Validity of results from EHR studies is dependent on how exposure (e.g. eczema) and outcome (e.g. mental illness) are defined. Dichotomization into having or not having eczema may be inadequately broad for research questions on adverse outcomes. Different phenotypes of eczema may need to be seen as different diseases entirely, as they are likely to come with different prognosis, treatment options, and adverse outcomes. Equally important is considering the context in which outcomes are recorded for people with eczema, with e.g. more frequent consultation to the GP for skin disease, a person may be more likely to get their diagnosis of mental illness. We conduct two studies, both making use of linkage between EHR primary care data and cohort study questionnaire responses; the first from the Avon Longitudinal Study of Parents and Children (ALSPAC), a cohort of people in southern England born in the 1990s (n=11,866); the second from UK Biobank, a database containing health information from people in the UK aged 40-69 years at recruitment (n=230,047). Study 1 aims to develop more granular eczema phenotypes for EHR studies. We replicate phenotypes that were derived using latent class analysis from ALSPAC in linked EHR data. We assess agreement between the data sources and construct models predicting the ALSPAC phenotype in EHR data and evaluate whether phenotypes can be used for EHR studies. Study 2 aims to evaluate the adequacy of using mental illness diagnoses from primary care as outcome definitions. We compare associations found between eczema and mental illness between UK Biobank and linked EHR data. We find that in primary care data, the strength of cross-sectional associations may be slightly overestimated, potentially due to more frequent GP consultations in people with skin disease. Together, the studies highlight the importance of carefully choosing exposure and outcome definitions in EHR studies on skin disease, and considering the use of multiple linked data sources.

BackgroundInfluenza is a highly infectious viral disease that is particularly common in the winter months. Oscillococcinum is a patented, commercially available homoeopathic medicine. The rationale for its use in influenza comes from the homoeopathic principle of 'let like be cured by like'. This medicine is manufactured from wild duck heart and liver, which are said to be reservoirs for influenza viruses.ObjectivesTo determine whether homoeopathic Oscillococcinum or similar medicines are more effective than placebo in the prevention and treatment of influenza and influenza-like syndromes.Search strategyWe updated the electronic searches on the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006); MEDLINE (January 1966 to February 2006) and EMBASE (1980 to February 2006). The manufacturers of Oscillococcinum were contacted for information.Selection criteriaPlacebo-controlled trials of Oscillococcinum or homeopathically-prepared influenza virus, influenza vaccine or avian liver in the prevention and treatment of influenza and influenza-like syndromes.Data collection and analysisTwo authors extracted data and assessed methodological quality independently.Main resultsSeven studies were included in the review, three prevention trials (number of participants (n) = 2265) and four treatment trials (n = 1194). Only two studies reported sufficient information to complete data extraction fully. There was no evidence that homoeopathic treatment can prevent influenza-like syndrome (relative risk (RR) 0.64, 95% confidence interval (CI) 0.28 to 1.43). Oscillococcinum treatment reduced the length of influenza illness by 0.28 days (95% CI 0.50 to 0.06). Oscillococcinum also increased the chances that a patient considered treatment to be effective (RR 1.08; 95% CI 1.17 to 1.00).Authors' conclusionsThough promising, the data were not strong enough to make a general recommendation to use Oscillococcinum for first-line treatment of influenza and influenza-like syndromes. Further research is warranted but the required sample sizes are large. Current evidence does not support a preventative effect of Oscillococcinum-like homeopathic medicines in influenza and influenza-like syndromes.

Introduction. Combinations of disease-modifying anti-rheumatic drugs (DMARDs) are increasingly used to treat rheumatoid arthritis (RA). Early trials showed their toxicity while recent trials suggest superior efficacy. Trials of DMARD combinations have enrolled different types of patient (early or established RA), used different designs (step-up, parallel or step-down) and utilized a range of outcome measures. We undertook a systematic review of combination DMARD therapy for RA and carried out a meta-analysis to evaluate the evidence for efficacy and toxicity.Method. Medline, PubMed and EmBase were searched using MESH headlines 'arthritis, rheumatoid', 'drug therapy, combination' and 'randomized controlled trial' (RCT) for papers published from 1975 to April 2004. References from published articles were also searched. Three independent assessors evaluated abstracts and selected trials for detailed examination. Trials were excluded if their quality was poor, were not published in English or studied DMARDs not licensed to treat RA. Two independent assessors extracted data. Efficacy was assessed by the numbers of patients withdrawn due to lack of efficacy. Toxicity was assessed by the numbers of patients withdrawn due to adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were calculated and meta-analysis was carried out based on a random effects model. Sensitivity analyses evaluated different treatment combinations, trial designs, study populations and outcome measures.Results. Fifty-three potentially relevant RCTs were identified. Twelve were excluded due to: using unlicensed DMARDs (n = 3); reporting in journal supplements of RCTs already included (n = 2); follow-up of an earlier RCT, report of biological outcomes or pharmacokinetics (n = 5); and non-English language publications (n = 2). Forty-one RCTs were evaluated in detail and another five excluded (three open-labelled studies and two with high patient attrition); 36 studies were included in the meta-analysis. These comprised 13 step-up, 16 parallel and 7 step-down trials. Nine assessed early RA and 27 established RA. Seven added steroids to DMARD monotherapy and one study added steroids to DMARD combinations. Six assessed methotrexate (MTX) plus tumour necrosis factor (TNF) inhibitors. Overall, combination DMARD therapy was more effective than monotherapy (RR 0.35; 95% CI 0.28, 0.45) although the risk of toxicity was also slightly higher (RR 1.37; 95% CI 1.16, 1.62). Combinations of MTX with TNF inhibitors and MTX with sulphasalazine or anti-malarials showed good efficacy/toxicity ratios.Conclusions. DMARD combinations vary in their efficacy/toxicity ratio. MTX plus sulphasalazine and/or anti-malarials and MTX plus TNF inhibitors have particularly favourable benefit/risk ratios.

Rheumatoid arthritis (RA) has important impacts on health that can be related to the World Health Organization's new International Classification of Functioning, Disability and Health (ICF framework). The physical consequences of RA for the individual relate to body functions and structures in the ICF framework. The functional consequences of RA are related to activity in the ICF framework, and the impact of RA on society relates to participation in the ICF framework. Despite conventional treatment, early RA continues to result in significant physical consequences for most patients. From the patients' perspective, this primarily results from persistent pain, although symptoms such as fatigue and depression are also relevant. This is confirmed from the clinician's perspective by the infrequency of remission, persistence of disease activity and unrelenting radiographic progression in early RA. Patients with early RA often progress, within only a few years, to significant disability. This has mainly been shown in studies using the Health Assessment Questionnaire as the disability measure, although a small number of studies using generic health measures such as Short Form-36 have reached similar conclusions. RA patients and their friends and families incur the majority of costs associated with early RA. Many patients are not able to continue to work at the same level as they would have anticipated had they not developed RA. Later on, society bears an increased load, especially in patients with higher levels of disability; this results from major social care costs and interventions such as surgery. However, the evidence favouring expensive biological therapies, even in early RA, is likely to turn this analysis on its head in the near future.