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 fármacos

RESUMEN

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.

Asunto(s)

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 fármacos

RESUMEN

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 , Pronóstico

RESUMEN

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 Cuestionarios

RESUMEN

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) , Alemania

RESUMEN

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 Enfermedad

RESUMEN

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/sangre

RESUMEN

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/métodos

RESUMEN

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.

Asunto(s)

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 terapéutico

RESUMEN

Background: High interleukin-6 levels correlate with diseases like cancer, autoimmune disorders, and infections. IL-6 receptor inhibitors (IL-6Ri), used for rheumatoid arthritis and COVID-19, may have wider uses. We apply drug-target Mendelian Randomization (MR) to study IL-6Ri's effects. Method: To simulate the effects of genetically blocking the IL-6R, we selected single nucleotide polymorphisms (SNPs) within or near the IL6R gene that show significant genome-wide associations with C-reactive protein. Using rheumatoid arthritis and COVID-19 as positive controls, our primary research outcomes included the risk of asthma, asthmatic pneumonia, cor pulmonale, non-small cell lung cancer, small cell lung cancer, Parkinson's disease, Alzheimer's disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type 1 diabetes, and type 2 diabetes. The Inverse Variance Weighted (IVW) method served as our principal analytical approach, with the hypotheses of MR being evaluated through sensitivity and colocalization analyses. Additionally, we conducted Bayesian Mendelian Randomization analyses to minimize confounding and reverse causation biases to the greatest extent possible. Results: IL-6 inhibitors significantly reduced the risk of idiopathic pulmonary fibrosis (OR= 0.278, 95% [CI], 0.138-0.558; P <0.001), Parkinson's disease (OR = 0.354, 95% CI, 0.215-0.582; P <0.001), and positively influenced the causal relationship with Type 2 diabetes (OR = 0.759, 95% CI, 0.637-0.905; P = 0.002). However, these inhibitors increased the risk for asthma (OR = 1.327, 95% CI, 1.118-1.576; P = 0.001) and asthmatic pneumonia (OR = 1.823, 95% CI, 1.246-2.666; P = 0.002). The causal effect estimates obtained via the BWMR method are consistent with those based on the IVW approach. Similarly, sIL-6R also exerts a significant influence on these diseases.Diseases such as Alzheimer's disease, Crohn's disease, pulmonary heart disease, systemic lupus erythematosus, Type 1 diabetes, Non-small cell lung cancer and ulcerative colitis showed non-significant associations (p > 0.05) and were excluded from further analysis. Similarly, Small cell lung cancer were excluded due to inconsistent results. Notably, the colocalization evidence for asthmatic pneumonia (coloc.abf-PPH4 = 0.811) robustly supports its association with CRP. The colocalization evidence for Parkinson's disease (coloc.abf-PPH4 = 0.725) moderately supports its association with CRP. Conclusion: IL-6Ri may represent a promising therapeutic avenue for idiopathic pulmonary fibrosis, Parkinson's disease, and Type 2 diabetes.

Asunto(s)

Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-6 , Humanos , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Estudio de Asociación del Genoma Completo , COVID-19/genética , Teorema de Bayes , SARS-CoV-2/fisiología , Asma/genética , Asma/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19 , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Interleucina-6/genética , Interleucina-6/antagonistas & inhibidores

RESUMEN

INTRODUCTION: In rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and infections. As such, there is an unmet need for novel treatments that selectively target the pathogenic immune response in RA by inducing tolerance to autoantigens. Autologous cell therapy using antigen-loaded tolerogenic dendritic cells (tolDCs) aims to reinstate autoantigen-specific immunological tolerance in RA and could potentially meet this need. METHODS AND ANALYSIS: We report here the design of the phase I/II, investigator-initiated, open-label, dose-escalation trial TOLERANT. In this study, we will evaluate the intranodal administration of tolDCs in patients with RA that are in remission under immunosuppressive therapy. The tolDCs in this trial are loaded with the heat shock protein 70-derived peptide mB29a, which is an effective surrogate autoantigen in animal models of arthritis. Within this study, three dose-escalation cohorts (two intranodal injections of 5×106, 10×106 and 15×106 tolDCs), each consisting of three patients, are evaluated to identify the highest safe dose (recommended dose), and an extension cohort of nine patients will be treated with the recommended dose. The (co-)primary endpoints of this study are safety and feasibility, which we assess by the number of AEs and the successful production of tolDCs. The secondary endpoints include the immunological effects of the treatment, which we assess with a variety of high-dimensional and antigen-specific immunological assays. Clinical effects are exploratory outcomes. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the Netherlands Central Committee on Research Involving Human Subjects. The outcomes of the trial will be disseminated through publications in open-access, peer-reviewed scientific journals, scientific conferences and to patient associations. TRIAL REGISTRATION NUMBERS: NCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register).

Asunto(s)

Artritis Reumatoide , Autoantígenos , Células Dendríticas , Humanos , Artritis Reumatoide/inmunología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/terapia , Células Dendríticas/inmunología , Autoantígenos/inmunología , Tolerancia Inmunológica , Proteínas HSP70 de Choque Térmico/inmunología , Masculino , Femenino , Ensayos Clínicos Fase I como Asunto , Adulto , Persona de Mediana Edad , Ensayos Clínicos Fase II como Asunto , Trasplante Autólogo

RESUMEN

The management of rheumatic diseases has noticeably changed in recent years with the development of targeted therapeutic agents, namely, biological disease-modifying antirheumatic drugs. Identifying essential signaling pathways and factors crucial for the development and progression of these diseases remains a significant challenge. Therapy could be used to delay the onset or reduce harm. The endocannabinoid system's presence within the synovium can be identified as a suggested target for therapeutic interventions due to its role in modulating pain, inflammation, and joint metabolism. This review brings together the most pertinent information concerning the actions of the endocannabinoid system present in inflamed synovial tissue and its interaction with phytocannabinoids and synthetic cannabinoids, which can be used from a therapeutic perspective to minimize the inflammatory and pain processes typical of osteoarthritis and rheumatoid arthritis.

Asunto(s)

Cannabinoides , Membrana Sinovial , Humanos , Cannabinoides/uso terapéutico , Cannabinoides/farmacología , Cannabinoides/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/efectos de los fármacos , Animales , Endocannabinoides/metabolismo , Enfermedades Reumáticas/tratamiento farmacológico , Enfermedades Reumáticas/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Antirreumáticos/uso terapéutico , Antirreumáticos/farmacología

RESUMEN

BACKGROUND: There have been only few reports on Rhupus syndrome with severe visceral involvement. Moreover, there was little consensus regarding its treatment. Belimumab is one of the options for treating this disease. For patients with clinical symptoms and elevated levels of anti CCP antibodies and anti-double stranded DNA antibodies, and it suggests Rhupus syndrome. After effective treatment, the decrease in levels of anti CCP antibodies and anti-double stranded DNA (ds-DNA) antibodies can effectively delay the progression of the disease and protect target organs. METHODS: We used a chemiluminescence instrument, (Yahuilong; Shenzhen, China), to measure the changes in CCP and dsDNA before and after treatment. RESULTS: Prior to treatment, the patient presented with symptoms of rheumatoid arthritis and systemic lupus erythematosus. Her laboratory tests showed dsDNA (214 IU/mL) and CCP level of ˃ 3,000 U/mL. After treatment with belimumab, the clinical symptoms were significantly relieved, and the patient's CCP IgG level decreased to 263.5 U/mL. A blood test found that her anti-dsDNA was negative. CONCLUSIONS: CCP and dsDNA can serve as indicators for the diagnosis and treatment of Rhupus syndrome.

Asunto(s)

Anticuerpos Antinucleares , Anticuerpos Monoclonales Humanizados , ADN , Humanos , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Antinucleares/sangre , Anticuerpos Antinucleares/inmunología , ADN/inmunología , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/sangre , Persona de Mediana Edad , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Artritis Reumatoide/sangre , Inmunosupresores/uso terapéutico , Resultado del Tratamiento , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Adulto , Biomarcadores/sangre

RESUMEN

Using a new red blood cell (RBC) metabolite extraction protocol, we performed a metabolomic analysis on RBCs in rheumatoid arthritis (RA) patients treated or not with methotrexate (MTX), with the two following objectives: to compare the RBC metabolic profiles of MTX-naïve RA patients and healthy controls (HC), and to investigate whether RBC profiles before and after MTX treatment in RA differed between responders and non-responders. Plasma analysis was performed in parallel. Metabolites were extracted and identified in RBCs and plasma by liquid chromatography-mass spectrometry. We compared the metabolomic fingerprints of 31 DMARD-naïve RA patients and 39 HCs. We also compared the RBC and plasma metabolomes of 25 RA patients who responded or not to MTX therapy before (M0) and after a 3-month treatment period (M3). Significance was determined by Storey's false discovery rate (FDR) q-values to correct for multiple testing. RA patients and HCs differed in the metabolomic signature of RBCs. The signature mainly contained amino acids (AA). Eleven metabolites, including 4 metabolites belonging to the carbohydrate subclass and 2 amino acids (creatine and valine) showed accumulation in RBCs from RA patients. Conversely, citrulline (fold change = 0.83; q = 0.025), histidine (fold change = 0.86; q = 0.014) and ergothioneine (EGT) (fold change = 0.66; q = 0.024), were lower in RBC of RA patients. Five plasma metabolites, including succinic acid and hydroxyproline, were higher in RA patients, and 7 metabolites, including DHEA sulfate, alanine, threonine and ornithine, were lower. Among RA patients undergoing MTX treatment pre-treatment (M0), EGT values were significantly lower in non-responders. In conclusion, low RBC levels of EGT, a food-derived AA barely detectable in plasma, characterize DMARD naïve RA patients and lack of response to MTX treatment.

Asunto(s)

Antirreumáticos , Artritis Reumatoide , Ergotioneína , Eritrocitos , Metabolómica , Metotrexato , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/sangre , Artritis Reumatoide/metabolismo , Metotrexato/uso terapéutico , Ergotioneína/sangre , Eritrocitos/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Metabolómica/métodos , Antirreumáticos/uso terapéutico , Adulto , Anciano , Metaboloma/efectos de los fármacos

Asunto(s)

Amiloidosis , Artritis Reumatoide , Edema , Nefritis Lúpica , Proteinuria , Anciano , Femenino , Humanos , Diagnóstico Diferencial , Edema/diagnóstico , Edema/tratamiento farmacológico , Edema/etiología , Riñón/patología , Riñón/diagnóstico por imagen , Proteinuria/diagnóstico , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Dolor Abdominal/diagnóstico , Dolor Abdominal/etiología , Fiebre/diagnóstico , Fiebre/etiología , Mano/diagnóstico por imagen , Biopsia con Aguja Gruesa , Nefritis Lúpica/complicaciones , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/patología , Amiloidosis/sangre , Amiloidosis/diagnóstico , Amiloidosis/tratamiento farmacológico , Artritis Reumatoide/sangre , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Proteína Amiloide A Sérica/análisis

RESUMEN

Rheumatoid arthritis (RA) involves chronic inflammation, oxidative stress, and complex immune cell interactions, leading to joint destruction. Traditional treatments are often limited by off-target effects and systemic toxicity. This study introduces a novel therapeutic approach using hyaluronic acid (HA)-conjugated, redox-responsive polyamino acid nanogels (HA-NG) to deliver tacrolimus (TAC) specifically to inflamed joints. The nanogels' disulfide bonds enable controlled TAC release in response to high intracellular glutathione (GSH) levels in activated macrophages, prevalent in RA-affected tissues. In vitro results demonstrated that HA-NG/TAC significantly reduced TAC toxicity to normal macrophages and showed high biocompatibility. In vivo, HA-NG/TAC accumulated more in inflamed joints compared to non-targeted NG/TAC, enhancing therapeutic efficacy and minimizing side effects. Therapeutic evaluation in collagen-induced arthritis (CIA) mice revealed HA-NG/TAC substantially reduced paw swelling, arthritis scores, synovial inflammation, and bone erosion while suppressing pro-inflammatory cytokine levels. These findings suggest that HA-NG/TAC represents a promising targeted drug delivery system for RA, offering potential for more effective and safer clinical applications.

Asunto(s)

Artritis Experimental , Artritis Reumatoide , Ácido Hialurónico , Nanogeles , Péptidos , Tacrolimus , Animales , Ácido Hialurónico/química , Artritis Reumatoide/tratamiento farmacológico , Ratones , Tacrolimus/farmacología , Tacrolimus/uso terapéutico , Tacrolimus/química , Tacrolimus/farmacocinética , Artritis Experimental/tratamiento farmacológico , Péptidos/química , Péptidos/farmacología , Nanogeles/química , Masculino , Células RAW 264.7 , Sistemas de Liberación de Medicamentos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos DBA , Portadores de Fármacos/química , Humanos

RESUMEN

BACKGROUND/AIMS: To compare the effects of abatacept and conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the progression and development of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: This multi-center retrospective study included RA patients receiving abatacept or csDMARDs who underwent at least two pulmonary function tests and/or chest high-resolution computed tomography (HRCT). We compared the following outcomes between the groups: progression of RA-ILD, development of new ILD in RA patients without ILD at baseline, 28-joint Disease Activity Score with the erythrocyte sedimentation rate (DAS28-ESR), and safety. Longitudinal changes were compared between the groups by using a generalized estimating equation. RESULTS: The study included 123 patients who were treated with abatacept (n = 59) or csDMARDs (n = 64). Nineteen (32.2%) and 38 (59.4%) patients treated with abatacept and csDMARDs, respectively, presented with RA-ILD at baseline. Newly developed ILD occurred in one patient receiving triple csDMARDs for 32 months. Among patients with RA-ILD at baseline, ILD progressed in 21.1% of cases treated with abatacept and 34.2% of cases treated with csDMARDs during a median 21-month follow-up. Longitudinal changes in forced vital capacity and diffusing capacity for carbon monoxide were comparable between the two groups. However, the abatacept group showed a more significant decrease in DAS28-ESR and glucocorticoid doses than csDMARDs group during the follow-up. The safety of both regimens was comparable. CONCLUSION: Abatacept and csDMARDs showed comparable effects on the development and stabilization of RA-ILD. Nevertheless, compared to csDMARDs, abatacept demonstrated a significant improvement in disease activity and led to reduced glucocorticoid use.

Asunto(s)

Abatacept , Antirreumáticos , Artritis Reumatoide , Enfermedades Pulmonares Intersticiales , Humanos , Abatacept/uso terapéutico , Abatacept/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/complicaciones , Femenino , Persona de Mediana Edad , Masculino , Estudios Retrospectivos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/fisiopatología , Enfermedades Pulmonares Intersticiales/diagnóstico , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversos , Anciano , Resultado del Tratamiento , Progresión de la Enfermedad , Factores de Tiempo , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Pulmón/diagnóstico por imagen , Factores de Riesgo , Adulto , República de Corea , Tomografía Computarizada por Rayos X

RESUMEN

BACKGROUND: Rheumatoid arthritis (RA) is classically considered a systemic disorder, but the role of local factors in driving synovial inflammation is increasingly being recognized. These joint-specific factors may consequently modulate disease phenotype. OBJECTIVES: Our goal was to study the spatial distribution of swelling, tenderness and erosions in a large cohort of early RA (ERA) patients, to assess for patterns of simultaneously-involved joint clusters. We also aimed to investigate the link between arthritis localization and phenotypic features such as bone erosions and response to methotrexate therapy. METHODS: DMARD-naive patients from the ERA UCLouvain Brussels cohort were included. Forty-four joints were clinically assessed for swelling and tenderness before treatment, and 6 months later for methotrexate-treated patients. Clusters of joints were identified using Principal component analysis and Cramer's correlation coefficients. Frequency of bone erosions and joint-specific response to methotrexate were compared across different clusters. RESULTS: 452 ERA patients were included. Analysis of the spatial distribution of swelling and tenderness allowed for the identification of 3 joint clusters that showed significant simultaneous involvement: (i) MTP1-5 joints, (ii) hand joints (MCPs and PIPs), and (iii) larger joints. These clusters were associated with different susceptibility to bone erosions and distinct clinical features, but similar local response (joint swelling resolution) to methotrexate. CONCLUSION: This is the first study investigating the spatial distribution of arthritis in a large cohort of early RA using an unbiased approach. We identify clusters of simultaneously involved joints, supporting the importance of local factors in driving synovitis in RA.

Asunto(s)

Antirreumáticos , Artritis Reumatoide , Metotrexato , Sinovitis , Humanos , Artritis Reumatoide/tratamiento farmacológico , Sinovitis/tratamiento farmacológico , Femenino , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Antirreumáticos/uso terapéutico , Adulto , Anciano , Articulaciones de la Mano/diagnóstico por imagen , Articulaciones de la Mano/patología

RESUMEN

OBJECTIVE: To assess relationships between the timing of glucocorticoid (GC) initiation, entrance into rheumatology care, and the duration of GC use in older adults with early rheumatoid arthritis (eRA) in the U.S. METHODS: Data from the Rheumatology Informatics System for Effectiveness (RISE) registry and Medicare (2016-2018) were linked. Patients with ≥2 RA ICD codes in RISE were included; the first being the index date which signaled entrance into rheumatology care. GC initiation (between 3 months before to 6 months after the index date) and continuous GC use up to 12 months after the index date were captured using Medicare claims. Cox proportional hazards models with adjustment for confounders assessed differences in the duration of GC use for patients initiating GCs before versus after the index date. Average daily GC doses were estimated. RESULTS: 1,733 patients (67 % female; mean age 76 ± 6 years) were included. 41 % initiated GCs, on average 16 ± 58 days before entering rheumatologic care. The mean duration of GC use was 157 days (95 %-CI 143 to 170). GC initiation before rheumatologic care was associated with longer GC use, even after adjustment for confounders (hazard ratio 0.61; 95 %-CI [0.51 to 0.74]). For patients using GCs for ≥3 months, average daily GC doses were <5 mg/d prednisone equivalent. CONCLUSION: GCs are regularly used in eRA and most often initiated before patients enter rheumatology care. Long-term, low-dose GC use is common and associated with initiation before rheumatology care. Earlier referral to rheumatology might reduce GC exposure among U.S. patients with eRA.

Asunto(s)

Artritis Reumatoide , Glucocorticoides , Medicare , Humanos , Artritis Reumatoide/tratamiento farmacológico , Masculino , Femenino , Glucocorticoides/uso terapéutico , Glucocorticoides/administración & dosificación , Anciano , Estados Unidos , Anciano de 80 o más Años , Sistema de Registros , Reumatología

RESUMEN

The mechanisms of endotoxin tolerance (ET), which down-regulate inflammation, are well described in response to exogenous toll-like receptor ligands, but few studies have focused on ET-associated mechanisms in inflammatory disease. As blocking TNF can attenuate the development of ET, the effect of anti-TNF on the expression of key ET-associated molecules in inflammatory auto-immune disease was measured; changes in inflammatory gene expression were confirmed using an ET bioassay. The expression of immunomodulatory molecules was measured in a murine model of arthritis treated with anti-TNF and the expression of ET-associated molecules was measured in whole blood in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) patients, before and after therapy. The expression of ET-associated genes was also measured in RA patient monocytes before and after therapy, in anti-TNF responders and non-responders. Tnfaip3, Ptpn6 and Irak3 were differentially expressed in affected paws, spleens, lymph nodes and circulating leucocytes in experimental murine arthritis treated with anti-TNF. Prior to therapy, the expression of TNFAIP3, INPP5D, PTPN6, CD38 and SIGIRR in whole blood differed between human healthy controls and RA or AS patients. In blood monocytes from RA patients, the expression of TNFAIP3 was significantly reduced by anti-TNF therapy in non-responders. Prior to therapy, anti-TNF non-responders had higher expression of TNFAIP3 and SLPI, compared to responders. Although the expression of TNFAIP3 was significantly higher in RA non-responders prior to treatment, the post-treatment reduction to a level similar to responders did not coincide with a clinical response to therapy.

Asunto(s)

Artritis Reumatoide , Endotoxinas , Tolerancia Inmunológica , Espondilitis Anquilosante , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Factor de Necrosis Tumoral alfa , Animales , Humanos , Ratones , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Endotoxinas/inmunología , Espondilitis Anquilosante/tratamiento farmacológico , Espondilitis Anquilosante/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/genética , Femenino , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Artritis Experimental/inmunología , Artritis Experimental/tratamiento farmacológico , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/efectos de los fármacos , Persona de Mediana Edad , Adulto , Inflamación/inmunología , Modelos Animales de Enfermedad