Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
29748892 Updated pharmacological management of rheumatoid arthritis for women before, during, and a 2019 Feb BACKGROUND: Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can cause significant disability, morbidity, mortality, and impaired fertility. It commonly affects women of childbearing age. Managing rheumatoid arthritis (RA) in the perinatal period poses challenges. There is concern about the teratogenic effects of many traditional disease-modifying anti-rheumatic drugs (DMARDs) and an ever-growing list of new therapeutic options with limited data in pregnancy and breastfeeding. AIMS: We aimed to create a standardized approach to pharmacological management of RA patients seen in our newly established Rheumatology and Reproductive Health Service. METHODS: We reviewed relevant publications on the use of anti-rheumatic drugs in pregnancy. These include recent guidelines from The British Society for Rheumatology (BSR) and British Health Professionals in Rheumatology (BHPR) and the European League Against Rheumatism (EULAR). RESULTS: After considering relevant publications, we developed a Saint Vincent's University Hospital/National Maternity Hospital consensus protocol for evidence-based medication in pregnancy in RA. CONCLUSIONS: RA tends to improve during pregnancy and flare postpartum. Several anti-rheumatic medication options during pregnancy and breastfeeding are now available including anti-tumor necrosis factor (anti-TNF) agents. Good disease control at all stages of reproduction is important to ensure best outcome for both mother and baby.
28944421 Metabolic abnormalities in rheumatoid arthritis patients with comorbid diabetes mellitus. 2018 Jan The metabolic characteristics of rheumatoid arthritis (RA) or diabetes mellitus (DM) have been studied, but the metabolic abnormalities of RA patients complicated with DM are not completely understood. Therefore, we recruited RA patients with DM to investigate the metabolic abnormalities in these patients. We collected data of RA patients with DM and age- and sex-matched RA and DM patients from Changhai Hospital's electronic medical record system. Data of demographically matched healthy controls were also collected from the health management system of the Hangzhou Sanatorium of People's Liberation Army. Blood pressure, uric acid, glucose, and lipid levels were compared. The clinical data of RA with DM (n = 104), DM (n = 100), and RA (n = 100) patients and healthy controls (n = 100) were collected and compared. RA patients with DM had higher blood pressure and lower high-density lipoprotein cholesterol levels than the other three groups, a higher triglycerides (TG) level than healthy controls and RA patients, and a lower TG level than DM patients. RA patients with DM exhibited a relatively high proportion of metabolic abnormalities based on existing standards. Our study examined metabolic abnormalities in RA patients with DM for the first time, and our results suggest that clinicians should pay more attention to the metabolic abnormalities of RA patients with DM.
29621504 Interleukin10-1082 A/G polymorphism: Allele frequency, correlation with disease markers, m 2018 May BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder of unknown etiology. IL-10 stimulates B cell survival and is involved in antibody isotype switching. The serum IL-10 levels are increased in RA patients. Ethnicity influences polymorphisms in cytokine genes. Therefore, this study was designed to explore possible association, if any, between polymorphism of IL10-1082 A/G, serum cytokine levels, inflammatory markers and gene expression in RA patients of North India. METHODOLOGY: A total of 187 RA patients classified according to American college of rheumatology 2010 criteria and 214 controls were included in the study. Levels of serum IL-10 and inflammatory markers were estimated by ELISA. PCR-RFLP was used to analyze IL10-1082 A/G polymorphism. Quantitative real time PCR was used to measure the mRNA expression of IL-10 gene. RESULTS: The serum inflammatory markers were significantly higher in RA patients. Circulating IL-10 levels were positively and significantly correlated with RF (r = 0.28), anti-CCP (r = 0.26), CRP (r = 0.17) and mRNA expression levels (r = 0.59) among RA patients. Homozygous mutant variant (GG) and heterozygous mutant variant (AG) were associated with patients of RA (OR = 2.87 and 1.55, p < 0.05) as compared to controls. The association still persisted when the heterozygous and homozygous mutants (AG + GG) were clubbed together (OR = 1.67, p < 0.05). The mRNA expression of IL-10 was found to be 3.63 folds higher (housekeeping gene, β-actin) and 2.42 folds higher (housekeeping gene, 18S rRNA) in RA patients as compared to controls. CONCLUSION: The results indicate that IL10-1082 A/G polymorphism is associated with genetic susceptibility/predisposition to RA in North Indian population.
29428486 Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal ce 2018 Apr BACKGROUND: In this study, we intend to assess the safety and tolerability of intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in patients with rheumatoid arthritis (RA) and to determine the preliminary clinical efficacy data in this population. The trial registration numbers are as follows: Royan Institute Ethics Committee: AC/91/1133; NCT01873625. METHODS: This single-center, randomized, triple-blind, placebo-controlled phase 1/2 clinical trial randomized RA patients with knee involvement to receive either an intra-articular knee implantation of 40 million autologous bone marrow-derived MSCs per joint or normal saline (placebo). Patients were followed up for 12 months to assess therapy outcomes. RESULTS: A total of 30 patients, 15 in the MSC group and 15 in the placebo group, enrolled in this study. There were no adverse effects reported after MSC administration or during follow-up. Patients who received MSCs had superior findings according to the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analogue scale (VAS), time to jelling and pain-free walking distance. However, this improvement could not be significantly sustained beyond 12 months. The MSC group exhibited improved standing time (P = 0.01). In addition, the MSCs appeared to contribute to reductions in methotrexate and prednisolone use. CONCLUSION: Intra-articular knee implantation of MSCs appeared to be safe and well tolerated. In addition, we observed a trend toward clinical efficacy. These results, in our opinion, have justified the need for further investigations over an extended assessment period with larger numbers of RA patients who have knee involvement.
29168210 Abrupt generalized pustules in patients with rheumatoid arthritis and interstitial lung di 2018 Feb We report a case of a 30-year-old Chinese woman with rheumatoid arthritis and interstitial lung disease who abruptly developed generalized pustules and a high fever for 10 days. She had been taking oral prednisone, iguratimod and total glucosides of peony regularly for 5 months prior. In addition, she had taken metronidazole for 3 days 20 days prior which she had used before with no adverse reaction. She had no history of similar lesions and psoriasis. A biopsy of a pustule on the back showed spongiform pustule of Kogoj. She was suspected of having generalized pustular psoriasis or acute generalized exanthematous pustulosis. Finally, she was diagnosed with generalized pustular psoriasis (von Zumbusch type) considering the characteristics and clinical course of the rash. In addition to the above three drugs, systemic cyclosporin (5 mg/kg per day) was applied, and the lesions and fever resolved within the proceeding 2 months.
29742751 Slowly Repeated Evoked Pain as a Marker of Central Sensitization in Fibromyalgia: Diagnost 2018 Jul/Aug OBJECTIVE: This study examined the diagnostic accuracy and test-retest reliability of a novel dynamic evoked pain protocol (slowly repeated evoked pain [SREP]) compared with temporal summation of pain (TSP), a standard index of central sensitization. METHODS: Thirty-five fibromyalgia (FM) patients and 30 rheumatoid arthritis (RA) patients completed, in pseudorandomized order, a standard mechanical TSP protocol (10 stimuli of 1-second duration at the thenar eminence using a 300-g monofilament with 1 second interstimulus interval) and the SREP protocol (9 suprathreshold pressure stimuli of 5-second duration applied to the fingernail with a 30-second interstimulus interval). To evaluate reliability for both protocols, they were repeated in a second session 4-7 days later. RESULTS: Evidence for significant pain sensitization over trials (increasing pain intensity ratings) was observed for SREP in FM (p < .001) but not in RA (p = .35), whereas significant sensitization was observed in both diagnostic groups for the TSP protocol (p < .008). Compared with TSP, SREP demonstrated higher overall diagnostic accuracy (87.7% versus 64.6%), greater sensitivity (0.89 versus 0.57), and greater specificity (0.87 versus 0.73) in discriminating between FM and RA patients. Test-retest reliability of SREP sensitization was good in FM (intraclass correlations = 0.80), and moderate in RA (intraclass correlations = 0.68). CONCLUSIONS: SREP seems to be a dynamic evoked pain index tapping into pain sensitization that allows for greater diagnostic accuracy in identifying FM patients compared with a standard TSP protocol. Further research is needed to study mechanisms underlying SREP and the potential utility of adding SREP to standard pain evaluation protocols.
29195001 Foot Barriers in Patients With Early Rheumatoid Arthritis: An Interview Study Among Swedis 2018 Sep OBJECTIVE: Foot impairments are related to reduced mobility and participation restrictions in daily activities in patients with established rheumatoid arthritis (RA). The new biologic medications are effective and reduce disease activity, but not disability to the same extent. Foot impairments are assumed to be related to participation restrictions also in patients with early RA, diagnosed after the introduction of biologic medications. Knowledge of foot impairments needs to be explored further after the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs). The aim of this study was to explore the patients' perspective of foot impairments related to early RA. METHODS: The sample included 59 patients (ages 20-63 years) who were interviewed about participation dilemmas in daily life using the critical incident technique. The interviews were audio-recorded and transcribed. Data related to foot impairments were extracted and analyzed thematically. A research partner validated the analysis. RESULTS: Patients with early RA described a variety of participation restrictions related to foot impairments: foot hindrances in domestic life, foot impairments influencing work, leisure activities restricted by one's feet, struggling to be mobile, and foot impairments as an early sign of rheumatic disease. CONCLUSION: There is a need to focus on foot impairments related to early RA, and for health care professionals to understand these signs. A suggestion for future research is to conduct a longitudinal followup of foot impairment related to medication, disease activity, and disability in patients diagnosed after the introduction of bDMARDs.
29371695 Metformin ameliorates experimental-obesity-associated autoimmune arthritis by inducing FGF 2018 Jan 26 Rheumatoid arthritis (RA) is a systemic autoimmune disease involving excessive inflammation. Recently, RA associated with a metabolic disorder was revealed to be non-responsive to RA medications. Metformin has been reported to have a therapeutic effect on RA and obesity. The aim of this investigation was to study the therapeutic effect and the underlying mechanism of metformin's action in an experimental model of collagen-induced arthritis (CIA) associated with obesity. Metformin was administered daily for 13 weeks to mice with CIA that had been fed a high-fat diet. Metformin ameliorated the development of CIA in obese mice by reducing autoantibody expression and joint inflammation. Furthermore, metformin decreased the expression levels of pSTAT3 and pmTOR and had a small normalizing effect on the metabolic profile of obese CIA mice. In addition, metformin increased the production of pAMPK and FGF21. Metformin also induced the differentiation of brown adipose tissue (BAT), which led to a reciprocal balance between T helper (Th) 17 and regulatory T (Treg) cells in vitro and in vivo. These results suggest that metformin can dampen the development of CIA in obese mice and reduce metabolic dysfunction by inducing BAT differentiation. Thus, metformin could be a therapeutic candidate for non-responsive RA.
29070531 Affinity maturation shapes the function of agonistic antibodies to peptidylarginine deimin 2018 Jan OBJECTIVES: The citrullinating enzyme peptidylarginine deiminase type 4 (PAD4) is the target of a polyclonal group of autoantibodies in patients with rheumatoid arthritis (RA). A subgroup of such antibodies, initially identified by cross-reactivity with peptidylarginine deiminase type 3 (PAD3), is strongly associated with progression of radiographic joint damage and interstitial lung disease and has the unique ability to activate PAD4. The features of these antibodies in terms of their T cell-dependent origin, genetic characteristics and effect of individual antibody specificities on PAD4 function remain to be defined. METHODS: We used PAD4 tagged with the monomeric fluorescent protein mWasabi to isolate PAD4-specific memory B cells from anti-PAD4 positive patients with RA and applied single cell cloning technologies to obtain monoclonal antibodies. RESULTS: Among 44 single B cells, we cloned five antibodies with PAD4-activating properties. Sequence analysis, germline reversion experiments and antigen specificity assays suggested that autoantibodies to PAD4 are not polyreactive and arise from PAD4-reactive precursors. Somatic mutations increase the agonistic activity of these antibodies at low calcium concentrations by facilitating their interaction with structural epitopes that modulate calcium-binding site 5 in PAD4. CONCLUSIONS: PAD4-activating antibodies directly amplify a key process in disease pathogenesis, making them unique among other autoantibodies in RA. Understanding the molecular basis for their functionality may inform the design of future PAD4 inhibitors.
30236749 Clinical, Patient-Reported, and Ultrasound Outcomes from an Open-Label, 12-week Observatio 2020 Sep OBJECTIVES: To assess the effectiveness and safety of certolizumab pegol (CZP) in Spanish patients with RA. MATERIALS AND METHODS: SONAR (NCT01526434), a 12-week, open-label, prospective, observational, multicenter study. Patients with active RA for ≥3 months, according to ACR criteria, were treated with CZP (400mg at Weeks 0, 2 and 4, then 200mg every 2 weeks). The primary effectiveness endpoint was change from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12. Other assessments included DAS28(ESR), patient's assessment of arthritis pain (PtAAP-VAS) and Short Form 36-item Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS). Joint inflammation was investigated using Power Doppler (PD) ultrasound (US), to detect effusion, synovial hypertrophy and synovial PD signal. PDUS outcomes assessed CFB to Week 12 in synovial hypertrophy, effusion and PD signal indices. RESULTS: A total of 77/80 enrolled patients received ≥1 dose of CZP. The 12-week mean reduction from baseline (SD) was -0.6 (0.6) for HAQ-DI and -2.2 (1.5) for DAS28(ESR). PtAAP-VAS was reduced from baseline (mean [SD]: -36.8 [26.8]) and improvements in SF-36 PCS and SF-36 MCS were reported. Synovial hypertrophy, effusion and PD signal indices were reduced from baseline to Week 12. One death was reported during the study. CONCLUSIONS: Spanish patients with RA demonstrated improvements in clinical, PDUS and patient-reported outcomes over 12 weeks of CZP treatment. No new safety signals were identified, and the safety profile was in line with previous CZP studies. These results support previous clinical trial findings investigating CZP treatment for active RA.
29974186 Non-obese visceral adiposity is associated with the risk of atherosclerosis in Japanese pa 2018 Sep Rheumatoid arthritis (RA) patients often have altered body composition including reduced muscle mass and increased fat mass. Some RA patients are likely to increase visceral fat without obesity [Body Mass Index (BMI) ≥ 25]. The objective of the study was to determine the association between obesity and/or visceral adiposity and the risk for atherosclerosis in Japanese RA patients. Obesity was evaluated using the BMI, with visceral adiposity evaluated using the visceral fat area (VFA) and the visceral/subcutaneous fat ratio (V/S ratio), quantified using the dual bioelectrical impedance method. Atherosclerosis was evaluated based on the intima-media thickness (IMT) and Plaque score (PS) of the carotid artery, measured using ultrasonography. Multivariate analysis was performed to determine the factors associated with IMT and PS. IMT and PS were compared among groups of patients sub-classified according to BMI and VFA levels. The V/S ratio was higher in RA patients than healthy controls, after adjustment for age, BMI, and waist circumference. On multivariate analysis, the V/S ratio, but not the BMI, was independently associated with the IMT and PS. Among the sub-classifications for BMI and VFA, non-obese patients with a high visceral adiposity (18.5 ≤ BMI < 25 kg/m(2) and VFA ≥ 100 cm(2)) had the highest IMT (mean IMT, 0.93 ± 0.29 mm; maximum IMT, 1.44 ± 0.71 mm) and PS (1.43 ± 0.61), compared to all other BMI and VFA subgroups. RA patients have increased visceral adiposity, which is associated with a high prevalence of atherosclerotic of plaques. Non-obese RA patients who have visceral adiposity have a specifically higher risk for atherosclerosis.
29720240 Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease 2018 May 2 BACKGROUND: Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE. METHODS: RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target. RESULTS: We demonstrated that the plasma cell/plasmablast-related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from patients with arthralgia, undifferentiated arthritis (UA), early RA and established RA as compared to healthy controls and control patients with osteoarthritis. In addition, the highest CD38 expression was observed on plasma cells and plasmablasts compared to natural killer (NK) cells, classical dendritic cells (DCs), plasmacytoid DCs (pDCs) and T cells, in blood from healthy controls and patients with SLE and RA. Furthermore, IHC showed CD38 staining in the same region as CD3 and CD138 staining in synovial tissue biopsies from patients with early RA. Most importantly, our data show for the first time that daratumumab effectively depletes plasma cells/plasmablasts in PBMC from patients with SLE and RA in a dose-dependent manner ex vivo. CONCLUSION: These results indicate that CD38 may be a potential target for RA disease interception and daratumumab should be evaluated clinically for the treatment of both RA and SLE.
29495891 Tocilizumab in the treatment of adult rheumatoid arthritis. 2018 Mar 1 Rheumatoid arthritis (RA) is the most prevalent immune-mediated chronic rheumatic disease and is associated with joint destruction and disability. Therapeutic strategies, including biological disease-modifying antirheumatic drugs (bDMARDs) have improved the prognosis and quality of life of RA patients. Tocilizumab (TCZ) is a humanized monoclonal antibody against IL-6 receptor licensed in 2009 that has demonstrated clinical efficacy in various adult RA populations. RA management guidelines and recommendations consider TCZ as one of the bDMARDS indicated after methotrexate or other conventional synthetic DMARDs and/or TNF inhibitors failure in adult RA. Of particular interest is the demonstration of its effectiveness in monotherapy in comparison with other bDMARDs. Recent observational studies have shown good results for the safety profile of TCZ with no new alert signals.
29316201 Women's situation-specific strategies in managing participation restrictions due to early 2018 Jun INTRODUCTION: The present study explored how women describe their use of situation-specific strategies when managing rheumatoid arthritis (RA). The aim was also to compare women's strategies with those of men, and see the extent to which they used the same strategies. METHODS: The data were collected using semi-structured interviews based on the critical incident technique. The sample consisted of women with early rheumatic arthritis (n = 34), and the results were compared with data reported in a previous study on men (n = 25) from the same cohort. The patient-described participation restrictions due to RA were firstly linked to the domains of the International Classification of Functioning, Disability and Health (ICF). The different strategies used were then categorized. The study was approved by the Research Ethics Committee of the Faculty of Health Sciences, Linköping University, Sweden. RESULTS: The study found that women used four situation-specific strategies: adjustment, avoidance, interaction and acceptance. The same strategies had been found previously in interviews with men with RA. Women and men used these strategies to a similar extent in the ICF domains of mobility; major life arenas; domestic life; interpersonal interactions and relationships; and community, social and civic life. However, some differences were found, relating to the reported activities in self-care and domestic life, in which women reported using strategies to a greater extent than men. CONCLUSIONS: Women and men used four types of situation-specific strategies in managing RA; adjustment, avoidance, interaction and acceptance. These situation-specific strategies provide useful knowledge, in terms of multidisciplinary rehabilitation and for patients' significant others.
29350566 ABP 501 for the treatment of rheumatoid arthritis. 2018 Mar Rheumatoid arthritis (RA) is an autoimmune disease, which has a negative impact on the ability to perform activities daily. Tumour necrosis factor α (TNF) is a cytokine with diverse cellular effects, and a key regulator of the inflammatory response. ABP 501 is a biosimilar to adalimumab, a TNF inhibitor. Areas covered: In this review, we examined ABP 501, as a biosimilar candidate to adalimumab in the treatment of RA focusing on the available data. Current data indicate that ABP 501 is a highly similar alternative to adalimumab in terms of safety, efficacy, tolerability and immunogenicity. ABP 501 has already been approved by health authorities in Europe and the United States of America, as a subcutaneous (s.c.) therapy option for the treatment of patients with RA, but also for the full spectrum approved for its bio-originator adalimumab. Expert opinion: Current body of evidence suggests that all biologic activities have been demonstrated to be equivalent between ABP 501 and the originator, including binding rates and affinity to TNF, and also the effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC). Therefore, it is fully expected to have same efficacy and safety in all indications.
29500799 Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is t 2018 Jul Two different Janus kinase (JAK) inhibitors-baricitinib and tofacitinib-are effective and licensed in active rheumatoid arthritis (RA). There have been recent concerns about potential thromboembolic risks with these drugs. Concerns about baricitinib focus on clinical trial findings. Using all publically available data, we estimate thromboembolic risks are approximately five events per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib have been raised by analyses of the Federal Drug Administration Adverse Event Reporting System (FAERs). These show some evidence of increased risks of pulmonary thrombosis, though not pulmonary embolism or venous thrombosis. Observational studies suggest in the general population and non-RA controls there are one to four thromboembolic events per 1000 patient years. In RA, thromboembolic risks increase to three to seven per 1000 patient years. The impact of biologics and disease-modifying anti-rheumatic drugs (DMARDs) on disease risk appears minimal, and the number of thromboembolic events is between four and eight per 1000 patient years. In the short term, full details of thromboembolic events in trials of JAK inhibitors need to be published. As the numbers of thromboembolic events will be small and patients enrolled in trials are not representative of all RA patients who may receive JAK inhibitors, this information is unlikely to provide definitive answers. Consequently, in the longer term, large observational studies are needed to accurately quantify thromboembolic risks attributable to JAK inhibitors and other drugs used to treat RA, and differentiate these from risks attributable to RA itself and its comorbidities.
30418113 Agreement between semiquantitative and quantitative Doppler scoring systems for the assess 2018 Nov OBJECTIVES: To compare colour Doppler (CD) versus power Doppler (PD) semiquantitative and quantitative scoring of synovial vascularisation and to evaluate the relationship between semiquantitative and quantitative scores in patients with rheumatoid arthritis (RA). METHODS: One hundred RA patients underwent B-mode, PD, and CD assessments of 12 joints at two European centres. Each joint with synovial hypertrophy (SH) detected on B-mode was semiquantitatively scored (0-3) for PD (SPD score) and CD (SCD score) synovial signal. PD and CD synovial signal were also quantitatively scored (0-100%) (QPD and QCD scores, respectively) using a software integrated in the US equipment for counting the colour fraction. RESULTS: We found SH in 184 joints. SPD and SCD agreed in 92.3% (95%CI: 88.4; 96.2%) of paired scores, with Kendall rank correlation coefficient tau-b=0.95. QPD and QCD scores were highly correlated (Pearson's coefficient=0.70) but Blamd-Altman plot showed insufficient agreement, being the QCD scores systematically slightly higher than the QPD scores. The comparison of mean values of QPD and QCD between scores of SPD and SCD, respectively, showed significant differences between grade 0 and grade 1 (p<0.001), and grade 2 and grade 3 (p=0.042 and p=0.007, respectively) but not between grade 1 and 2 (p=0.154 and p=0.150, respectively). CONCLUSIONS: The SPD and SCD scores were concordant and the QPD and QCD scores highly correlated but were not concordant. There was an overlap between SPD and SCD mild and moderate scores regarding QPD and QCD scores.
29888275 Azilsartan as "Add-On" Treatment with Methotrexate Improves the Disease Activity of Rheuma 2018 OBJECTIVE: The present study aimed to evaluate the efficacy and safety of azilsartan (Azil) as "add-on" treatment with methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: This single center, randomized, placebo-controlled, double-blind, pilot study included 64 patients with active RA. Patients received either placebo or Azil in addition to their currently used MTX doses for 90 days. The primary outcomes were DAS-28, SDAI, HAQ-DI, CDAI, EGA, and swollen and tender joints count. The secondary outcomes were the changes in the pain visual analogue scale (VAS-100), serum levels of TNF-α, IL-1β, IL-6, and anti-CCP, the lipid profile, and the markers of kidney and liver functions in the two groups at baseline and after 90 days. RESULTS: After 90 days, most clinical scores were significantly better in the Azil-treated group than in the placebo group. All inflammatory biomarkers were significantly improved after treatment with MTX + Azil compared to baseline and placebo group. No safety concerns were reported during the study period. CONCLUSIONS: Azilsartan improved the effects of methotrexate on the clinical scores and certain inflammatory biomarkers of patients with active RA. TRIAL REGISTRATION: The protocol was registered under the number 507/SA/1024 at the local clinical studies database, College of Medicine, Sulaimani University.
30471320 Anti-rheumatoid arthritis effects in adjuvant-induced arthritis in rats and molecular dock 2018 Sep BACKGROUND AND PURPOSE: Polygonum orientale L. (family: Polygonaceae), named Hongcao in China, has effects of dispelling wind and dampness, promoting blood circulation, and relieving pain. Our group has already studied and confirmed that POEa and POEe (ethyl acetate and ethyl ether extract of P. orientale, respectively) had anti-inflammatory and analgesic effects in early research, which was mainly relevant to the existence of flavonoids. According to the clinical application of P. orientale in traditional Chinese medicine, it has long been used for rheumatic arthralgia and rheumatoid arthritis. Therefore, our group further explored whether flavonoids of P. orientale have anti-rheumatoid arthritis effect and how does they play this role. METHODS: Dried small pieces of the stems and leaves of P. orientale were decocted with water and partitioned successively to obtain POEa and POEe, respectively. The anti-rheumatoid arthritis effect of P. orientale was studied by using a Freund's complete adjuvant (FCA)-induced arthritis (AIA) in a rat model. The levels of PGE2, TNF-α, and IL-1β in serum of AIA rats were detected by enzyme linked immunosorbent assay (ELISA) to explore its mechanisms. In addition, we computationally studied the relationships between the 15 chemical components of POEa and POEe, and the currently focused 9 target proteins of rheumatoid arthritis by molecular docking. RESULTS: Pharmacological experiments showed that POEa and POEe significantly ameliorate symptoms of rheumatoid arthritis via reducing paw swelling volume, arthritis score, and thymus and spleen indices, as well as increasing body weight in AIA rats. Simultaneously, the concentrations of PGE2, TNF-α, and IL-1β were significantly decreased by POEa and POEe. Histopathology revealed noticeable reduction in bone and cartilage, synovial hyperplasia, inflammatory cell infiltration, cartilage surface erosion, and joint degeneration by POEa and POEe treatment. In addition, the molecular docking studies showed that docking scores of 14 chemical compositions (including 12 flavonoids and 2 phenolic acids) of POEa and POEe with anti-rheumatoid arthritis protein targets were better than the complexed ligands of the anti-rheumatoid arthritis protein targets. Among them, six flavonoids in POEa and POEe had more docking protein targets (n ≥ 3). Five anti-rheumatoid arthritis targets including high-temperature requirement A1 protease (HtrA1), janus kinase 1 (JAK1), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (i-NOS), and prostaglandin E2 (PGE2) had better docking score compared with the complexed ligands. Moreover, most of the chemical components in POEa and POEe showed strong interaction with HtrA1. CONCLUSIONS: The flavonoids of P. orientale have anti-rheumatoid arthritis effect. In addition, the molecular docking results indicate that quercetin, catechol, orientin, and other six flavonoids may be closely related to HtrA1, JAK1, COX-2, i-NOS, and PGE2 protein target receptors. It suggests that these chemical compositions form strong protein-ligand complexes with these protein targets, especially HtrA1 to exert anti-rheumatoid arthritis. Further experimental studies show that mechanisms of anti-rheumatoid arthritis effects may also be relevant to inhibit the levels of PGE2, TNF-α, and IL-1β in serum. Therefore, our group can further explore the possible active ingredients and mechanisms of the anti-rheumatoid arthritis effects of flavonoids, and focus on the inhibition of the expression of inflammatory factors and the TGF-β1/Smad signaling pathway associated with HtrA1 protein target receptors, which can provide a direction and powerful reference for the action mechanism and drug research of anti-rheumatoid arthritis of flavonoids in P. orientale.
28741989 Mithramycin has inhibitory effects on gliostatin and matrix metalloproteinase expression i 2018 May OBJECTIVES: Gliostatin (GLS) has angiogenic and arthritogenic activities and enzymatic activity as thymidine phosphorylase. Aberrant GLS production has been observed in the synovial membranes of patients with rheumatoid arthritis (RA). Matrix metalloproteinases (MMPs) are involved in joint destruction. Promoters of GLS and some MMP genes contain Sp1 binding sites. We examined the inhibitory effect of the Sp1 inhibitor mithramycin on GLS-induced GLS and MMP expression in cultured fibroblast-like synoviocytes (FLSs). METHODS: Synovial tissue samples were obtained from patients with RA. FLSs pretreated with mithramycin were cultured with GLS. The mRNA expression levels of GLS and MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13 were determined using reverse transcription polymerase chain reactions. Protein levels were measured using enzyme immunoassay and gelatin zymography. RESULTS: GLS upregulated the expression of GLS itself and of MMP-1, MMP-3, MMP-9, and MMP-13, an effect significantly reduced by treatment with mithramycin. GLS and mithramycin had no effect on MMP-2 expression. CONCLUSIONS: Mithramycin downregulated the increased expression of GLS and MMP-1, MMP-3, MMP-9, and MMP-13 in FLSs treated with GLS. Because GLS plays a pathological role in RA, blocking GLS stimulation using an agent such as mithramycin may be a novel approach to antirheumatic therapy.