The establishes an electrical-coupling substance delivery interfaces with the skin through template-free conductive polymer microneedles exhibit high capacitance, low impedance, appropriate mechanical properties. electronics drive microneedle-skin to monitor tissue impedance on-demand drug delivery. Studies in vitro demonstrated anti-inflammatory effect electrical stimulation on macrophages revealed molecular mechanism. In rodent model, sensing was validated hint inflammation condition facilitate diagnosis machine learning model. outcome subsequent showed notable relief symptoms, elimination synovial inflammation, avoidance bone destruction.

Язык: Английский

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IBD Matchmaking - Rational Combination Therapy

Clinical Gastroenterology and Hepatology, Год журнала: 2024, Номер 23(3), С. 469 - 479

Опубликована: Июль 25, 2024

Язык: Английский

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Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Окт. 4, 2024

Autoimmune disorders are characterized by aberrant T cell and B reactivity to the body's own components, resulting in tissue destruction organ dysfunction. diseases affect a wide range of people many parts world have become one major concerns public health. In recent years, there been substantial progress our understanding epidemiology, risk factors, pathogenesis mechanisms autoimmune diseases. Current approved therapeutic interventions for mainly non-specific immunomodulators may cause broad immunosuppression that leads serious adverse effects. To overcome limitations immunosuppressive drugs treating diseases, precise target-specific strategies urgently needed. date, significant advances made immune tolerance, offering new avenue developing antigen-specific immunotherapies These approaches shown great potential various preclinical animal models recently evaluated clinical trials. This review describes common manifestation with focus on typical including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, sjögren's syndrome. We discuss current therapeutics developed this field, highlight use nanomaterials mRNA vaccine techniques induce tolerance.

Язык: Английский

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Graphene oxide quantum dots-loaded sinomenine hydrochloride nanocomplexes for effective treatment of rheumatoid arthritis via inducing macrophage repolarization and arresting abnormal proliferation of fibroblast-like synoviocytes

Journal of Nanobiotechnology, Год журнала: 2024, Номер 22(1)

Опубликована: Июль 1, 2024

The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing suitable therapeutic strategy for RA that targets macrophages fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), successfully constructed new nanodrug system named HA@RFM@GP@SIN NPs target therapy inflammatory articular lesions. Mechanistic studies showed nanomedicine was effective against by facilitating transition M1 to M2 inhibiting abnormal proliferation FLSs vitro. vivo potential investigation demonstrated its effects on macrophage polarization hyperplasia, ultimately preventing cartilage destruction bone erosion preclinical models adjuvant-induced collagen-induced rats. Metabolomics indicated were mainly associated regulation steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, tyrosine metabolism. More notably, transcriptomic analyses revealed suppressed cell cycle pathway while inducing apoptosis pathway. Furthermore, protein validation disrupted excessive growth RAFLS interfering PI3K/Akt/SGK/FoxO signaling cascade, resulting decline cyclin B1 expression arrest G2 phase. Additionally, considering favorable biocompatibility biosafety, these multifunctional nanoparticles offer promising approach patients RA.

Язык: Английский

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Deciphering hub genes and immune landscapes related to neutrophil extracellular traps in rheumatoid arthritis: insights from integrated bioinformatics analyses and experiments

Frontiers in Immunology, Год журнала: 2025, Номер 15

Опубликована: Янв. 8, 2025

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive joint destruction. Neutrophil extracellular traps (NETs), microreticular structure formed after neutrophil death, have recently been implicated in RA pathogenesis pathological mechanisms. However, the underlying molecular mechanisms key genes involved NET formation remain largely unknown. We obtained single-cell RNA sequencing data of tissues from Gene Expression Omnibus (GEO) database performed cellular annotation intercellular communication analyses. Subsequently, three microarray datasets were collected for training cohort correlated with bulk RNA-seq dataset associated NETs. Differentially expressed identified, weighted gene correlation network analysis was used to characterize association. Using machine learning techniques, we identified most important hub develop evaluate nomogram diagnostic model. CIBERSORT elucidate relationship between immune cells. An external validation verify pivotal expression construct co-regulatory networks using NetworkAnalyst platform. further investigated immunohistochemistry (IHC) an adjuvant-induced rat model real-time quantitative polymerase chain reaction (RT-qPCR) clinical cohort. Seven subpopulations through downscaling clustering, neutrophils likely crucial cell clusters RA. Intercellular highlighted fibroblasts. In this context, 4 (CRYBG1, RMM2, MMP1, SLC19A2) NETs identified. A value developed evaluated. Immune infiltration indicated associations landscape IHC RT-qPCR findings showed high CRYBG1, MMP1 neutrophilic cells, lower SLC19A2. Correlation emphasized close laboratory markers patients This study first elucidated heterogeneity microenvironment SLC19A2 validated as potential NET-associated biomarkers, offering insights tools immunotherapeutic strategies

Язык: Английский

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Safety and efficacy of filgotinib in patients with rheumatoid arthritis: final results of the DARWIN 3 long-term extension study

RMD Open, Год журнала: 2025, Номер 11(1), С. e004857 - e004857

Опубликована: Янв. 1, 2025

Objectives DARWIN 3 (ClinicalTrials.gov: NCT02065700 ) assessed the safety and efficacy of filgotinib in a long-term extension (LTE) two phase II randomised controlled rheumatoid arthritis (RA) trials. Methods Eligible patients completing 24-week 1 (filgotinib plus methotrexate) 2 monotherapy) trials could enrol. Patients received 200 mg/day, except 15 men who 100 mg/day. The primary endpoints were tolerability, which by incidence treatment-emergent adverse events (TEAEs). Safety analyses included all enrolled ≥1 dose 3. Results 739 entered LTE. total patient-years exposure (PYE) to was 3706.3 years; mean duration 259.8 weeks. 497 (67.3%) discontinued prematurely (including 266 TEAEs 172 withdrawals due patient’s decision or ‘sponsor request’). Overall exposure-adjusted rate (EAIR) 67 (95% CI 62 72.2)/100 PYE for 3.8 3.2 4.5)/100 serious TEAEs. EAIR infections 23.3 21.2 25.6)/100 PYE, 1.3 0.9 1.7)/100 herpes zoster. EAIRs major cardiovascular (0.19 0.8 0.39)/100 PYE) malignancies (0.6 0.4 0.9)/100 low. Disease response using non-responder imputation plateaued at LTE week 12 before slowly declining over time, with overall American College Rheumatology (ACR)20/50/70 rates 26.9%/20.2%/14.7% 396. Conclusion Filgotinib well tolerated RA up 8 years. profiles maintained previously receiving either methotrexate monotherapy.

Язык: Английский

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Genistein alleviates rheumatoid arthritis by inhibiting fibroblast-like synovial exosome secretion regulated by the Rab27/nSMase2/Mfge8 pathway

Food & Function, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

The therapeutic potential of genistein (GEN) in rheumatoid arthritis (RA), particularly with regard to its role exosome secretion and the inflammatory microenvironment through Rab27/Mfge8/nSMase2 pathway.

Язык: Английский

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