Search

To investigate how social support, financial status, and lifestyle influence the development of excess disability in rheumatoid arthritis (RA). Data were obtained from the Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR) cohort study of people with RA. A previous analysis identified groups with similar inflammation trajectories but markedly different disability over 10 years; those in the higher disability trajectory groups were defined as having “excess disability.” Self‐reported data regarding contextual factors (social support, financial situation, lifestyle) were obtained from participants, and they completed patient‐reported outcome measures (pain, fatigue, anxiety, depression) at baseline. The direct effect of the contextual factors on excess disability and the effect mediated by patient‐reported outcome measures were assessed using structural equation models. Findings were validated in 2 independent data sets (Norfolk Arthritis Register [NOAR], Early Rheumatoid Arthritis Network [ERAN]). Of 538 included ESPOIR participants (mean age ± SD 48.3 ± 12.2 years; 79.2% women), 200 participants (37.2%) were in the excess disability group. Less social support (β = 0.17 [95% confidence interval (95% CI) 0.08, 0.26]), worse financial situation (β = 0.24 [95% CI 0.14, 0.34]), less exercise (β = 0.17 [95% CI 0.09–0.25]), and less education (β = 0.15 [95% CI 0.06, 0.23]) were associated with excess disability group membership; smoking, alcohol consumption, and body mass index were not. Fatigue and depression mediated a small proportion of these effects. Similar results were seen in NOAR and ERAN. Greater emphasis is needed on the economic and social contexts of individuals with RA at presentation; these factors might influence disability over the following decade.

To determine the association between osteoarthritis (OA), rheumatoid arthritis (RA), and frailty and to determine whether comorbidities interact with OA and RA to further increase the likelihood of frailty. Participants of the UK Biobank age 40–69 years at baseline were included. Demographic, lifestyle, and clinical data were collected at baseline and follow‐up in a subset. Frailty was assessed using a frailty index (FI) (continuous) and a modified frailty phenotype (robust, pre‐frail, frail). The association between RA and OA and frailty at baseline and follow‐up was assessed using multiple regression models. We looked at whether comorbidities, including cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, and depression interacted additively with OA and RA to increase the likelihood of frailty. In total, 457,561 participants contributed data. Those with (versus without) RA (n = 4,894) and OA (n = 35,884), respectively, were more likely to be frail (adjusted relative risk ratio 10.7 [95% confidence interval (95% CI) 9.7, 11.7] and 3.4 [95% CI 3.3, 3.6]) and were more likely to have a higher FI at baseline. There was evidence of additive interaction between RA, OA, and common comorbidities increasing the occurrence of prevalent frailty. Among 25,163 participants included in longitudinal analysis, patients with RA (n = 202) and OA (n = 1,811) at baseline had an increased adjusted frailty incidence rate ratio (2.8 [95% CI 1.7, 4.6] and 1.7 [95% CI 1.3, 2.1], respectively) and also a higher FI during follow‐up. Individuals with RA and OA are more likely to have, or develop, frailty. Common comorbidities interact with OA and RA to further increase the likelihood of frailty.

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P< 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

As young people enter adulthood, the interchangeable use of child and adult outcome measures may inaccurately capture changes over time. This study aimed to use item response theory (IRT) to model a continuous score for functional ability that can be used no matter which questionnaire is completed. Adolescents (ages 11–17 years) in the UK Childhood Arthritis Prospective Study (CAPS) self‐completed an adolescent Childhood Health Assessment Questionnaire (CHAQ) and a Health Assessment Questionnaire (HAQ). Their parents answered the proxy‐completed CHAQ. Those children with at least 2 simultaneously completed questionnaires at initial presentation or 1 year were included. Psychometric properties of item responses within each questionnaire were tested using Mokken analyses to assess the applicability of IRT modeling. A previously developed IRT model from the Pharmachild‐NL registry from The Netherlands was validated in CAPS participants. Agreement and correlations between IRT‐scaled functional ability scores were tested using intraclass correlations and Wilcoxon’s signed rank tests. In 303 adolescents, the median age at diagnosis was 13 years, and 61% were female. CHAQ scores consistently exceeded HAQ scores. Mokken analyses demonstrated high scalability, monotonicity, and the fact that each questionnaire yielded reliable scores. There was little difference in item response characteristics between adolescents enrolled in CAPS and Pharmachild‐NL (maximum item residual 0.08). Significant differences were no longer evident between IRT‐scaled HAQ and CHAQ scores. IRT modeling allows the direct comparison of function scores regardless of different questionnaires being completed by different people over time. IRT modeling facilitates the ongoing assessment of function as adolescents transfer from pediatric clinics to adult services.

Seropositivity for anti-citrullinated peptide antibodies (ACPA) in patients with rheumatoid arthritis (RA), a chronic autoimmune arthritis, is associated with worse long-term disease outcomes. ACPA is ubiquitously tested in RA patients, but other autoantibodies exist (in both citrullinated and non-citrullinated form) which may provide additional information on RA subtypes and/or treatment response. We used a multiplex bead-based assay of 376 autoantibodies to test associations between these autoantibodies and treatment response in RA patients. Clusters of patients with similar autoantibody expression were defined and cluster membership was associated with treatment response. Thirty-four autoantibodies were differentially expressed in RA patients compared with healthy controls; citrullinated vimentin was associated with treatment response. A selection of citrullinated autoantibodies was found to be associated with treatment response in a subanalysis of ACPA-negative RA patients. Finer ACPA specificities in ACPA-negative RA patients may be predictive of treatment response and could represent a rich vein of future study.

In pediatric research, investigators rely on proxy reports of outcome, such as the proxy‐completed Childhood Health Assessment Questionnaire (C‐HAQ), to assess function in juvenile idiopathic arthritis (JIA). As children mature, they may self‐complete the adult HAQor the unvalidated adolescent‐specific C‐HAQ. It is unclear how these measures compare and whether they are directly interchangeable. The present study was undertaken to compare agreement between the proxy‐completed C‐HAQ, adolescent‐specific C‐HAQ, and the HAQ at initial presentation to pediatric rheumatologic care and 1 year following the first presentation in adolescents with JIA. Adolescents ages 11–17 years participating in the Childhood Arthritis Prospective Study (CAPS), a UKmulticenter inception cohort, were included. In a CAPSsubstudy, adolescents self‐completed the adolescent‐specific C‐HAQand the HAQ, and proxies simultaneously completed the proxy‐completed C‐HAQat baseline and 1 year. Correlation and agreement between scores were assessed at baseline. Agreement and ability to similarly classify clinically important changes over time were assessed at 1 year following initial presentation to rheumatologic care. A total of 107 adolescents (adolescent‐specific C‐HAQand HAQ) or their proxies (proxy‐completed C‐HAQ) had completed all 3 measures at baseline. Median age at diagnosis was 13 years, and 61% were female. Although the 3 scores demonstrated strong correlations (r > 0.8), they were not completely interchangeable, with agreement ranging between 70% and 80%. There was similar agreement between the changes in scores between baseline and 1 year. Using proxy‐completed C‐HAQminimum clinically important cutoffs, the adolescent‐specific C‐HAQand the HAQsimilarly classified 80% to 90% of adolescents as having improved or worsened. While there is relatively high agreement and similar classification of change between HAQand the 2 C‐HAQscores, these are not completely interchangeable. This impacts the comparison of function when measured in different ways over the lifespan.

Objective.Nonadherence to medications is common in rheumatic conditions and associated with increased morbidity. Heterogeneous outcome reporting by researchers compromises the synthesis of evidence of interventions targeting adherence. We aimed to assess the scope of outcomes in interventional studies of medication adherence.Methods.We searched electronic databases to February 2019 for published randomized controlled trials and observational studies of interventions with the primary outcome of medication adherence including adults with any rheumatic condition, written in English. We extracted and analyzed all outcome domains and adherence measures with prespecified extraction and analysis protocols.Results.Overall, 53 studies reported 71 outcome domains classified into adherence (1 domain), health outcomes (38 domains), and adherence-related factors (e.g., medication knowledge; 32 domains). We subdivided adherence into 3 phases: initiation (n = 13 studies, 25%), implementation (n = 32, 60%), persistence (n = 27, 51%), and phase unclear (n = 20, 38%). Thirty-seven different instruments reported adherence in 115 unique ways (this includes different adherence definitions and calculations, metric, and method of aggregation). Forty-one studies (77%) reported health outcomes. The most frequently reported were medication adverse events (n = 24, 45%), disease activity (n = 11, 21%), bone turnover markers/physical function/quality of life (each n = 10, 19%). Thirty-three studies (62%) reported adherence-related factors. The most frequently reported were medication beliefs (n = 8, 15%), illness perception/medication satisfaction/satisfaction with medication information (each n = 5, 9%), condition knowledge/medication knowledge/trust in doctor (each n = 3, 6%).Conclusion.The outcome domains and adherence measures in interventional studies targeting adherence are heterogeneous. Consensus on relevant outcomes will improve the comparison of different strategies to support medication adherence in rheumatology.

Objective.The Outcome Measures in Rheumatology (OMERACT) Worker Productivity Group continues efforts to assess psychometric properties of measures of presenteeism.Methods.Psychometric properties of single-item and dual answer multiitem scales were assessed, as well as methods to evaluate thresholds of meaning.Results.Test-retest reliability and construct validity of single item global measures was moderate to good. The value of measuring both degree of difficulty and amount of time with difficulty in multiitems questionnaires was confirmed. Thresholds of meaning vary depending on methods and external anchors applied.Conclusion.We have advanced our understanding of the performance of presenteeism measures and have developed approaches to describing thresholds of meaning.

Oral methotrexate (MTX) is the first-line therapy for patients with rheumatoid arthritis (RA). However, approximately one quarter of patients discontinue MTX within 12 months. MTX failure, defined as MTX cessation or the addition of another anti-rheumatic drug, is usually due adverse event(s) and/or inefficacy. The aims of this study were to evaluate the rate and predictors of oral MTX failure. Subjects were recruited from the Norfolk Arthritis Register (NOAR), a primary care-based inception cohort of patients with early inflammatory polyarthritis (IP). Subjects were eligible if they commenced MTX as their first DMARD and were recruited between 2000 and 2008. Patient-reported reasons for MTX failure were recorded and categorised as adverse event, inefficacy or other. The addition of a second DMARD during the study period was categorised as failure due to inefficacy. Cox proportional hazards regression models were used to assess potential predictors of MTX failure, accounting for competing risks. A total of 431 patients were eligible. The probability of patients remaining on MTX at 2 years was 82%. Competing risk analysis revealed that earlier MTX failure due to inefficacy was associated with rheumatoid factor (RF) positivity, younger age at symptom onset and higher baseline disease activity (DAS-28). MTX cessation due to an adverse event was less likely in the RF-positive cohort. RF-positive inflammatory polyarthritis patients who are younger with higher baseline disease activity have an increased risk of MTX failure due to inefficacy. Such patients may require combination therapy as a first-line treatment.

Methotrexate (MTX) remains the disease-modifying anti-rheumatic drug of first choice in rheumatoid arthritis (RA) but response varies. Predicting non-response to MTX could enable earlier access to alternative or additional medications and control of disease progression. We aimed to identify baseline predictors of non-response to MTX and combine these into a prediction algorithm. This study included patients recruited to the Rheumatoid Arthritis Medication Study (RAMS), a UK multi-centre prospective observational study of patients with RA or undifferentiated polyarthritis, commencing MTX for the first time. Non-response to MTX at 6 months was defined as “no response” using the European League Against Rheumatism (EULAR) response criteria, discontinuation of MTX due to inefficacy or starting biologic therapy. The association of baseline demographic, clinical and psychosocial predictors with non-response was assessed using logistic regression. Predictive performance was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots. Of 1050 patients, 449 (43%) were classified as non-responders. Independent multivariable predictors of MTX non-response (OR (95% CI)) were rheumatoid factor (RF) negativity (0.62 (0.45, 0.86) for RF positivity versus negativity), higher Health Assessment Questionnaire score (1.64 (1.25, 2.15)), higher tender joint count (1.06 (1.02, 1.10)), lower Disease Activity score in 28 joints (0.29 (0.23, 0.39)) and higher Hospital Anxiety and Depression Scale anxiety score (1.07 (1.03, 1.12)). The optimism-corrected AUC was 0.74. This is the first model for MTX non-response to be developed in a large contemporary study of patients commencing MTX in which demographic, clinical and psychosocial predictors were considered. Patient anxiety was a predictor of non-response and could be addressed at treatment commencement.

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3(p= 10−7for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Epidemiological studies have been affected by environmental (or technological and societal) changes in the last 10 years, such as the emergence of registries, big data and machine learning algorithms, epigenetics, data protection regulations or a more solid presence of the patient perspective in outcomes research. As a consequence we, epidemiologists, are facing challenges in the design, conduct, and analysis of the studies, as well as on the interpretation of the results. Not everything that is new may be better than the old ways of doing epidemiology. In this article, we will review pros and cons of new technologies and regulations on epidemiological research, as well as ways to tackle obstacles and co-living of old and new methods.

ObjectivesPain is a very common symptom of juvenile idiopathic arthritis (JIA). Disease activity alone cannot explain symptoms of pain in all children, suggesting other factors may be relevant. The objectives of this study were to describe the different patterns of pain experienced over time in children with JIA and to identify predictors of which children are likely to experience ongoing pain.MethodsThis study used longitudinal-data from patients (aged 1–16 years) with new-onset JIA. Baseline and up to 5-year follow-up pain data from the Childhood Arthritis Prospective Study (CAPS) were used. A two-step approach was adopted. First, pain trajectories were modelled using a discrete mixture model. Second, multinomial logistic regression was used to determine the association between variables and trajectories.ResultsData from 851 individuals were included (4 years, median follow-up). A three-group trajectory model was identified: consistently low pain (n=453), improved pain (n=254) and consistently high pain (n=144). Children with improved pain or consistently high pain differed on average at baseline from consistently low pain. Older age at onset, poor function/disability and longer disease duration at baseline were associated with consistently high pain compared with consistently low pain. Early increases in pain and poor function/disability were also associated with consistently high pain compared with consistently low pain.ConclusionsThis study has identified routinely collected clinical factors, which may indicate those individuals with JIA at risk of poor pain outcomes earlier in disease. Identifying those at highest risk of poor pain outcomes at disease onset may enable targeted pain management strategies to be implemented early in disease thus reducing the risk of poor pain outcomes.

Objective.The importance of contextual factors (CF) for appropriate patient-specific care is widely acknowledged. However, evidence in clinical trials on how CF influence outcomes remains sparse. The 2014 Outcome Measures in Rheumatology (OMERACT) Handbook introduced the role of CF in outcome assessment and defined them as “potential confounders and/or effect modifiers of outcomes in randomized controlled trials.” Subsequently, the CF Methods Group (CFMG) was formed to develop guidance on how to address CF in clinical trials.Methods.First, the CFMG conducted an e-mail survey of OMERACT working groups (WG) to analyze how they had addressed CF in outcome measurement so far. The results facilitated an informed discussion at the OMERACT 2016 CFMG Special Interest Group (SIG) session, with the aim of gaining preliminary consensus regarding an operational definition of CF and to make a first selection of potentially relevant CF.Results.The survey revealed that the WG had mostly used the OMERACT Handbook and/or the International Classification of Functioning, Disability and Health (ICF) definition. However, significant heterogeneity was found in the methods used to identify, refine, and categorize CF candidates. The SIG participants agreed on using the ICF as a framework along with the OMERACT Handbook definition. A list with 28 variables was collected including person-related factors and physical and social environments. Recommendations from the SIG guided the CFMG to formulate 3 preliminary projects on how to identify and analyze CF.Conclusion.New methods are urgently needed to assist researchers to identify and characterize CF that significantly influence the interpretation of results in clinical trials. The CFMG defined first steps to develop further guidance.

The contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies. A population-based Japanese cohort (n= 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands (n= 678), the United Kingdom (n= 761), and Sweden (n= 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression. In the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32–6.58). In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78–1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04–1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53–2.73). Smoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA.

Background: Haplotypes defined by amino acids at HLA-DRB1 positions 11, 71 and 74 associated with susceptibility to rheumatoid arthritis (RA) are associated with radiological outcome, anti-TNF response and all cause-mortality in RA. RA is associated with cardiovascular (CV) morbidity and mortality, but the increased prevalence of risk factors of CV disease in RA only partially explains this association. The aim of this study was to investigate whether amino acids at positions 11, 71 and 74 of HLA-DRB1 are associated with cardiovascular (CV) mortality in inflammatory polyarthritis (IP). Methods: The Norfolk Arthritis Register (NOAR) is an incidence register of IP: recruitment 1990–2007, final follow-up 2011. Two thousand five hundred fourteen patients had available genetic and mortality data. Amino acids at positions 11, 71 and 74 of HLA-DRB1 were determined. Univariate Cox proportional hazard models were applied to assess the association of genetic markers and both all-cause mortality and cardiovascular mortality. Results: Among 2514 participants, 643 (25.6%) died during the study, and 343 (53.3%) of these deaths were attributed to CV causes. One thousand six hundred fifty (65.6%) participants were female, 709 (32.3%) were anti-CCP-positive and the median age of participants was 54. Conclusions: HLA-DRB1 haplotypes associated with susceptibility to RA also predispose to increased risk of CV mortality in IP, independent of known CV risk factors. Associations were independent of anti-CCP status, which suggests in the future, genetic factors will add to the prediction of risk of cardiovascular mortality beyond serological markers.

Objective.Indicators of work role functioning (being at work, and being productive while at work) are important outcomes for persons with arthritis. As the worker productivity working group at OMERACT (Outcome Measures in Rheumatology), we sought to provide an evidence base for consensus on standardized instruments to measure worker productivity [both absenteeism and at-work productivity (presenteeism) as well as critical contextual factors].Methods.Literature reviews and primary studies were done and reported to the OMERACT 12 (2014) meeting to build the OMERACT Filter 2.0 evidence for worker productivity outcome measurement instruments. Contextual factor domains that could have an effect on scores on worker productivity instruments were identified by nominal group techniques, and strength of influence was further assessed by literature review.Results.At OMERACT 9 (2008), we identified 6 candidate measures of absenteeism, which received 94% endorsement at the plenary vote. At OMERACT 11 (2012) we received over the required minimum vote of 70% for endorsement of 2 at-work productivity loss measures. During OMERACT 12 (2014), out of 4 measures of at-work productivity loss, 3 (1 global; 2 multiitem) received support as having passed the OMERACT Filter with over 70% of the plenary vote. In addition, 3 contextual factor domains received a 95% vote to explore their validity as core contextual factors: nature of work, work accommodation, and workplace support.Conclusion.Our current recommendations for at-work productivity loss measures are: WALS (Workplace Activity Limitations Scale), WLQ PDmod (Work Limitations Questionnaire with modified physical demands scale), WAI (Work Ability Index), WPS (Arthritis-specific Work Productivity Survey), and WPAI (Work Productivity and Activity Impairment Questionnaire). Our future research focus will shift to confirming core contextual factors to consider in the measurement of worker productivity.

Objective.Several global measures to assess at-work productivity loss or presenteeism in patients with rheumatic diseases have been proposed, but the comparative validity is hampered by the lack of data on test-retest reliability and comparative concurrent and construct validity. Our objective was to test-retest 5 global measures of presenteeism and to compare the association between these scales and health-related well-being.Methods.Sixty-five participants with inflammatory arthritis or osteoarthritis in paid employment were recruited from 7 countries (UK, Canada, Netherlands, France, Sweden, Romania, and Italy). At baseline and 2 weeks later, 5 global measures of presenteeism were evaluated: the Work Productivity Scale–Rheumatoid Arthritis (WPS-RA), Work Productivity and Activity Impairment Questionnaire (WPAI), Work Ability Index (WAI), Quality and Quantity questionnaire (QQ), and the WHO Health and Performance Questionnaire (HPQ). Agreement between the 2 timepoints was assessed using single-measure intraclass correlations (ICC) and correlated between each other and with visual analog scale general well-being scores at followup by Spearman correlation.Results.ICC between measures ranged from fair (HPQ 0.59) to excellent (WPS-RA 0.78). Spearman correlations between measures were moderate (Qqualityvs WAI, r = 0.51) to strong (WPS-RA vs WPAI, r = 0.88). Correlations between measures and general well-being were low to moderate, ranging from −0.44 ≤ r ≤ 0.66.Conclusion.Test-retest results of 4 out of 5 global measures were good, and the correlations between these were moderate. The latter probably reflect differences in the concepts, recall periods, and references used in the measures, which implies that some measures are probably not interchangeable.

Biologic therapies are efficacious but costly. A number of health economic models have been developed to determine the most cost-effective way of using them in the treatment pathway. These models have produced conflicting results, driven by differences in assumptions, model structure, and data, which undermine the credibility of funding decisions based on modeling studies. A Consensus Working Party met to discuss recommendations and approaches for future models of biologic therapies. Our working party consisted of clinical specialists, modelers, and policy makers. Two 1-day meetings were held for members to arrive at consensus positions on model structure, assumptions, and appropriate data sources. These views were guided by clinical aspects of rheumatoid and psoriatic arthritis and the principles of evidence-based medicine. Where opinions differed, we sought to identify a research agenda that would generate the evidence needed to reach consensus. We gained consensus in four areas of model development: initial response to treatment; long-term disease progression; lifetime costs and benefits; and model structure. Consensus was also achieved on some key parameters such as choices of outcome measures, methods for extrapolation beyond trial data, and treatment switching. A research agenda to support further consensus was also identified. Consensus guidance that fully reflects current evidence and clinical understanding was gained successfully. In addition, research needs have been identified. Such guidance can be updated as evidence develops and policy questions change and need not be prescriptive as long as deviations from consensus are clearly explained and justified. Arthritis Research UK and the UK Medical Research Council Network of Hubs for Trials Methodology Research.

Comparisons of data from different registries can be helpful in understanding variations in many aspects of rheumatoid arthritis (RA). The study aim was to assess and improve the comparability of demographic, clinical, and comorbidity data from 5 international RA registries. Using predefined definitions, 2 subsets of patients (main cohort and subcohort) from 5 international observational registries (Consortium of Rheumatology Researchers of North America Registry [CORRONA], the Swedish Rheumatology Quality of Care Register [SRR], the Norfolk Arthritis Register [NOAR], the Institute of Rheumatology Rheumatoid Arthritis cohort [IORRA], and CORRONA International) were evaluated and compared. Patients ages >18 years with RA, and present in or recruited to the registry from January 1, 2000, were included in the main cohort. Patients from the main cohort with positive rheumatoid factor and/or erosive RA who had received ≥1 synthetic disease‐modifying antirheumatic drug (DMARD), and switched to or added another DMARD, were included in the subcohort at time of treatment switch. Age and sex distributions were fairly similar across the registries. The percentage of patients with a high Disease Activity Score in 28 joints score varied between main cohorts (17.5% IORRA, 18.9% CORRONA, 24.7% NOAR, 27.7% CORRONA International, and 36.8% SRR), with IORRA, CORRONA, and CORRONA International including more prevalent cases of RA; the differences were smaller for the subcohort. Prevalence of comorbidities varied across registries (e.g., coronary artery disease ranged from 1.5% in IORRA to 7.9% in SRR), partly due to the way comorbidity data were captured and general cultural differences; the pattern was similar for the subcohorts. Despite different inclusion criteria for the individual RA registries, it is possible to improve the comparability and interpretability of differences across RA registries by applying well‐defined cohort definitions.

To review the literature on contextual factors (CoFas) and their relationship to work outcomes in individuals with ankylosing spondylitis (AS). Articles that quantified the relationship between CoFas and employment status, sick leave, or presenteeism in individuals with AS were systematically identified. CoFas were classified into 5 domains for personal factors and 8 domains for environmental factors. We defined criteria for best‐evidence synthesis for each CoFa domain based on the number of studies exploring that domain, and the quality of evidence of individual studies based on the risk of bias, adjustment of multivariable analyses for disease activity and physical function, and sample size. Twenty‐five studies met our inclusion criteria: 20 addressed employment status, 6 examined sick leave, and 3 presenteeism. For employment, there was strong evidence for the role of age, moderate evidence for related skills/abilities, the absence of work accommodations, the nature of work and absence of workplace support, and poor evidence for the role of marital status. Evidence was insufficient for sex, education, and physical environment. For sick leave and presenteeism there were too few studies to perform a best‐evidence synthesis for the role of CoFas. Using a newly proposed set of criteria for determining the best‐evidence of the association between CoFa domains and work outcome, the following factors emerged: age, related skills/abilities, work accommodations, nature of work, and workplace support. In addition to disease‐related variables, these CoFa domains seem important to include when designing and interpreting studies on work outcomes.

For patients with rheumatoid arthritis (RA), being in paid work is very important, and it increases self-esteem and financial independence. Although the management of RA has changed in the last 15 years to early aggressive treatment and the introduction of biologic treatments, many patients still have to take sick leave or even stop working because of their RA (i.e., absenteeism). For those remaining in paid work, patients may experience problems due to RA resulting in productivity loss while at work (i.e., presenteeism). The costs attributed to absenteeism and presenteeism (i.e., indirect costs) have been estimated to be very high, and they even exceed direct costs. However, there is no consensus on how to calculate these costs. This manuscript examines the relationship between the use of biologic therapy and absenteeism, with a focus on sick leave, and on presenteeism, and it provides an overview of indirect costs of absenteeism and presenteeism in those treated with biologic therapies.

Objective.Fatigue is common and burdensome in rheumatoid arthritis (RA). Despite RA fatigue progression varying significantly between individuals in practice, existing longitudinal analyses only examine symptom advancement on a population level. This study aimed to determine fatigue trajectories at an individual level and to characterize those patients with the poorest prognosis, with a view to enabling earlier interventions.Methods.Patients with RA reporting clinically relevant baseline fatigue (≥ 20 mm on a 0–100 mm visual analog scale) were identified from a longterm inflammatory polyarthritis cohort (the Norfolk Arthritis Register). Fatigue changes from baseline to 1- and 4-year followups were calculated, and sex-stratified group-based trajectory modeling (GBTM) determined trajectories of the symptom between which baseline characteristics were compared.Results.Among 338 patients, only minimal average changes were observed between recruitment to 1 year (6.0 mm, SD 26.9) and 4 years (5.5 mm, SD 29.3). This was despite 45.6% and 40.7% of participants reporting clinically significant improvements (≥ 10 mm) at these respective followups. GBTM revealed varied trajectories of fatigue, which for both sexes consisted of Improved (men, n = 48 and women, n = 81) or persistent Moderate-high paths (n = 54, n = 105), and further included a persistent High trajectory in women (n = 50). Participants who followed persistent trajectories were best distinguished from improvers by patient-reported rather than demographic or clinical variables.Conclusion.Among patients with RA presenting with clinically relevant fatigue, distinct longitudinal symptom trajectories were identified on an individual level despite nominal average changes in fatigue on a group level. It is possible to identify and characterize subgroups of participants who report persistent fatigue and should therefore be targeted to receive future fatigue-alleviating interventions.

Objectives.To explore the change in direct medical costs associated with inflammatory polyarthritis (IP) 10 to 15 years after its onset.Methods.Patients from the Norfolk Arthritis Register who had previously participated in a health economic study in 1999 were traced 10 years later and invited to participate in a further prospective questionnaire-based study. The study was designed to identify direct medical costs and changes in health status over a 6-month period using previously validated questionnaires as the primary source of data.Results.A representative sample of 101 patients with IP from the 1999 cohort provided complete data over the 6-month period. The mean disease duration was 14 years (SD 2.1, median 13.6, interquartile range 12.6–15.4). The mean direct medical cost per patient over the 6-month period was £1496 for IP (inflated for 2013 prices). This compared with £582 (95% CI £355–£964) inflated to 2013 prices per patient with IP 10 years earlier in their disease. The increased cost was largely associated with the use of biologics in the rheumatoid arthritis subgroup of patients (51% of total costs incurred). Other direct cost components included primary care costs (11%), hospital outpatient (19%), day care (12%), and inpatient stay (4%).Conclusion.The direct healthcare costs associated with IP have more than doubled with increasing disease duration, largely as a result of the use of biologics. The results showed a shift in the direct health costs from inpatient to outpatient service use.

This study aimed to investigate rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status and levels as predictors of mortality in two large cohorts of patients with early inflammatory arthritis (EIA). Data from the Norfolk Arthritis Register (NOAR) and Leiden Early Arthritis Clinic (EAC) cohorts were used. At baseline, patients had demographic data and smoking status recorded; RF, ACPA and inflammatory markers were measured in the local laboratories. Patients were flagged with national death registers until death or censor date. Antibody status was stratified as negative, low or high positive by RF and ACPA levels individually. In addition, patients were grouped as seronegative, RF positive, ACPA positive or double antibody (RF and ACPA) positive. Cox regression models explored associations between antibody status and mortality adjusting for age, sex, smoking status, inflammatory markers and year of enrolment. A total of 4962 patients were included, 64% were female. Median age at onset was 56 (NOAR) and 54 (EAC) years. In NOAR and EAC respectively, 35% and 42% of patients were ACPA/RF positive. When antibody status was stratified as negative, low or high positive, there were no consistent findings between the two cohorts. Double antibody positivity was associated with excess mortality in both cohorts compared to seronegative patients: NOAR and EAC respective adjusted HR (95% confidence interval) 1.35 (1.09 to 1.68) and 1.58 (1.16 to 2.15). Patients with EIA who are seropositive for both RF and ACPA have increased mortality compared to those who are single positive or seronegative. Antibody level in seropositive patients was not consistently associated with excess mortality.

Objective.To examine the pattern of disease severity in patients with rheumatoid arthritis (RA) at presentation to the Norfolk Arthritis Register (NOAR) over 20 years.Methods.NOAR is a primary-care–based cohort of patients with recent-onset inflammatory polyarthritis. At baseline, subjects are assessed and examined by a research nurse. The Health Assessment Questionnaire (HAQ) is administered and the DAS28 (28-joint Disease Activity Score) is calculated. Information is collected on disease-modifying antirheumatic drug exposure. In this study, patients (symptom duration of < 2 years at baseline) were grouped into 4 cohorts (Cohort 1: 1990–1994; Cohort 2: 1995–1999; Cohort 3: 2000–2004; Cohort 4: 2005–2008). The American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 criteria for RA were applied retrospectively at baseline. Regression analyses were used to examine whether calendar year of presentation to NOAR was associated with baseline HAQ and DAS28 scores. Potential confounders included age at symptom onset, sex, rheumatoid factor, and anticyclic citrullinated peptide antibody positivity.Results.A total of 1724 patients met the ACR/EULAR 2010 RA criteria at baseline. Unadjusted mean DAS28 scores decreased over time. Calendar year of presentation to NOAR was significantly associated with lower DAS28 scores over time [Y = 4.51 + (–0.56 × year) + (0.44 × year2)]. Although unadjusted median HAQ scores increased over time, calendar year of presentation to NOAR was not significantly associated with HAQ scores [Y = (1.1) + (0.023 × year) + (0.05 × year2)]. Similar results were observed in each subpopulation of patients.Conclusion.While baseline disease activity has lessened slightly over time, there has been no improvement in baseline levels of functional disability.

The objective of the Outcome Measures in Rheumatology (OMERACT) Worker Productivity working group is to identify worker productivity outcome measures that meet the requirements of the OMERACT filter. At the OMERACT 11 Workshop, we focused on the at-work limitations/productivity component of worker productivity (i.e., presenteeism) — an area with diverse conceptualization and instrumentation approaches. Various approaches to quantify at-work limitations/productivity (e.g., single-item global and multi-item measures) were examined, and available evidence pertaining to OMERACT truth, discrimination, and feasibility were presented to conference participants. Four candidate global measures of presenteeism were put forth for a plenary vote to determine whether current evidence meets the OMERACT filter requirements. Presenteeism globals from the Work Productivity and Activity Impairment Questionnaire (72% support) and Rheumatoid Arthritis-specific Work Productivity Survey (71% support) were endorsed by conference participants; however, neither the presenteeism global item from the Health and Work Performance Questionnaire nor the Quantity and Quality method achieved the level of support required for endorsement at the present time. The plenary was also asked whether the central item from the Work Ability Index should also be considered as a candidate measure for potential endorsement in the future. Of participants at the plenary, 70% supported this presenteeism global measure. Progress was also made in other areas through discussions at individual breakout sessions. Topics examined include the merits of various multi-item measures of at-work limitations/productivity, methodological issues related to interpretability of outcome scores, and approaches to appraise and classify contextual factors of worker productivity. Feedback gathered from conference participants will inform the future research agenda of the working group.

With the establishment of the new American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 criteria for rheumatoid arthritis (RA) to diagnose patients earlier and with the introduction of early and aggressive treatment, the current aim is remission resulting in less functional disability, halting of radiographic damage, less pain, less fatigue and no loss of employment. These outcomes can be related to the World Health Organization International Classification of Functioning, Disability and Health (the WHO ICF framework). This framework includes the component body functions, body structures, activities and participation related to the disease. These components are related to each other in a bidirectional way and can be influenced by contextual factors including environmental and personal factors. This framework can be used to describe trends in RA outcomes and the impact of contextual factors on these outcomes. Despite aggressive treatment strategies, patients with RA still experience loss of function, pain and fatigue, and a relatively high proportion of patients have to take sick leave or become work disabled within the first few years of the disease. There is evidence that more stringent definitions of remission lead to greater improvement of outcomes and that the aim should be sustained remission and not just remission. There is, however, a need for a better understanding of the relation between contextual factors and activity and participation outcomes to better guide therapy decisions by rheumatologists and provide information to patients, families and policymakers about the impact of RA on their lives and to the society. The overall aim of this overview is to highlight the important contextual factors and consequences that relate to outcomes typically measured in RA studies and to demonstrate the additional benefits that can be achieved with remission and sustained remission.

OBJECTIVE: To explore the influence of tender points (TP) on the Disease Activity Score assessing 28 joints (DAS28) in patients with rheumatoid arthritis (RA). METHODS: In 200 consecutive patients with RA from the outpatient clinic, DAS28 and its components, tender and swollen joint counts (TJC, SJC, respectively), visual analog scale (VAS) for patient’s general health (GH), and erythrocyte sedimentation rate (ESR), along with a tender point count (TPC) were assessed. Patients were categorized according to 4 TPC classes: zero, 1–5, 6–10, and ≥ 11 TP. The influence of TPC classes on DAS28 and its individual components was determined with Kruskal-Wallis tests and correlations between TP and DAS28 and its components were calculated. RESULTS: In 196 eligible patients, 70% were female, mean age was 59 years, and median disease duration was 3.9 years; median DAS28 was 3.1; and 49% had active disease, defined as DAS28 > 3.2. In 15% of patients, the TPC was ≥ 11, in 12% 6–10, in 30% 1–5, and in 43% zero. TPC significantly influenced the DAS28 and its less objective components TJC and VAS-GH (i.e., based on patient’s report), but not the more objective DAS28 components SJC and ESR (i.e., observer- and laboratory-based). CONCLUSION: DAS28 is influenced by tender points, even in the non-fibromyalgia range, falsely suggesting higher disease activity and decreasing the sensitivity of the DAS28 criterion of low disease activity or remission. When applying DAS28-guided "tight control" or "treat-to-target" treatment strategies in RA, evaluation of not only the DAS28, but also its individual components along with a full joint and physical evaluation including assessment of TP is required to reliably estimate the individual’s disease activity, which guides therapeutic decisions.

Patients with established rheumatoid arthritis (RA) may incur important resource utilisation and work productivity loss, resulting in high costs of illness. Impairment in physical function, which increases with disease duration, is the main variable driving all aspects of these costs. The large variation of costs across administrations is a complex issue and results not only from differences in access to and provision of care but also from absolute differences in the prices for health-care or loss of paid work. Despite the major effects of biologicals on almost all aspects of health, the literature shows that in established RA, the cost–utility ratios are high when compared to adjusting or switching non-biological disease-modifying anti-rheumatic drugs (DMARD) sequences. Until the prices of the biologicals can be reduced, the challenge for optimising the use of biologicals in treatment sequences in RA is to improve selection of patients that would be unresponsive to non-biological DMARDs in an early phase of the disease and identification of patient groups in which biologicals can be successfully stopped.

There are secular trends in improvement in disease activity and X-ray damage at baseline and cross-sectionally in prevalent cases of rheumatoid arthritis (RA) in recent years. These changes should translate into improved physical function and mortality, but evidence for this is lacking, perhaps because the mean age at RA diagnosis and of prevalent cases is increasing, mainly as a consequence of demographic changes. This trend is accompanied by an increasing prevalence of co-morbidities, in particular cardiovascular and respiratory disease. The higher prevalence of smoking, diabetes and physical inactivity in RA cases contributes to the burden of co-morbidity. Predictors of poorer treatment response and thus a worse prognosis include female gender, being a smoker, autoantibody positivity, high baseline disease activity and co-morbidities such as depression. There is a need for better understanding of predictors of treatment response to guide the right choice of therapy and thus improve outcome further.

Leading up to the Outcome Measures in Rheumatology (OMERACT) 10 meeting, the goal of the Worker Productivity Special Interest Group (WP-SIG) was to make progress on 3 key issues that relate to the application and interpretation of worker productivity outcomes in arthritis: (1) to review existing conceptual frameworks to help consolidate our intended target and scope of measurement; (2) to examine the methodologic issues associated with our goal of combining multiple indicators of worker productivity loss (e.g., absenteeism <—> presenteeism) into a single comprehensive outcome; and (3) to examine the relevant contextual factors of work and potential implications for the interpretation of scores derived from existing outcome measures. Progress was made on all 3 issues at OMERACT 10. We identified 3 theoretical frameworks that offered unique but converging perspectives on worker productivity loss and/or work disability to provide guidance with classification, selection, and future recommendation of outcomes. Several measurement and analytic approaches to combine absenteeism and presenteeism outcomes were proposed, and the need for further validation of such approaches was also recognized. Finally, participants at the WP-SIG were engaged to brainstorm and provide preliminary endorsements to support key contextual factors of worker productivity through an anonymous "dot voting" exercise. A total of 24 specific factors were identified, with 16 receiving ≥ 1 vote among members, reflecting highly diverse views on specific factors that were considered most important. Moving forward, further progress on these issues remains a priority to help inform the best application of worker productivity outcomes in arthritis research.

OBJECTIVE: To identify disease activity, smoking, and reproductive-related predictors of a poor prognosis in patients with very early inflammatory polyarthritis (IP). METHODS: Patients with very early IP (symptom duration 4–11 weeks) included in our study were participants in the STIVEA (Steroids In Very Early Arthritis) randomized placebo-controlled trial. At baseline, disease-related variables were measured and patients were asked to complete a questionnaire covering smoking status and reproductive questions. Baseline predictors of poor prognosis [i.e., the need to start disease-modifying antirheumatic drug (DMARD) therapy by 6 months or the clinical diagnosis of rheumatoid arthritis (RA) at 12 months] were identified, applying logistic regression analyses adjusted for treatment group. RESULTS: Rheumatoid factor (RF) positivity was one of the strongest clinical predictors of a poor prognosis: OR for DMARD therapy at 6 months, 4.00 (95% CI 2.00–8.00) and OR for a diagnosis of RA at 12 months, 9.48 (95% CI 4.48–20.07). There was a significant association between current smoking at baseline compared to never smoking and a diagnosis of RA at 12 months (OR 3.15, 95% CI 1.16–8.56). CONCLUSION: About 6 in 7 patients with very early RF-positive IP were diagnosed with RA 1 year later. In addition, 1 in 4 IP patients who smoke will develop RA later. It is recommended to treat RF-positive patients who have IP with DMARD at presentation and to advise patients to stop smoking.

OBJECTIVE: To investigate basic assumptions of prediction models for future vertebral fractures. METHODS: Lateral radiographs of the spine were obtained from 314 Portuguese individuals aged 60 years or older (205 women and 109 men) with bone mineral density (BMD) measurements at several sites. Associations between BMD at various sites, participant characteristics, and vertebral fractures were investigated. For men and women separately, logistic regression analyses and analyses of areas under the receiver-operating characteristic (ROC) curves were performed to determine the accuracy of BMD measurment at predicting the presence of vertebral deformities. RESULTS: BMD measurements at all sites significantly predicted the presence of osteoporotic vertebral deformities in women but not in men. Similarly, in analyses of areas under ROC curves, BMD assessments were statistically significantly related to vertebral deformities in women but not in men. In multivariate analyses, BMD measurements of the lumbar spine and of the forearm, adjusted for gender, age, and body mass index, significantly predicted the presence of vertebral deformity, but BMD of the hip sites did not. CONCLUSION: Prediction of fractures is specific for gender and site of BMD measurement. This challenges the use of similar algorithms for men and women as well as the use of hip BMD data to accurately estimate future vertebral fracture risk.

OBJECTIVE: To evaluate the association between clinical, demographic, and psychological factors and the functional Health Assessment Questionnaire (HAQ) and psychological HAQ (PSHAQ) in patients with rheumatoid arthritis (RA). METHODS: After a mean followup time of 7 years after diagnosis, 112 patients with RA were asked to fill out the HAQ and the PSHAQ. Several clinical variables [erythrocyte sedimentation rate (ESR), visual analog scale (VAS) pain, VAS general well-being, Thompson joint score, and morning stiffness] had been assessed at diagnosis and at followup. In addition, the Impact of Rheumatic diseases on General health and Lifestyle questionnaire, comprising different domains of psychological distress, was assessed at diagnosis. Spearman correlations were calculated to determine associations between functional HAQ and clinical and psychological variables at baseline and to determine the associations between clinical variables and the HAQ and PSHAQ score at followup. Univariate logistic regression analyses were performed to identify possible predictors at diagnosis for a worse HAQ score and PSHAQ score (score > 1) at followup. RESULTS: At followup the functional HAQ score was associated with all clinical variables, whereas the PSHAQ was only associated with more subjective patient related variables (VAS pain, VAS general well-being, and morning stiffness). The final model of the multivariate regression analyses to predict a worse HAQ score at followup only included worse functional ability [odds ratio (OR) 2.63, 95% confidence interval (CI) 1.30-5.32, p = 0.007]. Anxiety (OR 1.13, 95% CI 1.03-1.24, p = 0.007) and a lower ESR value (OR 0.98, 95% CI 0.96-1.00, p = 0.05) assessed at diagnosis were included into the final model as predictors for a high PSHAQ score. CONCLUSION: Overall, the HAQ score, reflecting limitations of daily functioning, is a good representation of disease activity at diagnosis and after a mean disease duration of 7 years, whereas PSHAQ is not.

Consistent evidence suggests a relationship between lower educational attainment and total obesity defined using body mass index (BMI); however, a comparison of the relationships between educational attainment and total obesity (BMI ≥30 kg/m2) and central obesity (waist circumference (WC) > 102 cm for men and WC > 88 cm for women) has yet to be carried out. This systematic literature review (SLR) and meta-analyses aimed to understand whether i) the associations between education and obesity are different depending on the measures of obesity used (BMI and WC), and ii) to explore whether these relationships differ by gender and region.

Musculoskeletal (MSK) diseases occur commonly in the community, comprising approximately 20% of UK primary care consultations. The term encompasses a wide range of mechanical and inflammatory disorders, and although they can occur at any stage of life, even in young children, they increase in prevalence with age. As well as being common, they are associated with significant morbidity through disability, and cause the second most years lived with disability globally after mental health disorders. As a result, MSK disorders have significant financial consequences for the individual and society. This ‘cost of MSK disease’ includes not only cost to the health service in terms of primary and secondary care appointments, treatments and surgical interventions, but also loss to the economy including absenteeism from work and presenteeism; further costs relate to social care, both formal and informal from family and friends. Finally, many MSK diseases are associated with reduced life expectancy, which is often underestimated because of the long-term nature of the conditions.

Rheumatoid arthritis (RA) is associated with pain, disability and increased risk of developing comorbidities and premature mortality. While these poor outcomes have improved in line with advances in the treatment of RA, they still persist to some degree today. Physical activity and smoking are two areas of patients’ lives where changes may have a substantial impact on the poor outcomes associated with RA. Physical activity in RA has been well studied, with many randomised trials indicating the benefits of physical activity on pain and disability. A number of observational studies have assessed the impact of smoking on RA, also indicating the benefits of quitting smoking on RA-related outcomes, but with less consistent findings, potentially due to epidemiological challenges (e.g. collider bias, recall bias). There are also a number of barriers preventing patients making these positive lifestyle changes, such as lack of time and motivation, lack of knowledge and advice, as well as disease-specific barriers, such as pain and fatigue.

Anti-citrullinated protein antibodies (ACPA) predict increased disease activity and disability in patients with inflammatory arthritis such as rheumatoid arthritis. However, the absence of these antibodies does not confer universally good prognosis. Recently, a new set of antibodies, anti-carbamylated (anti-CarP) antibodies, have been identified in patients with rheumatoid arthritis. This study aimed to investigate the association between anti-CarP antibodies, disability, and disease activity in these patients.