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ID PMID Title PublicationDate abstract
32927842 Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Ef 2020 Sep 10 BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease in which synovial fibroblasts (SF) play a key role. Baricitinib and Tofacitinib both act intracellularly, blocking the ATP-binding side of JAK proteins and thereby the downstream signalling pathway via STAT-3. Therefore, we investigated the role of organic cation transporters (OCTs) in Baricitinib and Tofacitinib cellular transport. METHODS: OCT expression was analysed in SF isolated from RA and osteoarthritis (OA) patients, as well as peripheral blood mononuclear cells. The interaction of Baricitinib and Tofacitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of both drugs was quantified using LC/MS. Target inhibition for both drugs was tested using Western blot for phosphorylated JAK1 and STAT3 upon stimulation with IL-6. RESULTS: MATE-1 expression increased in OASF compared to RASF. The other OCTs were not differentially expressed. The transport of Baricitinib was not OCT dependent. Tofacitinib; however, was exported from RASF in a MATE-1 dependent way. Tofacitinib and Baricitinib showed comparable inhibition of downstream signalling pathways. CONCLUSION: We observed different cellular uptake strategies for Baricitinib and Tofacitinib. Tofacitinib was exported out of healthy cells due to the increased expression of MATE1. This might make Tofacitinib the favourable drug.
32478484 Risk of incident autoimmune diseases in patients with thymectomy. 2020 Jul OBJECTIVES: The data concerning the association between Tx and ADs remain unclear and are scarce. This study was undertaken to investigate whether people with Tx are more likely to develop ADs, compared to those without Tx. METHODS: Individuals who received Tx between 2002 and 2015 were identified and matched on age and sex with individuals without Tx. We performed multivariate and stratified analysis using the Kaplan-Meier method and Cox proportional hazards models in order to estimate the association between Tx and the risk of developing ADs. RESULTS: A total of 2550 thymectomized (Txd) patients and 24,664.941 non-Txd comparison subjects were selected from NHIRD. Tx-MG (myasthenia gravis) as compared with general population (nonTx-nonMG), adjusted hazard ratio (aHR) were higher for incident Addison disease (aHR = 10.40, 95% CI 1.01-107), autoimmune hemolytic anemia (aHR = 21.54, 95% CI 2.06-14.8), Hashmoto thyroiditis (aHR = 5.52, 95% CI 1.34-34.7), ankylosing spondylitis (aHR = 2.73, 95% CI 1.09-6.84), rheumatoid arthritis (aHR = 5.25, 95% CI 1.79-15.47), primary Sjogren syndrome (pSS) (aHR = 3.77, 95% CI 1.30-11.0), and systemic lupus erythemtoasus (aHR = 10.40). Tx-nonMG as compared with general population, aHR were higher for incident autoimmune hemolytic anemia (aHR = 25.50), Hashmoto thyroiditis (aHR = 6.75) and systemic lupus erythematosus (SLE) (aHR = 13.38). NonTx-MG as compared with general population, aHR were higher for incident Hashmoto thyroiditis (aHR = 6.57), pSS (aHR = 4.50), SLE (aHR = 17.29), and systemic vasculitis (aHR = 25.86). INTERPRETATION: In conclusion, based on a retrospective cohort study throughout Taiwan, patients with Tx have a higher risk of new onset ADs than patients without Tx.
31650297 Association between rainfall and readmissions of rheumatoid arthritis patients: a time-str 2020 Jan It has been reported that local weather is associated with the symptoms of joint pain in patients with rheumatoid arthritis (RA), and many people believe their pain becomes worse when facing rainy days. However, limited studies explored the effects of weather on RA patients' healthcare-seeking behavior. Our study aimed to investigate the relationship between rainfall and readmission behavior of patients with RA in Hefei, China, based on hospitalization data from the First Affiliated Hospital of Anhui University of Chinese Medicine from May 2012 to June 2016 and weather data from National Meteorological Information Center during the same study period. Using a time-stratified case-crossover study design and conditional logistic regression, we found a negative association between current day rainfall and readmission (unadjusted: OR = 0.82, p < 0.05; adjusted: OR = 0.83, p < 0.1), which is contrary to our common belief. In lagged models, we observed that rainfall was significantly and positively associated with readmissions at lag 6 days (unadjusted: OR = 1.12, p < 0.1; adjusted: OR = 1.17, p < 0.05) and lag 7 days (unadjusted: OR = 1.13, p < 0.05; adjusted: OR = 1.21, p < 0.01). Additionally, stratified analyses showed the unanticipated finding was only statistically significant for younger patients (< 65 years) and females. Our study adds new evidence that the association between the healthcare-seeking behavior of patients with RA and local rainfall may be different, compared with the positive relationship between symptoms of joint pain and rainfall.
33168080 Gene expression identifies patients who develop inflammatory arthritis in a clinically sus 2020 Nov 9 BACKGROUND: Established rheumatoid arthritis (RA) patients display differentially expressed genes coding for cytokine/chemokine-mediated immunity compared to healthy controls. It is unclear, however, if in the pre-arthritis phase of clinically suspect arthralgia (CSA) expression of immune genes differ between patients who do or do not develop clinically evident inflammatory arthritis (IA). METHODS: Two hundred thirty-six consecutive patients presenting with arthralgia clinically suspected for progression to RA were followed until IA development or else for median 24 months (IQR 12-26). Baseline whole blood RNA expression was determined for a previously identified set of 133 genes associated with the innate and adaptive immune system by dual-color reverse-transcription multiplex ligation-dependent probe amplification (dcRT-MLPA) profiling. Cox proportional hazard models were used. RESULTS: Twenty percent of CSA patients developed IA. After correction for multiple testing, expression levels of six genes (IFNG, PHEX, IGF-1, IL-7R, CD19, CCR7) at the time of presentation were associated with progression to IA. PHEX and IGF-1 were highly correlated with each other (ρ = 0.97). In multivariable analysis correcting for the different genes, expressions of IL-7R and IGF-1 were independently associated with IA development (p = 0.025, p = 0.046, respectively). Moreover, IL-7R and IGF-1 remained significantly associated even after correction for known predictors (ACPA, CRP, imaging-detected subclinical joint inflammation; p = 0.039, p = 0.005, respectively). These genes are also associated with RA development. CONCLUSIONS: IL-7R and IGF-1 were differentially expressed between CSA patients who did or did not progress to IA, independent from regularly used predictors. These biomarkers may become helpful in prognostication of CSA patients. Furthermore, because both genes are associated with T cell functioning, T cell dysregulation may mediate progression from arthralgia to arthritis.
31853959 Carbamylation reduces the capacity of IgG for hexamerization and complement activation. 2020 Apr Carbamylation is a post-translational modification that can be detected on a range of proteins, including immunoglobulin (Ig)G, in several clinical conditions. Carbamylated IgG (ca-IgG) was reported to lose its capacity to trigger complement activation, but the mechanism remains unclear. Because C1q binds with high affinity to hexameric IgG, we analyzed whether carbamylation of IgG affects binding of C1q, hexamerization and complement-dependent cytotoxicity (CDC). Synovial tissues of rheumatoid arthritis (RA) patients were analyzed for the presence of ca-IgG in vivo. Synovial tissues from RA patients were analyzed for the presence of ca-IgG using mass spectrometry (MS). Monomeric or hexameric antibodies were carbamylated in vitro and quality in solution was controlled. The capacity of ca-IgG to activate complement was analyzed in enzyme-linked immunosorbent (ELISAs) and cellular CDC assays. Using MS, we identified ca-IgG to be present in the joints of RA patients. Using in vitro carbamylated antibodies, we observed that ca-IgG lost its capacity to activate complement in both solid-phase and CDC assays. Mixing ca-IgG with non-modified IgG did not result in effective inhibition of complement activation by ca-IgG. Carbamylation of both monomeric IgG and preformed hexameric IgG greatly impaired the capacity to trigger complement activation. Furthermore, upon carbamylation, the preformed hexameric IgG dissociated into monomeric IgG in solution, indicating that carbamylation influences both hexamerization and C1q binding. In conclusion, ca-IgG can be detected in vivo and has a strongly reduced capacity to activate complement which is, in part, mediated through a reduced ability to form hexamers.
32034029 Association between vitamin D and fatigue in patients with rheumatoid arthritis: a cross-s 2020 Feb 6 OBJECTIVES: In rheumatoid arthritis (RA), fatigue is an important complaint with a significant impact on quality of life. Vitamin D has modulatory effects on cells of the immune system and may potentially affect RA disease activity and thereby RA-related fatigue. The purpose of this study was to explore associations between fatigue and vitamin D status in patients with RA. DESIGN: Hypothesis-generating cross-sectional study. SETTING: Scheduled follow-up visits at a hospital-based general rheumatology clinic. PARTICIPANTS: Patients (n=169) with established RA. PRIMARY OUTCOME MEASURES AND ANLYSES: Fatigue, assessed by the Chalder fatigue questionnaire, and serum concentrations of 25-hydroxyvitamin D (25(OH)D), assessed by liquid chromatography-tandem mass spectrometry. Associations were analysed by correlation, and multivariate linear regression with adjustments for age, sex, body mass index, RA disease activity as measured by the Disease Activity Score 28-joint count C reactive protein (DAS28-CRP), psychological distress, pain and sleep. Fatigue was also compared across four groups based on the levels of serum 25(OH)D with cut points at 30, 50 and 75 nmol/L using one-way analysis of variance. RESULTS: Two-thirds of the patients (116/169, 69%) were classified with low RA disease activity, that is, a DAS28-CRP score below 3.2. Their mean (SD) serum 25(OH)D concentration was 56.3 (21.2) nmol/L, with 77 (45.6%) having values below 50 nmol/L and 12 patients (7.1%) below 30 nmol/L. The correlation between fatigue and serum concentrations of 25(OH)D was weak and not statistically significant, r = -0.14 (95% CI: -0.29 to 0.03, p=0.08). In the multivariate model, fatigue was significantly associated with RA disease activity, psychological distress and pain, but not with serum 25(OH)D. Fatigue did not differ across groups with varying levels of serum 25(OH)D. CONCLUSION: This cross-sectional study found no evidence of association between vitamin D and fatigue in patients with RA.
33066816 T helper cells in synovial fluid of patients with rheumatoid arthritis primarily have a Th 2020 Oct 16 BACKGROUND: The majority of CD4(+) T helper (Th) cells found in the synovial fluid (SF) of patients with rheumatoid arthritis (RA) express CXCR3, a receptor associated with Th1 cells. In blood, subsets of Th2 and Th17 cells also express CXCR3, but it is unknown if these cells are present in RA SF or how cytokines from these subsets affect cytokine/chemokine secretion by fibroblast-like synoviocytes (FLS) from patients with RA. METHODS: We examined the proportions of Th1, Th2, CXCR3(+)Th2, Th17, CXCR3(+)Th17, Th1Th17, peripheral T helper (TPh) and T follicular helper (TFh) cells in paired SF and blood, as well as the phenotype of TPh and TFh cells in RA SF (n = 8), by the use of flow cytometry. We also examined the cytokine/chemokine profile in paired SF and plasma (n = 8) and in culture supernatants of FLS from patients with chronic RA (n = 7) stimulated with Th-associated cytokines, by the use of cytometric bead arrays and ELISA. Cytokine receptor expression in FLS (n = 3) were assessed by the use of RNA sequencing and qPCR. RESULTS: The proportions of Th1 and CXCR3(+)Th2 cells were higher in SF than in blood (P < 0.05). TPh and PD-1(high)TFh in RA SF were primarily of a Th1 and a CXCR3(+)Th2 phenotype. Moreover, the levels of CXCL9, CXCL10, CCL20, CCL2, CXCL8, IL-6 and IL-10 were higher in SF than in plasma (P < 0.05). Lastly, IL-4, IL-13 and IL-17A induced RA FLS to secrete proinflammatory IL-6, CCL2, CXCL1 and CXCL8, while IFNγ mainly induced CXCL10. CONCLUSION: These findings indicate that not only Th1 but also CXCR3(+)Th2 cells may have a pathogenic role in RA synovial inflammation.
33401055 How should we treat palindromic rheumatism? A systematic literature review. 2021 Feb OBJECTIVES: To perform a systematic literature review (SLR) analysing all studies that reported on the efficacy and safety of pharmacological treatments for palindromic rheumatism (PR). METHODS: We performed a SLR using PubMed, Embase and Cochrane databases. Three main aspects of PR were considered: treating flares, preventing recurrence of flares (i.e. achieving remission), and preventing progression to RA or to other persistent arthritis. Quality assessment of the studies was performed using the Newcastle-Ottawa Scale (NOS). RESULTS: Twenty-seven articles met the inclusion criteria: 6 (22.2%) retrospective studies, 8 (29.6%) longitudinal studies, and 13 (48.1%) case series/case reports. No randomized controlled trials (RCTs) were found. Most of the studies (21/27, 77.7%) had a high risk of bias according to NOS. Non-steroidal anti-inflammatory drugs were the most commonly reported treatments for flares of PR, with variable results. Anti-malarials, such as hydroxychloroquine and chloroquine phosphate, showed efficacy in reducing the frequency of the flares and, to a lesser extent, in preventing progression to RA. There was minimal evidence in support of other conventional/biological disease modifying anti-rheumatic treatments, or corticosteroids. CONCLUSION: Although a frequent clinical dilemma for rheumatologists, the pharmacological management of PR has not been thoroughly evaluated, with no RCTs reported. Of all therapies, antimalarials have been the best studied and may be capable of reducing the recurrence of flares. The optimum treatment strategy for PR remains largely undefined and should be evaluated by robust RCTs in well-defined PR cohorts.
33087159 ASP5094, a humanized monoclonal antibody against integrin alpha-9, did not show efficacy i 2020 Oct 21 BACKGROUND: Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune condition characterized by joint synovial inflammation. Current treatments include methotrexate (MTX), biologic agents, and Janus kinase (JAK) inhibitors. However, these agents are not efficacious in all patients and there are concerns regarding side effects and risk of infection as these treatments target immune-related pathways. Overexpression and activation of integrin alpha-9 (α9) on fibroblast-like synoviocytes are associated with RA disease onset and exacerbation. The humanized immunoglobulin G1 monoclonal antibody ASP5094 was designed to inhibit human α9 and is currently under investigation for the treatment of RA. METHODS: This phase 2a, multicenter, randomized, placebo-controlled, double-blind, parallel-group study (NCT03257852) evaluated the efficacy, safety, and biological activity of intravenous ASP5094 10 mg/kg in patients with moderate to severe RA that was refractory to MTX. Patients received ASP5094 or placebo every 4 weeks for a total of three administrations. Both treatment groups used concomitant MTX. The primary efficacy endpoint was the proportion of patients who responded per American College of Rheumatology 50% improvement using C-reactive protein (ACR50-CRP) after 12 weeks of treatment. Biological activity of ASP5094 was assessed via pharmacokinetics and pharmacodynamics of known downstream effectors of α9. Safety was also assessed. RESULTS: Sixty-six patients were enrolled and randomized to placebo (n = 33) or ASP5094 (n = 33). In the primary efficacy analysis, ACR50-CRP response rates were 6.3% and 18.2% at week 12 in the ASP5094 and placebo groups, respectively; a difference of - 11.9, which was not significant (2-sided P value = 0.258). No trends in ACR50 response rates were observed in subgroups based on demographics or baseline disease characteristics, and no significant differences between placebo and ASP5094 were identified in secondary efficacy or pharmacodynamic endpoints, despite achievement of target serum concentrations of ASP5094. Most treatment-emergent adverse events were mild to moderate in severity, and ASP5094 was considered safe and well tolerated overall. CONCLUSION: Although no notable safety signals were observed in this study, ASP5094 was not efficacious in patients with moderate to severe RA with an inadequate response to MTX. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03257852 . Registered on 22 Aug. 2017.
32532753 Prevalence of hospital PCR-confirmed COVID-19 cases in patients with chronic inflammatory 2020 Sep BACKGROUND: The susceptibility of patients with rheumatic diseases and the risks or benefits of immunosuppressive therapies for COVID-19 are unknown. METHODS: We performed a retrospective study with patients under follow-up in rheumatology departments from seven hospitals in Spain. We matched updated databases of rheumatology patients with severe acute respiratory syndrome coronavirus 2-positive PCR tests performed in the hospital to the same reference populations. Rates of PCR+ confirmed COVID-19 were compared among groups. RESULTS: Patients with chronic inflammatory diseases had 1.32-fold higher prevalence of hospital PCR+ COVID-19 than the reference population (0.76% vs 0.58%). Patients with systemic autoimmune or immune-mediated disease (AI/IMID) showed a significant increase, whereas patients with inflammatory arthritis (IA) or systemic lupus erythematosus did not. COVID-19 cases in some but not all diagnostic groups had older ages than cases in the reference population. Patients with IA on targeted-synthetic or biological disease-modifying antirheumatic drugs (DMARDs), but not those on conventional-synthetic DMARDs, had a greater prevalence despite a similar age distribution. CONCLUSION: Patients with AI/IMID show a variable risk of hospital-diagnosed COVID-19. Interplay of ageing, therapies and disease-specific factors seem to contribute. These data provide a basis to improve preventive recommendations to rheumatic patients and to analyse the specific factors involved in COVID-19 susceptibility.
32353972 Vitamin D's Effect on Immune Function. 2020 Apr 28 Ever since its discovery by Windhaus, the importance of the active metabolite of vitamin D (1,25-dihydroxyvitamin D(3); 1,25-(OH)2D(3)) has been ever expanding. In this review, the attention is shifted towards the importance of the extra-skeletal effects of vitamin D, with special emphasis on the immune system. The first hint of the significant role of vitamin D on the immune system was made by the discovery of the presence of the vitamin D receptor on almost all cells of the immune system. In vitro, the overwhelming effect of supra-physiological doses of vitamin D on the individual components of the immune system is very clear. Despite these promising pre-clinical results, the translation of the in vitro observations to solid clinical effects has mostly failed. Nevertheless, the evidence of a link between vitamin D deficiency and adverse outcomes is overwhelming and clearly points towards avoidance of vitamin D deficiency especially in early life.
32514745 Evaluation of dose-tapering strategies for intravenous tocilizumab in rheumatoid arthritis 2020 Oct PURPOSE: Tocilizumab is a humanized monoclonal antibody approved for rheumatoid arthritis treatment. In clinical practice, empirical dose-tapering strategies are implemented in patients showing sustained remission or low disease activity (LDA) to avoid overtreatment and reduce costs. Since rational adaptive-dosing algorithms taking the full pharmacokinetic (PK)/pharmacodynamic (PD) characteristics into account are currently lacking, we aimed to develop novel tapering strategies and compare them with currently used empirical ones. METHODS: Four strategies were simulated on a virtual population. In all of them, the same initial dose was administered every 28 days for six consecutive months. Then, different strategies were considered: (1) label-dosing; (2) mild empirical dose-tapering; (3) intense empirical dose-tapering; (4) therapeutic drug monitoring (TDM)-guided dose-tapering. The different strategies were evaluated on the proportion of patients who maintain remission/LDA 1 year after the intervention. Cost-savings of direct drug costs were also estimated as relative dose intensity. RESULTS: The overall proportion of simulated patients in remission/LDA after 1 year of the intervention was comparable between the mild empirical and the TDM-guided dose-tapering strategies, and much lower for the intense empirical dose-tapering strategy (80.3%, 78.2%, and 69.0%, respectively). Likewise, 1-year flare rates were lower for the mild empirical and TDM-guided tapering strategies. The relative dose intensity was lowest for the intense empirical dose-tapering, followed by the TDM-guided and the mild empirical dose-tapering approaches (61.2%, 71.0%, and 80.4%, respectively). CONCLUSION: We demonstrated that the TDM-guided strategy using model-based algorithms performed similarly to mild empirical dose-tapering strategies in overall remission/LDA rates but is superior in cost-savings.
32105179 Treatment Patterns and Costs in Biologic DMARD-Naive Patients with Rheumatoid Arthritis In 2020 Mar BACKGROUND: Etanercept (ETN) and adalimumab (ADA) are tumor necrosis factor inhibitors indicated for treatment of moderate to severe rheumatoid arthritis (RA) and are used as monotherapy or in combination with conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX). Data on treatment patterns and costs of ETN and ADA as monotherapies or in combination therapy with MTX are lacking in biologic DMARD (bDMARD)-naive patients with RA. OBJECTIVE: To evaluate treatment patterns and costs of ETN and ADA monotherapy and combination therapy in bDMARD-naive patients with RA. METHODS: Data from adult bDMARD-naive patients with RA were evaluated according to index therapy (ADA or ETN as monotherapy or combination therapy with MTX) in a retrospective cohort study using the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental Databases from January 1, 2010, to June 30, 2017. Participants were bDMARD-naive for ≥ 12 months before initial ETN or ADA pharmacy claim (index date) and had continuous enrollment for ≥ 12 months pre-index and 24 months post-index. Combination therapy cohorts had an MTX claim within 30 days of the index date. Outcomes included persistence (no treatment changes or gap [≥ 60 days]); modifications to index therapy (discontinuation or switching without prior gap, restarting as switch or restart after gap, or MTX initiation/discontinuation); and mean total bDMARD costs for 2 years post-index. RESULTS: Patients on ETN monotherapy (n = 2,064) had higher persistence (26.8% vs. 21.1%, respectively; P < 0.001) on index treatment and received treatment for a longer duration (mean 375.9 days vs. 339.7 days, respectively; P < 0.001) than those on ADA monotherapy (n = 1,528). Regimen changes were more common in patients on ADA monotherapy than patients on ETN monotherapy (38.0% vs. 33.4%, respectively; P = 0.004). More patients on ADA monotherapy added MTX than those on ETN (17.5% vs. 12.6%, respectively; P < 0.001). Overall, 790 patients receiving index monotherapy had a regimen change following a gap (≥ 60 days), with a similar proportion between cohorts. Among these patients, 13.8% restarted index therapy, and 7.9% switched from index therapy. Significantly more patients receiving ETN monotherapy restarted their index regimen after a gap than those receiving ADA monotherapy (14.9% vs. 12.2%, respectively; P = 0.023). The proportion of patients persistent on combination therapy was similar between the ETN and ADA combination therapy cohorts (21.9% vs. 22.2%, respectively; P = 0.818). Treatment pattern rates were similar regardless of index combination therapy. Overall, costs for ADA were consistently higher within the index regimen throughout the follow-up period irrespective of MTX. CONCLUSIONS: ETN monotherapy as first-line treatment was associated with higher persistence, lower rate of MTX supplementation, and lower bDMARD costs than ADA monotherapy. ETN monotherapy may represent a less costly option for achieving treatment targets in bDMARD-naive patients with RA. DISCLOSURES: This study was sponsored by Amgen. Tkacz, Henderson DeYoung, and Wilson are employees of IBM Watson Health, which received funding from Amgen for this study. Collier and Oko-osi are employees and shareholders of Amgen. Gharaibeh was an employee of Amgen at the time of study execution and manuscript drafting. Data pertaining to this study were presented in a poster at AMCP Nexus 2018; October 25-28, 2018; Orlando, FL.
33299019 The prevalence of rheumatoid arthritis in Spain. 2020 Dec 9 Rheumatoid arthritis (RA) prevalence is believed to be around 1% worldwide, although it varies considerably among different populations. The aim of EPISER2016 study was to estimate the prevalence of RA in the general adult population in Spain. We designed a population-based cross-sectional study. A national survey was conducted between November 2016 and October 2017 involving a probabilistic sample from the general population aged 20 years or older. Subjects were randomly selected for phone screening using a computer-assisted telephone interviewer system. Positive RA screening results were evaluated by a rheumatologist. Cases fulfilled the 1987 ACR and/or the 2010 ACR/EULAR criteria; previous diagnosis established by a rheumatologist and clearly identified in medical records were also accepted regardless of the criteria used. Prevalence estimates with 95% CI were calculated taking into account the design of the sample (weighting based on age, sex, and geographic origin using as a reference the distribution of the population in Spain). 4916 subjects participated in the study and 39 RA cases were confirmed. RA estimated prevalence was 0.82% (95% CI 0.59-1.15). Mean age of RA cases was 60.48 (14.85) years, they were more frequently women (61.5%), from urban areas (74.4%), non-smokers (43.6%), and with a high body mass index (53.8% with overweight). Extrapolating to the population in Spain (approximately 37 million are ≥ 20 years old), it was estimated that there were between 220,000 and 430,000 people aged 20 years or older with RA. No undiagnosed cases were detected, which could be related to the establishment of early arthritis clinics around the country, increasing the rates of diagnosis during early phases of RA.
32033937 Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature res 2020 Jun OBJECTIVES: To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA). METHODS: A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019. RESULTS: 234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products. CONCLUSION: This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR's RA management recommendation.
31971852 Oridonin suppresses autophagy and survival in rheumatoid arthritis fibroblast-like synovio 2020 Dec Context: Oridonin exhibits various pharmacological and physiological activities, including antioxidant, antibacterial, anti-inflammatory, pro-apoptotic, anticancer and neurological effects. However, its role in rheumatoid arthritis (RA) is yet to be revealed.Objective: We evaluated the effects of oridonin on the survival and autophagy of RA-fibroblast-like synoviocytes (FLSs).Materials and methods: RA-FLSs were treated with oridonin at serial concentrations of 0, 2, 4, 6, 8 and 10 µg/mL for 24, 48 and 72 h. Then, cell proliferation and apoptosis were measured. A GFP-LC3 plasmid was transfected into the cells to determine autophagy.Results: Oridonin suppressed RA-FLS proliferation in a dose-dependent manner. The half maximal inhibitory concentrations (IC(50)) of oridonin at 24, 48 and 72 h were 8.28, 7.88 and 8.35 µg/mL, respectively. Treatment with oridonin for 24 h increased apoptosis by 4.1%, and increased the protein levels of Bax and cleaved caspase-3 but significantly decreased the levels of IL-1β in the culture supernatant (p < 0.05). In addition, 6 h of oridonin treatment significantly decreased the number of GFP-LC3 punctate dots and inhibited the protein levels of ATG5 and Beclin1 by 80.01% and 42.12%, respectively. Chloroquine (CQ) significantly reinforced the effects of oridonin on inhibition of autophagy, suppression of proliferation, and induction of apoptosis in RA-FLSs (p < 0.05).Conclusions: Our results indicate that treatment with oridonin in combination with CQ inhibits autophagy and cell proliferation and induces apoptosis in RA-FLSs more effectively than treatment oridonin alone. This finding indicates that oridonin is a potential therapeutic agent for RA.
32561603 Combination of human umbilical cord mesenchymal stem (stromal) cell transplantation with I 2020 Oct OBJECTIVES: To clarify the key role of circulating interferon-γ (IFN-γ) and to improve the clinical efficacy of mesenchymal stem cell (MSC) transplantation (MSCT) in patients with rheumatoid arthritis (RA). METHODS: Study of wild-type or IFN-γR(-/-) MSCT was first evaluated in a murine model of collagen-induced arthritis (CIA) following which a phase 1/2 randomised controlled study was conducted in 63 patients with RA who responded poorly to regular clinical treatments. Subjects were randomly assigned to an MSCT monotherapy group (n=32) or an MSCT plus recombinant human IFN-γ treatment group (n=31), with 1 year of follow-up. The primary end points consisted of efficacy as assessed as good or moderate EULAR response rates and the proportion of patients at 3 months attaining American College of Rheumatology 20 (ACR20) response rates. RESULTS: In the murine studies, wild-type MSCT significantly improved the clinical severity of CIA, while IFN-γR(-/-) MSCT aggravated synovitis, and joint and cartilage damage. Transitioning from the murine to the clinical study, the 3-month follow-up results showed that the efficacy and ACR20 response rates were attained in 53.3% patients with MSCT monotherapy and in 93.3% patients with MSCT combined with IFN-γ treatment (p<0.05). No new or unexpected safety issues were encountered in 1-year follow-up for either treatment group. CONCLUSIONS: The results of this study show that IFN-γ is a key factor in determining the efficacy of MSCT in the treatment of RA, and that an MSC plus IFN-γ combination therapeutic strategy can greatly improve the clinical efficacy of MSC-based therapy in RA patients.
33315881 Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antib 2020 This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.
32937124 The Natural Compound Notopterol Binds and Targets JAK2/3 to Ameliorate Inflammation and Ar 2020 Sep 15 The traditional Chinese medicinal herb Notopterygium incisum Ting ex H.T. Chang has anti-rheumatism activity, and a mass spectrometry assay of patients' serum after administration of the herb revealed that notopterol is the most abundant component enriched. However, the functions of notopterol and its molecular target in rheumatoid arthritis (RA) treatment remain unknown. Here, we show in different RA mouse strains that both oral and intraperitoneal administration of notopterol result in significant therapeutic effects. Mechanistically, notopterol directly binds Janus kinase (JAK)2 and JAK3 kinase domains to inhibit JAK/signal transducers and activators of transcription (JAK-STAT) activation, leading to reduced production of inflammatory cytokines and chemokines. Critically, combination therapy using both notopterol and tumor necrosis factor (TNF) blocker results in enhanced therapeutic effects compared to using TNF blocker alone. We demonstrate that notopterol ameliorates RA pathology by targeting JAK-STAT signaling, raising the possibility that notopterol could be effective in treating other diseases characterized by aberrant JAK-STAT signaling pathway.
32662411 Iguratimod ameliorates rheumatoid arthritis progression through regulating miR-146a mediat 2021 Mar OBJECTIVES: This study aimed to evaluate the therapeutic effect of iguratimod and its regulatory role on microRNA (miR-146a) and the downstream genes in treating rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis (CIA) rat model. METHODS: RA-FLS was isolated from knee synovial tissue of an active RA patient. In vitro, the effect of miR-146a mimic/inhibition on RA-FLS functions was investigated. Then the effect of Iguratimod on cell viability, proliferation, apoptosis, migration, invasion, inflammatory cytokines, miR-146a and its downstream gene/pathway in RA-FLS was evaluated. In vivo, the collagen induced arthritis (CIA) rat model was constructed, then the effects of iguratimod, miR-146a inhibition and their combination on treating CIA rat were assessed. RESULTS: Iguratimod treatment increased miR-146a while decreased cell proliferation, IRAK1 and TRAF6/JNK1 pathway in RA-FLS in a dose-dependent manner. Notably, iguratimod treatment repressed cell proliferation, migration, invasion, TNF-α, IL-1β, IL-6, IL-17, IRAK1 and TRAF6/JNK1 pathway in RA-FLS, while miR-146a inhibition alleviated the abovementioned effects of Iguratimod on RA-FLS. The in vivo experiments disclosed that iguratimod reduced systemic arthritis score, and decreased TNF-α, IL-1β, IL-6, IL-17, IRAK1 as well as TRAF6/JNK1 pathway, while enhanced apoptosis in synovial tissue of CIA rat model; and in miR-146a inhibition treated CIA rat model, the effect of iguratimod was diminished. CONCLUSIONS: Iguratimod ameliorates RA progression via regulating miR-146a mediated IRAK1 expression and TRAF6/JNK1 pathway.