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ID PMID Title PublicationDate abstract
33740479 Emerging role of selenium in treatment of rheumatoid arthritis: An insight on its antioxid 2021 Jul Rheumatoid Arthritis is an inflammatory disease primarily involves the inflamed synovium, affecting about 0.5-1 % population worldwide. It is the assumption from many years that oxidative stress is involved in the pathophysiology of inflammatory disorders like RA and many others. The significance of micronutrients in arthritis is linked to their role as a cofactor for the activation of selenoenzymes. Dietary interventions can manage the clinical symptoms of RA like pain, swelling and tenderness of joints and their associated disability along the progression of disease. This review highlights the antioxidant potential of selenium in treatment of RA along with the scientific evidence that Se supplementation can reduce disease progression by managing its clinical symptoms.
33789847 Systematic review and meta-analysis of the risk of rheumatoid arthritis-associated interst 2021 Mar 31 OBJECTIVE: To clarify the risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) related to anti-cyclic citrullinated peptide (CCP) antibody. ELIGIBILITY CRITERIA: Patients with RA with and without ILD were eligible. The primary outcome was the prevalence or incidence of ILD. Primary studies of any design aside from a case report were eligible. INFORMATION SOURCES: Medline, EMBASE, Science Citation Index Expanded and Cochrane Central Register of Controlled Trials were searched from the inception through 12 November 2019. DATA EXTRACTION AND RISK OF BIAS: Two reviewers independently selected eligible reports, extracted relevant data and assessed risk of bias using a modified Quality in Prognostic Studies tool. DATA SYNTHESIS: Meta-analysis was conducted using a random-effects model. QUALITY OF EVIDENCE: The Grades of Recommendation, Assessment, Development and Evaluation system was applied. RESULTS: Among 29 out of 827 records retrieved through electronic databases and four additional reports identified from other sources, 29 studies were focused for the review. A total of 10158 subjects were included and the mean age at inclusion was between 45.8 and 63.9 years. The mean RA duration was between 4.3 and 14.9 years. The positivity of anti-CCP antibody ranged from 50.7% to 95.8%. All studies except for two were deemed as high risk of bias. A pooled analysis of univariate results demonstrated that the presence of anti-CCP antibody was significantly associated with RA-ILD with an OR of 2.10 (95% CI: 1.59 to 2.78). Similarly, the titre of anti-CCP antibody was significantly higher for RA-ILD with a standardised mean difference of 0.42 (95% CI: 0.20 to 0.65). These results were confirmed by multivariate analysis in the majority of studies and consistent by any subgroup and sensitivity analyses. CONCLUSION: The presence and higher titres of anti-CCP antibody were suggested to be significantly associated with an increased risk of RA-ILD. However, the quality of evidence was rated as low or very low.
33955670 Medium-Term Clinical Results of High-Flexion Knee Prostheses in Patients with Rheumatoid A 2021 Jun OBJECTIVE: This study was performed to evaluate the function and satisfaction outcome of patients with rheumatoid arthritis (RA) who underwent total knee arthroplasty (TKA) with high-flexion prostheses. MATERIALS AND METHODS: Twenty-two patients (35 knees) using high-flexion prostheses (Zimmer, Warsaw, IN) were followed up for a period of 7-11 years from February 2007 to December 2009. Clinical and radiographic follow-up was performed using Hospital for Special Surgery (HSS), Short-Form 36 scores (SF-36), American Knee Society score (KSS), and Knee Society Total Knee Arthroplasty Roentgenographic Evaluation and Scoring System. Patient satisfaction assessments took place at the final follow-up sessions using the Marsh Satisfaction Questionnaire. RESULTS: The average ROM improved from preoperative 68.43° ± 33.78° to 95.54° ± 7.03° at the final follow-up. The HSS score and KSS score for pain improved from (46.49 ± 12.73) points to (85.46 ± 3.90) points and from 20.57 ± 5.91 points to 47.43 ± 3.51 points at the follow-up evaluation, respectively. Physical Component Summary(PCS) and Physical Component Summary (MCS) scores were 45.38 and 52.56, respectively by the end of follow-up. Deep venous thrombosis developed in one patient and one patient required surgical revision due to infection. There were no instances of prosthetic loosening. The satisfaction rate of patients was 95.5%. CONCLUSION: Although this particular model of TKA did not yield high-flexion angles (ie, 140°) required for kneeling, squatting, or rising from the floor, significant clinical and radiographic gains were evident in these patients with RA.
32530346 Twenty years' follow-up of radiocarpal arthrodesis for rheumatoid wrists. 2021 Mar OBJECTIVES: A pain-free stable wrist is a prerequisite for patients with rheumatoid arthritis to improve their activity of daily life. The present study investigated whether or not radiocarpal arthrodesis yielded good results for more than 20 years. METHODS: A retrospective study was performed on 20 unstable wrists in 17 patients with rheumatoid arthritis. Radiocarpal arthrodesis combined with synovectomy and the Darrach procedure was performed. Wrist pain, grip power, the range of motion, pharmacotherapy, ESR, CRP, and serial radiographs were investigated at the baseline and 20 years after the operation. Patient-reported outcomes using the mHAQ, DASH and patient's satisfaction level were investigated at the final follow-up. RESULTS: Pain had disappeared completely in all patients at 20 years after the operation. The average grip power increased in 16 wrists (80%) and decreased in 4 wrists (20%). Wrist extension and flexion significantly decreased, and supination and pronation remained within the functional range. Radiographically, ulnar shift and palmar subluxation initially improved and remained unchanged for a long time. Fourteen patients (82.4%) with 17 wrists were satisfied with this operation. CONCLUSION: Radiocarpal arthrodesis for rheumatoid wrists provided painless stability for a long period for 20 years or more.
32801134 The Risk of Cardiovascular Events Associated With Disease-modifying Antirheumatic Drugs in 2021 May OBJECTIVE: To examine the comparative effects of biologic disease-modifying antirheumatic drugs (bDMARD) and tofacitinib against conventional synthetic DMARD (csDMARD) on incident cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA). METHODS: RA patients with ≥ 1 year of participation in the FORWARD study, from 1998 through 2017, were assessed for incident composite CVD events (myocardial infarction, stroke, heart failure, and CVD-related death validated from hospital/death records). DMARD were categorized into 7 mutually exclusive groups: (1) csDMARD-referent; (2) tumor necrosis factor-α inhibitor (TNFi); (3) abatacept (ABA); (4) rituximab; (5) tocilizumab; (6) anakinra; and (7) tofacitinib. Glucocorticoids (GC) were assessed using a weighted cumulative exposure model, which combines information about duration, intensity, and timing of exposure into a summary measure by using the weighted sum of past oral doses (prednisolone equivalent). Cox proportional hazard models were used to adjust for confounders. RESULTS: During median (IQR) 4.0 (1.7-8.0) years of follow-up, 1801 CVD events were identified in 18,754 RA patients. The adjusted model showed CVD risk reduction with TNFi (HR 0.81, 95% CI 0.71-0.93) and ABA (HR 0.50, 95% CI 0.30-0.83) compared to csDMARD. While higher GC exposure as weighted cumulative exposure was associated with increased CVD risk (HR 1.15, 95% CI 1.11-1.19), methotrexate (MTX) use was associated with CVD risk reduction [use vs nonuse HR 0.82, 95% CI 0.74-0.90, and high dose (> 15 mg/week) vs low dose (≤ 15 mg/week) HR 0.83, 95% CI 0.70-0.99]. CONCLUSION: ABA and TNFi were associated with decreased risk of CVD compared to csDMARD. Minimizing GC use and optimizing MTX dose may improve cardiovascular outcomes in patients with RA.
32506311 Clinical effectiveness of iguratimod based on real-world data of patients with rheumatoid 2021 Jan OBJECTIVES: Iguratimod (IGU) is a conventional synthetic disease-modifying drug that has been approved based on its additive effects with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). The objective of the study is to establish the effectiveness of IGU with versus IGU without MTX irrespective of whether MTX is well tolerated or not by the patients. METHODS: Disease activity scores in 177 RA patients treated using IGU were retrospectively evaluated at baseline and after 4, 12, and 24 weeks, and adverse events (AEs) were noted. RESULTS: IGU reduced the disease activity parameters, disease activity score (DAS)-ESR, DAS-CRP, the simplified disease activity index (SDAI), and clinical disease activity index (CDAI) in the concomitant MTX and non-MTX, female and male, and young and elderly patient groups after 24 weeks. Multivariate analysis demonstrated that IGU was more effective with concomitant MTX and in elderly and male patients. Severe AEs were observed only in the elderly group: two cases of pneumonia, 1 of pneumocystis pneumonia, 1 of heart failure, and 1 of salivary gland adenoma. CONCLUSIONS: IGU is effective for RA, especially with concomitant MTX, and in elderly and male patients. Key Points • Iguratimod is effective for RA, especially with concomitant MTX, and in elderly and male patients. • Since all serious adverse events were in the elderly group in this study, sufficient monitoring for adverse events, especially for elderly RA patients, is needed during iguratimod therapy.
34526577 Differential inflammation-mediated function of prokineticin 2 in the synovial fibroblasts 2021 Sep 15 Prokineticin 2 (PK2) is a secreted protein involved in several pathological and physiological processes, including the regulation of inflammation, sickness behaviors, and circadian rhythms. Recently, it was reported that PK2 is associated with the pathogenesis of collagen-induced arthritis in mice. However, the role of PK2 in the pathogenesis of rheumatoid arthritis (RA) or osteoarthritis (OA) remains unknown. In this study, we collected synovial tissue, plasma, synovial fluid, and synovial fibroblasts (SF) from RA and OA patients to analyze the function of PK2 using immunohistochemistry, enzyme-linked immunosorbent assays, and tissue superfusion studies. PK2 and its receptors prokineticin receptor (PKR) 1 and 2 were expressed in RA and OA synovial tissues. PKR1 expression was downregulated in RA synovial tissue compared with OA synovial tissue. The PK2 concentration was higher in RA synovial fluid than in OA synovial fluid but similar between RA and OA plasma. PK2 suppressed the production of IL-6 from TNFα-prestimulated OA-SF, and this effect was attenuated in TNFα-prestimulated RA-SF. This phenomenon was accompanied by the upregulation of PKR1 in OA-SF. This study provides a new model to explain some aspects underlying the chronicity of inflammation in RA.
32940699 Association of altered folylpolyglutamate synthetase pre-mRNA splicing with methotrexate u 2021 Mar 2 OBJECTIVES: An efficient pharmacological response to MTX treatment in RA patients relies on the retention and accumulation of intracellular MTX-polyglutamates catalysed by the enzyme folylpolyglutamate synthetase (FPGS). We recently identified a partial retention of FPGS intron 8 (8PR) as a prominent splice variant conferring FPGS dysfunction and decreased MTX polyglutamylation in acute lymphoblastic leukaemia. Here, we explored the association between FPGS 8PR levels and lack of MTX responsiveness in RA patients. METHODS: Thirty-six patients undergoing MTX treatment were enrolled from the Combinatie behandeling Reumatoide Artritis (COBRA)-light trial. RNA was isolated from blood samples at baseline, 13 weeks and 26 weeks of therapy, from patients in either COBRA-light (n = 21) or COBRA (n = 15) treatment arms. RT-qPCR analysis was used to assess RNA levels of FPGS 8PR over wild-type FPGS (8WT). RESULTS: In the COBRA-light treatment arm, higher baseline ratios of 8PR/8WT were significantly associated with higher 44-joint disease activity score (DAS44) at 13 and 26 weeks. Higher baseline ratios of 8PR/8WT also trended towards not obtaining low disease activity (DAS <1.6) and becoming a EULAR non-responder at 13 and 26 weeks. In the COBRA-treatment arm, a significant association was observed between high baseline 8PR/8WT ratios and higher DAS44 score at 26 weeks. Higher 8PR/8WT ratios were associated with non-response at week 26 based on both low disease activity and EULAR criteria. CONCLUSION: This study is the first to associate alterations in FPGS pre-mRNA splicing levels with reduced responsiveness to MTX treatment in RA patients. TRIAL REGISTRATION: ISRCTN55552928.
31733042 Intersectional Inequalities and Individual Heterogeneity in Chronic Rheumatic Diseases: An 2021 Feb OBJECTIVE: To examine how intersections of multiple sociodemographic variables explain the individual heterogeneity in risk of being diagnosed with any of following chronic rheumatic diseases (CRDs): osteoarthritis (OA), gout, rheumatoid arthritis (RA), or spondyloarthritis (SpA). METHODS: We identified individuals ages 40-65 years residing in Skåne, Sweden by December 31, 2013 and having done so from January 1, 2000 (n = 342,542). We used a Skåne health care register to identify those with a diagnosis of the CRD of interest between January 1, 2014 and December 31, 2015, with no previous such diagnosis during 2000-2013. We created 144 intersectional social strata (ISS) using categories of age, sex, education, income, civil status, and immigration. For individuals nested within ISS, we applied multilevel logistic regression models to estimate the variance partition coefficient (VPC) as a measure of discriminatory accuracy of the ISS and the predicted absolute risks and 95% credible intervals for each stratum. RESULTS: Overall, 3.5%, 0.5%, 0.2%, and 0.2% of the study population were diagnosed with OA, gout, RA, and SpA, respectively. The VPC ranged from 16.2% for gout to 0.5% for SpA. Sex explained the largest proportion of between-strata variation in risk of RA, gout, and SpA, while age was the most important factor for OA. The most between-strata differences in risk of these CRDs were due to the additive main effects. CONCLUSION: Despite meaningful between-strata inequalities in the risk of being diagnosed with CRDs (except SpA), there were substantial within-strata heterogeneities that remain unexplained. There was limited evidence of intersectional interaction effects.
33726834 A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 2021 Mar 16 BACKGROUND: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA). METHODS: Patients with moderate to severe RA who had received ≥12 weeks' stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85. RESULTS: A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints-C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms. CONCLUSIONS: These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.
34488430 Multiple time-point assessment of lncRNA MEG3 shows potential to monitor treatment efficac 2021 Oct Background: This study explored the clinical role of lncRNA MEG3 in rheumatoid arthritis (RA) management. Materials & methods: Totally, 191 active RA patients were enrolled, and their lncRNA MEG3 expressions in peripheral blood monoclonal cells were detected. Results: LncRNA MEG3 expression was downregulated, and it negatively correlated with lesion joints, inflammation and disease activity in RA patients. Moreover, lncRNA MEG3 expression was increased during treatment; meanwhile its increment correlated with treatment response and remission. Conclusion: LncRNA MEG3 may serve as a potential biomarker for monitoring treatment efficacy in RA management.
32285716 The Arabic Arthritis Self-Efficacy Scale-8 (ASES-8): a valid and reliable measure of evalu 2021 Dec BACKGROUND: The Arthritis Self-Efficacy Scale-8 (ASES-8) is one of the most commonly used scales to measure patient-reported arthritis-specific self-efficacy. However, evidence about the validity and reliability of ASES-8 in an Arabic-speaking arthritis population is lacking. OBJECTIVE: This study aimed to cross-culturally adapt and assess aspects of validity and reliability of the Arabic version of the ASES-8. METHODS: The ASES-8 was translated into the Arabic language using the back-translation method, and administered to 67 patients with rheumatoid arthritis (RA). Construct validation methods used exploratory factor analysis and correlating the ASES-8 scores with disease-related variables expected to be related to the arthritis self-efficacy construct. An internal consistency test was conducted. Floor and ceiling effects were considered present if more than 15% of patients achieved high (=10) and low (=1) scores on the Arabic ASES-8 for both the scale and item scores. RESULTS: Exploratory factor analysis demonstrated a one-factor solution (factor loadings: 0.54-0.81). ASES-8 scores were correlated with all measures assessed (r = -0.24 to -0.57 and r = 0.06-0.66), demonstrating construct validity. Internal consistency was acceptable for measures of Cronbach's alpha (0.86-0.88). The scale did not exhibit ceiling or floor effects. CONCLUSIONS: The Arabic version of ASES-8 is valid and reliable for evaluating self-efficacy in patients with rheumatoid arthritis.Implications for rehabilitationThe Arthritis Self-Efficacy Scale (ASES-8) questionnaire was translated and adapted for use in Arabic language.This questionnaire is a valid and reliable instrument for evaluating self-efficacy among Arabic individuals with rheumatoid arthritis.This will support greater use of this tool worldwide in clinical and research practices that include Arabic people.
33763493 Anti-TROVE2 Antibody Determined by Immune-Related Array May Serve as a Predictive Marker f 2021 Anti-drug antibody (ADAb) development is associated with secondary therapeutic failure in biologic-treated rheumatoid arthritis (RA) patients. With a treat-to-target goal, we aimed to identify biomarkers for predicting ADAb development and therapeutic response in adalimumab-treated patients. Three independent cohorts were enrolled. In Cohort-1, 24 plasma samples (6 ADAb-positive and 6 ADAb-negative patients at baseline and week 24 of adalimumab therapy, respectively) were assayed with immune-related microarray containing 1,636 correctly folded functional proteins. Next, we executed statistically powered autoantibody profiling analysis of 50 samples in Cohort-2 (24 ADAb-positive and 26 ADAb-negative patients). Subsequently, immunofluorescence assay was performed on 48 samples in Cohort-3 to correlate with ADAb titers and drug levels. The biomarkers were identified for predicting ADAb development and therapeutic response using the immune-related microarray and machine learning approach. ADAb-positive patients had lower drug levels at week 24 (median = 0.024 μg/ml) compared with ADAb-negative patients (median = 6.38 μg/ml, p < 0.001). ROC analysis based on the ADAb status revealed the top 20 autoantibodies with AUC ≥ 0.7 in differentiating both groups in Cohort-1. Analysis of Cohort-2 dataset identified a panel of 8 biomarkers (TROVE2, SSB, NDE1, ZHX2, SH3GL1, CARD9, PTPN20, and KLHL12) with 80.6% specificity, 77.4% sensitivity, and 79.0% accuracy in discriminating poor from EULAR responders. Immunofluorescence assay validated that anti-TROVE2 antibody could highly predict ADAb development and poor EULAR response (AUC 0.79 and 0.89, respectively). Multivariate regression analysis proved anti-TROVE2 antibody to be an independent predictor for developing ADAb. Immune-related protein microarray and replication analysis identified anti-TROVE2 antibody as a useful biomarker for predicting ADAb development and therapeutic response in adalimumab-treated patients.
34294369 Linalyl acetate as a potential preventive agent against muscle wasting in rheumatoid arthr 2021 Sep Cigarette smoking has detrimental effects on rheumatoid arthritis (RA), characterized by muscle wasting. Linalyl acetate (LA), the main component of Lavandula angustifolia Mill (lavender) oil, has anti-inflammatory properties. We investigated the detrimental effects of chronic nicotine exposure in rats with RA, as well as the abilities of lavender oil and LA to prevent muscle wasting. Rats with RA induced by type II collagen were exposed to nicotine for 22 days from day 1. Lavender oil or LA was administered twice a week during the experiment. Compared with control, collagen-induced arthritis (CIA) and chronic nicotine exposure plus CIA (NicoCIA) showed increases in hind paw thickness and serum interleukin (IL)-6 and decreases in body weight and serum insulin-like growth factor (IGF)-1 levels. Moreover, weight and fiber cross-sectional area of the gastrocnemius muscle were much lower, and mitochondrial membrane potential of the gastrocnemius muscle was higher, in the NicoCIA than in the CIA. These alterations in the NicoCIA were prevented by lavender oil and LA. Importantly, LA showed greater activity than lavender oil in preventing IGF-1 reduction in the NicoCIA. These findings suggest that lavender oil and LA may have preventive benefit in RA by counteracting muscle wasting associated with chronic nicotine exposure.
34896445 Intravenous pegylated liposomal prednisolone outperforms intramuscular methylprednisolone 2022 Jan Glucocorticoids (GCs) are potent anti-inflammatory drugs but their use is limited by systemic exposure leading to toxicity. Targeted GC delivery to sites of inflammation via encapsulation in long-circulating liposomes may improve the therapeutic index. We performed a randomized, double-blind, active-controlled, multi-center study in which intravenously (i.v.) administered pegylated liposomal prednisolone sodium phosphate (Nanocort) was compared to equipotent intramuscular (i.m.) methylprednisolone acetate (Depo-Medrol®; i.e. a current standards-of-care for treating flares in rheumatoid arthritis patients). We enrolled 172 patients with active arthritis who met all eligibility criteria, eventually resulting in 150 patients randomized in three groups: (1) Nanocort 75 mg i.v. infusion plus i.m. saline injection; (2) Nanocort 150 mg i.v. infusion plus i.m. saline injection; and (3) Depo-Medrol® 120 mg i.m. injection plus i.v. saline infusion. Dosing in each group occurred at baseline and on day 15 (week 2). Study visits occurred at week 1, 2, 3, 4, 6, 8 and 12, to assess both efficacy and safety. The primary endpoint was the "European League Against Rheumatism" (EULAR) responder rate at week 1. Safety was determined by the occurrence of adverse events during treatment and 12 weeks of follow-up. Treatment with Nanocort was found to be superior to Depo-Medrol® in terms of EULAR response at week 1, with p-values of 0.007 (good response) and 0.018 (moderate response). Treatments were well tolerated with a comparable pattern of adverse events in the three treatment groups. However, the Nanocort groups had a higher incidence of hypersensitivity reactions during liposome infusion. Our results show that liposomal Nanocort is more effective than Depo-Medrol® in treating patients with rheumatoid arthritis flares and has similar safety. This is the first clinical study in a large patient population showing that i.v. administered targeted drug delivery with a nanomedicine formulation improves the therapeutic index of glucocorticoids.
33468512 Mycoplasma hominis septic arthritis in a patient with hypogammaglobinaemia and rheumatoid 2021 Jan 19 We describe the case of Mycoplasma hominis septic arthritis in a 58-year-old woman with a history of rheumatoid arthritis and ulcerative colitis on immunosuppressive therapy with rituximab. Treatment with anti-CD20 antibodies (eg, rituximab) leads to an immediate depletion of B cells and hence risk of reductions in immunoglobulins and increased risk of infections. This effect may last long after drug cessation. M. hominis is commensal to the genitourinary tract in sexually active adults. Extragenital M. hominis infections including septic arthritis are rare, but hypogammaglobulinaemia is a predisposing factor. As M. hominis requires extended culture, special media or PCR analysis, it is not tested routinely, which in many cases delays diagnosis and correct treatment. In our case, a diagnosis of M. hominis septic arthritis was made after 9 weeks by PCR analysis and culture of joint fluid. The patient responded well to an 8-week treatment course of moxifloxacin and doxycycline.
32507051 IRAK1 Gene Polymorphism in Rheumatoid Arthritis. 2021 Feb Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. The present study intends to specify rs1059703, rs4810485, and rs1883832 gene polymorphisms of interleukin-1 receptor-associated kinase (IRAK1) and cluster of differentiation 40 (CD40) in RA. IRAK1 is a serine/threonine kinase and CD40 is a tumor necrosis factor receptor, both of which are involved in RA. There are conflicting results on functional effects of these polymorphisms, so we performed this research for a more accurate estimation on rheumatoid arthritis risk. Methods: Two-hundred RA patients diagnosed according to ACR criteria and 200 normal controls participated in this case-control study. DNA Purification kit (Gene Transfer Pioneers, GTP) was used for genomic DNA extraction and three SNPs, including IRAK1 rs1059703 (C/T), CD40 rs1883832 (C/T) and rs4810485 (G/T), were genotyped by PCR-RFLP. The genotypes and allele frequencies of SNPs were analyzed by chi-square test to detect their contribution to RA. Results: A significant correlation was found between rs1059703 T allele (OR = 2.36, 95% CI = 1.7-3.1, p = .0001) and TT and CT genotypes (TT genotype, OR = 2.54, 95%CI = 1.2-3.3, P = .0078, CT genotype; OR = 2.18 95%CI = 1.4-3.2P = .0002) of rs1059703 C/T polymorphism in terms of susceptibility to RA in recessive and over-dominant models. Alleles and genotypes of CD40 SNPs were not significantly different between RA cases and controls. The findings showed significant differences in rs1059703 IRAK1 genotypes with medical and laboratory features of patients. Conclusion: Our results showed that the rs1059703 T allele (risk allele) of IRAK1 gene increases the risk of RA and the severity of disease, affecting the onset age of RA in Iranian patients.
34798162 Intestinal metabolism and absorption mechanism of multi-components in Gaultheria leucocarp 2022 Mar 25 ETHNOPHARMACOLOGICAL RELEVANCE: Dianbaizhu (Gaultheria leucocarpa var. yunnanensis) as a Chinese folk medicine exerts significant treatment effects on rheumatoid arthritis (RA) with a long historical time. Our previous reports showed that the anti-rheumatic arthritis fraction (ARF) extracted and enriched from Dianbaizhu possessed good druggability, which was better than its single active ingredients. However, the intestinal transport characteristics and mechanism of ARF have not been elucidated to date. AIM OF THE STUDY: In order to illustrate the role of active ingredients of ARF in alleviating RA and promoting the development of dosage forms, the intestinal metabolism, absorption properties and mechanism of ARF in vitro and in situ models were investigated. MATERIALS AND METHODS: Firstly, after incubating with 4 intestinal segments (duodenum, jejunum, ileum, and colon), 7 key components in ARF, including MATG-B, (+)-catechin, MSTG-A, Gaultherin, chlorogenic acid, quercetin, and kaempferol were quantitatively analyzed by a high-performance liquid chromatography (HPLC). Secondly, combining the physiological and pathological rats, the in situ single-pass intestinal perfusion and in vitro everted gut sacs of rats were performed to investigate the absorption features and transport mechanisms of ARF using HPLC and HPLC-Q-TOF-MS/MS. Subsequently, in situ studies were employed to determine the effect of P-glycoprotein (P-gp) inhibitor (verapamil) on the transport characteristics of ARF in RA model rats. RESULTS: Comparing the absorption parameters of ARF incubated in different intestinal segments, data showed that the absorption of ARF in the small intestine was significantly stronger than that of the colon (P < 0.01). The number of characterized prototype components was subjected to the incubation time, drug concentration and rat body condition, but not the intestinal segments. There were no significant differences in the number of metabolites among different intestinal segments, administration concentrations and incubation time. The best small intestinal absorption site of ARF was duodenum and ileum in normal and model rats, respectively. The P(eff) values of 7 index compounds were all higher than 0.2 × 10(-4)cm/s, and the F(a) values of 7 index compounds were all greater than 20% in the in situ perfusion investigation. The results showed that MSTG-B, MSTG-A and Gaultherin were likely to be substrates of P-gp as verapamil significantly enhanced their P(eff) and K(a) values, while other ingredients were not P-gp substrates. CONCLUSIONS: The intestinal membrane permeability of ARF was good. Its intestinal absorption mechanisms mainly involved active transportation processes and passive diffusion. Besides, this report provided data support and basis for clinical development, bioavailability improvement and formulation design.
33518384 Defects in ubiquitination and NETosis and their associations with human diseases. 2021 Jun Various autoimmune diseases are associated with defects in protein degradation and NETosis. This review aims to examine defects in ubiquitination and NETosis and their associations with human disease. This study involved a systematic search of electronic databases, including PubMed, EBSCO, and LILACS, to locate articles on the relationship between human disease and defects in protein degradation and NETosis. Ubiquitination and NETosis can trigger a cascade of events that affect immune system function and impact the body's ability to fight disease. Ubiquitination is implicated in various disorders, such as Liddle's syndrome, Alzheimer's disease, and other neurodegenerative disorders, whereas NETosis has been linked to antineutrophil cytoplasmic antibody associated vasculitis, accelerated atherosclerosis, thrombosis, rheumatoid arthritis, antiphospholipid antibody syndrome, type 1 diabetes mellitus, and renal inflammatory complications. Researchers have attempted for years to identify the link between neurodegenerative disease and ubiquitination. Previous studies analysed the relationships between different autoimmune disorders and NETosis and identified various ubiquitin conjugates and NET remnants that trigger disease development and progression. Ubiquitination and NETosis play key roles in the emergence and progression of neurodegenerative and autoimmune disorders. Further investigation is needed to elucidate the mechanisms underlying the relationships between these disorders and biological processes.
32841693 Alternative therapy of rheumatoid arthritis with a novel transdermal patch containing Sieg 2021 Jan 30 ETHNOPHARMACOLOGICAL RELEVANCE: Siegesbeckiae Herba (SiH) is a traditional anti-rheumatic herbal medicine in China. A SiH derived product, Phynova Joint and Muscle Relief Tablets™, has been granted the UK license in 2015. Although transdermal delivery provides better patient compliance and relative constant plasma drug concentration, the feasibility of transdermal delivery of SiH was not clear. AIM OF THE STUDY: The aim of the present study was to develop a novel transdermal patch containing SiH extract for alternative therapy of rheumatoid arthritis. MATERIALS AND METHODS: SiH extract containing 48.5% (w/w) of kirenol was prepared from Siegesbeckia pubescens Makino. Then transdermal patches containing SiH extract were prepared by the solvent evaporation technique. The formulation of the transdermal patch was optimized based on the in vitro skin permeation experiment. Finally, the anti-inflammatory and analgesic activity of the optimal patch were evaluated by chronic inflammation model induced by complete Freund's adjuvant (CFA) and writhing model induced by acetic acid, separately. RESULTS: Oleic acid (OA) showed the maximum permeation enhancement effect with the enhancement ratio (ER) values of 3.32. Therefore, OA was used as a permeation enhancer in the transdermal patch. The optimal formulation consisted of SiH extract (10% of the matrix, w/w), OA (10% of the matrix, w/w), DURO-TAK® 87-2287 (pressure sensitive adhesive matrix) and Scotchpak™ 9701 (backing layer). The optimal transdermal patch containing SiH extract significantly reduced the degree of paw swelling and number of writhing in inflammation model and writhing model, respectively. CONCLUSIONS: The developed transdermal patch containing Siegesbeckiae Herba extract showed good anti-inflammatory and analgesic effects, which demonstrated a great potential for alternative therapy of rheumatoid arthritis.