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In 2018, the "Ateliers de Giens" (Giens Workshops) devoted a workshop to artificial intelligence (AI) and led its experts to confirm the potential contribution and theoretical benefit of AI in clinical research, pharmacovigilance, and in improving the efficiency of care. The 2022 workshop is a continuation of this reflection on AI and intelligent automation (IA) by focusing on its contribution to pharmacovigilance and the applications and tasks could be optimized to preserve and strengthen medical and pharmacological expertise in pharmacovigilance. The evolution of pharmacovigilance work is characterized by many tasks with low added value, a growing volume of pharmacovigilance reporting of suspected side effects, and a scarcity of medical staff with expertise in clinical pharmacology and pharmacovigilance and human resources to support this growing need. Together, these parameters contribute to an embolization of the pharmacovigilance system at risk of missing its primary mission: to identify and characterize a risk or even a health alert on a drug. The participants of the workshop (representatives of the Regional Pharmacovigilance Centres (CRPV), the French National Agency for Safety of Medicinal Products (ANSM), patients, the pharmaceutical industry, or start-ups working in the development of AI in the field of medicine) shared their experiences, their pilot projects and their expectations on the expected potential, theoretical or proven, AI and IA. This work has made it possible to identify the needs and challenges that AI or IA represent, in the current or future modes of organization of pharmacovigilance activities. This approach led to the development of a SWOT matrix (strengths, weaknesses, opportunities, threats), a basis for reflection to identify critical points and consider four main recommendations: (1) preserve and develop business expertise in pharmacovigilance (including research and development in methods) with the integration of new technologies; (2) improve the quality of pharmacovigilance reports; (3) adapt technical and regulatory means; (4) implement a development strategy for AI and IA tools at the service of expertise.

International audience; Since pandemic start, patients may have faced difficulties in accessing to care and treatment. This study aimed at assessing the impact of COVID-19 pandemic and its control measures on the use of drugs indicated in cardiovascular prevention and diabetes mellitus in France. From 09/17/2018 to 09/20/2020, a repeated cohort analysis was performed using the French nationwide health insurance databases. The pandemic impact was assessed using time-series analyses and unobserved components model for the weekly number of patients with (i) drug dispensing, (ii) ongoing treatment, (iii) treatment initiation, (iv) treatment disruption. Overall, 14,822,132 patients with cardiovascular drug dispensings and 3,231,618 with antidiabetic ones were identified. After a sharp spike in the amount of dispensings in the week the first national lockdown was announced, the period was marked by decreased levels and trends. Altogether, the estimated impact of the pandemic on dispensings appeared limited over the lockdown period (1-3% lack in dispensings). During lockdown, the weekly numbers of treatment disruptions remained stable whereas a significant decrease in treatment initiations was observed for almost all drug classes (e.g. β-blockers initiations: - 8.9%). Conversely, the post-lockdown period showed increases in treatment disruptions especially for antihypertensive and lipid lowering drugs (e.g. statins disruptions: + 4.9%). The pandemic and associated measures had a significant impact on cardiovascular and antidiabetic drugs use in France, mostly consisting in decreases of treatment initiations over lockdown and increases in treatment disruptions afterwards. Both could result in increased morbimortality that remains to be assessed.

Immune checkpoint inhibitors (ICI) restore immune response against cancer cells that can lead to immune-related adverse effects. While cardiovascular immune-related adverse effects are known to be associated with checkpoint inhibitors, recent case reports have raised concerns about the potential association with pulmonary hypertension (PH). By using the global pharmacovigilance database VigiBase, we investigated the onset of PH associated with ICI and propose a comprehensive description of the 42 cases of PH reported with ICI recorded in this database. Through this study and review of the cases published in the literature, we discuss the possible link between PH and ICI in the context of cancer in order to better understand this rare but potentially fatal event.

Summary The pathophysiological study of diabetes mellitus took an important place in the school of Montpellier since the end of the XIXth century with Emmanuel Hedon's (1863–1933) contribution to the demonstration of the endocrine function of the pancreas. In 1942, a new sulfonamide compound (2254RP) was tested in the infectious diseases department of Pr M. Janbon (1898–1996) on cases of typhoid fever, leading to several deaths rapidly related to hypoglycaemia. The physiologist Auguste Loubatieres (1912–1977) rapidly demonstrated that this hypoglycaemic effect required the presence of pancreas and was explained by stimulation of insulin secretion. He contributed to the description of a hypoglycaemic effect of several other sulphonamide compounds. He considered the diagnostic and therapeutic relevance of this class of drugs. This is a good example of a medical discovery combining a favourable local environment, serendipity and perfect experimental approach.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors might increase the risk of intestinal obstruction, but real-world evidence for this severe adverse event is lacking. Thus, the objective of this study was to determine whether GLP-1 RAs and DPP-4 inhibitors are associated with an increased risk of intestinal obstruction compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. We used the United Kingdom Clinical Practice Research Datalink and linked databases to assemble two new-user, active comparator cohorts (2013-2019). The first included 25,617 and 67,261 GLP-1 RA and SGLT-2 inhibitor users, respectively. The second included 131,927 and 40,615 DPP-4 inhibitor and SGLT-2 inhibitor users, respectively. Propensity score fine stratification weighted Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of intestinal obstruction requiring hospitalization. GLP-1 RAs were associated with an increased risk of intestinal obstruction compared with SGLT-2 inhibitors (1.9 vs. 1.1 per 1,000 person-years, respectively; HR: 1.69, 95% CI: 1.04-2.74). The highest HR was observed after 1.6 years of use (HR: 3.48, 95% CI: 1.79-6.79). DPP-4 inhibitors were also associated with an increased risk (2.7 vs. 1.0 per 1,000 person-years; HR: 2.59, 95% CI: 1.52-4.42), with the highest HR observed after 1.8 years of use (HR: 9.53, 95% CI: 4.47-20.30). The number needed to harm after 1 year of use was 1,223 and 603 for GLP-1 RAs and DPP-4 inhibitors, respectively. In this large real-world study, GLP-1 RAs and DPP-4 inhibitors were associated with an increased risk of intestinal obstruction.

Cases of adult-onset Still's disease (AOSD) have been reported after COVID-19 vaccination. Here we provide a comprehensive description and analysis of all cases of AOSD reported in the literature and in pharmacovigilance databases through April 2022. Disproportionality analyses of pharmacovigilance data were performed in order to further explore the association between vaccination and AOSD. We included 159 patients, 144 from the World Health Organization pharmacovigilance database and 15 from the literature. Detailed clinical characteristics were described for the cases from the literature and from the French pharmacovigilance database (n = 9). The cases of AOSD after COVID-19 vaccination concerned women in 52.2% of cases. The median age was 43.4 years. More than 80% of AOSD reports occurred during the first three weeks and concerned mostly the BNT162b2 mRNA vaccine. We identified 14.5% of disease flare with a median time-to-onset of AOSD flare-up significantly shorter than for the new onset form. More than 90% patients received steroids. Although all cases were considered serious and required hospitalization, most cases presented a favorable outcome (67.1%) with a good response to corticosteroid therapy with a mean time to recovery of 7.2 days. Disproportionality analyses suggested that AOSD was associated with COVID-19 vaccines as well as other vaccines. AOSD was nearly five times more frequently reported with COVID-19 vaccines than with all other drugs. Clinicians should be informed about the potential risk of AOSD onset or flare following COVID vaccines and the importance of its early detection to optimize its management.

Levamisole was initially prescribed for the treatment of intestinal worms. Because of immunomodulatory properties, levamisole has been used in inflammatory pathologies and in cancers in association with 5-fluorouracil. Levamisole is misused as a cocaine adulterant. Post-marketing reports have implicated levamisole in the occurrence of adverse drug reactions (ADRs) and its use is now limited in Europe and North America. In contrast, all other parts of the World continue to use single-dose levamisole as an anthelmintic. The aim of this study was to identify ADRs reported after levamisole exposure in VigiBase, the World Health Organisation's pharmacovigilance database, and analyse their frequency compared to other drugs and according to levamisole type of use.All levamisole-related ADRs were extracted from VigiBase. Disproportionality analyses were conducted to investigate psychiatric, hepatobiliary, renal, vascular, nervous, blood, skin, cardiac, musculoskeletal and general ADRs associated with levamisole and other drugs exposure. In secondary analyses, we compared the frequency of ADRs between levamisole and mebendazole and between levamisole type of use.Among the 1763 levamisole-related ADRs identified, psychiatric disorders (reporting odds ratio with 95% confidence intervals: 1.4 [1.2-2.6]), hepatobiliary disorders (2.4 [1.9-4.3]), vasculitis (6.5 [4.1-10.6]), encephalopathy (22.5 [17.4-39.9]), neuropathy (4.3 [2.9-7.1]), haematological disorders, mild rashes and musculoskeletal disorders were more frequently reported with levamisole than with other drug. The majority of levamisole-related ADRs occurred when the drug was administrated for a non-anti-infectious indication.The great majority of the levamisole-related ADRs concerned its immunomodulatory indication and multiple-dose regimen. Our results suggest that single-dose treatments for anthelmintic action have a good safety profile.

In the last French study in 2007, the incidence of hospital admissions (HAs) related to adverse drug reactions (ADRs) was 3.6%. The objective was to assess the current ADR-HA incidence in France and to describe both its characteristics and preventability.A prospective multicentre study was conducted among randomly selected French public hospital medical wards (April-July 2018). Patients admitted during a week period were included. ADR-HA cases were collected by the French Regional Pharmacovigilance Centres network. An independent committee validated potential cases and ADR preventability.ADR-HA incidence was 8.5% (95% confidence interval [CI]: 7.6-9.4%), increasing with age (3.3% [95%CI: 1.8-5.5%] ≤16 y vs. 10.6% [95%CI: 9.3-12.0%] ≥65 y). The most common ADRs were haemorrhagic events (8.8%), haematological disorders (6.5%), acute renal failure (6.3%), fluid and electrolyte disorders (6.0%), and falls (5.2%). New drugs were involved: targeted therapies (22.8% of antineoplastics), direct oral anticoagulants (29.6% of antithrombotics) and incretin-based drugs (20.0% of antidiabetics). ADRs were preventable in 16.1% of cases because the drugs involved had not been used in accordance with monographies, package leaflets or other therapeutic guidelines. The main situations of noncompliance addressed either dose or duration of use (27.9%), warning (23.2%), use precaution (18.6%) and inappropriate self-medication or misuse by patients (11.6%).In France, ADR-HA incidence dramatically increased over the last decade. A significant proportion was related to new pharmacological classes and considered as preventable. These findings should lead to in-depth thought on preventive actions on at-risk drug classes.

BackgroundImmune checkpoint inhibitors (ICI) have transformed cancer treatment over the last decade. Alongside this therapeutic improvement, a new variety of side effects has emerged, called immune-related adverse events (irAEs), potentially affecting any organ. Among these irAEs, myocarditis is rare but life-threatening.MethodsWe conducted a multicenter cross-sectional retrospective study with the aim of better characterizing ICI-related myocarditis. Myocarditis diagnosis was based on the recent consensus statement of the International Cardio-Oncology Society.ResultsTwenty-nine patients were identified, from six different referral centers. Most patients (55%) were treated using anti-programmed-death 1, rather than ICI combination (35%) or anti-programmed-death-ligand 1 (10%). Transthoracic echocardiography was abnormal in 52% of them, and cardiac magnetic resonance showed abnormal features in 14/24 patients (58%). Eleven patients (38%) were classified as severe. Compared with other patients, they had more frequently pre-existing systemic autoimmune disease (45% vs 6%, p=0.018), higher troponin level on admission (42-fold the upper limit vs 3.55-fold, p=0.001), and exhibited anti-acetylcholine receptor autoantibodies (p=0.001). Seven patients (24%) had myocarditis-related death, and eight more patients died from cancer progression during follow-up. Twenty-eight patients received glucocorticoids, 10 underwent plasma exchanges, 8 received intravenous immunoglobulins, and 5 other immunosuppressants. ICI rechallenge was performed in six patients, with only one myocarditis relapse.DiscussionThe management of ICI-related myocarditis may be challenging and requires a multidisciplinary approach. Prognostic features are herein described and may help to allow ICI rechallenge for some patients with smoldering presentation, after an accurate evaluation of benefit–risk balance.

Diarrhoea is an adverse drug reaction of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril + valsartan. It was also described with olmesartan and more recently with other angiotensin receptor blockers. The study was performed to compare diarrhoea reports in pharmacovigilance databases with sacubitril + valsartan and valsartan. The study used reports of diarrhoea with the ARNI sacubitril + valsartan registered: first in the French PharmacoVigilance Database (FPVD) and second in Vigibase®, the WHO Global Individual Case Safety Report database. After description of the main characteristics, disproportionality analyses were performed. Results are reported as reporting odds ratios (ROR) with 95% confidence interval. We found 29 reports of diarrhoea with sacubitril + valsartan in the FPVD and 686 in Vigibase®. With sacubitril + valsartan, diarrhoea occurred more frequently in males around 70 years with a median delay of 3 days. With valsartan, diarrhoea occurred more frequently in females around 68 years with a median delay of 0.5 days. In the FPVD, a significant association was found with sacubitril + valsartan in comparison with valsartan alone before (ROR = 8.78 [5.19-14.85]) and after (ROR = 11.19 [5.89-21.25]) exclusion of concomitant drugs known to be associated with diarrhoea. A significant association was also found in Vigibase® after adjustment on age, sex, reporter and its location (ROR = 1.31 [1.14-1.50]). Diarrhoea reported with sacubitril + valsartan has marked differences in gender, delay of occurrence and frequency of reporting in comparison with diarrhoea with valsartan. From a pharmacodynamic point of view, these results suggest a specific role of sacubitril in diarrhoea.

Resume La diversite et la complexite des toxicites immunes des inhibiteurs de checkpoint immunologique imposent une approche multidisciplinaire pour leur prise en charge. Nous rapportons l’experience de la reunion de concertation pluridisciplinaire « toxicites et immuno-oncologie » (« ToxImmun ») recemment mise en place en Occitanie-Est, et decrivons 114 dossiers presentes entre le 17 decembre 2018 et le 20 janvier 2020, concernant une majorite de cancers pulmonaires. Le principal motif de recours etait la confirmation et la prise en charge d’un effet indesirable immuno-induit suivi de la discussion d’une reintroduction (re-challenge) et enfin de celle de l’introduction de l’immunotherapie en cas d’antecedent de pathologie dysimmune. Les colites, les hepatites et les myocardites etaient les effets indesirables immuno-induits tout grade et de grade ≥ 3 les plus frequents. Le syndrome sec, avec ou sans criteres pour un syndrome de Gougerot–Sjogren, etait frequent (26 % des cas) et semblait associe a la survenue d’une toxicite severe et d’une multi-toxicite. Le delai moyen de survenue etait de 3,8 mois. Ce delai etait plus court en cas de combinaison d’immunotherapie et en cas de traitement par un anti-PDL-1. Une majorite des situations examinee provenait d’une prise en charge initiale par un interniste, confirmant le role precoce et central de cette specialite dans la gestion de l’immunotoxicite. La generalisation des RCP regionales, coordonnees par internistes et oncologues medicaux, pourrait permettre d’optimiser cette prise en charge aux benefices des patients.

International audience; OBJECTIVE: To determine whether use of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) is associated with increased risk of thyroid cancer. RESEARCH DESIGN AND METHODS: A nested case-control analysis was performed with use of the French national health care insurance system (SNDS) database. Individuals with type 2 diabetes treated with second-line antidiabetes drugs between 2006 and 2018 were included in the cohort. All thyroid cancers were identified through hospital discharge diagnoses and medical procedures between 2014 and 2018. Exposure to GLP-1 RA was measured within the 6 years preceding a 6-month lag-time period and considered as current use and cumulative duration of use based on defined daily dose (≤1, 1 to 3, >3 years). Case subjects were matched with up to 20 control subjects on age, sex, and length of diabetes with the risk-set sampling procedure. Risk of thyroid cancer related to use of GLP-1 RA was estimated with a conditional logistic regression with adjustment for goiter, hypothyroidism, hyperthyroidism, other antidiabetes drugs, and social deprivation index. RESULTS: A total of 2,562 case subjects with thyroid cancers were included in the study and matched with 45,184 control subjects. Use of GLP-1 RA for 1-3 years was associated with increased risk of all thyroid cancer (adjusted hazard ratio [HR] 1.58, 95% CI 1.27-1.95) and medullary thyroid cancer (adjusted HR 1.78, 95% CI 1.04-3.05). CONCLUSIONS: In the current study we found increased risk of all thyroid cancer and medullary thyroid cancer with use of GLP-1 RA, in particular after 1-3 years of treatment. ARTICLE HIGHLIGHTS: Preclinical studies suggest that GLP-1 receptor agonists have specific effects on the thyroid gland, potentially involving the development of thyroid cancer. Studies on this subject produced conflicting results, potentially due to a lack of statistical power. The results of this nationwide population-based study suggest that use of GLP-1 receptor agonists is associated with increased risk of thyroid cancer. The increased risk was higher in the case of 1-3 years of GLP-1 receptor agonist use. Clinicians should be aware of this potential risk in initiating a GLP-1 receptor agonist and carefully monitor exposed patients.

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting.

Background: Acquired hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition characterized by hyperactivation of macrophages and cytotoxic lymphocytes, combining a series of non-specific clinical symptoms and laboratory disorders. Etiologies are multiple: infectious (mainly viral) but also oncologic, autoimmune or drug-induced. Immune checkpoint inhibitors (ICI) are recent anti-tumor agents associated with a novel profile of adverse events triggered by immune system over-activation. Here, we sought to provide a comprehensive description and analysis of HLH cases reported with ICI since 2014. Methods: Disproportionality analyses were performed in order to further explore the association between ICI therapy and HLH. We selected 190 cases, 177 from the World Health Organization pharmacovigilance database and 13 from the literature. Detailed clinical characteristics were retrieved from the literature and from the French pharmacovigilance database. Results: The cases of HLH reported with ICI concerned men in 65% of cases with a median age of 64 years. HLH occurred in an average of 102 days after the initiation of ICI treatment and mostly concerned nivolumab, pembrolizumab and nivolumab/ipilimumab combination. All cases were considered serious. Most cases presented a favorable outcome (58.4%); however, death was reported for 15.3% of patients. Disproportionality analyses showed that HLH was seven times more frequently reported with ICI therapy than with other drugs and three times more than with other antineoplastic agents. Conclusions: Clinicians should be aware of the potential risk of ICI-related HLH to improve the early diagnosis of this rare immune-related adverse event.

According to previous reports, diabetes seems to be a risk factor which worsens the serious clinical events caused by COVID-19. But is diabetes per se a risk factor that increases the probability of getting the virus? This paper will discuss this point. There are not many research data on antidiabetic drugs in this context. The potential influence of glucose-lowering agents on the severity of COVID-19 has not been described yet. Dipeptidylpeptidase-4 (DPP-4) is a cell surface protein ubiquitously expressed in many tissues and it is also a soluble molecule found in serum/plasma fluids. DPP-4 is involved in infection of cells by some viruses. This paper reviews data about the use of DPP-4 inhibitors and others diabetes drugs on COVID-19 patients. As such, no available evidence has yet suggested that glucose-lowering drugs - including those targeting DPP4-related pathways - produce any significant harm or benefit in the context of human infections. However, insulin must remain the first-choice agent in the management of critically ill-hospitalized patients, while it is recommended to suspend other agents in unstable patients. This paper provides related French and international recommendations for people with diabetes who got infected by COVID-19 and upholds that infections may alter glucose control and may require additional vigilance., D’après les dernières analyses de cas notamment en Chine et en Italie, le diabète semble être un facteur de risque d’aggravation de l’état clinique d’un patient atteint par le COVID-19 mais est-il un facteur de susceptibilité ? Une analyse de la littérature à la date du 6 mai 2020 tente de répondre à la question. Les données concernant le type de traitement antidiabétique à utiliser dans ces circonstances et son impact éventuel sur l’état clinique d’un patient infecté par le COVID-19 sont très rares. La dipeptidylpeptidase 4 (DPP-4), glycoprotéine membranaire ubiquitaire présente à la surface de nombreuses cellules et existant aussi sous forme soluble, est impliquée dans les réponses immunitaires inflammatoires en modifiant la production de plusieurs cytokines. La DPP-4 est impliquée dans l'infection des cellules par certains virus. Nous abordons la question de l’utilisation des inhibiteurs des DPP-4 chez les patients diabétiques et il n’y a pas à ce jour de données qui indiquent que l’état clinique des patients dépend de leur utilisation. De la même façon, l’utilisation de la metformine, des sulfamides hypoglycémiants, des analogues du GLP1 comme de l’insuline n’ont pas fait l’objet d’études dans ce contexte. Il nous parait prudent en phase aigüe de la maladie, en particulier chez les patients nécessitant un séjour en unités de soins intensifs de privilégier l’insuline chez eux. A la lumière d’une revue des recommandations sur la prise en charge des diabétiques,l’optimisation du contrôle glycémique est à privilégier et plusieurs messages clefs délivrés par les Sociétés savantes concluent ce travail.

Contexte : Les premières épreuves classantes nationales informatisées (ECNi) clôturant le deuxième cycle des études médicales en France ont eu lieu en juin 2016 et ont comporté des dossiers cliniques progressifs (DCP), des questions isolées (QI), ainsi qu’une épreuve de lecture critique d’articles (LCA). Les QI représentaient une nouveauté de cet examen puisque les DCP et la LCA étaient utilisés depuis 2004. But : Analyse de la validité du contenu et de la qualité formelle des QI des premières épreuves ECNi. Méthodes : Un questionnaire contenant les critères docimologiques à recueillir a été défini et validé au préalable. Les 120 QI de l’ECNi 2016 ont été analysées par un binôme indépendant. Les discordances entre les évaluateurs ont été interprétées. Toutes les analyses ont été colligées sur tableur Excel puis les statistiques ont été réalisées sur Graphpad Prism version 6 et Stata v12. Résultats : Les rédacteurs des QI ont majoritairement respecté les consignes de forme. Les niveaux d’habiletés intellectuelles requis concernaient majoritairement les processus de mémorisation, de simple récupération de l’information et de compréhension (82 % des QI). Dans 7 à 23 % des QI, l’utilisation de distracteurs était jugée inappropriée. Une prédominance de QI portait sur les disciplines médicales (72,5 %). L’unité d’enseignement (« Circulation – Métabolismes ») était la plus représentée (26 %). Les discordances étaient faibles (6,2 % des évaluations). Conclusion : Il s’agit de la première analyse de la validité du contenu et de la qualité formelle des QI des ECNi. Leur format de rédaction a été largement respecté par les auteurs. Elles ont peu fait appel à des processus de raisonnement complexe. Il semblerait utile de favoriser les courtes vignettes cliniques pour améliorer cet aspect.

Therapies - Sous presse. Epreuves corrigees par l'auteur. Disponible en ligne depuis le vendredi 29 janvier 2021

Summary Aims To investigate the risk of intestinal obstruction associated with incretin-based drugs by performing a disproportionality analysis of adverse reaction reports in a global pharmacovigilance database. Methods We conducted a case/non-case analysis using VigiBase, the World Health Organization's adverse drug reactions (ADR) database, to assess intestinal obstruction reporting associated with incretin-based drugs (glucagon-like peptide 1 analogues [GLP-1a] and dipeptidyl peptidase 4 inhibitors [DPP-4i]. Cases were defined as reports of gastrointestinal stenosis and obstruction (MedDRA High Level Group Term) and non-cases were all other reactions recorded. Disproportionality analysis were performed by computing reporting odds ratios (ROR) with their 95% confidence interval (95%CI) within all ADR reports concerning diabetes drugs from January 2007 to January 2018 and in a restricted sample including only serious reports. Results A total of 501,244 ADR with diabetes drugs were reported in VigiBase during the study period. We identified 452 intestinal obstructions involving an incretin-based drug. In disproportionality analyses, intestinal obstructions were more than 4.5 times more frequently reported with incretin-based drugs than with other diabetes drugs (ROR 4.52, 95% CI: 3.87–5.28) with a higher signal for serious cases and for DPP-4i (ROR 8.66, 95% CI: 7.27–10.32) compared to GLP-1a (ROR 3.05, 95% CI: 2.54–3.66). Conclusions We identified a pharmacovigilance signal that suggests a risk of potentially serious intestinal obstruction associated with incretin-based drugs, as a class and with a greater signal for DPP4-i. Other studies are needed to confirm and better understand the potential risk of intestinal obstruction associated with incretin-based drugs.

Introduction La lymphohistiocytose hemophagocytaire (HLH) acquise est un syndrome rare mais potentiellement fatal, associant un ensemble de symptomes clinico-biologiques non specifiques. Un score diagnostique (score de Saint Antoine) permet d’estimer le risque d’HLH [1] . Les etiologies sont multiples, infectieuse dans pres de 50 % des cas et majoritairement d’origine virale (EBV). Les autres etiologies concernent les pathologies tumorales, les maladies auto-immunes, telles que le lupus systemique et la maladie de Still ou encore les etiologies iatrogenes. Les inhibiteurs du point de controle immunologique (ICI) representent une revolution therapeutique anticancereuse mais presentent des effets indesirables, en lien avec leur mecanisme d’action. La litterature rapporte plusieurs cas de HLH sous ICI [2] . Nous proposons ici une analyse descriptive de l’ensemble des cas rapportes de HLH recenses dans les bases de donnees de pharmacovigilance. Materiels et methodes Nous avons tout d’abord recherche tous les cas de lymphohistiocytose hemophagocytaire (terme MedDRA, Medical Dictionnary of Regulatory Activities), associes a au moins un ICI (anti-CTLA-4, anti-PD1 ou anti-PD-L1) rapportes dans la base de donnees internationale de pharmacovigilance de l’Organisation Mondiale de la Sante (OMS), VigiBase®, au 24/01/2021. Nous presentons les donnees demographiques, les indications, les delais d’apparition ainsi que les evolutions des HLH developpees sous ICI. Dans un deuxie temps, une requete dans la Base Nationale de Pharmacovigilance francaise, presentant des descriptions cliniques plus detaillees, a permis l’analyse des criteres du score de Saint-Antoine. Resultats Sur 2317 cas de HLH recenses dans VigiBase®, pour lesquels une etiologie iatrogene a ete suspectee, 5,5 % (n = 127) etaient associes aux ICI. Tous ces cas etaient graves et 23 % ont ete d’evolution fatale. Plus de la moitie des cas etaient associes au nivolumab (53,6 %), en bitherapie avec l’ipilimumab dans 47,8 % des cas, ICI plus rarement utilise en monotherapie (22 %). Le pembrolizumab represente 35,4 % de ces cas et l’atezolizumab, 9,4 %. L’ICI est le seul medicament suspect dans pres de 40 % des cas. Les medicaments le plus souvent co-rapportes avec les ICI etaient le trametinib (anti-MEK) et le dabrafenib (anti-BRAF), dans respectivement 6,3 et 3,9 % des cas. Les principales indications des ICI etaient le melanome (38 %), les cancers pulmonaires (28 %), les cancers hematologiques (6 %), les cancers du rein (4,7 %) et de la vessie (3,9 %). L’âge moyen des patients etait de 60 ans (2-85), le rapport homme/femme de 1,76. Le delai moyen de survenue (disponible pour 50 cas) etait de 129 jours avec une mediane de 49 jours. L’evolution de la HLH (disponible pour 61 cas) etait resolue dans 59 %. Le delai moyen de resolution quand il etait disponible (n = 16), etait de 46 jours. Les criteres diagnostiques les plus frequemment retrouves, a la lumiere de l’analyse des 23 cas francais, etaient la fievre (74 %) et l’hyperferritinemie (valeur moyenne 17 521 μg/L) (74 %), associes dans plus de 50 % des cas, et l’anemie (61 %). Ces cas etaient d’evolution favorable dans pres de 80 % avec une reponse a la corticotherapie dans plus de 75 %. Conclusion Nous presentons ici la plus grande serie de cas d’HLH en lien avec les ICI. Les resultats obtenus apparaissent coherents avec les autres cas decrits dans la litterature, lies ou non aux ICI. Le traitement par ICI s’inscrit dans le cadre d’une prise en charge oncologique qui reste l’une des etiologies majeures des HLH reactionnelles. Toutefois ces resultats interrogent le lien qui pourrait exister entre le point de controle immunologique et l’immunite innee, impliquant les macrophages, alors que le mecanisme d’action des ICI concerne theoriquement l’immunite cellulaire T.

Introduction Les inhibiteurs du checkpoint immunologique (ICIs) ont revolutionne la prise en charge de nombreux cancers solides au prix de la survenue de toxicites immunologiques inedites [1] . La gestion de ces effets indesirables (IRAEs, immune-related adverse events) fait intervenir differentes specialites d’organes ainsi que des disciplines transversales (dont la « medecine interne & immunologie clinique ») et requiert une organisation en reseau, ou l’interniste peut occuper un role central de coordination. Nous rapportons l’experience de la reunion de concertation pluridisciplinaire « Toxicites et Immuno-oncologie » (« ToxImmun ») recemment mise en place en Occitanie-Est, dediee a la gestion de ces toxicites, coordonnees par le Departement de Medecine Interne de l’Hopital Saint Eloi. Patients et methodes Nous avons realise un recueil retrospectif de donnees issues des cas presentes lors de la RCP coordonnee par le Departement de Medecine interne, Maladies Multi-Organiques (MIMMO) du CHU de Montpellier et le Departement d’Oncologie Medicale de l’Institut du Cancer de Montpellier (ICM), entre le 17 decembre 2018 et le 20 janvier 2020. Le grade de chaque toxicite est evalue selon les recommandations europeennes de la gestion des immunotoxicites [1] . L’objectif principal de cette etude etait d’evaluer les caracteristiques des requetes transmises a la RCP, les caracteristiques des IRAEs confirmes. L’objectif secondaire etait de rechercher des facteurs predictifs potentiels d’IRAEs severe et de multi-toxicite. Une multitoxicite est definie par l’apparition d’une toxicite sur au moins 2 organes chez un meme patient. Resultats En 1 an, 114 situations, concernant 87 patients, ont ete discutees lors de 25 RCP avec une moyenne de 4,6 situations par seance. L’âge moyen etait de 66 ans (± 11) pour un sexe ratio H/F de 3. Les cas provenaient de 6 centres differents dont une majorite issue de l’ICM ou du CHU. Quatre-vingt-cinq cas (75 %) etaient presentes apres un avis, une consultation ou une hospitalisation de medecine interne. Le motif de presentation en RCP etait la confirmation et la prise en charge d’une toxicite pour 68 dossiers (60 %), une discussion de reintroduction pour 31 dossiers (27,2 %), une evaluation a but diagnostique pour 20 dossiers (17,5 %) ou pre-therapeutique en cas d’antecedent d’auto-immunite ou de syndrome paraneoplasique pour 16 dossiers (14,3 %). Une majorite des cas concernait un cancer pulmonaire, cutane ou digestif. Le nivolumab, le pembrolizumab, le durvalumab, l’ipilimumab et l’atezolizumab etaient prescrits dans respectivement 43,8 %, 25,4 %, 16,7 %, 14 % et 4,4 % des cas. Une combinaison d’immunotherapie concernait 16 dossiers (14 %). Une immunotoxicite etait decrite dans 74 dossiers (65 %) dont 46 % de grade ≥ 3 et une multi-toxicite dans 31 cas (27,2 %). Le delai moyen de survenue de la toxicite etait de 3,8 mois (0,1-21). Ce delai etait plus court en cas de combinaison d’immunotherapie et en cas de traitement par un anti-PDL-1. Les atteintes les plus frequentes etaient cutanees (28,4 %), endocriniennes (24,3 %) et musculo-squelettiques (18,9 %), incluant l’association entre myosite, myocardite et myasthenie (syndrome 3 M). Les toxicites de grade ≥ 3 les plus frequentes concernaient les atteintes digestives (9,5 %), hepatiques (8,1 %) et cardiaques (8,1 %). Le syndrome sec, avec ou sans criteres pour un syndrome de Gougerot-Sjogren, etait frequent (26 % des cas) et semblait associe a la survenue d’une toxicite severe et d’une multi-toxicite. Discussion La repartition des atteintes d’organes, tous grades et de grade ≥ 3, est similaire aux donnees de la litterature a l’exception de certains IRAEs tels que l’asthenie ou la fievre peu frequemment rapportes en RCP qui selectionne probablement les cas les plus graves [1] , [2] , [3] . Nous retrouvons un nombre eleve de syndrome sec et/ou de syndrome de Gougerot-Sjogren, egalement decrits dans la litterature, notamment sous anti-PD-1/PD-L1. La survenue d’un syndrome sec sous immunotherapie pourrait etre predictive de toxicites plus severes ou multiples. Trois quarts des situations examinees proviennent d’une prise en charge initiale par un interniste. Ces donnees soulignent le role pivot de notre specialite dans la coordination du parcours de ces patients et doivent nous encourager a promouvoir la generalisation des RCP pilotes par les internistes et les oncologues medicaux. Conclusion Les toxicites induites par les ICIs sont frequentes, mutisystemiques et potentiellement severes. La mise en place de RCP regionales, coordonnee par l’interniste et l’oncologue medical, peut permettre d’ameliorer leur prise en charge.

Introduction Le traitement du cancer a ete profondement modifie ces dernieres annees avec l’introduction des inhibiteurs du checkpoint immunologiques (ICI). Le pronostic de certains cancers, tels le melanome ou le cancer pulmonaire non a petites cellules s’en est trouve largement ameliore [1] , [2] . Ces traitements sont cependant a l’origine d’effets secondaires appeles effets indesirables lies a l’immunotherapie (EILI), dont les atteintes les plus frequentes (digestives, cutanees, endocriniennes) sont maintenant bien decrites, et relativement simples a diagnostiquer et traiter [3] . A contrario, certaines atteintes plus rares comme la myocardite sont peu decrites, alors que le taux de mortalite est eleve (jusqu’a 40 %) et de prise en charge plus delicate. Patients et methodes Nous avons conduit une etude transversale retrospective multicentrique sur une periode allant de juillet 2019 a novembre 2020. Les criteres d’inclusion etaient : traitement par un inhibiteur du checkpoint immunologique, survenue d’une suspicion de myocardite en s’appuyant sur les criteres de la societe europeenne de cardiologie, donnees de suivi disponibles pour chaque patient. Les myocardites etaient classees en possible/probable/definies selon des criteres internationaux, la severite a ete cotee en utilisant la classification CTCAE v5.0. Resultats Vingt-neuf patients ont ete inclus, de 6 centres differents, avec un âge median de 69 (32-83) ans. Les cancers traites etaient majoritairement pulmonaires (10 patients), des melanomes (8 patients), ou urotheliaux (4 patients). La myocardite survenait dans un delai median de 39 (2-181) jours, principalement avec des anti-PD1 (16 patients, 55 %). La plupart des patients (83 %) etaient symptomatiques, la dyspnee etant le symptome le plus frequent (17 patients, 59 %). Tous avaient une troponine HS elevee, avec une mediane de 5,35 fois la normale superieure, l’ECG montrait des anomalies chez 19 patients (68 %), alors que l’ETT etait disponible chez 27 patients et montrait une FEVG alteree chez 10 d’entre eux (37 %). Une IRM cardiaque a ete realisee chez 24 patients, montrant une prise de contraste tardive chez 9 d’entre eux (37 %). Quatorze patients (48 %) ont subi une coronarographie, et 6 ont beneficie d’une biopsie endomyocardique. Ces dernieres montraient chez 5 patients une infiltration lymphocytaire, majoritairement CD8+. Parmi les toxicites associees, la myosite etait la plus frequente (13 patients, 45 %), suivie du syndrome sec (11 patients, 38 %). Les patients les plus severes (CTCAE grade 4 et 5, n = 11) avaient un taux plus important de maladies auto-immunes systemiques preexistantes (5 patients contre 1, p = 0,018), une frequence cardiaque plus elevee a l’admission (113 contre 79,5, p = 0,001), une troponinemie d’entree plus elevee (42 fois la norme superieure contre 3,55, p = 0,001), et presentaient plus souvent des anticorps anti-recepteur de l’acetylcholine (5 contre 0, p = 0,001). L’analyse en courbe ROC nous a permis de selectionner une valeur seuil de troponinemie a 4,89 fois la norme superieur (sensibilite = 90,9 %, specificite 66,7 %) pour predire l’evolution vers une forme grave. Concernant le traitement, la plupart des patients (28) ont recu des corticoides, le plus souvent apres des bolus initiaux (19 patients, 68 %). Les autres modalites de traitement concernaient les plasmaphereses (10 patients), les immunoglobulines polyvalentes (8 patients), et d’autres immunosuppresseurs (5 patients). 7 patients (24 %) sont morts lors de la prise en charge initiale. Nous disposions d’une evaluation de la reponse carcinologique chez 21 patients, dont seulement 1 presentait une progression de la maladie. Au cours du suivi (d’une mediane de 4 mois), 7 patients supplementaires sont decedes. 6 patients ont recu a nouveau un traitement par ICI, seulement 1 ayant presente une rechute de myocardite. Conclusion Certains facteurs de mauvais pronostic ont ete mis en evidence, comme un taux eleve de troponine a l’admission, ce qui pourrait aider a la decision therapeutique. La mortalite est moindre dans notre serie, possiblement par le depistage de formes subintrantes en dosant la troponine de facon systematique. Cependant, la contre-indication definitive de l’immunotherapie sera peut etre a rediscuter selon la balance benefice/risque.

Background The value of intravenous oxycodone compared to morphine remains controversial. The purpose of this trial was to compare opioid-related adverse events (ORAES) of intravenous oxycodone and morphine after total hip arthroplasty. Methods Patients scheduled for total hip arthroplasty were enrolled in this study of postoperative pain treatment with intravenous oxycodone or intravenous morphine (ratio 1:1). After surgery, patients received similar drug regimens for titration in the postoperative care unit followed by intravenous patient-controlled analgesia (PCA). The primary outcome was the number of patients with ≥1 ORAEs within the first 24 hours defined as either nausea, vomiting, respiratory depression, pruritus, urinary retention requiring evacuation, allergy, hallucinations. Secondary outcomes included pain scores and opioid consumption. Results The analysis included 238 patients with similar characteristics. There were 55 patients with at least one ORAEs in the oxycodone group versus 46 in the morphine group: 48% vs 40%, p=0.19; relative risk= 1.22 (0.91:1.63). Intravenous oxycodone vs intravenous morphine requirements were respectively (median, IQR): 6 (0-11) versus 8 (0-12) mg (p=0.06) for titration, 15 (8-26) vs 8 (5-16) mg (p=0.001) for PCA, and 22 (12-37) mg vs 19 (11-28) mg for cumulated intravenous consumption (p=0.048). During the first 24hr, there was no difference in secondary outcomes (oxycodone versus morphine, respectively, in %): nausea (15 vs 13), vomiting (5 vs 5), urinary retention (20 vs 12) or pain scores. Conclusion This study demonstrates that IV oxycodone did not significantly reduce ORAEs within the first 24 hours compared to similar ratio of IV morphine.

Resume D’apres les dernieres analyses de cas notamment en Chine et en Italie, le diabete semble etre un facteur de risque d’aggravation de l’etat clinique d’un patient atteint par le COVID-19 mais est-il un facteur de susceptibilite ? Une analyse de la litterature a la date du 17 avril 2020 tente de repondre a la question. Les donnees concernant le type de traitement antidiabetique sont tres rares. La dipeptidylpeptidase-4 (DPP-4), glycoproteine membranaire ubiquitaire presente a la surface de nombreuses cellules et existant aussi sous forme soluble, est impliquee dans les reponses immunitaires inflammatoires en modifiant la production de plusieurs cytokines. La DPP-4 est impliquee dans l’infection des cellules par certains virus. Nous abordons la question de l’utilisation des inhibiteurs des DPP-4 chez les patients diabetiques. Une revue des recommandations sur la prise en charge des diabetiques conclut ce travail.

As shown by Kostine et al ,1 and recently underlined by Ceccarelli et al ,2 rheumatic inflammatory disorders induced by anticancer therapy are becoming a major concern for rheumatologists at the era of immune checkpoint inhibitors (ICIs). Beyond inflammatory arthritis, which may concern 10%–20% of patients, myositis represents a rare (

Bacground: Intravenous oxycodone compared to morphine for postoperative pain relief is controversial. The purpose of this study was to assess opioid-related adverse events of oxycodone versus morphine in opioid-naive patients after orthopaedic surgery. Methods: Patients scheduled for total hip arthroplasty under general anesthesia combined with a multimodal analgesia (acetamnophen, nonsteroidal anti-inflammatory) were randomized in a triple-blinded trial to postopertaive pain treatment with either intravenous oxycodone or morphine (potency ratio 1:1). After surgery, patients received similar drug regimen for titration in the postoperative care unit (bolus 2-3 mg, 5 min period, when pain score was >3/10) followed by an intravenous patient controlled analgesia (bolus 1 mg, lockout time 7 min) postoperatively. The primary outcome was number of patients with ≥1 opioid-related adverse events within the first 24 hours (at least one of the following complications: nausea, vomiting, respiratory depression, pruritus, urinary retention requiring evacuation, allergy, hallucination). Secondary outcomes included pain scores, opioid consumption. Patients were followed up to 4 months. Results: The intention-to-treat analysis included 241 patients with similar characteristics. There were 55 patients with at least one opioid-related adverse events in oxycodone group versus 46 in morphine group (48% vs 40%, p=0.19; relative risk= 1.22 [0.91; 1.63]). Oxycodone versus morphine requirements were respectively: 6 [0-11] versus 8 [0-12] mg (p=0.06) for titration, 15 [8-26] versus 8 [5-16] mg (p=0.001) for PCA dose, and 22 [12-37] mg versus 19 [11-28] mg for the titration and PCA accumulated consumption (p=0.048). During the first 24 hours, there were no other differences in secondary outcomes between both drugs for (respectively oxycodone versus morphine in %): nausea (15 versus 13), vomiting (5 versus 5 ), urinary retention (20 versus 12 ) and pain scores. Conclusion: This study demonstrated that oxycodone required lower doses for titration in postoperative care unit, but did not significantly reduce opioid-related adverse events within the first 24 hours compared to morphine.

Introduction: After a safety warning was issued for a risk of muscular injury associated with dipeptidyl peptidase-4 (DPP-4) inhibitor use, especially when co-prescribed with statins, spontaneous reporting analyses provided conflicting results. Objective: The aim of this study was to investigate the association between DPP-4 inhibitor use and the risk of muscular injury in individuals with type 2 diabetes mellitus using statins or fibrates. Methods: We conducted a nested case-control study amongst a cohort of individuals with type 2 diabetes using statins or fibrates, identified from a nationwide French health insurance database (2009–2014). Cases of serious muscular injury were defined as subjects hospitalized for rhabdomyolysis or myopathy, or for whom testing for myoglobin or creatine phosphokinase followed by a change in statin or fibrate prescription (dose decrease, treatment switch, or stop) was identified. Up to ten controls were matched to each case according to sex, age, and type of lipid-lowering agent. Associations between DPP-4 inhibitor use and serious muscular injury were estimated using a multivariate conditional logistic regression model, providing odds ratios (ORs) adjusted for alcoholism, chronic renal failure, hypothyroidism, and number of concomitant drugs. Results: Within the 35,117 individuals with type 2 diabetes mellitus constituting the source cohort, 437 statin-user cases were identified who were matched to 4358 statin-user controls. Similarly, 54 fibrate-user cases were identified who were matched to 540 fibrate-user controls. The adjusted OR for DPP-4 inhibitor use and serious muscular injury was estimated at 1.0 (95% confidence interval [CI] 0.7–1.2) in statin users and 0.8 (95% CI 0.4–1.9) in fibrate users. Conclusion: In this study, DPP-4 inhibitor use was not associated with an increased risk of serious muscular injury among patients with type 2 diabetes mellitus using statins or fibrates.

International audience; We thank Brož et al. for their interest in our study aiming to determine if drug-induced hypoglycemia could be a class effect for opioids [1] and for their useful comments.The French PharmacoVigilance Database (FPVD) contains a narrative description of cases provided by the declarant, which we examined for this study. The description of the report’s narrative in pharmacovigilance study is a complement to disproportionality analysis that may identify potential mechanisms underlying the associations found between drugs and adverse drug reactions. We are glad that they shared our interest in finding such mechanisms to further investigate the link between hypoglycemia and opioids. As they accurately mentioned, 45 of the 93 tramadol-associated hypoglycemia cases included in our descriptive study in the FPVD were related to diabetic patients. Indeed, hypoglycemia in these patients could have been favored by the antihyperglycemic treatment they received. We agree with them that sleepiness, one of the common side effect of opioids, combined to the use of those antihyperglycemic treatments could have been one of the factors leading to the onset of hypoglycemia in those patients. However, not all the reports mentioned sleepiness and the prescription of opioids appeared to be the trigger factor causing the hypoglycemia even in diabetic patients, regardless of the underlying mechanism.

Nicorandil-induced ulcers remain often poorly recognised, with a late diagnosis and an inadequate management. We aimed to provide a clinical overview of the 148 spontaneously reported cases of nicorandil-induced ulcers to the French pharmacovigilance network between 2005 and 2014 and to complete this picture with worldwide published cases over the same period. Spontaneously reported nicorandil-induced ulcers were mainly mucosal (oral and anal) with a previous trauma in 23·0% of patients, revealed by a severe complication in 12·8% of cases. The mean cumulative dose of nicorandil was higher in serious cases. The median delay between the start of nicorandil use and the onset of the ulcer was 23·4 months, and after the ulcer was diagnosed, the median time to incriminate nicorandil was still 3·3 months, being shorter for mucosal ulcerations than for cutaneous ulcerations (5·2 versus 14·0 months, P = 0·001). The anatomic distribution in the 199 published cases differed slightly, but delays were similar. The hypothesis of mechanism becomes more precise, leaving no doubt about the necessity to discontinue the treatment. Practitioners need to be aware that nicorandil-induced ulcers can occur in many locations, possibly multiple and complicated, and should be simply managed by discontinuing treatment with no further reintroduction of nicorandil.

International audience; Case-non case studies belongs to the methods assessing drug safety by analyzing the disproportionality of notifications of adverse drug reactions in pharmacovigilance databases. Used for the first time in the 1980s, the last few decades have seen a significant increase in the use of this design. The principle of the case-non case study is to compare drug exposure in cases of a studied adverse reaction with that of cases of other reported adverse reactions and called "non cases". Results are presented in the form of a reporting odds ratio (ROR), the interpretation of which makes it possible to identify drug safety signals. This article describes the principle of the case-non case study, the method of calculating the ROR and its confidence interval, the different modalities of analysis and how to interpret its results with regard to the advantages and limitations of this design.; Les études de type cas–non cas appartiennent aux méthodes ayant pour objectif d’évaluer la sécurité d’emploi des médicaments en analysant la disproportionnalité des notifications d’effets indésirables médicamenteux dans les bases de données de pharmacovigilance. Utilisé pour la première fois dans les années 1980, les dernières décennies ont vu une augmentation importante de l’utilisation de ce design d’étude. Le principe des études cas–non cas réside dans la comparaison de l’exposition médicamenteuse de cas d’un effet indésirable d’intérêt avec celle de cas ayant présenté d’autres effets et appelés « non cas ». Leurs résultats sont présentés sous la forme de reporting odds ratio (ROR) dont l’interprétation permet de mettre en évidence des signaux de pharmacovigilance. Cet article décrit le principe des études cas–non cas, la méthode de calcul du ROR et de son intervalle de confiance, les différentes modalités d’analyse et présente comment interpréter ses résultats au regard des avantages et des limites de ce type d’étude.

A partir de 48 heures du post-partum, 78 meres ont repondu a l’autoquestionnaire MIBS (Mother-to-Infant Bonding Scale) traduit en francais ainsi qu’a 3 autres questionnaires. Vingt-quatre heures plus tard, un entretien pedopsychiatrique permettait d’evaluer la relation mere-enfant. Les puericultrices remplissaient le MIBS, en imaginant les reponses des meres.Le MIBS permettait un depistage satisfaisant des difficultes du lien mere-enfant (sensibilite = 0,9 et specificite = 0,8 pour un seuil superieur ou egal a 2). Les scores MIBS etaient independants de l’humeur maternelle (EPDS) et du style d’attachement de la mere (AAQ). Par contre, il existait un lien avec les caracteristiques comportementales du bebe (MAIB). Les scores MIBS de la mere et de la puericultrice etaient faiblement correles et les reponses rarement concordantes ; 100 % des puericultrices estimaient que le MIBS aidait a l’evaluation du lien mere-enfant et 85 % des meres trouvaient un benefice a la passation du questionnaire.

Objectives The objective of the study was to develop and validate an adequate tool to evaluate the risk of bias of randomized controlled trials, observational studies, and systematic reviews assessing drug adverse events. Study Design and Setting We developed a structured risk of bias checklist applicable to randomized trials, cohort, case–control and nested case–control studies, and systematic reviews focusing on drug safety. Face and content validity was judged by three experienced reviewers. Interrater and intrarater reliability were determined using 20 randomly selected studies, assessed by three other independent reviewers including one performing a 3-week retest. Results The developed checklist examines eight domains: study design and objectives, selection bias, attrition, adverse events information bias, other information bias, statistical methods to control confounding, other statistical methods, and conflicts of interest. The total number of questions varied from 10 to 32 depending on the study design. Interrater and intrarater agreements were fair with Kendall's W of 0.70 and 0.74, respectively. Median time to complete the checklist was 8.5 minutes. Conclusion The developed checklist showed face and content validity and acceptable reliability to assess the risk of bias for studies analyzing drug adverse events. Hence, it might be considered as a novel useful tool for systematic reviews and meta-analyses focusing on drug safety.

International audience; BACKGROUND:Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal.METHODS:We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (

International audience; Objective: Drug-induced hypoglycaemia has been described with the use of tramadol and methadone. The authors aimed to determine if drug-induced hypoglycaemia could be a class effect for opioids. Methods: The authors performed a disproportionality analysis in VigiBase®, the WHO global individual case safety report database with nine opioids (codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, tramadol, buprenorphine and nalbuphine) using the broad Standardised MedDRA Query for hypoglycaemia. The authors also carried out a descriptive study of opioid-induced hypoglycaemia in the French PharmacoVigilance DataBase (FPVDB) using the MedDRA Preferred Term 'hypoglycaemia'. Results: The global adjusted Reporting Odds Ratio (aROR) value for the 9 opioids was 1.53 (95% CI 1.52-1.54). The aROR ranged from 1.09 to 1.97 depending on the opioid, but all were statistically significant. A sex ratio of 0.74 was found for the reports of opioid-induced hypoglycaemia in Vigibase®. The authors also found 133 reports of hypoglycaemia in the FPVDB related to opioids. Among the reports, 55 were glycaemic imbalances in diabetics occurring shortly after the start of opioid treatment. Conclusion: This work highlighted a significant association between all opioids and hypoglycaemia, thereby indicating that opioid-induced hypoglycaemia is probably a class effect. Women and/or diabetics seem to be more at risk for developing opioid-induced hypoglycaemia.

International audience; INTRODUCTION:Osteomalacia and osteoporosis are two metabolic bone disorders that increase the risk of fracture due to several causes. In terms of drugs, apart from corticosteroids, which are known to induce bone disorders, several other drugs used in chronic disease management have also been linked with an increased risk of osteoporosis and osteomalacia.PURPOSE:The aim of this study was to describe spontaneous reports of drug-induced osteoporosis and osteomalacia in the French (FPVDB) and Spanish (SPVDB) pharmacovigilance databases.METHODS:Data were provided by the FPVDB and SPVDB. All reports of osteoporosis and osteomalacia recorded from 1985 up to 31 December 2015 inclusive were selected. Taking the time to onset of bone loss into account, all cases occurring in less than 1 month were excluded.RESULTS:A total of 369 reports (44 cases of osteomalacia, 325 cases of osteoporosis) were registered in the FPVDB and 64 (22 cases of osteomalacia, 42 cases of osteoporosis) in the SPVDB. In France, the top 5 drugs involved in the onset of osteoporosis were corticosteroids accounting for approximately half of the reports (n = 170) followed by systemic antiviral (n = 87), antacid (n = 29), antiepileptic (n = 27) and antithrombotic (n = 24) drugs. The 2 main classes of drugs implicated in osteomalacia were systemic antiretroviral drugs for half of the reports (n = 21) and antiepileptic drugs (n = 15). In Spain, corticosteroids were involved in 35.7% of reported cases of osteoporosis (n = 15) followed by systemic antiviral drugs (n = 12). There was no spontaneous report for antacid drugs. For osteomalacia, the 2 main drug classes were systemic antiretroviral drugs (n = 18, 81.8%) followed by antiepileptics (n = 2, 9.0%). In both countries, concomitant administration of systemic corticosteroids with other suspected drugs did not significantly modify the time to onset of drug-induced osteoporosis.CONCLUSION:Despite some differences between the French and Spanish PVDBs, our data consistently show that bone loss is not only restricted to glucocorticoids but also involves antivirals, antiepileptic drugs, antacid drugs or antidepressants. Further analysis might prove useful in exploring the characteristics of drug-induced bone loss on a larger scale.

International audience; In the field of diabetes, pharmacoepidemiologic (PE) studies are numerous and represent an essential tool to assess the real life effects of diabetes drugs. However, the specificity of the study of drugs used in diabetes, characterized by a high frequency of switches, interruptions and add-on, must be kept in mind by pharmacoepidemiologists in order to perform well-conducted studies and avoid several biases. In this article, the authors discussed the specific interest of PE studies in the field of diabetes, provide a brief overview of biases that can affect those studies, and suggest pragmatic solutions for more correct results and appropriate interpretation.

International audience; Case-non-case studies are among the methods used to assess drug safety by analyzing the disproportionality of adverse drug reaction reports in pharmacovigilance databases. First used in the 1980s, the last few decades have seen a significant increase in the use of this study design. The principle of case-non-case studies is to compare the drug exposure of cases of an adverse reaction of interest with that of cases with other reported reactions and called "non-cases". Their results are presented in the form of reporting odds ratio (ROR), the interpretation of which makes it possible to highlight pharmacovigilance signals. This article describes the principle of case-non-case studies, the calculation method of the ROR and its confidence interval, the different analytical modalities and how to interpret its results with regard to the advantages and limitations of this type of study.

International audience; Post-marketing data regarding brentuximab vedotin (BV) are sparse. The aim of this study was to assess the frequency and nature of significant adverse drug reactions (ADRs) in patients treated with BV in a real-world setting. We conducted a systematic retrospective study of patients treated with BV in a French university hospital. Significant ADRs were collected using the electronic patient records. Between January 2009 and December 2016, 39 patients received BV. Median age was 43.2 and 53.8% were males. Overall, 20 patients (51.3%) experienced at least one significant ADR and 24 reactions were reported in total. Twelve (50%) out of 24 ADRs were severe. The most frequently observed significant ADRs were peripheral sensory neuropathy and CMV reactivation. ADRs led to drug discontinuation for 4 patients and dose reduction for 6 patients. Only 29.2% of the events were spontaneously reported. Prospective monitoring is needed to better assess BV safety.

International audience; The aim of this article is to discuss the contribution of pharmacoepidemiology to pharmacovigilance in the context of drug safety monitoring. Because this contribution requires a comparison of the approaches and a presentation of their respective merits, we have tried to show that this comparison did not necessarily mean opposing these methods, which would not serve any useful purpose. We wanted to underline the fact that the notion of contribution of one to the other implied a complementarity that we propose to demonstrate. Pharmacovigilance is essentially based on the study of spontaneous reports and the clinical and pharmaceutical analysis of the implication of given drugs in adverse drug reactions. It yields performances that are unequalled to this day when safety warning signs relate to rare adverse events or to drugs that are rarely used, or when the drug-related event has specificities that are not found for other aetiologies. Pharmacoepidemiology for its part, through its population-related studies and the possible use of a comparison group, enables a quantification of risks that is impossible to carry out using spontaneous reporting alone. It also enables the highlighting and quantification of safety signals for events that are frequent and multifactorial, where the role of a drug in individual cases can be difficult to detect, and therefore difficult to identify from spontaneous reporting. All in all, this is the major contribution of pharmacoepidemiology to pharmacovigilance, where it can be said that it complements pharmacovigilance in drug safety monitoring but in no way could replace it.

The aim of this article is to discuss the contribution of pharmacoepidemiology to pharmacovigilance in the context of drug safety monitoring. Because this contribution requires a comparison of the approaches and a presentation of their respective merits, we have tried to show that this comparison did not necessarily mean opposing these methods, which would not serve any useful purpose. We wanted to underline the fact that the notion of contribution of one to the other implied a complementarity that we propose to demonstrate. Pharmacovigilance is essentially based on the study of spontaneous reports and the clinical and pharmaceutical analysis of the implication of given drugs in adverse drug reactions. It yields performances that are unequalled to this day when safety warning signs relate to rare adverse events or to drugs that are rarely used, or when the drug-related event has specificities that are not found for other aetiologies. Pharmacoepidemiology for its part, through its population-related studies and the possible use of a comparison group, enables a quantification of risks that is impossible to carry out using spontaneous reporting alone. It also enables the highlighting and quantification of safety signals for events that are frequent and multifactorial, where the role of a drug in individual cases can be difficult to detect, and therefore difficult to identify from spontaneous reporting. All in all, this is the major contribution of pharmacoepidemiology to pharmacovigilance, where it can be said that it complements pharmacovigilance in drug safety monitoring but in no way could replace it., L’objectif de cet article est de présenter l’apport de la pharmaco-épidémiologie à la pharmacovigilance. Nous avons choisi de présenter cet apport dans le contexte de l’activité de surveillance de la sécurité du médicament. Si l’étude de l’apport de la pharmaco-épidémiologie à la pharmacovigilance nécessite une comparaison des méthodes et une présentation de leurs mérites respectifs, nous nous sommes efforcés de démontrer que comparaison n’était pas opposition, et qu’il y avait plus à perdre qu’à gagner à placer ces deux approches en compétition. Enfin, nous avons souhaité souligner que la notion d’apport de l’une à l’autre impliquait une complémentarité que nous nous sommes efforcés de présenter. La pharmacovigilance repose essentiellement sur l’étude de la notification spontanée et l’analyse clinique et pharmacologique de la responsabilité du médicament dans la survenue de cas individuels d’événements indésirables. Elle offre, par cet exercice, des performances à ce jour inégalées quand la détection des signaux de sécurité concerne des événements rares ou des médicaments d’utilisation rare, ou lorsque l’événement d’origine médicamenteuse présente des spécificités non retrouvées avec d’autres étiologies. La pharmaco-épidémiologie, par son approche populationnelle et l’utilisation possible d’un groupe de comparaison, permet la quantification des risques impossible à effectuer à partir des données de notification spontanée. Elle autorise aussi la mise en évidence et la quantification de signaux de sécurité pour des événements fréquents, multifactoriels, où le rôle du médicament dans la survenue de cas individuels peut être difficile à percevoir et donc, à être identifié par la notification spontanée. C’est là l’apport majeur de la pharmaco-épidémiologie à la pharmacovigilance, dont on peut dire pour conclure qu’elle complète la pharmacovigilance dans la surveillance de la sécurité du médicament, mais ne pourrait en aucun cas s’y substituer.

International audience