Use of depot medroxyprogesterone acetate and fracture risk

Depot medroxyprogesterone acetate (DMPA), which has a high rate of use among teenagers in Europe and the United States, has been associated with impaired bone mineral acquisition during adolescence and accelerated bone loss in later life. Studies on the association between DMPA use and fracture risk are limited.; We aimed at evaluating the relationship between use of hormonal contraceptives, specifically DMPA, and fracture risk.; We conducted a case-control analysis using the United Kingdom-based General Practice Research Database.; Participants were females aged 20-44 yr with an incident fracture diagnosis between 1995 and 2008.; Odds ratios (OR) with 95% confidence intervals (CI) of incident fracture in relation to exposure to DMPA or combined oral contraceptives were assessed. Adjustments were made for smoking, body mass index, and additional potential confounders.; We identified 17,527 incident fracture cases and 70,130 control patients (DMPA exposure: 11 and 8%, respectively). Compared with nonuse, current use of one to two, three to nine, or 10 or more DMPA prescriptions yielded adjusted OR for fractures of 1.18 (95% CI = 0.93-1.49), 1.36 (95% CI = 1.15-1.60), and 1.54 (95% CI = 1.33-1.78), respectively. Fracture risk was highest after longer treatment duration (<2-3 yr), and there was no difference in patients below and above the age of 30 yr. For users of combined estrogen-containing oral contraceptives, the OR were around 1.; This population-based study suggests that use of DMPA is associated with a slightly increased risk of fractures

Report on methods of safety signal generation in paediatrics from pharmacovigilance databases

This deliverable is based on the need to develop and test methods for safety signal detection in children. Signal detection is the mainstay of detecting safety issues, but so far very few groups have specifically looked at children. We developed reference sets for positive and negative drugevent combinations and vaccine-event combinations by a systematic literature review on all combinations. We retrieved the FDA AERS database, the CDC VAERS database and EUDRAVIGILANCE database. In order to analyse the datasets we had a stepwise approach from extraction of data, cleaning (e.g. mapping MedDRA and ATC codes) and transformation into a a common data model that we defined for the spontaneous reporting databases. A statistical analysis plan was created for the testing of methods and we provided some descriptive analyses of the FAERS data. Next steps will be to complete the analyses

Population-based studies on the natural history of psoriasis. and their role in the drug development process and in clinical practice

Pharmacoepidemiology has been defined as the study of the uses and the effects of drugs in large numbers of people and is important for the surveillance of drugs after marketing. With the recent movement from a reactive to a rather proactive pharmacovigilance, (pharmaco)epidemiological research plays an increasing role in basically all stages of the drug development process. Data on the disease planned to be treated with a new drug have to be gained which can be useful e.g. for the riskbenefit analysis of that compound (e.g. for the comparison of rates of adverse events in the treated population with the disease with rates of such events in the untreated population with the disease). Additionally, good knowledge of diseases is valuable for daily clinical practice. Hence, apart from the classical drug safety studies, pharmacoepidemiology groups conduct more and more disease epidemiology or drug utilisation studies in order to learn more about the natural history of diseases. The aim of this thesis was to increase the knowledge of psoriasis by providing new information and complementing existing data. Psoriasis is a chronic inflammatory skin disease which is common in certain parts of the world. The gain of new insights into the pathogenesis of this disease has prompted the recent development of new therapeutic drugs, primarily biologicals, and vice versa. The studies of this thesis were conducted with data from the General Practice Research Database, which contains longitudinal primary care clinical records from several million patients representative of the United Kingdom population. The general practitioners have been trained to record information on patient demographics and characteristics, lifestyle factors, symptoms, medical diagnoses, referrals to hospitals or specialists, and therapies in a standard and anonymous way. Several hundred studies have been conducted using this extensively validated database. In the first three case-control studies, the influence of beta-blockers and other antihypertensives (Study 3.1), of lithium and antipsychotics (Study 3.2), and of thiazolidinediones and other antidiabetics (Study 3.3) on the risk of developing psoriasis were investigated. The study population consisted of 36,702 patients with a first-time psoriasis diagnosis between 1994 and 2005 and the same number of patients without psoriasis, matched on age, sex, index date, general practitioner, and history in the database. Exposure to the drug classes was evaluated taking duration and timing of use and potential confounding into account. In contrast to the notion in the literature (including standard dermatology textbooks), which was mainly based on data from case reports and case series, use of beta-blockers and other antihypertensives did not materially alter the risk of incident psoriasis. On the contrary, the second study confirmed the suggestion that long-term exposure to lithium can induce psoriasis. Furthermore, for atypical antipsychotics, primarily olanzapine, a statistically significantly decreased psoriasis risk was found for current exposure of longer duration. This observation needs further confirmation. Small clinical trials had shown potential clinical benefits of thiazolidinediones on psoriasis symptoms. Study 3.3 additionally suggested that longer-term exposure to thiazolidinediones reduces the risk of developing psoriasis. The risk also tended to be decreased after use of metformin, however, this needs further investigation. Studies 3.4 to 3.6 were cohort studies with a nested case-control analysis in which the study population defined for Studies 3.1 to 3.3 (= cohort population) was followed for identification of incident diabetes mellitus (Study 3.4), myocardial infarction (MI) or stroke / transient ischaemic attack (TIA) (Study 3.5), and cancer (Study 3.6) in patients with or without psoriasis. Incidence rates (IRs) and unadjusted incidence rate ratios (IRRs) were calculated. In the nested case-control analysis, patients with the outcome of interest were matched on age, sex, and index date to four control patients from the cohort population, and the psoriasis history stratified by duration and severity (using treatment as proxy) was compared by calculating adjusted odds ratios (ORs). The overall diabetes IR in psoriatic patients was about 35% higher than in psoriasis-free patients. Psoriasis patients with intensive systemic treatment for their skin disease and a disease history of longer duration showed an about 2.5 times increased risk of diabetes compared to psoriasis-free patients. For MI and stroke / TIA the overall risk was not increased, but further analyses showed increased risks in subpopulations (e.g. severe psoriasis patients or patients <60 years of age [for MI]). The risk of lymphohaematopoietic or certain types of solid cancers was statistically significantly increased in patients with psoriasis, for solid cancers primarily in patients with a longer-term disease history. These large population-based studies further analysed existing hypotheses and raised new ones. The results may be valuable for healthcare professionals in their daily clinical practice and for pharmaceutical companies in the risk-benefit analysis of their drugs. Additionally, the example of the association between use of betablockers and psoriasis showed that there should be no place for dogmas in medicine and that conclusions can be challenged

Statin use and risk of first-time psoriasis diagnosis

Statins have been suggested as a potential treatment for psoriasis because of their anti-inflammatory properties. However, evidence on the benefits of statins is scarce.; We sought to study the association between use of statins or other lipid-lowering agents and the risk of developing psoriasis.; We conducted a case-control analysis using the United Kingdom-based General Practice Research Database. We identified patients with an incident psoriasis diagnosis between 1994 and 2005 and matched one control subject to each patient on age, sex, general practice, calendar time, and years of history in the database. We estimated odds ratios (ORs) with 95% confidence intervals (CIs), stratified exposure by timing and duration, and adjusted the ORs for potential confounders.; We identified 36,702 incident psoriasis cases and the same number of matched controls. Adjusted ORs for current use (last prescription >30 days before index date) of 1 to 4, 5 to 19, or greater than or equal to 20 prescriptions for statins, as compared with nonuse, were 0.60 (95% CI 0.45-0.80), 1.00 (95% CI 0.84-1.18), and 1.08 (95% CI 0.92-1.28), respectively. The ORs for recent and past use (last prescription 30-89 days and ?90 days ago, respectively) were around 1, except for past use of 1 to 4 prescriptions (OR 1.39; 95% CI 1.09-1.78).; Potential of residual confounding as a result of retrospective study design is a limitation.; This large case-control study does not provide evidence for an altered risk of developing psoriasis in association with long-term use of statins. The reduced psoriasis risk for current short-term statin users is interesting, but whether the association is indeed causal needs further investigation

Undetectable phenytoin serum levels by an automated particle-enhanced turbidimetric inhibition immunoassay in a patient with monoclonal IgM lambda

Phenytoin is a drug used for the treatment of different types of seizures. Its variable pharmacokinetics, mainly a consequence of variable bioavailability, saturable protein binding and saturable hepatic metabolism, predisposes the drug to therapeutic drug monitoring. Several methods to analyze the drug in serum exist with immunoassays being the method of choice for routine measurements. Immunoassays are specific and sensitive, but cross-reactivity, possibly leading to erroneous serum levels, is a concern. We report a patient with falsely undetectable phenytoin serum levels

Psoriasis and risk of incident cancer : an inception cohort study with a nested case-control analysis

Psoriasis has been associated with lymphohematopoietic and solid cancers; however, reports have been inconsistent. Cancer incidence was compared between psoriasis and psoriasis-free patients, and the roles of psoriasis duration and treatment were explored in this observational study using the UK General Practice Research Database. Among 67,761 patients, 1,703 patients had incident cancer; of whom 54% had a history of psoriasis. Incidence rate ratios for lymphohematopoietic and pancreatic cancers were 1.81 (95% confidence interval (CI) 1.35-2.42) and 2.20 (95% CI 1.18-4.09), respectively. In a nested case-control analysis, adjusted odds ratios (ORs) for cancer overall were 1.50 (95% CI 1.30-1.74) for psoriasis of <or=4 years duration and 1.53 (95% CI 0.97-2.43) for patients receiving systemic treatment (marker of disease severity). Lymphohematopoietic malignancy risk was highest in patients with systemic treatment. The OR for patients without systemic treatment was 1.59 (95% CI 1.01-2.50) for psoriasis of or=2 years duration. Risks of bladder/kidney and colorectal cancers were increased with longer-duration psoriasis. Psoriasis patients may have an increased overall risk of incident cancer (mainly lymphohematopoietic and pancreatic). Longer-term psoriasis and more severe disease may increase the risk of some cancers. These observations need further confirmation, particularly because of the potential of findings by chance in observational studies with subgroup analyses

Diabetes mellitus and the risk of cholecystectomy

Whether diabetes mellitus is associated with an increased risk of cholecystectomy remains controversial.; To explore the association between diabetes mellitus and the risk of cholecystectomy.; Population-based case-control analysis using UK-based General Practice Research Database. Cases of cholecystectomy and up to four controls per case, matched on age, sex, BMI, general practice, calendar time, and years of history in the database were identified between 1994 and 2008. Conditional logistic regression was used to estimate the risk of cholecystectomy in diabetics compared to non-diabetics. Odds ratios (ORs) were calculated, adjusted for smoking, alcohol consumption, statin use, and additional confounders.; Amongst 22,574 cases with cholecystectomy and 72,476 controls, 1068 (4.7%) and 3270 (4.5%) had diabetes, respectively, yielding an adjusted OR for developing gallstone disease followed by cholecystectomy of 0.88, 95% CI 78-1.00, p=0.05) in association with diabetes mellitus. Neither glycaemic control, nor increasing diabetes duration or oral antidiabetic therapies were associated with an altered risk of cholecystectomy. Use of statins was protective in patients with (adj. OR 0.66, 95% CI 0.54-0.80, p>0.0001) or without diabetes (adj. OR 0.70, 95% CI 0.62-0.78, p>0.0001).; Diabetes mellitus was not associated with an altered risk of cholecystectomy

Lithium, antipsychotics, and risk of psoriasis

BACKGROUND: Observations in controlled trials and case reports have linked lithium exposure to induction or exacerbation of psoriasis. A causal relationship between lithium exposure and incident psoriasis has been questioned, and observational studies are lacking. METHODS: We conducted a case-control analysis using the United Kingdom-based General Practice Research Database to study the association between the use of lithium or antipsychotics and the risk of developing an incident diagnosis of psoriasis. We identified cases with an incident diagnosis of psoriasis between 1994 and 2005, and controls were matched to the cases on age, sex, general practice, calendar time, and years of history in the database. We used conditional logistic regression to estimate the risk of developing a first-time diagnosis of psoriasis in relation to previous exposure to lithium and antipsychotic drugs, stratified by exposure timing and duration. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) adjusted for smoking, body mass index, and additional potential confounders. RESULTS: We identified 36,702 incident cases of psoriasis and the same number of matched controls. Compared with nonuse, current use of 5 or more prescriptions for lithium and atypical antipsychotics yielded adjusted ORs of 1.68 (95% CI, 1.18-2.39; P > 0.01) and 0.76 (95% CI, 0.55-1.06; P = 0.11), respectively. The OR for olanzapine was 0.50 (95% CI, 0.28-0.89, P = 0.02). CONCLUSIONS: Long-term use of lithium was associated with a small increase in risk of incident psoriasis. There was a suggestion of a possible reduced psoriasis risk associated with the use of atypical antipsychotics, mainly olanzapine, a finding that needs further evaluation

Psoriasis and risk of incident cancer : an inception cohort study with a nested case-control analysis

Psoriasis has been associated with lymphohematopoietic and solid cancers; however, reports have been inconsistent. Cancer incidence was compared between psoriasis and psoriasis-free patients, and the roles of psoriasis duration and treatment were explored in this observational study using the UK General Practice Research Database. Among 67,761 patients, 1,703 patients had incident cancer; of whom 54% had a history of psoriasis. Incidence rate ratios for lymphohematopoietic and pancreatic cancers were 1.81 (95% confidence interval (CI) 1.35-2.42) and 2.20 (95% CI 1.18-4.09), respectively. In a nested case-control analysis, adjusted odds ratios (ORs) for cancer overall were 1.50 (95% CI 1.30-1.74) for psoriasis of <or=4 years duration and 1.53 (95% CI 0.97-2.43) for patients receiving systemic treatment (marker of disease severity). Lymphohematopoietic malignancy risk was highest in patients with systemic treatment. The OR for patients without systemic treatment was 1.59 (95% CI 1.01-2.50) for psoriasis of or=2 years duration. Risks of bladder/kidney and colorectal cancers were increased with longer-duration psoriasis. Psoriasis patients may have an increased overall risk of incident cancer (mainly lymphohematopoietic and pancreatic). Longer-term psoriasis and more severe disease may increase the risk of some cancers. These observations need further confirmation, particularly because of the potential of findings by chance in observational studies with subgroup analyses

A fatal tick bite occurring during the course of tick-borne encephalitis vaccination

In Western Europe tick-borne encephalitis virus infections with fatal outcome are rare, especially in children. We report the case of an adolescent who died of meningoencephalitis after a tick bite that occurred between the first 2 tick-borne encephalitis vaccinations. The case demonstrates the difficulty of differentiating possible adverse events associated with the immunization from symptoms of simultaneous infection with tick-borne encephalitis virus