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.

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.

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.

[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.

[Cutaneous adverse drug reactions]. / Toxidermies.

Cutaneous adverse drug reactions (CADR) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Exanthematous eruptions, urticaria and vasculitis are the most common forms of CADR. Fixed eruption is uncommon in western countries. Serious reactions (fatal outcome, sequelae) represent 2% of CADR: bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), DRESS (drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome) and acute generalized exanthematous pustulosis (AGEP). These forms must be quickly diagnosed to guide their management. The main risk factors are immunosuppression, autoimmunity and some HLA alleles in bullous reactions and DRESS. Most systemic drugs may induce cutaneous adverse reactions, especially antibiotics, anticonvulsivants, antineoplastic drugs, non-steroidal anti-inflammatory drugs, allopurinol and contrast media. Pathogenesis includes immediate or delayed immunologic mechanism, usually not related to dose, and pharmacologic/toxic mechanism, commonly dose-dependent or time-dependent. In case of immunologic mechanism, allergologic exploration is possible to clarify drug causality, with a variable sensitivity according to the drug and to the CADR type. It includes epicutaneous patch testing, prick test and intradermal test. However, no in vivo or in vitro test can confirm the drug causality. To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis is required, completed with a literature search. A reporting to pharmacovigilance network is essential in case of a serious CADR whatever the suspected drug and in any case if the involved drug is a newly marketed one or unusually related to cutaneous reactions.

Intravenous immunoglobulins-induced eczematous eruption: a long-term follow-up study.

BACKGROUND: High-dose intravenous immunoglobulins have emerged as an important therapy for various diseases. Vesicular eczematous eruption has recently been described as an intravenous immunoglobulins adverse effect. Little is known about patients' characteristics, administration regimens and long-term outcomes. METHODS: We retrospectively examined a series of 9 patients which had been notified to the Regional Pharmacovigilance Center for an eczematous skin reaction after intravenous immunoglobulins infusion. RESULTS: There were 8 men and 1 woman. Mean age was 56.4 years. Seven patients were treated with intravenous immunoglobulins for neurological disease. Eruption was mostly localized to palms and soles. All patients improved, either spontaneously or with systemic or topical steroid treatment. Rash recurred in 4 out of 5 patients in which immunoglobulins were readministered. Eruption did not relapse in 3 patients when immunoglobulins preparation was switched for another one. CONCLUSIONS: Eczematous eruption due to infusion of immunoglobulins is rare although mostly benign side effect. Treatment withdrawal is usually not required if there is a major clinical benefit. Switching the type of IVIg is often a useful strategy.

[Cutaneous EBV-associated lymphoproliferative disorder in a dermatomyositis treated with immunosuppressive agents]. / Syndrome lymphoprolifératif cutané lié à l'EBV au cours d'une dermatomyosite traitée par immunosuppresseurs.

We report a case of Epstein Barr virus-associated large B cell lymphoproliferative disorder, with an abdominal cutaneous localization, in an adult treated for 10 years with immunosuppressive agents for a dermatomyositis. This is the third case of immunosuppressive induced lymphoproliferative disorder localized to skin in a patient with dermatomyositis. Diagnosis was unexpectedly obtained by the histologic examination of surgical samples of skin necrosis possibly induced by edetate calcium disodium subcutaneous injections in calcinosis cutis.

[Skin signs associated with epidermal growth factor inhibitors]. / Manifestations cutanées des inhibiteurs du récepteur du facteur de croissance épidermique.

BACKGROUND: Inhibitors of epidermal growth factor receptors (EGFR) constitute a new alternative treatment for patients presenting certain advanced stage solid cancers (bowel, breast, ovary). Adverse cutaneous effects of these drugs are now starting to be described. OBSERVATIONS: Our study involved 2 men and 2 women with no previous history of acne included in a treatment protocol comprising EGFR inhibitors. Mean age was 52 years. The primary cancers were breast, ovary, bowel and unidentified. The EGFR inhibitors used were gefitinib (ZD1839) (2 cases), carnetinib (Cl1033) and cetuximab (IMC-C225). Skin lesions appeared after 7 days and included erythematous papules and follicular pustules of the face, back and upper chest. No comedons were seen, and there were no nodules or cysts. The severity of the rash resulted in discontinuation of treatment in 2 patients with complete disappearance of skin lesions in both cases. In one patient, reduction of the dosage of gefitinib (IMC-C225) led to gradual resolution of the rash. Histological examination of papules and pustules concluded on an acute suppurative folliculitis. Smears and cultures ofa nasal lesion and pustules revealed coagulase-positive Staphylococcus aureus in 2 patients. Combined doxycycline 100 mg daily and benzoyl peroxide was prescribed for 3 months and a favourable outcome was achieved after a mean 2 weeks. DISCUSSION: EGFR inhibitors act by inhibiting mechanisms oftumour proliferation in certain cancers at advanced stages or refractory to other treatments. Our findings in these four patients are similar to the published cases in terms of rapid onset of monomorphous, papulopustular, follicular eruption without comedons. Rapid response to cyclines and benzoyl peroxide is also reported in literature. This treatment must be instituted rapidly and patients must be informed about the cutaneous side-effects of EGFR inhibitors before the start of therapy. The pathophysiology of these eruptions is still unknown. Skin signs are probably due to interaction with EGFR functions, including overexpression of EGFR in keratinocytes and hair follicles.

[Topical corticosteroids]. / Dermocorticoïdes.

Therapeutics in dermatology underwent complete change after the introduction of topical hydrocortisone in the Fifties. At the time, stronger derivatives than hydrocortisone were synthetised and the indications for topical corticosteroids were expanded. Around twenty different molecules, classified according to their strength, are currently available for prescription in France. Many inflammatory or tumoral skin diseases respond to these products. The choice of a topical corticosteroid (strength, vehicle.) and of its mode of application (technique, rhythm of application) is oriented by the context (dermatitis treated, localization) and must respect "Good clinical practice" guidelines so as to select the best benefit/risk ratio.

[Kaposi-Juliusberg's syndrome complicating Darier's disease"]. / Syndrome de Kaposi-Juliusberg compliquant une maladie de Darier.

INTRODUCTION: Kaposi-Juliusberg's syndrome is a severe herpes simplex virus cutaneous infection, accompanied by general signs. Darier's disease is a rare genodermatosis characterised by keratinisation disorders. OBSERVATION: In a 51 year-old patient suffering from Darier's disease since the age of 20, a diffuse vesicular eruption occurred following a herpes eruption on the lower lip. Culture of a vesicle revealed a type 1 Herpes simplex virus. The diagnosis of Kaposi-Juliusberg's syndrome was made. COMMENTS: Kaposi-Juliusberg's syndrome is a "classical" herpes complication of atopic dermatitis. It may also develop on other predisposing territories such as acantholytic dermatitis: pemphigus vulgaris, Hailey-Hailey's disease and Darier's disease. Although a rare complication and life threatening for the patient, Kaposi-Juliusberg's syndrome can now be treated efficiently with intravenous and subsequently oral aciclovir.

[Cutaneous necrosis is predictive of cancer in adult dermatomyositis]. / Les nécroses cutanées dans les dermatomyosites de l'adulte sont prédictives de l'association à une néoplasie.

INTRODUCTION: Adult dermatomyositis is associated with cancer in 15 p. 100 to 50 p. 100 of cases and, hence, investigations should be systematically performed to search for cancer. A number of predictive factors have been reported. The aim of our study was to search for predictive factors of cancer, among adults with dermatomyositis. METHODS: We prospectively assessed 26 adults presenting with dermatomyositis, hospitalised in our department of dermatology from January 1993 to June 2000. The parameters assessed were: association with a cancer, age, gender, cutaneous necrosis, muscular weakness, electromyographic abnormalities, erythrocyte sedimentation rate, and muscular enzyme levels. RESULTS: Mean age was of 52 years and sex ratio (M/F) was of 0.53. Cancers were diagnosed in eight cases (31 p. 100) (mean age: 59.5 years; sex ratio=1; cancer localization: lung (2), breast (2), ovary, endometrium, bladder, and melanoma). Five patients in the cancer group had cutaneous necrosis and only 2 in the without cancer (p=0.01; PPV=71.4 p.100). Elevation of muscular enzyme was also associated with cancer. CONCLUSION: Our report demonstrates that cutaneous necrosis is closely associated with cancer and it suggests that in selected patients with dermatomyositis and cutaneous necrosis, more exhaustive and repeated investigations should be performed to search for cancer. The interest of elevation in muscular enzyme as a predictive factor of cancer is discussed.

[Retroperitoneal fibrosis secondary to metastatic neoplasm revealed by a leg lymphedema]. / Lymphoedème du membre inférieur révélant une fibrose rétropéritonéale d'origine métastatique.

INTRODUCTION: Diagnosis of retroperitoneal fibrosis is generally delayed and revealed by various non-specific signs. We report the case of an isolated lymphedema of the lower limb revealing retroperitoneal fibrosis complicating a metastatic squamous cell carcinoma. CASE REPORT: In an 83-year-old women, a lymphedema appeared that remained isolated for several months before being associated with alteration in general health. Morphological examinations showed bilateral compression of the urinary excretory tracts and led to the diagnosis of retroperitoneal fibrosis. Histological examination of a sub-clavicular adenopathy that had evolved over 9 months, confirmed the diagnosis of a metastatic squamous cell carcinoma of pulmonary cancer. DISCUSSION: Retroperitoneal fibrosis is an exceptional etiology that must be recognized in isolated lymphadomas of the lower limbs. In view of the possible tumoral origin of retroperitoneal fibrosis, any evocative sign accompanying the lymphedema must be searched for.

Bullous pemphigoid in a leg affected with hemiparesia: a possible relation of neurological diseases with bullous pemphigoid?

We report a typical case of bullous pemphigoid (BP) associated with a neurological disorder and study a possible link between neurological disorders and BP. An 84-year-old hemiplegic woman presented with unilateral BP on the hemiparetic side. BP was confirmed by histological and immunofluorescence data. The medical records of the previous 46 consecutive patients with BP were retrospectively analyzed (average age: 79; median age: 85). Thirty of the 46 patients with BP had neurological disorders. These disorders included dementia, epilepsy, multiple sclerosis, cerebral stroke, Parkinson's disease, gonadotropic adenoma, trembling, dyskinesia, lumbar spinal stenosis. In a control group of the 46 consecutive oldest patients (older than 71; average age: 82,5; median age: 80) with another skin disease referred during the previous two-year-period to our one-day-unit only, 13 patients had a neurological disorder. This study demonstrates that there is a high prevalence of neurological disorders in patients with BP (p = 0.0004). A prospective case control study with neurological examination and psychometrical evaluation is warranted to confirm these data. We speculate that neuroautoimmunity associated with the aging process or neurological disorders may be involved in pemphigoid development via an autoimmune response against dystonin which shares homology with bullous pemphigoid antigen 1. Bullous pemphigoid could be considered to be a marker of neurological disorder.

[Mycobacterium malmoense cutaneous infection in an immunocompetent patient]. / Infection cutanée à Mycobacterium malmoense chez une malade immunocompétente.

BACKGROUND: Mycobacterium malmoense is a mycobacterium rarely described as a human pathogen. We report the first case of cutaneous infection in an immunocompetent patient. CASE REPORT: A 75-year-old woman presented with a cutaneous nodula on the back of her left hand. Histology of the node biopsy showed non caseating granuloma with giant and epithelioid cells. Acid-fast bacilli were isolated at direct smear and after culture. Mycobacterium malmoense was identified. The lesion has healed after surgery. DISCUSSION: Mycobacterium malmoense is an environmental mycobacterium isolated from soil and water. Typically, most patients with Mycobacterium malmoense infections are old people with previously lung disease. A few cervical lymphadenitis in children and rare cases of tenosynovitis of the hand have been reported. Disseminated infections with cutaneous lesions have been exceptionally described in immunocompromised patients. Mycobacterium malmoense is slow growing and its identification is hard, sometimes requiring molecular analysis. Probably it's the reason why we present the first description of a cutaneous infection in an immunocompetent patient. This case indicates that Mycobacterium malmoense is also a cutaneous pathogen.

[Delayed appearance of maculopapular eruptions induced by tamoxifen]. / Eruption maculopapuleuse d'apparition retardée induite par le tamoxifène.

BACKGROUND: Prescriptions of tamoxifen can be expected to increase over the next few years, particularly for primary prevention of breast cancer. We report a case of a delayed tamoxifen-induced skin reaction. CASE REPORT: A 50-year-old woman was hospitalized for a diffuse maculopapulous eruption which developed four months after beginning a tamoxifen regimen instituted to prevent recurrence of breast cancer after surgery, chemotherapy and radiotherapy. The eruption resolved rapidly after withdrawal of tamoxifen. The same skin reaction occurred 9 hours after rechallenge with tamoxifen. Patch tests performed later with Nolvadex tablets crushed in vaseline were negative. DISCUSSION: Tamoxifen-induced skin reactions are uncommon. The likelihood that tamoxifen was the cause in this case was very high (C3S3 = I4, B2). The late onset (4 months) in this case is remarkable and misled us to look for another cause which could not be found. Challenge with tamoxifen confirmed its causal role. Once again, negative patch tests were found in this type of skin reaction.

[Methotrexate in dermatology: pharmacology, indications, applications and prudent use]. / Le méthotrexate en dermatologie: pharmacologie, indications, utilisation et précautions d'emploi.

High dosage methotrexate is currently used in the treatment of malignancies. When used at low- or moderate doses, methotrexate has antiproliferative and antiinflammatory effects and is a useful drug in skin diseases. The aim of this review is to describe pharmacology, indications, adverse effects and practical use in Dermatology. Pharmacodynamics of methotrexate is especially related to antifolic activity. Methotrexate is officially approved in the treatment of severe psoriasis, but many other proliferative or inflammatory diseases with cutaneous manifestations may benefit from this drug, usually in association with corticosteroids. The use of methotrexate needs some precautions and a precise follow-up to minimise the risk of severe adverse effects. However, efficacy of methotrexate was reported in open and retrospective small size studies. Prospective and comparative trials are required to confirm the indications, advantages and tolerance of methotrexate in dermatology.