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1. Exploiting heterogeneous publicly available data sources for drug safety surveillance: computational framework and case studies

Author

Vassilis Koutkias, Agnès Lillo-Le Louët, Marie-Christine Jaulent, Institute of Applied Biosciences, Centre for Research and Technology-Hellas, Thessaloniki, Greece, Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris 13 (UP13), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé ( LIMICS ), Université Paris 13 ( UP13 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Pharmacovigilance ( CRPV ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris 13 ( UP13 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université Paris 13 (UP13)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Drug-Related Side Effects and Adverse Reactions, Pyridones, social media, Information Storage and Retrieval, joint exploitation, Adverse drug events, 030226 pharmacology & pharmacy, case studies, computational framework, Pharmacovigilance, 03 medical and health sciences, Adverse Event Reporting System, 0302 clinical medicine, Data acquisition, emerging data sources for pharmacovigilance, Robustness (computer science), Adverse Drug Reaction Reporting Systems, Humans, Medicine, Pharmacology (medical), Social media, 030212 general & internal medicine, spontaneous reporting systems, Clozapine, Cerebral Hemorrhage, heterogeneous public data, Safety surveillance, business.industry, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, General Medicine, Data science, Cardiotoxicity, 3. Good health, Visualization, Identification (information), [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Haloperidol, Pyrazoles, bibliographic databases, business, Antipsychotic Agents, Factor Xa Inhibitors
Abstract

International audience; Objective: Driven by the need of pharmacovigilance centres and companies to routinely collect and review all available data about adverse drug reactions (ADRs) and adverse events of interest, we introduce and validate a computational framework exploiting dominant as well as emerging publicly available data sources for drug safety surveillance.Methods: Our approach relies on appropriate query formulation for data acquisition and subsequent filtering, transformation and joint visualization of the obtained data. We acquired data from the FDA Adverse Event Reporting System (FAERS), PubMed and Twitter. In order to assess the validity and the robustness of the approach, we elaborated on two important case studies, namely, clozapine-induced cardiomyopathy/myocarditis versus haloperidol-induced cardiomyopathy/myocarditis, and apixaban-induced cerebral hemorrhage.Results: The analysis of the obtained data provided interesting insights (identification of potential patient and health-care professional experiences regarding ADRs in Twitter, information/arguments against an ADR existence across all sources), while illustrating the benefits (complementing data from multiple sources to strengthen/confirm evidence) and the underlying challenges (selecting search terms, data presentation) of exploiting heterogeneous information sources, thereby advocating the need for the proposed framework.Conclusions: This work contributes in establishing a continuous learning system for drug safety surveillance by exploiting heterogeneous publicly available data sources via appropriate support tools.

Published
2016
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2. Changing spectrum of suspected drugs of epidermal necrolysis: A World Health Organization pharmacovigilance database analysis from 1997-2020

Author

N. de Prost, T. Bettuzzi, C. Chinchilla Purtillo, Bénédicte Lebrun-Vignes, P. Maison, Laurence Le Cleach, Emilie Sbidian, Pierre Wolkenstein, S. Ingen-Housz Oro, Service de dermatologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
medicine.medical_specialty, Databases, Factual, Drug-Related Side Effects and Adverse Reactions, business.industry, Database analysis, MEDLINE, Dermatology, Antibodies, Monoclonal, Humanized, World Health Organization, medicine.disease, Toxic epidermal necrolysis, Pharmacovigilance, Pharmaceutical Preparations, Epidermal necrolysis, Stevens-Johnson Syndrome, medicine, Adverse Drug Reaction Reporting Systems, Humans, business, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Retrospective Studies
Abstract

International audience

Published
2021
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3. Erreurs médicamenteuses en Auvergne Rhône-Alpes : étude pilote descriptive collaborative entre structures régionales de vigilance et d’appui (SRVA)

Author

Pauline Rascle, Nathalie Paret, Marie Zenut, Benjamin Grenier, Michel Roy, Amélie Faudel, Marion Lepelley, Jean-Marc Sapori, Catherine Stamm, Laurence Gilles-Afchain, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hospices Civils de Lyon (HCL), Centre Régional de Pharmacovigilance [CHU Clermont-Ferrand] (CRPV), CHU Gabriel Montpied [Clermont-Ferrand], and CHU Clermont-Ferrand-CHU Clermont-Ferrand

Subjects
business.industry, [SDV]Life Sciences [q-bio], Poison control, medicine.disease, 030226 pharmacology & pharmacy, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Pharmacovigilance, Ambulatory, Health care, Medicine, Pharmacology (medical), 030212 general & internal medicine, Medical emergency, business
Abstract

Medication errors (ME) are frequently encountered and present at every step of the therapeutic process. This study's aims were to take stock of the ME reported to the region's pharmacovigilance (CRPV) and poison control centers (CAPTV) and to identify potential regional actions. A 2-months (January and February 2017) prospective gathering of the calls to the CAPTV regarding the ME and of the ME declarations to the region's CRPV (Clermont-Ferrand, Grenoble, Lyon, Saint-Etienne) has been carried out. The place of occurrence, the event's description and its consequences and data regarding the patient were collected. In addition to that, the regional drug observatory OMEDIT analysis has allowed to determine the ME's types (REMED characterization, never event?) and to look for the results of a potential thorough analysis. The study reported 580 calls for 590 ME and 583 patients. ME mostly affected the ambulatory/domicile sector (76%), the medico-social sector (14%) and the healthcare facilities sector (7%). It usually was about dose errors, medication errors and patient errors with a different profile in each sector. The majority of errors (85%) occurred at the administration step. Almost all the observed ME were confirmed errors having reached the patient (99.5%) but only a few had serious consequences. One out of 5 ME was eligible for a thorough analysis but even less were subjected to that kind of analysis. The main never event concerned the unidose in the ambulatory sector. The health products involved were mostly a single medication (75%) and then the patient's full treatment (12%). The CRPV/CAPTV/OMEDIT's skills are complementary for the gathering, the analysis and the management of the ME. Training campaigns and support are to be considered for the professionals and especially within the medico-social facilities.

Published
2020
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4. Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database

Author

Lee S. Nguyen, Leslie T. Cooper, Mathieu Kerneis, Christian Funck-Brentano, Johanne Silvain, Nicolas Brechot, Guillaume Hekimian, Enrico Ammirati, Badr Ben M’Barek, Alban Redheuil, Estelle Gandjbakhch, Kevin Bihan, Bénédicte Lebrun-Vignes, Stephane Ederhy, Charles Dolladille, Javid J. Moslehi, Joe-Elie Salem, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CMC Ambroise Paré [Neuilly-sur-Seine], Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Mayo Clinic [Jacksonville], Groupe Action, Institut de cardiologie [CHU Pitié-Salpêtrière], Service de Réanimation Médicale [CHU Pitié-Salpétrière], Ospedale Niguarda, Service de Radiologie Polyvalente et Oncologique = Service d'Imagerie Spécialisées et des Urgences [CHU Pitié-Salpêtrière] (SISU), Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Cardiologie [CHU Pitié-Salpêtrière], Département de Pharmacologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Vanderbilt University [Nashville], Gestionnaire, Hal Sorbonne Université, and Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN)

Subjects
Systems Analysis, Databases, Factual, Science, Cardiology, General Physics and Astronomy, Antineoplastic Agents, World Health Organization, Article, General Biochemistry, Genetics and Molecular Biology, Pharmacovigilance, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Adverse Drug Reaction Reporting Systems, Humans, Data Management, Multidisciplinary, Adverse effects, Bayes Theorem, General Chemistry, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Myocarditis, Cross-Sectional Studies, Pharmaceutical Preparations, Risk factors, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Immunotherapy, Antipsychotic Agents
Abstract

While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 [interquartile range: 10; 23] days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis., Multiple drugs have been in the past associated with myocarditis. Here the authors perform a pharmacovigilance study and analyze 5108 reports of drug-induced myocarditis reporting temporal trends and overall mortality and identifying emerging drug classes among the treatments associated with myocarditis.

Published
2022
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5. Hospitalization for adverse events under abiraterone or enzalutamide exposure in real-world setting: a French population-based study on prostate cancer patients

Author

Boris Campillo-Gimenez, Emmanuel Oger, André Happe, Romain Mathieu, Lucie-Marie Scailteux, Fabien Despas, Sandrine Kerbrat, Sébastien Vincendeau, Emmanuel Nowak, Frédéric Balusson, CHU Pontchaillou [Rennes], Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Pharmaco-Épidémiologie des Produits de Santé (PEPS), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), French Drugs Agency, National Health Insurance, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Jonchère, Laurent

Subjects
Male, safety, medicine.medical_specialty, 030204 cardiovascular system & hematology, Rate ratio, QT interval, Brain Ischemia, 03 medical and health sciences, Prostate cancer, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, abiraterone, Atrial Fibrillation, Nitriles, Phenylthiohydantoin, Pharmacovigilance, medicine, Humans, Enzalutamide, castration-resistant prostate cancer, Pharmacology (medical), liver test monitoring, Adverse effect, Pharmacology, [SDV.IB] Life Sciences [q-bio]/Bioengineering, enzalutamide, business.industry, Atrial fibrillation, medicine.disease, adverse events, 3. Good health, Hospitalization, Stroke, Prostatic Neoplasms, Castration-Resistant, Treatment Outcome, chemistry, acute kidney injury, 030220 oncology & carcinogenesis, Heart failure, Benzamides, Androstenes, [SDV.IB]Life Sciences [q-bio]/Bioengineering, business
Abstract

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.

Published
2022
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6. Psychotic Episode following Treatment with Hydroxychloroquine in a 17- Year-Old Female Adolescent with Cutaneous Lupus Erythematosus: A Drug Causality Supported by a Literature Review and a Worldwide Pharmacovigilance Database Search

Author

Miguel Hie, Bénédicte Lebrun-Vignes, David Cohen, Stéphane Barete, Cora Cravero, Julie Brunelle, Solène Spiers, Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], Service de Dermatologie [CHU Pitié-Salpêtrière], Centre Hospitalier le Vinatier [Bron], Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], Institut des Systèmes Intelligents et de Robotique (ISIR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [CHU Pitié-Salpêtrière]

Subjects
Drug, medicine.medical_specialty, business.industry, Drug Imputability, media_common.quotation_subject, Hydroxychloroquine, Case Report, General Medicine, Female adolescent, Psychosis, Dermatology, Causality, 3. Good health, Suicide Attempt, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Pharmacovigilance, Cutaneous Lupus Erythematosus, Medicine, Database search engine, business, medicine.drug, media_common
Abstract

International audience; Background: Hydroxychloroquine (HCQ), a useful treatment for chronic dermatologic or rheumatologic diseases, has recently gathered widespread attention as a possible treatment for COVID-19 infection. However, its rare et severe neuropsychiatric side effects (NSE), such as psychosis and suicidal tendencies, are poorly documented, especially in youths.Case presentation: We present the first case on a 17-yearold girl of severe acute psychosis with a suicide attempt during HCQ treatment in association with thalidomide for chronic and refractory discoid lupus erythematosus. Drug causality was evaluated using the updated French causality assessment method. We performed a literature review and a worldwide pharmacovigilance database search on psychotic features after HCQ and thalidomide treatment. We found six cases in the literature and 53 cases (psychotic disorder: N=45, 3.7% and acute psychosis: N=8, 0.7%) in the pharmacovigilance database reporting the occurrence of psychotic symptoms under HCQ and none under thalidomide. The intrinsic and extrinsic imputability scores support the hypothesis that HCQ induced psychosis and suicide attempt in our patient. Withdrawing HCQ resulted in a dramatically improved situation, which remained perfectly stable after 3 years of follow-up.Conclusion: In HCQ-induced psychosis, recovery may be obtained with HCQ withdrawal, no future HCQ reintroduction, and, for the most serious manifestations, a short period of antipsychotic medication. Clinicians need to be aware of the NSE of HCQ and the appropriate interventions to be carried out.

Published
2021
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7. Anticancer drug-induced life-threatening ventricular arrhythmias: a World Health Organization pharmacovigilance study

Author

Javid Moslehi, Dan M. Roden, Christian Funck-Brentano, Paul Gougis, Bénédicte Lebrun-Vignes, Joe-Elie Salem, Stéphane Ederhy, Lee S. Nguyen, Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de REcherche en Cardio Oncologie [CHU Saint-Antoine] (GRC 27 GRECO), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Vanderbilt University School of Medicine [Nashville], Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CMC Ambroise Paré [Neuilly-sur-Seine], and Service de Cardiologie [CHU Saint-Antoine]

Subjects
medicine.medical_specialty, long QT, medicine.medical_treatment, Concordance, Torsades de pointes, Antineoplastic Agents, 030204 cardiovascular system & hematology, World Health Organization, Sudden death, QT interval, World health, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Torsades de Pointes, Neoplasms, Internal medicine, Pharmacovigilance, medicine, Adverse Drug Reaction Reporting Systems, Humans, Disproportionality analysis, business.industry, ventricular arrhythmias, Bayes Theorem, Immunotherapy, medicine.disease, 3. Good health, Clinical trial, Long QT Syndrome, anticancer drugs, 030220 oncology & carcinogenesis, pharmacovigilance, torsade de pointes, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Aims With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA). Methods and results We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de pointes (TdP, n = 8163) reporting for 663 anticancer drugs vs. all other drugs until 01/01/2019. The analysis used the 95% lower-end credibility interval of the information component (IC025), an indicator for disproportionate Bayesian reporting; significant when IC025 >0. There were 2301 reports (13.8% fatal) for 40 anticancer drugs significantly associated with diLQT (with 27 also associated with VA or SD) and 9 drugs associated with VA without diLQT. Half of these (46.9%, 23/49) were associated with SD. Most (41%, 20/49) were kinase inhibitors, 8% (4/49) were hormonal therapies, 6% (3/49) were immunotherapies, 24% (12/49) were cytotoxics, and 20% (10/49) were miscellaneous. In VigiBase, reports of diLQT, TdP, or VA increased from 580 in the period 1967–83 to 15 070 in 2014–18 with the proportion related to anticancer drugs increasing from 0.9% (5/580) to 14.0% (2115/15 070) (P Conclusion This list of liable anticancer drugs may prove useful for physicians and regulatory authorities to re-evaluate cardiac monitoring requirements. Clinical trial registration NCT03530215.

Published
2021
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8. Immune checkpoint inhibitor–associated hypophysitis—World Health Organisation VigiBase report analysis

Author

Elisa Guerrero, Anne Bachelot, Bénédicte Lebrun-Vignes, Douglas B. Johnson, Javid Moslehi, Joe-Elie Salem, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC Paris Est, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Adult, Male, Cancer Research, Databases, Factual, Hypophysitis, [SDV]Life Sciences [q-bio], Immune checkpoint inhibitors, Programmed Cell Death 1 Receptor, MEDLINE, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, World Health Organization, B7-H1 Antigen, World health, Pharmacovigilance, Young Adult, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Humans, CTLA-4 Antigen, Young adult, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, biology, business.industry, Antibodies, Monoclonal, Middle Aged, medicine.disease, Ipilimumab, 3. Good health, Nivolumab, Oncology, 030220 oncology & carcinogenesis, Monoclonal, Immunology, biology.protein, Female, Antibody, business
Abstract

International audience

Published
2019
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9. How to interact with medical terminologies? Formative usability evaluations comparing three approaches for supporting the use of MedDRA by pharmacovigilance specialists

Author

Sébastien Ferré, Laura Douze, Carlos Bobed, Cédric Bousquet, Jean-Baptiste Lamy, Bissan Audeh, Romaric Marcilly, Agnès Lillo-Le Louët, Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Semantics, Logics, Information Systems for Data-User Interaction ( SemLIS), GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), ANR-16-CE23-0011, Agence Nationale de la Recherche, ANR-16-CE23-0011,PEGASE,Pharmacovigilance Enrichie par des Groupements Améliorant la détection des Signaux Émergents(2016), Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Jonchère, Laurent, Pharmacovigilance Enrichie par des Groupements Améliorant la détection des Signaux Émergents - - PEGASE2016 - ANR-16-CE23-0011 - AAPG2016 - VALID, Université de Lille, CHU Lille, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Semantics, Logics, Information Systems for Data-User Interaction [ SemLIS], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé [LIMICS], and Centre Régional de Pharmacovigilance [CRPV]

Subjects
Drug-Related Side Effects and Adverse Reactions, 020205 medical informatics, Cognitive walkthrough, Computer science, MedDRA, Health Informatics, Formative evaluation, 02 engineering and technology, lcsh:Computer applications to medicine. Medical informatics, Health informatics, Formative assessment, 03 medical and health sciences, Pharmacovigilance, 0302 clinical medicine, Usability testing, Adverse Drug Reaction Reporting Systems, Humans, Specialization, Systematized Nomenclature of Medicine, 0202 electrical engineering, electronic engineering, information engineering, 030212 general & internal medicine, [SDV.IB] Life Sciences [q-bio]/Bioengineering, SNOMED CT, Information retrieval, business.industry, Health Policy, System usability scale, Usability, 3. Good health, Computer Science Applications, lcsh:R858-859.7, [SDV.IB]Life Sciences [q-bio]/Bioengineering, business, Research Article
Abstract

Background Medical terminologies are commonly used in medicine. For instance, to answer a pharmacovigilance question, pharmacovigilance specialists (PVS) search in a pharmacovigilance database for reports in relation to a given drug. To do that, they first need to identify all MedDRA terms that might have been used to code an adverse reaction in the database, but terms may be numerous and difficult to select as they may belong to different parts of the hierarchy. In previous studies, three tools have been developed to help PVS identify and group all relevant MedDRA terms using three different approaches: forms, structured query-builder, and icons. Yet, a poor usability of the tools may increase PVS’ workload and reduce their performance. This study aims to evaluate, compare and improve the three tools during two rounds of formative usability evaluation. Methods First, a cognitive walkthrough was performed. Based on the design recommendations obtained from this evaluation, designers made modifications to their tools to improve usability. Once this re-engineering phase completed, six PVS took part in a usability test: difficulties, errors and verbalizations during their interaction with the three tools were collected. Their satisfaction was measured through the System Usability Scale. The design recommendations issued from the tests were used to adapt the tools. Results All tools had usability problems related to the lack of guidance in the graphical user interface (e.g., unintuitive labels). In two tools, the use of the SNOMED CT to find MedDRA terms hampered their use because French PVS were not used to it. For the most obvious and common terms, the icons-based interface would appear to be more useful. For the less frequently used MedDRA terms or those distributed in different parts of the hierarchy, the structured query-builder would be preferable thanks to its great power and flexibility. The form-based tool seems to be a compromise. Conclusion These evaluations made it possible to identify the strengths of each tool but also their weaknesses to address them before further evaluation. Next step is to assess the acceptability of tools and the expressiveness of their results to help identify and group MedDRA terms.

Published
2020
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10. Heart failure and atrial tachyarrhythmia on abiraterone: A pharmacovigilance study

Author

Dan M. Roden, Marie Bretagne, Javid Moslehi, Antoine Pariente, Camille Potey, Pauline Dureau, Christian M. Shaffer, Gabriel G. Malouf, Joe-Elie Salem, Bénédicte Lebrun-Vignes, Christian Funck-Brentano, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], CHU Strasbourg, Centre Régional de PharmacoVigilance Nord-Pas-de-Calais [CHU Lille] (CRPV), and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine

Subjects
Male, Time Factors, Databases, Factual, 030204 cardiovascular system & hematology, Androgen deprivation therapy, chemistry.chemical_compound, Prostate cancer, Pharmacovigilance, 0302 clinical medicine, Risk Factors, Tachycardia, Supraventricular, Medicine, 030212 general & internal medicine, Abiraterone, Aged, 80 and over, Atrial fibrillation, General Medicine, Middle Aged, 3. Good health, Benzamides, Androstenes, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Abiratérone, Heart failure, [SDV.CAN]Life Sciences [q-bio]/Cancer, Risk Assessment, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Nitriles, Phenylthiohydantoin, Enzalutamide, Adverse Drug Reaction Reporting Systems, Humans, Aged, Retrospective Studies, PharmacoEpi-Drugs, business.industry, Prostatic Neoplasms, Androgen Antagonists, Odds ratio, medicine.disease, Cardiotoxicity, Insuffisance cardiaque, Fibrillation auriculaire, chemistry, Anti-androgène, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Observational study, business
Abstract

International audience; Background: Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) compared with other ADTs.Aim: To determine if abiraterone was associated with an increased proportion of AT and HF reports among all suspected adverse drug reactions (ADRs) reported in several pharmacovigilance databases compared with enzalutamide, other ADTs and all other drugs.Methods: In this observational retrospective pharmacovigilance study, we performed a disproportionality analysis of reports of suspected ADRs in men in the French pharmacovigilance database, the European pharmacovigilance database and the international pharmacovigilance database VigiBase, to evaluate the reporting odds ratios (RORs) of AT and HF for abiraterone compared with enzalutamide, other ADTs and all other drugs.Results: In the 5,759,781 ADR reports in men in VigiBase, 55,070 pertained to ADTs. The RORs for AT for abiraterone versus enzalutamide, other ADTs and all other drugs were 4.1 (95% confidence interval 3.1-5.3), 3.7 (3-4.5) and 3.2 (2.7-3.7), respectively (P

Published
2020
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11. Cytopenia induced by low-dose methotrexate: An analysis of 433 cases from the French pharmacovigilance database

Author

Laurence Fardet, Bénédicte Lebrun-Vignes, Delphine Laugier, Corinne Simon, Sophie Lalevée, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
musculoskeletal diseases, Male, Databases, Factual, Pancytopenia, 030204 cardiovascular system & hematology, computer.software_genre, Low dose methotrexate, 03 medical and health sciences, Pharmacovigilance, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Internal Medicine, medicine, Humans, Medication Errors, heterocyclic compounds, In patient, 030212 general & internal medicine, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Aged, 80 and over, Cytopenia, Leukopenia, Database, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Methotrexate, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, France, medicine.symptom, business, computer, medicine.drug
Abstract

Up to 5% of individuals exposed to low-dose methotrexate (MTX) (i.e., ≤30 mg/week) may develop cytopenia. However, MTX-induced cytopenia have been poorly described.All cases of cytopenia (i.e., anaemia, leukopenia, thrombocytopenia, bi- or pancytopenia) in patients receiving low-dose MTX reported to the French pharmacovigilance database during 2006-2016 were analysed. Three groups were defined: cytopenia due to MTX medication errors (e.g., daily rather than weekly administration), cytopenia in people receiving several medications including MTX, cytopenia in people receiving only MTX.433 cases were analysed. Eighty-four cases (19.4%) were due to medication errors, 180 (41.6%) occurred in individuals exposed both to MTX and other drugs, and 169 (39.0%) occurred in individuals only exposed to MTX. By comparison to other patients, those with cytopenia due to medication errors were older (74 ± 13 vs 69 ± 15 years, p = 0.002), received more frequently MTX orally (92.9% vs 65.3%, p0.001) and had more frequently pancytopenia (71.4% vs 54.4%, p = 0.005). By comparison to individuals exposed to multiple drugs (n = 180), those exposed only to MTX (n = 169) were older (71 ± 15 vs 67 ± 14, p = 0.02), and had more often pancytopenia (62.7% vs 46.7%, p = 0.001). Among those only exposed to MTX, most cases (n = 140, 82.8%) were considered as toxic rather than idiosyncratic reactions and a trigger (e.g. diarrhoea) was found in 59.3% of those cases. Overall 30 (6.9%) deaths occurred, including 8 in the "medication error" group and 8 in the "MTX only" group.These data may be useful for defining optimal biological monitoring of patients prescribed low-dose MTX.

Published
2019
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12. Methylprednisolone-related liver injury: A descriptive study using the French pharmacovigilance database

Author

Aurore Gouraud, Jérôme Dumortier, Véronique Pizzoglio, Corinne Simon, Geneviève Durrieu, Nathalie Bleyzac, Sabrina Pierre, Judith Cottin, Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Hôpital Edouard Herriot [CHU - HCL], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CCSD, Accord Elsevier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Databases, Factual, [SDV]Life Sciences [q-bio], Liver injury, Gastroenterology, Methylprednisolone, 03 medical and health sciences, Route of administration, Pharmacovigilance, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Adverse effect, Child, Aged, Autoimmune disease, Aged, 80 and over, Hepatology, business.industry, Multiple sclerosis, Infant, Middle Aged, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Concomitant, Child, Preschool, 030211 gastroenterology & hepatology, Female, France, Safety, Chemical and Drug Induced Liver Injury, business, medicine.drug
Abstract

International audience; Purpose: Hepatotoxicity associated with methylprednisolone (MP) is rarely reported in the literature. The aim of the present study was to review the characteristics of acute liver injury associated with intravenous (IV) or oral MP registered in the French pharmacovigilance database (FPD).Methods: All cases with MP coded as suspected, concomitant, or interacting drug associated with liver injury as the adverse effect reported up to May 2016 were extracted from the FPD. Cases were identified using the "Drug related hepatic disorders" Standard Medical Query.Results: A total of 97 cases of liver injury associated with MP were analysed; 58.8% were women and the median age was 46 years (range: 1-91). MP was used for an autoimmune disease in 47.6% of cases including 26 cases of multiple sclerosis, and was IV in 79.4% of cases. Nearly three-quarters of patients (73,2%) had a hepatocellular type of injury, the severity of which was mainly mild (45%) or moderate (31%). Most patients (92%) spontaneously and fully recovered within a mean 38.4 days. A rechallenge using the IV route was performed in 13 patients and for 10 (76.9%) this was positive (the initial type of injury was hepatocellular for all these cases). Regarding IV route of administration (n=77), MP was coded as the only suspected drug in 22% of cases.Discussion: The results suggest that IV MP causality should be considered in case of acute liver injury while data for oral MP is insufficient; systematic liver monitoring for high-dose IV MP may be recommended.

Published
2019
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13. Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes and the French pharmacovigilance database

Author

Franck Morschhauser, Chouki Chenaf, Alexis B. Cortot, Nicolas Etienne, Laurent Mortier, Aurélie Grandvuillemin, Christine Le Beller, Delphine Staumont-Sallé, David Launay, Solenn Brousseau, Guillaume Lefèvre, Matthieu Groh, Johana Béné, Sophie Gautier, Jean-Emmanuel Kahn, Eric Hachulla, Alexandra Forestier, Myriam Labalette, Quentin Scanvion, service de médecine interne et immunologie clinique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des maladies auto-immunes systémiques rares du Nord et Nord Ouest [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Régional de PharmacoVigilance Nord-Pas-de-Calais [CHU Lille] (CRPV), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Centre Régional de Pharmacovigilance, de Renseignement sur le Médicament et de Pharmaco épidémiologie de Bourgogne [Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Régional de Pharmacovigilance [CHU Clermont-Ferrand] (CRPV), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Service d’oncologie thoracique et essais précoces [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Hôpital Foch [Suresnes], Institut d'Immunologie [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Ambroise Paré [AP-HP], The authors would like to thank all the physicians who contributed adverse drug reaction reports to the French pharmacovigilance system., Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Faculté de Médecine Henri Warembourg - Université de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-UNICANCER

Subjects
0301 basic medicine, Moderate to severe, medicine.medical_specialty, Databases, Factual, Immune checkpoint inhibitors, Immunology, Early detection, emergent adverse event, immune checkpoint inhibitors, 03 medical and health sciences, Pharmacovigilance, 0302 clinical medicine, Antineoplastic Agents, Immunological, Internal medicine, Hypereosinophilic Syndrome, Eosinophilia, Immunology and Allergy, Medicine, Humans, Adverse effect, RC254-282, business.industry, Brief Report, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, RC581-607, respiratory system, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, immune-related adverse events, Observational study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, Immunologic diseases. Allergy, business
Abstract

International audience; A better understanding of immune-related adverse events is essential for the early detection and appropriate management of these phenomena. We conducted an observational study of cases recorded at the French reference center for hypereosinophilic syndromes and in the French national pharmacovigilance database. Thirty-seven reports of eosinophilia induced by treatment with immune checkpoint inhibitors (ICIs) were included. The median [range] time to the absolute eosinophil count (AEC) peak was 15 [4─139] weeks. The median AEC was 2.7 [0.8─90.9] G/L. Eosinophil-related manifestations were reported in 21 of the 37 cases (57%). If administered, corticosteroids were always effective (n = 10 out of 10). Partial or complete remission of eosinophilia was obtained in some patients not treated with corticosteroids, after discontinuation (n = 12) or with continuation (n = 4) of the ICI. The AEC should be monitored in ICI-treated patients. If required by oncologic indications, continuation of ICI may be an option in asymptomatic hypereosinophilic patients, and in corticosteroid responders.

Published
2019
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14. Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

Author

Javid Moslehi, Justin M. Balko, Joe-Elie Salem, Ali Manouchehri, Alexandra M Haugh, Bénédicte Lebrun-Vignes, Henry T. Quach, Andrew L. Mammen, Douglas B. Johnson, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), National Institutes of Health [Bethesda] (NIH), Gestionnaire, Hal Sorbonne Université, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Cancer Research, MedDRA, [SDV]Life Sciences [q-bio], Guillain-Barre syndrome, Pharmacovigilance, 0302 clinical medicine, PD-1, Immunology and Allergy, Myasthenia gravis, Incidence (epidemiology), lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Encephalitis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Immunotherapy, Meningitis, Research Article, PD-L1, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Drug-Related Side Effects and Adverse Reactions, Immunology, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, medicine, Neurotoxicity, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Adverse effect, Retrospective Studies, Pharmacology, business.industry, Odds ratio, medicine.disease, Neuropathy, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, CTLA-4, Nervous System Diseases, business, 030215 immunology
Abstract

Background Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized. Methods We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. Results Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5–18.9]; IC025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2–11.8]; IC025 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5–3.9]; IC025 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6–12%), later onset (median 61–80 days), and were non-overlapping. Conclusions ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations. Electronic supplementary material The online version of this article (10.1186/s40425-019-0617-x) contains supplementary material, which is available to authorized users.

Published
2019
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15. Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database

Author

Laurent Arnaud, Thierry Martin, Philippe Mertz, Aude Lambert, François Chasset, Martine Tebacher-Alt, Joe-Elie Salem, Jean Sibilia, P.E. Gavand, Charlotte Muller, Bénédicte Lebrun-Vignes, CHU Strasbourg, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg (UNISTRA), Service de dermatologie et allergologie [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], and CHU Pitié-Salpêtrière [AP-HP]

Subjects
Male, 0301 basic medicine, Databases, Factual, [SDV]Life Sciences [q-bio], computer.software_genre, Etanercept, 0302 clinical medicine, systemic lupus erythematosus, Lupus Erythematosus, Systemic, Immunology and Allergy, skin and connective tissue diseases, media_common, Systemic lupus erythematosus, Database, Middle Aged, Hydralazine, 3. Good health, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Antirheumatic Agents, Female, medicine.drug, Adult, Drug, media_common.quotation_subject, Immunology, Procainamide, World Health Organization, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Rheumatology, Pharmacovigilance, medicine, Adalimumab, Humans, Adverse effect, Retrospective Studies, 030203 arthritis & rheumatology, business.industry, drug-induced lupus, medicine.disease, Infliximab, 030104 developmental biology, adverse-drug reaction, pharmacovigilance, business, computer, Adverse drug reaction
Abstract

ObjectiveDrug-induced lupus (DIL) is an idiosyncratic side effect of treatments in which symptoms overlap with those of systemic lupus erythematosus (SLE). The spectrum of DIL constantly evolves with that of the pharmacopoeia. Here, we used VigiBase, the WHO global individual case safety reports (ICSRs) database, to identify the main drugs associated with DIL.MethodsWe analysed all ICSRs classified as ‘systemic lupus erythematosus’ according to the Medical Dictionary for Drug Regulatory Activities term (preferred term level) in VigiBase. The drugs considered in the analysis were those not used to treat SLE, with a positive lower end of the 95% credibility interval for the information component (IC025) ≥0, an indicator value for disproportionate Bayesian reporting.ResultsA total of 12 166 DIL ICSRs were identified using VigiBase. From those, 8163 ICSRs reporting on 118 suspected drugs with IC025 ≥0 were extracted. The median age at DIL onset was 49 years and the female to male sex ratio was 4.3. The median delay between start of suspected treatment and DIL occurrence was 172 days. DIL was reported as serious adverse event in 55.4%. Among the 118 suspected drugs, 42 had not been previously reported in association with DIL. The drugs associated with the highest number of DIL cases were infliximab, adalimumab, etanercept, procainamide and hydralazine.ConclusionThis study enables the identification of 118 drugs associated with DIL. The list of suspected drugs may prove useful to physicians when confronted with potential DIL cases.Trial registration numberNCT03480529.

Published
2019
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16. Mining Patients' Narratives in Social Media for Pharmacovigilance: Adverse Effects and Misuse of Methylphenidate

Author

Xiaoyi Chen, Carole Faviez, Stéphane Schuck, Agnès Lillo-Le-Louët, Nathalie Texier, Badisse Dahamna, Charles Huot, Pierre Foulquié, Suzanne Pereira, Vincent Leroux, Pierre Karapetiantz, Armelle Guenegou-Arnoux, Sandrine Katsahian, Cédric Bousquet, Anita Burgun, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Kappa, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Equipe Traitement de l'information en Biologie Santé (TIBS - LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Expert Systems, VIDAL S.A., Institut de Santé Urbaine, École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Service d'informatique biomédicale [Rouen], CHU Rouen, Normandie Université (NU), Département d’informatique médicale, de biostatistique et de santé publique [AP-HP Hôpital européen Georges-Pompidou], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Topic model, drug misuse, 020205 medical informatics, social media, methylphenidate, 02 engineering and technology, computer.software_genre, [INFO.INFO-SI]Computer Science [cs]/Social and Information Networks [cs.SI], 03 medical and health sciences, 0302 clinical medicine, Text mining, Named-entity recognition, Pharmacovigilance, 0202 electrical engineering, electronic engineering, information engineering, Pharmacology (medical), Social media, [INFO]Computer Science [cs], 030212 general & internal medicine, natural language processing, Adverse effect, ComputingMilieux_MISCELLANEOUS, Original Research, Pharmacology, business.industry, lcsh:RM1-950, data mining, Relationship extraction, 3. Good health, [INFO.INFO-TT]Computer Science [cs]/Document and Text Processing, Identification (information), lcsh:Therapeutics. Pharmacology, pharmacovigilance, drug-related side effects and adverse reactions, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Artificial intelligence, business, Psychology, computer, Natural language processing
Abstract

International audience; Background: The Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) have recognized social media as a new data source to strengthen their activities regarding drug safety. Objective: Our objective in the ADR-PRISM project was to provide text mining and visualization tools to explore a corpus of posts extracted from social media. We evaluated this approach on a corpus of 21 million posts from five patient forums, and conducted a qualitative analysis of the data available on methylphenidate in this corpus. Methods: We applied text mining methods based on named entity recognition and relation extraction in the corpus, followed by signal detection using proportional reporting ratio (PRR). We also used topic modeling based on the Correlated Topic Model to obtain the list of the matics in the corpus and classify the messages based on their topics. Results: We automatically identified 3443 posts about methylphenidate published between 2007 and 2016, among which 61 adverse drug reactions (ADR) were automatically detected. Two pharmacovigilance experts evaluated manually the quality of automatic identification, and a f-measure of 0.57 was reached. Patient's reports were mainly neuro-psychiatric effects. Applying PRR, 67% of the ADRs were signals, including most of the neuro-psychiatric symptoms but also palpitations. Topic modeling showed that the most represented topics were related to Childhood and Treatment initiation, but also Side effects. Cases of misuse were also identified in this corpus, including recreational use and abuse. Conclusion: Named entity recognition combined with signal detection and topic modeling have demonstrated their complementarity in mining social media data. An in-depth analysis focused on methylphenidate showed that this approach was able to detect potential signals and to provide better understanding of patients' behaviors regarding drugs, including misuse.

Published
2018
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17. The Adverse Drug Reactions from Patient Reports in Social Media Project: Five Major Challenges to Overcome to Operationalize Analysis and Efficiently Support Pharmacovigilance Process

Author

Cedric, Bousquet, Badisse, Dahamna, Sylvie, Guillemin-Lanne, Stefan J, Darmoni, Carole, Faviez, Charles, Huot, Sandrine, Katsahian, Vincent, Leroux, Suzanne, Pereira, Christophe, Richard, Stéphane, Schück, Julien, Souvignet, Agnès, Lillo-Le Louët, Nathalie, Texier, Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), Equipe Traitement de l'information en Biologie Santé (TIBS - LITIS), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Temis, Kappa, IBM France (IBM), IBM, Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Original Paper, big data, pharmacovigilance, social media, medical terminology, [INFO]Computer Science [cs], natural language processing
Abstract

Background Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Classical Pharmacovigilance process is limited by underreporting which justifies the current interest in new knowledge sources such as social media. The Adverse Drug Reactions from Patient Reports in Social Media (ADR-PRISM) project aims to extract ADRs reported by patients in these media. We identified 5 major challenges to overcome to operationalize the analysis of patient posts: (1) variable quality of information on social media, (2) guarantee of data privacy, (3) response to pharmacovigilance expert expectations, (4) identification of relevant information within Web pages, and (5) robust and evolutive architecture. Objective This article aims to describe the current state of advancement of the ADR-PRISM project by focusing on the solutions we have chosen to address these 5 major challenges. Methods In this article, we propose methods and describe the advancement of this project on several aspects: (1) a quality driven approach for selecting relevant social media for the extraction of knowledge on potential ADRs, (2) an assessment of ethical issues and French regulation for the analysis of data on social media, (3) an analysis of pharmacovigilance expert requirements when reviewing patient posts on the Internet, (4) an extraction method based on natural language processing, pattern based matching, and selection of relevant medical concepts in reference terminologies, and (5) specifications of a component-based architecture for the monitoring system. Results Considering the 5 major challenges, we (1) selected a set of 21 validated criteria for selecting social media to support the extraction of potential ADRs, (2) proposed solutions to guarantee data privacy of patients posting on Internet, (3) took into account pharmacovigilance expert requirements with use case diagrams and scenarios, (4) built domain-specific knowledge resources embeding a lexicon, morphological rules, context rules, semantic rules, syntactic rules, and post-analysis processing, and (5) proposed a component-based architecture that allows storage of big data and accessibility to third-party applications through Web services. Conclusions We demonstrated the feasibility of implementing a component-based architecture that allows collection of patient posts on the Internet, near real-time processing of those posts including annotation, and storage in big data structures. In the next steps, we will evaluate the posts identified by the system in social media to clarify the interest and relevance of such approach to improve conventional pharmacovigilance processes based on spontaneous reporting.

Published
2017
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18. Adverse Drug Reaction Mining in Pharmacovigilance data using Formal Concept Analysis

Author

Yannick Toussaint, Agnès Lillo-Le Louet, Jean Villerd, Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Nancy 2-Université Henri Poincaré - Nancy 1 (UHP), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), and Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adverse Drug Reactions, Computer science, Association (object-oriented programming), Formal Concept Analysis, Population, 02 engineering and technology, 030226 pharmacology & pharmacy, Health informatics, Task (project management), [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 03 medical and health sciences, 0302 clinical medicine, Pharmacovigilance, 0202 electrical engineering, electronic engineering, information engineering, Formal concept analysis, medicine, Adverse effect, education, Data mining, education.field_of_study, business.industry, medicine.disease, Data science, 020201 artificial intelligence & image processing, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Adverse drug reaction
Abstract

International audience; In this paper we discuss the problem of extracting and evaluating associations between drugs and adverse effects in pharmacovigilance data. Approaches proposed by the medical informatics community for mining one drug - one effect pairs perform an exhaustive search strategy that precludes from mining high-order associations. Some specificities of pharmacovigilance data prevent from applying pattern mining approaches proposed by the data mining community for similar problems dealing with epidemiological studies. We argue that Formal Concept Analysis (FCA) and concept lattices constitute a suitable framework for both identifying relevant associations, and assisting experts in their evaluation task. Demographic attributes are handled so that the disproportionality of an association is computed w.r.t. the relevant population stratum to prevent confounding. We put the focus on the understandability of the results and provide evaluation facilities for experts. A real case study on a subset of the French spontaneous reporting system shows that the method identifies known adverse drug reactions and some unknown associations that has to be further investigated.

Published
2010
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19. Complémentarité des méthodes numériques et symboliques en pharmacovigilance

Author

Jean Villerd, Yannick Toussaint, Agnès Lillo-Le Louet, Knowledge representation, reasonning (ORPAILLEUR), INRIA Lorraine, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP)-Université Nancy 2-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Sylvie Desprès, and Villerd, Jean

Subjects
[INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Pharmacovigilance, Extraction de connaissances, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-IR]Computer Science [cs]/Information Retrieval [cs.IR], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-IR] Computer Science [cs]/Information Retrieval [cs.IR], Fouille de données, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract

National audience; La pharmacovigilance a pour objet la surveillance du risque d'effet indésirable résultant de l'utilisation des médicaments et produits à usage humain. Elle consiste à détecter des « signaux » correspondant à des corrélations suspectes entre la prise d'un médicament et l'observation d'un effet indésirable. Les professionnels de santé sont tenus de signaler tout effet indésirable inattendu en envoyant un rapport a leur centre régional de pharmacovigilance, alimentant ainsi une base nationale. Pour faire face à la quantité de rapports stockés, des méthodes numériques fondées sur des mesures de disproportionnalité été proposées ; elles extraient efficacement les couples (médicament, effet indésirable) sur-représentés dans la base, en vue de leur evaluation par un expert. Toutefois, ces approches fournissent peu d'information aux experts pour leur permettre de comprendre pour quelles raisons ces signaux ont eté retenus. De plus, aucune information ne leur est transmise concernant la spécificité eventuelle d'un signal qui concernerait plus particulièrement une sous-population (sexe, âge). L'utilisation d'une approche symbolique comme l'Analyse de Concepts Formels (ACF), en complément des méthodes numériques existantes, nous a permis d'obtenir une meilleure « tracabilité » des signaux extraits en fournissant aux experts une vue synthétique du contenu de la base. De plus, l'utilisation d'une approche fondée sur les treillis permet de réduire l'espace de recherche, de détecter des associations complexes impliquant plusieurs médicaments et effets indésirables et d'identifier les spécificités liées aux diverses sous-populations. Nous illustrons ces atouts par une expérimentation sur la base régionale HEGP.

Published
2010

20. VigiTermes : une plateforme de recherche et d'analyse des publications scientifiques au service de la pharmacovigilance

Author

Thebault, Mathilde, Amardeilh, Florence, Delamarre, Denis, Guillemin-Lanne, Sylvie, Jamet, Anne, Lillo-Le Louet, Agnès, Thebault, Mathilde, Technologies pour la santé - Vers une meilleure détection du signal et gestion des connaissances en pharmacovigilance - - VigiTermes2007 - ANR-07-TECS-0026 - TECSAN - VALID, Sylvie DESPRES, Temis, Mondeca, Modélisation Conceptuelle des Connaissances Biomédicales, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Vigitermes ANR-07-TECSAN-026, ANR-07-TECS-0026,VigiTermes,Vers une meilleure détection du signal et gestion des connaissances en pharmacovigilance(2007), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
[INFO.INFO-TT]Computer Science [cs]/Document and Text Processing, recherche PubMed, [INFO.INFO-CL] Computer Science [cs]/Computation and Language [cs.CL], [INFO.INFO-IR]Computer Science [cs]/Information Retrieval [cs.IR], annotation sémantique, pharmacovigilance, [INFO.INFO-TT] Computer Science [cs]/Document and Text Processing, bases de connaissance, text mining, modélisations des connaissances, [INFO.INFO-IR] Computer Science [cs]/Information Retrieval [cs.IR], [INFO.INFO-CL]Computer Science [cs]/Computation and Language [cs.CL]
Abstract

National audience; La réglementation impose une identification systématique des effets indésirables des médicaments. La plupart des pays se sont dotés de systèmes d'information d'aide à la documentation de ces effets. La tâche est rendue difficile par la multiplicité des sources et le peu d'outils fédérateurs existant pour accéder, rechercher et analyser l'information autour des médicaments. L'objectif du projet VigiTermes est de développer une plateforme pour améliorer la documentation des rapports de cas de pharmacovigilance et de proposer des outils d'accès et d'analyse pour les experts pharmacovigilants, dont l'objectif est d'enquêter sur la détection de nouveaux cas (signaux). Dans ce cadre, nous avons développé un prototype qui reproduit et standardise les stratégies de recherche documentaire formulées par les pharmacovigilants, récupère les résumés PubMed pertinents et en extrait de l'information autour des médicaments et de leurs effets secondaires potentiels.

Published
2010

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