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TNFα inhibitors, including adalimumab, are widely used in inflammatory rheumatologic and bowel diseases. Well-known adverse effects include: opportunistic infections, immunogenicity and new inflammatory manifestations. Myositis is an inflammatory disease, which manifests with muscle symptoms and can be life-threatening. Little is known about drug-induced myositis. We aimed to describe a case of myositis induced by adalimumab and reviewed national and international pharmacovigilance databases for other cases until 01/02/2019. This was a 63 years old woman with Crohn's disease, who developed muscle weakness, and rhabdomyolysis 3 months after starting adalimumab. Diagnosis of myositis was suspected and confirmed with electromyography and muscle biopsy. Improvement in muscle symptoms was observed after stopping adalimumab and starting corticosteroids. Muscular adverse effects are well-known and usually benign with adalimumab. However, five cases of myositis during treatment with adalimumab were registered in French PharmacoVigilance Database (FPVD) with muscle symptoms observed 3 months to 7 years after starting adalimumab. In VigiBaseⓇ, 90 cases of myositis associated with adalimumab with some similar characteristics were registered. When a patient treated with adalimumab complains of muscular symptoms, inflammatory myopathies should be considered. This adverse effect should be mentioned in a 'Summary of Product Characteristics' to alert healthcare professionals.

Purpose/background Alzheimer disease (AD) is a public health issue because of the low number of symptomatic drugs and the difficulty to diagnose it at the prodromal stage. The need to develop new treatments and to validate sensitive tests for early diagnosis could be met by developing a challenge model reproducing cognitive impairments of AD. Therefore, we implemented a 24-hour sleep deprivation (SD) design on healthy volunteers in a randomized, double-blind, placebo-controlled, crossover study on 36 healthy volunteers. Methods/procedure To validate the SD model, cognitive tests were chosen to assess a transient worsening of cognitive functions after SD and a restoration under modafinil as positive control (one dose of 200 mg). Then, the same evaluations were replicated after 15 days of donepezil (5 mg/d) or memantine (10 mg/d). The working memory (WM) function was assessed by the N-back task and the rapid visual processing (RVP) task. Findings/results The accuracy of the N-back task and the reaction time of the RVP revealed the alteration of the WM with SD and its restoration with modafinil (changes in score after SD compared with baseline before SD), respectively, in the placebo group and in the modafinil group (-0.2% and +1.0% of satisfactory answers, P = 0.022; +21.3 and +1.9 milliseconds of reaction time, P = 0.025). Alzheimer disease drugs also tended to reverse this deterioration: the accuracy of the N-back task was more stable through SD (compared with -3.0% in the placebo group, respectively, in the memantine group and in the donepezil group: -1.4% and -1.6%, P = 0.027 and P = 0.092) and RVP reaction time was less impacted (compared with +41.3 milliseconds in the placebo group, respectively, in the memantine group and in the donepezil group: +16.1 and +29.3 milliseconds, P = 0.034 and P = 0.459). Implications/conclusions Our SD challenge model actually led to a worsening of WM that was moderated by both modafinil and AD drugs. To use this approach, the cognitive battery, the vulnerability of the subjects to SD, and the expected drug effect should be carefully considered.

Summary Introduction Immune checkpoint inhibitor-induced diabetes mellitus (ICI-DM) is an immune-related adverse drug reaction (irADR). Hyperglycemia can be linked to endogenous insulin deficiency with ketoacidosis or associated with preserved beta-cell function. Objectives We aimed to identify the characteristics of both types of ICI-DM (type 1 and type 2 DM), to improve our understanding of this irADR and its management. Methods Data for ICI-DM recorded in the French Pharmacovigilance Database from 2015 to October 2019 were analyzed according to the French causality assessment. Results In total, 60 subjects were included. Anti-PD1/PDL1 pathway blockade therapy (nivolumab: 61.7% + 3.3% in association with ipilimumab pembrolizumab: 28.3%) was most frequently implicated in ICI-DM, but some reports involved anti-CTLA4 drug (ipilimumab: 6.7% + 3.3% in association with nivolumab). One third of reports occurred within one month of the initiation of immunotherapy. Decreased insulin secretion (defined by the presence of ketone bodies) were confirmed in 80% of reports. Among them, 54% of patients met the diagnostic criteria for fulminant diabetes. Overall, 17.7% of the reports had pre-existing type 2 diabetes T2D. Four deaths due to hyperglycemia were declared, with altered insulin secretion in only two of these reports. BMI was lower in the insulinopenic group (23.4 ± 0.7 vs. 27.9 ± 1.6, P = 0.004) and other irADRs were more frequently observed in patients with persistent insulin secretion (66.7 vs. 18.8%, P = 0.02). We found no difference in age, indication or cumulative ICI dose between the two groups (with and without insulinopenia). The presence of GAD antibodies was associated with a shorter time to diabetes onset (42.6 ± 6.1 vs. 208.1 ± 41.6 days, P = 0.029). Conclusions ICI-DM is a rare but serious irADR triggered by all classes of immunotherapy. The observation period for ICI-DM can be shortened for patients positive for anti-GAD antibodies. Endogenous insulin deficiency did not appear to be the only mechanism involved in ICI-DM, as beta-cell function was preserved in 20% of reports. Improvements in our understanding of this complication will be required for its prevention.

Immune checkpoint inhibitor (ICI)-related cytopenias have been poorly described. This study aimed to further characterize ICI-related cytopenias, using the French pharmacovigilance database. All grade ≥ 2 hematological adverse drug reactions involving at least one ICI coded as suspected or interacting drug according to the World Health Organization criteria and reported up to 31 March 2022, were extracted from the French pharmacovigilance database. Patients were included if they experienced ICI-related grade ≥ 2 cytopenia. We included 68 patients (75 ICI-related cytopenias). Sixty-three percent were male, and the median age was 63.0 years. Seven patients (10.3%) had a previous history of autoimmune disease. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were the most frequently reported (50.7% and 25.3%, respectively). The median time to onset of ICI-related cytopenias was 2 months. Nearly half were grade ≥ 4, and three patients died from bleeding complications of refractory ITP and from thromboembolic disease with active AIHA. Out of 61 evaluable responses, complete or partial remission was observed after conventional treatment in 72.1% of ICI-related cytopenias. Among the 10 patients with ICI resumption after grade ≥ 2 ICI-related cytopenia, three relapsed. ICI-related cytopenias are rare but potentially life-threatening. Further studies are needed to identify risk factors of ICI-related cytopenias.

BackgroundSafety of rechallenge of immune checkpoint inhibitor (ICI) after grade ≥2 immune-related adverse events (irAEs) leading to ICI discontinuation remains unclear.MethodsAll adverse drug reactions involving at least one ICI reported up to December 31, 2019 were extracted from the French pharmacovigilance database. Patients were included if they experienced at least one grade ≥2 irAE resulting in ICI discontinuation, with subsequent ICI rechallenge. The primary outcome was the recurrence of at least one grade ≥2 irAE in these patients after ICI rechallenge.ResultsWe included 180 patients: 61.1% were men (median age of 66 years), 43.9% had melanoma and 78.9% were receiving anti-programmed cell death 1. First ICI discontinuation was related to 191 irAEs. After ICI rechallenge, 38.9% of the patients experienced at least one grade ≥2 irAE. Among them, 70.0% experienced the same irAE, 25.7% a distinct irAE, and 4.3% both the same and a distinct irAE. Lower recurrence rates of irAEs were associated with rechallenge with the same ICI treatment (p=0.02) or first endocrine irAEs (p=0.003). Gastrointestinal irAEs were more likely to recur (p=0.007). The median duration from ICI discontinuation to rechallenge and the severity of the initial irAE did not predict recurrent irAEs after ICI rechallenge (p=0.53 and p=0.40, respectively).ConclusionsIn this study, 61.1% of the patients who discontinued ICI treatment for grade ≥2 irAEs experienced no recurrent grade ≥2 irAEs after ICI rechallenge. Although ICI rechallenge appears to be safe under close monitoring, it should always be discussed balancing usefulness of rechallenge, patient comorbidities and risk of recurrence of first irAE(s). Due to inherent bias associated with pharmacovigilance studies, further prospective studies are needed to assess risk factors that may influence patient outcomes after ICI rechallenge.

Resume Recommandation phare du Comite d’orientation de la conference citoyenne sur la vaccination, l’obligation vaccinale etendue a 11 vaccins pour les nourrissons nes depuis le 1er janvier 2018, s’inscrit dans un ensemble de recommandations devant etre considere comme un tout dont chaque composante apparait indispensable a la realisation des objectifs vises : retablir la confiance dans la vaccination et augmenter la couverture vaccinale. Les participants a la table ronde n° 6 ont identifie une dizaine d’initiatives concretes pouvant repondre, au moins pour partie, aux recommandations du Comite, parmi lesquelles : developper des systemes d’information et la generation de donnees ; simplifier le parcours vaccinal et multiplier les opportunites de vaccination ; developper la formation des professionnels de sante ; apprendre les vaccins a l’ecole ; utiliser l’entretien motivationnel en intervention educative ; entreprendre des initiatives locales ; ameliorer l’approvisionnement et communiquer sur la valeur des vaccins. Pour mener a bien ces actions, il a ete propose que soit cree, au niveau national, un Comite interministeriel regroupant les differentes parties prenantes afin d’impulser leur mise en œuvre et assurer leur suivi et au niveau regional, la mise en place d’un plan de sensibilisation des Agences regionales de sante faisant de la prevention vaccinale un axe prioritaire.

International audience; Isolated cases of acute coronary syndrome (ACS) associated with immune checkpoint inhibitors (ICIs) have been described without the establishment of a formal cause-and-effect relationship between treatment and adverse event. We reported a case of ACS after the first administration of an ICI and with a fatal recurrence in another coronary area immediately after readministration. According to guidelines, causality was considered to be certain. Subsequently, we queried the French pharmacovigilance database and found 4 cases of ACS with coronary artery thrombosis. Causality was probable in those patients. These data suggest that ACS may be another life-threatening cardiac adverse event occurring with ICI exposure.

Immunotherapy with immune checkpoint inhibitors (ICIs) for cancer has become increasingly prescribed in recent years. Indeed, it is used to treat both solid and hematological malignancies due to their considerable potential in treating melanoma, non-small cell lung and other cancers. Immune-mediated related adverse endocrine toxicity, and especially thyroiditis, is seen as a growing problem needing specific screening and management. This study aims at describing thyroid dysfunctions induced by the ICIs marketed in France, which are registered in the French Pharmacovigilance database. This database was queried for nivolumab, pembrolizumab, and ipilimumab-induced adverse drug reactions reported before April 30, 2017. Both a pharmacologist and an endocrinologist have reviewed each case to select only those of peripheral thyroiditis (thyrotoxicosis and hypothyroidism). During this period, 110 thyroiditis following ICI therapy were reported. Sex/ratio was around one. Most of the cases (47.2%) were asymptomatic. Although some thyrotoxicosis cases were severe, no orbitopathy was reported. Hypothyroidism and thyrotoxicosis were equally described. Antithyroid antibodies were positive in only 16% patients. The ultrasonography was informative in 19% patients. Levothyroxine supplementation was necessary in 57% patients, leading to 19% recovery. With a dedicated optimized management, most of the cases did not require immunotherapy discontinuation. Finally, immune-mediated related thyroiditis is increasing due to a wider prescription of ICI therapy in various cancer conditions and systematic screening. Often asymptomatic, they lead to a local activation accompanied by hormonal deficiency in the long run. It is necessary to carry out an early and sustained multidisciplinary screening to allow immunotherapy continuation.

International audience; Hearing loss is defined as a decrease in the ability to perceive sounds which can occur suddenly or gradually and affects one ear or both. It is related to various etiologies, in particular drugs. The identification of all drugs that could be associated with hearing loss is essential for the patients' life quality. The objective of our study was to identify signals of hearing loss involving drugs approved in the last 20 years. The occurrence in association with drugs known for their ototoxicity was also analyzed. We used a case/non-case method in the French Pharmacovigilance Database (FPVD). The cases were reports of hearing loss in the FPVD between January 2007 and August 2017. Non-cases were all reports over the same period. We calculated the reporting odds ratio (ROR) with 95% confidence intervals. Among the 555 reports of hearing loss, significant RORs were found for 68 drugs. The main therapeutic classes implicated were antineoplastic agents (n = 240), systemic anti-infective agents (n = 182), immunosuppressants (n = 42) loop diuretics (n = 26), and salicylate analgesics (n = 26). We found signals of hearing loss with azacitidine, vaccines and nevirapine, immunosuppressants such as leflunomide, and biotherapies such as panitumumab and vandetanib. Prescribers should be informed about the potential associations with all these drugs. The role of the pathology itself and the known ototoxic drugs that can be associated do not allow to conclude definitively. Audiograms for the early detection of hearing loss induced by drugs known to be ototoxic are rarely carried out. Preventive treatments exist and must be considered.

International audience; A flagship recommendation of the citizen's steering committee on immunization, the mandatory immunization for infants extended to 11 vaccines, introduced in January 2018, is part of a set of recommendations that must be considered as a whole, each component being indispensable to the achievement of objectives: restore confidence in vaccination and increase immunization coverage. Roundtable # 6 participants identified a decade of concrete initiatives that could address, at least in part, the committee's recommendations, including: developing information systems and data generation; simplify the vaccination journey and increase vaccination opportunities; developing training of health professionals; learning vaccines at school; using motivational interviewing in educational intervention; undertaking local initiatives; improving supply and communicate on the value of vaccines. To carry out these actions, it has been proposed that a joint ministerial task-force bringing together the different stakeholders at the national level should be set up to promote their implementation and follow-up, and at regional level, the establishment of an Agences régionales de santé awareness plan making vaccination a priority.

International audience; Aims Gemcitabine has been associated with thrombotic microangiopathy (TMA). We conducted a national retrospective study of gemcitabine-associated TMA (G-TMA). Methods From 1998 to 2015, all cases of G-TMA reported to the French Pharmacovigilance Network and the French TMA Reference Center, and cases explored for complement alternative pathway abnormalities, were analysed. Results G-TMA was diagnosed in 120 patients (median age 61.5 years), after a median of 210 days of treatment, and a cumulative dose of 12 941 mg m(-2). Gemcitabine indications were: pancreatic (52.9%), pulmonary (12.6%) and breast (7.6%) cancers, metastatic in 34.2% of cases. Main symptoms were oedema (56.7%) and new-onset or exacerbated hypertension (62.2%). Most patients presented with haemolytic anaemia (95.6%) and thrombocytopenia (74.6%). Acute kidney injury was reported in 97.4% and dialysis was required in 27.8% of patients. Treatment consisted of: plasma exchange (PE; 39.8%), fresh frozen plasma (21.4%), corticosteroids (15.3%) and eculizumab (5.1%). A complete remission of TMA was obtained in 42.1% of patients and haematological remission in 23.1%, while 34.7% did not improve. The survival status was known for 52 patients, with 29 deaths (54.7%). Patients treated with PE, despite a more severe acute kidney injury, requiring dialysis more frequently, displayed comparable rates of remission, but with more adverse events. No abnormality in complement alternative pathway was documented in patients explored. Conclusion This large cohort confirms the severity of G-TMA, associated with severe renal failure and death. Oedema and hypertension could be monitored in patients treated with gemcitabine to detect early TMA. The benefit of PE or eculizumab deserves further investigation.

International audience; Because national data on proton pump inbibitors (PPIs) consumption in France are scarce and because there is a growing literature on potential adverse drug reaction induced by this pharmacological class, we would like to more describe the main evolution of PPI use and the main characteristics of its users in France. We used a 1/97th representative sample of beneficiaries of the French health insurance called "échantillon généraliste des bénéficiaires" (EGB) to describe PPIs' use over time (duration of use by year) from 2006 to 2016. In 2016, 108,249 patients had at least 1 dispensing of PPI (i.e. 19.5% of EGB versus 16.5% in 2006). The part of patients with only 1 reimbursement of PPI by years decreased from 43.9% in 2006 to 39.0% in 2016. Among the patient with at least 2 PPI dispensing/years, the mean number of dispensing increased from 6.2±4.2 in 2006 to 6.9 in 2016. The over 75 year's old group is particularly concerned by the increase in both duration and dosage over the period of study, as mean DDD per year increased by 31% and mean number of dispensing per year by 17% from 2006 to 2016. Based on these results, PPI users could almost represent 11 million peoples in France (13 million on a whole population) in 2016. Initiatives to assess the appropriateness of use of these drugs might be warranted.

Background: Nivolumab is approved worldwide as second-line treatment for metastatic non-small cell lung cancer (NSCLC). Despite the fact that most of these cancers are being diagnosed in the older patients, few of the patients were included in pivotal trials. We aimed to describe efficacy and safety in a ``real-world'' older population. Patients and Methods: We retrospectively collected data from older patients (>= 70 years old) with advanced or metastatic NSCLC treated with Nivolumab in our institution. We analyzed safety (CTCAE v4.0 criteria), efficacy (clinical benefit rate, progression-free survival, and overall survival), and correlated these features to geriatric parameters and PD-L1 expression. Along with this cohort, we assessed safety at a national level by retrieving all cases of Nivolumab (prescribed for NSCLC) induced adverse events analyzed by the French pharmacovigilance network during the inclusion period. Results: From July 2015 to September 2016, 30 patients were enrolled with a median age of 752. Clinical benefit rate was 30.6%. Median progression-free survival and overall survival were 33 and 7.1 months, respectively. Fifteen patients (50%) presented an immune-related adverse event (IrAE) of any grade, including four high grade IrAEs. Two hundred and eighty IrAEs had been notified to the French pharmacovigilance network including 91 (35.2%) concerning older patients. Frequency and pattern of IrAEs were similar for older patients and younger subjects. Conclusions: Even though frequency and patterns of IrAEs are different from pivotal studies, these results don't seem specific to older patients. Further prospective investigations are needed to better characterize and predict the impact of Nivolumab on older patients with NSCLC. (C) 2018 Elsevier Ltd. All rights reserved.

IF 2.314; International audience

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Resume L’utilisation des generiques est generatrice d’economies pour le budget de l’assurance maladie, et aucun acteur de sante ne pourrait en remettre serieusement en cause le principe. Le medicament generique d’une specialite de reference se definit comme un medicament ayant la meme composition qualitative et quantitative en principes actifs, la meme forme pharmaceutique et dont la bioequivalence avec cette specialite de reference a ete demontree par des etudes appropriees de biodisponibilite. C’est le droit de substitution accorde aux pharmaciens en 1999 qui est a l’origine du veritable essor de ces specialites sur le marche pharmaceutique francais. Neanmoins, pres de 10 apres, il apparait que le systeme en place n’offre pas toutes les securites necessaires en ce qui concerne la Pharmacovigilance, notamment s’agissant des produits a marge therapeutique etroite. En renforcant et/ou en completant le role joue par les professionnels de sante et les institutions concernes, il est tout a fait possible d’ameliorer la robustesse du systeme. De meme, l’arrivee recente en Europe des biosimilaires, molecules similaires mais non bioequivalentes aux produits biologiques entraine une situation specifique encore plus delicate, que celle des generiques du fait de leur nature, de la difficulte a les produire et du risque d’immunogenicite. Si la substitution n’est pas permise dans plusieurs pays europeens incluant la France, d’autres problemes peuvent apparaitre notamment en cas d’interchangeabilite necessitant la encore, le renforcement de certaines mesures. Les differents aspects sont abordes dans cet article avec des propositions concretes de securisation du systeme actuel, tant pour les generiques que les biosimilaires.

Objective To identify possible electroencephalographic (EEG) markers of donepezil’s effect on cortical activity in young, healthy adult volunteers at the group level. Methods Thirty subjects were administered a daily dose of either 5 mg donepezil or placebo for 15 days in a double-blind, randomized, cross-over trial. The electroencephalogram during an auditory oddball paradigm was recorded from 58 scalp electrodes. Current source density (CSD) transformations were applied to EEG epochs. The event-related potential (ERP), inter-trial coherence (ITC: the phase consistency of the EEG spectrum) and event-related spectral perturbation (ERSP: the EEG power spectrum relative to the baseline) were calculated for the target (oddball) stimuli. Results The donepezil and placebo conditions differed in terms of the changes in delta/theta/alpha/beta ITC and ERSP in various regions of the scalp (especially the frontal electrodes) but not in terms of latency and amplitude of the P300-ERP component. Conclusion Our results suggest that ITC and ERSP analyses can provide EEG markers of donepezil’s effects in young, healthy, adult volunteers at a group level. Significance Novel EEG markers could be useful to assess the therapeutic potential of drug candidates in Alzheimer’s disease in healthy volunteers prior to the initiation of Phase II/III clinical studies in patients.

Background Two methods have been recently developed from a drug reimbursement database to provide useful indicators for public health authorities concerning the abuse potential of psychotropic drugs. The doctor-shopping indicator (DSI) measures the proportion of the drug obtained by doctor shopping among the overall quantity of the drug reimbursed and the clustering method reveals subgroups of deviant patients. Objective The objective of the study was to analyze and compare indicators resulting from these two methods, applied to High Dosage Buprenorphine (HDB) (a product well-known to be diverted in France), in order to determine which public health authorities needs they answer. Data analysis The patients with reimbursed HDB were grouped using the clustering method in terms of drug dispensations characteristics over a nine month period. The characteristics of the resulting subgroups, including their DSI, were then compared. Results 4787 Patients (73.4%) had no measurable doctor-shopping behaviour. But the comparison of the two methods demonstrated that the more a patient's profile was characterized by deviant behavior, the higher was the DSI: from 0.4% in a subgroup with a median profile to 72% in a subgroup with a deviant profile. Conclusion These two methods are useful surveillance tools for public health authorities: the clustering method may help devise pertinent intervention strategies to reduce prescription drug abuse while the DSI method provides quantitative information demonstrating whether these strategies are useful. We discuss the advantages and disadvantages of using these two methods as useful indicators for public health authorities.

ERMA; International audience; The use of generics results in savings for the budget of the health insurance, and no player of health could question seriously the principle. The generic drug of a reference medicinal product defines itself as a drug having the same qualitative and quantitative composition in active ingredients, the same dosage form and the bioequivalence with this reference medicinal product was demonstrated by appropriate studies of bioavailability. It is the right to switch granted to the pharmacists in 1999 that is at the origin of the real development of these specialties on the French pharmaceutical market. Nevertheless, about 10 years later, it seems that the system in place does not offer all the necessary securities with regard to pharmacovigilance, notably for the products with narrow therapeutic margin. By strengthening and/or by completing the role played by the health care professionals and the public institutions concerned, it is highly possible to improve the robustness of the system. Also, the recent arrival in Europe of the biosimilars, similar molecules but not bioequivalent to biological products, cause an even more tricky specific situation than that of the generics because of their nature, of the difficulty to manufacture them, and of the risk of immunogenicity. If the substitution is not permitted in several European countries including France, the other issues can appear especially in case of interchangeability requiring also, the reinforcement of certain measures.The various aspects are described in this article with concrete proposals on how the current system can be made safer, both for the generics and the biosimilars.