Compliance with the pregnancy prevention program among women initiating isotretinoin treatment between 2014 and 2021: A nationwide cohort study on the French Health Data System (SNDS).

BACKGROUND: Despite the French pregnancy prevention program (PPP), a considerable number of pregnancies are potentially exposed to oral isotretinoin. New measures were taken by the French Medicines Agency, including the restriction of initial isotretinoin prescriptions to dermatology specialists in May 2015 and a new information campaign on teratogenicity in January 2019. OBJECTIVES: The aims were to: describe, between 2014 and 2021, compliance with PPP recommendations: isotretinoin use as a second-line treatment, first prescription by a dermatology specialist, monthly prescription renewal and pregnancy testing (PT); assess the effect of the 2015 and 2019 measures on PT compliance; and identify the determinants of PT noncompliance. METHODS: A retrospective cohort study was conducted among women aged 11-50 years initiating isotretinoin between 2014 and 2021 using the French Health Data System. PT compliance corresponded to pregnancy test completion and specific delays between prescription and dispensation. Time series analyses were performed to evaluate the effect of the 2015 and 2019 measures on PT compliance, and log-binomial and Poisson multivariate regression models were used to identify the determinants of PT noncompliance. RESULTS: Isotretinoin was prescribed as a second-line treatment in 64% of initiations, mainly by dermatology specialists (92%). A new monthly prescription was observed in 98% of dispensations. PT compliance reached 61%, 72% and 25% at initiation, renewals and end of treatment, respectively. The 2015 measure was associated with better PT compliance at initiation and renewals. The 2019 measure had no significant effect on PT compliance at the initiation or end of treatment but was associated with a decrease in PT compliance at renewals. Age, low socioeconomic level, initiation by a nondermatology specialist and during summer were associated with PT noncompliance. CONCLUSIONS: Understanding factors associated with PT noncompliance could help to target specific subpopulations of women treated with isotretinoin.

Towards a better understanding of adult idiopathic epidermal necrolysis: a retrospective study of 19 cases.

BACKGROUND: Most cases of Stevens-Johnson syndrome and toxic epidermal necrolysis are drug-induced. A small subset of cases remain with unknown aetiology (idiopathic epidermal necrolysis [IEN]). OBJECTIVE: We sought to better describe adult IEN and understand the aetiology. METHODS: This retrospective study was conducted in 4 centres of the French national reference centre for epidermal necrolysis. Clinical data were collected for the 19 adults hospitalized for IEN between January 2015 and December 2019. Wide toxicology analysis of blood samples was performed. Histology of IEN cases was compared with blinding to skin biopsies of drug-induced EN (DIEN, 'controls'). Available baseline skin biopsies were analysed by shotgun metagenomics and transcriptomics and compared to controls. RESULTS: IEN cases represented 15.6% of all EN cases in these centres. The median age of patients was 38 (range 16-51) years; 68.4% were women. Overall, 63.2% (n = 12) of cases required intensive care unit admission and 15.8% (n = 3) died at the acute phase. Histology showed the same patterns of early- to late-stage EN with no difference between DIEN and IEN cases. One toxicology analysis showed unexpected traces of carbamazepine; results for other cases were negative. Metagenomics analysis revealed no unexpected pathological microorganism. Transcriptomic analysis highlighted a different pro-apoptotic pathway in IEN compared to DIEN, with an overexpression of apoptosis effectors TWEAK/TRAIL. CONCLUSIONS: IEN affects young people and is a severe form of EN. A large toxicologic investigation is warranted. Different pathways seem involved in IEN and DIEN, leading to the same apoptotic effect, but the primary trigger remains unknown.

Drug-induced sarcoidosis: an overview of the WHO pharmacovigilance database.

BACKGROUND: There is a documented association between drug exposure and sarcoidosis-like reactions. In this study, we used the largest pharmacovigilance database to describe drug-induced sarcoidosis. METHODS: Data were collected from the World Health Organization (WHO) pharmacovigilance database (VigiBase). We excluded steroids and vaccines from the analysis. The primary end-point was the lower end-point of the 95% credibility interval for the information component (IC025 ). RESULTS: A total of 127 reports had significant IC025 values for drug-induced sarcoidosis, and 110 were included in the final analysis, accounting for 2425 adverse drug reactions. Overall, 2074 (85.5%) reactions were considered 'serious' and 86 (3.5%) were fatal. Most of the drugs that led to sarcoidosis adverse reactions were TNF-alpha antagonists, interferon or peg-interferon therapeutics, and immune checkpoint inhibitors. Other biologic drugs were less frequently associated with sarcoidosis adverse events. Cancer-targeted therapies such as BRAF or MEK inhibitors were associated with sarcoidosis reactions in 37 cases. Pulmonary hypertension drugs were also reported for drug-induced sarcoidosis. Amongst the 55 drugs considered as potential sarcoidosis inducers, 25 (45.4%) were never reported in Medline as drug-induced sarcoidosis. CONCLUSIONS: We provide a detailed list of suspected drugs associated with drug-induced sarcoidosis that will improve the recognition of this drug-induced adverse event.

Incidence of and mortality from epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) in France during 2003-16: a four-source capture-recapture estimate.

BACKGROUND: Because of its rarity, the exact incidence of and mortality from epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) is difficult to establish and closely depends on the size and type of the data source. OBJECTIVES: To estimate the incidence of and mortality due to epidermal necrolysis in France over a 14-year period. METHODS: Data from four national databases were analysed. A capture-recapture analysis was performed. RESULTS: A total of 2635 incident cases of epidermal necrolysis were recorded in at least one of the four databases during the study period [males: 47·9%; median age: 52 (interquartile range 25-72) years]. On capture-recapture analysis, the estimated total number of cases was 5686, for an overall estimated annual incidence of 6·5 (95% confidence interval 4·1-8·9) cases per million inhabitants. The estimated annual incidence rates were 4·1 (0·3-7·9) cases per million inhabitants < 20 years of age, 3·9 (1·5-6·3) cases per million inhabitants aged 20-64 years and 13·7 (5·4-22·0) cases per million inhabitants ≥ 65 years of age. The estimated overall annual mortality rate from epidermal necrolysis was 0·9 (0·1-1·8) case per million inhabitants. It was 0·6 (0·1-1·5) case per million inhabitants aged 20-64 years and 2·8 (0·9-6·6) cases per million inhabitants ≥ 65 years of age (deaths in people < 20 years old were too rare to provide an accurate estimate). CONCLUSIONS: The annual incidence of epidermal necrolysis is higher than the one to five cases per million inhabitants usually reported. Such estimations could be helpful in establishing appropriate healthcare plans for people with epidermal necrolysis, in particular the need for specialized care units. What's already known about this topic? Few data are available regarding incidence of and mortality from epidermal necrolysis in the general population. Experts in epidermal necrolysis have recently proposed an annual incidence of one to five cases per million individuals. The overall mortality rate is usually reported to be between 10% and 20%. What does this study add? Using a four-source capture-recapture method and data from a 14-year period (2003-16), the annual incidence of and mortality from epidermal necrolysis were estimated to be 6·5 (95% confidence interval 4·1-8·9) and 0·9 (0·1-1·8) cases per million French inhabitants, respectively. Such estimations could be helpful in establishing appropriate healthcare plans, in particular the need for specialized care units.

Severe cutaneous adverse reactions due to inappropriate medication use.

BACKGROUND: The proportion of severe cutaneous adverse reactions (SCARs) that could be avoided if medication use was consistent with good medical practice is unknown. OBJECTIVES: To estimate the proportion of SCARs related to inappropriate medication use. METHODS: We carried out a retrospective study of all validated SCARs collected in a French registry between 2003 and 2016. For each case, all plausible drugs suspected of inducing SCARs (i.e. not just the drug regarded as 'the most probable') were considered with regard to (i) prescription for an inappropriate indication, (ii) unintentional rechallenge despite a previous allergy to the drug or (iii) self-medication with prescription medicines. RESULTS: In total, 602 cases were included in the analyses. Antibiotics, anticonvulsants and allopurinol were the drugs most frequently involved, accounting for more than 50% of all cases. All suspected medications were considered to have been appropriately used for 417 of the 602 individuals included in the study population [69·3%, 95% confidence interval (CI) 65·6-73·0] and inappropriately used for 144 individuals (23·9%, 95% CI 20·5-27·3). These inappropriate uses were due mainly to prescriptions for an inappropriate indication (65·8%, 95% CI 58·4-73·2) or unintentional rechallenge (20·9%, 95% CI 14·6-27·2). Allopurinol and co-trimoxazole were the drugs most frequently involved in inappropriate indications. Antibiotics were the largest group involved in unintentional rechallenge. Nonsteroidal anti-inflammatory drugs, available on prescription, were most frequently involved in inappropriate self-medication. CONCLUSIONS: Our results underline the need for respecting the appropriate indication for drugs in order to reduce the incidence of SCARs. Reducing unintentional rechallenge also seems to be a necessary preventive measure.

[Prevalence of hydroxychloroquine-induced side-effects in dermatology patients: A retrospective survey of 102 patients]. / Prévalence des effets indésirables de l'hydroxychloroquine (Plaquenil®) dans une population dermatologique : étude rétrospective sur 102 patients.

AIM: Our aim was to assess the prevalence of adverse effects (AEs) pertaining to the use and withdrawal of hydroxychloroquine (HCQ) in dermatological outpatients. PATIENTS AND METHODS: We conducted a retrospective study between January 2013 and June 2014 that included consecutive patients currently or previously receiving HCQ seen in our department. AEs were collated using a standardized questionnaire and validated by clinical and laboratory examination. Drug causality was evaluated using the updated French drug reaction causality assessment method. The main evaluation criterion was the prevalence of AEs in which HCQ had an intrinsic imputability score of I>2. RESULTS: We included 102 patients (93 of whom were women, with a median age of 44.5; range: 22-90years). HCQ was given for cutaneous lupus in most cases (n=70). At least one AE was reported for 55 patients. Among the 91 reported AEs, 59 (65%) had an HCQ intrinsic imputability score I>2. AEs were responsible for permanent HCQ discontinuation in 19 cases. Of these, 8 were unrelated to HCQ based on imputability score. The most common AEs associated with HCQ were gastrointestinal and cutaneous signs. Of the 8 patients diagnosed with retinopathy, only 3 were confirmed after reevaluation. CONCLUSION: AEs associated with HCQ were reported for over 50% of patients and were responsible for permanent HCQ discontinuation in one-third of cases. A more in-depth evaluation of imputability seems necessary, particularly regarding ophthalmological symptoms, since in two thirds of cases the reasons for discontinuation were not related to HCQ.

[Amiodarone-induced immune complex cutaneous vasculitis]. / Vascularite cutanée induite par l'amiodarone.

BACKGROUND: A wide variety of drugs can cause cutaneous vasculitis. Herein we report a case of immune complex vasculitis induced by amiodarone. PATIENTS AND METHODS: A 57-year-old patient reported a recent history of pruritus associated with large erythematous, inflammatory, necrotic plaques localized on the lower limbs and back. These cutaneous lesions had appeared less than 2 months after initiation of amiodarone for supra-ventricular arrhythmia. Histological and direct immunofluorescence examinations of a skin biopsy sample revealed vasculitis with the presence of IgM and C3 immune complexes in vessels. The remaining laboratory tests were unremarkable (in particular, cryoglobulin and autoantibody tests were negative). The patient himself attributed his symptoms to the recent administration of amiodarone and spontaneously stopped the drug without medical advice. No other therapy was prescribed. Following drug withdrawal, the lesions that had been present for more than 4 months completely disappeared. No recurrence occurred after follow-up of over 6 months. The diagnosis of amiodarone-induced vasculitis was retained. DISCUSSION: Fewer than 10 cases of amiodarone-induced vasculitis have been reported in the medical literature. It is not known whether this entity is rare, under-diagnosed or under-reported.

[Acute blue urticaria following subcutaneous injection of patent blue dye]. / Urticaire bleue aiguë après injection sous-cutanée de bleu patenté.

BACKGROUND: Patent blue (PB) is a lymphatic vessel dye commonly used in France for sentinel lymph node detection in breast cancer, and less frequently in melanoma, and which may induce hypersensitivity reactions. We report a case of acute blue urticaria occurring within minutes of PB injection. PATIENTS AND METHODS: Ten minutes after PB injection for sentinel lymph node detection during breast cancer surgery, a 49-year-old woman developed generalised acute blue urticaria and eyelid angioedema without bronchospasm or haemodynamic disturbance, but requiring discontinuation of surgery. Skin testing using PB and the anaesthetics given were run 6 weeks after the episode and confirmed PB allergy. PB was formally contra-indicated. DISCUSSION: Immediate hypersensitivity reactions to PB have been reported for between 0.24 and 2.2% of procedures. Such reactions are on occasion severe, chiefly involving anaphylactic shock. Two mechanisms are probably associated: non-specific histamine release and/or an IgE-mediated mechanism. Skin tests are helpful in confirming the diagnosis of PB allergy. CONCLUSION: Blue acute urticaria is one of the clinical manifestations of immediate hypersensitivity reactions to patent blue dye. Skin tests must be performed 6 weeks after the reaction in order to confirm the diagnosis and formally contra-indicate this substance.

Linear IgA bullous dermatosis: comparison between the drug-induced and spontaneous forms.

BACKGROUND: Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering skin disorder characterized by linear deposits of IgA along the dermoepidermal junction, visualized by direct immunofluorescence (DIF). It is usually spontaneous and drug induced. OBJECTIVES: To compare the clinical and histological forms of LABD. METHODS: This retrospective single-centre cohort study concerned 28 patients diagnosed with LABD between 1 January 1995 and 31 December 2010. Imputability, determined according to the French imputability method (modified Bégaud score) and Naranjo score, enabled classification into drug-induced and spontaneous LABD groups. Clinical and histological features were compared by blinded analysis of images and histological patterns. RESULTS: Sixteen patients had spontaneous LABD and 12 had drug-induced LABD. Nikolsky sign and large erosions were significantly more frequent in drug-induced than spontaneous LABD (P = 0.003 and P = 0.03, respectively), with no between-group differences for erythematous plaques, target or target-like lesions, string of pearls, location, mucosal involvement or histological features. CONCLUSIONS: Drug-induced LABD was more severe than the spontaneous form, with lesions mimicking toxic epidermal necrolysis. Because LABD may be polymorphic and sometimes life threatening, DIF assay is recommended for all patients with Nikolsky sign and large erosions.

Comparative analysis of adverse drug reactions to tetracyclines: results of a French national survey and review of the literature.

BACKGROUND: The question of quantitative and qualitative differences between adverse drug reactions (ADRs) to tetracyclines was raised many years ago, especially for minocycline and doxycycline. OBJECTIVES: To assess and compare ADRs related to tetracyclines according to sales figures in France through a national survey. METHODS: ADR data were collected from the French Pharmacovigilance Database (FPD), marketing authorization holders (MAH) and the literature. Sales analyses were based on MAH data provided annually to the French Drugs Agency. RESULTS: Among the tetracyclines available in France, doxycycline and minocycline are the most frequently used. However, their sales decreased between 1995 and 2007, more sharply for minocycline than doxycycline. According to the FPD, based on MAH data and published reports, minocycline-associated ADRs were more serious and were reported more frequently than for the other tetracyclines. Minocycline and doxycycline ADR patterns differed: gastrointestinal disorders (especially oesophageal lesions) predominated with doxycycline, while intracranial hypertension and hepatic disorders were primarily reported with minocycline. Autoimmune disorders, drug reaction with eosinophilia and systemic symptoms (DRESS) and other hypersensitivity reactions were also more frequent with minocycline. ADRs reported with lymecycline and metacycline were essentially cutaneous and gastrointestinal disorders. CONCLUSIONS: In the absence of markedly better efficacy against the various indications for tetracyclines, the minocycline benefit/risk ratio was clearly lower than that of doxycycline, and possibly those of lymecycline and metacycline. In light of these findings, minocycline should no longer be considered first-line therapy for inflammatory skin disorders, especially acne.

[Skin toxicity related to Percutalgine(®): analysis of the French pharmacovigilance database]. / Toxicité cutanée liée à la Percutalgine(®) : analyse de la base nationale de pharmacovigilance.

BACKGROUND: Percutalgine(®) (dexamethasone acetate, salicylamide and hydroxyethyl salicylate) is a topical drug marketed for treatment of benign joint conditions such as mild tendinitis, small joint arthritis and sprains. The aim of the study was to describe the cutaneous side effects of Percutalgine(®) in terms of clinical signs, seriousness and causal relationship of the different components. METHODS: We extracted from the French Pharmacovigilance database all cases of adverse skin reactions occurring after application of Percutalgine(®) and reported for the period between 1st January 2000 and 31st October 2010. The only files selected were those in which Percutalgine(®) was the sole suspected drug and/or allergological tests were positive for Percutalgine(®) or its components. RESULTS: Fifty-three cases were ultimately retained and analysed. The main cutaneous side effect of Percutalgine(®) (n=41) was contact dermatitis with secondary extension in 15 cases. Onset was immediate in 12 cases, delayed in 32 cases and unspecified in eight cases. Twelve patients were hospitalized for inefficiency of the symptomatic treatment, extended lesions or generalized associated signs. Allergological tests were described in 14 cases and were positive for Percutalgine(®) (eight cases), hydroxyethyl salicylate (seven cases), salicylamide (six cases), dexamethasone (three cases), and propylene glycol (two cases). CONCLUSION: Cutaneous side effects with Percutalgine(®) appear to be rare or infrequently reported. They consist chiefly of contact allergy. The component responsible for the reaction can be determined using allergological patch tests.

Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes.

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. RESULTS: Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSION: QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.