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Objective To develop prediction models for individual patient harm and benefit outcomes in elderly patients with RA and comorbidities treated with chronic low-dose glucocorticoid therapy or placebo. Methods In the Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis (GLORIA) study, 451 RA patients ≥65 years of age were randomized to 2 years 5 mg/day prednisolone or placebo. Eight prediction models were developed from the dataset in a stepwise procedure based on prior knowledge. The first set of four models disregarded study treatment and examined general predictive factors. The second set of four models was similar but examined the additional role of low-dose prednisolone. In each set, two models focused on harm [the occurrence of one or more adverse events of special interest (AESIs) and the number of AESIs per year) and two on benefit (early clinical response/disease activity and a lack of joint damage progression). Linear and logistic multivariable regression methods with backward selection were used to develop the models. The final models were assessed and internally validated with bootstrapping techniques. Results A few variables were slightly predictive for one of the outcomes in the models, but none were of immediate clinical value. The quality of the prediction models was sufficient and the performance was low to moderate (explained variance 12–15%, area under the curve 0.67–0.69). Conclusion Baseline factors are not helpful in selecting elderly RA patients for treatment with low-dose prednisolone given their low power to predict the chance of benefit or harm. Trial registration https://clinicaltrials.gov ; NCT02585258. [ABSTRACT FROM AUTHOR]

Comments on the prognosis of rheumatoid arthritis (RA). Antirheumatic agents and the length of time needed for follow up studies; The phenotype of RA differing between men and women; Association of RA and its manifestations with sex and related factors, such as pregnancy; The traditional therapeutic approach being challenged by early intervention strategy.

Background: An unfavorable body composition is often present in chronic arthritis patients. This unfavorable composition is a loss of muscle mass, with a stable or increased (abdominal) fat mass. Since it is unknown when this unfavorable composition develops, we compared body composition in disease-modifying antirheumatic drugs (DMARD)-naive early arthritis patients with non-arthritis controls and explored the association, in early arthritis patients, with disease activity and traditional cardiovascular risk factors. Methods: 317 consecutive early arthritis patients (84% rheumatoid arthritis according to 2010 ACR/EULAR criteria) and 1268 age-/gender-/ethnicity-matched non-arthritis controls underwent a Dual-energy X-ray absorptiometry scan to assess fat percentage, fat mass index, fat mass distribution and appendicular lean (muscle) mass index. Additionally, disease activity, health assessment questionnaire (HAQ), acute phase proteins, lipid profile and blood pressure were evaluated. Results: Loss of muscle mass (corrected for age suspected muscle mass) was 4–5 times more common in early arthritis patients, with a significantly lower mean appendicular lean mass index (females 6% and males 7% lower, p<0.01). Patients had more fat distributed to the trunk (females p<0.01, males p = 0.07) and females had a 4% higher mean fat mass index (p<0.01). An unfavorable body composition was associated with a higher blood pressure and an atherogenic lipid profile. There was no relationship with disease activity, HAQ or acute phase proteins. Conclusion: Loss of muscle mass is 4–5 times more common in early arthritis patients, and is in early arthritis patients associated with a higher blood pressure and an atherogenic lipid profile. Therefore, cardiovascular risk is already increased at the clinical onset of arthritis making cardiovascular risk management necessary in early arthritis patients. [ABSTRACT FROM AUTHOR]

Objective. To assess the efficacy and safety of initial COBRA-light vs COBRA therapy in RA patients after a 4-year follow-up period. Methods. In the COBRA-light trial, 162 consecutive patients with recent-onset RA were randomized to either COBRA-light (prednisolone and MTX) or COBRA therapy (prednisolone, MTX and SSZ) for 1 year. After 1 year, treatment was continued without protocol, and adjusted by the treating physician according to clinical judgement, preferably with a treat-to-target strategy. Four years after trial initiation, all patients were invited to participate in the COBRA-light extension study, in which patients were interviewed and physically examined, patient reported outcomes were assessed, radiographs were made and clinical records were examined for comorbidities and medication use. Results. In the extension study, 149 out of 162 (92%) original trial patients participated: 72 COBRA-light and 77 COBRA patients. Initial COBRA-light and COBRA therapy showed similar effect on disease activity, physical functioning, radiological outcome and Boolean remission over the 4-year follow-up period. In addition, both treatment groups showed similar survival and major comorbidities, although the power to detect differences was limited. Besides protocolled differences in prednisolone, MTX and SSZ use, the use of other synthetic and biologic DMARDs and intra-articular and intramuscular glucocorticoid injections was similar in both treatment groups over the 4-year period. Conclusion. Early RA patients initially treated with COBRA-light or COBRA therapy had similar efficacy and safety outcomes over a 4-year follow-up period. [ABSTRACT FROM AUTHOR]

Purpose: To relate [18F]fluoride uptake on PET with abnormalities on magnetic resonance imaging (MRI) and conventional radiography (CR) in ankylosing spondylitis (AS) patients. Methods: Ten clinically active AS patients (female 6/10, age 38 ± 11 years) were included, and both spine and SI-joints were examined. PET scans were dichotomously scored for enhanced [18F]fluoride uptake, MRI scans were scored for fatty lesions, erosions, ankylosis, and bone marrow edema (BME), and CR was scored for erosions, syndesmophytes, and ankylosis. The overlap of lesions across all modalities was evaluated through univariate and multivariate analyses using a generalized mixed model. Results: In the spine, 69 lesions with enhanced [18F]fluoride uptake, 257 MRI lesions, and 88 CR lesions were observed. PET lesions were mostly located in costovertebral and facet joints, outside the field of view (FOV) of the MRI and CR. However, PET lesions inside the FOV of MRI and CR partially showed no abnormality on MRI and CR. In lesions with abnormalities on multiple modalities, both univariate and multivariate analysis showed that PET activity had the strongest association with BME on MRI and ankylosis on CR. In the SI joints, 15 lesions (75%) with PET uptake were found, with 87% showing abnormalities on MRI and CR. Conclusion: [18F]fluoride PET lesions are often found outside the scope of MRI and CR, and even in the same location show only partial overlap with abnormalities on MRI (especially BME) and CR (especially ankylosis). This suggests that [18F]fluoride PET partially visualizes aspects of AS separate from MRI and CR, providing novel information. Clinical trial registration: NL43223.029.13 registered at 02-05-2013. https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=C1257BA2002CC066C1257B4E0049A65A [ABSTRACT FROM AUTHOR]

Background: The development and application of standardised sets of outcomes to be measured and reported in clinical trials have the potential to increase the efficiency and value of research. One of the most notable of the current outcome sets began nearly 20 years ago: the World Health Organization and International League of Associations for Rheumatology core set of outcomes for rheumatoid arthritis clinical trials, originating from the OMERACT (Outcome Measures in Rheumatology) Initiative. This study assesses the use of this core outcome set by randomised trials in rheumatology.Methods: An observational review was carried out of 350 randomised trials for the treatment of rheumatoid arthritis identified through The Cochrane Library (up to and including September 2012 issue). Reports of these trials were evaluated to determine whether or not there were trends in the proportion of trials reporting on the full set of core outcomes over time. Researchers who conducted trials after the publication of the core set were contacted to assess their awareness of it and to collect reasons for non-inclusion of the full core set of outcomes in the study.Results: Since the introduction of the core set of outcomes for rheumatoid arthritis, the consistency of measurement of the core set of outcomes has improved, although variation in the choice of measurement instrument remains. The majority of trialists who responded said that they would consider using the core outcome set in the design of a new trial.Conclusions: This observational review suggests that a higher percentage of trialists conducting trials in rheumatoid arthritis are now measuring the rheumatoid arthritis core outcome set. Core outcome sets have the potential to improve the evidence base for health care, but consideration must be given to the methods for disseminating their availability amongst the relevant communities. [ABSTRACT FROM AUTHOR]

Objectives. To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA. Methods. Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE). Results. A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates. Conclusion. Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs. Systematic review registration number. PROSPERO CRD42014014842. [ABSTRACT FROM AUTHOR]

Objective. To investigate the effect of two different high-dose, step-down prednisolone regimens on body composition in early RA patients after 26 weeks of treatment. Methods. Prednisolone-naive patients with recent-onset RA (n = 108) were randomized to either COBRA (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks; MTX and SSZ) or COBRA-light therapy (prednisolone 30 mg/day, tapered to 7.5 mg/day in 8 weeks and MTX). Body composition was assessed at baseline (before or soon after start of treatment) and after 26 weeks with DXA, and recorded as total body mass (TBM), total fat mass (FM), total lean mass (LM) and trunk/peripheral fat ratio. Log-ratio analyses assessed the proportional distribution of TBM (between LM, FM and bone mass) and FM (between trunk, extremities and head). The subgroup of patients with a DXA before start of treatment (n = 38) was analysed separately. Results. In the subgroup of patients with a DXA before start of treatment, TBM increased by 1.6 kg (P < 0.001) and total FM by 1.3 kg (P < 0.001). The trunk/peripheral fat ratio and the proportional distribution of TBM and FM remained stable over time. There were no differences between the treatment groups. Similar results were obtained in the study population as a whole. Conclusion. Both high-dose, step-down prednisolone regimens caused increases in TBM, mainly caused by an increase in FM, but we found no fat redistribution from peripheral to central tissues. This absence in fat redistribution contradicts the widely held assumption of rapid adverse effects of prednisolone on body composition in RA. Trial registration: ISRCTNregistry, http://www.isrctn.com, ISRCTN55552928 [ABSTRACT FROM AUTHOR]

Objective: We developed a smartphone application for patients with rheumatoid arthritis (RA) that allows them to self‐monitor their disease activity in between clinic visits by answering a weekly Routine Assessment of Patient Index Data 3. This study was undertaken to assess the safety (noninferiority in the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28‐ESR]) and efficacy (reduction in number of visits) of patient‐initiated care assisted using a smartphone app, compared to usual care. Methods: A 12‐month, randomized, noninferiority clinical trial was conducted in RA patients with low disease activity and without treatment changes in the past 6 months. Patients were randomized 1:1 to either app‐supported patient‐initiated care with a scheduled follow‐up consultation after a year (app intervention group) or usual care. The coprimary outcome measures were noninferiority in terms of change in DAS28‐ESR score after 12 months and the ratio of the mean number of consultations with rheumatologists between the groups. The noninferiority limit was 0.5 difference in DAS28‐ESR between the groups. Results: Of the 103 randomized patients, 102 completed the study. After a year, noninferiority in terms of the DAS28‐ESR score was established, as the 95% confidence interval (95% CI) of the mean ΔDAS28‐ESR between the groups was within the noninferiority limit: −0.04 in favor of the app intervention group (95% CI −0.39, 0.30). The number of rheumatologist consultations was significantly lower in the app intervention group compared to the usual care group (mean ± SD 1.7 ± 1.8 versus 2.8 ± 1.4; visit ratio 0.62 [95% CI 0.47, 0.81]). Conclusion: Patient‐initiated care supported by smartphone self‐monitoring was noninferior to usual care in terms of the ΔDAS28‐ESR and led to a 38% reduction in rheumatologist consultations in RA patients with stable low disease activity. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the changes in the laboratory network of the Animal Health and Veterinary Laboratories Agency (AHVLA).

Reflects on medical error and a situation in which a young patient had myocardial infarction. Way that the physician refused to look at an electrocardiogram because he had assumed it would be normal; View that pattern recognition must be balanced by a strong reflex of self-doubt and appraisal of all evidence.

Objectives To investigate the dynamics of response of synovitis to IL-17A inhibition with secukinumab in patients with active PsA using Power Doppler ultrasound. Methods The randomized, placebo-controlled, Phase III ULTIMATE study enrolled PsA patients with active ultrasound synovitis and clinical synovitis and enthesitis having an inadequate response to conventional DMARDs and naïve to biologic DMARDs. Patients were randomly assigned to receive either weekly subcutaneous secukinumab (300 or 150 mg according to the severity of psoriasis) or placebo followed by 4-weekly dosing thereafter. The primary outcome was the mean change in the ultrasound Global EULAR and OMERACT Synovitis Score (GLOESS) from baseline to week 12. Key secondary endpoints included ACR 20 and 50 responses. Results Of the 166 patients enrolled, 97% completed 12 weeks of treatment (secukinumab, 99%; placebo, 95%). The primary end point was met, and the adjusted mean change in GLOESS was higher with secukinumab than placebo [−9 (0.9) vs −6 (0.9), difference (95% CI): −3 (−6, −1); one-sided P= 0.004] at week 12. The difference in GLOESS between secukinumab and placebo was significant as early as one week after initiation of treatment. All key secondary endpoints were met. No new or unexpected safety findings were reported. Conclusion This unique ultrasound study shows that apart from improving the signs and symptoms of PsA, IL-17A inhibition with secukinumab leads to a rapid and significant reduction of synovitis in PsA patients. Trial registration ClinicalTrials.gov; NCT02662985. [ABSTRACT FROM AUTHOR]

The article reports a response after switching from prednisole to dexamethasone in three D2T-RA patients with active disease despite prednisolone. Topics discussed include possible mechanisms why response to different glucocorticoids (GCs) may vary, pharmacodynamic differences between GCs, and characteristics of 3 ACPA-positive patients switched from prednisolone to dexamethasone.

Background Recent qualitative research has shown that stiffness is an important symptom for patients to identify remission. However, it is unclear how to measure stiffness in low disease activity. This systematic review aims to summarise the existing literature on validity of patient reported outcomes to measure stiffness in RA low disease activity states, to aid the choice for a measurement instrument. Methods An extensive pubmed-search was undertaken, identifying measurement instruments for patient perceived stiffness used in low disease activity. Eligible studies reported on 1) stiffness as an outcome in relation to other core set measures, 2) development of a patient reported tool to measure stiffness, or 3) comparison of two different tools to measure aspects of stiffness, all in low disease activity. Results Of 788 titles, only two studies report on validity of stiffness measures within low disease activity. Morning stiffness (MS) is reported in 44 to 80% of patients in low disease activity. A difference of 40 to 60 minutes in duration until maximum improvement is observed between active and inactive patients. Severity of MS might discriminate better between high and low disease activity compared to measurement of duration of MS. Conclusions There is insufficient data on measurement of stiffness in the spectrum of low disease activity or remission. [ABSTRACT FROM AUTHOR]

Objectives Although there is a general focus on early diagnosis and treatment of hip OA, there are no validated diagnostic criteria for early-stage hip OA. The current study aimed to take the first steps in developing diagnostic criteria for early-stage hip OA, using factors obtained through history taking, physical examination, radiography and blood testing at the first consultation in individuals presenting with hip pain, suspicious for hip OA, in primary care. Methods Data of the 543 individuals with 735 symptomatic hips at baseline who had any follow-up data available from the prospective CHECK cohort study were used. A group of 26 clinical experts [general practitioners (GPs), rheumatologists and orthopaedic surgeons] evaluated standardized clinical assessment forms of all subjects on the presence of clinically relevant hip OA 5–10 years after baseline. Using the expert-based diagnoses as reference standard, a backward selection method was used to create predictive models based on pre-defined baseline factors from history taking, physical examination, radiography and blood testing. Results Prevalence of clinically relevant hip OA during follow-up was 22%. Created models contained four to eight baseline factors (mainly WOMAC pain items, painful/restricted movements and radiographic features) and obtained area under the curve between 0.62 (0.002) and 0.71 (0.002). Conclusion Based on clinical and radiographic features of hip OA obtained at first consultation at a GP for pain/stiffness of the hip, the prediction of clinically relevant hip OA within 5–10 years was 'poor' to 'fair'. [ABSTRACT FROM AUTHOR]

Purpose: To develop an algorithm for the diagnosis of Behçet's disease (BD) uveitis based on ocular findings. Methods: Following an initial survey among uveitis experts, we collected multi-center retrospective data on 211 patients with BD uveitis and 207 patients with other uveitides, and identified ocular findings with a high diagnostic odds ratio (DOR). Subsequently, we collected multi-center prospective data on 127 patients with BD uveitis and 322 controls and developed a diagnostic algorithm using Classification and Regression Tree (CART) analysis and expert opinion. Results: We identified 10 items with DOR >5. The items that provided the highest accuracy in CART analysis included superficial retinal infiltrate, signs of occlusive retinal vasculitis, and diffuse retinal capillary leakage as well as the absence of granulomatous anterior uveitis or choroiditis in patients with vitritis. Conclusion: This study provides a diagnostic tree for BD uveitis that needs to be validated in future studies. [ABSTRACT FROM AUTHOR]

Background older people remain underrepresented in clinical trials, and evidence generated in younger populations cannot always be generalized to older patients. Objective to identify key barriers and to discuss solutions to specific issues affecting recruitment and retention of older participants in clinical trials based on experience gained from six current European randomised controlled trials (RCTs) focusing on older people. Methods a multidisciplinary group of experts including representatives of the six RCTs held two networking conferences and compiled lists of potential barriers and solutions. Every item was subsequently allocated points by each study team according to how important it was perceived to be for their RCTs. Results the six RCTs enrolled 7,612 older patients. Key barriers to recruitment were impaired health status, comorbidities and diverse health beliefs including priorities within different cultural systems. All trials had to increase the number of recruitment sites. Other measures felt to be effective included the provision of extra time, communication training for the study staff and a re-design of patient information. Key barriers for retention included the presence of severe comorbidities and the occurrence of adverse events. Long study duration, frequent study visits and difficulties accessing the study site were also mentioned. Solutions felt to be effective included spending more time maintaining close contact with the participants, appropriate measures to show appreciation and reimbursement of travel arrangements. Conclusion recruitment and retention of older patients in trials requires special recognition and a targeted approach. Our results provide scientifically-based practical recommendations for optimizing future studies in this population. [ABSTRACT FROM AUTHOR]

The use of nonstandardized and inadequately validated outcome measures in atopic eczema trials is a major obstacle to practising evidence-based dermatology. The Harmonising Outcome Measures for Eczema ( HOME) initiative is an international multiprofessional group dedicated to atopic eczema outcomes research. In June 2011, the HOME initiative conducted a consensus study involving 43 individuals from 10 countries, representing different stakeholders (patients, clinicians, methodologists, pharmaceutical industry) to determine core outcome domains for atopic eczema trials, to define quality criteria for atopic eczema outcome measures and to prioritize topics for atopic eczema outcomes research. Delegates were given evidence-based information, followed by structured group discussion and anonymous consensus voting. Consensus was achieved to include clinical signs, symptoms, long-term control of flares and quality of life into the core set of outcome domains for atopic eczema trials. The HOME initiative strongly recommends including and reporting these core outcome domains as primary or secondary endpoints in all future atopic eczema trials. Measures of these core outcome domains need to be valid, sensitive to change and feasible. Prioritized topics of the HOME initiative are the identification/development of the most appropriate instruments for the four core outcome domains. HOME is open to anyone with an interest in atopic eczema outcomes research. [ABSTRACT FROM AUTHOR]

Little is known about the effects of cumulative trauma and whether traumatized individuals are more vulnerable. In 2000, a fireworks disaster created the possibility to examine this issue among World WarII survivors who were part of an ongoing longitudinal study. Between 1998 and 2000 posttraumatic stress increased in disaster exposed respondents as opposed to the control group. War-related reexperiencing and avoidance also increased. The strongest increase occurred in disaster-exposed respondents who had low levels of wartime stress and a slight decrease occurred in those who had high wartime exposure. This unique controlled observation suggests that disasters do increase the levels of posttraumatic stress, and that reactivation of previous traumatic events generally occurs. However, the vulnerability hypothesis was not supported. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis is a chronic inflammatory disease, which affects 1% of the population. Hands and feet are most commonly involved followed by the cervical spine. The spinal column consists of vertebrae stabilized by an intricate network of ligaments. Especially in the upper cervical spine, rheumatoid arthritis can cause degeneration of these ligaments, causing laxity, instability and subluxation of the vertebral bodies. Subsequent compression of the spinal cord and medulla oblongata can cause severe neurological deficits and even sudden death. Once neurological deficits occur, progression is inevitable although the rapidity of progression is highly variable. The first signs and symptoms are pain at the back of the head caused by compression of the major occipital nerve, followed by loss of strength of arms and legs. The severity of the subluxation can be observed with radiological investigations (MRI, CT) with a high sensitivity. The authors have sent a Delphi Questionnaire about the current treatment strategies of craniocervical involvement by rheumatoid arthritis to an international forum of expert rheumatologists and surgeons. The timing of surgery in patients with radiographic instability without evidence of neurological deficit is an area of considerable controversy. If signs and symptoms of myelopathy are present there is little chance of recovery to normal levels after surgery. Design: In this international multicenter randomized clinical trial, early surgical atlantoaxial fixation in patients with rheumatoid arthritis and radiological abnormalities without neurological deficits will be compared with prolonged conservative treatment. The main research question is whether early surgery can prevent radiological and neurological progression. A cost-effectivity analysis will be performed. 250 patients are needed to answer the research question. Discussion: Early surgery could prevent serious neurological deficits, but may have peri-operative morbidity and loss of rotation of the head and neck. The objective of this study is to identify the best timing of surgery for patients at risk for the development of neurological signs and symptoms. [ABSTRACT FROM AUTHOR]

Objective: To test the reliability of two radiologic scoring methods in rheumatoid arthritis (RA)—the Sharp/van der Heijde (SvH) and the Larsen/Scott (LS)—with generalizability analyses.Study design and setting: Films of 51 patients representing the spectrum of early RA were read by two raters for each method. The discriminative ability and responsiveness were expressed as: intraclass correlation coefficients (ICCs), two types of smallest detectable difference (SDD), and two types of smallest detectable change (SDC); reflecting measurement error when discriminating between or detecting changes within (1) individuals or (2) groups. They were calculated for (average) scores of one to three raters.Results: The discriminative capacity (0.85–0.97) and responsiveness (0.91–0.97) were good when expressed by ICC. On the group level the SDDs and SDCs ranged between 0.6–3.3% of the max. obtainable score. On the individual level, the scores showed better reliability measured with the SvH (SDDs 2.0–3.4%) than with the LS (SDDs 5.3–9.2%). The SvH also assessed changes in scores in individuals with less measurement error (SDCs 1.3–2.2%) than the LS (SDCs 2.3–3.9%).Conclusion: For early RA patients, the SvH seems preferable if analyses on individual level are included. [Copyright &y& Elsevier]

Background: A substantial proportion of rheumatoid arthritis (RA) patients discontinues treatment with tumour necrosis factor inhibitors (TNFi) due to inefficacy or intolerance. After the failure of treatment with a TNFi, treatment can be switched to another TNFi or a bDMARD with a different mode of action (non-TNFi). Measurement of serum drug concentrations and/or anti-drug antibodies (therapeutic drug monitoring (TDM)) may help to inform the choice for the next step. However, the clinical utility of TDM to guide switching has not been investigated in a randomised test-treatment study.Methods: ADDORA-switch is a 24-week, multi-centre, triple-blinded, superiority test-treatment randomised controlled trial. A total of 84 RA patients failing adalimumab treatment (treatment failure defined as DAS28-CRP > 2.9) will be randomised in a 1:1 ratio to a switching strategy to either TNFi or non-TNFi based on adalimumab serum trough level (intervention group) or random allocation (control group). The primary outcome is the between-group difference in mean time-weighted DAS28 over 24 weeks.Discussion: The trial design differs in many aspects from previously published and ongoing TDM studies and is considered the first blinded test-treatment trial using TDM in RA. Several choices in the design of this trial are described, and overarching principles regarding test-treatment trials and clinical utility of TDM are discussed in further detail.Trial Registration: Dutch Trial Register NL8210 . Registered on 3 December 2019 (CMO NL69841.091.19). [ABSTRACT FROM AUTHOR]

OBJECTIVE: To identify barriers and solutions for the recruitment and retention of older (aged ≥65 years) people in clinical trials. DESIGN: Systematic literature review. METHODS: Three databases (Medline, Embase, and CENTRAL) were searched for articles reporting on barriers or solutions regarding the recruitment or retention of older people. Only original research articles were included. RESULTS: Fifty eligible articles were identified. Exclusion criteria were the most common cause of poor recruitment of older adults (mainly age and comorbidities). Patients' families or physicians often advised against participation (22% of included studies). Lack of interest (18%) and problems with transportation (18%) were also commonly cited as challenges. Fourteen trials (28%) reported that monitoring and adapting their recruitment methods helped, along with a flexible research team (26%) and provision of transportation (24%). Retention was impaired by death (12%), illness (8%), and loss of interest (6%). Methods with a positive effect on retention included financial incentives and regular information about the progress of the study (12%), a low staff turnover (12%), flexibility in appointment making (10%), and expression of appreciation by the staff through letters, gifts, and cards to the participants (10%). CONCLUSION: We identified several barriers and have listed potential solutions that may improve recruitment and lead to fewer dropouts in trials involving older populations. Implementation of our findings may help mitigate the manifold challenges that come with running a trial with older people. See related editorial by Robison et al. in this issue. [ABSTRACT FROM AUTHOR]

Objectives. Several chronic inflammatory diseases are associated with cardiovascular disease, but the risk in ANCA-associated vasculitis is poorly quantified. The aim of the present study was to review the evidence for an increased cardiovascular risk, including ischaemic heart disease, cerebrovascular accidents and peripheral arterial disease, in patients with ANCA-associated vasculitis. Methods. A comprehensive systematic review was conducted in accordance with guidelines of preferred reporting items for systematic reviews and meta-analyses. The databases PubMed, Embase.com and the Cochrane Library (Wiley) were searched for original observational studies comparing vasculitis patients with at least one control group. Summary estimates were derived with a random-effects model and reported as relative risks. Results. One thousand three hundred and seventy-five studies were identified. Seven studies were included, comprising almost 14 000 ANCA-associated vasculitis patients vs general population controls in six studies and chronic kidney disease patients in one study. ANCA-associated vasculitis carried a relative risk of 1.65 (95% CI: 1.23, 2.22) for all cardiovascular events, 1.60 (95% CI: 1.39, 1.84) for ischaemic heart disease and 1.20 (95% CI: 0.98, 1.48) for cerebrovascular accidents. We did not find studies that addressed the risk for peripheral arterial disease separately. No heterogeneity was seen in the estimates. Conclusion. This meta-analysis of observational studies supports an increase in cardiovascular risk in patients with ANCA-associated vasculitis of ~65%, similar to that found in other chronic inflammatory diseases. Hence, there is a clear need for active cardiovascular risk management in patients with ANCA-associated vasculitis. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints affecting 1% of the world population. It has major impact on patients through disability and associated comorbidities. Current treatment strategies have considerably improved the prognosis, but recent innovations (especially biologic drugs and the new class of so-called "JAK/STAT inhibitors") have important safety issues and are very costly. Glucocorticoids (GCs) are highly effective in RA, and could reduce the need for expensive treatment with biologic agents. However, despite more than 65 years of clinical experience, there is a lack of studies large enough to adequately document the benefit/harm balance. The result is inappropriate treatment strategies, i.e. both under-use and over-use of GCs, and consequently suboptimal treatment of RA.Methods: The GLORIA study is a pragmatic multicentre, 2-year, randomised, double-blind, clinical trial to assess the safety and effectiveness of a daily dose of 5 mg prednisolone or matching placebo added to standard of care in elderly patients with RA. Eligible participants are diagnosed with RA, have inadequate disease control (disease activity score, DAS28 ≥ 2.6), and are ≥ 65 years. The primary outcome measures are the time-averaged mean value of the DAS28 and the occurrence of serious adverse events or adverse events of special interest. During the trial, change in antirheumatic therapy is permitted as clinically indicated, except for GCs. Cost-effectiveness and cost-utility are secondary outcomes. The main challenge is the interpretation of the trial result with two primary endpoints and the pragmatic trial design that allows co-interventions. Another challenge is the definition of safety and the relative lack of power to detect differences between treatment groups. We have chosen to define safety as the number of patients experiencing at least one serious adverse event. We also specify a decision tree to guide our conclusion on the balance of benefit and harm, and our methodology to combat potential confounding caused by co-interventions.Discussion: Pragmatic trials minimise impact on daily practice and maximise clinical relevance of the results, but analysis and interpretation of the results is challenging. We expect that the results of this trial are of importance for all rheumatologists who treat elderly patients with RA.Trial Registration: ClinicalTrials.gov, NCT02585258 . Registered on 20 October 2015. [ABSTRACT FROM AUTHOR]

Objective. To assess the 10-year cardiovascular (CV) risk score and to identify treatment and undertreatment of CV risk factors in patients with established RA. Methods. Demographics, CV risk factors and prevalence of cardiovascular disease (CVD) were assessed by questionnaire. To calculate the 10-year CV risk score according to the Dutch CV risk management guideline, systolic blood pressure was measured and cholesterol levels were determined from fasting blood samples. Patients were categorized into four groups: indication for treatment but not treated; inadequately treated, so not meeting goals (systolic blood pressure ≤140mmHg and/or low-density lipoprotein ≤2.5mmol/l); adequately treated; or no treatment necessary. Results. A total of 720 consecutive RA patients were included, 375 from Reade and 345 from the Antonius Hospital. The mean age of patients was 59 years (S.D. 12) and 73% were female. Seventeen per cent of the patients had a low 10-year CV risk (<10%), 21% had an intermediate risk (10-19%), 53% a high risk (≥20%) and 9% had CVD. In total, 69% had an indication for preventive treatment (cholesterol-lowering or antihypertensive drugs). Of those, 42% received inadequate treatment and 40% received no treatment at all. Conclusion. Optimal CV risk management remains a major challenge and better awareness and management are urgently needed to reduce the high risk of CVD in the RA population. [ABSTRACT FROM AUTHOR]

Background: This masterclass introduces the topic of core outcome sets, describing rationale and methods for developing them, and providing some examples that are relevant for clinical research and practice. Method: A core outcome set is a minimum consensus-based set of outcomes that should be measured and reported in all clinical trials for a specific health condition and/or intervention. Issues surrounding outcome assessment, such as selective reporting and inconsistency across studies, can be addressed by the development of a core set. As suggested by key initiatives in this field (i.e. OMERACT and COMET), the development requires achieving consensus on: (1) core outcome domains and (2) core outcome measurement instruments. Different methods can be used to reach consensus, including: literature systematic reviews to inform the process, qualitative research with clinicians and patients, group discussions (e.g. nominal group technique), and structured surveys (e.g. Delphi technique). Various stakeholders should be involved in the process, with particular attention to patients. Results and conclusions: Several COSs have been developed for musculoskeletal conditions including a longstanding one for low back pain, IMMPACT recommendations on outcomes for chronic pain, and OMERACT COSs for hip, knee and hand osteoarthritis. There is a lack of COSs for neurological, geriatric, cardio-respiratory and pediatric conditions, therefore, future research could determine the value of developing COSs for these conditions. [ABSTRACT FROM AUTHOR]

Background: In cooperation with the Core Outcome Measures in Effectiveness Trials (COMET) initiative, the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) initiative aimed to develop a guideline on how to select outcome measurement instruments for outcomes (i.e., constructs or domains) included in a "Core Outcome Set" (COS). A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population.Methods: Informed by a literature review to identify potentially relevant tasks on outcome measurement instrument selection, a Delphi study was performed among a panel of international experts, representing diverse stakeholders. In three consecutive rounds, panelists were asked to rate the importance of different tasks in the selection of outcome measurement instruments, to justify their choices, and to add other relevant tasks. Consensus was defined as being achieved when 70 % or more of the panelists agreed and when fewer than 15 % of the panelists disagreed.Results: Of the 481 invited experts, 120 agreed to participate of whom 95 (79 %) completed the first Delphi questionnaire. We reached consensus on four main steps in the selection of outcome measurement instruments for COS: Step 1, conceptual considerations; Step 2, finding existing outcome measurement instruments, by means of a systematic review and/or a literature search; Step 3, quality assessment of outcome measurement instruments, by means of the evaluation of the measurement properties and feasibility aspects of outcome measurement instruments; and Step 4, generic recommendations on the selection of outcome measurement instruments for outcomes included in a COS (consensus ranged from 70 to 99 %).Conclusions: This study resulted in a consensus-based guideline on the methods for selecting outcome measurement instruments for outcomes included in a COS. This guideline can be used by COS developers in defining how to measure core outcomes. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study is to evaluate the efficacy of 18 F-FDG-PET as first-line diagnostic investigation, prior to performing a direct laryngoscopy with biopsy under general anesthesia, in patients suspected of recurrent laryngeal carcinoma after radiotherapy. Patients and methods 150 patients suspected of recurrent T2–4 laryngeal carcinoma at least two months after prior (chemo)radiotherapy with curative intent for resectable disease were randomized to direct laryngoscopy (CWU: conventional workup strategy) or to 18 F-FDG-PET only followed by direct laryngoscopy if PET was assessed ‘positive’ or ‘equivocal’ (PWU: PET based workup strategy), to compare the effectiveness of these strategies. Primary endpoint was the number of indications for direct laryngoscopies classified as unnecessary based on absence of recurrence, both on direct laryngoscopy and on six month follow up. Safety endpoints comprised resectability of recurrent lesions and completeness of surgical margins following salvage laryngectomy. Results Intention-to-treat analyses were performed on all randomized patients (CWU: n = 74, PWU: n = 76). Tumor recurrence was similar in both groups: 45 patients (30%; 21 CWU, 24 PWU) within six months. In 53 patients in the CWU arm (72%, 95% CI: 60–81) unnecessary direct laryngoscopies were performed compared to 22 in the PWU arm (29%, 95% CI: 19–40) ( p < 0·0001). The percentage of salvage laryngectomies (resectability) and positive surgical margins were similar between CWU and PWU (81%, 63% respectively, p = 0·17, and 29%, 7%, respectively, p = 0.20). The prevalence of the combination of local unresectability and positive margins is in the CWU group 24% and in the PWU group 8%. No difference ( p = 0.32) in disease specific survival between both groups was found. Conclusion In patients with suspected laryngeal carcinoma after radiotherapy, PET as the first diagnostic procedure can reduce the need for direct laryngoscopy by more than 50% without jeopardizing quality of treatment. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the content validity and measurement properties of the Patient-Reported Outcome Measurement Information System (PROMIS) physical function item bank and a 20-item short form in patients with RA in comparison with the HAQ disability index (HAQ-DI) and 36-item Short Form Health Survey (SF-36) physical functioning scale (PF-10). Methods. The content validity of the instruments was evaluated by linking their items to the International Classification of Functioning, Disability and Health (ICF) core set for RA. The measures were administered to 690 RA patients enrolled in the Dutch Rheumatoid Arthritis Monitoring registry. Measurement precision was evaluated using item response theory methods and construct validity was evaluated by correlating physical function scores with other clinical and patient-reported outcome measures. Results. All 207 health concepts identified in the physical function measures referred to activities that are featured in the ICF. Twenty-three of 26 ICF RA core set domains are featured in the full PROMIS physical function item bank compared with 13 and 8 for the HAQ-DI and PF-10, respectively. As hypothesized, all three physical function instruments were highly intercorrelated (r 0.74-0.84), moderately correlated with disease activity measures (r 0.44-0.63) and weakly correlated with age (rs 0.07-0.14). Item response theory-based analysis revealed that a 20-item PROMIS physical function short form covered a wider range of physical function levels than the HAQ-DI or PF-10. Conclusion. The PROMIS physical function item bank demonstrated excellent measurement properties in RA. A content-driven 20-item short form may be a useful tool for assessing physical function in RA. [ABSTRACT FROM AUTHOR]

The Dutch-Flemish PROMIS Group translated the adult PROMIS Pain Interference item bank into Dutch-Flemish. The aims of the current study were to calibrate the parameters of these items using an item response theory (IRT) model, to evaluate the cross-cultural validity of the Dutch-Flemish translations compared to the original English items, and to evaluate their reliability and construct validity. The 40 items in the bank were completed by 1085 Dutch chronic pain patients. Before calibrating the items, IRT model assumptions were evaluated using confirmatory factor analysis (CFA). Items were calibrated using the graded response model (GRM), an IRT model appropriate for items with more than two response options. To evaluate cross-cultural validity, differential item functioning (DIF) for language (Dutch vs. English) was examined. Reliability was evaluated based on standard errors and Cronbach’s alpha. To evaluate construct validity correlations with scores on legacy instruments (e.g., the Disabilities of the Arm, Shoulder and Hand Questionnaire) were calculated. Unidimensionality of the Dutch-Flemish PROMIS Pain Interference item bank was supported by CFA tests of model fit (CFI = 0.986, TLI = 0.986). Furthermore, the data fit the GRM and showed good coverage across the pain interference continuum (threshold-parameters range: -3.04 to 3.44). The Dutch-Flemish PROMIS Pain Interference item bank has good cross-cultural validity (only two out of 40 items showing DIF), good reliability (Cronbach’s alpha = 0.98), and good construct validity (Pearson correlations between 0.62 and 0.75). A computer adaptive test (CAT) and Dutch-Flemish PROMIS short forms of the Dutch-Flemish PROMIS Pain Interference item bank can now be developed. [ABSTRACT FROM AUTHOR]

Purpose: Inconsistent reporting of outcomes in clinical trials of patients with non-specific low back pain (NSLBP) hinders comparison of findings and the reliability of systematic reviews. A core outcome set (COS) can address this issue as it defines a minimum set of outcomes that should be reported in all clinical trials. In 1998, Deyo et al. recommended a standardized set of outcomes for LBP clinical research. The aim of this study was to update these recommendations by determining which outcome domains should be included in a COS for clinical trials in NSLBP. Methods: An International Steering Committee established the methodology to develop this COS. The OMERACT Filter 2.0 framework was used to draw a list of potential core domains that were presented in a Delphi study. Researchers, care providers and patients were invited to participate in three Delphi rounds and were asked to judge which domains were core. A priori criteria for consensus were established before each round and were analysed together with arguments provided by panellists on importance, overlap, aggregation and/or addition of potential core domains. The Steering Committee discussed the final results and made final decisions. Results: A set of 280 experts was invited to participate in the Delphi; response rates in the three rounds were 52, 50 and 45 %. Of 41 potential core domains presented in the first round, 13 had sufficient support to be presented for rating in the third round. Overall consensus was reached for the inclusion of three domains in this COS: 'physical functioning', 'pain intensity' and 'health-related quality of life'. Consensus on 'physical functioning' and 'pain intensity' was consistent across all stakeholders, 'health-related quality of life' was not supported by the patients, and all the other domains were not supported by two or more groups of stakeholders. Weighting all possible argumentations, the Steering Committee decided to include in the COS the three domains that reached overall consensus and the domain 'number of deaths'. Conclusions: The following outcome domains were included in this updated COS: 'physical functioning', 'pain intensity', 'health-related quality of life' and 'number of deaths'. The next step for the development of this COS will be to determine which measurement instruments best measure these domains. [ABSTRACT FROM AUTHOR]

Background Low back pain (LBP) is one of the most disabling and costly disorders affecting modern society, and approximately 90% of patients are labelled as having non-specific LBP (NSLBP). Several interventions for patients with NSLBP have been assessed in clinical trials, but heterogeneous reporting of outcomes in these trials has hindered comparison of results and performance of meta-analyses. Moreover, there is a risk of selective outcome reporting bias. To address these issues, the development of a core outcome set (COS) that should be measured in all clinical trials for a specific health condition has been recommended. A standardized set of outcomes for LBP were proposed in 1998 however, with evolution in COS development methodology, new instruments, interventions, and understanding of measurement properties, it is appropriate to update that proposal. This protocol describes the methods used in the initial step in developing a COS for NSLBP, namely, establishing a core domain set that should be measured in all clinical trials. Methods/Design An International Steering Committee including researchers, clinicians, and patient representatives from four continents was formed to guide the development of this COS. The approach of initiatives like Core Outcome Measures in Effectiveness Trials (COMET) and Outcome Measures in Rheumatology (OMERACT) was followed. Participants were invited to participate in a Delphi study aimed at generating a consensus-based core domain set for NSLBP. A list of potential core domains was drafted and presented to the Delphi participants who were asked to judge which domains were core. Participant suggestions about overlap, aggregation, or addition of potential core domains were addressed during the study. The patients' responses were isolated to assess whether there was substantial disagreement with the rest of the Delphi panel. A priori thresholds for consensus were established before each Delphi round. All participants' responses were analysed from a quantitative and qualitative perspective to ascertain that no substantial discrepancies between the two approaches emerged. Discussion We present the initial step in developing a COS for NSLBP. The next step will be to determine which measurement instruments adequately cover the domains. [ABSTRACT FROM AUTHOR]

This study aims to investigate how well the Assessment of SpondyloArthritis international Society (ASAS)/Outcome Measures in Rheumatology Clinical Trials (OMERACT) core set and response criteria for ankylosing spondylitis (AS) have been implemented in randomized controlled trials (RCTs) testing pharmacological and non-pharmacological interventions. A systematic literature search was performed up to June 2013 looking for RCTs in patients with axial spondyloarthritis (SpA) (AS and non-radiographic axial SpA). The assessed domains and instruments belonging to the core sets for disease-controlling anti-rheumatic therapy (DC-ART) and symptom-modifying anti-rheumatic drugs (SMARDs) were extracted. Results were reported separately for those trials published until 2 years after the publication of the core set (1 April 2001; 'control trials') and those trials published at least 2 years after the publication date ('implementation trials'). One hundred twenty-three articles from 99 RCTs were included in the analysis, comparing 48 'control trials' and 51 'implementation trials'. Regarding DC-ART core set, the following domains were significantly more frequently assessed in the 'implementation group' in comparison to the 'control group': 'physical function' (100 vs 41.7 %; p ≤ 0.001), 'peripheral joints/entheses' (100 vs 33.3 %; p ≤ 0.001) and 'fatigue' (100 vs 0 %; p ≤ 0.001). Three instruments were significantly more used in the 'implementation group': Bath Ankylosing Spondylitis Functional Index (BASFI) (100 vs 8.3 %; p = ≤ 0.001), CRP (92.3 vs 58.3 %; p = 0.01) and Bath Ankylosing Spondylitis Metrology Index (BASMI) (53.8 vs 0 %; p = 0.001). Regarding SMARD core set domains, physical function (92 vs 23 %; p ≤ 0.001) and fatigue (84 vs 17 %; p ≤ 0.001), as well as the instruments BASFI (88 vs 14 %; p ≤ 0.001) and BASMI (52 vs 0 %; p ≤ 0.001), increased significantly in the 'implementation group'. Twenty per cent of trials from the 'implementation group' but none from the 'control group' included all domains of the core set. In conclusion, this study provides evidence for the implementation of the ASAS/OMERACT core set in RCTs of both DC-ART and SMARD. This applies to the use of the domains and, to a lesser extent, to the specific instruments. [ABSTRACT FROM AUTHOR]

Background: Recent qualitative research has shown that stiffness is an important symptom for patients to identify remission. However, it is unclear how to measure stiffness in low disease activity. This systematic review aims to summarise the existing literature on validity of patient reported outcomes to measure stiffness in RA low disease activity states, to aid the choice for a measurement instrument.Methods: An extensive pubmed-search was undertaken, identifying measurement instruments for patient perceived stiffness used in low disease activity. Eligible studies reported on 1) stiffness as an outcome in relation to other core set measures, 2) development of a patient reported tool to measure stiffness, or 3) comparison of two different tools to measure aspects of stiffness, all in low disease activity.Results: Of 788 titles, only two studies report on validity of stiffness measures within low disease activity. Morning stiffness (MS) is reported in 44 to 80% of patients in low disease activity. A difference of 40 to 60 minutes in duration until maximum improvement is observed between active and inactive patients. Severity of MS might discriminate better between high and low disease activity compared to measurement of duration of MS.Conclusions: There is insufficient data on measurement of stiffness in the spectrum of low disease activity or remission. [ABSTRACT FROM AUTHOR]

Objective: To calibrate the Dutch-Flemish version of the PROMIS physical function (PF) item bank in patients with rheumatoid arthritis (RA) and to evaluate cross-cultural measurement equivalence with US general population and RA data. Methods: Data were collected from RA patients enrolled in the Dutch DREAM registry. An incomplete longitudinal anchored design was used where patients completed all 121 items of the item bank over the course of three waves of data collection. Item responses were fit to a generalized partial credit model adapted for longitudinal data and the item parameters were examined for differential item functioning (DIF) across country, age, and sex. Results: In total, 690 patients participated in the study at time point 1 (T2, N = 489; T3, N = 311). The item bank could be successfully fitted to a generalized partial credit model, with the number of misfitting items falling within acceptable limits. Seven items demonstrated DIF for sex, while 5 items showed DIF for age in the Dutch RA sample. Twenty-five (20%) items were flagged for cross-cultural DIF compared to the US general population. However, the impact of observed DIF on total physical function estimates was negligible. Discussion: The results of this study showed that the PROMIS PF item bank adequately fit a unidimensional IRT model which provides support for applications that require invariant estimates of physical function, such as computer adaptive testing and targeted short forms. More studies are needed to further investigate the cross-cultural applicability of the US-based PROMIS calibration and standardized metric. [ABSTRACT FROM AUTHOR]

Objective To compare rates of sustained low and minimal disease activity and remission according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria during 3-year followup in rheumatoid arthritis (RA) patients treated with etanercept and adalimumab in routine care. Methods Four hundred seven RA patients previously unexposed to tumor necrosis factor antagonists were treated with etanercept (n = 203) or adalimumab (n = 204) and assessed at 3- and later 6-month intervals. Treatment allocation was at the discretion of the treating rheumatologist. Clinical parameters were measured at each time point, as were anti-adalimumab antibodies in adalimumab-treated patients. Achievement of clinical outcome was defined as the occurrence of sustained (at least 12 consecutive months) low disease activity (28-joint Disease Activity Score [DAS28] <3.2), minimal disease activity (DAS28 <2.6), or ACR/EULAR remission based on the Simplified Disease Activity Index (SDAI). Non-overlapping response rates were calculated. Results Among the adalimumab group, 13% reached sustained low disease activity but not sustained minimal disease activity, 15% reached sustained minimal disease activity but not sustained remission according to the SDAI, and 16% reached sustained ACR/EULAR remission. In the etanercept group the corresponding rates were 16%, 11%, and 12%, respectively ( P = 0.42, overall test for linear trend). Adalimumab-treated patients without anti-adalimumab antibodies (n = 150 [74%]) had the best outcomes, and adalimumab-treated patients with anti-adalimumab antibodies the worst, with outcomes in etanercept-treated patients in between ( P < 0.0001). Differences were most apparent in the sustained SDAI remission and sustained minimal disease activity categories. For example, 40% of anti-adalimumab antibody-negative patients, 23% of etanercept-treated patients, and 4% of anti-adalimumab antibody-positive patients achieved at least sustained minimal disease activity. Conclusion Overall, etanercept and adalimumab treatment appear similar in inducing a good long-term clinical outcome. However, in the case of adalimumab this is strongly dependent on the presence or absence of anti-adalimumab antibodies. [ABSTRACT FROM AUTHOR]

Objective To evaluate the effects of oral nonsteroidal antiinflammatory drugs (NSAIDs) on C-reactive protein (CRP) levels in rheumatoid arthritis (RA) patients, with a prespecified focus on the different NSAIDs. Methods We performed a systematic search in Medline via PubMed, the Cochrane Central Register of Controlled Trials, EMBase via OVID, the Institute for Scientific Information Web of Science, and other sources. Eligible trials were parallel-group, randomized, placebo-controlled trials of oral NSAID therapy in RA patients for which there were extractable CRP data. Standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were calculated from the differences in means of CRP levels between groups (active treatment minus placebo) divided by the pooled SDs. For the meta-analysis, a random-effects model was used to estimate the overall change in CRP level, and stratified analysis was used to examine differences among NSAIDs. Results We included 19 trials of 10 different NSAIDs. Overall, NSAIDs showed no effect on the CRP level (SMD 0.01 [95% CI −0.03, 0.06], P = 0.62). However, the prespecified stratified analysis indicated varying effects on the CRP level according to the different NSAIDs; lumiracoxib caused a statistically significant and consistent (I2 = 0%) increase in the CRP level (SMD 0.13 [95% CI 0.01, 0.25], P = 0.037), whereas naproxen caused a statistically significant and consistent (I2 = 0%) decrease in the CRP level (SMD −0.11 [95% CI −0.20, −0.02], P = 0.022). Conclusion Overall, NSAIDs have no effect on the CRP level. However, the nonselective NSAID naproxen was associated with a significant decrease in the CRP level, whereas the cyclooxygenase 2-selective NSAID lumiracoxib was associated with a significant increase in the CRP level. This finding is interesting considering the suspected influence of NSAIDs on cardiovascular complications. [ABSTRACT FROM AUTHOR]

Content validity of patient-reported outcome measures (PROs) has been a focus of debate since the 2006 publication of the U.S. FDA Draft Guidance for Industry in Patient Reported Outcome Measurement. Under the auspices of the Patient Reported Outcomes Measurement Information System (PROMIS) initiative, a working meeting on content validity was convened with leading PRO measurement experts. Platform presentations and participant discussion highlighted key issues in the content validity debate, including inconsistency in the definition and evaluation of content validity, the need for empirical research to support methodological approaches to the evaluation of content validity, and concerns that continual re-evaluation of content validity slows the pace of science and leads to the proliferation of study-specific PROs. We advocate an approach to the evaluation of content validity, which includes meticulously documented qualitative and advanced quantitative methods. To advance the science of content validity in PROs, we recommend (1) development of a consensus definition of content validity; (2) development of content validity guidelines that delineate the role of qualitative and quantitative methods and the integration of multiple perspectives; (3) empirical evaluation of generalizability of content validity across applications; and (4) use of generic measures as the foundation for PROs assessment. [ABSTRACT FROM AUTHOR]

Objective. To compare the effects of aggressive tight control therapy and conventional care on radiographic progression and disease activity in patients with early mild inflammatory arthritis.Methods. Patients with two to five swollen joints, Sharp–van der Heijde radiographic score (SHS) <5 and symptom duration &leq;2 years were randomized between two strategies. Patients with a definite non-RA diagnosis were excluded. The protocol of the aggressive group aimed for remission (DAS < 1.6), with consecutive treatment steps: MTX, addition of adalimumab and combination therapy. The conventional care group followed a strategy with traditional DMARDs (no prednisone or biologics) without DAS-based guideline. Outcome measures after 2 years were SHS (primary), remission rate and HAQ score (secondary).Results. Eighty-two patients participated (60% ACPA positive). In the aggressive group (n = 42), 19 patients were treated with adalimumab. In the conventional care group (n = 40), 24 patients started with hydroxychloroquin (HCQ), 2 with sulfasalazine (SSZ) and 14 with MTX. After 2 years, the median SHS increase was 0 [interquartile range (IQR) 0–1.1] and 0.5 (IQR 0–2.5), remission rates were 66 and 49% and HAQ decreased with a mean of −0.09 (0.50) and −0.25 (0.59) in the aggressive and conventional care group, respectively. All comparisons were non-significant.Conclusion. In patients with early arthritis of two to five joints, both aggressive tight-control therapy including adalimumab and conventional therapy resulted in remission rates around 50%, low radiographic damage and excellent functional status after 2 years. However, full disease control including radiographic arrest in all patients remains an elusive target even in moderately active early arthritis.Trial registration. Dutch Trial Register, http://www.trialregister.nl/, NTR 144. [ABSTRACT FROM PUBLISHER]

The article presents a study which examines the effects and safety of selective estrogen receptor α (ERα) agonist Org 37663 in rheumatoid arthritis (RA) patients. It states that a 10-week, randomized, and proof-of-concept trial was initiated in RA postmenopausal female patients who receive background treatment with methotrexate or sulfasalazine. The results showed that Org 37663 was safe and well tolerated, but was not effective in influencing the disease activity in RA patients.

The author comments on getting patients involved in their rheumatology experience. Topics covered include the important role of clinicians in educating patients regarding how to effectively manage their health conditions. Also mentioned is the need for clinicians to help their patients understand the effects of inflammatory arthritis.

The article discusses the study on the association of rheumatoid arthritis (RA) with an increased risk of cardiovascular disease (CVD). It reveals that the incidence of CVD in patients with RA was nine percent and 4.3 percent in the general population. It is concluded that there is an increased risk of CVD in RA that is equivalent to the risk for CVD in type 2 diabetes mellitus (DM).

Abstract: Objective: To compare statistical models for the analysis of two-state disease processes. Study Design and Setting: A two-armed randomized trial of patients with early rheumatoid arthritis (RA) treated by either combination therapy (sulfasazaline, methotrextate, prednisolone) or monotherapy (sulfasazaline). Disease activity (remission or relapse) was analyzed with the logistic regression model, the proportional hazards regression model, and the continuous-time Markov process model for panel data. The dependence among the switching times was studied by (1) including correlated normal random patient effects for the relapse–remission and remission–relapse switching probabilities; (2) assuming the population to be a mixture of patients responsive and nonresponsive to therapy; (3) including separate parameters for the first and subsequent relapse–remission switch; and (4) combining (1) and (3). The four approaches were compared using parametric bootstrap checks. Results: The logistic regression model, the proportional hazards regression model, and the continuous-time Markov process model for panel data yielded similar combination therapy effects. The inclusion of random patient effects (approaches 1 and 4) gave the best fit to the observed disease activity pattern. Conclusion: Models with correlated random effects can provide a satisfactory fit to two-state disease patterns. [Copyright &y& Elsevier]

Abstract: Objective: Our purpose was to measure the agreement, reliability, construct validity, and feasibility of a measurement tool to assess systematic reviews (AMSTAR). Study Design and Setting: We randomly selected 30 systematic reviews from a database. Each was assessed by two reviewers using: (1) the enhanced quality assessment questionnaire (Overview of Quality Assessment Questionnaire [OQAQ]); (2) Sacks'' instrument; and (3) our newly developed measurement tool (AMSTAR). We report on reliability (interobserver kappas of the 11 AMSTAR items), intraclass correlation coefficients (ICCs) of the sum scores, construct validity (ICCs of the sum scores of AMSTAR compared with those of other instruments), and completion times. Results: The interrater agreement of the individual items of AMSTAR was substantial with a mean kappa of 0.70 (95% confidence interval [CI]: 0.57, 0.83) (range: 0.38–1.0). Kappas recorded for the other instruments were 0.63 (95% CI: 0.38, 0.78) for enhanced OQAQ and 0.40 (95% CI: 0.29, 0.50) for the Sacks'' instrument. The ICC of the total score for AMSTAR was 0.84 (95% CI: 0.65, 0.92) compared with 0.91 (95% CI: 0.82, 0.96) for OQAQ and 0.86 (95% CI: 0.71, 0.94) for the Sacks'' instrument. AMSTAR proved easy to apply, each review taking about 15 minutes to complete. Conclusions: AMSTAR has good agreement, reliability, construct validity, and feasibility. These findings need confirmation by a broader range of assessors and a more diverse range of reviews. [Copyright &y& Elsevier]

Abstract: The RELAPS study (REcurrent LAryngeal carcinoma PET Study) was designed to determine whether FDG–PET is of value in the selection of patients for direct laryngoscopy under general anesthesia in patients with suspicion of recurrent laryngeal carcinoma after radiotherapy. In a randomized controlled clinical trial the current diagnostic practice, i.e. all patients undergo direct laryngoscopy, will be compared to a strategy in which FDG–PET selects the patients for laryngoscopy. All eight head and neck cancer centers of the Dutch Head and Neck Oncology Cooperative Group NWHHT will participate in this multicenter trial. The study population consists of patients with clinical suspicion of recurrent T2–T4 laryngeal carcinoma after radiotherapy (without obvious signs of tumor) in whom a direct laryngoscopy under general anesthesia with taking of biopsies is indicated by the local physician. The primary efficacy endpoint is the difference in the number of futile indications for direct laryngoscopy between the conventional diagnostic arm and the FDG–PET based diagnostic arm. An indication for laryngoscopy is classified as futile if this laryngoscopy was negative and no recurrence was diagnosed within 6 months follow-up (gold standard). The FDG–PET based strategy may increase the risk of missing recurrent tumor compared to current practice. Safety endpoints include survival and morbidity due to laryngoscopy with taking of biopsies. Survival rates of both groups will have to be collected outside the time frame of the funded trial. Resectability of recurrent tumor and tumor negative surgical margins after total laryngectomy will be used as proxy endpoints. The trial will also compare quality of life and direct medical costs between both arms. [Copyright &y& Elsevier]