2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases.

OBJECTIVES: Fatigue is prevalent in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and recognised as one of the most challenging symptoms to manage. The existence of multiple factors associated with driving and maintaining fatigue, and the evidence about what improves fatigue has led to a multifaceted approach to its management. However, there are no recommendations for fatigue management in people with I-RMDs. This lack of guidance is challenging for those living with fatigue and health professionals delivering clinical care. Therefore, our aim was to develop EULAR recommendations for the management of fatigue in people with I-RMDs. METHODS: A multidisciplinary taskforce comprising 26 members from 14 European countries was convened, and two systematic reviews were conducted. The taskforce developed the recommendations based on the systematic review of evidence supplemented with taskforce members' experience of fatigue in I-RMDs. RESULTS: Four overarching principles (OAPs) and four recommendations were developed. OAPs include health professionals' awareness that fatigue encompasses multiple biological, psychological and social factors which should inform clinical care. Fatigue should be monitored and assessed, and people with I-RMDs should be offered management options. Recommendations include offering tailored physical activity and/or tailored psychoeducational interventions and/or, if clinically indicated, immunomodulatory treatment initiation or change. Patient-centred fatigue management should consider the individual's needs and preferences, their clinical disease activity, comorbidities and other psychosocial and contextual factors through shared decision-making. CONCLUSIONS: These 2023 EULAR recommendations provide consensus and up-to-date guidance on fatigue management in people with I-RMDs.

Relative Impact of Pain and Disease Activity on Improvements in Fatigue: Results From 2 Baricitinib Phase 3 Clinical Trials.

BACKGROUND/OBJECTIVE: Fatigue is common in patients with rheumatoid arthritis (RA). We assessed the relative impact of pain and disease activity on improvements in fatigue in 2 phase 3 baricitinib clinical trials. METHODS: RA-BEAM (NCT01710358) and RA-BEACON (NCT01721044) were randomized, double-blind, placebo-controlled studies in adults with moderate to severe RA. RA-BEAM assessed baricitinib + methotrexate (MTX) and adalimumab + MTX in patients with prior inadequate response/intolerance (IR) to MTX (MTX-IR). RA-BEACON assessed patients with IR to ≥1 biologic disease-modifying antirheumatic drug (bDMARD-IR). Measures included the Functional Assessment of Chronic Illness Therapy-Fatigue scale, Clinical Disease Activity Index (CDAI) for RA, and pain visual analog scale (VAS). Analyses were implemented separately for each study. RESULTS: Significant improvements were seen in disease activity and pain, which were greater with baricitinib versus adalimumab. A statistically significant improvement was seen in fatigue with both active treatments versus placebo. Moderate correlations were observed between improvements in disease activity and fatigue and between improvements in pain and fatigue in both MTX-IR and bDMARD-IR patients. Reductions in pain (≥50%) and remission or low disease activity (CDAI ≤10) had significant associations with fatigue improvement at week 24. In mediation analysis, improvements in fatigue attributable to CDAI and pain VAS in MTX-IR patients were 31% and 52%, respectively, for baricitinib, and 30% and 47%, respectively, for adalimumab. In bDMARD-IR patients, improvement in fatigue was attributed 48% to CDAI and 48% to pain VAS. CONCLUSIONS: In both MTX-IR and bDMARD-IR patients, a large proportion of improvements in fatigue across treatment arms were accounted for by improvements in pain and disease activity.

EULAR/eumusc.net standards of care for rheumatoid arthritis: cross-sectional analyses of importance, level of implementation and care gaps experienced by patients and rheumatologists across 35 European countries.

OBJECTIVE: As part of European League against Rheumatism (EULAR)/European Musculoskeletal Conditions Surveillance and Information Network, 20 user-focused standards of care (SoCs) for rheumatoid arthritis (RA) addressing 16 domains of care were developed. This study aimed to explore gaps in implementation of these SoCs across Europe. METHODS: Two cross-sectional surveys on the importance, level of and barriers (patients only) to implementation of each SoC (0-10, 10 highest) were designed to be conducted among patients and rheumatologists in 50 European countries. Care gaps were calculated as the difference between the actual and maximum possible score for implementation (ie, 10) multiplied by the care importance score, resulting in care gaps (0-100, maximal gap). Factors associated with the problematic care gaps (ie, gap≥30 and importance≥6 and implementation<6) and strong barriers (≥6) were further analysed in multilevel logistic regression models. RESULTS: Overall, 26 and 31 countries provided data from 1873 patients and 1131 rheumatologists, respectively. 19 out of 20 SoCs were problematic from the perspectives of more than 20% of patients, while this was true for only 10 SoCs for rheumatologists. Rheumatologists in countries with lower gross domestic product and non-European Union countries were more likely to report problematic gaps in 15 of 20 SoCs, while virtually no differences were observed among patients. Lack of relevance of some SoCs (71%) and limited time of professionals (66%) were the most frequent implementation barriers identified by patients. CONCLUSIONS: Many problematic gaps were reported across several essential aspects of RA care. More efforts need to be devoted to implementation of EULAR SoCs.

Evolving the comprehensive management of rheumatoid arthritis: identification of unmet needs and development of practical and educational tools.

OBJECTIVES: Despite availability of efficacious treatments, unmet needs still exist, preventing optimal and comprehensive management of rheumatoid arthritis (RA). Evolving the management of RA (eRA) is a European-wide educational initiative aiming to support improved patient care through practical and educational tools addressing specific unmet needs. METHODS: A multidisciplinary Steering Committee (17 members, 12 countries) identified unmet needs within the management of RA and prioritised those with the greatest impact on patient outcomes. Practical educational tools addressing priority needs were then developed for dissemination and implementation by the rheumatology community across Europe. RESULTS: Five areas of priority need were identified: increasing early recognition of RA and treatment initiation; treating RA to target; optimal, holistic approach to selection of treatment strategy, including shared decision-making; improving identification and management of comorbidities; and non-pharmacological patient management. A suite of 14 eRA tools included educational slides, best-practice guidance, self­assessment questionnaires, clinical checklists, a multidisciplinary team training exercise, an interactive patient infographic, and case scenarios. By April 2020, rheumatology professionals in 17 countries had been actively engaged in the eRA programme; in 11 countries, eRA tools were selected by national leaders in rheumatology and translated for local dissemination. A web platform, with country-specific pages, was developed to support access to the translated tools (https://www.evolvingthemanagementofra.com/). CONCLUSIONS: The eRA programme supports comprehensive management of RA across Europe through development and dissemination of practical educational tools. The eRA tools address priority needs and are available free of charge to the rheumatology community.

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.

Development and validation of a patient-reported gout attack intensity score for use in gout clinical studies.

OBJECTIVE: Inflammation-related symptoms such as pain, swelling and tenderness of the affected joint are frequently assessed using 5-point diary rating scales in gout clinical trials. Combining these into a single gout attack symptom intensity score may be a useful summary measure for these data, which is potentially more responsive to change compared with the individual components. The objective of this study was to develop a patient-reported gout flare intensity score, the Gout Attack Intensity Score (GAIS), for use in clinical studies, that includes components for gout-related pain, swelling and tenderness. METHODS: Data from a randomized controlled trial comparing anakinra to standard of care for the treatment of acute gout attacks were used for this study. A 7-day flare diary was completed by patients, including questions relating to intensity of pain, swelling and tenderness (5-point rating scales). Scalability of these items was assessed using Mokken Scale Analysis, and reliability using greatest lower bound reliability coefficients. Known-groups validity was evaluated, as well as the responsiveness to change and the presence of floor and ceiling effects. RESULTS: Scalability of the single items was supported, and GAIS scores were reliable (greatest lower bound >0.80). GAIS scores demonstrated responsiveness to change with high effect sizes (>0.8), and discriminated better between responders and non-responders compared with its single-item components. No floor and ceiling effects were found. CONCLUSION: The GAIS seems to be a reliable and responsive instrument for assessing patient-reported gout attack intensity that may be used in gout clinical studies.

Anakinra for the treatment of acute gout flares: a randomized, double-blind, placebo-controlled, active-comparator, non-inferiority trial.

OBJECTIVES: To evaluate the efficacy and safety of anakinra in treating acute gout flares in a randomized, double-blind, placebo-controlled, active comparator, non-inferiority (NI) trial. METHODS: Patients with a crystal-proven acute gout flare were randomized (1: 1) to treatment with anakinra or treatment as usual (free choice: either colchicine, naproxen or prednisone). The primary end point was the change in pain between baseline and the averaged pain score on days 2-4 measured on a five-point rating scale. NI of anakinra would be established if the upper bound of the 95% CI of the numeric difference in changed pain scores between treatment groups did not exceed the NI limit of 0.4 in favour of treatment as usual, in the per-protocol (PP) and intention-to-treat (ITT) populations, assessed in an analysis of covariance model. Secondary outcomes included safety assessments, improvement in pain, swelling, tenderness and treatment response after 5 days, assessed using linear mixed models and binary logistic regression models. RESULTS: Forty-three patients received anakinra and 45 treatment as usual. Anakinra was non-inferior (mean difference; 95% CI) to treatment as usual in both the PP (-0.13; -0.44, 0.18) and ITT (-0.18; -0.44, 0.08) populations. No unexpected or uncommon (serious) adverse events were observed in either treatment arm. Analyses of secondary outcomes showed that patients in both groups reported similar significant reductions in their gout symptoms. CONCLUSION: Efficacy of anakinra was shown to be non-inferior to treatment as usual for the treatment of acute gout flares, suggesting that anakinra is an effective treatment alternative for acute gout flares. TRIAL REGISTRATION: Het Nederlands Trial Register, www.trialregister.nl, NTR5234.

A systematic literature review of patient-reported outcome measures used in gout: an evaluation of their content and measurement properties.

BACKGROUND: Gout is a common, monosodium urate crystal-driven inflammatory arthritis. Besides its clinical manifestations, patients often also suffer from pain, physical impairment, emotional distress and work productivity loss, as a result of the disease. Patient-reported outcome measures (PROMs) are commonly used to assess these consequences of the disease. However, current instrument endorsements for measuring such outcomes in acute and chronic gout clinical settings are based on limited psychometric evidence. The objective of this systematic literature review was to identify currently available PROMs for gout, and to critically evaluate their content and psychometric properties, in order to evaluate the current status regarding PROMs for use in gout patients. METHODS: Systematic literature searches were performed in the PubMed and EMBASE databases. The methodological quality of included papers was appraised using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist, and evaluation of measurement properties (reliability, responsiveness, construct validity, floor and ceiling effects) was done in accordance with published quality criteria. Item content was appraised by linking health concepts to the International Classification of Functioning Disability and Health (ICF) framework. RESULTS: In total, 13 PROMs were identified, of which three were targeted specifically at gout patients. The majority of the PROMs were rated positively for content validity. For most instruments, limited evidence was available for construct validity and reliability. Instruments to assess pain scored well on responsiveness and floor and ceiling effects, but not much is known about their reliability in gout. CONCLUSIONS: The physical functioning subscale of the SF-36v2 (Short Form-36 item version 2) is the only PROM that had sufficient supporting evidence for all its psychometric properties. Many of the commonly used PROMs in gout are currently not yet well supported and more studies on their measurement properties are needed among both acute and chronic gout populations.

Psychometric properties and cross-language equivalence of the revised Bristol Rheumatoid Arthritis Fatigue and the Rheumatoid Arthritis Impact of Disease scales in rheumatoid arthritis.

OBJECTIVE: To assess psychometric properties and cross-language measurement equivalence of six versions of the Bristol Rheumatoid Arthritis Fatigue Scale (BRAF-MDQ) and the Rheumatoid Arthritis Impact of Disease Score (RAID in rheumatoid arthritis (RA). METHODS: Both questionnaires were completed by French (n = 206), German (n = 206), Dutch (n = 317), Spanish (n = 157), Swedish (n = 170) and UK (n = 210) RA patients. The presence of cross-language differential item functioning (DIF) was examined using the generalized partial credit model. The impact of DIF on the item and total scores was examined by comparing DIF unadjusted and DIF adjusted expected item and scale scores. IRT-based methods were used to assess psychometric properties of the instruments. RESULTS: 11 of the 20 BRAF-MDQ (55%) and 4 of the 7 RAID items (57%) exhibited significant DIF in at least one of the six countries. The mean number of items with DIF per country was 2.6 for BRAF-MDQ and 1.1 for RAID. However, the impact of DIF on the total RAID and BRAF-MDQ scores, as well as the BRAF subscales, was found to be negligible at the group level. Only for the BRAF physical subscale was there evidence of minor DIF. Marginal reliabilities of BRAF-MDQ (0.93) and RAID (0.89) were excellent, and precise scores could be obtained across the spectrum of disease impact and fatigue scores measured by these PROMs. CONCLUSION: This study supports the cross-language measurement equivalence of BRAF-MDQ and RAID and provides further support for the psychometric properties of these measures in RA.

Rasch measurement in rheumatoid arthritis: deriving psychometrically optimal measures from the Rasch Everyday Activity Limitation item bank.

Objective: Recently we developed the Rasch Everyday Activity Limitations (REAL) generic item bank for measuring physical function. In this study we evaluate the REAL item bank in 209 RA patients and demonstrate how computerized adaptive testing (CAT) and Optimal Test Assembly methods can be used to derive measures from the REAL item bank with superior measurement performance compared with the HAQ Disability Index (HAQ-DI). Methods: Structural validity of the item bank was assessed using confirmatory factor analysis. The validity of the REAL score metric in RA was evaluated by examining differential item functioning against the general population calibration sample. Besides the REAL-CAT, a 6-item short form (REAL-6) was developed using Optimal Test Assembly that was optimized with respect to common disability levels in RA, content and reading ease. Measurement precision of the different instruments was examined using item response theory methods. Construct validity was evaluated by testing hypothesized correlations with external measures. Results: Good model-data fit was observed for a one-dimensional model and only two items showed differential item functioning of substantial magnitude. The REAL-CAT had superior measurement precision compared with HAQ-DI and REAL-6. REAL-6 outperformed HAQ-DI across all but the very lowest level of physical function. All three instruments demonstrated good construct validity (>75% of hypotheses affirmed) and only HAQ-DI had a ceiling effect (23.9%). Conclusion: This study supports the validity of the REAL item bank and illustrates the potential of CAT and OTA applications based on the REAL item bank for assessing physical function in RA.

The eumusc.net standards of care for rheumatoid arthritis: importance and current implementation according to patients and healthcare providers in the Netherlands.

OBJECTIVES: The eumusc.net standards of care (SOCs) for rheumatoid arthritis (RA) aimed to improve quality of care across Europe. This study investigated importance and implementation of each standard according to patients and health care professionals (HCPs) in the Netherlands and identified barriers towards implementation. METHODS: Dutch patients, rheumatologists and rheumatology nurses rated importance and implementation (0-10 numeric rating scale (NRS); 10=most important/best implemented) for each of the 20 SOCs. A care gap, adjusted for importance, was calculated: (100=highest gap). Statistical differences between a) patients and HCPs and b) subgroups of patients (demographics, health) were tested. Additionally, patients indicated agreement (0-10) with 6 implementation barriers. RESULTS: 386 patients and 91 HCPs were included. Both ranked adequate disease modifying anti-rheumatic drug treatment (9.3(SD1.2), 9.2(SD0.8)), access to care in emergencies (9.2(SD1.2), 9.2(SD1.0)) and regular re-appraisal when treatment fails (9.2(SD1.3), 9.0(SD1.0)) the most important SOCs, and these were among the best implemented (NRS≥8.5) SOCs. After accounting for applicability, patients and HCP identified care gaps for early diagnosis (25.5(SD32.0), 22.3(SD16.3)), availability of a treatment plan (25.1(SD22.7), 25.7(SD18.5)) and patients also for a regular schedule of assessment of disease (28.6(SD25.5)).Patients with poorer health or higher education scored systematically lower on care received while sharing similar priorities. Patients and HCPs considered limited reimbursement of specific health services a main barrier for implementation and patients additionally identified limited time of physicians. CONCLUSIONS: Dutch patients and HCPs overall agreed on priorities in care and found relevant SOCs well implemented. However, suggestions for improvement were raised especially by patients with poorer health and/or higher education.

Measuring everyday functional competence using the Rasch assessment of everyday activity limitations (REAL) item bank.

OBJECTIVE: Traditional patient-reported physical function instruments often poorly differentiate patients with mild-to-moderate disability. We describe the development and psychometric evaluation of a generic item bank for measuring everyday activity limitations in outpatient populations. STUDY DESIGN AND SETTING: Seventy-two items generated from patient interviews and mapped to the International Classification of Functioning, Disability and Health (ICF) domestic life chapter were administered to 1128 adults representative of the Dutch population. The partial credit model was fitted to the item responses and evaluated with respect to its assumptions, model fit, and differential item functioning (DIF). Measurement performance of a computerized adaptive testing (CAT) algorithm was compared with the SF-36 physical functioning scale (PF-10). RESULTS: A final bank of 41 items was developed. All items demonstrated acceptable fit to the partial credit model and measurement invariance across age, sex, and educational level. Five- and ten-item CAT simulations were shown to have high measurement precision, which exceeded that of SF-36 physical functioning scale across the physical function continuum. Floor effects were absent for a 10-item empirical CAT simulation, and ceiling effects were low (13.5%) compared with SF-36 physical functioning (38.1%). CAT also discriminated better than SF-36 physical functioning between age groups, number of chronic conditions, and respondents with or without rheumatic conditions. CONCLUSION: The Rasch assessment of everyday activity limitations (REAL) item bank will hopefully prove a useful instrument for assessing everyday activity limitations. T-scores obtained using derived measures can be used to benchmark physical function outcomes against the general Dutch adult population.

Quality of care in gout: a clinical audit on treating to the target with urate lowering therapy in real-world gout patients.

The current paper aimed to describe the quality of care for gout patients by showing the clinical outcomes achieved in two patient cohorts in which differing targeted urate lowering therapy (ULT) treatment approaches were employed, both aiming to reach the European League Against Rheumatism recommended serum urate (sUA) targets. A retrospective medical chart review study was conducted. Data from the medical records of gout patients from two clinical centers in The Netherlands, both applying targeted ULT treatments (albeit using different approaches), were reviewed. Patients in cohort A were given a combination of xanthine oxidase inhibitors with uricosurics if treatment with allopurinol monotherapy failed to reach sUA target levels, whereas patients in cohort B were treated with sequential monotherapy. Data on patient characteristics and clinical outcomes were collected. A total of 177 patient dossiers were included: 99 from cohort A and 78 from cohort B. The great majority (n = 146, 82.5%) of the patients in both cohorts had a current sUA level <360 µmol/L. In addition, more than half (n = 104, 58.8%) of the patients met the stringent sUA target level of <300 µmol/L. The largest reductions in mean sUA levels were observed for patients who were treated with combination therapy. This clinical audit of two cohorts of gout patients provides initial-yet promising-results regarding the proportion of real-world gout patients in whom recommended that sUA target levels can be achieved, and demonstrates the added value that a targeted treatment approach may have in reaching these goals.

Development of a web-based patient decision aid for initiating disease modifying anti-rheumatic drugs using user-centred design methods.

BACKGROUND: A main element of patient-centred care, Patient Decision Aids (PtDAs) facilitate shared decision-making (SDM). A recent update of the International Patient Decision Aids Standards (IPDAS) emphasised patient involvement during PtDA development, but omitted a methodology for doing so. This article reports on the value of user-centred design (UCD) methods for the development of a PtDA that aims to support inflammatory arthritis patients in their choice between disease modifying anti-rheumatic drugs (DMARDs). METHODS: The IPDAS development process model in combination with UCD methods were applied. The process was overseen by an eight-member multidisciplinary steering group. Patients and health professionals were iteratively consulted. Qualitative in-depth interviews combined with rapid prototyping were conducted with patients to assess their needs for specific functionality, content and design of the PtDA. Group meetings with health professionals were organized to assess patients' needs and to determine how the PtDA should be integrated into patient pathways. The current literature was reviewed to determine the clinical evidence to include in the PtDA. To evaluate usability among patients, they were observed using the PtDA while thinking aloud and then interviewed. RESULTS: The combination of patient interviews with rapid prototyping revealed that patients wanted to compare multiple DMARDs both for their clinical aspects and implications for daily life. Health professionals mainly wanted to refer patients to a reliable, easily adjustable source of information about DMARDs. A web-based PtDA was constructed consisting of four parts: 1) general information about SDM, inflammatory arthritis and DMARDs; 2) an application to compare particular DMARDs; 3) value clarification exercises; and 4) a printed summary of patients' notes, preferences, worries and questions that they could bring to discuss with their rheumatologist. CONCLUSIONS: The study demonstrated that UCD methods can be of great value for the development of PtDAs. The early, iterative involvement of patients and health professionals was helpful in developing a novel user-friendly PtDA that allowed patients to choose between DMARDs. The PtDA fits the values of all stakeholders and easily integrates with the patient pathway and daily workflow of health professionals. This collaborative designed PtDA may improve SDM and patient participation in arthritis care.

Barriers and facilitators to disease-modifying antirheumatic drug use in patients with inflammatory rheumatic diseases: a qualitative theory-based study.

BACKGROUND: Although disease-modifying anti-rheumatic drugs (DMARDs) are the cornerstone of treatment for inflammatory rheumatic diseases, medication adherence to DMARDs is often suboptimal. Effective interventions to improve adherence to DMARDs are lacking, and new targets are needed to improve adherence. The aim of the present study was to explore patients' barriers and facilitators of optimal DMARD use. These factors might be used as targets for adherence interventions. METHODS: In a mixed method study design, patients (n = 120) with inflammatory arthritis (IA) completed a questionnaire based on an existing adapted Theoretical Domains Framework (TDF) to identify facilitators and barriers of DMARD use. A subgroup of these patients (n = 21) participated in focus groups to provide insights into their facilitators and barriers. The answers to the questionnaires and responses of the focus groups were thematically coded by three researchers independently and subsequently categorized. RESULTS: The barriers and facilitators that were reported by IA patients presented large inter-individual variations. The identified barriers and facilitators could be captured in the following domains based on an adapted TDF: (i) knowledge, (ii) emotions, (iii) attention, memory, and decision processes, (iv) social influences, (v) beliefs about capability, (vi) beliefs about consequences, (vii) motivation and goals, (viii) goal conflict, (ix) environmental context and resources, and (x) skills. CONCLUSIONS: Patients with IA have a variety of barriers and facilitators with regard to their DMARD use. All of these barriers and facilitators could be categorized into adapted domains of the TDF. Interventions that address individual facilitators and barriers, based on capability, opportunity, and motivation, are needed to develop strategies for medication adherence that are tailored to individual patient needs.

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.

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.

Inadequate pain relief and large functional loss among patients with knee osteoarthritis: evidence from a prospective multinational longitudinal study of osteoarthritis real-world therapies.

OBJECTIVE: To estimate the prevalence of inadequate pain relief (IPR) among patients with symptomatic knee OA prescribed analgesic therapy and to characterize patients with IPR. METHODS: Patients ≥50 years old with physician-diagnosed knee OA who had taken topical or oral pain medication for at least 14 days were recruited for this prospective non-interventional study in six European countries. Pain and function were assessed using the Brief Pain Inventory (BPI) and the WOMAC; quality of life (QoL) was assessed using the 12-item short form. IPR was defined as an average pain score of >4 out of 10 on BPI question 5. RESULTS: Of 1187 patients enrolled, 68% were female and the mean age was 68 years (s.d. 9); 639 (54%) met the definition of IPR. Patient responses for the BPI average pain question were well correlated with responses on the WOMAC pain subscale (Spearman r = 0.64, P < 0.001). In multivariate logistic regression, patients with IPR had greater odds of being female [adjusted odds ratio (adjOR) 1.90 (95% CI 1.46, 2.48)] and having OA in both knees [adjOR 1.48 (95% CI 1.15, 1.90)], higher BMI, longer OA duration, depression or diabetes. Patients with IPR (vs non-IPR) were more likely to have worse QoL, greater function loss and greater pain interference. CONCLUSION: IPR is common among patients with knee OA requiring analgesics and is associated with large functional loss and impaired QoL. Patients at particular risk of IPR, as characterized in this study, may require greater attention towards their analgesic treatment options. TRIAL REGISTRATION: https://clinicaltrials.gov/ (NCT01294696).

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.