Johana Béné

Cancer Risk of Anti-TNF-α at Recommended Doses in Adult Rheumatoid Arthritis: A Meta-Analysis with Intention to Treat and per Protocol Analyses

Background The risk of malignancies on TNF-α antagonists is controversial. The aim of this survey was to assess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, including the five marketed drugs (infliximab, etanercept, adalimumab, golimumab and certolizumab) used in line with the New Drug Application. Furthermore, the relative interest of modified intention to treat or per protocol analyses to assess such sparse events remains unknown. Methodology/Principal Findings Data sources were MEDLINE, CENTRAL, ISI Web of Science, ACR and EULAR meeting abstracts, scientific evaluation of the drugs leading to their marketing approval, and clinicaltrials.gov, until 31 December 2012.We selected double-blind randomized controlled trials in adult rheumatoid arthritis patients, including at least one treatment arm in line with New Drug Application. We performed random effect meta-analysis, with modified intention to treat and per protocol analyses. Thirty-three trials were included. There was no excess risk of malignancies on anti-TNF-α administered in line with New Drug Application in the per protocol model (OR, 0.93 95%CI[0.59–1.44]), as well as in the modified intention to treat model (OR, 1.27 95%CI[0.82–1.98]). There was a non-significant tendency for an excess non-melanoma skin cancer risk in both models (respectively, 1.37 [0.71–2.66] and 1.90 [0.98–3.67]). With fixed effect Peto model restricting to trials during at least 52 weeks, the overall cancer risk was respectively 1.60 [0.97–2.64] and 1.22 [0.72–2.08]. Whatever the model, modified intention to treat analysis led to higher estimations than per protocol analysis. The later may underestimate the treatment effect when assessing very sparse events and when many patients dropped out in placebo arms. In metaregression, there was no differential risk among the five drugs. Conclusions/Significance This study did not find any evidence for an excess cancer risk on TNF-α antagonists in adult rheumatoid arthritis patients, but an excess cancer risk after several years of exposure cannot be ruled out. Both modified intention to treat and per protocol analyses should be presented in such safety analyses.

Rectal Bleeding and Hemostatic Disorders Induced by Dabigatran Etexilate in 2 Elderly Patients

OBJECTIVE: To report rectal bleeding associated with hemostatic disorders in 2 elderly patients treated with dabigatran etexilate. CASE SUMMARY: A 79-year-old woman (weight, 69 kg) was hospitalized in a gastroenterology unit for severe rectal bleeding. She had been treated for 2 months with dabigatran etexilate 110 mg twice daily for chronic atrial fibrillation. On admission, her creatinine clearance (CrCl) was 20.7 mL/min/1.73 m2, prothrombin time (PT) less than 10% (reference range 70-130%), and international normalized ratio (INR) 14.5 (venous blood). Eleven days after admission, hematologic and renal function were normalized and rectal bleeding stopped. An 84-year-old man (weight, 71 kg) was admitted for rectal bleeding with acute renal failure and dehydration that began while he was treated with dabigatran etexilate 110 mg twice daily for atrial fibrillation. On admission, CrCl was 33.5 mL/min/1.73 m2, PT 13%, and INR 7.53 (venous blood). Dabigatran etexilate was stopped on admission. At the end of the hospitalization, CrCl was 66.5 mL/min/1.73 m2, PT 54%, and INR 1.53. In both cases, an objective causality assessment revealed that those adverse reactions were probably related to dabigatran etexilate. DISCUSSION: In these 2 cases of rectal bleeding during dabigatran etexilate therapy, coagulation monitoring showed elevated PT and INR; neither patient had been exposed to vitamin K antagonists. These cases indicate the importance of PT and INR monitoring when using dabigatran etexilate, mainly in patients with a high risk of overdose, such as elderly patients or those with renal function impairment. CONCLUSIONS: It is critical to identify and subsequently manage dabigatran etexilate toxicity because there is no specific antidote to reverse the drugs anticoagulant effects.

Bullous pemphigoid induced by vildagliptin: a report of three cases.

To report three cases of bullous pemphigoid in patients treated with vildagliptin. Case 1: An 86‐year‐old woman presented with bullous pemphigoid after 1 month of treatment with vildagliptin and metformin. After introduction of clobetasol, the symptoms resolved although vildagliptin was continued. However, the skin lesions reappeared 3 months later. Sustained remission was achieved only after definitive withdrawal of vildagliptin. Case 2: A 79‐year‐old man presented with bullous pemphigoid after 37‐month treatment with gliclazide, vildagliptin and metformin. The disease at first responded to clobetasol but 3 months later the lesions reappeared. They finally regressed when the gliptin was discontinued. Case 3: A 77‐year‐old woman, treated with gliclazide and vildagliptin for 26 months, presented with bullous pemphigoid, which responded well to discontinuation of the gliptin and topical clobetasol. Gliptins are new molecules for treatment of type 2 diabetes mellitus, which have been suspected of implication in bullous pemphigoid. Such cases have been described in the literature (seven with vildagliptin and three with sitagliptin). In nine of these cases, the gliptin was associated with metformin, but the latter had never been considered responsible. The mechanism implicated in the development of bullous pemphigoid has not yet been clearly identified, but may involve a modified immune response or alteration of the antigenic properties of the epidermal basement membrane. These reports support the risk of bullous pemphigoid in patients exposed to gliptins.

Eosinophilic esophagitis after desensitization to dust mites with sublingual immunotherapy

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa. The disease affects both children and adults, with a prevalence of 5 per 10,000 inhabitants in Europe and the United States.1 Childhood cases are generally diagnosed between 5 and 10 years of age and adult cases between 30 and 40 years of age. The male-female sex ratio is 3:1 in a published series.2 The symptoms vary according to the age of the individual and consist of difficulties in feeding and in gaining weight in small children, abdominal pain and vomiting in older children, and solid food dysphagia and symptoms that suggest gastroesophageal reflux in adults.3 Histopathologic examination revealing more than 15 polynuclear eosinophils (PNEs) per 40 field is indispensable to establish the diagnosis of EoE. An atopic or allergic history and genetic susceptibility are risk factors for the development of EoE.4 In predisposed individuals, exposure to certain food allergens and aeroallergens can trigger the disorder.Wedescribe thefirst reportedcase, toourknowledge, ofEoE ina child after sublingual immunotherapy (SLIT) for dustmite allergy. A 10-year-old girl, one of twins, with a history of asthma, allergic rhinitis, and dust mite allergy started daily SLIT (where drops are placed under the tongue for 2 minutes and then swallowed) for dust mite desensitization at the end of January 2013. SLIT wasmade of a Staloral (Stallergenes S.A., Antony, France) standardized Dermatophagoides pteronyssinus and Dermatophagoides farinae 50/50 extract at 300 IR concentration. In March 2013, six weeks after the start of SLIT, the patient attended the emergency department for reflux and vomiting of 1-month duration accompanied by pain, retrosternal chest discomfort, and weight loss. There was no trigger factor and no time pattern. She had no fever or abdominal injury. Local antacids and domperidone were not effective. During a previous emergency consultation, she had been prescribed proton pump inhibitors (PPIs), omeprazole (20 mg/d), and sodium alginate, which temporarily relieved the symptoms for 48 hours. The complete blood cell count, erythrocyte sedimentation rate, and liver function test results were normal. The C-reactive protein level was 14 mg/L. Upper endoscopy, performed 12 days after starting PPI treatment, revealed a slightly congested appearance of the lower third of the esophagus, without ulceration. The gastric mucosa revealed focal congestion, with no ulcer, ulceration, or nodular appearance. Eight esophageal biopsy specimens (3 from the distal third, 3 from the middle third, and 2 from the upper third), 5 stomach specimens (3 from the antrum and 2 from the fundus), and 2 duodenal specimens (1 from the bulb) were obtained. Histopathologic examination of these specimens

Are adverse drug reaction patterns different between romiplostim and eltrombopag? 2009–2013 French PharmacoVigilance assessment

BACKGROUND Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns. METHODS We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period. RESULTS We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48-4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23-383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73-119.08]). Dispensing data-adjusted comparisons led to similar results. CONCLUSIONS This study suggests different ADR patterns between romiplostim and eltrombopag.

Alteration of the Fetal Heart Rate Pattern Induced by the Use Of Clozapine during Pregnancy

Patients treated with clozapine show autonomic dysregulation and cardiac repolarisation changes. As clozapine crosses the placenta, it could have an impact on the fetus heart rate. We reported a case of reduction of the fetal heart rate variability in a patient treated with clozapine during her pregnancy. This anomaly disappeared with fetal maturation and it did not jeopardize the fetal well-being. This side effect had already been described and pharmacologists and obstetricians should be aware that clozapine may be responsible for these fetal heart rate alterations.

Acute kidney injury after high dose etoposide phosphate: A retrospective study in children receiving an allogeneic hematopoetic stem cell transplantation

Etoposide phosphate (EP; single injection, 60 mg/kg) followed by total body irradiation (TBI) at 12 Gy has been used as an allogeneic stem cell transplantation (allo‐SCT) conditioning regimen for children since 2010. In our institution, EP has been suspected of leading to acute nephrotoxicity. The aim of this study was to assess the potential renal toxicity of EP in this context.

HyperCKemia induced by levetiracetam.

La Presse Medicale - In Press.Proof corrected by the author Available online since vendredi 1 juillet 2016

Serotonin and yawning: A possible adverse drug reaction during antidepressant therapy

La Presse Medicale - In Press.Proof corrected by the author Available online since lundi 5 mai 2014

Nicorandil and cutaneous ulcerations, their misdiagnosis and consequences: Illustration by five cases reports and a review of the French pharmacovigilance database

While physicians increasingly recognize nicorandil-related mucocutaneous ulcerations, there are still misdiagnoses, particularly in the case of unusual location and late onset ulceration after nicorandil introduction. The goal of our study was to remind clinicians about the link between nicorandil use and the development of cutaneous ulcerations and to highlight the risk of misdiagnosis. We describe five reports diagnosed by the same dermatologist, complemented by an analysis of the French pharmacovigilance database (FPVD) from 1 January 1994 to 5 January 2017. During this period, 28 reports of strict cutaneous ulcerations due to nicorandil, in addition to our five reports, were registered in the FPVD. For those 28 reports, the time to onset between nicorandil introduction and cutaneous ulcerations was quite long and exceeded one year in 16 reports (information specified in 25 reports). The delay between ulcerations observation and nicorandil discontinuation was variable, with immediate diagnosis in seven reports, but ranged from fifteen days to twelve years in 21 reports. The main locations were lower limbs, thorax and face. Ulcerations could be localized on surgery or trauma scars. Regression after nicorandil discontinuation was observed in all but two reports and ranged from three days to three months. Characteristics were comparable in our five patients series. All patients exposed to nicorandil and healthcare practitioners prescribing nicorandil should be aware of the risk of cutaneous ulcerations to enable early diagnosis and drug withdrawal. The risk of misdiagnosis of this serious adverse drug reaction, along with the risk of sequelae, the costs of unnecessary additional investigations and the recent update on nicorandil as second-line treatment for stable angina, with existing alternative drugs, question about the benefit/risk balance of nicorandil.