Genetics of rheumatoid arthritis contributes to biology and drug discovery.

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Strategies for implementation of guideline recommended cardiovascular risk management for patients with rheumatoid arthritis: results from a questionnaire survey of expert rheumatology centers.

The aim was to study the different strategies used to implement cardiovascular risk evaluation and management for patients with rheumatoid arthritis (RA) in daily clinical practice. A questionnaire survey was performed among both the members of the international Trans-Atlantic Cardiovascular Risk Consortium for Rheumatoid Arthritis (ATACC-RA) as well as the Survey of cardiovascular disease risk factors (CVD-RF) in patients with RA (SURF-RA) group. The questionnaire included 18 questions with the overarching topics: (1) organization and responsibility of cardiovascular risk management (CVRM); (2) screening of CVD-RFs; (3) overview current CVRM status; and (4) availability of data regarding CVRM. Based on the answers, two researchers (JW, PR) independently categorized the different strategies. Thirteen out of 27 rheumatology centers responded to the questionnaire. One rheumatology center did not have organized CVRM for their RA patients. Among the other centers, three strategies to organize CVRM in daily practice were distinguished: (1) the rheumatologist performs CVRM during outpatient visits (n = 6); (2) cardiologists and rheumatologists co-operate in a cardio-rheuma-clinic/team with different tasks and responsibilities (n = 3); and (3) the general practitioner screens and intervenes on CVD-RFs (n = 3). Each CVRM strategy was based on agreements between medical professionals and was also dependent on the national healthcare system and available financial resources. Three strategies were identified for CVRM implementation in daily clinical practice based on who is primarily responsible for performing CVRM. More research is warranted to compare their relative merits and effectiveness in relation to CVRM.

Adalimumab drug and antidrug antibody levels do not predict flare risk after stopping adalimumab in RA patients with low disease activity.

OBJECTIVE: To establish whether serum adalimumab (ADA) trough level (ADA-TL) and antidrug antibody (ADA-ab) level predict flare after stopping ADA in established RA patients with long-standing low disease activity. METHODS: From the clinical trial Potential Optimalisation and Effectiveness of TNF-blockers, 210 RA patients stopping ADA, who had been using ADA (40 mg/2 weeks) for >1 year with conventional synthetic DMARDs and who had low disease activity (DAS28 < 3.2, or the rheumatologist's assessment of low disease activity with CRP < 10 mg/l) for at least 6 months prior to stopping, were followed for 1 year. The ADA-TL was measured (by ELISA) 12-17 days after the last ADA injection; if it was low, ADA-abs were measured (by an antigen-binding test). Association between time-to-flare and ADA-TL was evaluated by area under the receiver operating characteristic curve and Cox regression. RESULTS: A total of 106 (51%) patients flared within 1 year after stopping ADA. The area under the receiver operating characteristic curve for flare and ADA-TL was 0.50 (95% CI 0.42-0.58), P = 0.92. The hazard ratio for flare for ADA-TL ⩾ 5 µg/ml (adequate level) vs <5 µg/ml was 0.93 (95% CI: 0.63-1.36) (not significant). Of the 4 patients with high ADA-ab levels, 2 patients (50%) experienced a flare. CONCLUSION: Flare risk within the year following stopping ADA is not predicted by the ADA-TL or ADA-abs assessed at the moment of stopping. TRIAL REGISTRATION: Netherlands Trial Register, http://www.trialregister.nl, NTR3112.

Implementation of the EULAR cardiovascular risk management guideline in patients with rheumatoid arthritis: results of a successful collaboration between primary and secondary care.

The updated European League Against Rheumatism (EULAR) guideline recommends cardiovascular disease (CVD) risk assessment at least once every 5 years in all patients with rheumatoid arthritis (RA). This viewpoint starts with a literature overview of studies that investigated the level of CVD risk factor (CVD-RF) screening in patients with RA in general practices or in outpatient clinics. These studies indicate that CVD-RF screening in patients with RA is marginally applied in clinical practice, in primary as well as secondary care. Therefore, the second part of this viewpoint describes an example of the successful implementation of the EULAR cardiovascular disease risk management (CVRM) guideline in patients with RA in a region in the south of the Netherlands where rheumatologists and general practitioners (GPs) closely collaborate to manage the cardiovascular risk of patients with RA. The different components of this collaboration and the responsibilities of respectively primary and secondary care professionals are described. Within this collaboration, lipid profile was used as an indicator to assess whether CVD-RF screening was performed in the previous 5 years. In 72% (n=454) of the 628 patients with RA, a lipid profile was determined in the previous 5 years. As part of routine quality control, a reminder was sent to the GP in case a patient with RA was not screened. After sending the reminder letter, in 88% of all patients with RA, CVD risk assessment was performed. This collaboration can be seen as good practice to provide care in line with the EULAR guideline.

Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. METHODS: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. RESULTS: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). CONCLUSIONS: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

Tailored Therapist-guided Internet-based Cognitive-behavioural Treatment for Psoriasis and Rheumatoid Arthritis: Two Case Reports.

Chronic somatic conditions, such as psoriasis, arthritis psoriatica and rheumatoid arthritis, have a large impact on patients' lives. Tailored therapist-guided internet-based cognitive-behavioural therapy (ICBT) has been shown to be effective in improving physical and psychological well-being in these patients. Two cases are presented here, in order to provide an in-depth illustration of the course and content of this novel treatment and to investigate the therapeutic alliance in an online treatment. After face-to-face intakes, both patients received therapist-guided ICBT tailored to their specific problems and treatment goals. The treatment resulted in improved physical and psychological well-being and these clinically significant improvements were maintained at 6-month follow-up. In addition, the therapeutic relationship was evaluated positively by both patients and increased further during treatment, indicating an adequate therapeutic working alliance in this online treatment. These case reports show that tailored ICBT may contribute to improved care for patients with chronic somatic conditions.

Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).

Low disease activity (DAS28≤3.2) reduces the risk of first cardiovascular event in rheumatoid arthritis: a time-dependent Cox regression analysis in a large cohort study.

OBJECTIVE: Systemic inflammation appears to contribute to the excess risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA). The objective of this study was to investigate the effect of different levels of disease activity over time, particularly low disease activity and remission, on CVD risk in patients with RA. METHODS: Data from the Nijmegen early RA inception cohort were used. The primary outcome was first CVD events within the first 10 years of follow-up. Cut points of the DAS28 for remission (<2.6) and low (≤3.2), moderate (3.2-5.1) and high (>5.1) disease activity were used. The effect of disease activity on CVD risk was analysed using Cox-proportional hazards regression with DAS28 as a time-dependent covariate and also conventionally with time-averaged DAS28 as the primary dependent variable. RESULTS: Low DAS28 (≤3.2) was significantly associated with a reduced risk of CVD (HR 0.65, 95% CI 0.43 to 0.99) compared with DAS28 >3.2, both when included as a time-dependent covariate and as time-averaged DAS28 ≤3.2 (HR 0.52, 95% CI 0.33 to 0.81). Remission had a modest, non-significant protective effect against CVD (HR 0.67, 95% CI 0.43 to 1.07). CONCLUSION: Results of this study suggest that low disease activity is sufficient to achieve a protective effect against CVD in RA. Apparently, remission defined as DAS28 <2.6 has no additional protective effect against CVD compared with low disease activity. Our results strengthen the use of tight control strategies in daily clinical practice to achieve low stable disease activity or remission in patients with RA as soon as possible.

Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries.

Objectives: Cardiovascular disease (CVD) risk calculators developed for the general population do not accurately predict CVD events in patients with RA. We sought to externally validate risk calculators recommended for use in patients with RA including the EULAR 1.5 multiplier, the Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) and QRISK2. Methods: Seven RA cohorts from UK, Norway, Netherlands, USA, South Africa, Canada and Mexico were combined. Data on baseline CVD risk factors, RA characteristics and CVD outcomes (including myocardial infarction, ischaemic stroke and cardiovascular death) were collected using standardized definitions. Performance of QRISK2, EULAR multiplier and ERS-RA was compared with other risk calculators [American College of Cardiology/American Heart Association (ACC/AHA), Framingham Adult Treatment Panel III Framingham risk score-Adult Treatment Panel (FRS-ATP) and Reynolds Risk Score] using c-statistics and net reclassification index. Results: Among 1796 RA patients without prior CVD [mean ( s . d .) age: 54.0 (14.0) years, 74% female], 100 developed CVD events during a mean follow-up of 6.9 years (12430 person-years). Estimated CVD risk by ERS-RA [mean ( s . d .) 8.8% (9.8%)] was comparable to FRS-ATP [mean ( s . d .) 9.1% (8.3%)] and Reynolds [mean ( s . d .) 9.2% (12.2%)], but lower than ACC/AHA [mean ( s . d .) 9.8% (12.1%)]. QRISK2 substantially overestimated risk [mean ( s . d .) 15.5% (13.9%)]. Discrimination was not improved for ERS-RA (c-statistic = 0.69), QRISK2 or EULAR multiplier applied to ACC/AHA compared with ACC/AHA (c-statistic = 0.72 for all) or for FRS-ATP (c-statistic = 0.75). The net reclassification index for ERS-RA was low (-0.8% vs ACC/AHA and 2.3% vs FRS-ATP). Conclusion: The QRISK2, EULAR multiplier and ERS-RA algorithms did not predict CVD risk more accurately in patients with RA than CVD risk calculators developed for the general population.

Limited value for ultrasonography in predicting flare in rheumatoid arthritis patients with low disease activity stopping TNF inhibitors.

Objective: Ultrasonography (US) can be used for treatment decisions in RA patients. This study investigated the added value of US to clinical variables in predicting flare in RA patients with longstanding low disease activity when stopping TNF inhibitors (TNFi). Methods: Cox models with and without using US added to clinical variables were developed in the Potential Optimization of Expediency of TNFi-UltraSonography study. RA patients (n = 259), using >1 year TNFi and csDMARD with DAS28 < 3.2 for 6 months prior to inclusion, were followed for 52 weeks after stopping TNFi. The added value of US was assessed in two ways: first, by the extent to which individual predictions for flare at 52 weeks with and without US differed; and second, by comparing how US information improved the prediction to classify patients at 52 weeks in the low risk (<33% flare), intermediate risk (33-50%) and high risk (50-100%) groups. Results: Although US was predictive of flare at group level (multivariate hazard ratio = 1.7; 95% CI: 1.1, 2.5), individual predictions for flare at 52 weeks with and without US differed little (median difference 3.7%; interquartile range: -7.8 to 6.5%). With US, 15.9% of patients were designated low risk; without US, 14.6%. In fact, 12.0% of patients were US-classified as low risk with/without knowing US. Conclusion: In RA patients with longstanding low disease activity, at time of stopping TNFi, US is a predictor for flare at group level, but at the patient level, US has limited added value when common clinical parameters are used already, though the predictive value of clinical predictors is modest as well.

The influence of patient perceptions of disease on medication intensification in daily practice.

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.

The Disease Activity Score (DAS) and the Disease Activity Score using 28 joint counts (DAS28) in the management of rheumatoid arthritis.

In rheumatoid arthritis (RA), disease activity cannot be measured in all individual patients according to a single variable. The Disease Activity Score (DAS) and the DAS28 have been developed to measure disease activity in RA both in daily clinical practice as well as in clinical trials on a group as well as individual level. The DAS/DAS28 is a continuous measure of RA disease activity that combines information from swollen joints, tender joints, acute phase response and general health. The DAS-based EULAR response criteria were primarily developed to be used in clinical trials. The EULAR response criteria classify individual patients as non-, moderate, or good responders, dependent on the magnitude of change and level of disease activity reached. In addition, already in the early nineties, cut points were developed to categorise patients in remission. The DAS28 is incorporated in several electronic patient records and web-based systems for monitoring purposes in daily clinical practice. In addition to this, it is being used in combination with patient-reported outcome measures (PROMs) to facilitate self-monitoring.

A multidimensional 'path analysis' model of factors explaining fatigue in rheumatoid arthritis.

OBJECTIVES: 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. METHODS: 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-fatigue <35) and severely fatigued patients (CIS-fatigue ≥35) were tested. Structural equation modeling was used to test a hypothesised model for fatigue. RESULTS: 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 (ß=0.42, p<0.001) and less physical functioning (ß=0.65, p<0.001) are directly related to a higher level of fatigue. Less sense of control is related to more mood disturbance (ß=0.64, p<0.001), more pain (ß=0.389, p<0.001) and less physical functioning (ß=-0.24, p<0.001). More mood disturbance is related to poor sleep quality (ß=0.78, p<0.001) and higher pain level is related to less physical functioning (ß=0.75, p<0.001). CONCLUSIONS: 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.

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.

The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients.

OBJECTIVE: Disease duration and disease activity may be associated with an increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA). The objectives of this study were to investigate (1) the relationship between duration of inflammation and the development of CVD in RA patients and (2) the relationship between RA disease activity over time and CVD in patients with RA. METHODS: RA patients with a follow-up of ≥6 months in the Nijmegen early RA cohort without prior CVD were included. Disease activity over time was calculated using the time-averaged  28 joint disease activity score (DAS28) for each patient. Kaplan-Meier survival analysis and Cox proportional hazards regression were used for the analyses. RESULTS: During follow-up of the 855 patients that were included, 154 CV events occurred. The course of hazards over time did not indicate a change in the risk of CVD over the course of RA (disease duration), which is also reflected by the absence of a deflection in the survival curves. The survival distributions did not differ between patients with a disease duration of <10 years or >10 years (Log-rank test: p=0.82). Time-averaged DAS28 was significantly associated with CVD (p=0.002) after correction for confounders. CONCLUSIONS: Disease duration does not appear to independently affect the risk of CVD. The risk of CVD in RA patients was not increased after 10 years of disease duration compared with the first 10 years. Disease activity over time may contribute to the risk of CVD.

Estimation of heritability of different outcomes for genetic studies of TNFi response in patients with rheumatoid arthritis.

OBJECTIVES: Pharmacogenetic studies of tumour necrosis factor inhibitors (TNFi) response in patients with rheumatoid arthritis (RA) have largely relied on the changes in complex disease scores, such as disease activity score 28 (DAS28), as a measure of treatment response. It is expected that genetic architecture of such complex score is heterogeneous and not very suitable for pharmacogenetic studies. We aimed to select the most optimal phenotype for TNFi response using heritability estimates. METHODS: Using two linear mixed-modelling approaches (Bayz and GCTA), we estimated heritability, together with genomic and environmental correlations for the TNFi drug-response phenotype ΔDAS28 and its separate components: Δ swollen joint count (SJC), Δ tender joint count (TJC), Δ erythrocyte sedimentation rate (ESR) and Δ visual-analogue scale of general health (VAS-GH). For this, we used genome-wide single nucleotide polymorphism (SNP) data from 878 TNFi-treated Dutch patients with RA. Furthermore, a multivariate genome-wide association study (GWAS) approach was implemented, analysing separate DAS28 components simultaneously. RESULTS: The highest heritability estimates were found for ΔSJC (h(2)gbayz=0.76 and h(2)gGCTA=0.87) and ΔTJC (h(2)gbayz=0.62 and h(2)gGCTA=0.82); lower heritability was found for ΔDAS28 (h(2)gbayz=0.59 and h(2)gGCTA=0.71) while estimates for ΔESR and ΔVASGH were near or equal to zero. The highest genomic correlations were observed for ΔSJC and ΔTJC (0.49), and the highest environmental correlation was seen between ΔTJC and ΔVASGH (0.62). The multivariate GWAS did not generate excess of low p values as compared with a univariate analysis of ΔDAS28. CONCLUSIONS: Our results indicate that multiple SNPs together explain a substantial portion of the variation in change in joint counts in TNFi-treated patients with RA. In conclusion, of the outcomes studied, the joint counts are most suitable for TNFi pharmacogenetics in RA.

Predictors of satisfactory improvements in pain for patients with early rheumatoid arthritis in a treat-to-target study.

OBJECTIVE: The aim of this study was to identify baseline predictors of achieving patient-perceived satisfactory improvement (PPSI) in pain after 6 months of treat to target in patients with early RA. METHODS: Baseline and 6 month data were used from patients included in the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study. Simple and multivariable logistic regression analyses were used to identify significant predictors of achieving an absolute improvement of 30 mm or a relative improvement of 50% on a visual analogue scale for pain. RESULTS: At 6 months, 125 of 209 patients (59.8%) achieved an absolute PPSI and 130 patients (62.2%) achieved a relative PPSI in pain. Controlling for baseline pain, having symmetrical arthritis was the strongest independent predictor of achieving an absolute [odds ratio (OR) 3.17, P = 0.03] or relative (OR 3.44, P = 0.01) PPSI. Additionally, anti-CCP positivity (OR 2.04, P = 0.04) and having ≤12 tender joints (OR 0.29, P = 0.01) were predictive of achieving a relative PPSI. The total explained variance of baseline predictors was 30% for absolute and 18% for relative improvements, respectively. CONCLUSION: Symmetrical joint involvement, anti-CCP positivity and fewer tender joints at baseline are prognostic signs for achieving satisfactory improvement in pain after 6 months of treat to target in patients with early RA.

Validity and measurement precision of the PROMIS physical function item bank and a content validity-driven 20-item short form in rheumatoid arthritis compared with traditional measures.

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.

The EULAR Study Group for Registers and Observational Drug Studies: comparability of the patient case mix in the European biologic disease modifying anti-rheumatic drug registers.

OBJECTIVE: Under the auspices of the European League Against Rheumatism (EULAR), a study group of investigators representing European biologic DMARD (bDMARD) registers was convened. The purpose of this initial assessment was to collect and compare a cross section of patient characteristics and collate information on the availability of potential confounders within these registers. METHODS: Baseline characteristics of patients starting their first bDMARD in an arbitrary year (2008) for the treatment of RA, including demographic and disease characteristics, bDMARD drug details and co-morbidities, were collected and compared across 14 European bDMARD registers. RESULTS: A total of 5320 patients were included. Half the registers had restricted recruitment to certain bDMARDs during the study year. All registers` collected data on age, gender, disease duration, seropositivity for IgM-RF and 28-joint DAS (DAS28). The mean DAS28 ranged from 4.2 to 6.6 and the mean HAQ from 0.8 to 1.9. Current smoking ranged from 9% to 34%. Nine registers reported co-morbidities with varying prevalence. CONCLUSION: In addition to demonstrating European-wide collaboration across rheumatology bDMARD registers, this assessment identified differences in prescribing patterns, recruitment strategies and data items collected. These differences need to be considered when applying strategies for combined analysis. The lack of a common data model across Europe calls for further work to harmonize data collection across registers.