[Show abstract][Hide abstract] ABSTRACT: To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.
[Show abstract][Hide abstract] ABSTRACT: Greater body mass index (BMI) has been associated with less radiographic progression in rheumatoid arthritis (RA). We evaluated the association between BMI and joint damage progression as measured by X-ray and MRI.
[Show abstract][Hide abstract] ABSTRACT: Osteoarthritis (OA) is the fastest growing cause of disability worldwide. The aim of this study was to understand the impact of OA on individuals and to explore current treatment strategies. An online UK-wide survey of people with self-reported OA was conducted, composed of 52 questions exploring the impact of OA, diagnosis and treatment, the role of health professionals and self-management. Four thousand forty-three people were invited with 2,001 respondents (49 % response, 56 % women; mean age 65 years). Fifty-two percent reported that OA had a large impact on their lives. Fifteen percent of respondents had taken early retirement on average 7.8 years earlier than planned. In consultations with general practitioners, only half reported a discussion on pain; fewer reported discussing their fears (21 %) or management goals (15 %). Nearly half (48 %) reported not seeking medical help until pain was frequently unbearable. Oral analgesics (62 %), topical therapies (47 %), physiotherapy (38 %) and steroid injections (28 %) were commonly used. The majority (71 %) reported varying degrees of persistent pain despite taking all prescribed medication. Although 64 % knew that increasing exercise was important, only 36 % acted on this knowledge; 87 % who increased exercise found it beneficial. Over half had future concerns related to mobility (60 %), maintaining independence (52 %) and coping with everyday activities (51 %). OA had significant individual economic impact especially on employment. Current treatment strategies still leave most people in pain with significant fears for the future. There is considerable opportunity to improve the holistic nature of OA consultations especially in provision of information and promotion of self-management strategies.
[Show abstract][Hide abstract] ABSTRACT: Objectives: To review and synthesize the existing literature on the experience of living with a diagnosis of hip and/or knee osteoarthritis (OA). Method: A systematic review was undertaken using meta-ethnography. A search of both published (AMED, CINAHL, EMBASE, PsychINFO, SportsDisc, MEDLINE, Cochrane Clinical Trials Registry, PubMed) and unpublished/trial registry databases [World Health Organization (WHO) International Clinical Trials Registry Platform, Current Controlled Trials, the United States National Institute of Health Trials Registry, National Institute for Health Research (NIHR) Clinical Research Portfolio Database] was undertaken from their inception to 5 June 2013. Results: Thirty-two studies formed the meta-ethnography of the lived experiences of people with OA. In total, 1643 people with OA were sampled, the majority diagnosed with knee OA. The evidence base was weak to moderate in quality. The majority of studies indicated that people viewed living with OA negatively. Four key factors influenced their attitudes to the condition: the severity of their symptoms; the impact of these symptoms on their functional capability; their attitude towards understanding their disease; and their perceptions of other people's beliefs towards their disease. Conclusions: The current literature suggests that greater knowledge of the pathology of OA, management of symptoms, promotion of functional activity for patients and their family/friends networks, and understanding to better inform OA patient's role in society are all important elements that affect a person's attitude to OA. By better understanding these factors during future consultations, clinicians may forge stronger relationships with their patients to more effectively manage this long-term disabling condition.
[Show abstract][Hide abstract] ABSTRACT: To monitor progression to inflammatory arthritis (IA) in individuals with non-specific musculoskeletal (MSK) symptoms and positive anticyclic citrullinated peptide (anti-CCP) antibodies. To develop a pragmatic model to predict development of IA in this patient group.
In this prospective observational cohort, patients with new non-specific MSK symptoms and positive anti-CCP were recruited from regional primary care and secondary care referrals. Clinical, imaging and serological parameters were assessed at baseline. Cox regression analysis was performed to identify predictors of progression to IA and develop a risk score to stratify patients at presentation.
100 consecutive patients (73 women, mean age 51 years) were followed up for median 19.8 months (range 0.1-69.0); 50 developed IA after a median 7.9 months (range 0.1-52.4), 34 within 12 months. The majority (43/50) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis. A model for progression to IA was devised using four variables: tenderness of hand or foot joints, early morning stiffness ≥30 min, high-positive autoantibodies, and positive ultrasonographic power Doppler signal. None of the five individuals at low risk (score 0) progressed to IA, compared with 31% of 29 at moderate risk (1-2) and 62% of 66 at high risk (≥3). Adding shared epitope increased the number at low risk (score 0-1; 0/11 progressed).
In patients presenting with non-specific MSK symptoms and anti-CCP, the risk of progression to IA could be quantified using data available in clinical practice. The proposed risk score may be used to stratify patients for early therapeutic intervention.
NCT02012764 at ClinicalTrials.gov.
Annals of the rheumatic diseases 04/2014; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To develop and validate composite disease activity scores, based on widely available clinical measures, that would demonstrate improved correlation with detection of synovitis on magnetic resonance imaging (MRI) and radiographic progression, in comparison with conventional measures, in patients with rheumatoid arthritis (RA).
This study was conducted as a secondary study of 2 RA clinical trials, GO-BEFORE (development cohort) and GO-FORWARD (validation cohort). Generalized estimating equations were used to evaluate independent cross-sectional associations of component variables (from all time points) with concurrent MRI measures of synovitis and bone edema in the development cohort. Based on regression coefficients, modified versions of the Disease Activity Score in 28 joints (M-DAS28), Simplified Disease Activity Index (M-SDAI), and Clinical Disease Activity Index (M-CDAI) were generated for each subject in the validation cohort. The M-DAS28, M-SDAI, and M-CDAI scores were compared to conventional scores of disease activity with regard to associations with MRI measures of synovitis and radiographic progression, assessed using Pearson's and Spearman's correlations, linear/logistic regression, and receiver operating characteristic analysis.
Four variables were independently associated with MRI-detected synovitis and bone edema in the development cohort: C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), swollen joint count in 28 joints (SJC28), and evaluator's global assessment of disease activity using a visual analog scale (EvGA score). Modified disease activity scores were generated using the regression coefficients obtained in the synovitis models for all subjects in the validation cohort; modified scores were calculated as M-DAS28 = 0.49 × ln(CRP) + 0.15 × SJC28 + 0.22 × EvGA + 1 and M-SDAI = CRP + SJC28 + EvGA. Both modified and conventional disease activity scores correlated significantly with MRI measures of synovitis. Modified scores showed superior correlation with synovitis, as compared to conventional scores, at all time points (P < 0.05). Furthermore, the M-DAS28 and M-SDAI had superior test characteristics for prediction of radiographic progression at 52 weeks (both P < 0.05).
Modified disease activity scores demonstrated superior correlation with MRI detection of synovitis at all time points, and more accurately predicted radiographic progression in patients with RA in a clinical trial setting.
[Show abstract][Hide abstract] ABSTRACT: The "Discrimination" part of the OMERACT Filter asks whether a measure discriminates between situations that are of interest. "Feasibility" in the OMERACT Filter encompasses the practical considerations of using an instrument, including its ease of use, time to complete, monetary costs, and interpretability of the question(s) included in the instrument. Both the Discrimination and Reliability parts of the filter have been helpful but were agreed on primarily by consensus of OMERACT participants rather than through explicit evidence-based guidelines. In Filter 2.0 we wanted to improve this definition and provide specific guidance and advice to participants.
The Journal of Rheumatology 04/2014; · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Outcome Measures in Rheumatology (OMERACT) Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The "Truth" section of the OMERACT Filter requires that criteria be met to demonstrate that the outcome instrument meets the criteria for content, face, and construct validity.
Discussion groups critically reviewed a variety of ways in which case studies of current OMERACT Working Groups complied with the Truth component of the Filter and what issues remained to be resolved.
The case studies showed that there is broad agreement on criteria for meeting the Truth criteria through demonstration of content, face, and construct validity; however, several issues were identified that the Filter Working Group will need to address.
These issues will require resolution to reach consensus on how Truth will be assessed for the proposed Filter 2.0 framework, for instruments to be endorsed by OMERACT.
The Journal of Rheumatology 04/2014; · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Outcome Measures in Rheumatology (OMERACT) Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The "Truth" section of the OMERACT Filter presupposes an explicit framework for identifying the relevant core outcomes that are universal to all studies of the effects of intervention effects. There is no published outline for instrument choice or development that is aimed at measuring outcome, was derived from broad consensus over its underlying philosophy, or includes a structured and documented critique. Therefore, a new proposal for defining core areas of measurement ("Filter 2.0 Core Areas of Measurement") was presented at OMERACT 11 to explore areas of consensus and to consider whether already endorsed core outcome sets fit into this newly proposed framework.
Discussion groups critically reviewed the extent to which case studies of current OMERACT Working Groups complied with or negated the proposed framework, whether these observations had a more general application, and what issues remained to be resolved.
Although there was broad acceptance of the framework in general, several important areas of construction, presentation, and clarity of the framework were questioned. The discussion groups and subsequent feedback highlighted 20 such issues.
These issues will require resolution to reach consensus on accepting the proposed Filter 2.0 framework of Core Areas as the basis for the selection of Core Outcome Domains and hence appropriate Core Outcome Sets for clinical trials.
The Journal of Rheumatology 03/2014; · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoarthritis (OA) currently affects over 40 million Europeans, with its associated personal suffering and significant economic burden for health systems set to dramatically escalate in a rapidly ageing Europe. Given the very limited effective therapeutic options for OA, the European League Against Rheumatism (EULAR) created an ad hoc committee of OA researchers, clinicians and patients to consider a research agenda focussed on the areas of epidemiology, pathogenesis, imaging and biomarkers, and therapies. The committee deliberated and listed research needs in these areas and also established some cross-area priority themes: predictors of OA progression, especially where this might enable stratified interventions; understanding mechanisms of OA pain; improved understanding of tissue communication in a process where multiple tissue pathologies are common; developing concepts of, and consequently interventions for, early OA where both pain and structural processes may be more effectively targeted than in typical clinical presentations; and the need for new treatment strategies, with examples discussed on pathology-targeted therapies and optimal combinations of therapies. This research agenda should provide useful guidance for all researchers in this field and hopefully lead to improved OA care.
Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the efficacy of etanercept (ETN) and methotrexate (MTX) versus MTX monotherapy for remission induction in patients with early inflammatory arthritis.
In a 78-week multicentre randomised placebo-controlled superiority trial, 110 DMARD-naïve patients with early clinical synovitis (≥1 tender and swollen joint, and within 3 months of diagnosis) and either rheumatoid factor, anticitrullinated protein antibodies or shared epitope positive were randomised 1:1 to receive MTX+ETN or MTX+placebo (PBO) for 52 weeks. Injections (ETN or PBO) were stopped in all patients at week 52. In those with no tender or swollen joints (NTSJ) for >26 weeks, injections were stopped early. If patients had NTSJ >12 weeks after stopping the injections, MTX was weaned. The primary endpoint was NTSJ at week 52.
No statistically significant difference was seen for the primary endpoint (NTSJ at week 52 (32.5% vs 28.1% [adjusted OR 1.32 (0.56 to 3.09), p=0.522]) in the MTX+ETN and MTX+PBO groups, respectively). The secondary endpoints did not differ between groups at week 52 or 78. Exploratory analyses showed a higher proportions of patients with DAS28-CRP<2.6 in the MTX+ETN group at week 2 (38.5% vs 9.2%, adjusted OR 8.87 (2.53 to 31.17), p=0.001) and week 12 (65.1% vs 43.8%, adjusted OR 2.49 (1.12 to 5.54), p=0.026).
In this group of patients with early inflammatory arthritis, almost a third had no tender, swollen joints after 1 year. MTX+ETN was not superior to MTX monotherapy in achieving this outcome. Clinical responses, however, including DAS28-CRP<2.6, were achieved earlier with MTX+ETN combination therapy.
The EMPIRE trial is registered on the following trial registries: Eudract-2005-005467-29; ISRCTN 55428162 (http://www.controlled-trials.com/ISRCTN55428162/EMPIRE). The full trial protocol can be obtained from the corresponding author.
Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: RA is a very heterogeneous disease, recently highlighted by distinct differences in the genetic contribution to APCA(+) and ACAP(-) disease suggesting two divergent pathogenic models, with different rates of progression and response to treatment. Synovial tissue studies showed that the cellular composition of synovial membrane is relatively consistent however the size of the inflammatory cell infiltrate is variable in direct relation to local levels of inflammation and sometimes highly organised with germinal centre like structures (GCL). The role of IL-7 as an essential factor in tissue organisation has recently been recognised and we hypothesize that the synovial tissue architecture (TA) may be driven by IL-7 expression in RA.
Synovial tissue biopsies were obtained during arthroscopy (n = 93, distributed between studies). Histology, IHC and two TaqMan gene-arrays were used. Tissues were classified as diffuse infiltration, aggregates and GCL-structures (defined B and T-cell zones). Clustering was used to analyse gene expression data.
IL-7 was detected with large variation between samples. There was association between% of IL-7(+) cells and local inflammation (n = 30, rho = 0.620, p<0.0001), synovitis score (rho = 0.556, p = 0.001) but only in the sublining layer, as well as with increased TA-complexity (p = 0.001), CD3(+) cells (rho = 0.599, p = 0.002) and CD20(+) (rho = 0.605, p = 0.001) but not with CD68(+) cells. IL-7 gene expression was measured in 29 biopsies. IL-7 mRNA expression was significantly higher in tissue presenting aggregates over diffuse infiltration (p = 0.019) and GCL structure (p = 0.037). A first TaqMan-arrays (48-genes) of 44 RA biopsies generated a 2 groups samples hierarchy clearly associated with TA (p = 0.002) separating genes associated with B-cell biology from those associated with stroma, T cells and macrophages. IL-7 surprisingly clustered with the B-cell-group however its expression was highly correlated with CD4 (rho = 0.520, p<0.0001). A second array (96-genes) of 29 biopsies also showed association with TA (p = 0.032) and clustered B-cell maturation genes (CD80, CD86, CD40L, RAG-1, BLIMP, AIOLOS, XBP-1, all Ig-genes) but not CD19/CD20 therefore suggesting a plasma cell specific signature. CD68 and CD4 were excluded from this gene signature. IL-7 was included in the plasma-cell cluster and was closely associated with CD38 (rho = 0.381, p = 0.042) and CD31 (Rho = 0.381, p = 0.042). A regulatory loop between IL-6/IL-7 was also highlighted by the gene dendrogram.
Our data suggest that IL-7 could orchestrate the synovial tissue architecture providing a niche for B-cell maturation. Blocking IL-7 may therefore be of therapeutic value as was recently demonstrated in several animal models of auto-immune diseases.
Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A27-8. · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Outcome Measures in Rheumatology (OMERACT) initiative works to develop core sets of outcome measures for trials and observational studies in rheumatology. At the OMERACT 11 meeting, substantial time was devoted to discussing a conceptual framework and a proposal for a more explicit working process to develop what we now propose to term core outcome measurement sets, collectively termed "OMERACT Filter 2.0."
Preconference work included a literature review, and discussion of preliminary proposals through face-to-face discussions and Internet-based surveys with people within and outside rheumatology. At the conference, 5 interactive sessions comprising plenary and small-group discussions reflected on the proposals from the viewpoint of previous and ongoing OMERACT work. These considerations were brought together in a final OMERACT presentation seeking consensus agreement for the Filter 2.0 framework.
After debate, clarification, and agreed alterations, the final proposal suggested all core sets should contain at least 1 measurement instrument from 3 Core Areas: Death, Life Impact, and Pathophysiological Manifestations, and preferably 1 from the area Resource Use. The process of core set development for a health condition starts by selecting core domains within the areas ("core domain set"). This requires literature searches, involvement (especially of patients), and at least 1 consensus process. Next, developers select at least 1 applicable measurement instrument for each core domain. Applicability refers to the original OMERACT Filter and means that the instrument must be truthful (face, content, and construct validity), discriminative (between situations of interest) and feasible (understandable and with acceptable time and monetary costs). Depending on the quality of the instruments, participants formulate either a preliminary or a final "core outcome measurement set." At final vote, 96% of participants agreed "The proposed overall framework for Filter 2.0 is a suitable basis on which to elaborate a Filter 2.0 Handbook."
Within OMERACT, Filter 2.0 has made established working processes more explicit and includes a broadly endorsed conceptual framework for core outcome measurement set development.
The Journal of Rheumatology 03/2014; · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Outcome Measures in Rheumatology (OMERACT) Filter provides a framework for the validation of outcome measures for use in rheumatology clinical research. However, imaging and biochemical measures may face additional validation challenges because of their technical nature. The Imaging and Soluble Biomarker Session at OMERACT 11 aimed to provide a guide for the iterative development of an imaging or biochemical measurement instrument so it can be used in therapeutic assessment.
A hierarchical structure was proposed, reflecting 3 dimensions needed for validating an imaging or biochemical measurement instrument: outcome domain(s), study setting, and performance of the instrument. Movement along the axes in any dimension reflects increasing validation. For a given test instrument, the 3-axis structure assesses the extent to which the instrument is a validated measure for the chosen domain, whether it assesses a patient-centered or disease-centered variable, and whether its technical performance is adequate in the context of its application. Some currently used imaging and soluble biomarkers for rheumatoid arthritis, spondyloarthritis, and knee osteoarthritis were then evaluated using the original OMERACT Filter and the newly proposed structure. Breakout groups critically reviewed the extent to which the candidate biomarkers complied with the proposed stepwise approach, as a way of examining the utility of the proposed 3-dimensional structure.
Although there was a broad acceptance of the value of the proposed structure in general, some areas for improvement were suggested including clarification of criteria for achieving a certain level of validation and how to deal with extension of the structure to areas beyond clinical trials.
General support was obtained for a proposed tri-axis structure to assess validation of imaging and soluble biomarkers; nevertheless, additional work is required to better evaluate its place within the OMERACT Filter 2.0.
The Journal of Rheumatology 03/2014; · 3.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the past decade there have been significant advances in the field of musculoskeletal imaging, especially in the application of ultrasound (US) and magnetic resonance imaging (MRI) to the management of rheumatoid arthritis (RA). Both modalities offer significant advantages over the previous standards of clinical examination and radiography, and allow direct visualisation of both joint inflammation and structural damage. Although measuring similar pathology, each of these imaging tools has its own benefits and limitations; understanding these will help researchers and clinicians to determine the appropriate role for these tools in RA joint assessment. This review article seeks to compare the usefulness of US and MRI in RA diagnosis, prognosis and outcome assessment.
Clinical and experimental rheumatology 02/2014; · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the imaging-detected mechanism of reduction of structural joint damage progression by tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) using MRI.
In a substudy of a randomised, double-blind, phase 3b study (ACT-RAY) of biologic-naïve patients with RA who were methotrexate (MTX)-inadequate responders, 63 patients were randomised to continue MTX or receive placebo (PBO), both in combination with TCZ 8 mg/kg every 4 weeks, with optional additional disease-modifying antirheumatic drugs at week 24 if Disease Activity Score of 28 joints < 3.2. The most symptomatic hand was imaged with 0.2 Tesla extremity MRI at weeks 0, 2, 12 and 52. MR images were scored using Outcome Measures in Rheumatology-Rheumatoid Arthritis Magnetic Resonance Imaging Score. Predictors of week 52 erosion progression were determined by logistic regression analysis.
TCZ + PBO (n=32) demonstrated mean improvements in synovitis from baseline to weeks 2 (-0.92; p=0.0011), 12 (-1.86; p<0.0001) and 52 (-3.35; p<0.0001), while TCZ + MTX (n=31) had mean improvements in synovitis at week 12 (-0.88; p=0.0074), but not week 52 (-1.00; p=0.0711). TCZ+PBO demonstrated mean reductions in osteitis at weeks 12 (-5.10; p=0.0022) and 52 (-8.56; p=0.0006), while TCZ+MTX had mean reductions at weeks 2 (-0.21; p<0.05) and 12 (-3.63; p=0.0008), but not week 52 (-2.31; p=0.9749). Mean erosion scores did not worsen in either group. MRI erosion scores at weeks 12 and 52 correlated strongly with radiography erosion scores at week 52 (r>0.80). Baseline synovitis and worsening of osteitis predicted erosion progression.
Rapid suppression of synovitis and osteitis with reduction in structural joint damage progression occurred with TCZ, as monotherapy or in combination with MTX, through week 52.
Annals of the rheumatic diseases 02/2014; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives. The aims of this study were to examine the impact of peripheral joint OA across five large European countries and how people with OA use pharmacotherapies.Methods. People with self-reported peripheral joint OA were selected from the 2011 five European countries (5EU) National Health and Wellness Survey (NHWS), which included 57 512 respondents from France, Germany, Italy, Spain and the UK. Information was recorded on symptoms, health status, health care utilization, work productivity and medication usage. All variables were analysed descriptively for the total population and individual countries.Results. A total of 3750 respondents met the inclusion criteria: 1635 (43.6%) UK, 961 (25.6%) France, 570 (15.2%) Germany, 316 (8.4%) Spain and 268 (7.1%) Italy. The majority were ages 55-74 years and most were overweight or obese. Health status [12-item Short Form version 2 (SF12v2)] was similar across all countries, with a mean (s.d.) of 40.53 (10.99); 21.5% self-reported experiencing depression. Most had visited a health care provider in the previous 6 months (n = 3537; 94.3%). One third were employed: 7% reported absenteeism and 24% presenteeism. The use of prescription medication for OA was reported by 46.9% of patients, over-the-counter (OTC) medication by 26.5%, and both by 9.4%. Medication use increased with pain severity. NSAIDs were the most commonly used medication. Opioid use varied from 1.8% in Italy to 54.5% in France. Fifty per cent reported full adherence (4-point Morisky Medication Adherence Scale), but only 30% reported satisfaction with their OA medication. Most used medication for half the days of the month.Conclusion. Despite some wide variations in pharmacotherapy for OA treatment, the impact of OA on health status and work productivity is substantial and looks largely similar across major European countries.