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ID PMID Title PublicationDate abstract
30943138 Pain and bone damage in rheumatoid arthritis: role of leukotriene B4. 2019 Sep Rheumatoid arthritis is a chronic autoimmune disease characterised by unbearable joint pain as well as bone and cartilage destruction. Although RA development is greatly controlled, the pain and bone damage failed to be relieved and managed. Leukotriene B4 (LTB4) has been proved to play an essential role in the induction of pain and bone damage. The nerve injury of RA can promote the production of LTB4, which act on their receptors, leading to the increased release of pro-inflammatory cytokines and ROS to reduce neuron viability and pain threshold. Moreover, LTB4-BLT1 activation can also increase intracellular calcium concentration and neuron excitability as well as NF-κB pathway activation, which further promote the production of MMP-9 and CXC3R-1. The mutual promotion between LTB4 and neutrophil accumulation accelerates the release of TNF-α and IL-β, which enhance both peripheral and central nerve system sensitisation. LTB4 also involve in TrpV1 channel activation and modulation of P2X3 receptor activation. All above mechanisms contribute to the development of RA pain. IL-23, cPLA2 and PI3K increase the production of CD11b+Gr1high myeloid subtype and calcium concentration, which promote the production of LTB4 and further accelerate IL-17 and TNF activation as well as calcium influx to conduce to osteoclastogenesis, resulting in aggregated bone damage. Our review is the first to conclude the signalling pathways and associated molecules in LTB4-induced pain and bone damage.
31663390 Biologic discontinuation strategies and outcomes in patients with rheumatoid arthritis. 2019 Dec Introduction: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease, which affects joints as well as extra-articular tissues. In the last decades, increasing targeted therapeutic options dramatically improved RA management by doubling the rate of patients achieving clinical remission. Currently, there is a need for management strategies aimed at limiting treatment-related adverse events and costs in good responders.Areas covered: Data on de-escalation of biologic drugs (especially for anti-TNF agents) are mainly available from post-hoc analyses of randomized controlled trials and from registry-based observational studies. This narrative review illustrates the rationales for dose tapering and expands to provide an overview of the efficacy of the different available strategies for reducing the exposure to biologic drugs in patients achieving a sustained clinical response. Selected studies are discussed as illustrative examples.Expert opinion: Withdrawal of biologic therapy might be attempted in limited patients with very early RA; conversely, established RA is more suitably managed with a progressive decrease of drug regimen, by either dose reduction or injection/infusion spacing. Further studies investigating potential factors predicting post-tapering disease relapse are warranted, in order to better identify the best candidates for a decreased-dose approach.
30556738 Measuring disease activity and response to treatment in rheumatoid arthritis. 2019 Feb Introduction: Effective treatment of rheumatoid arthritis (RA) requires suppression of the underlying inflammation. Measurement of such inflammation, the disease activity, is mandatory to target treatment and maximize outcomes. However, this is not as straightforward as it may seem. Areas covered: The many tools developed to measure disease activity in RA, from composite scores and patient-reported outcomes, to laboratory markers and imaging are discussed, with a focus on their utility in guiding therapy and assessing response. The complex issues in measuring disease activity in RA, whether in clinical trials or normal clinical practice, and in the context of national guidelines and recommendations, available time, and resources are considered. Expert commentary: The key to effective management of RA is the rapid suppression of inflammation, ideally to remission, with maintenance of such remission. The aim is to prevent disability and maximize quality of life. Central to this is the ability to determine disease activity (potentially open to suppression) as opposed to damage (irreversible). A variety of measures are currently available, allowing better assessment of response to treatment. In the future, the development of predictive biomarkers allowing targeting of drugs may revolutionize this field and render the tools of today redundant.
31069051 RANKL is a therapeutic target of bone destruction in rheumatoid arthritis. 2019 Although remarkable advances have been made in the treatment of rheumatoid arthritis (RA), novel therapeutic options with different mechanisms of action and fewer side effects have been expected. Recent studies have demonstrated that bone-resorbing osteoclasts are critically involved in the bone destruction associated with RA. Denosumab, a human antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), efficiently suppressed the progression of bone erosion in patients with RA by suppressing osteoclast differentiation and activation in several clinical studies, although it had no effect on inflammation or cartilage destruction. Denosumab, in combination with anti-rheumatic drugs, is considered a pivotal therapeutic option for the prevention of bone destruction in RA.
31892234 Quantitative Predictive Modelling Approaches to Understanding Rheumatoid Arthritis: A Brie 2019 Dec 27 Rheumatoid arthritis is a chronic autoimmune disease that is a major public health challenge. The disease is characterised by inflammation of synovial joints and cartilage erosion, which lead to chronic pain, poor life quality and, in some cases, mortality. Understanding the biological mechanisms behind the progression of the disease, as well as developing new methods for quantitative predictions of disease progression in the presence/absence of various therapies is important for the success of therapeutic approaches. The aim of this study is to review various quantitative predictive modelling approaches for understanding rheumatoid arthritis. To this end, we start by briefly discussing the biology of this disease and some current treatment approaches, as well as emphasising some of the open problems in the field. Then, we review various mathematical mechanistic models derived to address some of these open problems. We discuss models that investigate the biological mechanisms behind the progression of the disease, as well as pharmacokinetic and pharmacodynamic models for various drug therapies. Furthermore, we highlight models aimed at optimising the costs of the treatments while taking into consideration the evolution of the disease and potential complications.
31062938 Rheumatoid arthritis patients' oral health and disease activity. 2019 Aug AIM: Rheumatoid arthritis (RA) and periodontal diseases (PD) are common chronic, inflammatory, destructive and progressive diseases that may have similar pathophysiological mechanisms and risk factors. RA affects more than 1.5% of the world's population, with a higher percentage of females than males. PD is present in around 20% of the population and has multifactorial etiology. The purpose of this study is to describe patients' self-reported oral health and the association with RA disease activity. METHOD: Three hundred patients under treatment for RA from the Division of Rheumatology, Clinical Medicine, North Jutland Region Hospital, Hjørring, Denmark and were eligible for the study. Questionnaires were emailed to the patients and 164 completed answers were received. RESULTS: The mean age of the group of 164 patients (61% female) was 65 ± 11 years. The average value of Disease Activity Score of 28 joints was 2.31 ± 0.83. Only 12% of responders were active smokers. Patients estimated their status of their teeth and gingiva respectively as poor in 13% and 11% of cases, good, in 46% and 49%, and excellent, both as 40%. Spontaneous and/or provoked gingival bleeding were experienced by 15% and 49% of patients. Only 14% of patients declared feelings of loose or movable teeth and 10% declared difficulties in biting or chewing. CONCLUSIONS: The status of oral cavity reported by Danish patients indicates a significant proportion with symptoms of gingival/periodontal disease, which may negatively influence RA activity and disease management. Cooperation between rheumatologists and dentists is important in oral health management in periodontal inflammation.
31062169 Genetic regulation of dimethylarginines and endothelial dysfunction in rheumatoid arthriti 2019 Jul Rheumatoid Arthritis (RA) confers an increased cardiovascular disease (CVD) risk which accounts for much of the premature morbidity and mortality observed in this population. Alterations in vascular function and morphology leading to increased atherosclerotic burden are considered the main drivers of CVD in RA individuals with systemic inflammation playing a key role in the dysregulation of endothelial homeostasis and initiation of vascular injury. Dimethylarginines are endogenous inhibitors of nitric oxide (NO) synthase and have emerged as novel, independent biomarkers of CVD in a wide range of conditions associated with vascular pathology. In RA several reports have demonstrated abnormal dimethylarginine metabolism attributable to various factors such as systemic inflammation, decreased degradation or upregulated synthesis. Although a causal relationship between dimethylarginines and vascular damage in RA has not been established, the tight interrelations between inflammation, dimethylarginines and endothelial dysfunction suggest that determination of dimethylarginine regulators may shed more light in the pathophysiology of the atherosclerotic process in RA and may also provide new therapeutic targets. The Alanine-Glyoxylate Aminotransferase 2 (AGTX2)-dependent pathway is a relatively recently discovered alternative pathway of dimethylarginine catabolism and its role on RA-related atherosclerotic disease is yet to be established. As factors affecting dimethylarginine concentrations linked to CVD risk and endothelial dysfunction are of prominent clinical relevance in RA, we present preliminary evidence that gene variants of AGTX-2 may influence dimethylarginine levels in RA patients and provide the rationale for larger studies in this field.
30019648 Metformin one in a Million Efficient Medicines for Rheumatoid Arthritis Complications: Inf 2019 BACKGROUND: Rheumatoid arthritis is a widespread autoimmune disease and inflammation and bone destruction are two main issues in rheumatoid arthritis. OBJECTIVE: To discussing metformin effects on rheumatoid arthritis complications. METHODS: We conducted a narrative literature search including clinical trials, experimental studies on laboratory animals and cell lines. Our search covered Medline, PubMed and Google Scholar databases from 1999 until 2018. We used the terms" Metformin; Rheumatoid arthritis; Cardiovascular disease; Cancer; Osteoblastogenesis. DISCUSSION: Inflammatory pro-cytokines such as Interlukin-6 play important roles in T. helper 17 cell lineage differentiation. Interlukin-6 and Tumor Necrosis Factor-α activate Janus kinase receptors signal through signaling transducer and activator of transcription signaling pathway which plays important role in inflammation, bone destruction and cancer in rheumatoid arthritis patients. Interlukin-6 and Tumor Necrosis Factor-α synergistically activate signaling transducer and activator of transcription and Nuclear Factor-kβ pathways and both cytokines increase the chance of cancer development in rheumatoid arthritis patients. Metformin is AMPK activators that can suppress mTOR, STAT3 and HIF-1 so AMPK activation plays important role in suppressing inflammation and osteoclastogenesis and decreasing cancer. CONCLUSION: Metformin effect on AMPK and mTOR pathways gives the capability to change Treg/Th17 balance and decrease Th17 differentiation and inflammation, osteoclastogenesis and cancers in RA patients. Metformin can be useful in protecting bones especially in first stages of RA and it can decrease inflammation, CVD and cancer in RA patients so Metformin beside DAMARs can be useful in increasing RA patients' life quality with less harm and cost.
31377812 Nanomedicine: an emerging era of theranostics and therapeutics for rheumatoid arthritis. 2019 Oct 1 RA is a multifactorial autoimmune inflammatory disease characterized by synovitis, bone destruction and joint dysfunction that leads to shortening of lifespan and increased mortality rates. Currently available treatments of RA, by controlling various symptoms, only delay disease progression and have their own side effects. Consequently, there is the need for a novel therapeutic strategy that offers a more sustainable and biocompatible solution. Nanomedicine is a modern branch of nanobiotechnology that provides targeted therapy to inflamed rheumatic joints and thus prevents unwanted off-target side effects. This review highlights various nanotheranostic and nanotherapeutic strategies that are currently being used for the treatment of RA.
30987474 Baricitinib for the treatment of rheumatoid arthritis and systemic lupus erythematosus: a 2019 Jul Introduction: JAK, which constitutively binds to some cytokine receptors, plays an important role in cytokine signaling. While JAK is comprised of JAK1, JAK2, JAK3, and Tyk2, more than 40 types of cytokines transmit signals through JAK. Baricitinib is reported to be highly effective in the treatment of rheumatoid arthritis (RA) and is the second drug launched as a JAK inhibitor for RA. Area covered: We provide an overview of the mechanisms of action of baricitinib and its clinical implications in RA and other autoimmune diseases based on recent reports. This review outlines the mechanisms of action of baricitinib on human immune cells, the results of Phase III trials for RA, and the results of Phase II trials on SLE. Expert opinion: Baricitinib has potential to fine-tune various immune networks through a variety of mechanisms. Precision medicine is required in order to achieve maximum effects of targeted synthetic DMARDs including baricitinib and biological DMARDs in the future.
30882346 [Medical audit guideline about rheumatoid arthritis diagnosis and treatment.]. 2019 Feb 27 INTRODUCTION: rheumatoid arthritis is a frequent inflammatory disease and a leading cause of potentially-treatable disability. Rheumatoid arthritis is associated with an increased risk of general morbidity and mortality. New therapeutic options have dramatically improved the evolution of patients. OBJECTIVES: in this joint work of the Association of Auditing and Quality of Medical Care of Córdoba (ASACAM) and the Argentine Society of Rheumatology (SAR), we generated recommendations to especially assist medical auditors in making decisions to improve the quality of the medical and life care of patients and reduce costs in the management of rheumatoid arthritis patients. in addition to medical auditors, these recommendations can be expanded to general practitioners, rheumatologists and clinicians, and eventually to the general public. Conclusions: suggestions for the diagnosis and treatment of patients with rheumatoid arthritis (including biological therapies) are described, based on the Clinical Practice Guidelines for the Treatment of Rheumatoid Arthritis (SAR, 2013), the resolutions of the Compulsory Medical Program and the Unique Reimbursement System currently used in INTENDED POPULATION: in addition to medical auditors, these recommendations can be expanded to general practitioners, rheumatologists and clinicians, and eventually to the general public. CONCLUSIONS: suggestions for the diagnosis and treatment of patients with rheumatoid arthritis (including biological therapies) are described, based on the Clinical Practice Guidelines for the Treatment of Rheumatoid Arthritis (SAR, 2013), the resolutions of the Compulsory Medical Program and the Unique Reimbursement System currently used in Argentina.
31650484 On Research Progress of Western and Chinese Medicine Treatment on Pre-Rheumatoid Arthritis 2019 Sep Pre-rheumatoid arthritis is the inevitable phase before the actual onset of rheumatoid arthritis and has the crucial clinical significance of early controlling and preventing disease progression. Full understanding, from both Western medicine (WM) and Chinese medicine (CM), could offer new ideas for decision making in clinical and mechanism research. This paper reviews the novel studies of WM and CM to discuss the advantages and potential mechanisms working behind.
30820026 Epigenetic analysis in rheumatoid arthritis synoviocytes. 2019 Feb 22 Rheumatoid arthritis (RA) is a complex chronic systematic disease with progressive destruction of the joints by invasive synoviocytes. To characterize the key regulators involved in the development of RA, we obtained multilayer epigenomics data including DNA methylation by whole-genome bisulfite sequencing, miRNA profiles, genetic variations by whole-exome sequencing, and mRNA profiles from synoviocytes of RA and osteoarthritis (OA) patients. The overall DNA methylation patterns were not much different between RA and OA, but 523 low-methylated regions (LMRs) were specific to RA. The LMRs were preferentially localized at the 5' introns and overlapped with transcription factor binding motifs for GLI1, RUNX2, and TFAP2A/C. Single base-scale differentially methylated CpGs were linked with several networks related to wound response, tissue development, collagen fibril organization, and the TGF-β receptor signaling pathway. Further, the DNA methylation of 201 CpGs was significantly correlated with 27 expressed miRNA genes. Our interpretation of epigenomic data of the synoviocytes from RA and OA patients is an informative resource to further investigate regulatory elements and biomarkers responsible for the pathophysiology of RA and OA.
31987125 Emotional eating is more frequent in obese rheumatoid arthritis patients. 2020 Feb BACKGROUND & AIM: Obesity is a risk factor for both cardiovascular mortality and poor disease control. Unfavourable eating behaviours may have a role in obesity and increase the risk for obesity. In this study, we evaluated the eating behaviours of the patients with rheumatoid arthritis and compare these with controls. Also, we assessed the eating behaviour differences between obese and non-obese rheumatoid arthritis patients. METHODS: It was a cross sectional case control study. We enrolled 157 rheumatoid arthritis patients and 60 controls to the study in one year period. We evaluated the eating behaviours of the patients with Three-Factor Eating Questionnaire R-18. Firstly, we compared eating behaviours of the rheumatoid arthritis patients with controls, and then we evaluated the differences in eating features between obese rheumatoid arthritis patients with non-obese rheumatoid arthritis patients. We compared the continuous variables with Mann-Whitney u test. Furthermore, categorical variables were compared with Chi-square test. RESULTS: Sixty-three (40.2%) of the rheumatoid arthritis patients were obese. Eating behaviours of rheumatoid arthritis patients and controls were similar, out of uncontrolled eating score. This score was found higher in control group than rheumatoid arthritis patients (p = 0.01). Moreover, emotional eating domain scores were higher in obese RA patients (p = 0.04). CONCLUSIONS: Even though there were no negative eating features in general rheumatoid arthritis population, obese rheumatoid arthritis patients may have an emotional eating problem. Herein, treatments that address psychosomatic sides of eating may be effective for treatment of obesity in rheumatoid arthritis.
30516104 The Urokinase Plasminogen Activation System in Rheumatoid Arthritis: Pathophysiological Ro 2019 Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease characterized in its early stages by synovial hyperplasia and inflammatory cell infiltration and later by irreversible joint tissue destruction. The plasminogen activation system (PAS) is associated with a wide range of physiological and pathophysiological states involving fibrinolysis, inflammation and tissue remodeling. Various components of the PAS are implicated in the pathophysiology of RA. Urokinase plasminogen activator (uPA) in particular is a pro-inflammatory mediator that appears to play an important role in the bone and cartilage destruction associated with RA. Clinical studies have shown that uPA and its receptor uPAR are overexpressed in synovia of patients with rheumatoid arthritis. Further, genetic knockdown and antibody-mediated neutralization of uPA have been shown to be protective against induction or progression of arthritis in animal models. The pro-arthritic role of uPA is differentiated from its haemodynamic counterpart, tissue plasminogen activator (tPA), which appears to play a protective role in RA animal models. This review summarises available evidence supporting the PAS as a critical determinant of RA pathogenesis and highlights opportunities for the development of novel uPAS-targeting therapeutics.
30759964 A paradigm shift in studies based on rheumatoid arthritis clinical registries. 2019 Sep Clinical research is the study of aspects of patient health or illness that are closely related to clinical practice. In the late 20th and early 21th century, outcomes for patients with rheumatoid arthritis (RA) improved dramatically due to breakthroughs in new drugs. Patient-reported outcome measures now play a significant role in the drug development process as study endpoints in clinical trials of new therapies, and this has led to increased interest in the patient's perspective, drug safety and treatment outcomes in clinical practice. In accordance with these needs, many prospective cohorts for RA patients and registries of biologic disease modifying anti-rheumatic drugs have been actively conducted in the United States and European and Asian countries. A gradual shift is taking place in the major outcomes of clinical research using these prospective cohorts and registries. This article will introduce representative registries for RA in each country set up in the early 2000s and will discuss future perspectives in clinical research on RA patients using such clinical registries.
31049664 [Comorbidities-Their role in the treat to target concept for rheumatoid arthritis]. 2019 Jun Treat to target (T2T) strategies and comorbidities are closely related. Strong evidence exists for reducing the risk and extent of comorbidities, such as cardiovascular (CV) diseases, depression and infections by implementing T2T concepts and inducing good disease control of rheumatoid arthritis (RA) in this way. On the other hand existing comorbidities may hinder implementation of T2T concepts by aggravating RA or influencing rheumatologists to overcautiously use DMARD treatment. Among a long list of potentially relevant comorbidities with RA, in this review two particularly relevant accompanying diseases with respect to T2T, CV diseases and infections, are selected for discussion in detail. The CV comorbidities are the main cause of death for RA patients and are triggered by RA-associated inflammatory mechanisms. Their negative influence on implementation of T2T strategies can be stopped or at least reduced by optimal control of RA activity with the help of selecting drugs with cardioprotective properties (such as biologicals, methotrexate and hydroxychloroquine) as well as assessing and treating traditional CV risk factors. Infections are among most important adverse events of DMARD treatment and can disturb the optimal use of these drugs and so hinder the success of the T2T strategy. Optimal infection prophylaxis and identification of high risk patients are particularly important and minimization of glucocorticoid use is critical to reduce the risk of infections. In summary, comorbidities are important potential risk factors for the success of T2T strategies.
31196647 Predicting Rheumatoid Arthritis in At-risk Individuals. 2019 Jul The typical evolution of rheumatoid arthritis (RA) is that a person with genetic risk factors develops autoantibodies and subclinical inflammation under relevant environmental influences, culminating in symptoms and finally clinically detectable arthritis. Because several of these characteristics can be present before the outbreak of clinical arthritis, it is possible to study the at-risk phase (the presence of ≥1 risk factors for RA in an individual) with the aim of quantifying the risk for that individual. As a person progresses through the different phases of disease development, different markers can be used for prediction. In the early asymptomatic phase, genetics, environmental factors, and autoantibodies are relevant, whereas in later phases additional markers, such as symptoms and imaging, come into play, conveying the risk of not only RA but sometimes even of imminent RA. Prediction is of limited use when not coupled with the possibility to intervene and lower the risk of RA. There is a clear need for effective preventive strategies that take the phase of disease development into account. On the other hand, selecting the right persons for preventive treatment according to their stage of disease development requires the improvement of current prediction models and strategies. This commentary presents an overview of risk factors and their combination into prediction models for use in different stages of RA development. Although clear progress has been made and assuming a future with effective options to intervene, there are still several gaps in our knowledge that need to be filled before it is clear who should be tested and when.
30635780 Genetic and clinical markers for predicting treatment responsiveness in rheumatoid arthrit 2019 Aug Although many drugs and therapeutic strategies have been developed for rheumatoid arthritis (RA) treatment, numerous patients with RA fail to respond to currently available agents. In this review, we provide an overview of the complexity of this autoimmune disease by showing the rapidly increasing number of genes associated with RA.We then systematically review various factors that have a predictive value (predictors) for the response to different drugs in RA treatment, especially recent advances. These predictors include but are certainly not limited to genetic variations, clinical factors, and demographic factors. However, no clinical application is currently available. This review also describes the challenges in treating patients with RA and the need for personalized medicine. At the end of this review, we discuss possible strategies to enhance the prediction of drug responsiveness in patients with RA.
31025926 FGF23-Klotho axis in patients with rheumatoid arthritis. 2020 Jan OBJECTIVES: We aimed to compare serum Klotho and fibroblast growth factor-23 (FGF-23) levels between rheumatoid arthritis (RA) patients and healthy controls. Possible association between FGF-23 and soluble Klotho with different characteristic of the disease as well as their potential role as surrogate markers of cardiovascular disease (CVD) were studied. METHODS: Sixty-three patients with RA recruited at Vega-Baja Hospital, Orihuela (Spain) from November 2016 to May 2018 and sixty-five age- and sex-matched healthy controls were included in this study. Serum Klotho and FGF-23 were analysed using ELISA. RESULTS: Patients had higher serum levels of Klotho than healthy controls (p˂0.0001). They were positively associated with the presence of anticitrullinated peptide antibody and rheumatic factor (p<0.05). Klotho serum levels were higher in RA patients treated with biologic agents than in those undergoing conventional therapy (p=0.008). However, no association with carotid intima media thickness was found. Although no significant differences in serum FGF-23 levels between patients and controls were found (p=0.43), FGF-23 levels were positively associated with low-density lipoprotein (LDL-c) level (p<0.05) and smoking (p=0.008) in patients with RA. CONCLUSIONS: The increased serum Klotho levels in RA patients, especially in those undergoing biologic therapy, may indicate a potential implication in the pathogenesis of the disease. Although levels of FGF-23 were related to LDL-c levels, the FGF-23-Klotho axis does not seem to be related to subclinical arteriosclerosis in RA.