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International audience; PURPOSE: Using large French retrospective study cohort of chemotherapy-naïve metastatic castration-resistant prostate cancer patients (mCRPC; n = 10,308) comparing survival between patients who initiated abiraterone (ABI; 64%) and those initiating enzalutamide (ENZ; 36%), the present objective was to describe treatment patterns in the 2 years following initiation. METHOD: Using the national health data system (SNDS) from 2014 to 2018, we first explored the number of treatment lines, and secondly, patterns of patient management using state sequence analysis; cluster analyses were performed on the 0 to 12 month and 13 to 24 month periods. Age, Charlson score, and duration of androgen deprivation therapy (ADT) were obtained for each cluster in the first year of follow-up. RESULTS: Patients with only 1 treatment line accounted for 52%. In the 0 to 12 month sequence analysis, the main clusters among ABI/ENZ new users involved patients who continued the initial treatment (54% of 65% respectively) and discontinued active treatment (14.5% for both). Less than 2 years exposure to ADT prior to ABI/ENZ initiation was frequently observed for noncontrolled mCRPC, as shown in the death and switch from ABI/ENZ to docetaxel clusters. The clusters for a switch ABI/ENZ to ENZ/ABI involved 6% to 11% of the patients. CONCLUSION: Our study suggested fairly similar patterns between ABI and ENZ initiation. The cluster of patients with active treatment discontinuation needs to be further investigated, as well as factors influencing therapeutic choice. Better understanding for the use of second-generation hormone therapy in mCRPC in real life, could improve its implementation by clinicians in the early stages of prostate cancer.

Background Several observational studies have reported a decreased response to immune checkpoint inhibitors (ICI) following antibiotic use. ICI activity has been hypothesized to be impaired by antibiotic-induced gut dysbiosis. Methods Patients with advanced melanoma receiving an anti-PD-1 antibody as a first-line therapy between 2015 and 2017 in France were selected using the French Health Insurance database. We compared overall survival and time-to-treatment discontinuation according to antibiotic exposure in the 3 months prior to the initiation of anti-PD-1 antibody. To disentangle a causal effect of antibiotics from a confounding bias, we balanced characteristics of patients exposed and nonexposed to antibiotics using an overlap weighting method based on a propensity score. We also evaluated a control cohort of patients with advanced melanoma receiving first-line targeted therapy, as there is no rationale for decreased efficacy of targeted therapy following antibiotic treatment. Results The anti-PD-1 antibody cohort comprised 2605 individuals. Antibiotic exposure in the 3 months prior to anti-PD-1 antibody initiation was not associated with shorter overall survival (weighted hazard ratio = 1.01, 95% confidence interval = 0.88 to 1.17) or time-to-treatment discontinuation (weighted hazard ratio = 1.00, 95% confidence interval = 0.89 to 1.11). Consistent results were observed when the time frame of antibiotics was narrowed to 1 month prior to anti-PD-1 initiation or when exposure was restricted to antibiotics leading to more profound gut dysbiosis. Similar results were observed in the targeted therapy cohort. Conclusions In a large cohort of advanced melanoma patients, we showed that antibiotic use preceding anti-PD-1 antibody was not associated with worse outcome. Physicians should not delay immunotherapy for patients who have recently received antibiotics.

International audience; BACKGROUND: Previous studies have reported inconsistent findings regarding the association between obstructive sleep apnea (OSA) and incident venous thromboembolism (VTE). More specifically, the association between OSA and unprovoked VTE was barely evaluated. We aimed to evaluate whether apnea hypopnea index (AHI) and nocturnal hypoxemia markers were associated with unprovoked VTE incidence in patients investigated for OSA. STUDY DESIGN AND METHODS: Data from the Pays de la Loire sleep cohort were linked to the French health administrative data to identify incident unprovoked VTE in patients suspected for OSA and no previous VTE disease. Cox proportional hazards models were used to evaluate the association of unprovoked VTE incidence with AHI and nocturnal hypoxemia markers including the time spend under 90% of saturation (T90), oxygen desaturation index and hypoxic burden (HB), a more specific marker of respiratory events related hypoxia. The impact of Continuous positive airway pressure (CPAP) was evaluated in the subgroup of patients who were proposed the treatment. RESULTS: After a median [inter-quartile range] follow-up of 6.3 [4.3-9.0] years, 104 of 7,355 patients developed unprovoked VTE, for an incidence rate of 10.8 per 1,000 patient-year. In a univariate analysis, T90 and HB predicted incident VTE. In the fully adjusted model, T90 was the only independent predictor (HR 1.06; 95%CI [1.01-1.02]; p=0.02). The CPAP treatment has no significant impact on VTE incidence. INTERPRETATION: Patients with more severe nocturnal hypoxia are more likely to have incident unprovoked VTE.

Background and ObjectiveTo describe the prescribing trends for sodium valproate (VPA) and alternative drugs during and around pregnancy, comparing 2016 (after the recommendations on valproate for women were reinforced by the European Medicines Agency [EMA]) with 2013 (before the recommendations).MethodsUsing the French National Health Insurance Database, a cross-sectional study was carried out in 2013 and in 2016, including women who became pregnant and had at least 1 reimbursement claim for VPA in the 2 years prior to pregnancy or during pregnancy. Exposure to VPA and its alternatives was then measured for each quarter, in the 2 years before pregnancy (preconception), during pregnancy, and in the year after pregnancy (postpartum).ResultsAmong pregnant women with epilepsy (n = 2,607 pregnancies), the proportion exposed to VPA during pregnancy decreased from 26.4% to 9.3% between 2013 and 2016, alongside an increase in lamotrigine and levetiracetam use. Among pregnant women with bipolar disorder (n = 4,278 pregnancies), the proportion of women exposed during pregnancy decreased from 3.7% in 2013 to 1.9% in 2016, without any switch to alternative drugs. In both populations, fewer than one third had consulted a specialist before pregnancy.DiscussionAs recommended by the EMA, a change in practice over the 2013–2016 period was observed, with fewer women exposed to VPA during pregnancy and before pregnancy. However, in 2016, a large number of women were exposed to VPA in the first trimester of pregnancy (n = 471), which could suggest that the timing of pregnancy should be better planned when possible.

International audience; Aims - Safety profiles of abiraterone and enzalutamide rely mainly on Phase III clinical trials. Our objective was to estimate the incidence rate ratio (IRR) for certain adverse events leading in real life to hospitalization (atrial fibrillation, acute heart failure, ischaemic heart disease, acute kidney injury [AKI], ischaemic stroke, torsade de pointe/QT interval prolongation, hepatitis and seizure), comparing abiraterone to enzalutamide. We also set out to discuss previously identified safety signals. Method - Using the French National Health Insurance System database, all patients newly exposed to abiraterone or enzalutamide between 2013 and 2017 and followed until 31 December 2018 were targeted. IRRs for each event were estimated using a Poisson model in a sub-population of patients without contraindications or precautions for use for either treatment. Results - Among 11 534 new users of abiraterone and enzalutamide, AKI (IRR 1.42, 95% CI: 1.01-2.00), liver monitoring suggestive of hepatic damage (IRR 3.06, 95% CI: 2.66-3.53) and atrial fibrillation (IRR 1.12, 95% CI: 1.05-1.19) were significantly more often observed with abiraterone than with enzalutamide. Conclusion - Our study provides knowledge on abiraterone and enzalutamide real-life safety profiles, especially for events leading to hospitalization. Despite several limitations, including the lack of clinical data, the safety signal for AKI under abiraterone is in line with results of an analysis of the French pharmacovigilance database, which requires further specific investigations. Enlightening the clinicians' therapeutic choices for patients treated for prostate cancer, our study should lead to clinicians being cautious in the use of abiraterone.

International audience; Purpose Low-dose parenteral anticoagulation has demonstrated its efficacy for venous thromboembolism prophylaxis in randomized trials. However, current practice is not widely documented. In ambulatory settings, we aimed to provide an overview of the clinical use of low-dose parenteral anticoagulation in France and to assess the incidence of major bleeding and death rates. Methods A population-based prospective cohort study using the French national health data system (SNIIRAM) identified 142,815 adults living in five well-defined geographical areas who had a course of low-dose parenteral anticoagulants (a total of 150,389 courses) in the period 2013-2015. The main outcome measures were the types of low-dose parenteral anticoagulant, the duration and the clinical context. Adjusted incidence rate ratios (IRR) were derived from Poisson models. Results Enoxaparin was the most frequently prescribed anticoagulant (58.9%) followed by tinzaparin (27.3%) and fondaparinux (10.9%). Patients receiving unfractionated heparin (N= 766, 0.53%) were older, more frequently had renal disease (48.75%) and had a higher modified HAS-B(L)ED score (>= 3 in 61.6%) than patients receiving low-molecular weight heparin (LMWH). Surgical thrombo-prophylaxis was the most frequent indication (47.6%), followed by medical prophylaxis (29.9%). Course durations were in line with regulatory agency specifications. Only 43 (0.028%) major bleeding events and 478 (0.32%) deaths were observed. Adjusted IRRs for major bleeding or death were not significantly different for dalteparin/nadroparin, tinzaparin or fondaparinux compared to enoxaparin. Conclusion Very low incidence rates of major bleeding and all-cause mortality were observed. Our study confirms the safety of LMWHs and fondaparinux in thrombo-prophylaxis in ambulatory settings.

International audience; BACKGROUND: Although the causal role of isotretinoin in suicidal behaviour is controversial, suicide attempts (SA) do occur among patients taking isotretinoin.OBJECTIVES: To describe patient profiles and the management of isotretinoin among patients who committed or attempted suicide under treatment. To assess the risk factors for SA under isotretinoin.METHODS: We performed a comprehensive case series of suicides and SAs under isotretinoin, and a case-control study, using Nationwide French Health Insurance database. The main analysis compared cases (subjects with a SA during a course of isotretinoin) to controls, individually matched for age, gender and rank of the current course; controls were to be exposed to isotretinoin at the index date (date of SA for the corresponding cases). The patients' psychiatric history at isotretinoin initiation was studied. In a secondary analysis, patients who continued their isotretinoin treatment after their SA were compared to patients who discontinued it.RESULTS: In all, 328 018 subjects started a course of isotretinoin between 1 January 2010 and 31 December 2014 and 184 patients were hospitalized for a SA; half of them had a psychiatric history at initiation. In the multivariate analysis, psychiatric history and history of anxiety alone were risk factors for SA [Odds ratio (OR), 18.21; 95% confidence interval (CI), 9.96-33.30 and 4.78; 95% CI, 2.44-9.33, respectively]. Among 176 cases of SA with sufficient follow-up, 103 (58.5%) carried on with their treatment after their SA. Treatment initiation by a dermatologist was inversely associated with the continuation of the treatment after a SA (OR, 0.38; 95% CI, 0.18-0.80).CONCLUSIONS: Suicide attempts under isotretinoin are rare events, and our results suggest that most of the patients concerned have a risk-prone profile detectable at the time of treatment initiation. The risk-benefit ratio of continuing isotretinoin after a SA warrants further careful evaluation.

ObjectiveTo describe pregnancies exposed to teriflunomide (TERIF) in women with multiple sclerosis (MS) in France over the period 2014–2016.MethodsAll 15- to 49-year-old women with MS in the national health insurance database were included. Pregnancies that had started between August 2014 and March 2016 were identified from their outcomes. Three groups according to treatment exposure were compared: TERIF, interferons (IFNs) or glatiramer acetate, and no medication.ResultsAmong the 44,008 women with MS followed 24.5 months on average, 2,639 pregnancies were identified. There were 1,538 pregnancies (58.3%) that were not exposed to any MS treatment in accordance with the guidelines. A total of 673 pregnancies (25.5%) were exposed to IFN and/or glatiramer acetate, and possible or probable exposure to contra-indicated treatments was observed in 428 pregnancies (16.2%), of whom 47 pregnancies were exposed to TERIF. The annual incidence rate of pregnancies exposed to TERIF was 1.4 per 100 patient-years; i.e., 3 times less than the 2 control groups (5.6 and 4.7, respectively). The median exposure duration to TERIF was 45 days after conception. The outcomes comprised 23 live births, 22 abortions (3 times more than the 2 other groups), and 2 miscarriages. All newborns were healthy at birth.ConclusionsDespite specific TERIF guidelines for pregnancy-related issues and the availability of alternative therapies, some pregnancies exposed to TERIF were identified. Most of the cases were because of the absence of the recommended accelerated elimination procedure and appeared to be mostly unplanned pregnancies that probably reflect a lack of effective contraception.

International audience; SNIIRAM/SNDS, the French administrative health care database, covers around 99% of the population. Its main limitation is the absence of clinical information and biological results. This report exposes the value of SNIIRAM/SNDS enrichment by external databases, and the linkage issues. It is illustrated by examples the well-known population-based cohort CONSTANCES created to answer to epidemiological research questions with a specific interest on occupational and social factors, chronic diseases, and aging; the CANARI study, a regional-based study that collected Gleason score in all pathology laboratories in Brittany and then, linked pathology results to an ad hoc extraction from SNIIRAM database; the goal was to investigate the risk of high grade prostate cancer in patients treated by 5-alpha-reductase inhibitors for a symptomatic benign prostatic hyperplasia; the SACHA study, that identified and medically validated major bleeding event referred to emergency wards, then linked those clinical data to SNIIRAM; the goal was to minimize misclassification bias when estimating bleeding risk in patients who were prescribed antithrombotic drugs; the ISO-PSY study linked the SNIIRAM with the national cause of death registry (CépiDc) and the nationwide emergency department surveillance system (OSCOUR network) to investigate the potential link between isotretinoin and suicidal risk; the EFEMERIS cohort that assesses drugs prescriptions in French pregnant women who delivered in the Haute-Garonne region; the EPI-GETB-AM study that derived a SNIIRAM/SNDS-based algorithm to identify venous thromboembolism and linked SNIIRAM/SNDS to the EPI-GETBO-III survey for validation. Another perspective of SNDS enrichment is clinical trials' data for medico-economic assessment, and extended follow-up without attrition bias. Linkage is not straightforward. Apart from regulatory approbation and authorized data center issues, which could be solved by the Health Data Hub Initiative, a multidisciplinary team with medical, pharmacological and methodological knowledge, as well as with technical skills is essential to handle the whole process.

International audience; Background - Atopic dermatitis (AD) has been linked to systemic infections in adulthood, but large-scale studies are few, and potential associations are unclear. Objective - To examine whether adults with AD have increased risk of developing systemic infections leading to hospital-based management. Methods - Nationwide register-based cohort study including all Danish adults from 1995 through 2017. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by using Cox models. Results - A total of 10,602 adults with AD (median age, 29.8 y; interquartile range, 22.6-44.8) and 106,020 reference individuals were included. The overall incidence rate per 10,000 person-years of systemic infections was 180.6 (95% CI, 172.6-189.0) among adults with AD compared with 120.4 (95% CI, 118.3-122.5) among reference adults. The association between AD and systemic infections was observed for musculoskeletal (adjusted HR [aHR], 1.81; 95% CI, 1.42-2.31), heart (aHR, 1.75; 95% CI, 1.21-2.53), and upper (aHR, 1.42; 95% CI, 1.15-1.73) and lower respiratory tract infections (aHR, 1.21; 95% CI, 1.10-1.33). The risk of sepsis (aHR, 1.19; 95% CI, 1.01-1.44) and skin infections (aHR, 2.30; 95% CI, 2.01-2.62) was also increased. Limitations - The findings cannot be generalized to adults with milder AD seen outside the hospital system. Conclusion - We found an increased risk of systemic infections among adults with hospital managed AD.

Abiraterone acetate (ABI) and enzalutamide (ENZ) are considered to be clinically relevant comparators among chemotherapy-naive patients with castration-resistant prostate cancer. No clinical trials comparing overall survival with ABI versus ENZ in a head-to-head approach have been published so far. A few observational studies with low power suggested a potential benefit of ENZ. We used the French National Health Data System to compare overall survival of new users of ABI and ENZ among chemotherapy-naive patients with castration-resistant prostate cancer in 2014–2017, followed through 2018 (the SPEAR cohort, a 2014–2018 cohort study). With an intent-to-treat approach, a survival analysis was performed, estimating hazard ratios for overall survival with the inverse probability weighted Cox model method. Among 10,308 new users, 64% were treated with ABI and 36% with ENZ. The crude mortality rate was 25.2 per 100 person-years (95% confidence interval (CI): 24.4, 26.0) for ABI and 23.7 per 100 person-years (95% CI: 22.6, 24.9) for ENZ. In the weighted analysis, ENZ was associated with better overall survival compared with ABI (hazard ratio = 0.90 (95% CI: 0.85, 0.96) with a median overall survival of 31.7 months for ABI and 34.2 months for ENZ). When restricting to 2015–2017 new users, the effect estimate shifted up to a hazard ratio of 0.93 (95% CI: 0.86, 1.01).

Importance: Ustekinumab, a monoclonal antibody targeting interleukin 12/23p40 (IL-12/23p40), is effective in the treatment of moderate to severe psoriasis, psoriatic arthritis, and Crohn disease. In 2011, a meta-analysis of randomized clinical trials reported a potential risk of severe cardiovascular events (SCEs) within the first few months after the initiation of anti-IL-12/23p40 antibodies. Objective: To assess whether the initiation of ustekinumab treatment is associated with increased risk of SCEs. Design, setting, and participants: This case-time-control study used data from the French national health insurance database, covering 66 million individuals, on all patients exposed to ustekinumab between April 1, 2010, and December 31, 2016, classified according to their cardiovascular risk level (high- and low-risk strata). The risk period was the 6 months before the SCE, defined as acute coronary syndrome or stroke, and the reference period was the 6 months before the risk period. Statistical analysis was performed from September 20, 2017, to July 6, 2018. Exposure: The initiation of ustekinumab treatment was screened during the risk and reference periods. Main outcomes and measures: Odds ratios for the risk of SCE after the initiation of ustekinumab treatment were calculated. Results: Of the 9290 patients exposed to ustekinumab (4847 men [52%]; mean [SD] age, 43 [14] years), 179 experienced SCEs (65 cases of acute coronary syndrome, 68 cases of unstable angina, and 46 cases of stroke). Among patients with a high cardiovascular risk, a statisically significant association between initiaton of ustekinumab treatment and SCE occurrence was identified (odds ratio, 4.17; 95% CI, 1.19-14.59). Conversely, no statistically significant association was found among patients with a low cardiovascular risk (odds ratio, 0.30; 95% CI, 0.03-3.13). Conclusions and relevance: This study suggests that the initiation of ustekinumab treatment may trigger SCEs among patients at high cardiovascular risk. In line with the current mechanistic models for atherosclerotic disease, the period after the initiation of anti-IL-12/23p40 may be associated with atherosclerotic plaque destabilization via the inhibition of helper T cell subtype 17. Although the study interpretation is limited by its observational design, these results suggest that caution may be needed in the prescription of ustekinumab to patients at high cardiovascular risk.

International audience; BACKGROUND: The European Medicines Agency (EMA) has developed risk minimization measures (RMMs) to reduce the use of the teratogenic drug, sodium valproate (VPA). The objective was to assess the impact of these RMMs among females with epilepsy in France. METHODS: We used data from the French National Health Insurance Database (SNDS), including 114,936 females aged under 50, with a reimbursement claim for an antiepileptic drug from January 2011 to December 2017, and identified as people with epilepsy. We used a controlled interrupted time series stratifying on age: girls (0-14 years old) and women of childbearing age (15-49 years), and with 129,917 males as controls. RESULTS: VPA prevalent use among girls and women of childbearing age with epilepsy decreased significantly after the issue of the RMMs (trend changes of, respectively, -5 and -4 users per 1000 females at-risk per quarter in comparison to the control group). We did not detect any significant change in VPA incident use. CONCLUSIONS: VPA use decreased over the study period among females with epilepsy but there were still 317 women and 206 girls started on VPA therapy VPA in 2017 (8 per 1000 at-risk and 18 per 1000, respectively). This suggests that either the measures should be strengthened or that the lowest level of VPA use has been reached. In this context, the introduction of a new RMM (in 2018) needs to be evaluated.

Objectifs Les profils d’effets indesirables d’abiraterone et enzalutamide reposent principalement sur les essais cliniques de phase III. Les donnees post-AMM soulevent plusieurs signaux de securite dont l’insuffisance renale aigue sous abiraterone. L’objectif de l’etude etait de comparer en vie reelle les taux d’incidence d’evenements indesirables ayant conduit a l’hospitalisation des patients nouveaux utilisateurs d’abiraterone versus enzalutamide et de discuter les signaux de securite precedemment identifies. Methodes Nous avons utilise le Systeme national des donnees de sante (SNDS) pour identifier les nouveaux utilisateurs d’abiraterone ou d’enzalutamide entre 2013 et 2017 et suivis jusqu’au 31/12/2018. Les evenements d’interet etaient une hospitalisation pour fibrillation auriculaire, insuffisance cardiaque, cardiopathie ischemique, insuffisance renale aigue, infarctus du myocarde, allongement du QT/torsade de pointe, AVC ischemique, hepatite ou convulsion. Les ratios de taux d’incidence (IRR) ont ete estimes pour chaque evenement independamment les uns des autres, en utilisant un modele de Poisson, a travers une sous-population de patients ne presentant pas de contre-indication ou de precaution d’emploi a l’un ou l’autre des traitements. Enzalutamide etait le groupe reference. Resultats Parmi 15 340 nouveaux utilisateurs d’abiraterone (70,5 %) et d’enzalutamide (29,5 %), pres de 51 % des patients ont presente au moins un evenement d’interet, dont 78 % n’en ont presente qu’un seul. Les evenements les plus frequemment observes etaient les hospitalisations pour fibrillation auriculaire, insuffisance cardiaque, ou encore insuffisance renale aigue ; a l’inverse, les hospitalisations pour AVC ischemique, allongement du QT, hepatite et convulsions survenaient chez moins de 10 cas pour 1000 personnes-annees exposees dans chacun des groupes. Les hospitalisation pour insuffisance renale aigue (IRR : 1,42, IC95 % : 1,01–2,00) et fibrillation auriculaire (IRR : 1,12, IC95 % : 1,05–1,19) ainsi qu’un bilan hepatique suggerant une hepatotoxicie (IRR : 3,06, IC95 % : 2,66–3,53) etaient significativement plus observes sous abiraterone que sous enzalutamide. Conclusion Notre etude permet d’apporter des informations complementaires concernant les evenements indesirables conduisant a une hospitalisation sous abiraterone et enzalutamide, en condition reelle d’utilisation. Malgre plusieurs limites dont le manque de donnees cliniques, le signal d’insuffisance renale aigue sous abiraterone reste coherent avec les resultats d’une precedente analyse de la base francaise de pharmacovigilance, et merite d’etre investigue plus en detail.

Introduction Les patients atteints de dermatite atopique (DA) ont un risque augmente d’infections cutanees. Une association potentielle entre DA de l’adulte et infections extra-cutanees a ete evoquee a partir d’etudes transversales avec diagnostics fondes sur auto-questionnaires. En theorie, les infections cutanees non traitees a Staphylococcus aureus notamment pourraient se compliquer d’infections systemiques (IS). L’objectif de ce travail est d’etudier si les adultes DA ont un risque augmente d’IS, a partir des registres exhaustifs medico-administratifs danois. Materiel et methodes Etude de cohorte incluant tous les adultes residents danois entre 1995 et 2017 (5 550 579). Les adultes DA etaient les sujets avec un code diagnostic DA renseigne a l’âge adulte par un dermatologue selon la classification internationale des maladies, 10e revision (CIM-10 L20). Chaque adulte avec DA etait apparie sur l’âge et le sexe a 10 adultes sans diagnostic de DA. Le critere de jugement etait les IS incidentes (hospitalisee ou consultation hospitaliere, selon CIM-10). Les hazard ratios (HR) avec leur intervalle de confiance (IC95 %) etaient estimes par un modele de Cox. Le modele etait ajuste sur les comorbidites atopiques et generales et la prise d’immunosuppresseur systemique de la DA. Resultats Au total, 10602 adultes avec DA (âge median 29 ans) et 106020 adultes de reference etaient inclus. Le taux d’incidence globale pour 10000 personne-annee d’IS etait de 180,6 (IC95 % 172,6-189,0) chez les adultes avec DA, compare a 120,4 (IC95 % 118,3-122,5) chez les adultes de reference. L’association entre DA et IS etait observee pour les infections osteoarticulaires (HR ajuste [aHR] 1,81 IC95 % 1,42-2,31), cardiaques (aHR 1,75 IC95 % 1,21-2,53), ORL (aHR 1,42 IC95 % 1,15-1,73) et pulmonaires (aHR 1,21 IC95 % 1,10-1,33). Le risque de sepsis (aHR 1,19 IC95 % 1,01-1,44) etait egalement augmente. Discussion Nos resultats apportent des arguments supplementaires d’association entre DA et IS. Ils supportent notamment les donnees de cas cliniques d’endocardites concomitantes de poussees d’eczema et de deux etudes transversales americaines sur donnees hospitalieres montrant une prevalence augmentee d’endocardite et de septicemie. Cependant ces resultats doivent etre interpretes avec prudence, la difference de risque absolu etant petite, correspondant ainsi a 1,8 infections cardiaques supplementaires parmi des adultes DA sur 20 ans de suivi. Les forces de l’etude sont : l’ensemble des patients DA vus par un dermatologue travaillant a l’hopital ou en clinique sans biais d’attrition, l’absence de perte de vue sur 20 ans et la prise en compte de differentes categories d’infections. Les limites sont l’absence de generalisation des resultats aux DA vues en soins primaires et d’informations cliniques detaillees. Les cliniciens doivent connaitre cette association potentielle lors de la prise en charge des DA de l’adulte.

Background Isotretinoin is the only effective treatment for severe acne. An isotretinoin-related suicide risk is still debated and under scrutiny by regulatory agencies. Our objectives were: to assess the risk of suicide attempt before, during and after isotretinoin treatment; to detect any potential triggering effect of isotretinoin initiation on suicide attempt. Methods We implemented a cohort and nested case-time-control study of subjects treated with oral isotretinoin (course or initiation) aged 10–50 years, using the Nationwide French Health Insurance data (2009–2016). The main outcome was hospitalized suicide attempt. Standardized incidence ratios for hospitalized suicide attempts were calculated before, during and after isotretinoin treatment. The number of isotretinoin initiations was compared in risk and control periods of 2 months using a case-time-control analysis. Results In all, 443 814 patients (median age 20.0 years; interquartile range 17.0–27.0 years) were exposed to isotretinoin, amounting to 244 154 person-years, with a marked seasonality for treatment initiation. Compared with the French general population, the occurrence of suicide attempts under isotretinoin treatment was markedly lower, with a standardized incidence ratio of 0.6 [95% confidence interval (CI) = 0.53–0.67]; the same applied, to a lesser extent, before and after isotretinoin treatment. In the case-time-control analysis, among cases of suicide attempt, 108 and 127 isotretinoin initiations were observed in the risk and control periods respectively (i.e. 0–2 months and 2–4 months before the date of suicide attempt). The comparison with the 1199 and 1253 initiations observed among matched controls in the same two periods yielded a case-time-control odds ratio of 0.89 (95% CI = 0.68–1.16). A sensitivity analysis using three-month periods and a complementary analysis adding completed suicides for case definition showed consistent results. Conclusion Compared with the general population, a lower risk of suicide attempt was observed among patients exposed to isotretinoin and there was no evidence for a triggering effect of isotretinoin initiation on suicide attempt. A selection of patients at lower risk for suicidal behaviour and appropriate treatment management could explain these findings. Risk management plans should therefore be maintained.

Immune checkpoint inhibitors and targeted therapies have profoundly altered the management of several cancers over the past decade. Metastatic melanoma has been at the forefront of these changes. We provide here a nationwide overview and an assessment of changes in survival in France. We included 10,936 patients receiving a systemic treatment for metastatic cutaneous melanoma between 2010 and 2017 using the French National Health Insurance database (Système National des Données de Santé). Over the study period, there was a doubling of the number of new patients receiving a systemic treatment. Cytotoxic chemotherapy was progressively replaced by targeted therapy and immune checkpoint inhibitors. Patients having initiated a first-line treatment since June 2015 gained 46% overall survival compared with those initiating treatment before 2012. Overall survival at 24 months rose from 21% to 44%. We provide real-world evidence for the improvement of overall survival in the past decade among patients with metastatic melanoma. Although the characteristics of the patients treated can vary across periods, this type of exhaustive real-world data provides evidence from broader populations than those included in clinical trials.

Introduction Le pronostic du melanome metastatique a ete considerablement ameliore par la mise a disposition de l’immunotherapie, ciblant notamment programmed cell death 1 (PD-1) depuis juin 2015. Cependant, plusieurs etudes recentes suggerent une perte d’efficacite de l’immunotherapie quand son initiation est immediatement precedee d’une antibiotherapie. Une dysbiose intestinale induite par l’antibiotherapie limiterait l’effet de l’immunotherapie sur les cellules tumorales. Notre objectif etait d’estimer l’effet de l’antibiotherapie dans le mois qui precede l’initiation d’un anti-PD-1, sur l’efficacite de l’immunotherapie, chez des patients atteints de melanome metastatique. Materiel et methodes Nous avons reconstruit a partir de la base de donnees de l’Assurance-Maladie (Systeme National des Donnees de Sante) une cohorte comprenant tous les patients ayant recu un anti-PD-1 en traitement de premiere ligne d’un melanome metastatique en France entre 2015 et 2017. Nous avons estime l’effet de l’antibiotherapie sur la survie globale et la duree de l’immunotherapie par un modele de Cox. Les potentiels facteurs de confusion concernant les caracteristiques des patients (âge, sexe, comorbidites), du melanome (sites de metastases, radiotherapie ou metastasectomie recentes), ont ensuite ete pris en compte par une analyse multivariee. La survie globale et la duree de traitement par anti-PD-1 ont ete representes en fonction de la prise ou non d’antibiotique par une courbe de Kaplan–Meier. Des analyses de sensibilite ont fait varier la fenetre d’exposition a l’antibiotherapie, et le type d’antibiotherapie recue. Resultats Parmi les 2605 patients ayant ete traites par anti-PD-1 en premiere ligne, 336 (12,9 %) ont recu un antibiotique dans le mois qui precedait. La survie etait similaire chez les patients ayant recu ou non un antibiotique dans le mois qui precedait, en analyse univariee (hazard ratio [HR], 0,97, intervalle de confiance a 95 % [IC95 %], [0,81–1,18]), ou multivariee (HR = 0,91 [0,75–1,10]). La duree de traitement par anti-PD-1 etait egalement similaire dans les 2 groupes, en analyse univariee (HR = 1,01 [0,87–1,16]), ou multivariee (HR = 0,99 [0,86–1,15]). Lorsque l’antibiotherapie etait recue entre 2 mois avant et 1 mois apres l’initiation de l’anti-PD-1, ou lorsque seule la prise d’amoxicilline-acide clavulanique etait consideree, la survie et la duree de traitement n’etaient pas non plus modifiees. Discussion Ces resultats, obtenus a partir de donnees exhaustives nationales et sans perdu de vue, contredisent les etudes precedentes, d’effectif plus faible. Ils doivent inciter a la prudence avant de remettre en question la prescription d’antibiotique precedant l’initiation d’un anti-PD-1 quand ils sont necessaires, voire de retarder l’initiation de l’immunotherapie.

Introduction Depuis 2014, l’Agence europeenne des medicaments a mis en place de nombreuses mesures de reduction des risques concernant la prescription de valproate de sodium (VPA) chez les femmes en âge de procreer et enceintes. Notre objectif est de decrire la prise en charge des femmes enceintes epileptiques autour de ces mesures. Methodes Etude observationnelle a partir de la base nationale de donnees de l’Assurance maladie incluant toutes les femmes ayant presente une grossesse entre janvier 2013 et decembre 2016, ayant recu du VPA au cours des deux annees precedant ou pendant la grossesse. Inclusion uniquement des femmes epileptiques grâce a un algorithme d’identification du contexte pathologique. Estimation de l’exposition au VPA et a ses alternatives a partir des delivrances en pharmacie pour decrire les sequences de traitement avant, pendant et apres la grossesse. Resultats Parmi les femmes enceintes epileptiques (N = 5119 grossesses), le nombre de femmes enceintes exposees au VPA diminue: de 55,8 % en 2013 a 21,3 % en 2016 au premier trimestre de grossesse et de 61,8 % en 2013 a 39 % en 2016 durant l’annee precedant la grossesse. Parmi les 1698 femmes ayant un desir de grossesse, 13 % seulement ont consulte un neurologue en amont de la grossesse et 36,2 % sont exposees au VPA au premier trimestre de grossesse. Presque 50 % des prescripteurs sont des medecins generalistes. Les neurologues sont peu representes. Discussion/conclusion L’exposition au VPA durant la grossesse persiste (2131 grossesses exposees, 41 %). Il ne s’agit pas d’une meconnaissance des prescripteurs puisqu’il existe un effort de modification de la prise en charge de la patiente epileptique durant la grossesse (report des prescriptions de VPA vers d’autres alternatives voire arret des traitements antiepileptiques). Au premier trimestre de la grossesse l’exposition restent elevee. Le plan de prevention des grossesses et la contre-indication de l’utilisation du VPA chez la femme en âge de procreer devraient jouer un role benefique a ce sujet, meme s’il est attendu qu’un nombre incompressible de femmes restent exposees au VPA.

OBJECTIVES: The safety of oral propranolol for infantile hemangioma has not yet been studied at population level since the pediatric use marketing authorization was obtained in Europe. METHODS: A survey of a nationwide, claim-based observational cohort of children RESULTS: In all, 1753 patients CONCLUSIONS: In this study on a large continuous nationwide claims database, we confirm the safety profile of oral propranolol in healthy children to be good.

Introduction Bien que le role causal de l’isotretinoine (ISO) sur les conduites suicidaires soit controverse, des tentatives de suicide (TS) et suicides peuvent survenir sous ISO. Les agences de securite du medicament en Europe et aux Etats-Unis ont cependant emis des recommandations aupres des professionnels de sante quant a ce risque psychiatriques potentiel. Aucune etude sur les facteurs de risque (FDR) de TS sous ISO n’a ete menee ; seuls quelques cas ont ete rapportes dans la litterature. Objectifs Decrire le profil des patients et la prise en charge de leur traitement chez les patients ayant commis un suicide ou une TS sous ISO. Evaluer les FDR de TS sous ISO. Materiel et methodes Nous avons decrit l’ensemble des suicides et TS survenus sous ISO et mene une etude cas-temoin, a partir de la base de donnees medico-administratives francaise (SNDS), entre 2010 et 2014. L’analyse principale comparait les cas (patients avec TS hospitalises pendant une cure d’ISO) a des temoins, individuellement apparies sur l’âge, le sexe et le rang de la cure ; les temoins etaient exposes a l’ISO a la date index (date de la TS du cas correspondant). Le profil psychologique des patients a l’initiation de la cure etait etudie selon trois profils : profil « psychiatrique » (antecedent de TS et/ou antecedent d’hospitalisation pour un motif psychiatrique et/ou ALD pour une maladie psychiatrique et/ou prise de psychotropes), profil « anxieux » (prise d’anxiolytiques sans aucun autre antecedent psychiatrique precite) et profil « sain » (aucun antecedent psychiatrique). Dans l’analyse secondaire, les patients ayant continue leur cure apres leur TS etaient compares avec les patients ayant arrete leur cure. Resultats Un total de 328 018 patients a debute une cure d’ISO entre le 1er janvier 2010 et le 31 decembre 2014 ; 184 ont ete hospitalises pour une TS et 17 sont morts par suicide sous ISO, correspondant a une TS pour 2107 patients debutant une cure et un suicide pour 22 802 cures. La moitie d’entre eux avait un profil « psychiatrique ». Dans l’analyse multivariee, le profil « psychiatrique » et le profil « anxieux » etaient un FDR de TS (OR, 18,21 ; IC95 %, 9,96–33,30 et 4,78 ; IC95 %, 2,44–9,33 respectivement). Parmi les 176 cas de TS ayant un suivi suffisant, 103 (58,5 %) ont continue leur traitement apres la TS. L’initiation d’un traitement par un dermatologue etait inversement associee avec la poursuite de la cure d’ISO apres une TS (OR, 0,38 ; CI95 %, 0,18–0,80). Conclusion Les FDR de TS sous ISO sont les FDR « classiques » de TS. L’evaluation de ces facteurs « psychiatriques » doit etre faite avant la prescription d’ISO. Dans la pratique courante, le rapport benefice-risque individuel, incluant l’evaluation du risque « psychiatrique » lie a l’acne, doit etre evalue avec attention.

Objectifs Chez les patients presentant un cancer de prostate resistant a la castration (CPRC) en echec de chimiotherapie par docetaxel, deux traitements hormonaux, abiraterone (ABI) et enzalutamide (ENZ), et une seconde ligne de chimiotherapie par cabazitaxel (CABA) apparaissent des options therapeutiques. Hormis quelques etudes observationnelles peu puissante (dont meta-analyses discordantes), aucun essai clinique n’a compare jusqu’a present l’efficacite d’AB, ENZ et CABA de facon directe. Methodes L’objectif de cette etude etait de comparer de facon directe la survie globale des patients francais initiant un traitement par ABI, ENZ ou CABA chez des patients CPRC metastatiques en echec de chimiotherapie. Utilisant les donnees du SNDS, une etude de cohorte a ete realisee incluant les nouveaux utilisateurs d’ABI, ENZ ou CABA entre 2014 et 2015 et suivis jusqu’a fin 2017. Avec une approche type en intention de traiter, une analyse de survie a ete conduite, estimant le HR de la survie globale avec un modele de Cox et utilisant un score de propension par la methode SIPTW. Resultats Parmi les 538 nouveaux utilisateurs, 56,1 % etaient traites par ABI, 26,2 % par ENZ et 17,3 % par CABA. Avec un suivi median de 25,8 mois (Q1–Q3, 12,2–37,8 mois) pour ABI, 25,8 mois (Q1–Q3, 15,5–35,8 mois) pour ENZ et 17,1 mois (Q1–Q3, 9,9–28,7 mois) pour CABA, le taux d’incidence des deces toutes causes etait de 30,4 pour 100 personnes-annees (PA) (IC95 % : 26,4–35,0) pour ABI, 28,7/100 PA (IC95 % : 23,3–35,4) pour ENZ et 47,4/100 PA (IC95 % : 37,7–59,7) pour CABA. Le suivi median des patients decedes etait de 15,7 mois (Q1–Q3, 8,4–25,4 mois) pour ABI, 19,3 mois (Q1–Q3, 11,0–27,3 mois) pour ENZ et 17,1 mois (Q1–Q3, 7,3–25,2) pour CABA. Comparativement a ABI, l’analyse multivariee suggere l’absence de difference en survie globale sous ENZ (HR : 1,01 [0,78–1,29]), et une augmentation du risque de deces sous CABA (HR : 1,46 [1,11–1,92]). Conclusion Nous reconnaissons l’absence de donnees cliniques pour categoriser le stade de la maladie ou le performans status, pouvant etre des facteurs de confusion. Notre etude sur base de donnees francaise suggere, chez les patients CRPC en echec de chimiotherapie, une survie globale similaire entre ABI et ENZ mais un sur-risque de deces sous CABA.

Introduction L’isotretinoine orale a ete accusee d’induire un risque suicidaire, en particulier dans la phase initiale du traitement. Nous avons analyse le risque de tentative de suicide (TS) sous isotretinoine a partir des donnees nationales exhaustives de l’assurance maladie (SNIIRAM 2009–2016) qui couvrent 98 % de la population francaise. Materiel et methodes Tous les sujets ayant eu au moins une delivrance d’isotretinoine entre 10 et 50 ans sur la periode 2009–2016 ont ete selectionnes. Le risque de TS (defini par une hospitalisation codee TS) a ete analyse, par periodes de 2 mois : avant, pendant, et apres l’initiation de l’isotretinoine, en etablissant des ratios standardises d’incidence (SIR) par rapport a la population francaise, en tenant compte du sexe, de l’âge, de l’annee et du mois. Une seconde analyse a recherche un sur-risque de TS dans les 2 mois qui suivent l’initiation d’isotretinoine par une analyse case-time-control qui compare la frequence d’initiation d’isotretinoine dans la periode « a risque » des 2 mois precedant la TS, a celle, chez le meme sujet, de la periode temoin qui precede la periode a risque, et qui tient compte de l’eventuelle evolution naturelle des initiations entre les deux periodes, mesuree par l’observation faite chez des temoins n’ayant pas fait de TS (10 temoins apparies par cas). Le risque pour une periode de 3 mois post-initiation a ete etudie en analyse secondaire. Resultats Au total, 4533 TS chez 3561 sujets ont ete observees dans notre « population isotretinoine » de 447 396 sujets. Les ratios standardises d’incidence de TS etaient inferieurs a 1, avant mais aussi apres l’initiation du traitement ( Fig. 1 ). Parmi les 3954 TS de la seconde analyse, et leurs 39 540 temoins, le risque de TS dans les 2 mois apres l’initiation etait de OR = 0,87 (IC95 % : 0,66–1,14 ; p = 0,30), et dans les 3 mois de OR = 0,87 (IC95 % : 0,64–0,99 ; p = 0,042). Discussion Cette etude depasse de beaucoup en nombre d’evenements et donc en puissance statistique toutes les etudes prealablement menees sur cette question. Nous mettons en evidence un risque abaisse de TS chez les patients recevant de l’isotretinoine, notamment dans les 2 a 3 mois qui suivent l’initiation. Pour en rendre completement compte, nous proposons la conjonction de 2 effets : (1) un processus de selection des patients par les dermatologues consistant a ecarter de la prescription d’isotretinoine les sujets les plus a risque de faire une TS ; (2) une diminution de la part du risque de TS lie a l’acne elle-meme, dans les 2 a 3 premiers mois de traitement consequence de l’efficacite therapeutique rapide de l’isotreninoine. Conclusion Les prescripteurs semblent avoir adapte les decisions d’indication de l’isotretinoine selon un rapport benefice–risque particulierement pertinent pour la sante publique.

Introduction L’Hemangiol® (chlorhydrate de propranolol) a eu une AMM pediatrique en 2014 pour traiter les hemangiomes infantiles. Un plan de gestion des risques a identifie les evenements indesirables potentiels graves suivants : cardiovasculaires (CV) : troubles de conduction, bradycardie, hypotension ; respiratoires (RE) : bronchospasme/hyperactivite bronchique ; et metaboliques (MET) : hypoglycemie et hyperkaliemie. De plus, un risque d’accident vasculaire ischemique cerebral (AVCi) est a ete evoque au cours du syndrome PHACES. L’objectif de ce travail etait d’evaluer la tolerance de l’Hemangiol®, a partir de la base de donnees medico-administrative de remboursement de l’assurance maladie francaise (SNIIRAM, Systeme national inter-regime de l’assurance maladie). Materiel et methodes Cohorte retrospective issue du SNIIRAM de patients ≤ 3 ans, avec au moins un remboursement d’Hemangiol®, entre juillet 2014 et juin 2016. Etaient recherches une hospitalisation pour un evenement d’interet CV, RE ou MET. Une hospitalisation pour AVCi etait egalement recherchee. L’analyse des evenements hospitalises (EH) sous Hemangiol® etait comparee aux memes EH survenus dans la population generale ≤ 3 ans estimes a partir de l’EGB (echantillon generaliste des beneficiaires : echantillon aleatoire a 1 % du SNIIRAM) en reference. L’analyse etait stratifiee sur la presence d’une maladie chronique CV, RE ou MET et d’une prematurite. Le nombre d’EH chez les exposes et dans la population generale etait compare par une standardisation indirecte. Le ratio observe/attendu (Standardized Morbidity Ratio : SMR) etait donne avec un IC95 % pour chaque EH. Resultats Un total de 1753 patients ont eu plus d’un remboursement d’Hemangiol® (âge median [Q1–Q3] de 5 mois [3,7], 1266 filles) ; 8,7 % avaient une maladie CV, 7,9 % une maladie RE et 3,9 % une maladie MET ; 21,5 % etaient prematures. Les troubles de conduction etaient plus frequents chez les patients exposes avec une maladie chronique CV sous-jacente (SMR = 13,7 [4,2–23,3] IC95 %). Aucun signal d’alerte n’a ete observe pour les evenements RE ou MET ( Fig. 1 ). Aucun AVCi n’a ete observe. Discussion Les troubles de conduction observes sous Hemangiol® chez les patients avec une maladie chronique CV survenaient sur le meme sejour hospitalier, associe a un diagnostic principal de cardiopathie congenitale, en majorite une tetralogie de Fallot. L’Hemangiol® est probablement donne dans le cadre de cette maladie chronique CV. Conclusion Hemangiol® est bien tolere et notre etude n’identifie aucun signal alarmant. L’augmentation des troubles de conduction semble limitee a une population ayant une cardiopathie congenitale identifiee, et suggere une indication pour d’autres motifs que l’hemangiome infantile. Ces donnees « en vraie vie » sur une population exhaustive a l’echelle nationale, complete celles issues des dossiers d’ATU.

Introduction Le melanome metastatique a connu des avancees therapeutiques majeures depuis 2011, avec la mise sur le marche des immunotherapies et des therapies ciblees. Notre objectif etait de decrire, a partir du systeme national des donnees de sante de l’Assurance maladie (SNDS-SNIIRAM), l’evolution de la prise en charge du melanome metastatique sur la periode 2010–2016. Materiel et methodes Les cas incidents de melanome metastatique traites, en France entre 2010 et 2016, ont ete identifies. Nous avons compare les parcours et le devenir des patients initiant une premiere ligne de traitement systemique en 2011, 2013 ou 2015. Les sequences therapeutiques ont ete decrites avec des diagrammes de Sankey. La survie globale (date de point : 31 decembre 2017) a ete analysee par la methode de Kaplan–Meier. Resultats Parmi 8956 cas incidents de melanome metastatique, 3157 patients etaient traites par therapie ciblee, 2009 par ipilimumab et 3138 par anti-PD1. Le recours a la chimiotherapie diminuait de facon continue sur la periode, au fur et a mesure de la disponibilite des nouveaux traitements. La comparaison des parcours des patients initiant une prise en charge en 2011, 2013 ou 2015 objectivait des differences majeures. La survie globale etait amelioree pour les patients dont le traitement avait debute en 2015 (survie globale a 2 ans : 48 %, IC95 % [0,46 ; 0,50] versus 40 % [0,37 ; 0,43] pour les patients debutant une 1re ligne de traitement en 2011) ( Fig. 1 ). Discussion Les donnees de l’Assurance maladie permettent de decrire les evolutions en « vie reelle », de facon exhaustive a l’echelle nationale, et sans perdu de vue. Meme si les donnees cliniques ne sont pas disponibles (caracteristiques du melanome, rechute, etc.), les traitements le sont de facon detaillee ; les sequences therapeutiques et le deces permettent d’evaluer la prise en charge et le pronostic. Il n’existe pas de donnees equivalentes dans un autre pays. Cette etude est toutefois restreinte aux melanomes traites, population non parfaitement superposable a l’ensemble des stades IV. Par ailleurs, au sein d’un parcours individuel, les periodes d’essais cliniques ne sont pas facilement identifiables. Conclusion Ce travail objective les changements majeurs de la prise en charge du melanome metastatique et permet de quantifier l’amelioration de la survie globale, en « vie reelle », a l’echelle nationale.

Introduction L’ustekinumab (Stelara®) est un anticorps monoclonal anti-interleukine (IL) 12/23 commercialise depuis mars 2010. Une meta-analyse a alerte en 2011 sur un possible risque d’evenements cardiovasculaires graves (ECVG). Aucun travail n’a ete mene par la suite pour confirmer ou infirmer ce risque potentiel. L’ustekinumab pourrait destabiliser les plaques d’atherome, via l’inhibition de la population lymphocytaire T helper 17. L’objectif etait de rechercher un effet declencheur d’ECVG a l’initiation de l’ustekinumab. Patients et methodes L’ensemble des patients exposes a l’ustekinumab entre 2010 et 2016 a ete identifie a partir des bases de donnees francaises de l’Assurance maladie (SNDS-SNIIRAM). Les ECVG retenus etaient les syndromes coronariens aigus (SCA) et accidents vasculaires cerebraux (AVC) ischemiques. L’hypothese d’une periode a risque de 6 mois suivant l’initiation de l’ustekinumab a ete testee par une analyse « case-time-control ». Elle compare, chez les sujets ayant fait un ECVG, le nombre d’initiations pendant les 6 mois qui precedent les ECVG a celui des 6 mois anterieurs. Resultats Parmi les 9290 patients exposes a l’ustekinumab, 75 ont presente un SCA, un AVC ou un angor instable en cours de traitement. L’incidence d’ECVG etait de 61 pour 100 000 personnes-mois, IC 95 % [43 ; 86] dans les 6 premiers mois apres l’initiation. L’analyse « case-time-control » des 98 ECVG survenus avant, pendant ou apres la cure, et des 392 « temoins pour la tendance temporelle », a montre des OR significativement differents selon le niveau de risque cardiovasculaire du patient, estime a partir de ses facteurs de risque cardiovasculaires. Chez les patients a faible risque cardiovasculaire, on n’observait pas d’effet declencheur de l’ustekinumab (OR = 0,30, IC 95 % [0,03 ; 3,13]). Chez les patients a risque cardiovasculaire eleve, on observait un risque significatif de declenchement d’ECVG par l’ustekinumab (OR = 4,17 [1,19 ; 14,59]). Ce risque persistait dans les analyses de sensibilite ( Fig. 1 ). Discussion Nos resultats suggerent un « effet declencheur » d’ECVG dans les mois qui suivent l’initiation de l’ustekinumab, identifie chez les patients a risque cardiovasculaire eleve, en coherence avec l’hypothese physiopathologique de destabilisation des plaques d’atherome. Conclusion Ces resultats incitent a des mesures de prudence dans l’indication d’ustekinumab chez des sujets a risque cardiovasculaire. Les autres biotherapies impliquant la voie lymphocytaire T helper 17 (anti-IL17A, anti-IL17RA, anti-IL23), recemment commercialisees, pourraient etre concernees par ce signal.