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Introduction Psoriasis is a chronic inflammatory skin disease. Adalimumab is an effective but previously expensive biological treatment for psoriasis. The introduction of biosimilars following the patent expiry of the originator adalimumab Humira has reduced the unit cost of treatment. However, the long-term effectiveness and safety of adalimumab biosimilars for treating psoriasis in real-world settings are uncertain and may be a barrier to widespread usage.Methods and analysis This study aims to compare the drug survival and safety of adalimumab biosimilars to adalimumab originator for the treatment of psoriasis. We will use both routinely collected healthcare databases and dedicated pharmacovigilance registries from the PsoNet initiative, including data from the UK, France and Spain. We will conduct a cohort study using a prevalent new user design. We will match patients on previous adalimumab exposure time to create two equal-sized cohorts of biosimilar and originator users. The coprimary outcomes are drug survival, defined by the time from cohort entry to discontinuation of the drug of interest; and risk of serious adverse events, defined by adverse events leading to hospitalisation or death. Cox proportional hazards models will be fitted to calculate HRs as the effect estimate for the outcomes.Ethics and dissemination The participating registries agree with the Declaration of Helsinki and received approval from local ethics committees. The results of the study will be published in scientific journals and presented at international dermatology conferences by the end of 2023.

It is well-known that mood and pain interact with each other, however individual-level variability in this relationship has been less well quantified than overall associations between low mood and pain. Here, we leverage the possibilities presented by mobile health data, in particular the "Cloudy with a Chance of Pain" study, which collected longitudinal data from the residents of the UK with chronic pain conditions. Participants used an App to record self-reported measures of factors including mood, pain and sleep quality. The richness of these data allows us to perform model-based clustering of the data as a mixture of Markov processes. Through this analysis we discover four endotypes with distinct patterns of co-evolution of mood and pain over time. The differences between endotypes are sufficiently large to play a role in clinical hypothesis generation for personalised treatments of comorbid pain and low mood.

Objective To assess the feasibility of using smartwatches in people with knee osteoarthritis (OA) to determine the day-to-day variability of pain and the relationship between daily pain and step count.Design Observational, feasibility study.Setting In July 2017, the study was advertised in newspapers, magazines and, on social media. Participants had to be living/willing to travel to Manchester. Recruitment was in September 2017 and data collection was completed in January 2018.Participants 26 participants aged>50 years with self-diagnosed symptomatic knee OA were recruited.Outcome measures Participants were provided with a consumer cellular smartwatch with a bespoke app that triggered a series of daily questions including two times per day questions about level of knee pain and one time per month question from the pain subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. The smartwatch also recorded daily step counts.Results Of the 25 participants, 13 were men and their mean age was 65 years (standard deviation (SD) 8 years). The smartwatch app was successful in simultaneously assessing and recording data on knee pain and step count in real time. Knee pain was categorised into sustained high/low or fluctuating levels, but there was considerable day-to-day variation within these categories. Levels of knee pain in general correlated with pain assessed by KOOS. Those with sustained high/low levels of pain had a similar daily step count average (mean 3754 (SD 2524)/4307 (SD 2992)), but those with fluctuating pain had much lower step count levels (mean 2064 (SD 1716)).Conclusions Smartwatches can be used to assess pain and physical activity in knee OA. Larger studies may help inform a better understanding of causal links between physical activity patterns and pain. In time, this could inform development of personalised physical activity recommendations for people with knee OA.

BackgroundThe past decade has seen an explosion of research in causal mediation analysis. However, most analytic tools developed so far rely on frequentist methods which may not be robust in the case of small sample sizes. In this paper, we propose a Bayesian approach for causal mediation analysis based on Bayesian g-formula, which will overcome the limitations of the frequentist methods.MethodsWe created BayesGmed, an R-package for fitting Bayesian mediation models in R. The application of the methodology (and software tool) is demonstrated by a secondary analysis of data collected as part of the MUSICIAN study, a randomised controlled trial of remotely delivered cognitive behavioural therapy (tCBT) for people with chronic pain. We tested the hypothesis that the effect of tCBT would be mediated by improvements in active coping, passive coping, fear of movement and sleep problems. We then demonstrate the use of informative priors to conduct probabilistic sensitivity analysis around violations of causal identification assumptions.ResultThe analysis of MUSICIAN data shows that tCBT has better-improved patients' self-perceived change in health status compared to treatment as usual (TAU). The adjusted log-odds of tCBT compared to TAU range from 1.491 (95% CI: 0.452-2.612) when adjusted for sleep problems to 2.264 (95% CI: 1.063-3.610) when adjusted for fear of movement. Higher scores of fear of movement (log-odds, -0.141 [95% CI: -0.245, -0.048]), passive coping (log-odds, -0.217 [95% CI: -0.351, -0.104]), and sleep problem (log-odds, -0.179 [95% CI: -0.291, -0.078]) leads to lower odds of a positive self-perceived change in health status. The result of BayesGmed, however, shows that none of the mediated effects are statistically significant. We compared BayesGmed with the mediation R- package, and the results were comparable. Finally, our sensitivity analysis using the BayesGmed tool shows that the direct and total effect of tCBT persists even for a large departure in the assumption of no unmeasured confounding.ConclusionThis paper comprehensively overviews causal mediation analysis and provides an open-source software package to fit Bayesian causal mediation models.

Abstract Background Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune condition for which there are limited licensed therapies. Clinical trial design is challenging in SLE due at least in part to imperfect outcome measures. Improved understanding of how disease activity changes over time could inform future trial design. The aim of this study was to determine whether distinct trajectories of disease activity over time occur in patients with active SLE within a clinical trial setting and to identify factors associated with these trajectories. Methods Latent class trajectory models were fitted to a clinical trial dataset of a monoclonal antibody targeting CD22 (Epratuzumab) in patients with active SLE using the numerical BILAG-2004 score (nBILAG). The baseline characteristics of patients in each class and changes in prednisolone over time were identified. Exploratory PK-PD modelling was used to examine cumulative drug exposure in relation to latent class membership. Results Five trajectories of disease activity were identified, with 3 principal classes: non-responders (NR), slow responders (SR) and rapid-responders (RR). In both the SR and RR groups, significant changes in disease activity were evident within the first 90 days of the trial. The SR and RR patients had significantly higher baseline disease activity, exposure to epratuzumab and activity in specific BILAG domains, whilst NR had lower steroid use at baseline and less change in steroid dose early in the trial. Conclusions Longitudinal nBILAG scores reveal different trajectories of disease activity and may offer advantages over fixed endpoints. Corticosteroid use however remains an important confounder in lupus trials and can influence early response. Changes in disease activity and steroid dose early in the trial were associated with the overall disease activity trajectory, supporting the feasibility of performing adaptive trial designs in SLE.

Objectives To identify predictors of overall lupus and lupus nephritis (LN) responses in patients with LN.Methods Data from the Aspreva Lupus Management Study (ALMS) trial cohort was used to identify baseline predictors of response at 6 months. Endpoints were major clinical response (MCR), improvement, complete renal response (CRR) and partial renal response (PRR). Univariate and multivariate logistic regressions with least absolute shrinkage and selection operator (LASSO) and cross-validation in randomly split samples were utilised. Predictors were ranked by the percentage of times selected by LASSO and prediction performance was assessed by the area under the receiver operating characteristics (AUROC) curve.Results We studied 370 patients in the ALMS induction trial. Improvement at 6 months was associated with older age (OR=1.03 (95% CI: 1.01 to 1.05) per year), normal haemoglobin (1.85 (1.16 to 2.95) vs low haemoglobin), active lupus (British Isles Lupus Assessment Group A or B) in haematological and mucocutaneous domains (0.61 (0.39 to 0.97) and 0.50 (0.31 to 0.81)), baseline damage (SDI>1 vs =0) (0.38 (0.16 to 0.91)) and 24-hour urine protein (0.63 (0.50 to 0.80)). LN duration 2–4 years (0.43 (0.19 to 0.97) vs

BackgroundSleep disturbances and poor health-related quality of life (HRQoL) are common in people with rheumatoid arthritis (RA). Sleep disturbances, such as less total sleep time, more waking periods after sleep onset, and higher levels of nonrestorative sleep, may be a driver of HRQoL. However, understanding whether these sleep disturbances reduce HRQoL has, to date, been challenging because of the need to collect complex time-varying data at high resolution. Such data collection is now made possible by the widespread availability and use of mobile health (mHealth) technologies. ObjectiveThis mHealth study aimed to test whether sleep disturbance (both absolute values and variability) causes poor HRQoL. MethodsThe quality of life, sleep, and RA study was a prospective mHealth study of adults with RA. Participants completed a baseline questionnaire, wore a triaxial accelerometer for 30 days to objectively assess sleep, and provided daily reports via a smartphone app that assessed sleep (Consensus Sleep Diary), pain, fatigue, mood, and other symptoms. Participants completed the World Health Organization Quality of Life-Brief (WHOQoL-BREF) questionnaire every 10 days. Multilevel modeling tested the relationship between sleep variables and the WHOQoL-BREF domains (physical, psychological, environmental, and social). ResultsOf the 268 recruited participants, 254 were included in the analysis. Across all WHOQoL-BREF domains, participants’ scores were lower than the population average. Consensus Sleep Diary sleep parameters predicted the WHOQoL-BREF domain scores. For example, for each hour increase in the total time asleep physical domain scores increased by 1.11 points (β=1.11, 95% CI 0.07-2.15) and social domain scores increased by 1.65 points. These associations were not explained by sociodemographic and lifestyle factors, disease activity, medication use, anxiety levels, sleep quality, or clinical sleep disorders. However, these changes were attenuated and no longer significant when pain, fatigue, and mood were included in the model. Increased variability in total time asleep was associated with poorer physical and psychological domain scores, independent of all covariates. There was no association between actigraphy-measured sleep and WHOQoL-BREF. ConclusionsOptimizing total sleep time, increasing sleep efficiency, decreasing sleep onset latency, and reducing variability in total sleep time could improve HRQoL in people with RA.

Background: Psoriasis is a common, lifelong inflammatory skin disease, the severity of which can range from limited disease involving a small body surface area to extensive skin involvement. It is associated with high levels of physical and psychosocial disability and a range of comorbidities, including cardiovascular disease, and it is currently incurable. Objectives: To (1) confirm which patients with psoriasis are at highest risk of developing additional long-term conditions and identify service use and costs to patient, (2) apply knowledge about risk of comorbid disease to the development of targeted screening services to reduce risk of further disease, (3) learn how patients with psoriasis cope with their condition and about their views of service provision, (4) identify the barriers to provision of best care for patients with psoriasis and (5) develop patient self-management resources and staff training packages to improve the lives of people with psoriasis. Design: Mixed methods including two systematic reviews, one population cohort study, one primary care screening study, one discrete choice study, four qualitative studies and three mixed-methodology studies. Setting: Primary care, secondary care and online surveys. Participants: People with psoriasis and health-care professionals who manage patients with psoriasis. Results: Prevalence rates for psoriasis vary by geographical location. Incidence in the UK was estimated to be between 1.30% and 2.60%. Knowledge about the cost-effectiveness of therapies is limited because high-quality clinical comparisons of interventions have not been done or involve short-term follow-up. After adjusting for known cardiovascular risk factors, psoriasis (including severe forms) was not found to be an independent risk factor for major cardiovascular events; however, co-occurrence of inflammatory arthritis was a risk factor. Traditional risk factors were high in patients with psoriasis. Large numbers of patients with suboptimal management of known risk factors were found by screening patients in primary care. Risk information was seldom discussed with patients as part of screening consultations, meaning that a traditional screening approach may not be effective in reducing comorbidities associated with psoriasis. Gaps in training of health-care practitioners to manage psoriasis effectively were identified, including knowledge about risk factors for comorbidities and methods of facilitating behavioural change. Theory-based, high-design-quality patient materials broadened patient understanding of psoriasis and self-management. A 1-day training course based on motivational interviewing principles was effective in increasing practitioner knowledge and changing consultation styles. The primary economic analysis indicated a high level of uncertainty. Sensitivity analysis indicated some situations when the interventions may be cost-effective. The interventions need to be assessed for long-term (cost-)effectiveness. Limitations: The duration of patient follow-up in the study of cardiovascular disease was relatively short; as a result, future studies with longer follow-up are recommended. Conclusions: Recognition of the nature of the psoriasis and its impact, knowledge of best practice and guideline use are all limited in those most likely to provide care for the majority of patients. Patients and practitioners are likely to benefit from the provision of appropriate support and/or training that broadens understanding of psoriasis as a complex condition and incorporates support for appropriate health behaviour change. Both interventions were feasible and acceptable to patients and practitioners. Cost-effectiveness remains to be explored. Future work: Patient support materials have been created for patients and NHS providers. A 1-day training programme with training materials for dermatologists, specialist nurses and primary care practitioners has been designed. Spin-off research projects include a national study of responses to psoriasis therapy and a global study of the prevalence and incidence of psoriasis. A new clinical service is being developed locally based on the key findings of the Identification and Management of Psoriasis Associated ComorbidiTy (IMPACT) programme. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 10, No. 3. See the NIHR Journals Library website for further project information.

Abstract. Introduction:. Previous studies on the association between weather and pain severity among patients with chronic pain have produced mixed results. In part, this inconsistency may be due to differences in individual pain responses to the weather. Methods:. To test the hypothesis that there might be subgroups of participants with different pain responses to different weather conditions, we examined data from a longitudinal smartphone-based study, Cloudy with a Chance of Pain, conducted between January 2016 and April 2017. The study recruited more than 13,000 participants and recorded daily pain severity on a 5-point scale (range: no pain to very severe pain) along with hourly local weather data for up to 15 months. We used a Bayesian multilevel model to examine the weather–pain association. Results:. We found 1 in 10 patients with chronic pain were sensitive to the temperature, 1 in 25 to relative humidity, 1 in 50 to pressure, and 3 in 100 to wind speed, after adjusting for age, sex, belief in the weather–pain association, mood, and activity level. The direction of the weather–pain association differed between people. Although participants seem to be differentially sensitive to weather conditions, there is no definite indication that participants' underlying pain conditions play a role in weather sensitivity. Conclusion:. This study demonstrated that weather sensitivity among patients with chronic pain is more apparent in some subgroups of participants. In addition, among those sensitive to the weather, the direction of the weather–pain association can differ.

Abstract Background Clinical prediction models (CPMs) predict the risk of health outcomes for individual patients. The majority of existing CPMs only harness cross-sectional patient information. Incorporating repeated measurements, such as those stored in electronic health records, into CPMs may provide an opportunity to enhance their performance. However, the number and complexity of methodological approaches available could make it difficult for researchers to explore this opportunity. Our objective was to review the literature and summarise existing approaches for harnessing repeated measurements of predictor variables in CPMs, primarily to make this field more accessible for applied researchers. Methods MEDLINE, Embase and Web of Science were searched for articles reporting the development of a multivariable CPM for individual-level prediction of future binary or time-to-event outcomes and modelling repeated measurements of at least one predictor. Information was extracted on the following: the methodology used, its specific aim, reported advantages and limitations, and software available to apply the method. Results The search revealed 217 relevant articles. Seven methodological frameworks were identified: time-dependent covariate modelling, generalised estimating equations, landmark analysis, two-stage modelling, joint-modelling, trajectory classification and machine learning. Each of these frameworks satisfies at least one of three aims: to better represent the predictor-outcome relationship over time, to infer a covariate value at a pre-specified time and to account for the effect of covariate change. Conclusions The applicability of identified methods depends on the motivation for including longitudinal information and the method’s compatibility with the clinical context and available patient data, for both model development and risk estimation in practice.

Abstract Background Propensity scores are widely used to deal with confounding bias in medical research. An incorrectly specified propensity score model may lead to residual confounding bias; therefore it is essential to use diagnostics to assess propensity scores in a propensity score analysis. The current use of propensity score diagnostics in the medical literature is unknown. The objectives of this study are to (1) assess the use of propensity score diagnostics in medical studies published in high-ranking journals, and (2) assess whether the use of propensity score diagnostics differs between studies (a) in different research areas and (b) using different propensity score methods. Methods A PubMed search identified studies published in high-impact journals between Jan 1st 2014 and Dec 31st 2016 using propensity scores to answer an applied medical question. From each study we extracted information regarding how propensity scores were assessed and which propensity score method was used. Research area was defined using the journal categories from the Journal Citations Report. Results A total of 894 papers were included in the review. Of these, 187 (20.9%) failed to report whether the propensity score had been assessed. Commonly reported diagnostics were p-values from hypothesis tests (36.6%) and the standardised mean difference (34.6%). Statistical tests provided marginally stronger evidence for a difference in diagnostic use between studies in different research areas (p = 0.033) than studies using different propensity score methods (p = 0.061). Conclusions The use of diagnostics in the propensity score medical literature is far from optimal, with different diagnostics preferred in different areas of medicine. The propensity score literature may improve with focused efforts to change practice in areas where suboptimal practice is most common.

Abstract Background Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) and mortality risk. Patients with RA are also frequently prescribed glucocorticoids (GCs) which have been associated with increased risk of mortality. In addition, for patients who have concomitant diabetes mellitus (DM), GCs are known to worsen glycaemic control and hence may further increase CV and mortality risk. This study aimed to understand the relationship between GCs, DM and mortality in patients with RA. Methods This was a retrospective cohort study of patients with incident RA identified from UK primary care electronic medical records. Patients with linkage to Office for National Statistics (ONS) for mortality data (N = 9085) were included. DM was identified through Read codes, prescriptions and blood tests, and GC use was identified through prescriptions. Mortality rate ratios (RR) and rate differences (RD) were calculated across the different exposure groups. Cox proportional hazards regression models were used to estimate interaction on the multiplicative and additive scales. Results In those without DM GC use had a 4.4-fold increased all-cause mortality RR (95% confidence interval (CI): 3.83 to 5.14) compared to non-use, whilst those with DM had a lower RR for GC use (3.02 (95% CI: 2.34, 3.90)). However, those with DM had a higher RD associated with GC use because of their higher baseline risk. In those with DM, GC use was associated with an additional 46.7 deaths/1000 person-years (pyrs) (95% CI: 34.1 to 59.3) compared to non-use, while in those without DM GC use was associated with an additional 36.2 deaths/1000 pyrs (95% CI: 31.6 to 40.8). A similar pattern was seen for CV mortality. The adjusted Cox proportional hazards model showed no evidence of multiplicative interaction, but additive interaction indicated a non-significant increased risk. For CV mortality there was no interaction on either scale. Conclusions GC use was associated with higher mortality rates in people with comorbid DM compared to people without DM, despite apparently reassuring similar relative risks. Clinicians need to be aware of the higher baseline risk in patients with DM, and consider this when prescribing GCs in patients with RA and comorbid DM.

BackgroundThe US opioid epidemic has led to similar concerns about prescribed opioids in the UK. In new users, initiation of or escalation to more potent and high dose opioids may contribute to long-term use. Additionally, physician prescribing behaviour has been described as a key driver of rising opioid prescriptions and long-term opioid use. No studies to our knowledge have investigated the extent to which regions, practices, and prescribers vary in opioid prescribing whilst accounting for case mix. This study sought to (i) describe prescribing trends between 2006 and 2017, (ii) evaluate the transition of opioid dose and potency in the first 2 years from initial prescription, (iii) quantify and identify risk factors for long-term opioid use, and (iv) quantify the variation of long-term use attributed to region, practice, and prescriber, accounting for case mix and chance variation.Methods and findingsA retrospective cohort study using UK primary care electronic health records from the Clinical Practice Research Datalink was performed. Adult patients without cancer with a new prescription of an opioid were included; 1,968,742 new users of opioids were identified. Mean age was 51 ± 19 years, and 57% were female. Codeine was the most commonly prescribed opioid, with use increasing 5-fold from 2006 to 2017, reaching 2,456 prescriptions/10,000 people/year. Morphine, buprenorphine, and oxycodone prescribing rates continued to rise steadily throughout the study period. Of those who started on high dose (120-199 morphine milligram equivalents [MME]/day) or very high dose opioids (≥200 MME/day), 10.3% and 18.7% remained in the same MME/day category or higher at 2 years, respectively. Following opioid initiation, 14.6% became long-term opioid users in the first year. In the fully adjusted model, the following were associated with the highest adjusted odds ratios (aORs) for long-term use: older age (≥75 years, aOR 4.59, 95% CI 4.48-4.70, p < 0.001; 65-74 years, aOR 3.77, 95% CI 3.68-3.85, p < 0.001, compared to ConclusionsOf patients commencing opioids on very high MME/day (≥200), a high proportion stayed in the same category for a subsequent 2 years. Age, deprivation, prescribing factors, comorbidities such as fibromyalgia, rheumatological conditions, recent major surgery, and history of substance abuse, alcohol abuse, and self-harm/suicide were associated with long-term opioid use. Despite adjustment for case mix, variation across regions and especially practices and prescribers in high-risk prescribing was observed. Our findings support greater calls for action for reduction in practice and prescriber variation by promoting safe practice in opioid prescribing.

Abstract Background Hypogonadism associates with increased cardiovascular morbidity/mortality in type 2 diabetes mellitus (T2DM) [1]. Increasing CAG repeat number within exon 1 of the androgen receptor gene associates with increased androgen receptor resistance/insulin resistance [2]. We here investigated the link between CAG repeat number and metabolic/cardiovascular outcomes in T2DM men. Methods We determined in a 14-year follow-up cohort of 274 T2DM Caucasian men in Salford UK, the association between baseline androgen status/CAG repeat number (determined by PCR followed by Sequenom sequencing) and metabolic trajectory plus mortality. Results Lower baseline testosterone was associated with higher Body Mass Index (BMI) (kg/m2) at 14-year follow-up: regression coefficient −0.30 (95% CI: −0.445 to −0.157), p = 0.0001 (total testosterone data) and higher HbA1c 2016. Higher baseline CAG repeat number associated with higher follow-up BMI in 2016 - each unit increase in CAG repeat associated with 0.43 increment in BMI 2016. At an average 14 year follow-up 55.8% of hypogonadal men had died vs 36.1% of eugonadal men (p = 0.001). 72% of deaths were from cardiovascular causes. There was a ‘u’ shaped relation between the number of CAG repeats and mortality such that 21–23 CAG repeats was associated with an up to 58% lower mortality rate than 23 CAG repeats (Figure 1). This was independent of baseline testosterone. Conclusion A higher number of CAG repeats at the testosterone receptor gene associates with higher future BMI/increased HbA1c. There was a ‘u’ shaped relation between CAG repeat number and mortality rate. CAG repeat number may become part of cardiovascular risk assessment in T2DM men. Figure 1 CAG_cat Mortality Proportional mortality rate Lower bound Upper bound ≤20 40 43 32 53 21 12 24 13 39 22–23 28 50 36 64 >23 34 45 34 57

[This corrects the article DOI: 10.1371/journal.pone.0215999.].

An amendment to this paper has been published and can be accessed via the original article.

Summary Introduction Hypogonadism is more prevalent in men with type 2 diabetes (T2DM) (25%‐40%) than in men without T2DM. Hypogonadism has been associated with poorer glycaemic outcomes and increased cardiovascular morbidity/mortality. We report a 14‐year follow‐up study to evaluate the influence of baseline testosterone level on T2DM outcomes. Research design and methods A total of 550 men with T2DM underwent baseline total testosterone and dihydrotestosterone measurement by tandem mass spectrometry. Mean age of the men was 59.7 ± 12 (mean ± SD) years. Sex hormone‐binding globulin (SHBG) was measured and free testosterone estimated. Patients were followed up between 2002 and 2016. Mean follow‐up period was 12.2 ± 4 years using the Salford (UK) Integrated Health Records system. Results Mean baseline total testosterone was 13.7 ± 5.8 nmol/L, and mean free testosterone was 245.7 ± 88.0 pmol/L. Mean for low total testosterone (

BackgroundUnited Kingdom guidelines for the use of biologic disease modifying anti-rheumatic drugs (bDMARDS) for rheumatoid arthritis (RA) require patients to have active disease (Disease Activity Score [DAS28] >5.1) and have failed ≥2 previous conventional synthetic DMARDs (csDMARD). Patients with moderate disease activity (MDA) do not meet these criteria, yet often have poor outcomes. This study aimed to identify trajectory groups of disability scores over three years in RA patients with MDA.MethodsThe study included biologic-naïve patients receiving csDMARDs only with MDA (3.2 ResultsIn total, 1274 patients were included (mean age: 61 years (standard deviation: 12), 71.4% women). The best fitting model included seven HAQ trajectories. These trajectories were horizontal over follow-up and were related to baseline HAQ: very-low (6.8%, baseline (BL) HAQ: 0.22), low (11.5%, BL HAQ: 0.41), low-moderate (17.0%, BL HAQ: 0.93), moderate (13.4%, BL HAQ: 1.09), high-moderate (19.5%, BL HAQ: 1.61), severe (23.2%, BL HAQ: 1.98) and very-severe (8.6%, BL HAQ: 2.54). Higher DAS28, older age, female gender, longer disease duration and more co-morbidities were independently associated with higher HAQ trajectory group.ConclusionThere is substantial heterogeneity in baseline HAQ scores in this population, and the trajectories of HAQ scores after baseline are, on average, relatively flat. As bDMARD therapy has been shown to improve HAQ scores, patients with MDA but high HAQ scores may benefit from a more aggressive approach to therapy.

Patients with rheumatoid arthritis (RA) who experience treatment failure with one anti–tumor necrosis factor (anti‐TNF) agent, due to either inefficacy or toxicity, are frequently switched to a second anti‐TNF agent, although the benefits of switching are unknown. The present study was undertaken to compare drug continuation rates between the first course and second course of anti‐TNF therapy.The study involved a prospective cohort of RA patients from a UK national register of new anti‐TNF treatment starts (n = 6,739; 876 starting adalimumab, 2,826 starting etanercept, and starting 3,037 infliximab). Over a mean 15 months of followup, 841 patients stopped taking the first drug due to inefficacy and 1,023 stopped the first drug due to toxicity, of whom 503 and 353, respectively, were switched to a second anti‐TNF agent. Kaplan‐Meier survival curves were plotted to determine continuation rates for each course, and Cox regression was used to compare each course for the risk of stopping and the reason for stopping (inefficacy or toxicity).Overall, 73% of patients who switched to a second anti‐TNF agent remained on the new therapy by the end of followup. First drug discontinuation due to inefficacy was associated with an increased rate of second drug discontinuation due to inefficacy (hazard ratio [HR] 2.7, 95% confidence interval [95% CI] 2.1–3.4) but not toxicity (HR 1.1, 95% CI 0.9–1.5). Similarly, first drug discontinuation due to toxicity was associated with an increased rate of second drug discontinuation due to toxicity (HR 2.3, 95% CI 1.9–2.9) but not inefficacy (HR 1.2, 95% CI 0.8–1.6).RA patients who are switched to a second anti‐TNF drug have high rates of continuation, although among those who must discontinue treatment, the reasons for stopping a second drug are related to the reasons for stopping the first drug. This large data set from the UK provides the first estimates of the magnitude of these effects in patients with long‐standing severe RA. [ABSTRACT FROM AUTHOR]

Background Syndromes for which no physical or pathological changes can be found tend to be researched and managed in isolation although hypotheses suggest that they may be one entity. The objectives of our study were to investigate the co-occurrence, in the general population, of syndromes that are frequently unexplained and to evaluate whether they have common associated factors.Methods We conducted a population-based cross-sectional survey that included 2299 subjects who were registered with a General Medical Practice in North-west England and who completed full postal questionnaires (response rate 72%). The study investigated four chronic syndromes that are frequently unexplained: chronic widespread pain, chronic oro-facial pain, irritable bowel syndrome, and chronic fatigue. Validated instruments were used to measure the occurrence of syndromes and to collect information on a variety of associated factors: demographic (age, gender), psychosocial (anxiety, depression, illness behaviour), life stressors, and reporting of somatic symptoms.Results We found that 587 subjects (27%) reported one or more syndromes: 404 (18%) reported one, 134 (6%) reported two, 34 (2%) reported three, and 15 (1%) reported all four syndromes. The occurrence of multiple syndromes was greater than would be expected by chance (P < 0.001). There were factors that were common across syndromes: female gender [odds ratio (OR) = 1.8; 95% confidence interval (95% CI) 1.5–2.2], high levels of aspects of health anxiety like health worry preoccupation (OR = 3.5; 95% CI 2.8–4.4) and reassurance seeking behaviour (OR = 1.4; 95% CI 1.1–1.7), reporting of other somatic symptoms (OR = 3.6; 95% CI 2.9–4.4), and reporting of recent adverse life events (OR = 2.3; 95% CI 1.9–2.8).Conclusion This study has shown that chronic syndromes that are frequently unexplained co-occur in the general population and share common associated factors. Primary care practitioners need to be aware of these characteristics so that management is appropriate at the outset. [ABSTRACT FROM AUTHOR]

Background Gulf War Veterans have previously been shown to have, in the short-term, an excess risk of death from external (i.e. non-disease) causes of death. This study aims to determine whether there remains an excess of non-disease-related deaths in Gulf Veterans, 13 years after deployment, and, for the first time, to determine whether there is a relationship between experiences reported in the Gulf, post-war symptoms, and subsequent mortality experience.Methods We conducted a cohort study with follow-up from April 1, 1991 (the end of the Gulf War) to June 30, 2004. Participants were 53 462 Gulf War Veterans and a cohort of military personnel, matched for age-group, sex, rank, service and level of fitness, who were not deployed to the Gulf. The outcome measure used was mortality as recorded on the NHS central register.Results There is no difference, 13 years after the end of the Gulf War, in the overall mortality experience of Gulf War Veterans. The excess in non-disease-related deaths previously reported is confined to the initial 7 years of follow-up [mortality rate ratio (MRR) 1.31, 95% confidence interval (CI) 1.061.63] rather than the more recent period (MRR 1.05, 95% CI 0.831.33). Overall experiences reported during Gulf deployment did not influence subsequent risk of dying, but there was non-significant increased risk of dying from a disease-related death (MRR 1.99, 95% CI 0.984.04) associated with reported exposure to depleted uranium and of a non-disease-related death associated with reporting handling of pesticides (MRR 2.05, 95% CI 0.914.61). Reporting of morbidity in the health surveys conducted was not related to future risk of death.Conclusion The higher rates of non-disease-related deaths in Gulf War Veterans is not evident in the period of follow-up since 1997. Neither the excess morbidity reported in health surveys nor the experiences during deployment significantly influenced future mortality. The two non-significant associations found (reported depleted uranium exposure and disease death, reporting handling pesticides and non-disease deaths) need to be considered in the context of the number of possible associations examined and potential biasesalthough they are biologically plausible. [ABSTRACT FROM AUTHOR]

The American College of Rheumatology (ACR) 1987 criteria for rheumatoid arthritis (RA) can be applied in 2 formats, a standard “x/y” list and a decision tree. This study evaluated the performance of the decision tree compared with the list approach in the ascertainment of RA in subjects with new‐onset inflammatory polyarthritis (IP) over the first 5 years of observation. Moreover, the use of clinical surrogates to substitute for missing rheumatoid factor (RF) and radiologic erosion data was assessed for validity and for its influence on the resulting RA prevalence estimates.In this population‐based prospective study, 848 subjects with new‐onset IP were interviewed and examined at baseline, with followup at 1, 2, 3, and 5 years. RF and erosion status were determined at prespecified time points. The list criteria were applied cumulatively, while the decision tree was applied cross‐sectionally using either data surrogates or the actual reported data. RA prevalence in the 848 subjects and agreement in classification between the 2 methods was assessed at each time point. The influence of using clinical surrogates on RA prevalence estimates at 5 years and the agreement between surrogate and real results were also analyzed.At baseline, RA prevalence was higher using the decision tree compared with the list approach (63% versus 47%; P = 0.0001); by 5 years of followup, RA estimates were approximately equal (69% versus 72%) and agreement between the approaches was good (κ = 0.67). The use of surrogates had little influence on RA prevalence at 5 years, although substitution of metacarpophalangeal joint swelling for erosion produced a higher RA prevalence estimate (78% versus 70%). Although there was only weak agreement between surrogate and real data, the use of the surrogate data provided good to very good agreement between the approaches in categorizing subjects as RA positive (κ = 0.61–0.72).Over 5 years, the 2 formats of the ACR criteria for RA performed similarly, with no important differences between them. The use of surrogates for missing radiologic and serologic data did not have any major influence on disease classification. Although the RA criteria were not originally derived from subjects with early disease in a population setting, this study shows that the use of the decision tree approach with the option of substituting clinical surrogates for missing laboratory data is an appropriate alternative to the conventional list approach. [ABSTRACT FROM AUTHOR]

To test the hypothesis that the C‐reactive protein (CRP) concentration at baseline is an independent predictor of death from cardiovascular disease (CVD) in newly diagnosed patients with inflammatory polyarthritis (IP).Patients with IP (n = 506) who were recruited from the Norfolk Arthritis Register between 1990 and 1992 were followed up to the end of 2001, and complete data on mortality were obtained. At baseline, subjects underwent a structured interview and joint examination and completed a Health Assessment Questionnaire (HAQ). Blood was obtained and analyzed for rheumatoid factor (RF) and CRP concentration. Cox regression was used to calculate hazards ratios (HRs) for risk of death from CVD.The median followup was 10.1 years (interquartile range 9.3–10.8). There were 104 deaths, 40 of which were the result of CVD. Elevated CRP levels (≥5 mg/liter) predicted death from CVD in univariate analyses: HR 3.9 (95% confidence interval [95% CI] 1.2–13.4) for men, and HR 4.22 (95% CI 1.4–12.6) for women. After adjusting for age and sex, the CVD mortality association was strongest in the subgroup of patients who were RF positive at baseline (adjusted HR 7.4 [95% CI 1.7–32.2]). Multivariate analysis revealed that elevated CRP levels remained a significant independent predictor of death from CVD, even after adjusting for age, sex, smoking status, HAQ score, RF positivity, and swollen joint counts (HR 3.3 [95% CI 1.4–7.6]).The CRP concentration at baseline is an important predictor of subsequent death from CVD in patients with new‐onset IP and is independent of other indicators of disease severity. This supports the theory that CRP may play a direct role in the pathogenesis of CVD. [ABSTRACT FROM AUTHOR]

To investigate the association of red meat and other specific dietary components in predicting the development of inflammatory polyarthritis. This nested case–control study was conducted within a prospective population‐based study of cancer incidence (European Prospective Investigation of Cancer in Norfolk [EPIC‐Norfolk]). EPIC‐Norfolk recruited 25,630 subjects ages 45–75 years between 1993 and 1997. Dietary intake was assessed at baseline using a 7‐day food diary, and the information was analyzed using dietary analysis software. Patients with new cases of inflammatory polyarthritis were identified by linkage with the Norfolk Arthritis Register, a primary care–based inception study of inflammatory polyarthritis, and were matched for age and sex to 2 controls from EPIC‐Norfolk. The risk for development of inflammatory polyarthritis was compared between subjects in the highest and lowest tertiles of dietary intake using conditional logistic regression and was expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). Between 1993 and 2002, 88 new patients with inflammatory polyarthritis were identified and matched with 176 controls. Among patients, the level of red meat intake was higher (P = 0.04) and that of vitamin C was lower (P = 0.03) compared with intake among controls, but no difference in total energy intake was observed. Patients were more likely to be smokers. After adjusting for total energy intake, smoking, and other possible dietary confounders, subjects with the highest level of consumption of red meat (OR 1.9, 95% CI 0.9–4.0), meat and meat products combined (OR 2.3, 95% CI 1.1–4.9), and total protein (OR 2.9, 95% CI 1.1–7.5) were at an increased risk for inflammatory polyarthritis. A high level of red meat consumption may represent a novel risk factor for inflammatory arthritis or may act as a marker for a group of persons with an increased risk from other lifestyle causes. [ABSTRACT FROM AUTHOR]

To establish linkage and replicate the association of macrophage migration inhibitory factor (MIF) with juvenile idiopathic arthritis (JIA). Three hundred twenty-one Caucasian simplex families from the UK were genotyped for polymorphisms of MIF using SNaPshot ddNTP primer extension, or by a fluorescently labeled primer method, and capillary gel electrophoresis. The functional significance of the promoter polymorphisms was studied using luciferase-based reporter gene assays in human T lymphoblast and epithelial cell lines. MIF was linked and associated with JIA (P = 0.0016). Specifically, a 2-point promoter haplotype, CATT7–MIF-173*C, was found to be transmitted in excess (38 transmitted: 21 not transmitted) in the JIA patients. Conditional extended transmission disequilibrium test and pairwise extended transmission disequilibrium test predicted functional interaction between the 2 polymorphic positions. The interaction of the CATT repeat with MIF-173*G/C was found to be specific to the cell type. Replication of an association and linkage of MIF with JIA has been established. Functional interaction between the polymorphic positions on the linked haplotype has also been shown. The molecular mechanism of this interaction is currently being investigated. [ABSTRACT FROM AUTHOR]

Abstract This study was undertaken to determine the degree of interaction between hormonal and athletic effects on changes in bone mineral density (BMD, g/cm2) with time in women around the menopause. Thirty-five elite female runners aged over 40 participated in a longitudinal cohort study of hip and spine bone density changes and had two measurements a mean of 4.1 years apart. Eighteen remained estrogenized throughout the study (E+ to +), ten remained postmenopausal throughout (E- to -), while seven showed a change in status (E- to +) or (E+ to -). At study exit, both postmenopausal E+ and E- subjects had significantly higher than expected broadband ultrasound attenuation (BUA) and velocity of sound (VOS) values at the calcaneus. However, Z-score 95% confidence intervals for BMD of the hip and spine embraced zero except at the femoral trochanter in E+ women. The E+ to + group did not lose bone at any site. The E- to - group lost bone significantly, but only at the femoral neck and spine at rates close to 1% annually. Multiple analysis of variance repeated measures analysis showed a significant interaction in the effects of estrogen exposure with DXA measurement site, with the femoral trochanter being less affected by E- status than the spine and femoral neck. Body mass index (BMI: weight/height2, kg/m2) had a significantly positive effect on total hip and femoral neck BMD independently of estrogen status. In conclusion, in this pilot study, postmenopausal elite runners not on hormone replacement therapy lost BMD from the femoral neck and spine at the expected rates but in the femoral trochanter bone loss appeared reduced and in the calcaneus BUA and VOS were maintained close to young normal values. [ABSTRACT FROM AUTHOR]

To address the functional and prognostic relevance of the -173 single-nucleotide G-to-C polymorphism of the macrophage migration inhibitory factor (MIF) gene in patients with systemic-onset juvenile idiopathic arthritis (systemic-onset JIA) by evaluating its association with serum and synovial fluid levels of MIF, with glucocorticoid requirement, and with the outcome of the disease. A total of 136 patients with systemic-onset JIA were studied, including 98 patients from the British Paediatric Rheumatology Study Group''s National Repository for JIA and 38 patients who were followed up at the IRCCS Policlinico San Matteo (Pavia, Italy) and the IRCCS G. Gaslini (Genoa, Italy). The MIF-173 polymorphism was genotyped using SnaPshot ddNTP primer extension and capillary electrophoresis. MIF levels were measured by enzyme-linked immunosorbent assay. The evaluation of the association of the MIF-173 polymorphism with outcome was performed only in Italian patients who were followed up for >5 years, by analyzing retrospectively 1) the number of joints with active arthritis and the number of joints with limited range of motion; 2) the score, at the last visit, on the Italian version of the Childhood Health Assessment Questionnaire (C-HAQ); and 3) data concerning the treatment regimens during the disease course. Systemic-onset JIA patients carrying a MIF-173*C allele had serum and synovial fluid levels of MIF significantly higher than those in patients with the GG genotype. The duration of glucocorticoid treatment on a daily regimen was significantly longer in patients carrying a MIF-173*C allele than in MIF-173 GG homozygous patients. Moreover, the duration of clinical response to intraarticular injection of triamcinolone hexacetonide was significantly shorter in patients carrying a MIF-173*C allele. At the last visit, the numbers of joints with active arthritis, the C-HAQ scores, and the numbers of joints with limited range of motion were significantly higher in patients carrying the MIF-173*C allele. Our study shows the functional relevance of the MIF-173 polymorphism and suggests that the MIF-173*C allele is a predictor of poor outcome in systemic-onset JIA. [ABSTRACT FROM AUTHOR]

A number of covariate-balancing methods, based on the propensity score, are widely used to estimate treatment effects in observational studies. If the treatment effect varies with the propensity score, however, different methods can give very different answers. The authors illustrate this effect by using data from a United Kingdom–based registry of subjects treated with anti–tumor necrosis factor drugs for rheumatoid arthritis. Estimates of the effect of these drugs on mortality varied from a relative risk of 0.4 (95% confidence interval: 0.16, 0.91) to a relative risk of 1.3 (95% confidence interval: 0.8, 2.25), depending on the balancing method chosen. The authors show that these differences were due to a combination of an interaction between propensity score and treatment effect and to differences in weighting subjects with different propensity scores. Thus, the methods are being used to calculate average treatment effects in populations with very different distributions of effect-modifying variables, resulting in different overall estimates. This phenomenon highlights the importance of careful selection of the covariate-balancing method so that the overall estimate has a meaningful interpretation. [ABSTRACT FROM AUTHOR]