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2.
BMJ Case Rep ; 17(6)2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38885997

RESUMEN

Rheumatoid pleurisy is common in patients with rheumatoid arthritis, but distinguishing it from other diseases, such as heart failure and tuberculous pleurisy, is often difficult. A man in his 70s with stable rheumatoid arthritis presented with cardiac enlargement and bilateral pleural effusion on chest radiography. Pleural fluid studies showed lymphocytosis, adenosine deaminase level of 51.6 U/L and rheumatoid factor level of 2245.3 IU/mL, suggestive of rheumatoid pleurisy and tuberculous pleurisy. Thoracoscopy under local anaesthesia revealed erythema of the parietal pleura, small papillary projections and fibrin deposits. H&E-stained biopsy specimens showed inflammatory granulomas with strong lymphocytic infiltration and non-caseating granulomas. He was diagnosed with rheumatoid pleurisy. His symptoms improved with 30 mg of prednisolone. This study highlights that biopsy using thoracoscopy under local anaesthesia effectively diagnoses rheumatoid pleurisy, which may be challenging to diagnose.


Asunto(s)
Anestesia Local , Pleuresia , Toracoscopía , Humanos , Masculino , Toracoscopía/métodos , Pleuresia/diagnóstico , Pleuresia/patología , Anciano , Biopsia/métodos , Pared Torácica/patología , Diagnóstico Diferencial , Artritis Reumatoide , Prednisolona/uso terapéutico , Prednisolona/administración & dosificación , Pleura/patología , Pleura/diagnóstico por imagen
3.
RMD Open ; 10(2)2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38886001

RESUMEN

OBJECTIVES: To train, test and validate the performance of a convolutional neural network (CNN)-based approach for the automated assessment of bone erosions, osteitis and synovitis in hand MRI of patients with inflammatory arthritis. METHODS: Hand MRIs (coronal T1-weighted, T2-weighted fat-suppressed, T1-weighted fat-suppressed contrast-enhanced) of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients from the rheumatology department of the Erlangen University Hospital were assessed by two expert rheumatologists using the Outcome Measures in Rheumatology-validated RA MRI Scoring System and PsA MRI Scoring System scores and were used to train, validate and test CNNs to automatically score erosions, osteitis and synovitis. Scoring performance was compared with human annotations in terms of macro-area under the receiver operating characteristic curve (AUC) and balanced accuracy using fivefold cross-validation. Validation was performed on an independent dataset of MRIs from a second patient cohort. RESULTS: In total, 211 MRIs from 112 patients (14 906 region of interests (ROIs)) were included for training/internal validation using cross-validation and 220 MRIs from 75 patients (11 040 ROIs) for external validation of the networks. The networks achieved high mean (SD) macro-AUC of 92%±1% for erosions, 91%±2% for osteitis and 85%±2% for synovitis. Compared with human annotation, CNNs achieved a high mean Spearman correlation for erosions (90±2%), osteitis (78±8%) and synovitis (69±7%), which remained consistent in the validation dataset. CONCLUSIONS: We developed a CNN-based automated scoring system that allowed a rapid grading of erosions, osteitis and synovitis with good diagnostic accuracy and using less MRI sequences compared with conventional scoring. This CNN-based approach may help develop standardised cost-efficient and time-efficient assessments of hand MRIs for patients with arthritis.


Asunto(s)
Aprendizaje Profundo , Imagen por Resonancia Magnética , Osteítis , Sinovitis , Humanos , Osteítis/diagnóstico por imagen , Osteítis/etiología , Osteítis/diagnóstico , Osteítis/patología , Sinovitis/diagnóstico por imagen , Sinovitis/etiología , Sinovitis/diagnóstico , Imagen por Resonancia Magnética/métodos , Masculino , Femenino , Persona de Mediana Edad , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/complicaciones , Mano/diagnóstico por imagen , Mano/patología , Artritis Psoriásica/diagnóstico por imagen , Artritis Psoriásica/diagnóstico , Adulto , Anciano , Curva ROC , Índice de Severidad de la Enfermedad , Redes Neurales de la Computación
4.
RMD Open ; 10(2)2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38886003

RESUMEN

OBJECTIVE: To compare longitudinal changes in spirometric measures between patients with rheumatoid arthritis (RA) and non-RA comparators. METHODS: We analysed longitudinal data from two prospective cohorts: the UK Biobank and COPDGene. Spirometry was conducted at baseline and a second visit after 5-7 years. RA was identified based on self-report and disease-modifying antirheumatic drug use; non-RA comparators reported neither. The primary outcomes were annual changes in the per cent-predicted forced expiratory volume in 1 s (FEV1%) and per cent predicted forced vital capacity (FVC%). Statistical comparisons were performed using multivariable linear regression. The analysis was stratified based on baseline smoking status and the presence of obstructive pattern (FEV1/FVC <0.7). RESULTS: Among participants who underwent baseline and follow-up spirometry, we identified 233 patients with RA and 37 735 non-RA comparators. Among never-smoking participants without an obstructive pattern, RA was significantly associated with more FEV1% decline (ß=-0.49, p=0.04). However, in ever smokers with ≥10 pack-years, those with RA exhibited significantly less FEV1% decline than non-RA comparators (ß=0.50, p=0.02). This difference was more pronounced among those with an obstructive pattern at baseline (ß=1.12, p=0.01). Results were similar for FEV1/FVC decline. No difference was observed in the annual FVC% change in RA versus non-RA. CONCLUSIONS: Smokers with RA, especially those with baseline obstructive spirometric patterns, experienced lower FEV1% and FEV1/FVC decline than non-RA comparators. Conversely, never smokers with RA had more FEV1% decline than non-RA comparators. Future studies should investigate potential treatments and the pathogenesis of obstructive lung diseases in smokers with RA.


Asunto(s)
Artritis Reumatoide , Fumar , Espirometría , Humanos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Estudios Longitudinales , Estudios Prospectivos , Fumar/efectos adversos , Fumar/epidemiología , Anciano , Volumen Espiratorio Forzado , Capacidad Vital , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/etiología , Adulto , Reino Unido/epidemiología
5.
RMD Open ; 10(2)2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38886005

RESUMEN

OBJECTIVES: To compare the risk of cardiovascular events among Janus kinase inhibitors (JAKIs), biological disease-modifying antirheumatic drugs (bDMARDs) (tumour necrosis factor inhibitors (TNFIs) and non-TNFIs) and methotrexate (MTX) in Japanese patients with rheumatoid arthritis (RA). METHODS: Using Japanese claims data, patients with RA were enrolled in this study if they had at least one ICD-10 code (M05 or M06), were new users of JAKIs, bDMARDs or MTX between July 2013 and July 2020 and being 18 years old or older. The incidence rate (IR), IR ratio and adjusted hazard ratio (aHR (95% CI)) of cardiovascular events including venous thromboembolism, arterial thrombosis, acute myocardial infarction and stroke were calculated. A time-dependent Cox regression model adjusted for patient characteristics at baseline was used to calculate aHR. RESULTS: In 53 448 cases, IRs/1000 patient-years of the overall cardiovascular events were 10.1, 6.8, 5.4, 9.1 and 11.3 under the treatments with JAKIs, bDMARDs, TNFIs, non-TNFIs and MTX, respectively. The adjusted HRs of JAKIs for overall cardiovascular events were 1.7 (1.1 to 2.5) versus TNFIs without MTX and 1.7 (1.1 to 2.7) versus TNFIs with MTX. CONCLUSIONS: Among patients with RA, individuals using JAKIs had a significantly higher risk of overall cardiovascular events than TNFIs users, which was attributed to the difference in the risk between JAKIs and TNFIs versus MTX. These data should be interpreted with caution because of the limitations associated with the claims database.


Asunto(s)
Antirreumáticos , Artritis Reumatoide , Enfermedades Cardiovasculares , Inhibidores de las Cinasas Janus , Metotrexato , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Femenino , Masculino , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Persona de Mediana Edad , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/efectos adversos , Japón/epidemiología , Anciano , Estudios Retrospectivos , Estudios Longitudinales , Metotrexato/uso terapéutico , Metotrexato/efectos adversos , Adulto , Incidencia , Bases de Datos Factuales , Factores de Riesgo , Seguro de Salud , Pueblos del Este de Asia
6.
Arthritis Res Ther ; 26(1): 120, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38867295

RESUMEN

BACKGROUND: Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in rheumatoid arthritis (RA). Oral inhibitors of Janus Kinase family (JAKs) are widely used in RA, while inhibitors of other kinase families e.g. phosphoinositide 3-kinase (PI3K) are under development. Most current biomarker platforms quantify mRNA/protein levels, but give no direct information on whether proteins are active/inactive. Phosphoproteome analysis has the potential to measure specific enzyme activation status at tissue level. METHODS: We validated the feasibility of phosphoproteome and total proteome analysis on 8 pre-treatment synovial biopsies from treatment-naive RA patients using label-free mass spectrometry, to identify active cell signalling pathways in synovial tissue which might explain failure to respond to RA therapeutics. RESULTS: Differential expression analysis and functional enrichment revealed clear separation of phosphoproteome and proteome profiles between lymphoid and myeloid RA pathotypes. Abundance of specific phosphosites was associated with the degree of inflammatory state. The lymphoid pathotype was enriched with lymphoproliferative signalling phosphosites, including Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted novel kinases not previously linked to RA, such as Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotype. Several phosphosites correlated with clinical features, such as Disease-Activity-Score (DAS)-28, suggesting that phosphosite analysis has potential for identifying novel biomarkers at tissue-level of disease severity and prognosis. CONCLUSIONS: Specific phosphoproteome/proteome signatures delineate RA pathotypes and may have clinical utility for stratifying patients for personalised medicine in RA.


Asunto(s)
Artritis Reumatoide , Fosfoproteínas , Proteómica , Transducción de Señal , Membrana Sinovial , Humanos , Artritis Reumatoide/metabolismo , Membrana Sinovial/metabolismo , Transducción de Señal/fisiología , Proteómica/métodos , Femenino , Fosfoproteínas/metabolismo , Fosfoproteínas/análisis , Persona de Mediana Edad , Masculino , Adulto , Anciano , Proteoma/análisis , Proteoma/metabolismo
7.
Zhongguo Zhen Jiu ; 44(6): 699-702, 2024 Jun 12.
Artículo en Chino | MEDLINE | ID: mdl-38867634

RESUMEN

The paper introduces professor WANG Haidong's clinical experience in treatment of wrist rheumatoid arthritis with acupotomy mobilization at the muscle regions (sinews/fascia) of three yang meridians of hand. Professor WANG Haidong believes that wrist rheumatoid arthritis belongs to the disorder of meridian muscle regions and is especially associated with the damage of the muscle regions of three yang meridians of hand running through the wrist. Under the guidance of meridian muscle region theory, on the basis of modern anatomy, and the treatment principle, "needling the affected areas may treat disorders of sinews/fascia and dysfunction of meridians simultaneously", acupotomy mobilization is adopted to balance sinews/fascia and bones, operated directly at the involved meridian muscle regions. Besides the foci (palpable knotted sites) on the distribution of muscle regions, acupoints along the affected meridians are stimulated in combination. With this therapy, after determining the location of illness, both the disorder of sinews/fascia and that of meridians can be treated.


Asunto(s)
Puntos de Acupuntura , Terapia por Acupuntura , Artritis Reumatoide , Meridianos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Artritis Reumatoide/terapia , Mano/fisiopatología , Músculo Esquelético , Muñeca/fisiopatología
8.
Front Immunol ; 15: 1377432, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38863716

RESUMEN

Objective: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Among its various complications, heart failure (HF) has been recognized as the second leading cause of cardiovascular death in RA patients. The objective of this study was to investigate the relationship between RA and HF using epidemiological and genetic approaches. Methods: The study included 37,736 participants from the 1999-2020 National Health and Nutrition Examination Survey. Associations between RA and HF in the US population were assessed with weighted multivariate logistic regression analysis. A two-sample Mendelian randomization (MR) analysis was employed to establish the causal relationship between the two variables. The primary analysis method utilized was inverse variance weighting (IVW). Additionally, horizontal pleiotropy and heterogeneity were assessed to account for potential confounding factors. In cases where multiple independent datasets were accessible during MR analysis, we combined the findings through a meta-analytical approach. Results: In observational studies, the prevalence of HF in combination with RA reached 7.11% (95%CI 5.83 to 8.39). RA was positively associated with an increased prevalence of HF in the US population [odds ratio (OR):1.93, 95% confidence interval (CI):1.47-2.54, P < 0.0001]. In a MR analysis utilizing a meta-analytical approach to amalgamate the results of the IVW method, we identified a significant causal link between genetically predicted RA and a heightened risk of HF (OR = 1.083, 95% CI: 1.028-1.141; P = 0.003). However, this association was not deemed significant for seronegative RA (SRA) (OR = 1.028, 95% CI: 0.992-1.065; P = 0.126). These findings were consistent across sensitivity analyses and did not indicate any horizontal pleiotropy. Conclusion: RA correlates with an elevated prevalence of HF within the US population. Furthermore, genetic evidence derived from European populations underscores a causal link between RA and the risk of HF. However this association was not significant in SRA.


Asunto(s)
Artritis Reumatoide , Insuficiencia Cardíaca , Análisis de la Aleatorización Mendeliana , Artritis Reumatoide/complicaciones , Artritis Reumatoide/epidemiología , Artritis Reumatoide/genética , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/genética , Estudios Transversales , Estados Unidos/epidemiología , Europa (Continente)/epidemiología , Humanos , Masculino , Femenino , Adulto , Prevalencia , Persona de Mediana Edad
9.
Autoimmunity ; 57(1): 2358069, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38869013

RESUMEN

Rheumatoid arthritis (RA) is the predominant manifestation of inflammatory arthritis, distinguished by an increasing burden of morbidity and mortality. The intricate interplay of genes and signalling pathways involved in synovial inflammation in patients with RA remains inadequately comprehended. This study aimed to ascertain the role of necroptosis in RA, as along with their associations with immune cell infiltration. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify central genes for RA. In this study, identified total of 28 differentially expressed genes (DEGs) were identified in RA. Utilising WGCNA, two co-expression modules were generated, with one module demonstrating the strongest correlation with RA. Through the integration of differential gene expression analysis, a total of 5 intersecting genes were discovered. These 5 hub genes, namely fused in sarcoma (FUS), transformer 2 beta homolog (TRA2B), eukaryotic translation elongation factor 2 (EEF2), cleavage and polyadenylation specific factor 6 (CPSF6) and signal transducer and activator of transcription 3 (STAT3) were found to possess significant diagnostic value as determined by receiver operating characteristic (ROC) curve analysis. The close association between the concentrations of various immune cells is anticipated to contribute to the diagnosis and treatment of RA. Furthermore, the infiltration of immune cells mentioned earlier is likely to exert a substantial influence on the initiation of this disease.


Asunto(s)
Artritis Reumatoide , Redes Reguladoras de Genes , Necroptosis , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Artritis Reumatoide/genética , Humanos , Necroptosis/inmunología , Perfilación de la Expresión Génica , Transcriptoma , Biología Computacional/métodos , Regulación de la Expresión Génica , Transducción de Señal/inmunología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Biomarcadores , Curva ROC
10.
Tunis Med ; 102(6): 348-353, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38864198

RESUMEN

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease frequently associated with comorbidities such as cardiovascular diseases. RA patients are more prone to physical inactivity than the general population. AIM: Our study aimed to evaluate physical activity (PA) in patients with RA and to assess barriers that influence it in RA characteristics. METHODS: This was a cross sectional study of 120 RA patients. Comorbidities, patients' characteristics, disease activity, function assessed by Health Assessment Questionnaire (HAQ), severity parameters, and extra-articular manifestations were assessed. PA was evaluated with the Short form of the International Physical Activity Questionnaire (IPAQ-S). Factors influencing PA were analyzed. RESULTS: Mean age was 56.1±10.1 years and sex-ratio was 0.14. Screening for comorbidities showed that 30.7% of patients had hypertension, 18.4% had diabetes, and 71.1% were obese or overweight. Moderate to high disease activity was found in 55.6% of patients. Mean HAQ was 0.9±0.6. Evaluation of PA revealed that mean continuous IPAQ-S was 4226.02±4703 MET-min per week [0-24276]. Physical activity level (categorical IPAQ-S) was low in 24.2% of patients, moderate in 30.8%, and high in 45%. Continuous IPAQ-S was negatively correlated with age (r=-0.18,p=0.045), age of disease onset (r=-0.18,p=0.049), and HAQ (r=-0.25,p=0.01). Besides, categorical IPAQ-S was significantly associated with the presence of hypertension (p=0.03) and gout (p=0.02). Concerning RA parameters, categorical IPAQ-S was significantly associated with HAQ (p=0.03). CONCLUSION: Our study showed that PA in RA patients can provide significant improvement in terms of quality of life and function. In RA, regular PA should be part of disease management.


Asunto(s)
Artritis Reumatoide , Ejercicio Físico , Humanos , Artritis Reumatoide/epidemiología , Artritis Reumatoide/fisiopatología , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Persona de Mediana Edad , Femenino , Estudios Transversales , Masculino , Ejercicio Físico/fisiología , Anciano , Adulto , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Comorbilidad , Calidad de Vida
11.
Clin Exp Hypertens ; 46(1): 2366270, 2024 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-38864268

RESUMEN

OBJECTIVE: To elucidate the underlying mechanism by which the proliferation and migration abilities of human umbilical cord mesenchymal stem cells (hUC-MSCs) determine their therapeutic efficacy in rheumatoid arthritis treatment. METHODS: The DBA/1J mice were utilized to establish a collagen-induced RA (CIA) mouse model and to validate the therapeutic efficacy of hUC-MSCs transfected with CD151 siRNA. RNA-seq, QT-PCR and western blotting were utilized to evaluate the mRNA and protein levels of the PI3K/AKT pathway, respectively. RESULTS: IFN-γ significantly enhanced the proliferation and migration abilities of hUC-MSCs, up-regulating the expression of CD151, a gene related to cell proliferation and migration. Effective inhibition of this effect was achieved through CD151 siRNA treatment. However, IFN-γ did not affect hUC-MSCs differentiation or changes in cell surface markers. Additionally, transplantation of CD151-interfered hUC-MSCs (siRNA-CD151-hUC-MSCs) resulted in decreased colonization in the toes of CIA mice and worse therapeutic effects compared to empty vector treatment (siRNA-NC-hUC-MSCs). CONCLUSION: IFN-γ facilitates the proliferation and migration of hUC-MSCs through the CD151/PI3K/AKT pathway. The therapeutic efficacy of siRNA-CD151-hUC-MSCs was found to be inferior to that of siRNA-NC-hUC-MSCs.


Asunto(s)
Artritis Reumatoide , Movimiento Celular , Proliferación Celular , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Ratones Endogámicos DBA , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Artritis Reumatoide/terapia , Artritis Reumatoide/metabolismo , Ratones , Células Madre Mesenquimatosas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Fosfatidilinositol 3-Quinasas/metabolismo , Humanos , Interferón gamma/metabolismo , Cordón Umbilical/citología , Artritis Experimental/terapia , Artritis Experimental/metabolismo , Masculino
14.
JCI Insight ; 9(11)2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38855867

RESUMEN

In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known. Sphingosine 1-phosphate receptor 1 (S1PR1), widely expressed on ECs, maintains the vascular barrier. Here, we assessed the contribution of vascular integrity and EC S1PR1 signaling to joint damage in mice exposed to serum-induced arthritis (SIA). EC-specific deletion of S1PR1 or pharmacological blockade of S1PR1 promoted vascular leak and amplified SIA, whereas overexpression of EC S1PR1 or treatment with an S1PR1 agonist delayed SIA. Blockade of EC S1PR1 induced membrane metalloproteinase-dependent cleavage of vascular endothelial cadherin (VE-cadherin), a principal adhesion molecule that maintains EC junctional integrity. We identified a disintegrin and a metalloproteinase domain 10 (ADAM10) as the principal VE-cadherin "sheddase." Mice expressing a stabilized VE-cadherin construct had decreased extravascular VE-cadherin and vascular leakage in response to S1PR1 blockade, and they were protected from SIA. Importantly, patients with active rheumatoid arthritis had decreased circulating S1P and microvascular expression of S1PR1, suggesting a dysregulated S1P/S1PR1 axis favoring vascular permeability and vulnerability. We present a model in which EC S1PR1 signaling maintains homeostatic vascular barrier function by limiting VE-cadherin shedding mediated by ADAM10 and suggest this signaling axis as a therapeutic target in inflammatory arthritis.


Asunto(s)
Proteína ADAM10 , Antígenos CD , Artritis Experimental , Artritis Reumatoide , Cadherinas , Células Endoteliales , Receptores de Esfingosina-1-Fosfato , Animales , Cadherinas/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Ratones , Artritis Experimental/metabolismo , Artritis Experimental/patología , Antígenos CD/metabolismo , Antígenos CD/genética , Células Endoteliales/metabolismo , Humanos , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Artritis Reumatoide/genética , Proteína ADAM10/metabolismo , Proteína ADAM10/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Transducción de Señal , Ratones Noqueados , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Masculino , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Lisofosfolípidos/metabolismo , Permeabilidad Capilar , Femenino
15.
Arthritis Res Ther ; 26(1): 117, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38845046

RESUMEN

BACKGROUND: The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF­06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18-70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03-6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3-10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant. RESULTS: In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4-121.4 h (SAD cohorts) and 162.0-234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3-99.3%/62.4-98.7% [SAD] and 91.1-99.6%/89.5-98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375. CONCLUSIONS: These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03334851.


Asunto(s)
Artritis Reumatoide , Lupus Eritematoso Sistémico , Receptores CXCR5 , Humanos , Persona de Mediana Edad , Adulto , Método Doble Ciego , Femenino , Masculino , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Anciano , Adulto Joven , Relación Dosis-Respuesta a Droga , Adolescente , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/farmacocinética , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos
16.
Medicine (Baltimore) ; 103(23): e38448, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38847705

RESUMEN

The current work aims to evaluate the association between genetic mutations in thymidylate synthetase (TYMS gene in exon1 and partial regions of promotor and intron 1 [877 bp, 657,220-658,096 bp]) and the therapeutic outcomes for rheumatoid arthritis (RA) Iraqi patients. An observational cross-sectional study involving 95 RA patients with established RA patients based on their methotrexate treatment responsiveness. Genetic sequencing of the TYMS gene was performed for all patients according to the instruction manuals of the sequencing company (Macrogen Inc. Geumchen, South Korea). Four polymorphisms were identified by sequencing 95 randomly selected patients in the noncoding region of TYMS. Three of these polymorphisms were found in the NCBI database's dbSNP (rs2853741, rs2606241, and rs2853742 SNPs), and one SNP polymorphism is novel (657334). The CTAT (657334, rs2853741, rs2606241, and rs2853742 SNPs) haplotype was significantly associated with responder with odd ratio, 95% confidence interval: 0.506, 0.281-0.912 (P value = .022). In contrast, the other haplotypes were not associated with MTX responsiveness. In the multivariate analysis, after adjusting to the effect of age, sex, smoking, and disease duration, the TCrs2853741 genotype was associated with non-responders (P value = .030). In contrast, the ACrs260641 genotype, after adjusting to the effect of age, sex, and smoking, was associated with non-responders (P value = .035). Genetic polymorphism of the TYMS gene, especially in TCrs2853741 and ACrs260641, predicts non-responder to MTX treatment in RA, while the presence of the CTAT haplotype predicts a good response to MTX treatment.


Asunto(s)
Antirreumáticos , Artritis Reumatoide , Metotrexato , Polimorfismo de Nucleótido Simple , Timidilato Sintasa , Humanos , Estudios Transversales , Masculino , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Femenino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Antirreumáticos/uso terapéutico , Adulto , Irak , Timidilato Sintasa/genética , Haplotipos , Resultado del Tratamiento
17.
Int J Rheum Dis ; 27(6): e15216, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38873756

RESUMEN

AIM: To determine whether the IG count (#) and IG percentage (%) are associated with disease activity in rheumatoid arthritis (RA). METHODS: This retrospective study included 65 RA patients and 65 healthy controls. Clinical and demographic characteristics of controls and RA patients (at active period and when the patients achieved remission) were obtained from medical records. Disease activity was defined by disease activity score 28 (DAS28). Furthermore, the clinical disease activity index (CDAI), and simple disease activity index (SDAI) were calculated. For the differential diagnosis of RA patients from healthy controls, the cut-off value was estimated by making receiver-operator curves (ROC). RESULTS: In active RA patients, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IG#, and IG% levels were significantly higher compared to the healthy controls (p < .001, for all). When the patients achieved remission, DAS28, CDAI, SDAI, ESR, CRP, IG#, and IG% values were significantly decreased (p < .001, for all). IG# and IG% were significantly positively correlated with DAS28, CDAI, SDAI, ESR, and CRP (p = .024, p = .008, p = .003, p < .001, p < .001, respectively). According to ROC curve analysis, IG% and IG# were the biomarkers to have a significant diagnostic value for RA with the area under the curve of 0.853 and 0.865 (p < .001, for all). CONCLUSION: The present study demonstrated that two novel inflammatory markers, IG# and IG%, can be useful for monitoring RA patients' disease activity. Furthermore, IG# and IG% can also be used as fast, inexpensive, and easily available complementary diagnostic markers to diagnose RA patients.


Asunto(s)
Artritis Reumatoide , Biomarcadores , Granulocitos , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Humanos , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Biomarcadores/sangre , Granulocitos/inmunología , Sedimentación Sanguínea , Anciano , Proteína C-Reactiva/análisis , Inducción de Remisión , Resultado del Tratamiento
18.
BMC Cardiovasc Disord ; 24(1): 291, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834973

RESUMEN

BACKGROUND: Patients with rheumatoid arthritis have significant cardiovascular mortality and morbidity. OBJECTIVE: To investigate the effects of chronic inflammation in rheumatoid arthritis on cardiovascular morbidity association with cardiovascular risk factors risk factors. Mortality report is secondary just to show trends without sufficient statistical power as it is accidental endpoint. METHODS: A total of 201 individuals without previous cardiovascular disease, 124 with rheumatoid arthritis (investigation group) and 77 with osteoarthritis (control group), were included in the study and followed up for an average of 8 years to assess the development of fatal or non-fatal cardiovascular diseases. The incidence and prevalence of cardiovascular risk factors were also investigated. RESULTS: The total incidence of one or more fatal or nonfatal cardiovascular events was 43.9% in the investigation group and 37.5% in the control group. Of these patients, 31.7% and 30.9% survived cardiovascular events in the investigation and control groups, respectively. The most common cardiovascular disease among participants who completed the study and those who died during the study was chronic heart failure. The results of the subgroup analysis showed that strict inflammation control plays a central role in lowering cardiovascular risk. CONCLUSION: A multidisciplinary approach to these patients is of paramount importance, especially with the cooperation of immunologists and cardiologists for early detection, prevention, and management of cardiovascular risks and diseases.


Asunto(s)
Artritis Reumatoide , Enfermedades Cardiovasculares , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Artritis Reumatoide/epidemiología , Artritis Reumatoide/mortalidad , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Masculino , Femenino , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/diagnóstico , Persona de Mediana Edad , Incidencia , Medición de Riesgo , Factores de Tiempo , Anciano , Prevalencia , Estudios de Casos y Controles , Pronóstico , Adulto , Osteoartritis/epidemiología , Osteoartritis/mortalidad , Osteoartritis/diagnóstico , Factores de Riesgo
19.
Arch Dermatol Res ; 316(7): 366, 2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38850409

RESUMEN

A knowledge gap exists regarding the association between vitiligo and rheumatoid arthritis (RA) due to the absence of large-scale cohort studies designed to investigate this association. To investigate the bidirectional epidemiological association between vitiligo and RA. A population-based study was conducted using Clalit Health Services (CHS) database (2002-2019) using both a cohort study and a case-control study design. Adjusted hazard ratio (HR) and odds ratio (OR) were calculated by multivariate Cox and logistic regressions, respectively. Overall, 20,851 vitiligo patients and 102,475 controls were included. The incidence of new-onset RA was 4.1 (95% CI 3.0-5.4) and 2.9 (95% CI 2.4-3.3) cases per 10,000 person-years among patients with vitiligo and controls, respectively. Patients with vitiligo had a significantly increased risk of developing new-onset RA (adjusted HR, 1.44; 95% confidence interval [CI], 1.02-2.02, P = 0.036). The likelihood of having vitiligo was significantly elevated after a preexisting diagnosis of RA (adjusted OR, 1.67; 95% CI, 1.38-2.03; P < 0.001). Relative to the remaining patients with vitiligo, those with vitiligo and comorbid RA demonstrated an elevated risk of all-cause mortality (adjusted HR, 1.61; 95% CI, 1.03-2.51; P = 0.037). Our study confirms the bidirectional association between vitiligo and RA. Physicians treating patients with vitiligo should be aware of the association in clinical practice.


Asunto(s)
Artritis Reumatoide , Vitíligo , Humanos , Vitíligo/epidemiología , Artritis Reumatoide/epidemiología , Artritis Reumatoide/complicaciones , Femenino , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Adulto , Incidencia , Anciano , Taiwán/epidemiología , Factores de Riesgo , Bases de Datos Factuales
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