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OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Objective Fatigue and pain are important symptoms for patients with rheumatoid arthritis (RA), but their temporal association is unknown. Therefore, the objective of this study was to investigate the longitudinal relationship between fatigue and pain in patients with RA using time-lag models. Methods Consecutive RA outpatients (n = 228) were enrolled for this 1-year study. Fatigue was assessed monthly with the Checklist Individual Strength (CIS; range 8–56) and pain was assessed monthly with the bodily pain subscale (inverted, range 0–100) of the Short Form 36. The association between monthly changes in fatigue and pain was analyzed using longitudinal regression (mixed models), using the same months and with a 1-month time lag. Results A total of 198 patients were included in the analyses. At baseline, the mean ± SD pain score was 35.23 ± 19.82 and the mean ± SD CIS fatigue score was 31.0 ± 12.4. Severe fatigue at baseline (CIS score ≥35) was present in 42% of the patients. The mean ± SD patient-averaged CIS fatigue score over 1 year was 30.9 ± 6.0 and the mean ± SD patient-averaged pain score over 1 year was 36.4 ± 18.3. The longitudinal regression analysis showed a significant positive relationship between fatigue and pain during the same month (β = 2.04; 95% confidence interval 1.82, 2.27). The models using a time lag showed no significant association between changes in pain and changes in fatigue. Conclusion In established RA, pain and fatigue show monthly fluctuations that are synchronous rather than showing a temporal relationship with a time lag; within this timeframe, the results do not indicate that one precedes the other.

Item does not contain fulltext OBJECTIVE: The introduction of effective treatment strategies in the past two decades has changed the management of RA dramatically. The objective was to analyse the changes in disease activity, function, joint damage and incidence of orthopaedic surgery over a period of 20 years (1989-2009) for patients with RA. METHODS: Data acquired from 1989 to 2008 inclusive from the Nijmegen RA inception cohort were studied. By repeated measures analysis the course of the population mean disease activity score (DAS28) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) corrected for age, gender, RF and disease duration was determined. Orthopaedic interventions were analysed as incidence rates with a Poisson distribution. We calculated the prevalence of the various therapies that patients were receiving. RESULTS: By 2009, 992 patients with RA had been included and 273 had been excluded. From 1989 onwards, the proportion of patients using MTX increased from 5% (8 of 164) to 62% (486 of 780), and biologic response modifiers from 0% to 22% (168 of 780) in 2008. The average MTX dosage increased to 16.1 +/- 5.5 mg/week in 2008. The mean DAS28 (3.1) and HAQ-DI (0.47) were least (P < 0.008) in 2008 compared with previous years. There was a significant trend towards lower incidence rates of orthopaedic intervention in the period 2006-2008 than in almost all previous years. CONCLUSION: Treatment strategy changed in a large inception cohort of patients with RA which coincided with decreased disease activity, increased functional ability and fewer orthopaedic interventions since the early 1990s.

Objective.Studies on mortality associated with patients with systemic sclerosis (SSc) and myopathy have been limited by heterogeneous definitions of muscle involvement. The objective of this study is to determine whether homogeneous-defined SSc/polymyositis overlap (SSc-PM overlap) is associated with a worse survival rate compared with SSc without PM.Methods.Data from the Nijmegen Systemic Sclerosis cohort were used. Incidence rates were calculated from the observed number of deaths and followup time. Survival analysis using Cox proportional hazard modeling was performed to compare survival among patients with SSc and patients with SSc-PM overlap, including controlling for confounders. All patients with SSc-PM fulfilled the Bohan and Peter criteria for PM.Results.There were 24 patients with SSc-PM (5.7%) and 396 patients with SSc (94.2%). The 5- and 10-year cumulative survival rates from diagnosis were 82% and 68% for the SSc-PM group and 93% and 87% for the SSc group, respectively. Multivariate survival analysis revealed an adjusted HR of 2.34 (95% CI 1.09–5.02) for SSc-PM compared with SSc, with age at diagnosis, modified Rodnan skin score, diffuse cutaneous subtype, and male sex included as confounders. The most common cause of death among patients with SSc-PM overlap was cardiopulmonary involvement (63%), which was similar to the patients with SSc (51%).Conclusion.Patients with SSc-PM overlap have a worse survival rate compared with patients with SSc.

Contains fulltext : 171906.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Gout is the most common inflammatory arthritis in men over 40 years of age. Long-term urate-lowering therapy is considered a key strategy for effective gout management. The primary outcome measure for efficacy in clinical trials of urate-lowering therapy is serum urate levels, effectively acting as a surrogate for patient-centred outcomes such as frequency of gout attacks or pain. Yet it is not clearly demonstrated that the strength of the relationship between serum urate and clinically relevant outcomes is sufficiently strong for serum urate to be considered an adequate surrogate. Our objective is to investigate the strength of the relationship between changes in serum urate in randomised controlled trials and changes in clinically relevant outcomes according to the 'Biomarker-Surrogacy Evaluation Schema version 3' (BSES3), documenting the validity of selected instruments by applying the 'OMERACT Filter 2.0'. METHODS AND ANALYSIS: A systematic review described in terms of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines will identify all relevant studies. Standardised data elements will be extracted from each study by 2 independent reviewers and disagreements are resolved by discussion. The data will be analysed by meta-regression of the between-arm differences in the change in serum urate level (independent variable) from baseline to 3 months (or 6 and 12 months if 3-month values are not available) against flare rate, tophus size and number and pain at the final study visit (dependent variables). ETHICS AND DISSEMINATION: This study will not require specific ethics approval since it is based on analysis of published (aggregated) data. The intended audience will include healthcare researchers, policymakers and clinicians. Results of the study will be disseminated by peer-reviewed publications. TRIAL REGISTRATION NUMBER: CRD42016026991.

Item does not contain fulltext OBJECTIVES: To compare the sensitivity and specificity of different classification criteria for gout in early and established disease. METHODS: This was a cross-sectional study of consecutive rheumatology clinic patients with joint swelling in which gout was defined by presence or absence of monosodium urate crystals as observed by a certified examiner at presentation. Early disease was defined as patient-reported onset of symptoms of 2 years or less. RESULTS: Data from 983 patients were collected and gout was present in 509 (52%). Early disease was present in 144 gout cases and 228 non-cases. Sensitivity across criteria was better in established disease (95.3% vs 84.1%, p

Contains fulltext : 171591.pdf (Publisher’s version ) (Open Access) Patient assessment of disease activity in rheumatoid arthritis (RA) may be useful in clinical practice, offering a patient-friendly, location independent, and a time-efficient and cost-efficient means of monitoring the disease. The objective of this study was to identify patient-reported outcome measures (PROMs) to assess disease activity in RA and to evaluate the measurement properties of these measures. Systematic literature searches were performed in the PubMed and EMBASE databases to identify articles reporting on clinimetric development or evaluation of PROM-based instruments to monitor disease activity in patients with RA. 2 reviewers independently selected articles for review and assessed their methodological quality based on the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) recommendations. A total of 424 abstracts were retrieved for review. Of these abstracts, 56 were selected for reviewing the full article and 34 articles, presenting 17 different PROMs, were finally included. Identified were: Rheumatoid Arthritis Disease Activity Index (RADAI), RADAI-5, Patient-based Disease Activity Score (PDAS) I & II, Patient-derived Disease Activity Score with 28-joint counts (Pt-DAS28), Patient-derived Simplified Disease Activity Index (Pt-SDAI), Global Arthritis Score (GAS), Patient Activity Score (PAS) I & II, Routine Assessment of Patient Index Data (RAPID) 2-5, Patient Reported Outcome-index (PRO-index) continuous (C) & majority (M), Patient Reported Outcome CLinical ARthritis Activity (PRO-CLARA). The quality of reports varied from poor to good. Typically 5 out of 10 clinimetric domains were covered in the validations of the different instruments. The quality and extent of clinimetric validation varied among PROMs of RA disease activity. The Pt-DAS28, RADAI, RADAI-5 and RAPID 3 had the strongest and most extensive validation. The measurement properties least reported and in need of more evidence were: reliability, measurement error, cross-cultural validity and interpretability of measures.

Contains fulltext : 171750.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The objectives of this study were twofold: to assess if there are independent effects of variables representing patients' perceptions of disease on intensification of drug therapy in patients with RA seen in daily practice; and to test the hypothesis that effects of patients' perceptions of disease are mediated through patient self-reported willingness to alter therapy. METHODS: Before being seen by a physician, consecutive patients with RA, attending the Radboudumc outpatient rheumatology clinic, were asked to fill out a short questionnaire regarding the following four items: perceived health change, satisfaction with current health, willingness to change therapy and expected health change until the next visit. Independent associations between these measures, registered clinical measures and synthetic DMARD/biologic DMARD (including CSs) intensification were studied with logistic regression. Mediation analysis was performed focusing on the strongest predictor and self-reported willingness as a mediator. RESULTS: Out of 453 patients with RA, 65% female, 67% RF positive, medication was intensified for 82 patients (18%). All patient perception measures exhibited significant associations, independent of clinical measures, of which patient satisfaction with current health state was the strongest [odds ratio (OR) 0.21, 95% CI: 0.10, 0.44]. Significant mediation of the effect of patient satisfaction through willingness to alter therapy on actual registered medication intensification was found. CONCLUSION: Treat to Target interventions should address patients' perceptions of their disease, and the related health goals patients aim to achieve, in addition to the attained level of disease activity.

Contains fulltext : 171428.PDF (Publisher’s version ) (Open Access) INTRODUCTION: The incidence of cardiovascular diseases (CVD) is increased in rheumatoid arthritis (RA) patients. It remains unclear whether the load of RA increases cardiovascular (CV) risk especially in female and in younger RA patients. In the present study we aim to analyse the influence of age and gender on CV risk in RA relative to the general population, using meta-analysis of direct comparative studies. METHOD: Systematic literature search was performed in MEDLINE for studies reporting on occurrence of CV events in RA as compared to the general population, stratified for gender and/or age. Quality was appraised using the Newcastle-Ottawa scale. Meta-analysis was performed on rate ratios using inverse variance methods. RESULTS: There were 1372 records screened and 13 studies included. RA females and males have a similar higher risk (95%CI) to develop stroke with RR 1.35 (1.30-1.40) and RR 1.31 (1.21-1.43); coronary artery disease with RR 1.65 (1.54-1.76) versus RR 1.55 ((1.41-1.69) in men; cardiovascular disease with RR 1.56 (1.49-1.62) versus 1.50 (1.41-1.60). The highest incidence of CV events was observed in the youngest patients, RR 2.59 (1.77-3.79), whereas older patients had the lowest relative risk when compared to the general population, RR 1.27 (1.16-1.38). CONCLUSION: The relative risk of RA patients for CVD is age dependent, but does not depend on gender: the relative risk on CVD appears to be equally raised for males and females, while relatively young RA patients (

BackgroundTumour necrosis factor (TNF)-inhibiting therapy increases the risk of serious infections in rheumatoid arthritis (RA). However, it is not clear whether this risk differs between TNF inhibitors.ObjectiveTo analyse whether the risk of serious infections in patients with RA treated with an anti-TNF inhibitor is different for adalimumab, infliximab and etanercept.MethodsData from the Dutch RA monitoring registry were used. Incidence rates were calculated from the observed number of first serious infections and follow-up time up to 5 years. A Cox proportional hazards model with time-to-first-serious infection was used to estimate risk differences among the anti-TNF treatment groups, with correction for confounders.ResultsThe unadjusted incidence rate of a first serious infection in patients with RA per 100 patient-years was 2.61 (95% CI 2.21 to 3.00) for adalimumab, 3.86 (95% CI 3.33 to 4.40) for infliximab and 1.66 (95% CI 1.09 to 2.23) for etanercept. Age, year of starting anti-TNF therapy, comorbidities at baseline and disease activity score 28 over time were included as confounders. No difference in risk for serious infections was found between adalimumab and infliximab with an adjusted HR (adjHR) of 0.90 (95% CI 0.55 to 1.48). The risk of serious infections was significantly lower in etanercept than in both infliximab (adjHR=0.49 (95% CI 0.29 to 0.83)) and adalimumab (adjHR=0.55 (95% CI 0.44 to 0.67)).ConclusionsThe risk of serious infections in patients with RA treated with adalimumab or infliximab was similar, while the risk of serious infections in patients with RA treated with etanercept was lower than with both adalimumab and infliximab.

Contains fulltext : 108460.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated. Our objective was to select a set of items potentially useful for the classification of SSc using consensus procedures, including the Delphi and nominal group techniques (NGT). METHODS: Items were identified through 2 independent consensus exercises performed by the Scleroderma Clinical Trials Consortium and the European League Against Rheumatism Scleroderma Trials and Research Group. The first-round items from both exercises were collated and redundancies were removed, leaving 168 items. A 3-round Delphi exercise was performed using a 1-9 scale (where 1 = completely inappropriate and 9 = completely appropriate) and a consensus meeting using NGT was conducted. During the last Delphi round, the items were ranked on a 1-10 scale. RESULTS: In round 1, 106 experts rated the 168 items. Those with a median score of

Item does not contain fulltext Objectives. To evaluate the prevalence of clinical remission and minimal disease activity according to the ACR/European League Against Rheumatism (EULAR) remission, DAS-28 1 occurred in, respectively, 67, 69 and 0% of the patients. Modification of the cut-point of the patient-reported outcome increased the prevalence of ACR/EULAR remission, but also the level of disability. Conclusion. MDA and DAS-28

Contains fulltext : 96381.pdf (Publisher’s version ) (Closed access) In our research on the role of apoptosis in the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE), we aim to evaluate the effects of early and late apoptotic cells and blebs on antigen presenting cells. This requires the in vitro generation of sufficiently large and homogeneous populations of early and late apoptotic cells. Here, we present a quick method encountered by serendipity that results in highly reproducible synchronized homogeneous apoptotic cell populations. In brief, granulocytic 32Dcl3 cells are incubated on ice for 2 h and subsequently rewarmed at 37 degrees C. After 30-90 min at 37 degrees C more than 80-90% of the cells become early apoptotic (Annexin V positive/propidium iodide negative). After 24 h of rewarming at 37 degrees C 98% of the cells were late apoptotic (secondary necrotic; Annexin V positive/propidium iodide positive). Cells already formed apoptotic blebs at their cell surface after approximately 20 min at 37 degrees C. Inter-nucleosomal chromatin cleavage and caspase activation were other characteristics of this cold-shock-induced process of apoptosis. Consequently, apoptosis could be inhibited by a caspase inhibitor. Finally, SLE-derived anti-chromatin autoantibodies showed a high affinity for apoptotic blebs generated by cold-shock. Overall, cold-shock induced apoptosis is achieved without the addition of toxic compounds or antibodies, and quickly leads to synchronized homogeneous apoptotic cell populations, which can be applied for various research questions addressing apoptosis.

Item does not contain fulltext OBJECTIVES: Experience with anti-TNF agents for a decade can be used to research the safety and effectiveness of anti-TNF agents in the long term. The objective of this article is to describe drug survival, disease activity, daily functioning, quality of life and adverse events of TNF-blocking agents in daily clinical practice after 5 years of follow-up. METHODS: Data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register of 1560 RA patients were used for analyses (5-year follow-up, n=174). Drug survival and time to first serious infection or malignancy were analysed by Kaplan-Meier analysis. Several outcome measures at several follow-up moments were analysed per intention to treat and per protocol. RESULTS: The 5-year drug survival of the first anti-TNF was 45%, and 60% for total use of TNF-blocking agents. Baseline 28-joint DAS (DAS-28) was 5.1 (s.d. 1.3). After 5 years, the mean DAS-28 was 3.2 (s.d. 1.3) in all patients who had started with TNF-blocking agents and 2.9 (s.d. 1.1) in patients who were still on TNF-blocking agents. In the latter group, the HAQ score was 0.88 (s.d. 0.7) and the EuroQol five dimensions (EQ-5D) utility score was 0.7 (s.d. 0.2). Incidence rates of serious infections and malignancies were 2.9 and 0.6 per 100 patient-years, respectively. CONCLUSION: Five-year follow-up of RA patients treated with TNF-blocking agents showed a 60% drug survival accompanied by sustained low disease activity, normalized function and quality of life similar to that in the general population. The benefit to risk ratio for long-term TNF-blocking therapy remains favourable.

Contains fulltext : 87712.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Tight control studies including regular assessments of disease activity have shown that this approach has beneficial effects on disease activity, disability and joint damage in treating RA patients. Some of these studies included tight control with protocolized treatment, while others applied tight control without protocolized treatment. The aim of this study was to compare the effects of tight control with usual care and to compare the effects of tight control studies with and without protocolized treatment adjustments. METHODS: A systematic literature search was performed to identify clinical trials in RA that evaluated tight control strategies in comparison with usual care. Two types of study were compared: (i) those using disease activity monitoring with protocolized treatment adjustments, and (ii) those using disease activity monitoring without protocolized treatment adjustments. The databases PubMed and Cochrane were searched from 1995 up to 2009. Primary outcome measure was the mean change in the 28-joint DAS (DAS-28), which was used in a random-effects meta-analysis. RESULTS: Six controlled trials regarding tight control in RA patients were included in the meta-analysis. In all trials, patients treated in the tight control arms had significantly higher DAS-28 responses than patients treated according to usual care [weighted mean difference (WMD) = 0.59, P < 0.001]. Moreover, tight control was significantly more effective (P < 0.001) by means of protocolized treatment adjustments (WMD = 0.97) compared with non-protocolized monitoring of disease activity (WMD = 0.25). CONCLUSION: Tight control in RA resulted in significantly better clinical outcomes than usual care. It is suggested but not proved that tight control with protocolized treatment adjustments is more beneficial than if no such protocol is used. 01 november 2010

Contains fulltext : 89257.pdf (Publisher’s version ) (Closed access) BACKGROUND: Most cases of acute gouty arthritis are diagnosed in primary care and without joint fluid analysis in many instances. Our objectives were to estimate the validity of this diagnosis by family physicians and to develop a diagnostic rule. METHODS: Patients with monoarthritis recruited in an open Dutch population with gout by family physician diagnosis were enrolled in a diagnostic study (March 24, 2004, through July 14, 2007). Validity variables were estimated using 2 x 2 tables, with the presence of synovial monosodium urate crystals as the reference test. For development of the diagnostic rule, clinical variables (including the presence of synovial monosodium urate crystals) were collected within 24 hours. Statistically significant variables and predefined variables were separately entered in multivariate logistic regression models to predict the presence of synovial monosodium urate crystals. Diagnostic performance of the models was tested by receiver operating characteristic curve analysis. The most appropriate model was transformed to a clinically useful diagnostic rule. RESULTS: Three hundred twenty-eight patients were included in the study. The positive and negative predictive values of family physician diagnosis of gout were 0.64 and 0.87, respectively. The most appropriate model contained the following predefined variables: male sex, previous patient-reported arthritis attack, onset within 1 day, joint redness, first metatarsophalangeal joint (MTP1) involvement, hypertension or 1 or more cardiovascular diseases, and serum uric acid level exceeding 5.88 mg/dL (to convert serum uric acid level to micromoles per liter, multiply by 59.485). The area under the receiver operating characteristic curve for this model was 0.85 (95% confidence interval, 0.81-0.90). Performance did not change after transforming the regression coefficients to easy-to-use scores and was almost equal to that of the statistically optimal model (area under the receiver operating characteristic curve, 0.87; 95% confidence interval, 0.83-0.91). CONCLUSIONS: The validity of family physician diagnosis of acute gouty arthritis was moderate in this study. An easy-to-use diagnostic rule without joint fluid analysis was developed for their use.

Objective.To investigate whether the reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent influences the effect of a second TNF blocking agent.Methods.Data were used from 2 Dutch registries including patients with rheumatoid arthritis (RA) treated with TNF blocking agents. Patients were divided into 3 groups based on reason for discontinuation of the first: nonresponse, loss of response, or adverse events. The primary outcome was the change from baseline of the disease activity (by DAS28) at 6 months, corrected for the baseline DAS28 score. Secondary outcomes were the change from baseline at 3 months, EULAR response rates, and the percentages of patients who reached a DAS28 score ≤ 3.2 at 3 and at 6 months.Results.In total, 49 patients who failed due to nonresponse, 75 due to loss of response, and 73 due to adverse events were included. At 6 months, the change of DAS28 score from baseline did not differ significantly between the groups (−0.6 to −1.3; p ≥ 0.173) and similar good and moderate response rates were found (12% to 18%, p ≥ 0.523, and 34% to 55%, p ≥ 0.078, respectively). The secondary outcomes were also comparable between the 3 groups.Conclusion.The results of our observational study suggest that a second TNF blocking agent may be effective after failure of the first, regardless of the reason for discontinuation of the first TNF blocking agent.

Contains fulltext : 70109.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The guanine-thymidine (GT)n repeat in the HMOX1 promoter determines the level of induction of the heme-degrading enzyme heme oxygenase 1 (HO-1), which protects against inflammatory and oxidative stress. In individuals with short (GT)n repeats (where n < 25; SS genotype), higher levels of HO-1 activity are induced more rapidly than in those with long (GT)n repeats (where n > or = 25; LL genotype). Recently, it was demonstrated that HO-1 activity protects against the onset of rheumatoid arthritis (RA). The aim of this study was to determine whether the (GT)n-repeat length within the HMOX1 promoter region is associated with RA disease severity and radiographic joint damage. METHODS: A cohort of 325 well-characterized RA patients and 273 controls was investigated by DNA fragment-length analysis for the association of (GT)n repeats in the HMOX1 promoter region with RA disease susceptibility and severity. RESULTS: Although no significant differences in genotype or allele frequency were found between controls and RA patients, the odds ratios corresponded well to those in the previously described cohort. Among patients, those carrying the SS genotype had a more favorable radiographic outcome over 9 years than those carrying the LL genotype. This was unexpected since no differences in disease activity were found between the genotypes or alleles. CONCLUSION: Patients with the SS genotype have a better long-term radiographic outcome despite poor prognostic markers at baseline and despite disease activity at followup similar to that of patients with the LL genotype. This suggests that the HMOX1/HO-1 system is involved in the uncoupling of disease activity and joint damage and may provide a novel target for the treatment of RA. 6 p.

Contains fulltext : 51734.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Randomized clinical trials that compare two treatments on a continuous outcome can be analyzed using analysis of covariance (ANCOVA) or a t-test approach. We present a method for the sample size calculation when ANCOVA is used. STUDY DESIGN AND SETTING: We derived an approximate sample size formula. Simulations were used to verify the accuracy of the formula and to improve the approximation for small trials. The sample size calculations are illustrated in a clinical trial in rheumatoid arthritis. RESULTS: If the correlation between the outcome measured at baseline and at follow-up is rho, ANCOVA comparing groups of (1-rho(2))n subjects has the same power as t-test comparing groups of n subjects. When on the same data, ANCOVA is used instead of t-test, the precision of the treatment estimate is increased, and the length of the confidence interval is reduced by a factor 1-rho(2). CONCLUSION: ANCOVA may considerably reduce the number of patients required for a trial.

Contains fulltext : 52915.pdf (Publisher’s version ) (Closed access) BACKGROUND: Macrophage migration inhibitory factor (MIF) is an inflammatory mediator associated with RA severity. In various diseases, MIF polymorphisms are associated with clinical response glucocorticoid (GC) treatment. It is unclear whether MIF polymorphisms determine GC response in rheumatoid arthritis (RA) and to other RA treatments. Therefore, the question of whether two functional variants in MIF are associated with the response to tumour necrosis factor (TNF)alpha-neutralising and GC treatments in RA was investigated. METHODS: Data from two cohorts of an RA registry were used. For patients who started with TNFalpha-neutralising (infliximab) or GC treatment, courses with a duration of at least 3 months were included and response to TNFalpha blockers or GC was calculated according to the European League Against Rheumatism response criteria. MIF -173G-->C genotyping was achieved using an assay-on-demand allelic discrimination assay, and alleles of the CATT repeat element were identified using a fluorescently labelled PCR primer and capillary electrophoresis. Logistic-regression modelling was used for the statistical analysis. RESULTS: In total, 192 courses of oral prednisone or methylprednisolone injections in 98 patients with RA and 90 patients with RA who were on TNFalpha-neutralising treatments were documented. In all, 27% of the patients with RA were found to be heterozygous for seven CATT repeats (CATT(7)) and 31% were heterozygous for -173C. Respectively, 4% and 6% of the patients with RA were homozygous for the MIF CATT(7) repeat or the MIF -173C allele. Carrier status and homozygosity for CATT(7 )repeat and the MIF -173C allele were not associated with response to GC (odds ratios (ORs) close to 1) or to TNFalpha-neutralising treatment (ORs close to 2). CONCLUSION: The MIF-CATT(7) repeat and the MIF-173G-->C functional variant are not strongly associated with a decreased clinical response to TNFalpha-neutralising or GC treatment in RA.

Contains fulltext : 52241.pdf (Publisher’s version ) (Closed access) BACKGROUND: Antigen-presenting cells (APC) and T cells are considered to play a significant role in the pathogenesis of rheumatoid arthritis (RA). CCL18 and CXCL16 are two chemokines that facilitate T cell attraction by APC, of which a role in the pathogenesis of RA has been suggested. OBJECTIVE: To compare the circulating levels of CXCL16 and CCL18 in RA with controls and to investigate the relation of CXCL16 and CCL18 with RA disease activity and joint damage. METHODS: Circulating CCL18 and CXCL16 levels were determined in 61 RA patients with a follow-up of 6 years and a group of 41 healthy controls with ELISA. Chemokine levels were correlated with demographic data, disease activity (DAS28) and joint damage (modified Sharp score). In addition, serum CCL18 and CXCL16 levels from a cohort of 44 RA patients treated with anti-TNF-alpha were correlated with disease activity. RESULTS: CCL18 levels in serum were significantly elevated in RA patients compared with controls, while serum CXCL16 levels were not. In contrast to CXCL16, serum CCL18 was positively correlated with disease activity. Both CCL18 and CXCL16 levels decreased upon treatment with anti-TNF-alpha. Neither CCL18 nor CXCL16 correlated with joint damage and progression. CONCLUSION: Here, we show, for the first time, that circulating CCL18 and not CXCL16 levels are elevated in RA patients as compared with controls and correlate with disease activity in RA. More knowledge regarding the regulation and function of both CCL18 and CXCL16 is essential to value their role in RA.

Contains fulltext : 52026.pdf (Publisher’s version ) (Closed access) Clinical assessment of established rheumatoid arthritis (RA) can have several purposes. It can be used to evaluate prognosis, disease course or interventions at both the individual and the group level (i.e. in a clinical trial), over the short or long term. The instruments used for the different purposes are not always the same. For example, information on prognosis is very useful when assessing the risk:benefit ratio of early aggressive pharmacotherapy; however, established prognostic factors are currently of limited use in individual patients with established RA. As, at the individual patient level, disease activity, disability and joint damage have variable courses, the course of the disease should be evaluated regularly both with process (i.e. erythrocyte sedimentation rate, joint counts) and with outcome (i.e. radiological progression, sum of past process) measures. For the evaluation of interventions, 'core sets' of valid measures to assess disease activity, outcome and specific criteria for improvement are used; these can, to some extent, be useful in clinical practice.

Early detection and preemptive treatment of patients at risk is of great importance in reducing the excess risk of cardiovascular (CV) disease in rheumatoid arthritis (RA). However, it is unclear how much screening is cost-effective in RA. The objective is to assess whether CV screening in RA proves to be cost-effective from a medical perspective, using different scenarios based on different guidelines.A Markov chain model was used with a time horizon of 10 years. Parameter values were mainly obtained from literature and from RA patients screened for CV diseases at the Radboud University Medical Centre, Nijmegen, The Netherlands. The primary outcome was incremental cost-effectiveness expressed as costs per quality-adjusted life year (QALY) gained. Probabilistic sensitivity analysis was performed and described in willingness-to-pay curves; several scenarios were built.In the base case scenario, in 82% of the simulations, screening proved to be dominant compared to no screening. The mean QALY gain was 0.09 (95% percentile -0.07, 0.27), and the mean cost savings were €-1,057 (95% percentile -€2,825, €333). Different scenarios showed small differences in cost-effectiveness; the probability that screening is dominant remained high with the lowest probability being 50% for a very conservative scenario.Screening for CV events in RA patients was estimated to be cost-effective with high chances of being less expensive and more effective. These results support endorsement of screening for CV risk in patients with RA.

OBJECTIVE: To determine which clinical, laboratory, and imaging features most accurately distinguished gout from non-gout. METHODS: We performed a cross-sectional study of consecutive rheumatology clinic patients with =1 swollen joint or subcutaneous tophus. Gout was defined by synovial fluid or tophus aspirate microscopy by certified examiners in all patients. The sample was randomly divided into a model development (two-thirds) and test sample (one-third). Univariate and multivariate association between clinical features and monosodium urate-defined gout was determined using logistic regression modeling. Shrinkage of regression weights was performed to prevent overfitting of the final model. Latent class analysis was conducted to identify patterns of joint involvement. RESULTS: In total, 983 patients were included. Gout was present in 509 (52%). In the development sample (n = 653), the following features were selected for the final model: joint erythema (multivariate odds ratio [OR] 2.13), difficulty walking (multivariate OR 7.34), time to maximal pain 6 mg/dl (0.36 mmoles/liter; multivariate OR 3.35), ultrasound double contour sign (multivariate OR 7.23), and radiograph erosion or cyst (multivariate OR 2.49). The final model performed adequately in the test set, with no evidence of misfit, high discrimination, and predictive ability. MTP1 joint involvement was the most common joint pattern (39.4%) in gout cases. CONCLUSION: Ten key discriminating features have been identified for further evaluation for new gout classification criteria. Ultrasound findings and degree of uricemia add discriminating value, and will significantly contribute to more accurate classification criteria.

To determine the acceptable level of positive predictive value (PPV) and negative predictive value (NPV) for classification criteria for gout, given the type of study.We conducted an international web-based survey with 91 general practitioners and rheumatologists experienced in gout. Conjoint analysis was used as the framework for designing and analyzing pairs of 2 profiles, each describing a study type, a PPV, and an NPV. There were 5 study types presented: a phase III randomized controlled trial (RCT) of a nonsteroidal antiinflammatory drug versus prednisone for acute gout flares, a phase III RCT of a biologic agent for acute gout flares, a phase II RCT of a novel uricosuric drug of unknown efficacy and limited toxicity data, a case-control, genome-wide association study of gout, and a cohort study examining long-term outcomes of gout. PPV and NPV both had 5 levels ranging from 60-99%.The panelists in majority were male (65%) rheumatologists (93%) with an average of 19 years of practice, seeing 5 to 60 gout patients monthly. PPV was most highly weighted in decision making: the relative importance was 59% for PPV, 29% for NPV, and 13% for study type. The preferred PPV was 90% or 80%, with an accompanying NPV of 70% or 80%, dependent on study type.Preferred PPVs and NPVs range between 70% and 90% and differ by study type. A single cut point can be a reasonable approach for all study types if a PPV of 90% and NPV of 80% is approximated.

Fatigue is one of the most commonly reported symptoms in rheumatoid arthritis (RA). Many factors may play a causal role on fatigue in RA patients, but their contribution and interplay is barely understood. The objective was to develop a multidimensional model of factors that explain fatigue severity in RA.A cross-sectional study (n=228) of consecutive patients with RA was performed. Fatigue, disease characteristics and psychosocial and behavioural outcomes were collected. Baseline differences between non severely fatigued patients (CIS-fatigue35) and severely fatigued patients (CIS-fatigue ≥35) were tested. Structural equation modeling was used to test a hypothesised model for fatigue.The final model includes pain, physical functioning, mood, sense of control, sleep quality and fatigue, with good fit (CFI=0.976) explaining 74% of the variance in RA fatigue. Accordingly, poor sleep quality (β=0.42, p0.001) and less physical functioning (β=0.65, p0.001) are directly related to a higher level of fatigue. Less sense of control is related to more mood disturbance (β=0.64, p0.001), more pain (β=0.389, p0.001) and less physical functioning (β=-0.24, p0.001). More mood disturbance is related to poor sleep quality (β=0.78, p0.001) and higher pain level is related to less physical functioning (β=0.75, p0.001).RA fatigue is directly influenced by poor sleep quality and physical functioning, and indirectly by sense of control, mood and pain. Treatment of these factors by psychological interventions and physical exercise could help to improve fatigue in patients with RA.

Objective.To compare the performance of an extended model and a simplified prognostic model for joint damage in rheumatoid arthritis (RA) based on 3 baseline risk factors: anticyclic citrullinated peptide antibodies (anti-CCP), erosions, and acute-phase reaction.Methods.Data were used from the Nijmegen early RA cohort. An extended model and a simplified baseline prediction model were developed to predict joint damage progression between 0 and 3 years. Joint damage progression was assessed using the Ratingen score. In the extended model, prediction factors were positivity for anti-CCP and/or rheumatoid factor, the level of erythrocyte sedimentation rate, and the quantity of erosions. The prediction score was calculated as the sum of the regression coefficients. In the simplified model, the prediction factors were dichotomized and the number of risk factors was counted. Performances of both models were compared using discrimination and calibration. The models were internally validated using bootstrapping.Results.The extended model resulted in a prediction score between 0 and 5.6 with an area under the receiver-operation characteristic (ROC) curve of 0.77 (95% CI 0.72–0.81). The simplified model resulted in a prediction score between 0 and 3. This model had an area under the ROC curve of 0.75 (95% CI 0.70–0.80). In internal validation, the 2 models showed reasonably well the agreement between observed and predicted probabilities for joint damage progression (Hosmer-Lemeshow test p > 0.05 and calibration slope near 1.0).Conclusion.A simple prediction model for joint damage progression in early RA, by only counting the number of risk factors, has adequate performance. This facilitates the translation of the theoretical prognostic models to daily clinical practice.

Item does not contain fulltext OBJECTIVE: This study was undertaken to assess the predictive ability of 4 established cardiovascular (CV) risk models for the 10-year risk of fatal and non-fatal CV diseases in European patients with rheumatoid arthritis. METHODS: Prospectively collected data from the Nijmegen early rheumatoid arthritis (RA) inception cohort was used. Discriminatory ability for CV risk prediction was estimated by the area under the receiver operating characteristic curve. Calibration was assessed by comparing the observed versus expected number of events using Hosmer-Lemeshov tests and calibration plots. Sensitivity and specificity were calculated for the cut-off values of 10% and 20% predicted risk. RESULTS: Areas under the receiver operating characteristic curve were 0.78-0.80, indicating moderate to good discrimination between patients with and without a CV event. The CV risk models Systematic Coronary Risk Evaluation (SCORE), Framingham risk score (FRS) and Reynolds risk score (RRS) primarily underestimated CV risk at low and middle observed risk levels, and mostly overestimated CV risk at higher observed risk levels. The QRisk II primarily overestimated observed CV risk. For the 10% and 20% cut-off values used as indicators for CV preventive treatment, sensitivity ranged from 68-87% and 40-65%, respectively and specificity ranged from 55-76% and 77-88%, respectively. Depending on the model, up to 32% of observed CV events occurred in patients with RA who were classified as low risk (

Contains fulltext : 152283.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. METHODS: An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multicriterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. RESULTS: The entry criterion for the new classification criteria requires the occurrence of at least 1 episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (i.e., synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy computed tomography, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). CONCLUSION: The new classification criteria, developed using a data-driven and decision analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout. 01 oktober 2015

Item does not contain fulltext OBJECTIVE: The gold standard for diagnosing gout is the identification of MSU crystals in joint fluid. In secondary care, the facilities or expertise to analyse joint fluid are not always available and gout is diagnosed clinically. To improve the predictive value of the clinical diagnosis of gout in secondary care, a diagnostic rule developed in primary care could be helpful. The aim of this study was to validate this diagnostic rule in a secondary care population with the gold standard as reference test. METHODS: Three hundred and ninety patients with monoarthritis were included. The variables of the diagnostic rule (male sex, previous arthritis attack, onset 5.88 mg/dl) were collected and scored. The affected joint was aspirated and joint fluid was analysed for the presence of MSU crystals. RESULTS: In 219 patients (56%) MSU crystals were found. The positive predictive value of a score of >/=8 points was 0.87, the negative predictive value of a score of

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Contains fulltext : 154099.PDF (Publisher’s version ) (Open Access) BACKGROUND: Presence of femoral atheromatic plaques, an emerging cardiovascular disease (CVD) biomarker additional to carotid plaques, is poorly investigated in conditions associating with accelerated atherosclerosis such as Rheumatoid Arthritis (RA), Human Immunodeficiency Virus (HIV) infection and Type 2 Diabetes Mellitus (T2DM). OBJECTIVE/METHODS: To assess the frequency of femoral/carotid subclinical atheromatosis phenotypes in RA, HIV and T2DM and search for each disease-specific probability of either femoral and/or carotid subclinical atheromatosis, we examined by ultrasound a single-center cohort of CVD-free individuals comprised of consecutive non-diabetic patients with RA (n=226) and HIV (n=133), T2DM patients (n=109) and non-diabetic individuals with suspected/known hypertension (n=494) who served as reference group. RESULTS: Subclinical atheromatosis - defined as local plaque presence in at least on arterial bed - was diagnosed in 50% of the overall population. Among them, femoral plaques only were found in 25% of either RA or HIV patients, as well as in 16% of T2DM patients and 35% of reference subjects. After adjusting for all classical CVD risk factors, RA and HIV patients had comparable probability to reference group of having femoral plaques, but higher probability (1.75; 1.17 - 2.63 (odds ratio; 95% confidence intervals), 2.04; 1.14 - 3.64, respectively) of having carotid plaques, whereas T2DM patients had higher probability to have femoral and carotid plaques, albeit, due to their pronounced dyslipidemic profile. CONCLUSION: RA and HIV accelerate predominantly carotid than femoral. A "two windows" carotid/femoral, rather than carotid alone ultrasound, screening improves substantially subclinical atheromatosis detection in patients at high CVD risk.

Contains fulltext : 49783.pdf (Publisher’s version ) (Closed access) BACKGROUND: In recent clinical trials in patients with psoriatic arthritis (PsA), the response criteria and disease activity measures that have been used were those developed for rheumatoid arthritis. However, these have not yet been validated in PsA. OBJECTIVE: To compare the responsiveness and discriminative capacity of the psoriatic arthritis response criteria (PsARC), American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria and the Disease Activity Score (DAS) and core-set measures in patients with PsA and peripheral arthritis, using the data from two randomised placebo-controlled trials of tumour necrosis factor inhibitors. METHODS: In an infliximab trial, 104 patients with active PsA were randomised to receive placebo or infliximab for 16 weeks. In an etanercept trial, 60 patients with active PsA were randomised to receive placebo or etanercept for 12 weeks. Data from baseline and the end of the intervention phase were used from each study. Responsiveness was assessed using the standardised response mean and effect size. Capacity to discriminate between the active drug and placebo was assessed using t values or a chi2 test. Measures were ranked in order of their t value or chi2 value. RESULTS: The EULAR criteria performed better in discriminating the active drug from placebo than the ACR20 improvement criteria, which in turn performed better than the PsARC. It was also found that the pooled indices (DAS and DAS28) were generally more responsive, and performed better in discriminating active drug from placebo, than the single core-set measures. CONCLUSION: Response criteria and pooled indices developed for rheumatoid arthritis are useful for the assessment of arthritis in PsA clinical trials.

Circulating chromatin-containing apoptotic material and/or neutrophil extracellular traps (NETs) have been proposed to be an important driving force for the antichromatin autoimmune response in patients with systemic lupus erythematosus (SLE). The aim of this study was to determine the exact nature of microparticles in the circulation of SLE patients and to assess the effects of the microparticles on the immune system.We analyzed microparticles isolated from the plasma of patients with SLE, rheumatoid arthritis (RA), and systemic sclerosis (SSc), as well as from healthy subjects. The effects of the microparticles on blood-derived dendritic cells (DCs) and neutrophils were assessed by flow cytometry, enzyme-linked immunosorbent assay, and immunofluorescence microscopy.In SLE patients, we identified microparticles that were highly positive for annexin V and apoptosis-modified chromatin that were not present in healthy subjects or in RA or SSc patients. These microparticles were mostly CD31+/CD45- (endothelial), partly CD45+/CD66b+ (granulocyte), and negative for B and T cell markers. Microparticles isolated from the plasma of SLE patients increased the expression of the costimulatory surface molecules CD40, CD80, CD83, and CD86 and the production of proinflammatory cytokines interleukin-6, tumor necrosis factor, and interferon-α by blood-derived plasmacytoid DCs (PDCs) and myeloid DCs (MDCs). SLE microparticles also primed blood-derived neutrophils for NETosis. Microparticles from healthy subjects and from RA or SSc patients exhibited no significant effects on MDCs, PDCs, and NETosis.Circulating microparticles in SLE patients include a population of apoptotic cell-derived microparticles that has proinflammatory effects on PDCs and MDCs and enhances NETosis. These results underline the important role of apoptotic microparticles in driving the autoimmune response in SLE patients.

Objective: To investigate the feasibility of a randomised controlled trial in a usual clinical setting and the effect of work rehabilitation on improvement to the ability to work in chronic pain patients. Design: 33 patients with chronic musculoskeletal pain, valid job contracts and absence from work, random allocation. The interdisciplinary work rehabilitation contained work-specific exercises and education and lasted 8 weeks, 3.5 hours each working day. The control treatment took place with the allocating physician, who received recommendations concerning physical therapy and the uptake of work. Assessments took place at 0, 8 and 32 weeks. Measurements: ability to work, actual work status in % of a full time job, functional capacity tasks measured in kilograms. Results: Feasibility: the recruitment was of a long duration due to the rather restrictive inclusion criteria. Actual work status: the improvement between the groups was not significantly different, but the ability to work improved significantly from an overall median of 0% to 50% at 8 weeks (p = 0.004 for the intervention group, p = 0.026 for the control group). Conclusions: The evaluation of a running work rehabilitation programme in a clinical outpatient setting in clinical science is feasible, but a more effective recruitment strategy for a main study is favoured by application of a multi-centric or company based setting.

OBJECTIVE: To systematically review educational or psychoeducational interventions for patients with rheumatoid arthritis focusing on long-term effects, especially health status. METHODS: Two independent reviewers appraised the methodologic quality of the included randomized controlled trials, published between 1980 and July 2002. RESULTS: Validity scores of studies ranged from 3 to 9 (of 11). The 7 educational programs mainly improved knowledge and compliance in the short and long term, but there was no improvement in health status. All 4 psychoeducational programs improved coping behavior in the short term, 2 of them showing a positive long-term effect on physical or psychological health variables. CONCLUSION: Methodologically better-designed studies had more difficulties demonstrating positive outcome results. Short-term effects in program targets are generally observed, whereas long-term changes in health status are not convincingly demonstrated. There is a need to find better strategies to enhance the transfer of short-term effects into gains in health status.

Objective. To assess rheumatologists’ opinions about the feasibility of a measurement feedback system in rheumatoid arthritis (RA) and to analyse if motivational aspects play a role in assessing the value of the system and in determining the extent to which it is used. Methods. A survey sample (n=105) was randomly selected from participants of a measurement feedback system. A survey questionnaire assessed opinions on system outcome, structures and processes, motivation and overall satisfaction. Survey results are given descriptively and groups differing in motivation are compared. Results. The overall response rate was 62%. The system was generally perceived to fulfil its aims, but the effort required to use the system was rated less positive. Rheumatologists had as their motivation either ‘science/obligation’ or ‘individual patient evaluation’. Rheumatologists with the latter motivation were more satisfied with the measurement feedback system, perceived its feasibility as better, and made more use of it. Conclusion. Motivation for participating in a measurement feedback system has a significant impact on overall satisfaction with the system and the use of the system. Influencing motivation and reduction of the amount of effort required to use the system might increase overall acceptance.

Item does not contain fulltext OBJECTIVE: To investigate by a cross sectional study in patients with rheumatoid arthritis (RA) the relationship between measures of impairment, activity limitation, and participation of the model of functioning and disability (ICIDH-2). METHODS: Inclusion data of patients with RA (n=803) from the Swiss Clinical Quality Management Group were used. Impairments were measured by the Short Form-36 (SF-36) bodily pain scale, rheumatoid arthritis disease activity index (RADAI), disease activity score (DAS28), and radiographic scoring (x ray). Activity limitation was measured with the Health Assessment Questionnaire (HAQ) and the SF-36 physical functioning scale. Participation was measured with the SF-36 role and social functioning scales. Spearman (partial) correlations were used for analysis. RESULTS: Impairment and activity limitation dimensions of the ICIDH-2 model are related; correlations with the HAQ were: SF-36 bodily pain (r(s)=-0.61), RADAI (r(s)=0.58), DAS28 (r(s)=0.49), and x ray (r(s)=0.35). Similar correlations were found for SF-36 physical functioning. Activity limitation and participation restriction dimensions are also related: the HAQ correlates well with SF-36 role-physical (r(s)=-0.53) and SF-36 social functioning (r(s)=-0.43); SF-36 physical functioning correlates similarly. For impairment and participation restriction dimensions only SF-36 bodily pain is substantially correlated (r(s)=0.47 and 0.48) with SF-36 role-physical, after correcting for the influence of the activity limitation dimension (HAQ and SF-36 physical functioning). CONCLUSIONS: In this cross sectional study of patients with RA, impairments are associated with activity limitations, and activity limitations are associated with participation restrictions. Pain is the only impairment directly associated with participation restrictions. Based on the results of this study, it is strongly recommended that the ICIDH-2 framework is used in clinical trials and observational studies including the assessment of disease consequences in RA.

Objective. There is an unmet need for a specific cardiovascular risk (CV) algorithm for rheumatoid arthritis (RA) patients. Lipoprotein data are often not available in RA cohorts but could be obtained from frozen blood samples. The objective of this study was to estimate the storage effect on lipoproteins in long-term (>10 years) frozen serum samples.Methods. Data were used from an inception RA cohort. Multiple serum samples from 152 patients were analyzed for lipoproteins, being frozen for 1–26 years at −20°C. Storage effect on lipoproteins was estimated using longitudinal regression analyses and a lipid decay correction factor was developed. Clinical impact of the storage effect on lipoproteins was assessed by calculating the number of patients reclassified to another CV risk group according to the SCORE risk calculator after applying the decay correction factor.Results. There was a significant effect of storage time on total cholesterol (TC) (P< 0.001) and high density lipoprotein cholesterol (HDL-c) levels (P< 0.001), not LDL-c (P= 0.83). The lipid decay correction factor was 0.03 mmol/L and 0.024 mmol/L per additional year of storage for TC and HDL-c, respectively. The TC : HDL ratio decreased after correction for storage effect. After correction, only 5% of patients were reclassified to another CV risk group.Conclusion. A modest storage decay effect on lipoproteins was found that is unlikely to significantly affect CV risk stratification. Serum samples that have been stored long-term (>10 years) can be used to obtain valid lipid levels for developing CV risk prediction models in RA cohorts, even without applying a decay correction factor.

Contains fulltext : 151809.pdf (Publisher’s version ) (Closed access) BACKGROUND: Concerns exist about a risk of non-melanoma skin cancer (NMSC) in psoriasis patients and rheumatoid arthritis (RA) patients treated with TNF-inhibitors. However, current data also show that in some psoriasis patients, NMSC is diagnosed relatively short after the start of TNF-inhibitors, which suggests that these NMSC can be explained by previous therapies instead of by TNF-inhibitor therapy. OBJECTIVE: To investigate whether there was a difference in time until first NMSC and the rate of NMSC between psoriasis and RA patients on TNF-inhibitors. METHODS: Time until first NMSC and the rate of NMSC were compared between psoriasis and RA patients from the same region treated with TNF-inhibitors and followed up for at least one year in prospective cohort studies, by using Cox regression and Poisson regression. Both analyses were corrected for confounders (age, gender, disease duration, prior NMSC, duration of anti-TNF and other systemic therapies). RESULTS: The NMSC risk was significantly higher in the psoriasis group [fully adjusted HR 6.0 (1.6-22.4 95%CI)] with a shorter time until first NMSC in psoriasis compared to RA. By Poisson regression, psoriasis patients had a 5.5 (2.2-13.4 95%CI) higher rate of NMSC. CONCLUSION: The time until first NMSC was significantly shorter and the rate of NMSC was significantly higher in psoriasis compared with RA. This indicates that disease-related factors like phototherapy may be important contributing factors to NMSC diagnosed in psoriasis patients treated with TNF-inhibitors.

Objective.Reduced work participation (WP) is a common problem for patients with rheumatoid arthritis (RA) and generates high costs for society. Therefore, it is important to explore determinants of WP at the start of tumor necrosis factor inhibitor (TNFi) treatment, and for changes in WP after 2 years of TNFi treatment.Methods.Within the Dutch Rheumatoid Arthritis Monitoring (DREAM) biologic register, WP data were available from 508 patients with RA younger than 65 years and without an (early) retirement pension. WP was registered at start of TNFi treatment and after 2 years of followup and was measured by single patient-reported binary questions whether they had work, paid or voluntary, or had a disability allowance or a retirement pension. Determinants measured at baseline were age, sex, disease duration, functional status [through Health Assessment Questionnaire-Disability Index (HAQ-DI)], 28-joint Disease Activity Score (DAS28), rheumatoid factor, presence of erosions, number of previous disease-modifying antirheumatic drugs, and number of comorbidities. During the 2 years of followup, HAQ-DI response and European League Against Rheumatism response were measured. Univariate analyses (excluded if p value was > 0.2) and multivariate (excluded if p value was > 0.1) logistic regression analyses were used.Results.Determinants associated with WP at baseline were having a better HAQ-DI (OR 0.32, p = 0.000) and male sex (OR 0.65, p = 0.065). After 2 years of TNFi therapy, 11.8% (n = 60) started to work and 13.6% (n = 69) stopped working. Determinants associated with starting to work were better baseline HAQ-DI (OR 0.58), positive RF (OR 2.73), and young age (OR 0.96); and for stopping work, worse baseline HAQ-DI (OR 2.74), low HAQ-DI response (OR 0.31), and comorbidity (OR 2.67), all with p < 0.1.Conclusion.Young patients with RA and a high functional status without any comorbidity will have a better chance of working. This supports the main goal in the management of RA: to suppress disease activity as soon and as completely as possible to prevent irreversible destruction of the joints, and thus maintain a good functional status of the patient. Because of the low proportion of variance explained by the models in this study, other factors besides the ones studied are associated with WP.

Objective.There are several new composite indices for assessing disease activity in psoriatic arthritis (PsA). Each may function as a disease state variable and a responder index. The aim of our study was to determine cutoffs for disease activity and response.Methods.Data from the Group for GRAPPA Composite Exercise (GRACE) study were used to develop cutoffs using a number of different approaches. Voting on choice of cutoff was undertaken at the 2013 GRAPPA Annual Meeting in Toronto, Ontario, Canada.Results.After voting, results for cutoffs for low/high disease activity for the Psoriatic ArthritiS Disease Activity Score (PASDAS), GRAppa Composite scorE (GRACE index), and Composite Psoriatic Disease Activity Index (CPDAI), respectively, were 3.2/5.4, 2.3/4.7, and 4/8. The measurement error for each composite score was estimated at 0.8, 1, and 2 for PASDAS, GRACE, and CPDAI, respectively.Conclusion.Response criteria for the new composite indices have been developed. These now require further validation and testing in other datasets.

In his letter, Jan Damoiseaux advocates testing of anti-RNA polymerase III antibodies (ARA), and also other (novel) systemic sclerosis (SSc)-associated antibodies, only for those patients who are really suspected for SSc.1 Damoiseaux argues that there is a necessity to provide clinical information together with the request for testing for rheumatic systemic autoimmune diseases. We very much agree that testing for SSc-associated antibodies should only be requested for those people who really are suspected to have SSc. We feel that a correct request of testing for these autoantibodies is, first and foremost, a responsibility of the requestor, that is, the rheumatologist. However, immunologists and rheumatologists almost certainly can learn from each other in optimising requests for antibody …

OBJECTIVES: To document biopsychosocial profiles of patients with rheumatoid arthritis (RA) by means of the INTERMED and to correlate the results with conventional methods of disease assessment and health care utilization. METHODS: Patients with RA (n = 75) were evaluated with the INTERMED, an instrument for assessing case complexity and care needs. Based on their INTERMED scores, patients were compared with regard to severity of illness, functional status, and health care utilization. RESULTS: In cluster analysis, a 2-cluster solution emerged, with about half of the patients characterized as complex. Complex patients scoring especially high in the psychosocial domain of the INTERMED were disabled significantly more often and took more psychotropic drugs. Although the 2 patient groups did not differ in severity of illness and functional status, complex patients rated their illness as more severe on subjective measures and on most items of the Medical Outcomes Study Short Form 36. Complex patients showed increased health care utilization despite a similar biologic profile. CONCLUSIONS: The INTERMED identified complex patients with increased health care utilization, provided meaningful and comprehensive patient information, and proved to be easy to implement and advantageous compared with conventional methods of disease assessment. Intervention studies will have to demonstrate whether management strategies based on INTERMED profiles can improve treatment response and outcome of complex patients.

Background Where health economic studies are frequently performed using modelling, with input from randomized controlled trials and best guesses, we used real-life data to analyse the cost-effectiveness and cost-utility of a treatment strategy aiming to the target of remission compared to usual care in early rheumatoid arthritis (RA). Methods We used real-life data from comparable cohorts in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry: the DREAM remission induction cohort (treat-to-target, T2T) and the Nijmegen early RA inception cohort (usual care, UC). Both cohorts were followed prospectively using the DREAM registry methodology. All patients fulfilled the American College of Rheumatology criteria for RA and were included in the cohort at the time of diagnosis. The T2T cohort was treated according to a protocolised strategy aiming at remission (Disease Activity Score in 28 joints (DAS28) Results Two year data were available for 261 T2T patients and 213 UC patients; an extended follow-up of three years was available for 127 and 180 patients, respectively. T2T produced higher remission percentages and a larger gain in QALYs than UC. The ICER was € 3,591 per patient in remission after two years and T2T was dominant after three years. The ICUR was € 19,410 per QALY after two years and T2T was dominant after three years. Conclusions We can conclude that treating to the target of remission in early RA is cost-effective compared with UC. The data suggest that in the third year, T2T becomes cost-saving.

This review examines the current use of health status instruments, such as questionnaires, in randomised clinical trials in rheumatoid arthritis (RA). A computer-assisted literature search was done using information from January 1996 until May 1997. The articles included were reviewed in a standardised way according to the kind of study-design, type of intervention, treatment arms, study population, follow-up, use of outcome measures, use of the core set and of the response criteria, and the results. 44 trials were identified and, of these, 31 were included. Of the 31 efficacy studies on RA patients, 10 did not use health status instruments. The most frequently used health status instruments were the Arthritis Impact Measurement Scales (AIMS) and the Stanford Health Assessment Questionnaire (HAQ). Of 21 studies, 5 showed a between-group difference with respect to health status. The main finding was that health status instruments are inconsistently used and lack full description and standardisation in their use as end-points in randomised clinical trials in RA.

Item does not contain fulltext OBJECTIVES: Arthritis of the first metatarsophalangeal joint has been considered pathognomonic for gout, but it is unknown how frequently other forms of arthritis occur in this joint. The aims were to determine the validity of the general practitioner's clinical diagnosis using joint fluid analysis as the reference test, the prevalence of other diagnoses than gout, and the signs and symptoms that discriminate between gout and non-gout patients. METHODS: This prospective cohort study comprised primary care patients with monoarthritis of the first metatarsophalangeal joint. After patient recruitment by general practitioners, patients' characteristics were collected by a rheumatologist. Joint fluid was analyzed for the presence of monosodium urate-crystals. If crystals were absent, patients entered a follow-up period of 6 years, or until a definite diagnosis. If during follow-up crystals were identified, the patient was classified as already having gout at baseline assessment. RESULTS: One hundred and fifty-nine primary care patients were included. At baseline the clinical diagnosis was gout in 98%. The positive and negative predictive values of the diagnosis of gout were 0.79 and 0.75, respectively. After follow-up 77% had gout, 8% had another rheumatic disease, and 15% had a transient unspecified monoarthritis. Gout patients had discriminating signs and symptoms from non-gout patients. CONCLUSIONS: Gout is an important but certainly not an exclusive cause of arthritis of the first metatarsophalangeal joint.

Pragmatic clinical trials have been proposed as a solution for nongeneralizability of randomized clinical trial (RCT) results. We investigated whether treatment effects of pragmatic clinical trials are indeed generalizable to clinical practice and how efficacy estimates from published RCTs can be translated to daily practice populations.Data from pragmatic clinical trials of the Utrecht Rheumatoid Arthritis Cohort and the observational Nijmegen Early Rheumatoid Arthritis inception cohort were used. The treatment effects of methotrexate and hydroxychloroquine as opposed to the pyramid approach were compared between the trials and observational study using a modified comprehensive cohort design analysis. The changes from baseline in disease activity (Disease Activity Score in 28 joints [DAS28]) and functional disability (Health Assessment Questionnaire [HAQ]) and European League Against Rheumatism (EULAR) response at 6 months were studied. The influence of population and treatment characteristics on the American College of Rheumatology 50% improvement criteria response compared with control therapy also at 6 months from RCTs was assessed using the relative risk (RR) and risk difference (RD).The DAS28 and HAQ generally improved more in patients in the pragmatic trials than in daily practice. However, using EULAR response as outcome, the treatment effect was not found to be different. In published RCT data, higher glucocorticoid use, disease duration, and cotreatment with disease-modifying antirheumatic drugs increased the RR. Use of glucocorticoids increased the RD, and higher values of baseline DAS28 and HAQ decreased the RR and RD.Pragmatic clinical trials might be directly generalizable only regarding relative treatment response. In extrapolating published RCT results to daily practice, population characteristics associated with disease severity, disease duration, and treatment history or cotreatment need to be taken into account.

Item does not contain fulltext OBJECTIVE: One of the disease hallmarks of RA is progressive cartilage and bone destruction in the joints. The exact mechanism underlying this disease process is largely unknown. Nod1, an intracellular pattern recognition receptor expressed by the innate immune system, has been previously shown to display anti-inflammatory effects in experimental arthritis. Furthermore, an insertion/deletion polymorphism in NOD1 has been demonstrated to modulate cytokine responses of immune cells. In this study, the effect of the insertion/deletion polymorphism in NOD1 on RA susceptibility and severity was assessed. METHODS: Ex vivo stimulation of primary immune cells and osteoclasts with microbial triggers was performed to measure cytokine responses and osteoclast-specific gene expression in relation to the NOD1 genotype. In total, 1047 RA patients from two centres were genotyped for the NOD1 polymorphism and compared with 431 healthy controls. Clinical scores of joint inflammation and destruction were correlated with the NOD1 genotype. RESULTS: Functional analysis revealed increased production of pro-inflammatory cytokines in cells from individuals bearing the NOD1 +32656 insertion allele. Furthermore, osteoclast bone resorption activity was elevated, as reflected by increased expression of the lysosomal protease cathepsin K. However, the insertion allele of the NOD1 +32656 polymorphism was not associated with either susceptibility to, or clinical parameters of, inflammation or bone destruction in RA patients. CONCLUSION: These findings demonstrate that the NOD1 polymorphism modulates pro-inflammatory cytokine responses induced through Toll-like receptor or Nod-like receptor ligands. Nevertheless, these effects of genetic variation in NOD1 appear to be redundant in RA susceptibility and severity.