Publications
scientifiques

INTRODUCTION: In France, pregabalin is widely prescribed in adults but still not approved for children. We aimed to investigate the incidence of pregabalin exposure in ≤6-year-old children, to describe the characteristics and outcome of ingestions involving pregabalin alone, and to estimate a clinically relevant toxic dose in this population. METHODS: Retrospective analysis of pregabalin exposures in ≤6-year-old children, collected by the French Poison Control Centers in 2004-2019. The incidence was estimated using pregabalin prescription data from the Health Improvement Network database (the French version of THIN). The poison severity score (PSS) was used to grade severity. RESULTS: We found 313 unintentional immediate-release pregabalin ingestions in ≤6-year-old children. The number of cases per 100,000 pregabalin-treated adults increased over time (  < 0.001). One hundred twenty-six cases involving pregabalin alone (age, 2 years [1.6-3.0] (median [25th-75th percentiles]); median ingested dose 6.4 mg/kg [3.6-10.9]) were analyzed. No child presented an underlying neurological/cardiac disease and/or took concomitant medications. Most of the children (77%) remained asymptomatic (PSS0) while 21% and 2% developed minor (PSS1) or moderate (PSS2) neurological symptoms, respectively. No severe complications/fatalities were reported. All symptomatic children recovered within 24 h. The ingested pregabalin dose was positively correlated with PSS (  < 0.0001). Using a ROC curve approach (area under the curve, 0.85;  < 0.001), ingestion of ≥19.4 mg/kg pregabalin was appropriate to recommend hospital referral (sensitivity, 39% [95% confidence interval (95% CI), 24-56], specificity, 100% [95% CI, 96-100], predictive positive value, 100% [95% CI, 64-100], and negative predictive value, 85% [95% CI, 82-89]). Symptomatic children who ingested <19.4 mg/kg pregabalin developed minor symptoms. CONCLUSION: Despite increasing prescriptions in adults in France, unintentional pregabalin ingestions in ≤6-year-old children remain rare and cause minimal toxicity. Children with no underlying neurological/cardiac disease and concomitant medication ingesting <19.4 mg/kg immediate-release pregabalin alone can be safely observed at home.

IMPORTANCE: Epidemiologic data on optic neuritis (ON) incidence and associations with immune-mediated inflammatory diseases (IMIDs) are sparse. OBJECTIVE: To estimate 22-year trends in ON prevalence and incidence and association with IMIDs in the United Kingdom. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data from The Health Improvement Network from January 1, 1995, to September 1, 2019. The study included 10 937 511 patients 1 year or older with 75.2 million person-years' follow-up. Annual ON incidence rates were estimated yearly (January 1, 1997, to December 31, 2018), and annual ON prevalence was estimated by performing sequential cross-sectional studies on data collected on January 1 each year for the same period. Data for 1995, 1996, and 2019 were excluded as incomplete. Risk factors for ON were explored in a cohort analysis from January 1, 1997, to December 31, 2018. Matched case-control and retrospective cohort studies were performed using data from January 1, 1995, to September 1, 2019, to explore the odds of antecedent diagnosis and hazard of incident diagnosis of 66 IMIDs in patients compared with controls. EXPOSURES: Optic neuritis. MAIN OUTCOMES AND MEASURES: Annual point prevalence and incidence rates of ON, adjusted incident rate ratios (IRRs) for risk factors, and adjusted odds ratios (ORs) and adjusted hazard ratios (HRs) for 66 IMIDs. RESULTS: A total of 10 937 511 patients (median [IQR] age at cohort entry, 32.6 [18.0-50.4] years; 5 571 282 [50.9%] female) were studied. A total of 1962 of 2826 patients (69.4%) with incident ON were female and 1192 of 1290 92.4%) were White, with a mean (SD) age of 35.6 (15.6) years. Overall incidence across 22 years was stable at 3.7 (95% CI, 3.6-3.9) per 100 000 person-years. Annual point prevalence (per 100 000 population) increased with database maturity, from 69.3 (95% CI, 57.2-81.3) in 1997 to 114.8 (95% CI, 111.0-118.6) in 2018. The highest risk of incident ON was associated with female sex, obesity, reproductive age, smoking, and residence at higher latitude, with significantly lower risk in South Asian or mixed race/ethnicity compared with White people. Patients with ON had significantly higher odds of prior multiple sclerosis (MS) (OR, 98.22; 95% CI, 65.40-147.52), syphilis (OR, 5.76; 95% CI, 1.39-23.96), Mycoplasma (OR, 3.90; 95% CI, 1.09-13.93), vasculitis (OR, 3.70; 95% CI, 1.68-8.15), sarcoidosis (OR, 2.50; 95% CI, 1.21-5.18), Epstein-Barr virus (OR, 2.29; 95% CI, 1.80-2.92), Crohn disease (OR, 1.97; 95% CI, 1.13-3.43), and psoriasis (OR, 1.28; 95% CI, 1.03-1.58). Patients with ON had a significantly higher hazard of incident MS (HR, 284.97; 95% CI, 167.85-483.81), Behçet disease (HR, 17.39; 95% CI, 1.55-195.53), sarcoidosis (HR, 14.80; 95% CI, 4.86-45.08), vasculitis (HR, 4.89; 95% CI, 1.82-13.10), Sjögren syndrome (HR, 3.48; 95% CI, 1.38-8.76), and herpetic infection (HR, 1.68; 95% CI, 1.24-2.28). CONCLUSIONS AND RELEVANCE: The UK incidence of ON is stable. Even though predominantly associated with MS, ON has numerous other associations with IMIDs. Although individually rare, together these associations outnumber MS-associated ON and typically require urgent management to preserve sight.

OBJECTIVES: Economic evaluations of lifestyle interventions, which aim to prevent diabetes/cardiovascular disease (CVD), have not included dementia. Lifestyle interventions decrease dementia risk and extend life expectancy, leading to competing effects on health care costs. We aim to demonstrate the feasibility of including dementia in a public health cost-effectiveness analysis and quantify the overall impacts accounting for these competing effects. METHODS: The School for Public Health Research (SPHR) diabetes prevention model describes individuals' risk of type 2 diabetes, microvascular outcomes, CVD, congestive heart failure, cancer, osteoarthritis, depression, and mortality in England. In version 3.1, we adapted the model to include dementia using published data from primary care databases, health surveys, and trials of dementia to describe dementia incidence, diagnosis, and disease progression. We estimate the impact of dementia on lifetime costs and quality-adjusted life years (QALYs) gained of the National Health Service diabetes prevention program (NHS DPP) from an NHS/personal social services perspective with 3 scenarios: 1) no dementia, 2) dementia only, and 3) reduced dementia risk. Subgroup, parameter, and probabilistic sensitivity analyses were conducted. RESULTS: The lifetime cost savings of the NHS DPP per patient were £145 in the no-dementia scenario, £121 in the dementia-only scenario, and £167 in the reduced dementia risk scenario. The QALY gains increased by 0.0006 in dementia only and 0.0134 in reduced dementia risk. Dementia did not alter the recommendation that the NHS/DPP is cost-effective. CONCLUSIONS: Including dementia into a model of lifestyle interventions was feasible but did not change policy recommendations or modify health economic outcomes. The impact on health economic outcomes was largest where a direct impact on dementia incidence was assumed, particularly in elderly populations.

OBJECTIVES: To study the effect of risk minimization measures taken in 2013 for cyproterone acetate/ethinylestradiol (CPA/EE) on initiation, concomitant use of other hormonal contraceptives (HC) and potential indications. STUDY DESIGN: This retrospective study included data on CPA/EE use in 2011-2017 from the Netherlands, UK, and Italy. RESULTS: The initiation rate of CPA/EE decreased by 44%-91% between 2011 and 2017. Proportions with concomitant use of other HC (<3%) and approved indications did not change over time. CONCLUSION: Apart from a strong reduction in CPA/EE use following risk minimization measures, no major changes were observed regarding concomitant use of other HC or potential reasons for use.

BACKGROUND: Good physical health monitoring can increase quality of life for people with dementia, but the monitoring may vary and ethnic inequalities may exist. AIM: To investigate UK primary care routine physical health monitoring for people with dementia by: (a) ethnic groups, and (b) comorbidity status. DESIGN & SETTING: A retrospective cohort study was undertaken using electronic primary care records in the UK. METHOD: Physical health monitoring was compared in people with dementia from white, black, and Asian ethnic groups and compared those with ≥1 comorbidity versus no comorbidity, from 1 April 2015 to 31 March 2016. Using the framework and expert consensus, good care was defined as receiving, within 1 year: a dementia review; a blood pressure (BP) check (at least one); a GP consultation (at least one); a weight and/or body mass index (BMI) recording (at least one); and an influenza vaccination. RESULTS: Of 20 821 people with dementia, 68% received a dementia review, 80% at least one BP recording, 97% at least one GP contact, 48% a weight and/or BMI recording, and 81% an influenza vaccination in 1 year. Compared with white people, black people were 23% less likely and Asian people 16% less likely to have weight recorded (adjusted incidence rate ratio [IRR] = 0.77, 95% confidence interval [CI] = 0.60 to 0.98/0.84, 0.71 to 1.00). People without comorbidities were less likely to have weight recorded (adjusted IRR = 0.74, 95% CI = 0.69 to 0.79) and BP monitored (adjusted IRR = 0.71, 95% CI = 0.68 to 0.75). CONCLUSION: Ethnic group was not associated with differences in physical health monitoring, other than weight monitoring. Comorbidity status was associated with weight and BP monitoring. Physical health monitoring in dementia, in particular nutrition, requires improvement.

Nontuberculous mycobacterial lung disease (NTMLD) is a rare lung disease often missed due to a low index of suspicion and unspecific clinical presentation. This retrospective study was designed to characterise the prediagnosis features of NTMLD patients in primary care and to assess the feasibility of using machine learning to identify undiagnosed NTMLD patients.IQVIA Medical Research Data (incorporating THIN, a Cegedim Database), a UK electronic medical records primary care database was used. NTMLD patients were identified between 2003 and 2017 by diagnosis in primary or secondary care or record of NTMLD treatment regimen. Risk factors and treatments were extracted in the prediagnosis period, guided by literature and expert clinical opinion. The control population was enriched to have at least one of these features.741 NTMLD and 112 784 control patients were selected. Annual prevalence rates of NTMLD from 2006 to 2016 increased from 2.7 to 5.1 per 100 000. The most common pre-existing diagnoses and treatments for NTMLD patients were COPD and asthma and penicillin, macrolides and inhaled corticosteroids. Compared to random testing, machine learning improved detection of patients with NTMLD by almost a thousand-fold with AUC of 0.94. The total prevalence of diagnosed and undiagnosed cases of NTMLD in 2016 was estimated to range between 9 and 16 per 100 000.This study supports the feasibility of machine learning applied to primary care data to screen for undiagnosed NTMLD patients, with results indicating that there may be a substantial number of undiagnosed cases of NTMLD in the UK.

BACKGROUND: Internationally, intimate partner violence (IPV) cohorts have demonstrated associations with depression and anxiety. However, this association has not yet been described in a UK population, nor has the association with serious mental illness (SMI). AIMS: To explore the relationship between IPV exposure and mental illness in a UK population. METHOD: We designed a retrospective cohort study whereby we matched 18 547 women exposed to IPV to 74 188 unexposed women. Outcomes of interest (anxiety, depression and SMI) were identified through clinical codes. RESULTS: At baseline, 9174 (49.5%) women in the exposed group had some form of mental illness compared with 17 768 (24.0%) in the unexposed group, described as an adjusted odds ratio of 2.62 (95% CI 2.52-2.72). Excluding those with mental illness at baseline, 1254 exposed women (incidence rate 46.62 per 1000 person-years) went on to present with any type of mental illness compared with 3119 unexposed women (incidence rate 14.93 per 1000 person-years), with an aIRR of 2.77 (95% CI 2.58-2.97). Anxiety (aIRR 1.99, 95% CI 1.80-2.20), depression (aIRR 3.05, 95% CI 2.81-3.31) and SMI (aIRR 3.08, 95% CI 2.19-4.32) were all associated with exposure to IPV. CONCLUSIONS: IPV remains a significant public health issue in the UK. We have demonstrated the significant recorded mental health burden associated with IPV in primary care, at both baseline and following exposure. Clinicians must be aware of this association to reduce mental illness diagnostic delay and improve management of psychological outcomes in this group of patients.

OBJECTIVES: The epidemiology of Behçet's disease (BD) has not been well characterized in the UK. Evidence on the risk of cardiovascular disease, thromboembolic disease and mortality in patients with BD compared with the general population is scarce. METHODS: We used a large UK primary care database to investigate the epidemiology of BD. A retrospective matched cohort study was used to assess the following outcomes: risk of cardiovascular, thromboembolic disease and mortality. Controls were selected at a 1:4 ratio (age and gender matched). Cox proportional hazard models were used to derive adjusted hazard ratios (aHR). RESULTS: The prevalence of BD was 14.61 (95% CI 13.35-15.88) per 100 000 population in 2017. A total of 1281 patients with BD were compared with 5124 age- and gender-matched controls. There was significantly increased risk of ischaemic heart disease [aHR 3.09 (1.28-7.44)], venous thrombosis [aHR 4.80 (2.42-9.54)] and mortality [aHR 1.40 (1.07-1.84)] in patients with BD compared with corresponding controls. Patients with BD were at higher risk of pulmonary embolism compared with corresponding controls at baseline [adjusted odds ratio 4.64 (2.66-8.09), P < 0.0001]. The majority of patients with pulmonary embolism and a diagnosis of BD had pulmonary embolism preceding the diagnosis of BD, not after (87.5%; n = 28/32). CONCLUSION: BD has a higher prevalence than previously thought. Physicians should be aware of the increased risk of developing ischaemic heart disease, stroke/transient ischaemic attack and deep venous thrombosis in patients with BD at an earlier age compared with the general population. Risk of embolism in patients with BD might vary across the disease course.

The elevated risk of Parkinson's disease in patients with diabetes might be mitigated depending on the type of drugs prescribed to treat diabetes. Population data for risk of Parkinson's disease in users of the newer types of drugs used in diabetes are scarce. We compared the risk of Parkinson's disease in patients with diabetes exposed to thiazolidinediones (glitazones), glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, with the risk of Parkinson's disease of users of any other oral glucose lowering drugs. A population-based, longitudinal, cohort study was conducted using historic primary care data from The Health Improvement Network. Patients with a diagnosis of diabetes and a minimum of two prescriptions for diabetes medications between January 2006 and January 2019 were included in our study. The primary outcome was the first recording of a diagnosis of Parkinson's disease after the index date, identified from clinical records. We compared the risk of Parkinson's disease in individuals treated with glitazones or DPP4 inhibitors and/or GLP-1 receptor agonists to individuals treated with other antidiabetic agents using a Cox regression with inverse probability of treatment weighting based on propensity scores. Results were analysed separately for insulin users. Among 100 288 patients [mean age 62.8 years (standard deviation 12.6)], 329 (0.3%) were diagnosed with Parkinson's disease during the median follow-up of 3.33 years. The incidence of Parkinson's disease was 8 per 10 000 person-years in 21 175 patients using glitazones, 5 per 10 000 person-years in 36 897 patients using DPP4 inhibitors and 4 per 10 000 person-years in 10 684 using GLP-1 mimetics, 6861 of whom were prescribed GTZ and/or DPP4 inhibitors prior to using GLP-1 mimetics. Compared with the incidence of Parkinson's disease in the comparison group (10 per 10 000 person-years), adjusted results showed no evidence of any association between the use of glitazones and Parkinson's disease [incidence rate ratio (IRR) 1.17; 95% confidence interval (CI) 0.76-1.63; P = 0.467], but there was strong evidence of an inverse association between use of DPP4 inhibitors and GLP-1 mimetics and the onset of Parkinson's disease (IRR 0.64; 95% CI 0.43-0.88; P < 0.01 and IRR 0.38; 95% CI 0.17-0.60; P < 0.01, respectively). Results for insulin users were in the same direction, but the overall size of this group was small. The incidence of Parkinson's disease in patients diagnosed with diabetes varies substantially depending on the treatment for diabetes received. The use of DPP4 inhibitors and/or GLP-1 mimetics is associated with a lower rate of Parkinson's disease compared to the use of other oral antidiabetic drugs.

BACKGROUND: Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect. OBJECTIVE: To estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time. DESIGN: Population-based cohort study. SETTING: The Health Improvement Network U.K. primary care database, 2010 to 2019. PATIENTS: Persons aged 45 years or older who initiated denosumab therapy for osteoporosis. MEASUREMENTS: Observational data were used to emulate an analysis of a hypothetical trial with 3 dosing intervals: subsequent denosumab injection given within 4 weeks after the recommended date ("on time"), delay by 4 to 16 weeks ("short delay"), and delay by more than 16 weeks ("long delay"). The primary outcome was a composite of all fracture types at 6 months after the recommended date. Secondary outcomes were major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture. RESULTS: Investigators identified 2594 patients initiating denosumab therapy. The risk for composite fracture over 6 months was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. Compared with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, 0.63 to 1.69) and long delay an HR of 1.44 (CI, 0.96 to 2.17) ( for trend = 0.093). For vertebral fractures, short delay had an HR of 1.48 (CI, 0.58 to 3.79) and long delay an HR of 3.91 (CI, 1.62 to 9.45). LIMITATION: Dosing schedules were not randomly assigned. CONCLUSION: Although delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk for vertebral fracture compared with on-time dosing, evidence is insufficient to conclude that fracture risk is increased at other anatomical sites with long delay. PRIMARY FUNDING SOURCE: National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation.

Previous studies comparing risk of fracture among Proton Pump Inhibitors (PPIs) users with that among non-users were susceptible to confounding by indication. Epidemiologic studies of this association using an active medication as a comparator would appropriately address this bias. We conducted a propensity-score matched cohort study to compare the risk of incident fracture over five years among initiators of PPIs with initiators of histamine 2 receptor antagonist (H2RA) using data collected from The Health Improvement Network (THIN) database in the United Kingdom (2000-2016). The prevalence of PPIs prescription increased 3.8-fold from 2000 (7.9%) to 2012 (30.3%) and remained stable since then. Of the 50,265 propensity-score matched participants in each cohort (mean age was 65 years, and 57% were women), 370 (1.9/1000 person-years) incident hip fracture occurred in the PPIs initiators and 294 (1.5/1000 person-years) in the H2RA initiators during the follow-up period. The rate difference of incident hip fracture for PPIs initiation was 0.4 (95% confidence interval [CI]: 0.2-0.7)/1000 person-years compared with H2RA initiation and the corresponding hazard ratio (HR) was 1.27 (95%CI: 1.09-1.48). Compared with non-PPI use, multivariable-adjusted odds ratios (ORs) of hip fracture were 1.17 (95%CI: 0.94-1.46), 1.55 (95%CI: 1.23-1.96), and 1.67 (95%CI: 1.33-2.10) for 1-2, 3-9 and ≥ 10 prescriptions of PPIs, respectively (P for trend = 0.001). We found that PPIs prescription has been increasing rapidly over the past decade in the United Kingdom, and the initiation of PPIs was associated with a higher risk of hip fracture than initiation of H2RA.