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ID PMID Title PublicationDate abstract
24151946 Monotherapy in rheumatoid arthritis. 2013 Therapeutic strategies for rheumatoid arthritis (RA) have evolved over time. Novel therapies have morphed in parallel to the ever-increasing understanding of RA pathogenesis, diagnosis and outcomes tools. For a century, the principal armamentarium was mainly composed by steroidal and non-steroidal anti-inflammatories. Over the last 25 years, however, the concept of disease-modifying anti-rheumatic drugs (DMARDs) has made possible the notion that the natural history of RA could actually be altered. Since then, synthetic DMARDs-particularly methotrexate (MTX) -have been used as monotherapy with significant success. This was followed by a revolutionary paradigm shift with the advent of anti-TNFα inhibitors and other "biologics" in the 1990s. Contemporary guidelines advocate for the use of a combina- tion therapy (i.e., MTX and a biologic) in aggressive RA cases given their proven additive effect. However, some patients are either intolerant to synthetic DMARDs or develop side effects that preclude their use. New data has recently emerged point- ing towards the potential for biologic monotherapy regimens in certain RA cases. This review will, therefore, describe the available evidence supporting the use of biologic DMARDs and the circumstances in which they are indicated.
23531111 Hypoxia-inducible factor: a potential therapeutic target for rheumatoid arthritis. 2013 Jun 1 The hypoxic microenvironment is a clinicopathological characteristic of many diseases, such as rheumatoid arthritis (RA). As a transcription factor activating the gene expression involved in processes such as cell metabolism and angiogenesis, hypoxia-inducible factor (HIF) has a central function in adaption to altered oxygen tension and even contributes to the progression of related diseases. In RA, HIF induces angiogenesis, cell migration, and cartilage destruction, inhibits the apoptosis of synovial cells and inflammatory cells and initiates glycolysis for energy supply by upregulating specific protein levels. HIF expression in RA can be regulated in both oxygen-dependent and independent fashions, leading to the aggravation of this disease. Therefore, HIF is one of the vital RA mediators. Based on the application of HIF-targeted drug research and development in tumors, HIF is a potential therapeutic target for treating RA.
23298444 Role of ultrasonography in diagnosing early rheumatoid arthritis and remission of rheumato 2013 Jan 8 INTRODUCTION: Ultrasonography (US) might have an added value to clinical examination in diagnosing early rheumatoid arthritis (RA) and assessing remission of RA. We aimed to clarify the added value of US in RA in these situations performing a systematic review. METHODS: A systematic literature search was performed for RA, US, diagnosis and remission. Methodological quality was assessed; the wide variability in the design of studies prohibited pooling of results. RESULTS: Six papers on the added value of US diagnosing early RA were found, in which at least bilateral metacarpophalangeal (MCP), wrists and metatarsophalangeal (MTP) joints were scanned. Compared to clinical examination, US was superior with regard to detecting synovitis and predicting progression to persistent arthritis or RA. Eleven papers on assessing remission were identified, in which at least the wrist and the MCP joints of the dominant hand were scanned. Often US detected inflammation in patients clinically in remission, irrespective of the remission criteria used. Power Doppler signs of synovitis predicted X-ray progression and future flare in patients clinically in remission. CONCLUSIONS: US appears to have added value to clinical examination for diagnosing of RA when scanning at least MCP, wrist and MTP joints, and, when evaluating remission of RA, scanning at least wrist and MCP joints of the dominant hand. For both purposes primarily power Doppler US might be used since its results are less equivocal than those of greyscale US.
24219038 The role of concomitant methotrexate in biologic therapy for rheumatoid arthritis. 2013 From the first use of biologic therapy for the management of rheumatoid arthritis, methotrexate (MTX) has been commonly used as co-therapy. There are a number of mechanistic reasons why MTX may improve the efficacy of biologics, including reduced antigenicity as well as reduced clearance of the biologic agent. Clinical trial data for tumor necrosis factor inhibitors and for other biologic agents does suggest added efficacy when these agents are used in combination with MTX. One exception may be the interleukin-6 receptor antibody tocilizumab, for which there is some data to suggest that monotherapy may be as effective as combined therapy with MTX. Post-marketing registry data also supports the concomitant use of MTX with biologics, with evidence for greater efficacy and longer persistence on treatment when compared with monotherapy.
23651870 Kinase inhibitors: a new tool for the treatment of rheumatoid arthritis. 2013 Jul Despite aggressive immunosuppression with biologics and traditional DMARDs, achieving disease remission remains an unmet goal for most rheumatoid arthritis (RA) patients. In this context, there is a demand for novel treatment strategies, with kinase inhibitors expected to enrich the existing therapeutic armamentarium. In RA some kinases participate in the generation of pathogenic signaling cascades. Pharmacologic inhibition of kinases that mediate pathogenic signal transduction heralds a new era for RA therapeutics. Oral inhibitors of JAKs, Syk, PI3Ks, MAPKs and Btk are under development or in clinical trials in patients with RA. In this review, we discuss the scientific rationale for the use of kinase inhibitors in RA and summarize the experience from clinical trials.
23572339 What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid 2014 May OBJECTIVE: Initiation of DMARD-therapy in the 'window of opportunity' is thought to result in a more effective modification of the processes underlying rheumatoid arthritis (RA). We questioned whether this effect is true or hyped and performed a systematic literature review. METHODS: Medical literature databases up to June 2012 were systematically reviewed for cohort studies and randomised controlled trials reporting outcome data of early RA in relation with symptom duration at treatment initiation. The quality of these studies was assessed by two independent reviewers using a criteria scoring system of 15 items. Studies were dichotomised with the median score (79%) as cut-off. Best-evidence synthesis was applied to determine the level of evidence per outcome category. A meta-analysis was performed on the studies reporting on achieving DMARD-free sustained remission (the reverse of disease persistency). RESULTS: Out of 836 screened articles, 18 fulfilled the selection criteria and were not duplicates. Ten were scored as high quality. Remission (various definitions) and radiographic progression were frequently studied outcomes. There was strong evidence for an association between symptom duration and radiographic progression. A meta-analysis on datasets evaluating DMARD-free sustained remission showed that symptom duration was independently associated with such remission; HR 0.989 (95% CI 0.983 to 0.995) per week increase in symptom duration. A moderate level of evidence was observed for other remission outcomes. CONCLUSIONS: Even when heterogeneity of patients is taken into account, prolonged symptom duration is associated with radiographic progression and a lower chance on DMARD-free sustained remission. These data may support the presence of a 'window of opportunity'.
23335492 Fatigue and factors related to fatigue in rheumatoid arthritis: a systematic review. 2013 Jul OBJECTIVE: Although patients with rheumatoid arthritis (RA) experience fatigue, little is known about its causes and consequences, and a fully developed theoretical model explaining the experience of fatigue in RA is lacking. Our goal was to systematically review studies in RA that examined factors related to fatigue to gain more insight into its possible causes and consequences. METHODS: Medline, Web of Science, Scopus, and PsycINFO were searched for relevant studies. All studies with RA samples about the relationship between fatigue and other variables that defined dependent and independent variables and used multivariate statistical methods were preliminarily included. After reviewing 129 full texts, we identified 25 studies on possible causes of fatigue and 17 studies on possible consequences of fatigue. RESULTS: The studies found possible causes of fatigue in illness-related aspects, physical functioning, cognitive/emotional functioning, and social aspects. Additionally, being a woman was related to higher levels of fatigue. Inflammatory activity showed an unclear relationship with fatigue in RA. Possible consequences of fatigue were also found among illness-related aspects, physical functioning, cognitive/emotional functioning, and social aspects. The strongest evidence for a relationship between fatigue and other variables was found regarding pain, physical functioning, and depression. CONCLUSION: This review summarizes the current knowledge in the field in order to inform future research on causes and consequences of fatigue in RA. However, the results are based on cross-sectional and longitudinal studies with different designs and different fatigue scales. For a better identification of causal associations between fatigue in RA and related factors, longitudinal prospective designs with adequate fatigue measurements are suggested.
25150878 Pharmacogenetics in rheumatoid arthritis. 2014 Rheumatoid arthritis (RA) is a systemic inflammatory arthritis leading to severe joint damage and associated with high morbidity and mortality. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment in RA. DMARDs not only relieve the clinical signs and symptoms of RA but also inhibit the radiographic progression of disease. In the last decade, a new class of disease-modifying medications, the biologic agents, has been added to the existing spectrum of DMARDs in RA. However, patients' response to these agents is not uniform with considerable variability in both efficacy and toxicity. There are no reliable means of predicting an individual patient's response to a given DMARD prior to initiation of therapy. In this chapter, the current published literature on the pharmacogenetics of traditional DMARDS and the newer biologic DMARDs in RA is highlighted. Pharmacogenetics may help individualize drug therapy in patients with RA in the near future.
25481548 Molecular and cellular heterogeneity in the Rheumatoid Arthritis synovium: clinical correl 2014 Aug Rheumatoid Arthritis is characterized by autoimmune-mediated attack of the joint synovial lining resulting in destruction of bone and cartilage, and is a clinically and biologically heterogenous disease with respect to both course of disease and outcome to therapy. The current armamentarium of approved therapies does not result in complete clinical response in all patients. Improved techniques for imaging and performing biopsies on the rheumatoid synovium have facilitated multiple studies of the dysregulated cellular and molecular pathways in disease, and have provided evidence for a spectrum of pathogenic phenotypes across RA patients. These phenotypes are differentially affected by targeted therapies such as anti-TNFα and anti-CD20, and their presence prior to treatment impacts upon subsequent clinical outcomes. Ongoing histologic and molecular assessment of these synovial phenotypes through the implementation of routine synovial biopsy or using systemic biomarkers will improve targeting of therapies to specific patient subsets in both clinical trials and practice.
24394994 CCR6 and CCL20: emerging players in the pathogenesis of rheumatoid arthritis. 2014 Apr The therapeutic targeting of pro-inflammatory TNF with neutralising biological anti-TNF agents, often in combination with other disease-modifying anti-rheumatic drugs, such as the purine synthesis inhibitor methotrexate has been the first major break-through in the treatment of chronic inflammatory diseases in decades. There are however, side effects and disadvantages of these treatments, such as general immunosuppression as well as therapy resistance in a large proportion of patients. This evokes the wish for other, more specialised forms of treatments. The targeting of chemokines and their receptors to disrupt cell movement specifically has been seen as a promising avenue of therapy for a considerable time. We will discuss one particular chemokine and its receptor, the C-C chemokine ligand CCL20 and the C-C chemokine receptor CCR6, and summarise its genetic and biological role in rheumatoid arthritis (RA). CCR6 has been associated with RA in genome-wide association studies and has been shown to be an interesting candidate for a therapeutic approach, considering its and CCL20's expression patterns within the tissue as well as the immune system.
24931356 Do statins reduce the cardiovascular risk in patients with rheumatoid arthritis? 2014 Jul OBJECTIVE: Patients with rheumatoid arthritis (RA) are at significantly higher risk of cardiovascular (CV) morbidity and mortality compared with the general population. Traditional CV risk factors cannot explain the total excess of CV morbidity and mortality in RA patients. At present, it is not clear whether treatment with statins might be of benefit in RA patients. The aim of the present systematic literature review is to summarize the published evidence concerning treatment with statins and its impact on CV events in RA patients. METHODS: A systematic literature review of studies on RA and statins was carried out in the database PubMed. Search terms were 'simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR pravastatin OR rosuvastatin OR statin AND arthritis'. Papers were included in this review when the reported outcome was on CV events in RA patients. After exclusion of the studies not fulfilling our inclusion criteria four studies were finally analyzed. The total number of RA patients included in these studies was 4896. RESULTS: Statins were associated with reduced CV events and mortality in RA in primary prevention but not in secondary prevention. In secondary prevention after myocardial infarction (MI) there was no statistically significant difference between RA or non-RA patients either receiving atorvastatin 80 mg or simvastatin 20-40 mg daily. Treatment with atorvastatin 80 mg led to a reduction in overall risk of CV disease in both patients with and without inflammatory joint disease compared to patients receiving the conventional/low-dose statin treatment. Statin discontinuation in RA patients was associated with an increased risk of acute myocardial infarction or CV mortality. Myalgia, diarrhoea, abdominal pain and nausea may be more frequent in RA patients than in controls. CONCLUSION: The published evidence shows that in RA patients statin treatment appears to reduce CV risk in primary prevention and that statin discontinuation is associated with an increased risk for CV events. However, the significance of statin treatment in RA patients still remains unclear as only very little evidence has been published. Whether all RA patients would benefit from treatment with statins still needs to be investigated.
25403741 High-resolution imaging of bone and joint architecture in rheumatoid arthritis. 2014 Dec INTRODUCTION: Rheumatoid arthritis (RA) is characterized by local and systemic bone loss caused by increased bone resorption. We describe the current utilization of high-resolution peripheral quantitative computed tomography (HR-pQCT) in the evaluation of bone and joint in RA. SOURCES OF DATA: PubMed was searched for publications using keywords that included 'bone microarchitecture', 'high-resolution peripheral quantitative computed tomography' and 'rheumatoid arthritis'. AREAS OF AGREEMENT: HR-pQCT may simultaneously allow assessment of trabecular and cortical bone parameters and be a useful method for depicting bone erosions. AREAS OF CONTROVERSY: HR-pQCT only assesses bone microarchitecture at the distal radius and tibia. Controversy exists regarding the optimal way to differentiate cortical and trabecular regions. GROWING POINTS: Although HR-pQCT is currently a research tool, there is potential for its use in the clinical diagnosis and management in RA. Further research is required to evaluate the clinical relevance of imaging abnormalities identified in RA patients.
24340846 Anti-citrullinated peptide antibodies is more than an accurate tool for diagnosis of rheum 2013 Sep Anti-citrullinated peptide antibodies (ACPA) are detected in the sera of rheumatoid arthritis (RA) patients and have a profound role in diagnosis of the disease. In this review we discuss the different cohorts of RA patients in whom the presence, sensitivity and specificity of ACPA were evaluated. The significance of ACPA in the pathogenesis and prognosis RA is also interpreted. Recent advances in the understanding of molecular pathways involved in the pathogenesis of RA have led to the identification of novel biologic agents that are now widely used in patients with RA.
24369601 [Assessment of disease activity of rheumatoid arthritis by ultrasonography]. 2013 Sep Rheumatoid arthritis (RA) is a typical autoimmune disease of connective tissue, with the synovial joints as the main site of the disease. Bone erosion occurs in the initial stage. A key factor in treating and understanding the prognosis of the disease is to determine which stage of the lesion is caused by rheumatoid arthritis. In order to assess bone erosion and determine the degree of synovial proliferation, ultrasonography has come into the spotlight as a method of visualizing the rheumatoid arthritis lesion, which cannot be distinguished superficially from the cutaneous condition. Joint ultrasonography is a relatively inexpensive procedure that can be used to examine patients repeatedly; therefore, we can compare serial data from such patients. The joint lesion, which we focused on, can be understood in real time and is superior in many respects. However, at present, there are problems with examiner bias and the lack of a standard assessment method, because joint ultrasonography alone does not provide objective imaging findings. Now, joint ultrasonography is also useful as a supportive method to clarify mobility around the articular region. Ultrasonography might be used as a supportive method for the early diagnosis, assessment of disease activity, evaluation of the drug efficacy, prognosis, and as part of the differential diagnosis.
25481554 Vagus nerve stimulation: a new bioelectronics approach to treat rheumatoid arthritis? 2014 Aug There has been a marked improvement in the treatment of rheumatoid arthritis (RA), but most patients do not achieve disease remission. Therefore, there is still a need for new treatments. By screening an adenoviral short hairpin RNA library, we discovered that knockdown of the nicotinic acetylcholine receptor type 7 (α7nAChR) in RA fibroblast-like synoviocytes results in an increased production of mediators of inflammation and degradation. The α7nAChR is intimately involved in the cholinergic anti-inflammatory pathway (CAP). This led us to study the effects of α7nAChR activation in an animal model of RA, and we could show that this resulted in reduced arthritis activity. Accordingly, stimulation of the CAP by vagus nerve stimulation improved experimental arthritis. Conversely, we found aggravation of arthritis activity after unilateral cervical vagotomy as well as in α7nAChR-knockout mice. Together, these data provided the basis for exploration of vagus nerve stimulation in RA patients as a novel anti-inflammatory approach.
23926091 Symptom complexes at the earliest phases of rheumatoid arthritis: a synthesis of the quali 2013 Dec OBJECTIVE: Understanding the features and patterns of symptoms that characterize the earliest stages of rheumatoid arthritis (RA) is of considerable importance if patients are to be identified and started on treatment early. However, little is known about the characteristics of symptoms at the onset of a disease that eventually progresses to RA. METHODS: A systematic review of qualitative peer-reviewed publications was conducted to identify the earliest symptoms associated with the onset of RA. A total of 1,736 abstracts were searched to identify relevant publications. Twenty-six publications were identified, assessed for quality, and subjected to analysis informed by thematic and grounded theory frameworks. RESULTS: Several interacting themes describing the early symptoms of RA were identified, including swelling, pain and tenderness, stiffness, fatigue and weakness, and the emotional impact of symptoms. For each symptom, different and evolving intensities were described; in some cases, patterns of symptom onset and symptom complexes at the onset of RA were highlighted. Importantly, this review has emphasized major deficiencies in the literature. None of the studies reviewed originally aimed to explore symptoms at RA onset (often discussions about symptom onset were secondary to the study's primary aim). Also, many of the articles identified sampled people diagnosed with RA many years previously, making their recollection of symptoms at onset less reliable. CONCLUSION: In order for clinicians to fully understand the earliest phases of disease, the nature of symptoms at onset needs to be understood. The current work represents a useful starting point, but this area needs further qualitative investigation, followed by quantitative explorations of symptom clusters and their associated features.
23414962 Physiotherapy co-management of rheumatoid arthritis: identification of red flags, signific 2013 Dec Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease. Physiotherapy interventions for people with RA are predominantly targeted at ameliorating disability resulting from articular and peri-articular manifestations of the disease and providing advice and education to improve functional capacity and quality of life. To ensure safe and effective care, it is critical that physiotherapists are able to identify potentially serious articular and peri-articular manifestations of RA, such as instability of the cervical spine. Additionally, as primary contact professionals, it is essential that physiotherapists are aware of the potentially serious extra-articular manifestations of RA. This paper provides an overview of the practice-relevant manifestations associated with RA that might warrant further investigation by a medical practitioner (red flags), their relevance to physiotherapy practice, and recommended management pathways.
22998801 Thoracic complications of rheumatoid disease. 2013 Mar Rheumatoid arthritis is a relatively common multisystem disease associated with significant mortality and morbidity. Thoracic disease, both pleural and pulmonary, is a frequent extra-articular manifestation of rheumatoid arthritis and responsible for approximately 20% of rheumatoid-associated mortality. Rheumatoid disease and its associated therapies can affect all compartments of the lung inciting a range of stereotyped pathological responses and it is not infrequent for multiple disease entities to co-exist. In some instances, development of pulmonary complications may precede typical rheumatological presentation of the disease and be the first indication of an underlying connective tissue disease. The spectrum of thoracic disease related to rheumatoid arthritis is reviewed.
23219766 Cost-effectiveness of biologic treatment for rheumatoid arthritis in clinical practice: an 2013 Jun The burden of illness of rheumatoid arthritis (RA) falls on patients, families and society through the direct costs, indirect costs, and intangible costs. A large number of RA cost-of-illness studies have been performed in recent decades with discrepant results due to patient heterogeneity, and different health-care organization, employment rate or social support, job opportunities, and methodologies used to calculate the costs. The greatest burden of RA is the indirect and the intangible costs, but how to estimate them remains controversial. The systematic use of traditional disease modifying anti rheumatic drugs has changed the evolution of the disease. However, a considerable improvement in the management of RA has been obtained since the advent of biologic response modifiers. The use of these drugs, which have demonstrated greater efficacy than conventional therapies, have tripled the direct costs of RA, which rose from about € 4000 to roughly € 12,000, in a period of five years, from 2000 to 2005. The present paper is aimed to examine the effects of this change in therapeutic strategy.
25150340 Assessing remission in rheumatoid arthritis on the basis of patient reported outcomes--adv 2014 Advances in the management of rheumatoid arthritis (RA) have rendered remission an increasingly achievable goal. However, a single, universal definition of remission in RA does not exist. Remission criteria were developed in 1981 by a committee of the American College of Rheumatology (ACR) and have been described according to different composite indices. In 2011, a committee of the ACR and the European League against Rheumatism (EULAR) has proposed two remission criteria sets to be applied in clinical trials, a Boolean criteria set and a simplified disease activity index (SDAI), which are more stringent than disease activity score with 28 swollen join count (DAS28) to identify remission. More recently, remission has been described based on routine assessment of patient index data (RAPID3), an index of only patient reported outcomes (PROs). Remission criteria of RAPID3 ≥ 3 and less than one swollen joint (RAPID3 SJ1) is comparable to Boolean criteria and can be implemented in busy clinical settings more easily than indices requiring a laboratory test or formal joint count.