The effects of an evidence- and theory-informed feedback intervention on opioid prescribing for non-cancer pain in primary care: A controlled interrupted time series analysis.

BACKGROUND: The rise in opioid prescribing in primary care represents a significant international public health challenge, associated with increased psychosocial problems, hospitalisations, and mortality. We evaluated the effects of a comparative feedback intervention with persuasive messaging and action planning on opioid prescribing in primary care. METHODS AND FINDINGS: A quasi-experimental controlled interrupted time series analysis used anonymised, aggregated practice data from electronic health records and prescribing data from publicly available sources. The study included 316 intervention and 130 control primary care practices in the Yorkshire and Humber region, UK, serving 2.2 million and 1 million residents, respectively. We observed the number of adult patients prescribed opioid medication by practice between July 2013 and December 2017. We excluded adults with coded cancer or drug dependency. The intervention, the Campaign to Reduce Opioid Prescribing (CROP), entailed bimonthly, comparative, and practice-individualised feedback reports to practices, with persuasive messaging and suggested actions over 1 year. Outcomes comprised the number of adults per 1,000 adults per month prescribed any opioid (main outcome), prescribed strong opioids, prescribed opioids in high-risk groups, prescribed other analgesics, and referred to musculoskeletal services. The number of adults prescribed any opioid rose pre-intervention in both intervention and control practices, by 0.18 (95% CI 0.11, 0.25) and 0.36 (95% CI 0.27, 0.46) per 1,000 adults per month, respectively. During the intervention period, prescribing per 1,000 adults fell in intervention practices (change -0.11; 95% CI -0.30, -0.08) and continued rising in control practices (change 0.54; 95% CI 0.29, 0.78), with a difference of -0.65 per 1,000 patients (95% CI -0.96, -0.34), corresponding to 15,000 fewer patients prescribed opioids. These trends continued post-intervention, although at slower rates. Prescribing of strong opioids, total opioid prescriptions, and prescribing in high-risk patient groups also generally fell. Prescribing of other analgesics fell whilst musculoskeletal referrals did not rise. Effects were attenuated after feedback ceased. Study limitations include being limited to 1 region in the UK, possible coding errors in routine data, being unable to fully account for concurrent interventions, and uncertainties over how general practices actually used the feedback reports and whether reductions in prescribing were always clinically appropriate. CONCLUSIONS: Repeated comparative feedback offers a promising and relatively efficient population-level approach to reduce opioid prescribing in primary care, including prescribing of strong opioids and prescribing in high-risk patient groups. Such feedback may also prompt clinicians to reconsider prescribing other medicines associated with chronic pain, without causing a rise in referrals to musculoskeletal clinics. Feedback may need to be sustained for maximum effect.

Geographical inequalities in uptake of NHS funded eye examinations: Poisson modelling of small-area data for Essex, UK.

Background: Small-area analysis of National Health Service (NHS)-funded sight test uptake in Leeds showed significant inequalities in access among people aged <16 or ≥60. Methods: Data were extracted from 604 126 valid General Ophthalmic Services (GOS)1 claim forms for eye examinations for Essex residents between October 2013 and July 2015. Expected GOS1 uptake for each lower super output area was based on England annual uptake. Poisson regression modelling explored associations in GOS1 uptake ratio with deprivation. Results: People aged ≥60 or <16 living in the least deprived quintile were 15% and 26%, respectively, more likely to have an NHS funded eye examination than the most deprived quintile, although all are equally entitled. GOS1 uptake is higher in the more deprived quintiles among 16-59-year old, as means tested social benefits are the main eligibility criteria in this age-group. Inequalities were also observed at local authority level. Conclusions: Inequalities in access among people ≥60 years were not as large as those reported in Leeds, although inequalities in <16-year old were similar. However, demonstrable inequalities in this data set over a longer time period and a larger and more diverse area than Leeds, reinforce the argument that interventions are needed to address eye examination uptake inequalities.

Association between Clostridium difficile infection and antimicrobial usage in a large group of English hospitals.

AIMS: This study aimed to determine the association between the reduction in the number of Clostridium difficile infection (CDI) cases reported by the English National Health Service (NHS) hospitals and concurrent antimicrobial use. METHODS: A retrospective ecological study for January 2005 to December 2008 was conducted using data from 26 of the 29 NHS trusts (i.e. a trust manages one or more hospitals) located in the North West Strategic Health Authority of England. Antimicrobial use data, for patients of all ages, were provided by IMS Health, and CDI case data for patients aged ≥65 years were provided by the Health Protection Agency. Antimicrobial use was converted into defined daily doses (DDDs). The overall association between antimicrobial use and CDI for the trusts was investigated using multilevel models. RESULTS: Our study shows a positive significant association between the CDI cases and the use of the following antimicrobials: 'third-generation cephalosporins' [11.62 CDI cases per 1000 DDDs; 95% confidence interval (CI), 5.92­17.31]; 'fluoroquinolones' (4.79 CDI cases per 1000 DDDs; 95% CI, 2.83­6.74); and 'second-generation cephalosporins' (4.25 CDI cases per 1000 DDDs; 95% CI, 1.66­6.83). The strength of this association was not significantly different (95% CI) among the antimicrobial groups. CONCLUSIONS: This study shows that the reduction in the number of CDI cases reported by the English NHS hospitals is associated with concurrent reductions in antimicrobial use. This means that the number of CDI cases over time decreased in a similar fashion to the usage of various antimicrobials.

Early treatment with, and time receiving, first disease-modifying antirheumatic drug predicts long-term function in patients with inflammatory polyarthritis.

OBJECTIVES: To investigate the influence of early disease-modifying antirheumatic drug (DMARD) treatment on long-term functional outcome in patients with recent-onset inflammatory polyarthritis (IP), and the impact of the duration of first and subsequent DMARD treatment. METHODS: 642 subjects from a primary care registry of patients with new-onset IP, recruited 1990-4, were followed up for 10 years. Mean change in Health Assessment Questionnaire (HAQ) scores between baseline and 10 years were compared by time to, and time receiving, first DMARD treatment and total time receiving treatment, using linear regression. Adjustment for time-dependent confounders and censoring was performed using marginal structural weights. RESULTS: When adjusted for baseline and subsequent disease severity, those treated early (<6 months from symptom onset) experienced a non-significant improvement in function compared with those never treated (adjusted mean difference in change (adj_MDIC) in HAQ -0.24; 95% CI -0.58 to 0.09); and a significant benefit for each additional month of treatment within 6 months of the onset of symptoms (adj_MDIC -0.10; 95% CI -0.19 to -0.02). Patients who discontinued their first DMARD within 6 months experienced a significant deterioration in long-term function (adj_MDIC in HAQ 0.28; 95% CI 0.04 to 0.52), while those who continued their first treatment for > 3 years experienced an improvement (adj_MDIC in HAQ -0.37; 95% CI -0.77 to 0.04). CONCLUSIONS: The importance of time to, and response to, first DMARD treatment and total duration of DMARD treatment in modifying the 10-year function in patients with IP has been demonstrated.

Excess risk of hospital admission for cardiovascular disease within the first 7 years from onset of inflammatory polyarthritis.

SUBJECTS: with rheumatoid factor positive inflammatory polyarthritis (IP) are known to have increased mortality from cardiovascular disease (CVD). A study was undertaken to examine the risk and baseline predictors of admission with CVD in patients with recent-onset IP. METHODS: Subjects are recruited by the Norfolk Arthritis Register if they present to primary or secondary care with > or =2 swollen joints lasting > or =4 weeks. This analysis includes subjects recruited between 1995 and 1999. Baseline data on lifestyle, demographic characteristics, disease and treatment characteristics were collected. CVD admissions were identified through record linkage with the only acute care hospital in the study region. First-episode hospitalisation rates were compared with those of the general population. Poisson regression was used to calculate the relative risk (RR) of admission for patients with IP (overall and for each risk factor). Death certificates were obtained from the national death register. RESULTS: 800 patients with recent-onset IP were followed for a median of 7.0 years. 64 CVD-related hospitalisations were observed (11.7 per 1000 person-years). Patients with IP were twice as likely (RR=2.0; 95% CI 1.5 to 2.5) to be hospitalised for CVD as the general population. Difficulty walking at baseline was a significant predictor of CVD admission and baseline non-steroidal anti-inflammatory drug use was associated with a reduced risk of CVD admission. CONCLUSIONS: Patients with IP are at increased risk of CVD-related hospitalisation, within 7 years of symptom onset. Informing patients about lifestyle modification may reduce the risk of CVD.

Predictors of response to anti-TNF therapy in ankylosing spondylitis: results from the British Society for Rheumatology Biologics Register.

OBJECTIVE: Few data exist on the use of anti-TNF drugs for AS during routine clinical use in the UK. This report describes an improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) after 6 months of therapy in 261 patients enrolled in a national prospective observational register. METHODS: The British Society for Rheumatology Biologics Register (BSRBR) recruited patients starting anti-TNF therapy for AS between 2002 and 2006. Multivariable linear regression models were used to estimate the predictors of absolute improvement in BASDAI and BASFI at 6 months. Covariates included age, gender, disease duration, baseline BASDAI and BASFI, presence of raised inflammatory markers (defined as twice the upper limit of normal) and DMARD therapy. RESULTS: The cohort was young (median age 43 years) and 82% were males. Median baseline BASDAI was 7.6 and BASFI 7.9. At 6 months, the mean improvements in BASDAI and BASFI were 3.6 and 2.6 U, respectively; 52% reached a BASDAI50. Patients with raised inflammatory markers at the start of therapy had a 0.9-U (95% CI 0.2, 1.5) better improvement in BASDAI compared with those without. Lesser responses were seen in those with higher baseline BASFI scores. Women had a 1.1-U (95% CI 0.3, 2.0) greater improvement in BASFI at 6 months, as did those who were receiving concurrent DMARD therapy [0.9 U (95% CI 0.2, 1.7)]. CONCLUSIONS: The majority of patients receiving anti-TNF therapy for AS during routine care demonstrated an improvement in disease activity. Raised inflammatory markers at the start of therapy predicted a greater improvement in BASDAI, identifying a group of patients who may be more responsive to anti-TNF therapies, although the results were not confined to this group.

Why do patients with inflammatory arthritis often score states "worse than death" on the EQ-5D? An Investigation of the EQ-5D classification system.

OBJECTIVE: Using inflammatory arthritis patients as an example, we investigate EuroQol-5D (EQ-5D) profiles resulting in states worse than death (WTD), and the heath status of patients occupying these states. METHODS: Baseline data from two UK trials were used that reflected the range of arthritis states/severity found in routine practice. EQ-5D profiles resulting in negative valuations (i.e., states WTD) based on UK weights were identified. EQ-5D scores for these profiles from alternative valuation sets, including a reanalysis of the UK weights, were compared. The health status and characteristics of patients, and factors associated with patients in the low distribution of the EQ-5D and those with WTD EQ-5D scores were identified. RESULTS: Seven hundred patients were included in the analysis. Sixty-two (9%) patients occupied states WTD. Patients occupied 9 of the possible 84 health profiles with negative scores (53% occupied one profile); this profile was not rated WTD by any of the alternative EQ-5D scoring algorithms. All WTD profiles included severe pain/discomfort plus moderate problems in >or=3 other domains. Patients with WTD valuations reported higher levels of pain, and feeling downhearted and low on alternative health status measures. CONCLUSIONS: Pain was the predominant factor in the WTD EQ-5D profiles occupied by arthritis patients. Patients occupying states WTD have poorer health-related quality of life than patients in low "better than death" states. Valuations of profiles vary according to how sets of preference weights for health profiles were developed. Further research should explore whether WTD valuations are supported by qualitative evidence and reflect the patient's health and experience of disease.

Monocular and binocular visual impairment in the UK Biobank study: prevalence, associations and diagnoses.

OBJECTIVE: To determine the prevalence of, associations with and diagnoses leading to mild visual impairment or worse (logMAR >0.3) in middle-aged adults in the UK Biobank study. METHODS AND ANALYSIS: Prevalence estimates for monocular and binocular visual impairment were determined for the UK Biobank participants with fundus photographs and spectral domain optical coherence tomography images. Associations with socioeconomic, biometric, lifestyle and medical variables were investigated for cases with visual impairment and matched controls, using multinomial logistic regression models. Self-reported eye history and image grading results were used to identify the primary diagnoses leading to visual impairment for a sample of 25% of cases. RESULTS: For the 65 033 UK Biobank participants, aged 40-69 years and with fundus images, 6682 (10.3%) and 1677 (2.6%) had mild visual impairment or worse in one or both eyes, respectively. Increasing deprivation, age and ethnicity were independently associated with both monocular and binocular visual impairment. No primary diagnosis for the recorded level of visual impairment could be identified for 49.8% of eyes. The most common identifiable diagnoses leading to visual impairment were cataract, amblyopia, uncorrected refractive error and vitreoretinal interface abnormalities. CONCLUSIONS: The prevalence of visual impairment in the UK Biobank study cohort is lower than for population-based studies from other industrialised countries. Monocular and binocular visual impairment are associated with increasing deprivation, age and ethnicity. The UK Biobank dataset does not allow confident identification of the causes of visual impairment, and the results may not be applicable to the wider UK population.

Variations in dementia diagnosis in England and association with general practice characteristics.

OBJECTIVES: Improving dementia diagnosis rates in England has been a key strategic aim of the UK Government but the variation and low diagnosis rates are poorly understood. The aim of this study was to explore the variation in actual versus expected diagnosis of dementia across England, and how these variations were associated with general practice characteristics. METHOD: A cross-sectional, ecological study design using secondary data sources and median regression modelling was used. Data from the year 2011 for 7711 of the GP practices in England (92.7%). Associations of dementia diagnosis rates (%) per practice, calculated using National Health Service England's 'Dementia Prevalence Calculator' and various practice characteristics were explored using a regression model. RESULTS: The median dementia diagnosis rate was 41.6% and the interquartile range was 31.2-53.9%. Multivariable regression analysis demonstrated positive associations between dementia diagnosis rates and deprivation of the population, overall Quality and Outcomes Framework performance, type of primary care contract and size of practice list. Negative associations were found between dementia diagnosis rates and average experience of GPs in the practice and the proportion of the practice caseload over 65 years old. CONCLUSION: Dementia diagnosis rates vary greatly across GP practices in England. This study has found independent associations between dementia diagnosis rates and a number of patient and practice characteristics. Consideration of these factors locally may provide targets for case-finding interventions and so facilitate timely diagnosis.

Empirically derived cut-points for sedentary behaviour: are we sitting differently?

Sedentary behaviour (SB) is associated with a number of adverse health outcomes. Studies that have used ActiGraph monitors to define sedentary time tend to use a threshold of <100 counts per minute (cpm) for classifying SB; however, this cut-point was not empirically derived for adults. It is not known whether ActiGraph cut-points for SB differ depending on the context in which it occurs. We aimed to: (1) empirically derive an optimal threshold for classifying SB, using the cpm output from the ActiGraph GT3X+, compared to the sedentary classification from the activPAL3™; and (2) ascertain whether this varied by day of the week and in working time versus non-working time. A convenience sample of 30 office-based university employees (females (66.67%); age 40.47 ± 10.95 years; BMI 23.93 ± 2.46 kg m-2) wore the ActiGraph GT3X+ and activPAL3™ devices simultaneously for seven days. Data were downloaded in 1 min epochs and non-wear time was removed. Generalised estimating equations were used to make minute by minute comparisons of sedentary time from the two devices, using sedentary minutes (when all 60 s were classified as sitting/lying) from the activPAL3™ as the criterion measure. After data reduction participants provided on average 11 h 27 min of data per day. The derived cut-points from the models were significantly higher on a Saturday (97 cpm) compared to weekdays (60 cpm) and Sunday (57 cpm). Derived cpm for sedentary time during working time were significantly lower compared to non-working time (35 (95%CI 30-41) versus 73 (54-113)). Compared to the 100 cpm and 150 cpm thresholds, the empirically derived cut-points were not significantly different in terms of area-under-the-curve, but had lower mean bias for working and non-working times. Accelerometer cut-points for SB can depend on day and also domain, suggesting that the nature of sitting differs depending on the context in which sedentary time is accrued.

Injecting drug use in prison: prevalence and implications for needle exchange policy.

PURPOSE: The purpose of this paper is to explore prison drug injecting prevalence, identify any changes in injecting prevalence and practice during imprisonment and explore views on prison needle exchange. DESIGN/METHODOLOGY/APPROACH: An empirical prospective cohort survey conducted between 2006 and 2008. The study involved a random sample of 267 remand and sentenced prisoners from a large male category B prison in England where no prison needle exchange operates. Questionnaires were administered with prisoners on reception and, where possible, at one, three and six months during their sentence. FINDINGS: In total, 64 per cent were injecting until admission into prison. The majority intended to stop injecting in prison (93 per cent), almost a quarter due to the lack of needle exchange (23 per cent). Yet when hypothetically asked if they would continue injecting in prison if needle exchange was freely available, a third of participants (33 per cent) believed that they would. Injecting cessation happened on prison entry and appeared to be maintained during the sentence. RESEARCH LIMITATIONS/IMPLICATIONS: Not providing sterile needles may increase risks associated with injecting for prisoners who continue to inject. However, providing such equipment may prolong injecting for other prisoners who currently cease injecting on account of needle exchange programmes (NEPs) not being provided in the UK prison setting. Practical implications - Not providing sterile needles may increase risks associated with injecting for prisoners who continue to inject. However, providing such equipment may prolong injecting for other prisoners who currently cease injecting on account of NEPs not being provided in the UK prison setting. ORIGINALITY/VALUE: This survey is the first to question specifically regarding the timing of injecting cessation amongst male prisoners and explore alongside intention to inject should needle exchange facilities be provided in prison.

Prevalence, Nature, Severity and Risk Factors for Prescribing Errors in Hospital Inpatients: Prospective Study in 20 UK Hospitals.

INTRODUCTION: It has been suggested that doctors in their first year of post-graduate training make a disproportionate number of prescribing errors. OBJECTIVE: This study aimed to compare the prevalence of prescribing errors made by first-year post-graduate doctors with that of errors by senior doctors and non-medical prescribers and to investigate the predictors of potentially serious prescribing errors. METHODS: Pharmacists in 20 hospitals over 7 prospectively selected days collected data on the number of medication orders checked, the grade of prescriber and details of any prescribing errors. Logistic regression models (adjusted for clustering by hospital) identified factors predicting the likelihood of prescribing erroneously and the severity of prescribing errors. RESULTS: Pharmacists reviewed 26,019 patients and 124,260 medication orders; 11,235 prescribing errors were detected in 10,986 orders. The mean error rate was 8.8 % (95 % confidence interval [CI] 8.6-9.1) errors per 100 medication orders. Rates of errors for all doctors in training were significantly higher than rates for medical consultants. Doctors who were 1 year (odds ratio [OR] 2.13; 95 % CI 1.80-2.52) or 2 years in training (OR 2.23; 95 % CI 1.89-2.65) were more than twice as likely to prescribe erroneously. Prescribing errors were 70 % (OR 1.70; 95 % CI 1.61-1.80) more likely to occur at the time of hospital admission than when medication orders were issued during the hospital stay. No significant differences in severity of error were observed between grades of prescriber. Potentially serious errors were more likely to be associated with prescriptions for parenteral administration, especially for cardiovascular or endocrine disorders. CONCLUSION: The problem of prescribing errors in hospitals is substantial and not solely a problem of the most junior medical prescribers, particularly for those errors most likely to cause significant patient harm. Interventions are needed to target these high-risk errors by all grades of staff and hence improve patient safety.

Seropositivity is associated with insulin resistance in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register (NOAR): an observational study.

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of death in patients with inflammatory polyarthritis (IP), especially in seropositive disease. In established rheumatoid arthritis (RA), insulin resistance (IR) is increased and associated with CVD. We investigated factors associated with IR in an inception cohort of patients with early IP. METHODS: Patients with early IP (two or more swollen joints for four or more weeks), aged 18 to 65 years, seen within 24 months of symptom onset were recruited from the Norfolk Arthritis Register (NOAR), a primary-care-based inception cohort. Assessment included joint examination, current and prior therapy and completion of the Health Assessment Questionnaire. Fasting blood was taken for measurement of CVD risk factors, rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), C-reactive protein (CRP), and insulin levels. IR was calculated using the homeostatic model assessment (HOMA-IR). We examined factors associated with IR using univariate and multivariable linear regression models. RESULTS: A total of 196 patients, including 59 (30%) males, were studied with a median (interquartile range, IQR) age and IP symptom duration of 49 (40 to 57) years and 6.7 (4.6 to 10.7) months, respectively. After age and gender adjustment, HOMA-IR was associated with obesity, (ß-Coefficient (95% CI); 1.60 (0.96, 2.24)), higher systolic and diastolic blood pressure (0.03 (0.01, 0.05) and 0.04 (0.01, 0.08) respectively), triglycerides (1.06 (0.54, 1.57)), and HDL (-1.38 (-2.17,-0.58)). HOMA-IR was associated with serological status and this association persisted after adjustment for classic CVD risk factors and other IP-related variables (RF ß-Coefficient (95% CI); 0.87 (0.20, 1.53) and ACPA ß-Coefficient (95% CI); 1.42 (0.70, 2.15)). CONCLUSIONS: Seropositivity for RF or ACPA was associated with IR in this early IP cohort. This association may, in part, explain why seropositive patients have excess CVD mortality.

Risk factors for onset of chronic oro-facial pain--results of the North Cheshire oro-facial pain prospective population study.

Due to the cross-sectional nature of previous studies, whether mechanical factors predict the onset of Chronic oro-facial pain remains unclear. Aims of the current study were to test the hypotheses that self-reported mechanical factors would predict onset of Chronic oro-facial pain and that any observed relationship would be independent of the confounding effects of psychosocial factors and reporting of other unexplained symptoms. About 1735 subjects who had completed a baseline questionnaire were assessed at 2year follow-up for the presence of Chronic oro-facial pain, psychosocial factors (anxiety and depression, illness behaviour, life stressors and reporting of somatic symptoms), mechanical dysfunction (facial trauma, grinding, phantom bite and missing teeth) and reporting of other unexplained symptoms (chronic widespread pain, irritable bowel syndrome and chronic fatigue). About 1329 subjects returned completed questionnaires (adjusted response rate 87%). About 56 (5%) reported new episodes of Chronic oro-facial pain at follow-up. Univariate analyses showed that age, gender, reporting of other unexplained symptoms, psychosocial factors and two self-report mechanical factors predicted the onset of Chronic oro-facial pain. However multivariate analysis showed that mechanical factors did not independently predict onset. The strongest predictors were health anxiety (Relative Risk (RR) 2.8, 95% CI 1.3-6.2), chronic widespread pain (RR 4.0 95% C.I. 2.2-7.4) and age (RR 0.2, 95% CI 0.1-0.7). The findings from this prospective study support the hypothesis that psychosocial factors are markers for onset of Chronic oro-facial pain. The efficacy of early psychological management of Chronic oro-facial pain to address these factors should be a priority for future investigations.

Benefit of early treatment in inflammatory polyarthritis patients with anti-cyclic citrullinated peptide antibodies versus those without antibodies.

OBJECTIVE: To compare the clinical utility of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) testing in predicting both functional outcome and response to treatment in early inflammatory polyarthritis (IP) patients. METHODS: A total of 916 IP subjects from a primary care incidence registry (1990-1994) had anti-CCP antibody and RF status determined at baseline. Mean change in Health Assessment Questionnaire (HAQ) score between baseline and 5 years was compared by antibody status. The effect of treatment with disease-modifying antirheumatic drugs and/or steroids over 5 years, early (<6 months of symptom onset) versus late initiation, and duration of treatment were also compared by anti-CCP antibody status. The analysis was adjusted for treatment decisions and censoring over the followup, using marginal structural models. RESULTS: Anti-CCP antibody-positive patients (n = 268) had more severe disease both at presentation and 5 years of followup, and this was independent of RF. On adjustment, anti-CCP antibody-negative patients treated early experienced a significant improvement in functional disability compared with anti-CCP antibody-negative patients who were never treated (-0.31; 95% confidence interval [95% CI] -0.53, -0.08), and experienced additional benefit for each additional month of early treatment. Anti-CCP antibody-positive patients treated early did not have a significant improvement in HAQ score compared with those not treated (-0.14; 95% CI -0.52, 0.24). CONCLUSION: In this first observational study to examine the influence of anti-CCP antibody status on treatment response, anti-CCP antibody-positive IP patients showed less benefit from treatment, particularly early treatment, than anti-CCP antibody-negative patients. This provides support for the inclusion of anti-CCP antibodies as well as RF in the classification criteria for rheumatoid arthritis and for stratification by anti-CCP antibody status in clinical trials.

Association of a rheumatoid arthritis susceptibility variant at the CCL21 locus with premature mortality in inflammatory polyarthritis patients.

OBJECTIVE: To investigate whether recently identified rheumatoid arthritis (RA) susceptibility loci are also associated with disease severity, specifically all-cause and cardiovascular disease (CVD) mortality, in patients with inflammatory polyarthritis (IP). METHODS: Subjects with recent-onset IP were recruited from the Norfolk Arthritis Register. Seventeen RA susceptibility single-nucleotide polymorphisms (SNPs) were tested using Sequenom MassArray iPLEX chemistry. Vital status was ascertained from central records. The association of SNP allele carriage with mortality risk was assessed using Cox proportional hazards models after adjusting by sex. The mortality risks of those SNP alleles found to be associated were then stratified by baseline anti-citrullinated peptide (anti-CCP) antibody and shared epitope (SE) status. RESULTS: All SNPs were successfully genotyped in 2,324 IP subjects. The presence of 2 copies of the risk allele rs2812378 mapping to the CCL21 gene predicted all-cause mortality (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.04-1.87), whereas risk allele carriage also predicted increased CVD mortality (HR 1.33, 95% CI 1.01-1.75). The highest mortality risks were seen in anti-CCP antibody-positive subjects with 2 copies of the CCL21 risk alleles and 2 copies of the SE (all-cause HR 3.20, 95% CI 1.52-6.72; CVD HR 3.73, 95% CI 1.30-10.72). CONCLUSION: In this large study, we found that carriage of CCL21 risk alleles was associated with premature mortality in IP independently of anti-CCP antibody and SE status. Interestingly, CCL21 expression has been reported in atherosclerotic plaques supporting the thesis that the increased CVD mortality in IP patients may be mediated by shared inflammatory mechanisms.

Association of functional outcome with both personal- and area-level socioeconomic inequalities in patients with inflammatory polyarthritis.

OBJECTIVE: To describe the relationship between baseline area- and person-level social inequalities and functional disability at 3 years in patients with early inflammatory polyarthritis (IP). METHODS: A total of 1,393 patients with new-onset IP were recruited and allocated an Index of Multiple Deprivation (IMD) 2004 score based on their area of residence, and a social class based on baseline self-reported occupation. Differences in the Health Assessment Questionnaire (HAQ) score at baseline and 3 years by IMD or social class were tested. The mean 3-year change in HAQ score was compared by IMD and social class, and interactions between these measures examined. RESULTS: Patients from more deprived areas had poorer 3-year HAQ outcome than those from less deprived areas (P = 0.019, adjusted for baseline HAQ score, age, sex, and symptom duration). The mean difference in HAQ change was most notable between the most deprived (IMD4) and least deprived areas (IMD1) (0.22; 95% confidence interval [95% CI] 0.11, 0.34). There was also a significant difference in HAQ score change between patients of the highest (SCI and II) and lowest social class (SCIV and V) (0.11; 95% CI 0.02, 0.20). For the mean (95% CI) 3-year change in HAQ score, a significant interaction exists between IMD score and social class and their association with HAQ scores (P = 0.001) to modify outcome: IMD1/SC I and II -0.23 (95% CI -0.40, -0.06) versus IMD 4/SC IV and V 0.15 (95% CI -0.05, 0.34). CONCLUSION: Person- and area-level inequalities combine to modify outcome for rheumatoid arthritis. A person's social circumstance and residential environment have independent effects on outcome and are not just alternative measures of the same exposure.

Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis.

OBJECTIVE: To examine the role of the variants of the PTPN22 and HLA-DRB1 genes as predictors of mortality in inflammatory polyarthritis (IP) and rheumatoid arthritis (RA). METHODS: Patients were recruited from a primary care-based inception cohort of patients with IP and were followed up prospectively. For patients who died, the cause and date of death was obtained. Cox proportional hazards regression models were used to assess the association of the HLA-DRB1 (including the shared epitope [SE]) and PTPN22 genes with the risk of death from all causes and from cardiovascular disease (CVD) and to assess the interactions between SE, smoking, and anti-cyclic citrullinated peptide (anti-CCP) status, adjusted by age at symptom onset and sex. RESULTS: DNA samples were available from 1,022 IP patients. During followup, 751 of them (74%) satisfied the American College of Rheumatology 1987 criteria for RA, and 242 of them (24%) died. Carriage of 2 copies of SE alleles predicted death from all causes (hazard ratio [HR] 1.57 [95% confidence interval (95% CI) 1.1-2.2]) and from CVD (HR 1.68 [95% CI 1.1-2.7]). This effect was most marked for individuals with the HLA-DRB1*01/*04 combination. An interaction of smoking, SE alleles, and anti-CCP antibodies was observed and was associated with the greatest risk of death from CVD (HR 7.81 [95% CI 2.6-23.2]). No association of the PTPN22 gene with mortality was detected. CONCLUSION: SE alleles, particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoantibody status. However, the combination of SE, smoking, and anti-CCP antibodies is associated with a high risk of premature death in patients with IP and RA, which raises the possibility of a targeted strategy to prevent CVD in these patients.

The influence of age at symptom onset and length of followup on mortality in patients with recent-onset inflammatory polyarthritis.

OBJECTIVE: To investigate the influence of age at symptom onset and length of followup on mortality in patients with recent-onset inflammatory polyarthritis (IP), and to examine predictors of mortality in relation to disease duration. METHODS: From 1990 to 1994, patients with recent-onset IP were registered with the Norfolk Arthritis Register (NOAR) and followed up prospectively. Standardized mortality ratios (SMRs) were calculated for all-cause and cardiovascular disease (CVD) mortality and for those who were younger than age 55 years at disease onset and for the first 5 and 10 years of followup. Cox proportional hazards models were developed to assess predictors of early and later mortality. RESULTS: Of 1,098 patients, 224 (20%) had died by the end of 2004. All-cause and CVD mortality were increased in rheumatoid factor (RF)-positive patients and in this subgroup, CVD mortality was increased at both early and later followup (SMR 5-year followup 1.93 [95% confidence interval 1.08-3.19]; SMR 10-year followup 2.00 [95% confidence interval 1.37-2.80]). CVD mortality was highest in seropositive patients<55 years of age at disease onset (SMR 5.58 [95% confidence interval 2.24-11.50]). In multivariate models, age at onset, male sex, RF positivity, Health Assessment Questionnaire score>or=1.5, and nodules were predictors of early and later mortality. CONCLUSION: Patients with IP had higher rates of CVD mortality throughout the followup period studied, and this was highest in seropositive patients who were <55 years of age at symptom onset. This subgroup deserves particular attention in terms of disease and risk factor modification. Nodules were independent predictors of CVD mortality, suggesting that extraarticular/vascular inflammation identifies patients at particularly high CVD risk.

Early functional disability predicts both all-cause and cardiovascular mortality in people with inflammatory polyarthritis: results from the Norfolk Arthritis Register.

OBJECTIVE: To investigate the predictive value of early functional disability in patients with inflammatory polyarthritis (IP), for all-cause and cardiovascular disease (CVD) mortality. METHODS: 1010 subjects with new-onset IP from the Norfolk Arthritis Register were studied. All were seen at baseline and at 1 year. Health Assessment Questionnaire (HAQ) scores were obtained at both time points. Vital status at 10 years from registration was established through central records. Mortality (all-cause and CVD) per 1000 person-years were calculated by HAQ stratum (HAQ scores<1, 1-2 and>or=2). The predictive value of HAQ (per unit increase) at the two time points, adjusted for age at onset of symptom, sex and other factors found to predict mortality, was assessed using Cox regression models. The analysis was repeated for those who satisfied the 1987 American College of Rheumatology criteria for rheumatoid arthritis (RA) by 5 years. RESULTS: By 10 years, 171 (16.9%) subjects had died. 89 deaths (52%) were attributed to CVD. Mortality was greatest in the highest HAQ group at both time points. Following adjustment for other predictors, HAQ score at year 1 remained a significant predictor of all-cause mortality (HR 1.46; 95% CI 1.15 to 1.85) and CVD mortality (HR 1.49; 95% CI 1.12 to 1.97). The predictive value of HAQ at year 1 was similar in the RA subgroup. CONCLUSIONS: Our data show that at 1 year of follow-up, HAQ score is an important independent predictor of subsequent all-cause and CVD mortalities in people with IP and RA. Baseline HAQ scores are of less value.