BACKGROUND:Inhibitors of dipeptidyl peptidase (DPP)-IV have been suspected in the onset of bullous pemphigoid for several years now. However, comparative studies assessing the link between DPP-IV inhibitor exposure and bullous pemphigoid have not yet been performed.OBJECTIVES:To detect, from the French Pharmacovigilance Database (FPVD), a signal of risk of bullous pemphigoid during DPP-IV inhibitor exposure by comparative study.METHODS:All spontaneous reports of DPP-IV inhibitor-related bullous pemphigoid recorded in the FPVD between April 2008 and August 2014 were described. We conducted disproportionality analyses (case-noncase method) to assess the link between DPP-IV inhibitors and bullous pemphigoid, calculating reporting odds ratios (RORs). We also compared DPP-IV inhibitor-induced bullous pemphigoid reports rated per million defined daily doses dispensed during the study period.RESULTS:Among 217 331 spontaneous adverse drug reaction reports registered in the FPVD, 1297 involved DPP-IV inhibitors. Among these observations, 42 were bullous pemphigoid (vildagliptin, n = 31; sitagliptin, n = 10; saxagliptin, n = 1). The ROR for pooled DPP-IV inhibitors was 67·5 [95% confidence interval (CI) 47·1-96·9]. Disproportionality was also observed for each DPP-IV inhibitor: vildagliptin (ROR 225·3, 95% CI 148·9-340·9), sitagliptin (ROR 17·0, 95% CI 8·9-32·5) and saxagliptin (ROR 16·5, 95% CI 2·3-119·1). Analyses adjusted on dispensing data led to similar results.CONCLUSIONS:These data confirm a strong signal for an increased risk of bullous pemphigoid during DPP-IV inhibitor exposure. This adverse drug reaction is observed for each DPP-IV inhibitor, suggesting a class effect. The signal was higher with vildagliptin than with the other DPP-IV inhibitors.

Oseltamivir is a neuraminidase inhibitor approved for the prevention and treatment of influenza. Few haematological side effects have been reported with oseltamivir. We report herein the case of an unexpected platelet increase in a 46-year-old woman with idiopathic thrombocytopenia (ITP) treated with oseltamivir for influenza. The mechanism may involve the neuraminidase inhibition which decrease platelet surface sialic acid content and reduce their removal by the reticuloendothelial system. Oseltamivir may be responsible for platelet increase especially in patients with ITP.

Ustekinumab, a monoclonal antibody that blocks interleukin-12 and interleukin-23, is a biological therapy used to treat moderate-to-severe psoriasis. Bullous pemphigoid (BP) induced by anti–tumor necrosis factor-alfa (TNF-α) agents has been described in the literature.1-3 No cases have been reported with ustekinumab. We report a case of BP occurring in a patient treated for 9 months with ustekinumab for severe psoriasis.

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.

OBJECTIVES:The aim of this research was to describe the cases of TNF-α antagonist-related alopecia reported in the French Pharmacovigilance Database (FPVD) and to investigate the association between exposure to TNF-α antagonists and occurrence of alopecia.METHODS:All spontaneous reports of TNF-α antagonist-related alopecia recorded in the FPVD between January 2000 and April 2012 were colligated and described. We conducted disproportionality analyses (case/non-case method) to assess the link between the occurrence of alopecia and exposure to TNF-α antagonists. Cases were all reports of alopecia and non-cases were all other reports recorded during the study period. Exposure to TNF-α antagonists was sought in cases and in non-cases. Reporting odds ratios (RORs) were calculated to assess the association. Docetaxel was used as positive control and acetaminophen as negative control. We performed sensitivity analyses excluding cases of androgenic alopecia and those occurring in psoriatic patients.RESULTS:Among 282 590 spontaneous reports of adverse drug reactions (ADRs) collated in the FPVD, 1068 cases (alopecia reports) were identified. Of these cases, 52 (4.9%) occurred during exposure to TNF-α antagonists (18 involved infliximab, 17 adalimumab, 15 etanercept and 2 certolizumab). Exposure to TNF-α antagonists was more frequent among alopecia reports than among other ADR reports for all TNF-α antagonists pooled (ROR 3.0, 95% CI 2.3, 4.0) as well as for each antagonist separately, with similar values. Sensitivity analyses yielded similar results. The RORs were 29.9 (95% CI 25.3, 35.5) with docetaxel and 0.3 (95% CI 0.2, 0.4) with acetaminophen.CONCLUSION:The present study confirms a strong link between TNF-α antagonist exposure (class effect) and the occurrence of alopecia.

A young girl aged 13-years-old treated with montelukast, fluticasone/salmeterol, desloratadine, fluticasone furoate and salbutamol has presented numerous spontaneous bruises after that treatment with montelukast was substituted by the generic form. Stopping montelukast allow a significant improvement in bruises.

L'ustekinumab, anticorps monoclonal anti-IL-12 IL-23 est une biothérapie utilisée depuis 2010 dans le traitement du psoriasis modéré à sévère. Des cas de pemphigoïdes induites par les anti-TNF alpha ont été décrites dans la littérature, mais aucune sous ustekinumab. Nous rapportons un cas de pemphigoïde bulleuse survenue au décours d'un traitement par ustekinumab. Un homme de 62 ans, suivi pour un psoriasis sévère, présentait une éruption bulleuse et prurigineuse 9 mois après l'instauration d'un traitement par ustekinumab. En dehors d'un traitement par metformine observé depuis de nombreuses années, le patient ne prenait aucun autre médicament. L'examen histologique et l'immunofluorescence directe confirmaient le diagnostic de pemphigoïde bulleuse. Un traitement par dermocorticoïdes de classe forte, associé à l'interruption de l'ustekinumab, permettait d'obtenir rapidement un blanchiment des lésions. Un an après l'arrêt de l'ustekinumab, et 8 mois après l'arrêt des dermocorticoïdes, il n'était pas observé de rechute. Les pemphigoïdes bulleuses induites par les anti-TNF alpha sont connues et décrites dans la littérature. Bien qu'aucun cas n'ait été rapporté sous ustekinumab, le mécanisme d'action de cette molécule, proche des anti-TNF alpha, rend son imputabilité possible, d'autant que d'autres effets cutanés d'ordre dysimmunitaire ont été décrits sous anti-IL-12 IL-23 (pelades, dermatoses à IgA linéaire). Le caractère particulièrement aigu de l'éruption, la régression rapide des lésions après l'arrêt de l'ustekinumab et l'absence de récidive à distance, plaident en faveur de cette origine iatrogène dans notre observation. À notre connaissance, il s'agit du premier cas de pemphigoïde bulleuse survenue sous ustekinumab.

Les anti-tumor necrosis factor (TNF) alpha (anticorps monoclonaux pour adalimumab et infliximab, récepteurs solubles pour étanercept) sont des molécules utilisées notamment dans les maladies inflammatoires chroniques de l’intestin. Leurs effets indésirables, la plupart communs aux trois molécules, sont désormais bien connus, avec parmi les plus fréquents, un risque de réactions à l’injection, de troubles gastro-intestinaux et d’infections. Nous rapportons ici une dysphonie apparue à deux reprises chez une patiente traitée par adalimumab pour une maladie de Crohn.

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 m(2), 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 m(2), 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 m(2), 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 drug's anticoagulant effects.

TO THE EDITOR: The multikinase inhibitorsorafenibwas recentlyapproved inEurope forthetreatment of advanced hepatic carcinoma (AHC). Wereporta case of hepaticencephalopathy inducedby sorafenib,with positive rechallenge. Case Report. A 63-year-old patientwasdiagnosed withAHCassociated with Child-PughClass A alcohol-relatedcirrhosis (prothrombin 61%; bilirubin 13 mg/dL,albumin 2.9 g/dL,no ascitesor encephalopathy).There was no portalthrombosis and the patienthad not used alcohol since 2006. Chronic medical therapy consisted of propranolol40 mg/day(for esophagealvarices),paroxetine20 mg/day,zopiclone7.5 mg/day, andoxybutynin 5 mg/day. In November 2008,sorafenib 400 mg twicedaily(approved dosing) was introduced.since chemoembolization had not succeeded.There were no complicationsfor 20 days after sorafenib initiation,except bloodpressurevaluesof 160/90mm Hg. The patientwas admittedto the hospital on day 21 due to confusion and asterixis. Results of an electroencephalogram revealed no lesionand computedtomography scan of the brainshoweddiffusesubcortical atrophy appropriate forage.Therewasnohemorrhage, infection, or renalinsufficiency. Drug-inducedhepatic encephalopathywas suspected and sorafenibwas discontinued. Within 24 hours,all neurologic symptoms resolved.The patient was discharged5 days later and sorafenib200 mg twicedailywasreintroduced. Eightdays later,the patientpresented with a new episodeof confusionand asterixis,as severeas the first one despite thedose reduction. Sorafenib was stopped,the symptoms resolved within 24 hours, and the patient no longerpresented hepatic encephalopathy. Discussion.The mostcommonadverseeffectsof sorafenibare liver dysfunction,diarrhea,and hand-footskin reaction.To our knowledge, this is thefirstpublished reportof hepatic encephalopathy induced by sorafenib. Use of the Naranjo probability scale indicates the role of sorafenib in hepaticencephalopathyto be probable.' The delay between sorafenib initiation and onset of neurotoxicity for both consecutive episodes is suggestive.The rapid improvementof symptomsafter sorafenib withdrawal and the positive rechallengestrengthenthe role of this drug in this case. Finally,comprehensive medicalexams and tests ruledoutcommon causesof hepatic encephalopathy. This adverse effectis notclearlyidentified. Hepatic encephalopathy is not reported in the safetydata frompivotal studies in patients withAHC treated with sorafenib.There is only one case mentioned in a Phase I clinical trial evaluating the doxorubicin/sorafenib combination in patients with AHC.1 However,preliminary results from a French study (unpublished results) reported 2 casesof hepatic encephalopathy in 2 patients with relapsed hepatocellularcarcinoma associated with ChildPugh Class A cirrhosis.3 In addition, we found 5 cases of hepatic encephalopathy associated withsorafenib reported by medical professionals to an independent drug database," None of these cases is well described, but 3 patients required hospitalizationand 2 patients died. Lastly, a recentstudysuggeststhat sorafenib used in AHC induced significant liverdysfunction/failure, whichis moreextensive if the associated livercirrhosis is severe.' As hepatic encephalopathy is a life-threatening complication, caution shouldbe takenin patients usingsorafenib for AHC,evenwhenconcomitantly diagnosed withChild-Pugh ClassA cirrhosis.

Alopecia induced by tumour necrosis factor-alpha antagonists: description of 52 cases and disproportionality analysis in a nationwide pharmacovigilance database Abstract Objectives. The aim of this research was to describe the cases of TNF-a antagonist-related alopecia reported in the French Pharmacovigilance Database (FPVD) and to investigate the association between exposure to TNF-a antagonists and occurrence of alopecia. Methods. All spontaneous reports of TNF-a antagonist-related alopecia recorded in the FPVD between January 2000 and April 2012 were colligated and described. We conducted disproportionality analyses (case/non-case method) to assess the link between the occurrence of alopecia and exposure to TNF-a antagonists. Cases were all reports of alopecia and non-cases were all other reports recorded during the study period. Exposure to TNF-a antagonists was sought in cases and in non-cases. Reporting odds ratios (RORs) were calculated to assess the association. Docetaxel was used as positive control and acetaminophen as negative control. We performed sensitivity analyses excluding cases of androgenic alopecia and those occurring in psoriatic patients. Results. Among 282 590 spontaneous reports of adverse drug reactions (ADRs) collated in the FPVD, 1068 cases (alopecia reports) were identified. Of these cases, 52 (4.9%) occurred during exposure to TNF-a antagonists (18 involved infliximab, 17 adalimumab, 15 etanercept and 2 certolizumab). Exposure to TNF-a antagonists was more frequent among alopecia reports than among other ADR reports for all TNF-a antagonists pooled (ROR 3.0, 95% CI 2.3, 4.0) as well as for each antagonist separately, with similar values. Sensitivity analyses yielded similar results. The RORs were 29.9 (95% CI 25.3, 35.5) with docetaxel and 0.3 (95% CI 0.2, 0.4) with acetaminophen. Conclusion. The present study confirms a strong link between TNF-a antagonist exposure (class effect) and the occurrence of alopecia.