BACKGROUND Prevalence of the main rheumatic diseases in the Republic of Sakha(Yakutia)[RS(Y)],one of the regions of the Russian Federation,differs from the other regions of the Russian Federation due to its ethnic and...BACKGROUND Prevalence of the main rheumatic diseases in the Republic of Sakha(Yakutia)[RS(Y)],one of the regions of the Russian Federation,differs from the other regions of the Russian Federation due to its ethnic and geographic features.Knowledge regarding the prevalence and structure of juvenile idiopathic arthritis(JIA)allows us to shape the work of the pediatric rheumatology service in the region correctly,and optimize the healthcare system and the need for medica-tions.AIM To describe the epidemiological,demographic,clinical,and laboratory characteristics of children with JIA in the RS(Y)and evaluate the main outcomes.METHODS This retrospective cohort study assessed all the data from the medical histories of the patients(n=225)diagnosed with JIA(2016-2023)in the Cardiorheumatology Department of the M.E.Nikolaev National Center of Medicine.Pearson'sχ²test,Fisher's exact test,Mann–Whitney and Kruskal-Wallis tests were used for statistical analyses.RESULTS The ethnic prevalence of JIA is higher in Sakha than in Russian children at 110.1 per 100000 children and 69.4 per 100000 children,respectively.The prevalence of JIA among boys and girls in Sakha was similar,unlike in Russians,where the number of girls predominated.The JIA categories were as follows:(1)Systemic arthritis:3.5%;(2)Oligoarthritis(persistent and extended):33.8%;(3)Rheumatoid factor(RF)(+)polyarthritis:0.9%;(4)RF(-)polyarthritis:14.7%;(5)Enthesitis-related arthritis(ERA):44%;and(6)Psoriatic arthritis:3.1%.Prevalence of the ERA category was 4.4 times higher in Sakha children,but the prevalence of systemic arthritis was 2.9 times lower compared to Russians(P=0.0005).The frequency of uveitis was 10.2%,and the frequency of human leukocyte antigen(HLA)B27 was 39.6%in JIA children.Biologic treatment was received by 40.4%of JIA children and 45.3%achieved remission.CONCLUSION Higher JIA prevalence,male and ERA predominance,related to a higher frequency of HLA B27 are typical in RS(Y).These data might improve the pediatric rheumatology health service.展开更多
Arthritis,encompassing osteoarthritis(OA),rheumatoid arthritis(RA),and gouty arthritis(GA),is a prevalent inflammatory disease that significantly impacts quality of life.Natural products(NPs),derived from animals,plan...Arthritis,encompassing osteoarthritis(OA),rheumatoid arthritis(RA),and gouty arthritis(GA),is a prevalent inflammatory disease that significantly impacts quality of life.Natural products(NPs),derived from animals,plants,marine organisms,and microorganisms,have demonstrated beneficial effects in arthritis treatment both domestically and internationally.These natural compounds offer advantages in drug discovery due to their skeletal diversity,structural complexity,and multi-effect,multi-target,and low-toxicity properties compared to conventional small-molecule medicines.However,unclear mechanisms have hindered the development and clinical application of NPs.This review summarizes recent experimental studies from the past decade on natural medicine for arthritis treatment,emphasizing key NPs with therapeutic effects on OA,RA,and GA.It examines the effects and molecular mechanisms of NPs acting on different cells to treat arthritis.Furthermore,this review provides insights into the future prospects of NP research in this field,which is crucial for advancing NP-based arthritis treatments.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19...Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.展开更多
Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflamm...Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.展开更多
Post-traumatic osteoarthritis(PTOA)is a complex and painful problem in the foot and ankle.Ninety percent of osteoarthritis cases in the foot and ankle can be classified as post-traumatic.PTOA can affect any of the 33 ...Post-traumatic osteoarthritis(PTOA)is a complex and painful problem in the foot and ankle.Ninety percent of osteoarthritis cases in the foot and ankle can be classified as post-traumatic.PTOA can affect any of the 33 joints in the foot and the ankle.Distraction arthroplasty is a method for treatment of early arthritic joints without fusing or replacing them and its effectiveness has been well documented.The purpose of this case series is to present our successful experiences and positive results using distraction arthroplasty to treat PTOA in the ankle,subtalar,first metatarsophalangeal,and second tarsometatarsal joints,and to present distraction arthroplasty as a viable alternative to invasive joint sacrificing procedures such as arthrodesis or arthroplasty.Distraction Arthroplasty effectively and safely treats PTOA and improves the stability of joints in the Foot and Ankle.Additionally,the use of bone marrow aspirate concentrate as an adjuvant can improve the long-term functional and structural outcomes of the joint,and can prolong the need for further,more aggressive surgical interventions such as fusion or arthroplasty.展开更多
Objective To reveal the therapeutic effects of moxibustion in collagen-induced arthritis(CIA)rat models using the combined analysis of plasma and synovial membrane lipidomic profil-ing and to enhance the understanding...Objective To reveal the therapeutic effects of moxibustion in collagen-induced arthritis(CIA)rat models using the combined analysis of plasma and synovial membrane lipidomic profil-ing and to enhance the understanding of how moxibustion affects lipid metabolism in rheumatoid arthritis(RA).Methods A total of 32 male Sprague-Dawley(SD)rats were randomly assigned to four groups:control,moxibustion control(MC),model,and moxibustion model(MM)groups,with 8 rats in each group.CIA was induced in SD rats by two immunizations.The paw volume was mea-sured before the induction of CIA.Following induction,after assessing paw volume and arthritis index(AI)scores,the MC and MM groups received treatment at bilateral Shenshu(BL23)and Zusanli(ST36)acupoints for 10 min per acupoint.The intervention included three treatment courses,each spanning 6 d and followed by a 1-d interval.Paw volume and AI scores were assessed after each treatment course.After the completion of the three treatment courses,serum,plasma,synovial tissue,and ankle joint samples were collected.Enzyme-linked immunosorbent assay(ELISA)was employed to quantify the levels of interleukin(IL)-6 and tumor necrosis factor(TNF)-αin serum.Hematoxylin and eosin(HE)staining was per-formed for histopathological examination of the ankle joint tissues.Meanwhile,ultra-high-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry(UHPLC-Q-Exactive Orbitrap MS)was utilized to analyze the plasma and synovial tissue sam-ples.In addition,multivariate statistical analysis was performed to identify differential lipid metabolites,and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis was applied to explore metabolic pathways modulated by moxibustion therapy.Results No significant difference in hind paw volume and AI scores was observed among the groups(P>0.05).After CIA induction,model group showed increased hind paw volume and AI scores compared with control group(P<0.05),which were significantly reduced after mox-ibustion treatment in MM group compared with model group(P<0.05).The levels of IL-6 and TNF-αwere significantly higher in model and MM groups compared with control group(P<0.05),but were lower in MM group than those in model group(P<0.05).Histopathologi-cal analysis showed improved cartilage and reduced inflammation in MM group.A total of 33 differential lipid metabolites in the plasma and 24 in the synovial membranes of CIA rat mod-els were identified when compared with control group.Among these lipid metabolites,31 in the plasma and all 24 in the synovial membranes were regulated by moxibustion treatment.Pathological analysis revealed upregulation of diacylglycerol(DG)and fatty acid(FA)levels,alongside downregulation of lysophosphatidylcholine(LPC),phosphatidylcholine(PC),and phosphatidylethanolamine(PE).Under physiological conditions,the treatment specifically reduced LPC and PC levels.Pathway enrichment analysis revealed that moxibustion predom-inantly affectedα-linolenic acid,glycerophospholipid,and sphingolipid metabolism under pathological conditions.Under physiological conditions,the regulation was centered aroundα-linolenic acid and glycerophospholipid metabolism.Conclusion The RA rat models exhibited significant lipid metabolic disturbances.Moxibus-tion alleviated paw swelling,reduced AI scores,modulated inflammatory cytokine levels,and partially corrected the altered levels of multiple lipid metabolites.The potential metabolic pathways implicated in the regulation of lipid metabolism under both physiological and pathological conditions includeα-linolenic acid,glycerophospholipid,and sphingolipid metabolism.展开更多
Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly ele...Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.展开更多
Rheumatoid arthritis(RA)is a common chronic autoimmune disease characterized by joint pain,swelling and dysfunction[1].According to epidemiologic statistics,the incidence of RA is 1%–2%,and in severe cases,it can dev...Rheumatoid arthritis(RA)is a common chronic autoimmune disease characterized by joint pain,swelling and dysfunction[1].According to epidemiologic statistics,the incidence of RA is 1%–2%,and in severe cases,it can develop into joint deformity and disability,which brings a heavy burden to the family and society[2].However,the pathogenesis of RA is complex and involves multiple cellular interactions,which increases the difficulty of curing RA.Current therapeutic options,such as disease-modifying antirheumatic drugs,non-steroidal anti-inflammatory drugs,and biologics,still face the challenge of relapse after drug discontinuation[3,4].Therefore,the pathogenesis of RA needs to be analyzed in depth to break through the existing therapeutic bottlenecks and promote the iterative innovation of individualized diagnosis and treatment.展开更多
Rheumatoid arthritis(RA)is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life.RA accelerates musculoskeletal aging,leading to complications such as mus...Rheumatoid arthritis(RA)is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life.RA accelerates musculoskeletal aging,leading to complications such as muscle degeneration and sarcopenia.Recent research has identified myopenia as a condition of significant muscle loss associated with illness,distinct from the muscle wasting seen in other chronic diseases like cancer cachexia or heart failure.In RA,myopenia is characterized by muscle depletion without concurrent significant fat loss,and it can affect individuals of all ages.While inflammation plays a central role,it is not the sole factor contributing to the high incidence of muscle wasting in RA.In subsequent discussions,secondary sarcopenia will be considered alongside myopenia,as both involve muscle wasting decline primarily due to disease.This review summarizes recent findings on the impact of RA-related myopenia and secondary sarcopenia on functional capacity,explores its underlying mechanisms,and discusses contemporary strategies to mitigate the process of musculoskeletal aging in RA patients.展开更多
BACKGROUND Juvenile arthritis damage index(JADI)is a tool that measures the degree of aggressiveness of the juvenile idiopathic arthritis(JIA)course and assesses articular[JADI-articular damage(JADI-A)]and extraarticu...BACKGROUND Juvenile arthritis damage index(JADI)is a tool that measures the degree of aggressiveness of the juvenile idiopathic arthritis(JIA)course and assesses articular[JADI-articular damage(JADI-A)]and extraarticular[JADI-extraarticular damage(JADI-E)]damage.While aggressive JIA often requires early bio-logic disease-modified antirheumatic drugs(bDMARDs),the utility of JADI as a predictor of treatment response remains underexplored.AIM To evaluate the potential of JADI as a predictor of bDMARD treatment response in JIA patients.METHODS This prospective study included 112 highly active non-systemic JIA biologic-naïve patients with a mean age of 12.2±4.6 years and a median disease duration of 2.5(interquartile range:1-5)years.Their clinical and radiological assessment,juvenile arthritis disease activity score 71,JADI-A,and JADI-E,were evaluated twice:Before the biologic initiation(baseline)and 12 months after(end of study).At baseline,50%had any damage,with 43%with articular damage and 23%with extraarticular damage.RESULTS During the study,JADI-A/JADI-E improved(33.9%/9.8%),worsened(8.9%/5.4%),or remained unchanged(57.1%/84.8%).Patients with baseline damage had higher markers of JIA activity:Polyarticular course,earlier onset age,ANA-positivity,and more active joints.Patients without initial structural damage(JADI“-”)were more likely(odds ratio=3.8,95%confidence interval:1.6-9.0,P<0.004)to achieve a low degree of activity or remission(46.2%),while on biological therapy,their scores were comparable to JADI-positive(18.3%).Pre-biological joint damage according to the JADI-A index(P=0.003),wrist(P=0.035),elbow(P=0.027),cervical spine limitation of motion(P=0.051),and erosions confirmed by magnetic resonance imaging(P=0.002),were associated with poor response to biological treatment and follow-up JIA activity.CONCLUSION Baseline structural damage in JIA is associated with diminished bDMARDs efficacy,increased disability,and shorter remission duration.JADI enhances conventional clinical risk stratification by facilitating timely initiation of bDMARDs,adherence to treat-to-target strategy and tailored patient care.展开更多
Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples...Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples from patients with different pathological processes were collected, and the correlations between the subsets of FLSs and STMs and pathological processes were analyzed via flow cytometry. In vitro experimental methods such as enzyme linked immunosorbent assay (ELISA), Western blotting, Transwell assays, CCK- 8 assays and cell coculture were used to assess cell proliferation, migration and secretion of inflammatory factors. A collagen- induced arthritis mouse model was constructed to investigate the therapeutic potential of emodin in RA by flow cytometry, micro- CT and staining. Results : Unique subsets of FLSs and STMs, namely, FAPα ^(+)THY1 − FLSs, FAPα ^(+)THY1 ^(+)FLSs, and MerTK ^(pos) TREM2 ^(high) STMs, were identified in synovial tissues from RA patients. The number of MerTK ^(pos) TREM2 ^(high) STMs was negatively correlated with the degree of damage in RA, while the number of FAPα ^(+)THY1 − FLSs was positively correlated with damage. On the one hand, emodin promoted the aggregation of MerTKposTREM2high STMs. Moreover, MerTK pos TREM2 high STM- mediated secretion of exosomes was promoted, which can inhibit the secretion of pro- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs and promote the secretion of anti- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs, thereby inhibiting FAPα ^(+)THY1 − FLS proliferation and migration, improving the local immune microenvironment, and inhibiting RA damage. Conclusion : Emodin was shown to regulate the aggregation of STM subsets and exosome secretion, affecting the secretion, proliferation and migration of inflammatory factors in FLS subsets, and ultimately achieving good therapeutic efficacy in RA patients, suggesting that it has important clinical value.展开更多
Rheumatoid arthritis(RA)is a chronic autoimmune disease that affects approxi-mately 0.46%of the global population.Conventional therapeutics for RA,including disease-modifying antirheumatic drugs(DMARDs),nonsteroidal a...Rheumatoid arthritis(RA)is a chronic autoimmune disease that affects approxi-mately 0.46%of the global population.Conventional therapeutics for RA,including disease-modifying antirheumatic drugs(DMARDs),nonsteroidal anti-inflammatory drugs(NSAIDs),and corticosteroids,frequently result in unintended adverse effects.Dexamethasone(DEX)is a potent glucocorticoid used to treat RA due to its anti-inflammatory and immunosuppressive properties.Liposomal delivery of DEX,particu-larly when liposomes are surface-modified with targeting ligands like peptides or sialic acid,can improve drug efficacy by enhancing its distribution to inflamed joints and minimizing toxicity.This study investigates the potential of liposomal drug delivery systems to enhance the efficacy and targeting of DEX in the treatment of RA.Results from various studies demonstrate that liposomal DEX significantly inhibits arthritis progression in animal models,reduces joint inflammation and damage,and alleviates cartilage destruction compared to free DEX.The liposomal formulation also shows better hemocompatibility,fewer adverse effects on body weight and immune organ index,and a longer circulation time with higher bioavailability.The anti-inflammatory mechanism is associated with the downregulation of pro-inflammatory cytokines like tumor necrosis factor-α(TNF-α)and B-cell-activating factor(BAFF),which are key players in the pathogenesis of RA.Additionally,liposomal DEX can induce the expres-sion of anti-inflammatory cytokines like interleukin-10(IL-10),which has significant anti-inflammatory and immunoregulatory properties.The findings suggest that lipo-somal DEX represents a promising candidate for effective and safe RA therapy,with the potential to improve the management of this debilitating disease by providing targeted delivery and sustained release of the drug.展开更多
Rheumatoid arthritis(RA) is a chronic inflammatory disease with multi-system damage and autoimmune features.The main clinical manifestations of RA include joint pain,swelling,and stiffness,and RA may lead to joint def...Rheumatoid arthritis(RA) is a chronic inflammatory disease with multi-system damage and autoimmune features.The main clinical manifestations of RA include joint pain,swelling,and stiffness,and RA may lead to joint deformity and dysfunction in severe cases.The pathologic development of RA involves complex interactions of multiple biomarkers,and detecting a single biomarker may produce falsepositive results due to other confounding factors.Therefore,fluorescent probes that can detect multiple biomarkers simultaneously are crucial for precise RA diagnosis.Peroxynitrite(ONOO^(-)) and viscosity are inflammation-related factors in cells.In this study,we developed a dual responsive near-infrared fluorescent probe,YLS,for ONOO^(-) and viscosity.The probe features dual-channel turn-on fluorescence responses at 625 and 760 nm upon the presence of ONOO^(-) and viscosity,respectively.Supported by YLS,we found that during RA pathology,lymphocyte infiltration not only increases the concentration of proteins in the joint fluid resulting in elevated viscosity;at the same time,the overproduction of ONOO^(-) exacerbates oxidative stress and inflammatory responses.This multiparameter assay is expected to improve the diagnostic accuracy of the early stages of RA,thus providing a scientific basis for early intervention and personalized treatment.展开更多
Objective To perform an in silico bioinformatics analysis to identify differentially expressed microRNAs(miRNAs)implicated in rheumatoid arthritis(RA)pathogenesis and evaluate their potential as biomarkers for assessi...Objective To perform an in silico bioinformatics analysis to identify differentially expressed microRNAs(miRNAs)implicated in rheumatoid arthritis(RA)pathogenesis and evaluate their potential as biomarkers for assessing therapeutic efficacy and monitoring acupuncture treatment.Methods miRNA microarray data(CEL and TXT formats)were acquired from human and murine RA models,with the latter undergoing acupuncture treatment.Data were normalized using the robust multi-array average(RMA)method and analyzed for differential expression.Differential expression analysis identified miRNAs through a comparative analysis of RA human tissues,acupuncture-treated murine RA models,and a bibliographic search for miRNAs implicated in RA pathogenesis and acupuncture treatment.Bioinformatics analysis was performed to identify potential target genes for each miRNA and signaling pathways via search tools for the Retrieval of Interacting Genes/Proteins(STRING)and ShinyGO.Gene-drug interaction analysis was performed through Drug-Gene Interaction Database(DGIdb)screening.Interaction networks were constructed with the Cytoscape v3.10.3 software.Results The hsa-miR-125a-5p and hsa-miR-125b-5p were identified as potential biomarkers associated with RA pathogenesis,presenting 468 and 455 target genes,respectively.These genes were enriched in 20 signaling pathways,including Janus kinasa-signal transducer and activator of transcription(JAK-STAT),mitogen-activated protein kinase(MAPK),phosphoinositide 3-kinase-protein kinase B(PI3K-Akt),and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)signaling pathway,which have been associated with RA pathogenesis and progression.Drug-gene interaction networks revealed that 22 genes were significantly associated with 58 RA treatment drugs,among which 13 genes interacted with members of the hsa-miR-125 family.Conclusion The hsa-miR-125a-5p and hsa-miR-125b-5p demonstrate critical regulatory role in RA pathogenesis by modulating signaling pathways,including JAK-STAT,MAPK,PI3K-Akt,and NF-κB.Our findings show that the hsa-miR-125a-5p and hsa-miR-125b-5p exhibit differential expression patterns in response to pharmacological intervention in various diseases,including RA management.This suggests their potential roles as biomarkers for monitoring acupuncture treatment.Although existing evidence indicates that acupuncture can modify miRNA expression profiles,rigorous validation through biological models remains essential to confirm these results.展开更多
Eosinophils are multifunctional granulocytes that contribute to the initiation and modulation of inflammation.Accumulating evidence suggests that eosinophils are adaptable leukocytes that orchestrate the resolution of...Eosinophils are multifunctional granulocytes that contribute to the initiation and modulation of inflammation.Accumulating evidence suggests that eosinophils are adaptable leukocytes that orchestrate the resolution of inflammatory responses.The most prevalent chronic inflammatory illness,rheumatoid arthritis(RA),is typified by persistent synovitis thatmakes it hard for the disease to go away on its own.Interestingly,a unique subset of eosinophils known as regulatory eosinophils has been found in RA patients’synovium,especially while the disease is in remission.Pro-resolving signatures of regulatory eosinophils in the synovium are distinct from those of their lung counterparts.The most recent research on eosinophils and their function in this disease pathogenesis is compiled in this review.Based on the role of regulatory eosinophils,a new pathological model of inflammation resolution in RA is proposed,and potential therapeutic strategies aimed at enhancing the action of regulatory eosinophils in RA are proposed.展开更多
BACKGROUND Uveitis associated with juvenile idiopathic arthritis(U-JIA)is a vision-threatening condition.Estimates of prevalence of uveitis in patients with known juvenile idiopathic arthritis range from 11.6%to 30.0%...BACKGROUND Uveitis associated with juvenile idiopathic arthritis(U-JIA)is a vision-threatening condition.Estimates of prevalence of uveitis in patients with known juvenile idiopathic arthritis range from 11.6%to 30.0%.First-line treatment includes topical glucocorticoids;methotrexate(MTX)is used if topical corticosteroids are ineffective.In severe cases biological therapy like adalimumab may be prescribed.Complications,including vision loss,may be related to the disease and the ongoing treatment(topical corticosteroids).In severe cases surgical intervention is often necessary and is typically associated with poor vision outcomes.AIM To highlight the characteristics of operated U-JIA and to identify predictors of treatment failure.METHODS A retrospective cohort study analyzed data from 68 pediatric patients(under 18 years old)with U-JIA between 2007 and 2023.The study focused on demographic,clinical,treatment,and outcome variables.Survival analysis using Kaplan-Meier curves and the Cox proportional hazards model was performed to estimate the impact of surgical intervention on the course of uveitis and to identify predictors of treatment failure.RESULTS Eye surgery was performed on 17(25%)patients with U-JIA.It was associated with an earlier onset of uveitis(P=0.017),lower uveitis remission rate[odds ratio=5.29,95%confidence interval(CI):1.23-24.90,P=0.015],longer time to remission(P=0.036),reduced probability of achieving remission on MTX(P=0.033),and the necessity of the following treatment with biological diseasemodifying antirheumatic drugs(odds ratio=5.60;95%CI:1.11-55.19,P=0.021)with similar efficacy with biological treatments in operated and non-operated cases.Kaplan-Meier curves showed a borderline difference in time to surgical intervention based on the MTX initiation cutoff(P=0.065)although earlier MTX initiation might be associated with a higher likelihood of deferred surgery.CONCLUSION Operated patients exhibited an aggressive early-onset uveitis profile that needed early and more intensive treatment.Delayed and failed MTX treatment as well as delayed switching to biologics often required subsequent eye surgery.展开更多
Abnormal activation of macrophages and osteoclasts(OCs)contributes significantly to rheumatoid arthritis(RA)development by secretion of numerous inflammatory factors.Notably,these cells exhibit significant upregulatio...Abnormal activation of macrophages and osteoclasts(OCs)contributes significantly to rheumatoid arthritis(RA)development by secretion of numerous inflammatory factors.Notably,these cells exhibit significant upregulation of folate receptor proteins on their surfaces.Unfortunately,there is a current lack of safe and effective therapeutic drugs for RA.Xuetongsu(XTS),a triterpenoid compound extracted fromKadsura heteroclita Roxb Craib,has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes(RAFLS).However,its clinical application is hampered by poor targeting and short half-life.To address these drawbacks,we previously developed a nano-drug system named HRPS nanoparticles(NPs),which effectively targets RAFLS and inhibits synovial hyperplasia.However,this system overlooked the essential role of OCs in RA-related bone destruction.Therefore,we designed a novel folate-modified biomimetic Prussian blue(PB)-XTS NP(FMPX NP)for the selective delivery of XTS into inflammatory macrophages and OCs.The NP exhibits an excellent photothermal effect when assisted by laser irradiation,facilitating targeted release of XTS within inflammatory macrophages and OCs.The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs.In vivo experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times,decreased hind foot swelling from 12.10±0.49 mm to 8.24±0.09 mm in the model group,and prevented bone damage.In conclusion,this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA.FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy,providing new insights for targeted drug therapies in clinical RA treatment.展开更多
Arthritis is an inflammatory joint disorder that progressively impairs function and diminishes quality of life.Conventional therapies often prove ineffective,as oral administration lacks specificity,resulting in off-t...Arthritis is an inflammatory joint disorder that progressively impairs function and diminishes quality of life.Conventional therapies often prove ineffective,as oral administration lacks specificity,resulting in off-target side effects like hepatotoxicity and GIT-related issues.Intravenous administration causes systemic side effects.The characteristic joint-localized symptoms such as pain,stiffness,and inflammation make the localized drug delivery suitable for managing arthritis.Topical/transdermal/intraarticular routes have become viable options for drug delivery in treating arthritis.However,challenges with those localized drug delivery routes include skin barrier and cartilage impermeability.Additionally,conventional intra-articular drug delivery also leads to rapid clearance of drugs from the synovial joint tissue.To circumvent these limitations,researchers have developed nanocarriers that enhance drug permeability through skin and cartilage,influencing localized action.Gel-based nanoengineered therapy employs a gel matrix to incorporate the drug-encapsulated nanocarriers.This approach combines the benefits of gels and nanocarriers to enhance therapeutic effects and improve patient compliance.This review emphasizes deep insights into drug delivery using diverse gelbased novel nanocarriers,exploring their various applications embedded in hyaluronic acid(biopolymer)–based gels,carbopol-based gels,and others.Furthermore,this review discusses the influence of nanocarrier pharmacokinetics on the localization and therapeutic manipulation of macrophages mediated by nanocarriers.The ELVIS(extravasation through leaky vasculature and inflammatory cell-mediated sequestration)effect associated with arthritis is advantageous in drug delivery.Simply put,the ELVIS effect refers to the extravasation of nanocarriers through leaky vasculatures,which finally results in the accumulation of nanocarriers in the joint cavity.展开更多
BACKGROUND Chronic idiopathic uveitis(CIU)and juvenile idiopathic arthritis-associated uveitis(U-JIA)are both vision-threatening conditions that share similar autoimmune mechanisms,but treatment approaches differ sign...BACKGROUND Chronic idiopathic uveitis(CIU)and juvenile idiopathic arthritis-associated uveitis(U-JIA)are both vision-threatening conditions that share similar autoimmune mechanisms,but treatment approaches differ significantly.In managing U-JIA,various treatment options are employed,including biological and non-biological disease-modifying anti-rheumatic drugs.These drugs are effective in clinical trials.Given the lack of established diagnostic and treatment guidelines as well as the limited number of therapeutic options available,patients with CIU frequently do not receive optimal and timely immunosuppression.This study highlighted the necessity for additional research to develop novel diag-nostic techniques,targeted therapies,and enhanced treatment outcomes for young individuals with CIU.AIM To compare the characteristics and outcomes of U-JIA and CIU.METHODS A retrospective cohort study analyzed data from 110 pediatric patients(under 18 years old)with U-JIA and 40 pediatric patients with CIU.Data was collected between 2012 and 2023.The study focused on demographic,clinical,treatment,and outcome variables.RESULTS The median onset age of arthritis was 6.4 years(2.7 years;9.3 years).In 28.2%of cases uveitis preceded the onset of arthritis.In 17.3%of cases it occurred simultan-eously.In 53.6%of cases it followed arthritis.Both groups had similar onset ages,antinuclear antibodies/human leukocyte antigen positivity rates,and ESR levels,with a slight predominance of females(60.9%vs 42.5%,P=0.062),and higher C-reactive protein levels in the U-JIA group.Anterior uveitis was more prevalent in patients with U-JIA(P=0.023),although the frequency of symptomatic,unilateral,and complicated forms did not differ significantly.The use of methotrexate(83.8%vs 96.4%)and biologics(64.7%vs 82.1%)was comparable,as was the rate of remission on methotrexate treatment(70.9%vs 56.5%)and biological therapy(77.8%vs 95%),but a immunosuppressive treatment delay in CIU observed.Patients with CIU were less likely to receive methotrexate[hazard ratio(HR)=0.48,P=0.005]or biological treatment(HR=0.42,P=0.004),but they were more likely to achieve remission with methotrexate(HR=3.70,P=0.001).CONCLUSION Treatment of uveitis is often limited to topical measures,which can delay systemic therapy and affect the outcome.Methotrexate and biological agents effectively manage eye inflammation.It is essential to develop standardized protocols for the diagnosis and management of uveitis,and collaboration between rheumatologists and ophthal-mologists is needed to achieve optimal outcomes in the treatment of CIU.展开更多
BACKGROUND Children with juvenile idiopathic arthritis(JIA)and inflammatory bowel disease(IBD)face an elevated risk of severe infection owing to their diseases and the immunosuppressive treatment for disease control.A...BACKGROUND Children with juvenile idiopathic arthritis(JIA)and inflammatory bowel disease(IBD)face an elevated risk of severe infection owing to their diseases and the immunosuppressive treatment for disease control.AIM To compare scheduled vaccination coverage and the levels of post-vaccine antibodies against measles,mumps,rubella(MMR)and hepatitis B in pediatric patients with IBD and JIA.METHODS A comparative cohort study included 97 patients with IBD and 170 patients with JIA.Vaccination history was obtained from medical records,while post-vaccination immunity was assessed prospectively by measuring specific IgG antibody titers using enzyme-linked immunosorbent assays(Vector-Best JSC,Russia;IBL International,Germany)during routine visits between January 2022 and April 2023.RESULTS A complete two-dose MMR course had been administered to 66.3%of IBD patients and 55.9%of JIA patients(P=0.121).By contrast,the three-dose hepatitis B schedule was completed in 74.2%of IBD and 100%of JIA patients(P<0.001).Protective level of anti-vaccine antibodies against measles(47.7%vs 57.7%;P=0.168);mumps(75.3%vs 80.0%;P=0.366);rubella(74.4%vs 98.2%;P<0.0001);and hepatitis B(44.8%vs 50.0%;P=0.514)were detected in IBD and JIA patients,respectively.CONCLUSION Patients with IBD and JIA demonstrated different vaccination coverage patterns and levels of anti-vaccine antibodies.Routine baseline serology and timely booster vaccination should be implemented for all pediatric patients receiving chronic immunosuppression.展开更多
文摘BACKGROUND Prevalence of the main rheumatic diseases in the Republic of Sakha(Yakutia)[RS(Y)],one of the regions of the Russian Federation,differs from the other regions of the Russian Federation due to its ethnic and geographic features.Knowledge regarding the prevalence and structure of juvenile idiopathic arthritis(JIA)allows us to shape the work of the pediatric rheumatology service in the region correctly,and optimize the healthcare system and the need for medica-tions.AIM To describe the epidemiological,demographic,clinical,and laboratory characteristics of children with JIA in the RS(Y)and evaluate the main outcomes.METHODS This retrospective cohort study assessed all the data from the medical histories of the patients(n=225)diagnosed with JIA(2016-2023)in the Cardiorheumatology Department of the M.E.Nikolaev National Center of Medicine.Pearson'sχ²test,Fisher's exact test,Mann–Whitney and Kruskal-Wallis tests were used for statistical analyses.RESULTS The ethnic prevalence of JIA is higher in Sakha than in Russian children at 110.1 per 100000 children and 69.4 per 100000 children,respectively.The prevalence of JIA among boys and girls in Sakha was similar,unlike in Russians,where the number of girls predominated.The JIA categories were as follows:(1)Systemic arthritis:3.5%;(2)Oligoarthritis(persistent and extended):33.8%;(3)Rheumatoid factor(RF)(+)polyarthritis:0.9%;(4)RF(-)polyarthritis:14.7%;(5)Enthesitis-related arthritis(ERA):44%;and(6)Psoriatic arthritis:3.1%.Prevalence of the ERA category was 4.4 times higher in Sakha children,but the prevalence of systemic arthritis was 2.9 times lower compared to Russians(P=0.0005).The frequency of uveitis was 10.2%,and the frequency of human leukocyte antigen(HLA)B27 was 39.6%in JIA children.Biologic treatment was received by 40.4%of JIA children and 45.3%achieved remission.CONCLUSION Higher JIA prevalence,male and ERA predominance,related to a higher frequency of HLA B27 are typical in RS(Y).These data might improve the pediatric rheumatology health service.
基金supported by the National Natural Science Foundation of China(No.82373887)。
文摘Arthritis,encompassing osteoarthritis(OA),rheumatoid arthritis(RA),and gouty arthritis(GA),is a prevalent inflammatory disease that significantly impacts quality of life.Natural products(NPs),derived from animals,plants,marine organisms,and microorganisms,have demonstrated beneficial effects in arthritis treatment both domestically and internationally.These natural compounds offer advantages in drug discovery due to their skeletal diversity,structural complexity,and multi-effect,multi-target,and low-toxicity properties compared to conventional small-molecule medicines.However,unclear mechanisms have hindered the development and clinical application of NPs.This review summarizes recent experimental studies from the past decade on natural medicine for arthritis treatment,emphasizing key NPs with therapeutic effects on OA,RA,and GA.It examines the effects and molecular mechanisms of NPs acting on different cells to treat arthritis.Furthermore,this review provides insights into the future prospects of NP research in this field,which is crucial for advancing NP-based arthritis treatments.
基金supported by GILO Foundation.This research is in part supported by Korea Drug Development Fund funded by Ministry of Science and ICT,Ministry of Trade,Industry,and Energy,and Ministry of Health and Welfare(RS-2023-00282595,Republic of Korea).
文摘Rheumatoid arthritis(RA)is an autoimmune disease characterized by inflammation and abnormal osteoclast activation,leading to bone destruction.We previously demonstrated that the large extracellular loop(LEL)of Tm4sf19 is important for its function in osteoclast differentiation,and LEL-Fc,a competitive inhibitor of Tm4sf19,effectively suppresses osteoclast multinucleation and prevent bone loss associated with osteoporosis.This study aimed to investigate the role of Tm4sf19 in RA,an inflammatory and abnormal osteoclast disease,using a mouse model of collagen-induced arthritis(CIA).Tm4sf19 expression was observed in macrophages and osteoclasts within the inflamed synovium,and Tm4sf19 expression was increased together with inflammatory genes in the joint bones of CIA-induced mice compared with the sham control group.Inhibition of Tm4sf19 by LEL-Fc demonstrated both preventive and therapeutic effects in a CIA mouse model,reducing the CIA score,swelling,inflammation,cartilage damage,and bone damage.Knockout of Tm4sf19 gene or inhibition of Tm4sf19 activity by LEL-Fc suppressed LPS/IFN-γ-induced TLR4-mediated inflammatory signaling in macrophages.LEL-Fc disrupted not only the interaction between Tm4sf19 and TLR4/MD2,but also the interaction between TLR4 and MD2.μCT analysis showed that LEL-Fc treatment significantly reduced joint bone destruction and bone loss caused by hyperactivated osteoclasts in CIA mice.Taken together,these findings suggest that LELFc may be a potential treatment for RA and RA-induced osteoporosis by simultaneously targeting joint inflammation and bone destruction caused by abnormal osteoclast activation.
基金the National Natural Science Foundation of China(82372412)the Social Development Project of Jiangsu Province(BE2022701)+4 种基金the Top Talent Support Program for Young and Middle-aged People of the Wuxi Health Committee(BJ2020044,BJ2020057,HB2020043)the Fundamental Research Funds of the Health and Family Planning Commission of Wuxi(M202024)the Special Program for Translational Medicine Research of the Wuxi Translational Medicine Center(2020DHYB07,2020DHYB03)the Key Special Project of Precision Medicine of the Wuxi Health Commission(J202101)peking union medical college hospital talent cultivation program(UHB50192).
文摘Rheumatoid arthritis(RA)is a systemic autoimmune disease in which synovial fibroblasts(SFs)maintain chronic inflammation by secreting proinflammatory mediators,leading to joint destruction.While the role of proinflammatory mediators in this process is well-established,the contribution of non-inflammatory regulators in SFs to joint pathology remains poorly understood.In this study,we investigated the non-inflammatory role of SFs in RA using a co-culture model,and found that SFs from RA patients promote apoptosis of human chondrocytes.Mechanistic investigations reveal that SFs can secrete small extracellular vesicles(sEVs),which are taken up by chondrocytes and induce chondrocyte apoptosis in both normal chondrocytes and chondrocytes from patients with RA.sEV-derived miRNA 15-29148 are identified as key signaling molecules mediating the apoptosis effects of chondrocytes.Further studies reveal that SF-derived miRNA 15-29148 targeting CIAPIN1 results in increased chondrocyte apoptosis.We further demonstrate that SF-derived miRNA 15-29148 is transferred to chondrocytes,exacerbating cartilage damage in vivo.Moreover,chondrocyte-specific aptamer-modified polyamidoamine nanoparticles not only ameliorated RA but also prevented its onset.This study suggests that,in RA,the secretion of specific sEV-miRNAs from SFs plays a crucial role in promoting chondrocyte apoptosis,potentially through non-inflammatory regulation,and that sEV-miRNA inhibition in SFs may represent an early preventive treatment strategy for cartilage degradation in RA.
文摘Post-traumatic osteoarthritis(PTOA)is a complex and painful problem in the foot and ankle.Ninety percent of osteoarthritis cases in the foot and ankle can be classified as post-traumatic.PTOA can affect any of the 33 joints in the foot and the ankle.Distraction arthroplasty is a method for treatment of early arthritic joints without fusing or replacing them and its effectiveness has been well documented.The purpose of this case series is to present our successful experiences and positive results using distraction arthroplasty to treat PTOA in the ankle,subtalar,first metatarsophalangeal,and second tarsometatarsal joints,and to present distraction arthroplasty as a viable alternative to invasive joint sacrificing procedures such as arthrodesis or arthroplasty.Distraction Arthroplasty effectively and safely treats PTOA and improves the stability of joints in the Foot and Ankle.Additionally,the use of bone marrow aspirate concentrate as an adjuvant can improve the long-term functional and structural outcomes of the joint,and can prolong the need for further,more aggressive surgical interventions such as fusion or arthroplasty.
基金National Natural Science Foundation of China(81774383)Major Project of Philosophy and Social Science Research in Colleges and Universities of Jiangsu Province (2020SJA0335)Graduate Research and Innovation Projects of Jiangsu Province (SJCX23_0735)。
文摘Objective To reveal the therapeutic effects of moxibustion in collagen-induced arthritis(CIA)rat models using the combined analysis of plasma and synovial membrane lipidomic profil-ing and to enhance the understanding of how moxibustion affects lipid metabolism in rheumatoid arthritis(RA).Methods A total of 32 male Sprague-Dawley(SD)rats were randomly assigned to four groups:control,moxibustion control(MC),model,and moxibustion model(MM)groups,with 8 rats in each group.CIA was induced in SD rats by two immunizations.The paw volume was mea-sured before the induction of CIA.Following induction,after assessing paw volume and arthritis index(AI)scores,the MC and MM groups received treatment at bilateral Shenshu(BL23)and Zusanli(ST36)acupoints for 10 min per acupoint.The intervention included three treatment courses,each spanning 6 d and followed by a 1-d interval.Paw volume and AI scores were assessed after each treatment course.After the completion of the three treatment courses,serum,plasma,synovial tissue,and ankle joint samples were collected.Enzyme-linked immunosorbent assay(ELISA)was employed to quantify the levels of interleukin(IL)-6 and tumor necrosis factor(TNF)-αin serum.Hematoxylin and eosin(HE)staining was per-formed for histopathological examination of the ankle joint tissues.Meanwhile,ultra-high-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry(UHPLC-Q-Exactive Orbitrap MS)was utilized to analyze the plasma and synovial tissue sam-ples.In addition,multivariate statistical analysis was performed to identify differential lipid metabolites,and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis was applied to explore metabolic pathways modulated by moxibustion therapy.Results No significant difference in hind paw volume and AI scores was observed among the groups(P>0.05).After CIA induction,model group showed increased hind paw volume and AI scores compared with control group(P<0.05),which were significantly reduced after mox-ibustion treatment in MM group compared with model group(P<0.05).The levels of IL-6 and TNF-αwere significantly higher in model and MM groups compared with control group(P<0.05),but were lower in MM group than those in model group(P<0.05).Histopathologi-cal analysis showed improved cartilage and reduced inflammation in MM group.A total of 33 differential lipid metabolites in the plasma and 24 in the synovial membranes of CIA rat mod-els were identified when compared with control group.Among these lipid metabolites,31 in the plasma and all 24 in the synovial membranes were regulated by moxibustion treatment.Pathological analysis revealed upregulation of diacylglycerol(DG)and fatty acid(FA)levels,alongside downregulation of lysophosphatidylcholine(LPC),phosphatidylcholine(PC),and phosphatidylethanolamine(PE).Under physiological conditions,the treatment specifically reduced LPC and PC levels.Pathway enrichment analysis revealed that moxibustion predom-inantly affectedα-linolenic acid,glycerophospholipid,and sphingolipid metabolism under pathological conditions.Under physiological conditions,the regulation was centered aroundα-linolenic acid and glycerophospholipid metabolism.Conclusion The RA rat models exhibited significant lipid metabolic disturbances.Moxibus-tion alleviated paw swelling,reduced AI scores,modulated inflammatory cytokine levels,and partially corrected the altered levels of multiple lipid metabolites.The potential metabolic pathways implicated in the regulation of lipid metabolism under both physiological and pathological conditions includeα-linolenic acid,glycerophospholipid,and sphingolipid metabolism.
基金supported by the National Natural Science Foundation of China(NSFC)(No.82130073,No.82372430,No.31871431,No.31821002,No.32101011,No.22177073)Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System+3 种基金Shanghai Science and Technology Committee(No.23ZR1437600,No.24410710600,No.24141901302)Shenzhen Medical Research Fund(No.B2302005)The Open Project Funding of Shanghai Key Laboratory of Orthopedics(No.KFKT202201)Biomaterials and Regenerative Medicine Institute Cooperative,Research Project,Shanghai Jiao Tong University School of Medicine(No.2022LHA01).
文摘Itaconate,a macrophage-specific anti-inflammatory metabolite,has recently emerged as a critical regulator in rheumatoid arthritis pathogenesis.We found that itaconate is a TNF-αresponsive metabolite significantly elevated in the serum and synovial fluid of rheumatoid arthritis patients and we demonstrated that itaconate is primarily produced by inflammatory macrophages rather than osteoclasts or osteoblasts.In TNF-transgenic and Irg1−/−hybrid mice,a more severe bone destruction phenotype was observed.
文摘Rheumatoid arthritis(RA)is a common chronic autoimmune disease characterized by joint pain,swelling and dysfunction[1].According to epidemiologic statistics,the incidence of RA is 1%–2%,and in severe cases,it can develop into joint deformity and disability,which brings a heavy burden to the family and society[2].However,the pathogenesis of RA is complex and involves multiple cellular interactions,which increases the difficulty of curing RA.Current therapeutic options,such as disease-modifying antirheumatic drugs,non-steroidal anti-inflammatory drugs,and biologics,still face the challenge of relapse after drug discontinuation[3,4].Therefore,the pathogenesis of RA needs to be analyzed in depth to break through the existing therapeutic bottlenecks and promote the iterative innovation of individualized diagnosis and treatment.
基金supported in part by the National Natural Science Foundation of China(Grant No.82350710800,82374470,82202757)Shenzhen Medical Research Fund B2302005,and NHMRC,APP1163933.
文摘Rheumatoid arthritis(RA)is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life.RA accelerates musculoskeletal aging,leading to complications such as muscle degeneration and sarcopenia.Recent research has identified myopenia as a condition of significant muscle loss associated with illness,distinct from the muscle wasting seen in other chronic diseases like cancer cachexia or heart failure.In RA,myopenia is characterized by muscle depletion without concurrent significant fat loss,and it can affect individuals of all ages.While inflammation plays a central role,it is not the sole factor contributing to the high incidence of muscle wasting in RA.In subsequent discussions,secondary sarcopenia will be considered alongside myopenia,as both involve muscle wasting decline primarily due to disease.This review summarizes recent findings on the impact of RA-related myopenia and secondary sarcopenia on functional capacity,explores its underlying mechanisms,and discusses contemporary strategies to mitigate the process of musculoskeletal aging in RA patients.
文摘BACKGROUND Juvenile arthritis damage index(JADI)is a tool that measures the degree of aggressiveness of the juvenile idiopathic arthritis(JIA)course and assesses articular[JADI-articular damage(JADI-A)]and extraarticular[JADI-extraarticular damage(JADI-E)]damage.While aggressive JIA often requires early bio-logic disease-modified antirheumatic drugs(bDMARDs),the utility of JADI as a predictor of treatment response remains underexplored.AIM To evaluate the potential of JADI as a predictor of bDMARD treatment response in JIA patients.METHODS This prospective study included 112 highly active non-systemic JIA biologic-naïve patients with a mean age of 12.2±4.6 years and a median disease duration of 2.5(interquartile range:1-5)years.Their clinical and radiological assessment,juvenile arthritis disease activity score 71,JADI-A,and JADI-E,were evaluated twice:Before the biologic initiation(baseline)and 12 months after(end of study).At baseline,50%had any damage,with 43%with articular damage and 23%with extraarticular damage.RESULTS During the study,JADI-A/JADI-E improved(33.9%/9.8%),worsened(8.9%/5.4%),or remained unchanged(57.1%/84.8%).Patients with baseline damage had higher markers of JIA activity:Polyarticular course,earlier onset age,ANA-positivity,and more active joints.Patients without initial structural damage(JADI“-”)were more likely(odds ratio=3.8,95%confidence interval:1.6-9.0,P<0.004)to achieve a low degree of activity or remission(46.2%),while on biological therapy,their scores were comparable to JADI-positive(18.3%).Pre-biological joint damage according to the JADI-A index(P=0.003),wrist(P=0.035),elbow(P=0.027),cervical spine limitation of motion(P=0.051),and erosions confirmed by magnetic resonance imaging(P=0.002),were associated with poor response to biological treatment and follow-up JIA activity.CONCLUSION Baseline structural damage in JIA is associated with diminished bDMARDs efficacy,increased disability,and shorter remission duration.JADI enhances conventional clinical risk stratification by facilitating timely initiation of bDMARDs,adherence to treat-to-target strategy and tailored patient care.
文摘Background : To study the relationships among emodin, synovial fibroblasts (FLSs), and macrophages (STMs) to provide guidance for the use of emodin in rheumatoid arthritis (RA) treatment. Methods : RA clinical samples from patients with different pathological processes were collected, and the correlations between the subsets of FLSs and STMs and pathological processes were analyzed via flow cytometry. In vitro experimental methods such as enzyme linked immunosorbent assay (ELISA), Western blotting, Transwell assays, CCK- 8 assays and cell coculture were used to assess cell proliferation, migration and secretion of inflammatory factors. A collagen- induced arthritis mouse model was constructed to investigate the therapeutic potential of emodin in RA by flow cytometry, micro- CT and staining. Results : Unique subsets of FLSs and STMs, namely, FAPα ^(+)THY1 − FLSs, FAPα ^(+)THY1 ^(+)FLSs, and MerTK ^(pos) TREM2 ^(high) STMs, were identified in synovial tissues from RA patients. The number of MerTK ^(pos) TREM2 ^(high) STMs was negatively correlated with the degree of damage in RA, while the number of FAPα ^(+)THY1 − FLSs was positively correlated with damage. On the one hand, emodin promoted the aggregation of MerTKposTREM2high STMs. Moreover, MerTK pos TREM2 high STM- mediated secretion of exosomes was promoted, which can inhibit the secretion of pro- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs and promote the secretion of anti- inflammatory factors by FAPα ^(+)THY1 ^(+)FLSs, thereby inhibiting FAPα ^(+)THY1 − FLS proliferation and migration, improving the local immune microenvironment, and inhibiting RA damage. Conclusion : Emodin was shown to regulate the aggregation of STM subsets and exosome secretion, affecting the secretion, proliferation and migration of inflammatory factors in FLS subsets, and ultimately achieving good therapeutic efficacy in RA patients, suggesting that it has important clinical value.
文摘Rheumatoid arthritis(RA)is a chronic autoimmune disease that affects approxi-mately 0.46%of the global population.Conventional therapeutics for RA,including disease-modifying antirheumatic drugs(DMARDs),nonsteroidal anti-inflammatory drugs(NSAIDs),and corticosteroids,frequently result in unintended adverse effects.Dexamethasone(DEX)is a potent glucocorticoid used to treat RA due to its anti-inflammatory and immunosuppressive properties.Liposomal delivery of DEX,particu-larly when liposomes are surface-modified with targeting ligands like peptides or sialic acid,can improve drug efficacy by enhancing its distribution to inflamed joints and minimizing toxicity.This study investigates the potential of liposomal drug delivery systems to enhance the efficacy and targeting of DEX in the treatment of RA.Results from various studies demonstrate that liposomal DEX significantly inhibits arthritis progression in animal models,reduces joint inflammation and damage,and alleviates cartilage destruction compared to free DEX.The liposomal formulation also shows better hemocompatibility,fewer adverse effects on body weight and immune organ index,and a longer circulation time with higher bioavailability.The anti-inflammatory mechanism is associated with the downregulation of pro-inflammatory cytokines like tumor necrosis factor-α(TNF-α)and B-cell-activating factor(BAFF),which are key players in the pathogenesis of RA.Additionally,liposomal DEX can induce the expres-sion of anti-inflammatory cytokines like interleukin-10(IL-10),which has significant anti-inflammatory and immunoregulatory properties.The findings suggest that lipo-somal DEX represents a promising candidate for effective and safe RA therapy,with the potential to improve the management of this debilitating disease by providing targeted delivery and sustained release of the drug.
基金the National Natural Science Foundation of China(Nos.22325703,22377071,U23A6009)Research Project Supported by Shanxi Scholarship Council of China(No.2022-002)+1 种基金the Shanxi Province Science Foundation(No.202203021221009)Shanxi Province Science and Technology activities for overseas people selected funding project(No.2024001)。
文摘Rheumatoid arthritis(RA) is a chronic inflammatory disease with multi-system damage and autoimmune features.The main clinical manifestations of RA include joint pain,swelling,and stiffness,and RA may lead to joint deformity and dysfunction in severe cases.The pathologic development of RA involves complex interactions of multiple biomarkers,and detecting a single biomarker may produce falsepositive results due to other confounding factors.Therefore,fluorescent probes that can detect multiple biomarkers simultaneously are crucial for precise RA diagnosis.Peroxynitrite(ONOO^(-)) and viscosity are inflammation-related factors in cells.In this study,we developed a dual responsive near-infrared fluorescent probe,YLS,for ONOO^(-) and viscosity.The probe features dual-channel turn-on fluorescence responses at 625 and 760 nm upon the presence of ONOO^(-) and viscosity,respectively.Supported by YLS,we found that during RA pathology,lymphocyte infiltration not only increases the concentration of proteins in the joint fluid resulting in elevated viscosity;at the same time,the overproduction of ONOO^(-) exacerbates oxidative stress and inflammatory responses.This multiparameter assay is expected to improve the diagnostic accuracy of the early stages of RA,thus providing a scientific basis for early intervention and personalized treatment.
基金Programa de Investigadores e Investigadoras of the Consejo Mexiquense de Ciencia y Tecnología(COMECYT)(EESP2024-0038)。
文摘Objective To perform an in silico bioinformatics analysis to identify differentially expressed microRNAs(miRNAs)implicated in rheumatoid arthritis(RA)pathogenesis and evaluate their potential as biomarkers for assessing therapeutic efficacy and monitoring acupuncture treatment.Methods miRNA microarray data(CEL and TXT formats)were acquired from human and murine RA models,with the latter undergoing acupuncture treatment.Data were normalized using the robust multi-array average(RMA)method and analyzed for differential expression.Differential expression analysis identified miRNAs through a comparative analysis of RA human tissues,acupuncture-treated murine RA models,and a bibliographic search for miRNAs implicated in RA pathogenesis and acupuncture treatment.Bioinformatics analysis was performed to identify potential target genes for each miRNA and signaling pathways via search tools for the Retrieval of Interacting Genes/Proteins(STRING)and ShinyGO.Gene-drug interaction analysis was performed through Drug-Gene Interaction Database(DGIdb)screening.Interaction networks were constructed with the Cytoscape v3.10.3 software.Results The hsa-miR-125a-5p and hsa-miR-125b-5p were identified as potential biomarkers associated with RA pathogenesis,presenting 468 and 455 target genes,respectively.These genes were enriched in 20 signaling pathways,including Janus kinasa-signal transducer and activator of transcription(JAK-STAT),mitogen-activated protein kinase(MAPK),phosphoinositide 3-kinase-protein kinase B(PI3K-Akt),and nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)signaling pathway,which have been associated with RA pathogenesis and progression.Drug-gene interaction networks revealed that 22 genes were significantly associated with 58 RA treatment drugs,among which 13 genes interacted with members of the hsa-miR-125 family.Conclusion The hsa-miR-125a-5p and hsa-miR-125b-5p demonstrate critical regulatory role in RA pathogenesis by modulating signaling pathways,including JAK-STAT,MAPK,PI3K-Akt,and NF-κB.Our findings show that the hsa-miR-125a-5p and hsa-miR-125b-5p exhibit differential expression patterns in response to pharmacological intervention in various diseases,including RA management.This suggests their potential roles as biomarkers for monitoring acupuncture treatment.Although existing evidence indicates that acupuncture can modify miRNA expression profiles,rigorous validation through biological models remains essential to confirm these results.
基金supported by NIH grants to M Bukrinsky P30 AI117970by the“Creation of Experimental Laboratories in the Natural Sciences Program”and Basic Research Program at the Higher School of Economics University.
文摘Eosinophils are multifunctional granulocytes that contribute to the initiation and modulation of inflammation.Accumulating evidence suggests that eosinophils are adaptable leukocytes that orchestrate the resolution of inflammatory responses.The most prevalent chronic inflammatory illness,rheumatoid arthritis(RA),is typified by persistent synovitis thatmakes it hard for the disease to go away on its own.Interestingly,a unique subset of eosinophils known as regulatory eosinophils has been found in RA patients’synovium,especially while the disease is in remission.Pro-resolving signatures of regulatory eosinophils in the synovium are distinct from those of their lung counterparts.The most recent research on eosinophils and their function in this disease pathogenesis is compiled in this review.Based on the role of regulatory eosinophils,a new pathological model of inflammation resolution in RA is proposed,and potential therapeutic strategies aimed at enhancing the action of regulatory eosinophils in RA are proposed.
文摘BACKGROUND Uveitis associated with juvenile idiopathic arthritis(U-JIA)is a vision-threatening condition.Estimates of prevalence of uveitis in patients with known juvenile idiopathic arthritis range from 11.6%to 30.0%.First-line treatment includes topical glucocorticoids;methotrexate(MTX)is used if topical corticosteroids are ineffective.In severe cases biological therapy like adalimumab may be prescribed.Complications,including vision loss,may be related to the disease and the ongoing treatment(topical corticosteroids).In severe cases surgical intervention is often necessary and is typically associated with poor vision outcomes.AIM To highlight the characteristics of operated U-JIA and to identify predictors of treatment failure.METHODS A retrospective cohort study analyzed data from 68 pediatric patients(under 18 years old)with U-JIA between 2007 and 2023.The study focused on demographic,clinical,treatment,and outcome variables.Survival analysis using Kaplan-Meier curves and the Cox proportional hazards model was performed to estimate the impact of surgical intervention on the course of uveitis and to identify predictors of treatment failure.RESULTS Eye surgery was performed on 17(25%)patients with U-JIA.It was associated with an earlier onset of uveitis(P=0.017),lower uveitis remission rate[odds ratio=5.29,95%confidence interval(CI):1.23-24.90,P=0.015],longer time to remission(P=0.036),reduced probability of achieving remission on MTX(P=0.033),and the necessity of the following treatment with biological diseasemodifying antirheumatic drugs(odds ratio=5.60;95%CI:1.11-55.19,P=0.021)with similar efficacy with biological treatments in operated and non-operated cases.Kaplan-Meier curves showed a borderline difference in time to surgical intervention based on the MTX initiation cutoff(P=0.065)although earlier MTX initiation might be associated with a higher likelihood of deferred surgery.CONCLUSION Operated patients exhibited an aggressive early-onset uveitis profile that needed early and more intensive treatment.Delayed and failed MTX treatment as well as delayed switching to biologics often required subsequent eye surgery.
基金supported by National Natural Science Foundation of China(82204766,82074122,82174078)Natural Science Foundation of Hunan province(2023JJ40490)+9 种基金Changjiang Scholars Program in Ministry Education,People’s Republic of China(T2019133)Xiaohe Sci-Tech Talents Special Funding under Hunan Provincial Sci-Tech Talents Sponsorship Program(2023TJ-X71)Science and Technology Innovation Program of Hunan Province(2024RC3201)Scientific research project of Hunan Provincial Education Department(21B0394,21A0239)Research Project of Hunan Administration of Traditional Chinese Medicine(B2023055)Changsha Outstanding Innovative Youth Training Program(kq2306021)Outstanding Youth Program of Hunan University of Chinese Medicine(202202)Postgraduate Innovation Project of Hunan University of Chinese Medicine(2024CX090)Open Foundation Project of Hunan International Joint Laboratory of Traditional Chinese Medicine(2022GJSYS02)Undergraduate Research and Innovation Foundation of Hunan University of Chinese Medicine(2023BKS097).
文摘Abnormal activation of macrophages and osteoclasts(OCs)contributes significantly to rheumatoid arthritis(RA)development by secretion of numerous inflammatory factors.Notably,these cells exhibit significant upregulation of folate receptor proteins on their surfaces.Unfortunately,there is a current lack of safe and effective therapeutic drugs for RA.Xuetongsu(XTS),a triterpenoid compound extracted fromKadsura heteroclita Roxb Craib,has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes(RAFLS).However,its clinical application is hampered by poor targeting and short half-life.To address these drawbacks,we previously developed a nano-drug system named HRPS nanoparticles(NPs),which effectively targets RAFLS and inhibits synovial hyperplasia.However,this system overlooked the essential role of OCs in RA-related bone destruction.Therefore,we designed a novel folate-modified biomimetic Prussian blue(PB)-XTS NP(FMPX NP)for the selective delivery of XTS into inflammatory macrophages and OCs.The NP exhibits an excellent photothermal effect when assisted by laser irradiation,facilitating targeted release of XTS within inflammatory macrophages and OCs.The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs.In vivo experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times,decreased hind foot swelling from 12.10±0.49 mm to 8.24±0.09 mm in the model group,and prevented bone damage.In conclusion,this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA.FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy,providing new insights for targeted drug therapies in clinical RA treatment.
文摘Arthritis is an inflammatory joint disorder that progressively impairs function and diminishes quality of life.Conventional therapies often prove ineffective,as oral administration lacks specificity,resulting in off-target side effects like hepatotoxicity and GIT-related issues.Intravenous administration causes systemic side effects.The characteristic joint-localized symptoms such as pain,stiffness,and inflammation make the localized drug delivery suitable for managing arthritis.Topical/transdermal/intraarticular routes have become viable options for drug delivery in treating arthritis.However,challenges with those localized drug delivery routes include skin barrier and cartilage impermeability.Additionally,conventional intra-articular drug delivery also leads to rapid clearance of drugs from the synovial joint tissue.To circumvent these limitations,researchers have developed nanocarriers that enhance drug permeability through skin and cartilage,influencing localized action.Gel-based nanoengineered therapy employs a gel matrix to incorporate the drug-encapsulated nanocarriers.This approach combines the benefits of gels and nanocarriers to enhance therapeutic effects and improve patient compliance.This review emphasizes deep insights into drug delivery using diverse gelbased novel nanocarriers,exploring their various applications embedded in hyaluronic acid(biopolymer)–based gels,carbopol-based gels,and others.Furthermore,this review discusses the influence of nanocarrier pharmacokinetics on the localization and therapeutic manipulation of macrophages mediated by nanocarriers.The ELVIS(extravasation through leaky vasculature and inflammatory cell-mediated sequestration)effect associated with arthritis is advantageous in drug delivery.Simply put,the ELVIS effect refers to the extravasation of nanocarriers through leaky vasculatures,which finally results in the accumulation of nanocarriers in the joint cavity.
文摘BACKGROUND Chronic idiopathic uveitis(CIU)and juvenile idiopathic arthritis-associated uveitis(U-JIA)are both vision-threatening conditions that share similar autoimmune mechanisms,but treatment approaches differ significantly.In managing U-JIA,various treatment options are employed,including biological and non-biological disease-modifying anti-rheumatic drugs.These drugs are effective in clinical trials.Given the lack of established diagnostic and treatment guidelines as well as the limited number of therapeutic options available,patients with CIU frequently do not receive optimal and timely immunosuppression.This study highlighted the necessity for additional research to develop novel diag-nostic techniques,targeted therapies,and enhanced treatment outcomes for young individuals with CIU.AIM To compare the characteristics and outcomes of U-JIA and CIU.METHODS A retrospective cohort study analyzed data from 110 pediatric patients(under 18 years old)with U-JIA and 40 pediatric patients with CIU.Data was collected between 2012 and 2023.The study focused on demographic,clinical,treatment,and outcome variables.RESULTS The median onset age of arthritis was 6.4 years(2.7 years;9.3 years).In 28.2%of cases uveitis preceded the onset of arthritis.In 17.3%of cases it occurred simultan-eously.In 53.6%of cases it followed arthritis.Both groups had similar onset ages,antinuclear antibodies/human leukocyte antigen positivity rates,and ESR levels,with a slight predominance of females(60.9%vs 42.5%,P=0.062),and higher C-reactive protein levels in the U-JIA group.Anterior uveitis was more prevalent in patients with U-JIA(P=0.023),although the frequency of symptomatic,unilateral,and complicated forms did not differ significantly.The use of methotrexate(83.8%vs 96.4%)and biologics(64.7%vs 82.1%)was comparable,as was the rate of remission on methotrexate treatment(70.9%vs 56.5%)and biological therapy(77.8%vs 95%),but a immunosuppressive treatment delay in CIU observed.Patients with CIU were less likely to receive methotrexate[hazard ratio(HR)=0.48,P=0.005]or biological treatment(HR=0.42,P=0.004),but they were more likely to achieve remission with methotrexate(HR=3.70,P=0.001).CONCLUSION Treatment of uveitis is often limited to topical measures,which can delay systemic therapy and affect the outcome.Methotrexate and biological agents effectively manage eye inflammation.It is essential to develop standardized protocols for the diagnosis and management of uveitis,and collaboration between rheumatologists and ophthal-mologists is needed to achieve optimal outcomes in the treatment of CIU.
文摘BACKGROUND Children with juvenile idiopathic arthritis(JIA)and inflammatory bowel disease(IBD)face an elevated risk of severe infection owing to their diseases and the immunosuppressive treatment for disease control.AIM To compare scheduled vaccination coverage and the levels of post-vaccine antibodies against measles,mumps,rubella(MMR)and hepatitis B in pediatric patients with IBD and JIA.METHODS A comparative cohort study included 97 patients with IBD and 170 patients with JIA.Vaccination history was obtained from medical records,while post-vaccination immunity was assessed prospectively by measuring specific IgG antibody titers using enzyme-linked immunosorbent assays(Vector-Best JSC,Russia;IBL International,Germany)during routine visits between January 2022 and April 2023.RESULTS A complete two-dose MMR course had been administered to 66.3%of IBD patients and 55.9%of JIA patients(P=0.121).By contrast,the three-dose hepatitis B schedule was completed in 74.2%of IBD and 100%of JIA patients(P<0.001).Protective level of anti-vaccine antibodies against measles(47.7%vs 57.7%;P=0.168);mumps(75.3%vs 80.0%;P=0.366);rubella(74.4%vs 98.2%;P<0.0001);and hepatitis B(44.8%vs 50.0%;P=0.514)were detected in IBD and JIA patients,respectively.CONCLUSION Patients with IBD and JIA demonstrated different vaccination coverage patterns and levels of anti-vaccine antibodies.Routine baseline serology and timely booster vaccination should be implemented for all pediatric patients receiving chronic immunosuppression.
