RESUMEN
Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.
Asunto(s)
Artritis Reumatoide , Desoxiglucosa , Dexametasona , Glucosa , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Animales , Glucosa/metabolismo , Dexametasona/farmacología , Dexametasona/uso terapéutico , Ratones , Desoxiglucosa/farmacología , Inflamación/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Polímeros/química , Ácido Hialurónico/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Masculino , Humanos , Proliferación Celular/efectos de los fármacosRESUMEN
BACKGROUND AND AIMS: Rheumatoid arthritis (RA) manifests through various symptoms and systemic manifestations. Diagnosis involves serological markers like rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). Past studies have shown the added value of likelihood ratios (LRs) in result interpretation. LRs can be combined with pretest probability to estimate posttest probability for RA. There is a lack of information on pretest probability. This study aimed to estimate pretest probabilities for RA. MATERIALS AND METHODS: This retrospective study included 133 consecutive RA patients and 651 consecutive disease controls presenting at a rheumatology outpatient clinic. Disease characteristics, risk factors associated with RA and laboratory parameters were documented for calculating pretest probabilities and LRs. RESULTS: Joint involvement, erosions, morning stiffness, and positive CRP, ESR tests significantly correlated with RA. Based on these factors, probabilities for RA were estimated. Besides, LRs for RA were established for RF and ACPA and combinations thereof. LRs increased with antibody levels and were highest for double high positivity. Posttest probabilities were estimated based on pretest probability and LR. CONCLUSION: By utilizing pretest probabilities for RA and LRs for RF and ACPA, posttest probabilities were estimated. Such approach enhances diagnostic accuracy, offering laboratory professionals and clinicians insights in the value of serological testing during the diagnostic process.
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Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Factor Reumatoide , Humanos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Factor Reumatoide/sangre , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anticuerpos Antiproteína Citrulinada/sangre , Masculino , Funciones de Verosimilitud , Probabilidad , Adulto , Autoanticuerpos/sangre , AncianoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Zhubi Decoction (ZBD) is a modified formulation derived from the classic traditional Chinese medicine prescription "Er-Xian Decoction" documented in the esteemed "Clinical Manual of Chinese Medical Prescription". While the utilization of ZBD has exhibited promising clinical outcomes in treating rheumatoid arthritis (RA), the precise bioactive chemical constituents and the underlying mechanisms involved in its therapeutic efficacy remain to be comprehensively determined. AIM OF THE STUDY: This study aims to systematically examine ZBD's pharmacological effects and molecular mechanisms for RA alleviation. MATERIALS AND METHODS: Utilizing the collagen-induced arthritis (CIA) rat model, we comprehensively evaluated the anti-rheumatoid arthritis effects of ZBD in vivo through various indices, such as paw edema, arthritis index, ankle diameter, inflammatory cytokine levels, pathological conditions, and micro-CT analysis. The UPLC-MS/MS technique was utilized to analyze the compounds of ZBD. The potential therapeutic targets and signaling pathways of ZBD in the management of RA were predicted using network pharmacology. To analyze comprehensive metabolic profiles and identify underlying metabolic pathways, we conducted a serum-based widely targeted metabolomics analysis utilizing LC-MS technology. Key targets and predicted pathways were further validated using immunofluorescent staining, which integrated findings from serum metabolomics and network pharmacology analysis. Additionally, we analyzed the gut microbiota composition in rats employing 16 S rDNA sequencing and investigated the effects of ZBD on the microbiota of CIA rats through bioinformatics and statistical methods. RESULTS: ZBD exhibited remarkable efficacy in alleviating RA symptoms in CIA rats without notable side effects. This included reduced paw redness and swelling, minimized joint damage, improved the histopathology of cartilage and synovium, mitigated the inflammatory state, and lowered serum concentrations of cytokines TNF-α, IL-1ß and IL-6. Notably, the effectiveness of ZBD was comparable to MTX. Network pharmacology analysis revealed inflammation and immunity-related signaling pathways, such as PI3K/AKT, MAPK, IL-17, and TNF signaling pathways, as vital mediators in the effectual mechanisms of ZBD. Immunofluorescence analysis validated ZBD's ability to inhibit PI3K/AKT pathway proteins. Serum metabolomics studies revealed that ZBD modulates 170 differential metabolites, partially restored disrupted metabolic profiles in CIA rats. With a notable impact on amino acids and their metabolites, and lipids and lipid-like molecules. Integrated analysis of metabolomics and network pharmacology identified 6 pivotal metabolite pathways and 3 crucial targets: PTGS2, GSTP1, and ALDH2. Additionally, 16 S rDNA sequencing illuminated that ZBD mitigated gut microbiota dysbiosis in the CIA group, highlighting key genera such as Ligilactobacillus, Prevotella_9, unclassified_Bacilli, and unclassified_rumen_bacterium_JW32. Correlation analysis disclosed a significant link between 47 distinct metabolites and specific bacterial species. CONCLUSION: ZBD is a safe and efficacious TCM formulation, demonstrates efficacy in treating RA through its multi-component, multi-target, and multi-pathway mechanisms. The regulation of inflammation and immunity-related signaling pathways constitutes a crucial mechanism of ZBD's efficacy. Furthermore, ZBD modulates host metabolism and intestinal flora. The integrated analysis presents experimental evidence of ZBD for the management of RA.
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Artritis Experimental , Artritis Reumatoide , Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Metabolómica , Farmacología en Red , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Masculino , Ratas , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Citocinas/sangre , Citocinas/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
This review delves into the effects of autoimmune conditions like rheumatoid arthritis, inflammatory disorders such as irritable bowel syndrome, cardiovascular disease, diabetes, infectious ailments like human immunodeficiency virus, and their medications on periodontal therapy outcomes. It also explores the influence of hormones. Understanding these systemic factors is crucial for optimizing periodontal health and treatment efficacy. The review underscores the necessity of considering these variables in periodontal care. Other vital systemic factors are addressed elsewhere in this special edition.
Asunto(s)
Enfermedades Periodontales , Humanos , Enfermedades Periodontales/terapia , Pronóstico , Enfermedades Cardiovasculares , Resultado del Tratamiento , Artritis Reumatoide , Síndrome del Colon Irritable/terapia , Enfermedades Autoinmunes , Infecciones por VIH/complicaciones , Diabetes Mellitus , Factores de RiesgoRESUMEN
OBJECTIVES: Exploring the effect of resilience and self-efficacy in mediating the chain between fatigue and quality of life(QOL) in patients with rheumatoid arthritis (RA). METHODS: From June 2022 to November 2022, 423 RA patients were chosen by a convenience sample method from two tertiary care facilities in Chengdu, Sichuan Province. General Information Questionnaire, Bristol Multidimensional Scale of Fatigue in Patients with Rheumatoid Arthritis, SF-12 Health Survey Short Form, Chinese version of the ten-item psychological Resilience Scale, and Chinese-language Arthritis Self-Efficacy Scale, an 8-element version, were among the questionnaires used. RESULTS: In the physical component summary( PCS), self-efficacy, psychological resilience, and self-efficacy were all significantly mediated by fatigue (total effect mediated 8.88%). In the mental component summary (MCS), fatigue (total effect mediated 10.79%), self-efficacy (total effect mediated 8.99%), psychological resilience, and self-efficacy (total effect mediated 2.01%) were all significantly mediated by fatigue. CONCLUSION: Fatigue in RA patients can affect the quality of life both directly and indirectly through the mediating effects of psychological resilience, self-efficacy, and the chain mediating effect of psychological resilience-self-efficacy.
Asunto(s)
Artritis Reumatoide , Fatiga , Calidad de Vida , Resiliencia Psicológica , Autoeficacia , Humanos , Artritis Reumatoide/psicología , Artritis Reumatoide/complicaciones , Fatiga/psicología , Fatiga/etiología , Femenino , Masculino , Persona de Mediana Edad , Adulto , Encuestas y Cuestionarios , China , AncianoRESUMEN
OBJECTIVE: To compare a 0-10 physician subglobal estimate of inflammatory activity (DOCINF) on a RheuMetric checklist to a formal swollen joint count (SJC) and other rheumatoid arthritis (RA) Core data set measures in a disease activity score 28 (DAS28), clinical disease activity index (CDAI), and simplified disease activity index (SDAI) in patients with RA, recognizing that RA measures, index scores and physician global assessment (DOCGL) may be elevated by joint damage and patient distress, independent of inflamamtory activity, and that formal joint counts are not recorded at most routine care visits. METHODS: A cross-sectional study at a routine care visit included a RheuMetric checklist completed by a rheumatologist, with four 0-10 visual numeric scales (VNS) for DOCGL, and three sub-global estimates for inflammatory activity (DOCINF), joint damage (DOCDAM), and patient distress (DOCDIS), e.g., anxiety, depression, and/or fibromyalgia, etc. Variation in SJC according to other individual measures in the DAS28, CDAI, and SDAI, and in the indices was analyzed using Spearman correlation coefficients and regressions with and without DOCINF as an independent variable. RESULTS: In 173 patients with long disease duration, regressions which included individual DAS28, CDAI or SDAI measures and added DOCINF as an independent variable explained 46 % of variation in SJC, compared to 23 % if DOCINF was not included. DOCINF was more explanatory of SJC than even the DAS28 or CDAI indices themselves, although SJC is a component of these indices. CONCLUSION: In routine care RA patients with long disease duration, DOCINF depicts SJC as effectively as RA indices which require 90-100 seconds to record, and may provide a feasible, informative quantitative clinical measure without recording formal joint counts.
Asunto(s)
Artritis Reumatoide , Índice de Severidad de la Enfermedad , Humanos , Artritis Reumatoide/fisiopatología , Estudios Transversales , Femenino , Masculino , Persona de Mediana Edad , Articulaciones/fisiopatología , Adulto , AncianoRESUMEN
OBJECTIVE: This study aimed to investigate the current status and performance of machine learning (ML) approaches in providing reproducible treatment response predictions. METHODS: This systematic review was conducted in accordance with the PRISMA statement and the CHARMS checklist. We searched PubMed, Cochrane Library, Web of Science, Scopus, and EBSCO databases for cohort studies that derived and/or validated ML models focused on predicting rheumatoid arthritis (RA) treatment response. We extracted data and critically appraised studies based on the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) and Prediction Model Risk of Bias Assessment Tool (PROBAST) guidelines. RESULTS: From 210 unduplicated records identified by the literature search, we retained 29 eligible studies. Of these studies, 10 developed a predictive model and reported a mean adherence to the TRIPOD guidelines of 45.6 % (95 % CI: 38.3-52.8 %). The remaining 19 studies not only developed a predictive model but also validated it externally, with a mean adherence of 42.9 % (95 % CI: 39.1-46.6 %). Most of the articles had an unclear risk of bias (41.4 %), followed by a high risk of bias, which was present in 37.9 %. CONCLUSIONS: In recent years, ML methods have been increasingly used to predict treatment response in RA. Our critical appraisal revealed unclear and high risk of bias in most of the identified models, suggesting that researchers can do more to address the risk of bias and increase transparency, including the use of calibration measures and reporting methods for handling missing data. FUNDING: None.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Aprendizaje Automático , Artritis Reumatoide/tratamiento farmacológico , Humanos , Antirreumáticos/uso terapéutico , Resultado del Tratamiento , PronósticoRESUMEN
OBJECTIVES: To explore the agreement between patient-reported flare status and clinically significant flare status in patients with rheumatoid arthritis (RA) in sustained remission. METHOD: Patients with RA in remission for ≥12 months on stable treatment were included in the ARCTIC REWIND tapering trials and pooled 12-month data used in current analyses. Patient-reported flare status was assessed according to the Outcome Measures in Rheumatology flare questionnaire; 'Are you having a flare of your RA at this time?' (yes/no). A clinically significant flare was defined as a combination of Disease Activity Score (DAS) >1.6, increase in DAS of ≥0.6 and 2 swollen joints, or the rheumatologist and patient agreed that a clinically significant flare had occurred. Agreement coefficient, sensitivity, specificity and predictive values of patient-reported flare status with regard to clinically significant flare status were determined. RESULTS: Of 248 patients, 64% were women, age 56.1 (11.8) years, disease duration 4.1 (2.8-7.4) years, DAS 0.8 (0.3). 35% of patients reported a flare at least once, clinically significant flares were recorded in 21%. 48/53 clinically significant flares (91%) led to an intensification of disease-modifying antirheumatic drugss. In 621/682 (91%) visits, patient-reported and clinically significant flare status were in agreement, agreement coefficient 0.89. Sensitivity and specificity were both 91%, positive predictive value of patient-reported flare status 46% and negative predictive value 99%. CONCLUSION: Among patients in sustained remission, patient-reported flare status was accurate in ruling out a clinically significant flare. About half of the patient-reported flares were assessed to be clinically significant. These findings support a potential for using patient-reported flare status in remote monitoring of patients with RA in sustained remission.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Medición de Resultados Informados por el Paciente , Inducción de Remisión , Índice de Severidad de la Enfermedad , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Antirreumáticos/uso terapéutico , Anciano , Brote de los Síntomas , Adulto , Resultado del Tratamiento , Encuestas y CuestionariosRESUMEN
Background: Safety recommendations for Janus kinase inhibitors (JAKi) issued by the European Medical Agency (EMA) in 2023 could potentially influence treatment patterns for rheumatoid arthritis (RA) drugs, but little is known about the impact of these recommendations in routine clinical care. Methods: We retrospectively analyzed the German RHADAR rheumatology database for adult patients with RA and documentation of a new therapy with a JAKi, tumor necrosis factor inhibitor (TNFi), or interleukin-6 receptor inhibitor (IL-6Ri). Data were grouped into half-yearly intervals from quarter (Q)2/2020 to Q3/2023. The period from Q4/2022 to Q1/2023 immediately followed the initial EMA endorsement of Pharmacovigilance Risk Assessment Committee (PRAC) recommendations and Q2/2023-Q3/2023 immediately followed the direct healthcare provider communication (DHPC) containing the new safety JAKi recommendations. Results: Between April 1, 2020 and September 23, 2023, 3008 newly initiated therapies for TNFi (1499 [49.8%]), JAKi (1126 [37.4%]), and IL-6Ri (383 [12.7%]) were documented by the treating physicians. JAKi were increasingly used in the first two half-year periods (from 29.7% of these therapies in Q2/2020-Q3/2020 to 46.7% in Q2/2021-Q3/2021; odds ratio [OR] 2.08; p<0.001). The proportion of initiated JAKi therapies decreased significantly after the PRAC recommendations (32.9%; OR vs peak 0.56; p=0.001) and the DHPC letter (26.1%; OR vs peak 0.40; p<0.001). JAKi were more likely to be used as >3rd-line therapy in later time periods. Conclusions: This exploratory study suggests that EMA safety recommendations for JAKi influenced treatment patterns of RA patients who received JAKi in Germany. Additional studies will be needed to confirm these findings.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Inhibidores de las Cinasas Janus , Humanos , Estudios Retrospectivos , Artritis Reumatoide/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Anciano , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Farmacovigilancia , Adulto , Europa (Continente) , AlemaniaRESUMEN
BACKGROUND: Equivalent efficacy and comparable pharmacokinetic, immunogenicity, and safety profiles of the biosimilar BAT1806/BIIB800 and reference tocilizumab (TCZ) in participants with moderate-to-severe rheumatoid arthritis (RA) have been reported up to week 24 (treatment period [TP] 1) of the phase 3 study. Here we present results for TP2 (study weeks 24-48). METHODS: In this phase 3, multicenter, multiregional, double-blind, active-controlled, equivalence study, participants with active RA despite methotrexate were randomized (1:1:2) to intravenous administration of 8 mg/kg TCZ every 4 weeks to week 48 (TCZ group), or TCZ to week 24 followed by BAT1806/BIIB800 to week 48 (TCZ to BAT1806/BIIB800 group), or BAT1806/BIIB800 to week 48 (BAT1806/BIIB800 group). Efficacy in TP2 was evaluated using American College of Rheumatology (ACR) response criteria (ACR20/50/70) and change from baseline in Disease Activity Score on 28 joints (DAS28). Pharmacokinetics (trough levels), safety, and immunogenicity were also evaluated. RESULTS: Of 621 randomized participants, 577 (92.9%) completed TP1 and entered TP2 (TCZ: N = 145 [93.5%]; TCZ to BAT1806/BIIB800: N = 142 [92.2%]; BAT1806/BIIB800: N = 290 [92.9%]). Proportions of ACR20 responders were similar between treatment groups throughout TP2 (87.8%, 90.3%, and 90.4%, respectively, at week 48), as were proportions of ACR50 and ACR70 responders, and reduction in DAS28. Drug trough levels and antidrug antibody incidences were comparable between the treatment groups. Adverse events were balanced across the treatment groups and no fatal events were reported. CONCLUSION: In TP2, efficacy, safety, immunogenicity, and pharmacokinetic profiles were comparable between the TCZ, TCZ to BAT1806/BIIB800, and BAT1806/BIIB800 groups. TRIAL REGISTRATION: NCT03830203 and EudraCT 2018-002202-31.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Antirreumáticos , Artritis Reumatoide , Biosimilares Farmacéuticos , Metotrexato , Humanos , Artritis Reumatoide/tratamiento farmacológico , Masculino , Metotrexato/uso terapéutico , Metotrexato/farmacocinética , Metotrexato/administración & dosificación , Femenino , Método Doble Ciego , Persona de Mediana Edad , Biosimilares Farmacéuticos/farmacocinética , Biosimilares Farmacéuticos/uso terapéutico , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/efectos adversos , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapéutico , Antirreumáticos/administración & dosificación , Adulto , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Resultado del Tratamiento , Anciano , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To explore the efficacy and safety of combination therapy with methotrexate (MTX) plus hydroxychloroquine (HCQ) vs. MTX monotherapy in patients with rheumatoid arthritis (RA). METHODS: Sixty patients without prior RA treatments were randomly allocated in a 1:1 ratio to two groups: one receiving MTX plus HCQ, and the other receiving MTX monotherapy. We conducted a comparative analysis before and after the 12-week trial, evaluating the visual analogue scale (VAS), the disease activity score in 28 joints (DAS), serum inflammatory factor (including serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), as well as the outcome of the World Health Organization Quality of Life Brief Version questionnaire (WHOQOL-BREF) and the treatment-emergent adverse events (TEAEs) for all the participants in the study. RESULTS: At the 12th week of the trial, a more remarkable decrease in pain score (VAS), disease activity score (DAS), and serum inflammatory factor levels could be noticed in individuals on the combination therapy. The quality of life score was as well found to be higher in the MTX + HCQ group than the MTX monotherapy group. The incidence of adverse reactions in the MTX + HCQ and the MTX monotherapy groups were 10.00% and 6.67%, respectively. However, no statistical significance could be observed (p > .05). CONCLUSION: In our study, both the MTX + HCQ combination therapy and MTX monotherapy demonstrated improvements in symptoms, conditions and quality of life for patients with RA. Notably, the combination therapy could achieve better outcomes across all indices compared to MTX monotherapy, highlighting its potential as the optimal first-line treatment for RA. © 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.
Asunto(s)
Antirreumáticos , Artritis Reumatoide , Quimioterapia Combinada , Hidroxicloroquina , Metotrexato , Calidad de Vida , Humanos , Metotrexato/efectos adversos , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Hidroxicloroquina/efectos adversos , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/sangre , Femenino , Antirreumáticos/efectos adversos , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Masculino , Resultado del Tratamiento , Persona de Mediana Edad , Adulto , Factores de Tiempo , Dimensión del Dolor , Biomarcadores/sangre , Anciano , Mediadores de Inflamación/sangreRESUMEN
Siweixizangmaoru decoction (SXD) is widely used as an anti-rheumatoid arthritis (RA) in Tibet, however, the specific anti-inflammatory mechanism of SXD is still unclear. This research attempts to examine the efficacy and possible mechanisms of SXD in treating RA. The primary chemical components of SXD were identified using UHPLC-Q-Exactive Orbitrap MS. We established a lipopolysaccharide (LPS)-induced RAW264.7 macrophage inflammatory injury model to explore the anti-inflammatory mechanism of SXD and validated it through in vivo experiments. According to our research in vitro as well as in vivo, SXD exhibits anti-inflammatory qualities. SXD can suppress nitric oxide (NO) and pro-inflammatory factor production in RAW264.7 cells activated by LPS. The mechanism underlying this effect might be connected to the janus tyrosine kinase 2-signal transducer and activator of transcription 3 (JAK2/STAT3) and nuclear factor-κB (NF-κB) signaling pathways. In vivo, SXD alleviates joint swelling, decreases the generation of inflammatory factors in the serum, lowers oxidative stress, and improves joint damage. In short, SXD improves joint degeneration and lowers symptoms associated with RA by regulating inflammation via the suppression of NF-κB and JAK2/STAT3 signaling pathway activation.
Asunto(s)
Antiinflamatorios , Artritis Experimental , Medicamentos Herbarios Chinos , Janus Quinasa 2 , FN-kappa B , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Janus Quinasa 2/metabolismo , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Células RAW 264.7 , Ratones , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Artritis Experimental/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ratas , Ratas Sprague-Dawley , Colágeno Tipo II/metabolismo , Lipopolisacáridos , Óxido Nítrico/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Estrés Oxidativo/efectos de los fármacos , Medicina Tradicional Tibetana/métodosRESUMEN
OBJECTIVES: To evaluate the tuberculin skin test (TST) conversion in chronic inflammatory arthropathies (CIA) patients on TNFα inhibitors (TNFi) and without previous latent tuberculosis infection (LTBI) treatment. METHODS: Patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) with negative LTBI were retrospectively evaluated for TST conversion and active tuberculosis (TB) after six months of exposition to TNFi. Two groups were compared: patients who repeated TST (TST-repetition) during the follow-up and patients who did not (non-TST-repetition). RESULTS: A total of 355 CIA patients on TNFi were screened and 138 (38.9%) did not fulfill the inclusion criteria. Of the remaining 217 CIA patients, 81 (37.3%) repeated TST during TNFi treatment. TST conversion rate was observed in 18 (22.2%) patients without significant differences among CIA (p = 0.578). The number of TB cases was low (n = 10; 4.6%) and was similar in TST-repetition and non-TST-repetition groups [2 (2.5%) vs. 8 (5.9%), p = 0.328]. Of note, 30% of active TB occurred early (6-12 months of TNFi exposure) and the median (full range) time to incident TB was 1.3 (0.6-10.6) years, whereas the median (full range) time to TST repetition was later [3.3 (0.5-13.4) years]. The incidence of active TB was lower among RA patients than AS patients [342 (95% CI 41 - 1446) vs. 1.454 (95% CI 594-2993)/100,000 patient-years, p = 0.049]. CONCLUSION: These results indicate that TST repetition is associated with a high conversion rate, suggesting the need for recommended treatment. The delayed repetition of TST and low number of active TB cases hampered the evaluation of this strategy effectiveness to prevent active infection. Larger studies with systematic repetition patterns are necessary. In addition, the study highlights the need for a greater surveillance for TB in AS patients.
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Artritis Psoriásica , Artritis Reumatoide , Tuberculosis Latente , Espondilitis Anquilosante , Prueba de Tuberculina , Factor de Necrosis Tumoral alfa , Humanos , Estudios Retrospectivos , Artritis Reumatoide/tratamiento farmacológico , Masculino , Femenino , Artritis Psoriásica/tratamiento farmacológico , Persona de Mediana Edad , Espondilitis Anquilosante/tratamiento farmacológico , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/epidemiología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Anciano , Estudios de Cohortes , Enfermedades Endémicas , Inhibidores del Factor de Necrosis Tumoral/uso terapéuticoRESUMEN
BACKGROUND: Ankylosing spondylitis (AS) has been known to have auto-inflammatory nature; hence, the efficacy of autoantibodies is low. However, studies on autoantibodies are ongoing, with some studies showing associations. Previous studies showed that anti-protein phosphatase magnesium-dependent 1A (PPM1A) IgG was increased in patients with AS and associated with radiographic progression. However, the diagnostic usefulness was limited due to relatively low sensitivity and specificity. This pilot study evaluated the diagnostic utility of anti-PPM1A-IgM and anti-PPM1A-IgG in patients with active AS. METHODS: Serum samples were obtained from the registry cohort of a single tertiary center in Korea. Serum levels of anti-PPM1A-IgG/IgM were measured by direct ELISA. Receiver operating characteristic (ROC) analysis was used to predict the diagnostic sensitivity and specificity of serum anti-PPM1A-IgG/IgM. RESULTS: Samples were collected from 28 patients with active AS, 16 healthy controls (HCs), and 28 patients with rheumatoid arthritis (RA). Although total serum IgM was lower in the RA and AS groups than in the HC group, anti-PPM1A-IgM was significantly lower in the AS group than in the other groups. In evaluating the diagnostic utility of anti-PPM1A-IgG/IgM for AS patients compared with HCs, the area under the curve (AUC) of anti-PPM1A-IgM was 0.998 (sensitivity 96.4%, specificity 100.0%). When ROC analysis of anti-PPM1A-IgM for AS patients compared with RA patients was conducted, sensitivity was 78.6% and specificity was 71.4%, with an AUC of 0.839. CONCLUSION: Decreased anti-PPM1A-IgM levels in AS patients suggests a potential role for anti-PPM1A-IgM in the diagnosis of active AS.
Asunto(s)
Autoanticuerpos , Biomarcadores , Inmunoglobulina M , Proteína Fosfatasa 2C , Curva ROC , Sensibilidad y Especificidad , Espondilitis Anquilosante , Humanos , Espondilitis Anquilosante/sangre , Espondilitis Anquilosante/diagnóstico , Masculino , Biomarcadores/sangre , Femenino , Adulto , Inmunoglobulina M/sangre , Autoanticuerpos/sangre , Proteína Fosfatasa 2C/sangre , Persona de Mediana Edad , Inmunoglobulina G/sangre , Estudios de Casos y Controles , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico , Proyectos Piloto , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease accompanied by local and systemic bone loss. FcγRs, especially FcγRIIa (hFcγRIIa), have been implicated in the pathogenesis of RA. However, the contribution of hFcγRIIa to bone loss has not been fully elucidated. In the present study, we demonstrated the double-edged sword role of hFcγRIIa on osteoclast differentiation through investigations involving hFcγRIIa-transgenic (hFcγRIIa-Tg) mice. Our findings reveal that hFcγRIIa-Tg mice, previously shown to exhibit heightened susceptibility to collagen-induced arthritis (CIA), displayed increased osteoporosis during CIA or at advanced ages (40 weeks), accompanied by heightened in vivo osteoclast differentiation. Notably, bone marrow cells from hFcγRIIa-Tg mice exhibited enhanced efficiency in differentiating into osteoclasts and bone resorption in vitro compared to wild-type mice when stimulated with receptor activators of NF-κB ligand (RANKL). Additionally, hFcγRIIa-Tg mice exhibited augmented sensitivity to RANKL-induced bone loss in vivo, highlighting the osteoclast-promoting role of hFcγRIIa. Mechanistically, bone marrow cells from hFcγRIIa-Tg mice displayed heightened Syk self-activation, leading to mTOR-pS6 pathway activation, thereby promoting RANKL-driven osteoclast differentiation. Intriguingly, while hFcγRIIa crosslinking hindered RANKL-induced osteoclast differentiation, it activated the kinase cAbl, subsequently triggering STAT5 activation and inhibiting the expression of osteoclast-associated genes. This study provides novel insights into hFcγRIIa-mediated osteoclast biology, suggesting promising therapeutic targets for managing bone remodeling disorders.
Asunto(s)
Resorción Ósea , Diferenciación Celular , Ratones Transgénicos , Osteoclastos , Osteogénesis , Receptores de IgG , Animales , Receptores de IgG/genética , Receptores de IgG/metabolismo , Ratones , Osteoclastos/metabolismo , Osteogénesis/genética , Resorción Ósea/genética , Resorción Ósea/metabolismo , Ligando RANK/metabolismo , Ligando RANK/genética , Artritis Experimental/inmunología , Artritis Experimental/genética , Transducción de Señal , Artritis Reumatoide/metabolismo , Artritis Reumatoide/inmunología , Artritis Reumatoide/genética , Osteoporosis/genética , Osteoporosis/etiología , Osteoporosis/metabolismoRESUMEN
miRNAs constitute fine-tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA); however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. Previous studies have shown that Mir221/222 expression is upregulated in RA SFs. Here, we demonstrate that TNF and IL-1ß but not IFN-γ activated Mir221/222 gene expression in murine SFs. SF-specific overexpression of Mir221/222 in huTNFtg mice led to further expansion of SFs and disease exacerbation, while its total ablation led to reduced SF expansion and attenuated disease. Mir221/222 overexpression altered the SF transcriptional profile igniting pathways involved in cell cycle and ECM (extracellular matrix) regulation. Validation of targets of Mir221/222 revealed cell cycle inhibitors Cdkn1b and Cdkn1c, as well as the epigenetic regulator Smarca1. Single-cell ATAC-seq data analysis revealed increased Mir221/222 gene activity in pathogenic SF subclusters and transcriptional regulation by Rela, Relb, Junb, Bach1, and Nfe2l2. Our results establish an SF-specific pathogenic role of Mir221/222 in arthritis and suggest that its therapeutic targeting in specific subpopulations could lead to novel fibroblast-targeted therapies.
Asunto(s)
MicroARNs , Animales , Ratones , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Ensamble y Desensamble de Cromatina , Fibroblastos/metabolismo , Regulación de la Expresión Génica , MicroARNs/metabolismo , MicroARNs/genética , Membrana Sinovial/metabolismo , Membrana Sinovial/patologíaRESUMEN
BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune, inflammatory joint disease. There is growing evidence that ferroptosis is involved in the pathogenesis of RA. This study aimed to search for diagnostic markers of ferroptosis in RA and to analyse the potential mechanisms and clinical value. MATERIALS AND METHODS: RA-associated datasets were used from the publicly available GEO database. Three methods of machine learning were applied to screen biomarkers. The diagnostic efficacy of the results was also verified by receiver operating characteristic (ROC) curve, external dataset, qRT-PCR and Western blot. Enrichment analysis was performed in this process, while protein-protein interaction (PPI) analysis and immune infiltration correlation analysis were performed using biomarkers, and competing endogenous RNA (ceRNA) networks were constructed to search for prospective therapeutic targets. RESULTS: MMP13 and GABARAPL1 can be used as ferroptosis diagnostic genes in RA. The ROC curve and PPI result demonstrated that MMP13 and GABARAPL1 had an excellent diagnostic value. The results of signature genes in the external dataset, qRT-PCR and Western blot further confirm our findings. The enrichment analysis showed that p53, MAPK and NOD-like receptor signalling pathways may be involved in the process of ferroptosis in RA. In addition, two ferroptosis diagnostic genes in RA participate in the occurrence of ferroptosis in RA via oxidative stress, metabolism and immune response. Immune infiltration analysis showed that RA extensively infiltrated B cells, T cells, macrophages and other immune cells. Persistent immune activation may be an essential reason for the progression of ferroptosis in RA. We also obtained five potential therapeutic agents for RA and some long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) regulating ferroptosis diagnostic genes. CONCLUSIONS: Our study suggests that MMP13 and GABARAPL1, which are closely linked with oxidative stress and immunological modulation, can be used as ferroptosis-related potential diagnostic markers in RA and provide new clues regarding the diagnostic and therapeutic targets of ferroptosis in RA.