Browse

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

ID PMID Title PublicationDate abstract
24718962 Characterising arthralgia in the preclinical phase of rheumatoid arthritis using MRI. 2015 Jun BACKGROUND: The phase of arthralgia is the earliest moment to clinically recognize patients who may develop Rheumatoid Arthritis (RA). Previous imaging studies in the arthralgia phase have shown that inflammation precedes RA development. It is unknown which symptoms/characteristics relate to subclinical joint inflammation as measured by MRI. Among all patients with arthralgia, those with clinically suspect arthralgia (CSA) are suspected to progress to arthritis according to the clinical judgement of their rheumatologists. We determined the symptoms/characteristics of patients with CSA who had inflammation on MRI. METHODS: 102 patients with CSA and without clinical arthritis were included. They completed questionnaires, underwent joint counts and unilateral 1.5 T MRI of MCP joints 2-4, wrist and MTP joints 1-5. Synovitis, bone marrow oedema (BME) and tenosynovitis were scored according to the OMERACT rheumatoid arthritis MRI scoring system. Symptoms and signs were related to MRI inflammation (based on MRI scores in symptom-free controls; a sum of synovitis, BME and tenosynovitis scores ≥3 was considered positive). Whether certain clinical characteristics frequently occurred together with MRI inflammation was studied by partial least squares analysis. RESULTS: MRI was performed in 93 patients with CSA, 44% of whom had subclinical MRI inflammation. Synovitis was the most prevalent inflammatory feature on MRI (20%). Patients with MRI inflammation were older and were more frequently positive for anti-citrullinated peptide antibodies than patients without MRI inflammation (p<0.001 and 0.049). In PLS analysis, including 16 clinical and serological characteristics as independent variables and MRI inflammation as dependent variable, no clear clusters of patients with and without MRI inflammation were identified. CONCLUSIONS: Subclinical inflammation as measured by MRI is present in 44% of patients with CSA. A combination of symptoms/characteristics incompletely differentiated patients with and without MRI inflammation.
24818516 Selective JAK inhibitors in development for rheumatoid arthritis. 2014 Aug INTRODUCTION: The JAK kinases are a family of four tyrosine receptor kinases that play a pivotal role in cytokine receptor signalling pathways via their interaction with signal transducers and activators of transcription proteins. Selective inhibitors of JAK kinases are viewed as of considerable potential as disease-modifying anti-inflammatory drugs for the treatment of rheumatoid arthritis. AREAS COVERED: This article provides a review of the clinical development and available clinical results for those JAK inhibitors currently under investigation. Phase II data for four JAK inhibitors (baricitinib, decernotinib, filgotinib and INCB-039110) are contrasted with that reported for the recently approved JAK inhibitor tofacitinib. The preclinical data on these, in addition to peficitinib, ABT-494, INCB-047986 and AC-410 are also discussed, as are some of the inhibitors in preclinical development. EXPERT OPINION: JAK inhibitors are effective in the treatment of rheumatoid arthritis as evidenced by several inhibitors enabling the majority of treated patients to achieve ACR20 responses, with baricitinib and INCB-039110 both effective when administered once daily. JAK inhibitors differ in isoform specificity profiles, with good efficacy achievable by selective inhibition of either JAK1 (filgotinib or INCB-039110) or JAK3 (decernotinib). It remains to be seen what selectivity provides the optimal side-effect profile and to what extent inhibition of JAK2 should be avoided.
24991663 Bone erosion is associated with reduction of circulating endothelial progenitor cells and 2014 Jun OBJECTIVE: To identify factors influencing endothelial progenitor cell (EPC) counts in patients with rheumatoid arthritis (RA). METHODS: The number of circulating CD34+/ vascular endothelial growth factor receptor 2-positive EPCs was measured in 126 RA patients and 46 non-RA control patients. Endothelial function was assessed by brachial flow-mediated dilation (FMD). Serum CXCL12 concentrations were determined using an enzyme-linked immunosorbent assay. EPCs and FMD were measured at baseline and after 24 weeks of anti-tumor necrosis factor (TNF) therapy in 29 patients with active RA. RESULTS: The numbers of circulating EPCs were significantly lower in the RA patients than in the non-RA controls. In multivariate analysis, older age, reduced levels of high-density lipoprotein cholesterol, and higher bone erosion scores were independent risk factors for reduced EPC counts in RA patients. Serum CXCL12 levels correlated negatively with EPC counts, but positively with bone erosion scores. FMD was impaired in RA patients, and a decreased FMD in RA was closely associated with a higher bone erosion score and a reduced EPC count. In addition, EPC counts were restored by anti-TNF therapy, and this increase was paralleled by improvement in FMD. Interestingly, restoration of EPC counts was attenuated in patients with higher bone erosion scores than in those with lower scores, despite similar levels of improvement in disease activity. CONCLUSION: The numbers of circulating EPCs in RA patients are reduced and are inversely correlated with serum levels of CXCL12. Reduced EPC counts are closely associated not only with bone erosion, but also with endothelial dysfunction.
24733962 Cytokines as biomarkers in rheumatoid arthritis. 2014 RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria) and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge's relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA.
23958797 Annexin A1: potential for glucocorticoid sparing in RA. 2013 Oct Glucocorticoids have broad-ranging and powerful anti-inflammatory and immunomodulatory effects. Unsurprisingly, therefore, glucocorticoids are widely and persistently used to treat a large number of inflammatory diseases, including rheumatoid arthritis (RA), despite the well-described adverse effects of these drugs. Annexin A1 is a glucocorticoid-induced molecule that is known to replicate many of the described anti-inflammatory effects of glucocorticoids. In addition to the well-documented roles of this protein in neutrophil function, emerging evidence suggests that annexin A1 is involved in the modulation of T-cell function and the adaptive immune responses relevant to RA. Interest in annexin A1 was renewed after the delineation of the receptors for this protein. This breakthrough also led to advances in our understanding of anti-inflammatory annexin A1 mimetic peptides and agonistic compounds targeting these receptors, particularly those specific for the receptor N-formyl peptide receptor 2 (FPR2). Herein, we review the current knowledge of the biological activities of annexin A1 and their relevance to RA pathogenesis. We also discuss the potential of annexin A1 mimics and strategies aimed at potentiating annexin A1 signalling to become viable approaches to minimizing glucocorticoid use in RA and other inflammatory disorders.
23339232 The relationship between EQ-5D, HAQ and pain in patients with rheumatoid arthritis. 2013 May OBJECTIVE: This study aims to provide robust estimates of EQ-5D as a function of the HAQ and pain in patients with RA. METHOD: Repeated observations were made of patients diagnosed with RA in a US observational cohort (n = 100 398 observations) who provided data on HAQ, pain on a visual analogue scale and the EQ-5D questionnaire. We used a bespoke statistical method based on mixture modelling to appropriately reflect the characteristics of the EQ-5D instrument and to compare this with results from standard multiple regression. RESULTS: EQ-5D can be predicted from summary HAQ and pain scores. We identify four different classes of respondents who differ in terms of disease severity. Unlike the multiple regression, the mixture model exhibits very good fit to the data and does not suffer from problems of bias or predict values outside the feasible range. CONCLUSION: It is appropriate to model the relationship between HAQ and EQ-5D but only if suitable statistical methods are applied. Linear models underestimate the quality-adjusted life year benefits, and therefore the cost-effectiveness, of therapies. The bespoke mixture model approach outlined here overcomes this problem. The addition of pain as an explanatory variable greatly improves the estimates. Reimbursement agencies rely on these types of analyses when formulating policy on the use of new drug therapies. Clinicians as well as economists should be concerned with these issues.
24938440 Ayurvedic medicine for rheumatoid arthritis. 2014 Aug Ayurvedic medicine is the traditional medicine of India, which originated over 5,000 years ago. Parts of this alternative medical system have become increasingly popular worldwide as patients seek approaches to medical care that they perceive as more holistic and less toxic than those offered by conventional Western medicine. Despite the advent of highly effective pharmacologic therapy, most individuals with rheumatoid arthritis (RA) continue to use alternative therapy at some point in the treatment of their disease. This report discusses some of the in-vitro data that suggest potential mechanisms through which Ayurvedic herbal medicines might have beneficial actions in rheumatoid arthritis, and the available clinical data evaluating the use of Ayurvedic medicine for RA.
24528527 Ultrasonography in rheumatoid arthritis. 2014 Jan The use of musculoskeletal ultrasonography (US) is widely established in patients with rheumatoid arthritis (RA). Grey-scale (GS) and power Doppler (PD) are more sensitive in detecting synovitis than clinical examination. This increased sensitivity has led to the application of US also in patients with early-onset arthritis, to improve the certainty of diagnosis and to give prognostic information, while the use of US for classificative purposes has been proposed but not yet defined. US has proven its value also in patients in clinical remission, in which the presence of PD predicts radiographic progression and relapse. There is still a debate on the optimal number of joints to be scanned in patients with RA and several US scores have been proposed so far. US has therefore a relevant role in the management of RA patients, and the ongoing developments of this technique will probably lead to its wider application.
24530143 Update on the surgical treatment for rheumatoid arthritis of the wrist and hand. 2014 Apr Surgical procedures for the treatment of rheumatoid arthritis are aimed at restoring function and decreasing pain. Over the past four decades multiple procedures have been described in the management of early and late disease. This article will review the most common forms of surgery used in the treatment of rheumatoid arthritis.
24497172 Disease activity after the discontinuation of biological therapy in inflammatory rheumatic 2014 Mar The objectives of this study are to explore the causes of permanent discontinuation of biological therapies in inflammatory rheumatic diseases and to analyse the subsequent course of the disease activity. In this multi-centre retrospective cohort study, data on 126 rheumatoid arthritis, 38 ankylosing spondylitis and 11 psoriatic arthritis patients were analysed, in whom biological therapies had been permanently discontinued. The reasons for the cessation of biologics, the DAS28 or BASDAI disease activity indices at the time of discontinuation and thereafter, and the subsequent occurrence of relapses and the duration of remission or low disease activity were investigated. The most common causes of discontinuation were adverse events (45%), inefficacy (16%) or remission (10%). In rheumatoid arthritis, 33.3% remained in low disease activity after a mean follow-up of 22 months. If the biologic was stopped when the disease was inactive, 60.6% remained inactive, and in all the patients in whom the biologic was discontinued because of long-standing remission, the disease remained inactive. Predictors of remission after discontinuation were low disease activity at stopping the biologic and shorter duration of biological therapy. In contrast, 50% of the ankylosing spondylitis patients relapsed after the withdrawal of anti-TNF therapy. Biologic-free low disease activity can be achieved in at least one third of rheumatoid arthritis patients, and low disease activity at the time of discontinuation is a strong predictor of a subsequent favourable disease course. The likelihood of continued remission after the cessation of a biological therapy is much lower in ankylosing spondylitis.
23096407 Low aerobic capacity and physical activity not associated with fatigue in patients with rh 2013 Feb OBJECTIVE: To explore whether low aerobic capacity and physical activity are associated with fatigue, when controlling for age, gender, pain and depressive symptoms in persons with rheumatoid arthritis. METHODS: In 60 individuals fatigue (Multidimensional Assessment of Fatigue scale; MAF), disease activity (Disease Activity Score-28; DAS 28), pain, physical and psychological status (Arthritis Impact Measurement Scales 2; AIMS 2), depression (Hospital Anxiety and Depression Scale; HADS), aerobic capacity and physical activity (Short Questionnaire to Assess Health-enhancing physical activity; SQUASH) were measured. Regression was performed to study the variance of fatigue explained by aerobic capacity and physical activity. RESULTS: Mean (standard deviation (SD)) age of participants was 51.8 (SD 10.4) years and 73.3% were women. Duration of disease was 10.2 (SD 0-41) years and mean disease activity score was 3.4 (SD 1.4). Mean Global Fatigue Index was 20.3 (SD 10.5). Physical function was 1.6 (SD 1.1) and psychological status 3.1 (SD 0-8) on the AIMS2. Pain score was 4.1 (SD 2.0) and median depression score was 3.2 (range 0-15). Total amount of physical activity was 176.9 (10.6-1,492.3) METhours/week and VO2max was 27.8 (SD 3.8) ml/kg/min. Backward multiple regression showed a statistically significant relationship with depressive symptoms only (t = 5.4, p < 0.001), which explained 33% of variance of fatigue in patients with RA. CONCLUSION: Depression, but not aerobic capacity or physical activity, contributed to fatigue. However, no relationship was found between aerobic capacity and fatigue.
23985241 [A woman with a swelling of the right elbow]. 2013 A 74-year-old woman with longlasting rheumatoid arthritis came to our clinic because of a swollen bursa olecrani. Aspiration of the swelling yielded a yellow fluid; polarized light microscopy showed cholesterol crystals.
24620738 What is the future of targeted therapy in rheumatology: biologics or small molecules? 2014 Mar 13 BACKGROUND: Until late in the 20th century, the therapy of rheumatic diseases relied on the use of drugs that had been developed through empirical approaches without detailed understanding of the molecular mechanisms involved. That approach changed with the introduction of biologic therapeutics at the end of the 20th century and by the recent development of small-molecule inhibitors of intracellular signal transduction pathways. Here we compare and discuss the advantages and disadvantages of those two groups of targeted anti-inflammatory therapeutics. DISCUSSION: TNF-blocking biologic agents were introduced into the therapy of rheumatoid arthritis and other autoimmune and inflammatory diseases in the late 1990s. Further biologic agents targeting cytokine networks or specific lymphocyte subsets have since been added to the armamentarium of anti-rheumatic therapy. During the last few years, another wave of novel discoveries led to the development of a new class of small molecule anti-inflammatory compounds targeting intracellular signal transduction molecules, such as tyrosine kinases. In all those cases, the specific targets of the drugs are well defined and significant knowledge about their role in the disease pathomechanism is available, qualifying them for being targeted therapeutics for inflammatory rheumatic diseases. While both groups of targeted therapeutics offer significant clinical benefit, they clearly differ in several aspects, such as the localization of their targets, their route of administration and target specificity, as well as technical details such as manufacturing procedures and cost basis. In this debate paper, we compare the advantages and disadvantages of the two different approaches, aiming to shed light on the possible future of targeted therapies. SUMMARY: Biologic therapeutics and small-molecule inhibitors both have significant advantages and disadvantages in the therapy of rheumatic diseases. The future of targeted therapies is one of the most exciting questions of current rheumatology research and therapy.
25367713 Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from 2015 Jan OBJECTIVES: To evaluate clinical remission with subcutaneous abatacept plus methotrexate (MTX) and abatacept monotherapy at 12 months in patients with early rheumatoid arthritis (RA), and maintenance of remission following the rapid withdrawal of all RA treatment. METHODS: In the Assessing Very Early Rheumatoid arthritis Treatment phase 3b trial, patients with early active RA were randomised to double-blind, weekly, subcutaneous abatacept 125 mg plus MTX, abatacept 125 mg monotherapy, or MTX for 12 months. Patients with low disease activity (Disease Activity Score (DAS)28 (C reactive protein (CRP)) <3.2) at month 12 entered a 12-month period of withdrawal of all RA therapy. The coprimary endpoints were the proportion of patients with DAS28 (CRP) <2.6 at month 12 and both months 12 and 18, for abatacept plus MTX versus MTX. RESULTS: Patients had <2 years of RA symptoms, DAS28 (CRP) ≥3.2, anticitrullinated peptide-2 antibody positivity and 95.2% were rheumatoid factor positive. For abatacept plus MTX versus MTX, DAS28 (CRP) <2.6 was achieved in 60.9% versus 45.2% (p=0.010) at 12 months, and following treatment withdrawal, in 14.8% versus 7.8% (p=0.045) at both 12 and 18 months. DAS28 (CRP) <2.6 was achieved for abatacept monotherapy in 42.5% (month 12) and 12.4% (both months 12 and 18). Both abatacept arms had a safety profile comparable with MTX alone. CONCLUSIONS: Abatacept plus MTX demonstrated robust efficacy compared with MTX alone in early RA, with a good safety profile. The achievement of sustained remission following withdrawal of all RA therapy suggests an effect of abatacept's mechanism on autoimmune processes. TRIAL REGISTRATION NUMBER: NCT01142726.
24782180 Increased Th17 cell frequency and poor clinical outcome in rheumatoid arthritis are associ 2014 May OBJECTIVE: The minor allele of the IL4R gene single-nucleotide polymorphism, rs1805010, confers impaired interleukin-4 (IL-4) signaling and has been associated with an aggressive destructive course of rheumatoid arthritis (RA). IL-4 inhibits the development of Th17 cells, a cell population recently identified as being prominent in RA patients and being associated with cartilage and bone destruction. The purpose of the present study was to investigate whether rs1805010 modulates Th17 cell development and, hence, subsequent clinical outcome in RA. METHODS: A total of 90 patients with early, active RA (mean ± SD Disease Activity Score in 28 joints 4.6 ± 1.1) and 39 control subjects (24 healthy subjects and 15 patients with osteoarthritis [OA]) were genotyped. Serum levels of IL-17 and IL-22 as well as frequencies of Th17 cells were analyzed by enzyme-linked immunosorbent assay and flow cytometry. Clinical and radiographic data were collected and evaluated at baseline and 1 year after disease onset. RESULTS: Twenty-six percent of the RA patients were homozygous for the major allele of rs1805010, 60% were heterozygous, and 14% were homozygous for the minor allele. The RA patients who were homozygous for the minor allele demonstrated significantly higher clinical activity associated with the presence of erosions after 1 year of followup as compared to the other RA patients. The inhibitory effect of IL-4 on Th17 cell development in these patients was significantly less prominent. Accordingly, the frequencies of Th17 cells and serum levels of IL-17 and IL-22 were significantly increased. CONCLUSION: The data indicate that the rs1805010 minor allele contributes to increased Th17 cell frequency, enhanced clinical activity, and accelerated radiographic progression in RA by rendering CD4 T cells from RA patients insensitive to the attenuating effect of IL-4 on Th17 cell development.
25491492 Tocilizumab for treating rheumatoid arthritis: an evaluation of pharmacokinetics/pharmacod 2015 Feb INTRODUCTION: Dysregulated overproduction of IL-6 has important roles in the pathogenesis of rheumatoid arthritis (RA). Tocilizumab (TCZ) is the only approved biologic agent inhibiting the IL-6 pathway for RA treatment, and is the focus of this review. AREAS COVERED: This review summarizes the pharmacologic characteristics, clinical efficacy and safety profile of TCZ therapy in RA patients. The data reviewed were based mainly on Phase III randomized clinical trials and the literature until 2014 regarding TCZ in RA treatment. EXPERT OPINION: Being a first-line biologic agent for RA, TCZ is especially suitable for RA patients who have shown an inadequate response to TNF-α inhibitors or who cannot tolerate methotrexate. In view of its advantage in suppressing acute-phase reactions and as the only approved inhibitor of IL-6 signaling, TCZ might be particularly effective for RA patients with a high systemic inflammatory response, anemia, AA amyloidosis and other diseases mediated by IL-6. Being able to identify reliable predictors of response to TCZ, and finding more effective new biologic and treatment options, will reduce the number of patients who fail to respond to TCZ.
24553677 Toll-like receptor-4 signaling: a new potential therapeutic pathway for rheumatoid arthrit 2014 Nov The Toll-like receptor-4 signaling (TLR-4) has been found to be over-expressed in rheumatoid arthritis (RA) synovium. Furthermore, it regulates the expression of pro-inflammatory cytokines. Based on the current evidences, TLR-4 may be a new potential therapeutic pathway for RA.
23925935 Usefulness of power Doppler ultrasound for prediction of re-therapy with rituximab in rheu 2014 Feb OBJECTIVE: To assess the value of gray-scale (GS) and power Doppler (PD) ultrasound (US) in detecting inflammatory/destructive changes and for prediction of necessity of re-therapy with rituximab (RTX) in patients with rheumatoid arthritis (RA) over 1 year of followup. METHODS: GSUS and PDUS were performed to assess synovitis, tenosynovitis, and erosions on the clinically dominant hand and forefoot of 20 patients with RA before and after therapy with RTX. US parameters were compared with clinical (Disease Activity Score in 28 joints, tender/swollen joint counts, and patients' visual analog scale of disease activity) and laboratory parameters (C-reactive protein level and erythrocyte sedimentation rate). Results were compared for patients with and without re-therapy with RTX. RESULTS: Significant decreases in clinical and laboratory parameters were observed after 6 and 12 months. US synovitis scores significantly decreased after 6 and 12 months (P < 0.05 for each). Regarding patients who received re-therapy between 6 and 9 months after the start of therapy (n = 9), a fair therapy response was still detectable before re-therapy. In these patients, PD-positive synovitis was the only parameter that increased up to the 6-month examination. All patients negative for rheumatoid factor and anti-cyclic citrullinated peptide (n = 4) were in the group of patients receiving a second course of treatment. Seropositive patients showed a better response to treatment with less need for re-therapy. CONCLUSION: Response to therapy was measurable by clinical and laboratory parameters as well as by US. Since PDUS was able to detect the onset of disease activity before worsening of clinical symptoms occurred, PDUS is most helpful in evaluating disease activity and making earlier therapy decisions.
26866084 RHEUMATOID ARTHRITIS ASSOCIATED WITH PULMONARY FIBROSIS IN NIGERIANS: TWO CASE REPORTS. 2014 Sep Rheumatoid arthritis may sometimes present with extra-articular involvement, pulmonary involvement is not common. Rheumatoid arthritis has been reported among Nigerians and extra-articular manifestations are rarely seen. One of the patients was misdiagnosed and mismanaged as a patient with pulmonary tuberculosis. The study is to demonstrate that rheumatoid arthritis is not as rare as previously reported in Nigeria and its pulmonary involvement can mimic tuberculosis or other granulomatous lung disorder. Clinical and serological acumen are necessary to distinguish between the two. Two diagnosed patients with rheumatoid arthritis and pulmonary involvement seen at Olabisi Onabanjo University Teaching Hospital (OOUTH), are hereby presented.
24166210 Examining radiographic outcomes over time. 2014 Feb Statistical analysis plays a critical role in data interpretation in all fields and particularly so for clinical data where important treatment decisions are made. We provide here an in-depth and illustrative analysis to examine patterns and radiographic scores in an early disease rheumatoid arthritis cohort over a 3-year follow-up period. The total Sharp radiographic scores were interpolated from the rates at 6 months, 1, 2, and 3 years and were transformed to count data after rounding. The generalized estimating equations approach and two-part models were applied to analyze the longitudinal radiographic scores using the clinical, demographic, and therapeutic characteristics of the patients after adjusting for the pattern outcomes. Total Sharp scores were modeled, assuming that they were Poisson distributed or had a negative binomial distribution with either an AR(1) working correlation matrix or an exchangeable working correlation matrix. To account for the excessive zero counts, we used two-part models that include the zero-inflated Poisson and the zero-inflated negative binomial to fit the data. This is an innovation because two-part models have not been used in rheumatology even though they are highly appropriate for analyzing data from rheumatic studies. In addition, we analyzed data using generalized estimating equations and compared results from different models using formal statistical goodness-of-fit criteria and arrive at the best model for predicting purposes.