S. Rivière

Bevacizumab in Patients With Hereditary Hemorrhagic Telangiectasia and Severe Hepatic Vascular Malformations and High Cardiac Output

CONTEXT The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti-vascular endothelial growth factor treatments such as bevacizumab may be an effective treatment. OBJECTIVES To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life. DESIGN, SETTING, AND PATIENTS Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT. INTERVENTION Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment. MAIN OUTCOME MEASURE Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography. RESULTS A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response [CR]) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m(2) (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m(2) (range, 2.9-5.2; P < .001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m(2); range, 3.0-5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P = .008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated. CONCLUSION In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00843440.

Adverse Drug Events Associated with Hospital Admission

OBJECTIVE To increase the knowledge base on the frequency, causality, and avoidability of adverse drug events (ADEs) as a cause for admission in internal medicine or when occurring during hospitalization. METHODS A prospective study was performed for 6 periods of 8 days each. Epidemiologic data (e.g., age, gender, medical history), drug utilization, and adverse drug reactions on patients hospitalized during these periods were collected by a pharmacy student. RESULTS A total of 156 patients (70 men and 86 women) were included in the study. The patients’ mean age ± SD was 66.5 ± 18.1 years and mean length of stay was 13.2 ± 9 days. Renal and hepatic insufficiency and previous history of drug intolerance were observed in 17.9%, 10.2%, and 2% of the hospitalized patients, respectively. Thirty-eight ADEs occurred in 32 patients; in 15 cases, ADEs were identified as the reason for admission, 10 cases occurred during hospitalization, and 13 cases were present at admission, but were not the cause of admission. The most frequent ADEs involved the neurologic (23.6%), renal (15.7%), and hematologic (13.1%) systems. Among these 38 ADEs, 22 were considered avoidable (57.9%); 20 of these were associated with therapeutic errors (inappropriate administration, drug–drug interactions, dosage error, drug not stopped despite the onset of ADEs). Patients with ADEs stayed longer in the hospital and took more drugs both before and during their hospital stay (p < 0.05). CONCLUSIONS Most of the ADEs observed in this study were avoidable. The risk/benefit ratio of administered drugs could be improved with better knowledge of the patients’ medical history and the risk factors of ADEs.

Kinetic profiles and management of hepatitis B virus reactivation in patients with immune-mediated inflammatory diseases.

Immunosuppressive therapy may trigger hepatitis B virus (HBV) reactivation for increased morbidity and mortality. We aimed to describe HBV reactivation in patients receiving treatment for immune‐mediated inflammatory diseases (IMIDs) and to evaluate a predefined algorithm for its prevention.

Treatment strategies and outcome of induction-refractory Wegener's granulomatosis or microscopic polyangiitis: analysis of 32 patients with first-line induction-refractory disease in the WEGENT trial

Objectives To study the efficacy of rescue treatment strategies and outcomes in patients with Wegeners granulomatosis (WG) and microscopic polyangiitis (MPA) not achieving remission with first-line induction with corticosteroids (CS) and intravenous cyclophosphamide (CYC). Methods 159 eligible patients in the Wegeners Granulomatosis-Entretien (WEGENT) trial newly diagnosed with systemic or renal WG or MPA with ≥1 poor prognosis factors were included in this prospective study. Rescue treatment strategies and outcomes in patients with induction-refractory disease were analysed and patient characteristics at diagnosis were compared with those of induction-responders. Results Most patients (n=126, 79.2%) achieved remission; 1 stopped induction because of allergy and 32 were induction-refractory (24 WG and 8 MPA); 11 died rapidly within a median of 2.5 months, 6 of uncontrolled disease, 1 of an infectious complication and 4 of both. Treatment was discontinued in 1 patient with MPA with end-stage renal disease. Induction was switched to oral CYC in 20 patients, combined with infliximab in 1; 15 (75%) achieved remission or low disease activity state, 3 subsequently died of uncontrolled disease and 2 entered remission using several other agents including biological agents. Alveolar haemorrhage and a creatinine level >200 μmol/l were independently associated with induction-refractory disease. Among patients with induction-refractory disease, massive alveolar haemorrhage was associated with higher mortality. Conclusion Switching to oral CYC can be an effective rescue treatment for patients with systemic forms of WG or MPA who fail to achieve remission with first-line CS and intravenous CYC. However, a more rapidly effective regimen remains to be identified for most severely affected patients whose outcomes can be rapidly fatal.

Infliximab Versus Adalimumab in the Treatment of Refractory Inflammatory Uveitis: A Multicenter Study From the French Uveitis Network

To analyze the factors associated with response to anti–tumor necrosis factor (anti‐TNF) treatment and compare the efficacy and safety of infliximab (IFX) and adalimumab (ADA) in patients with refractory noninfectious uveitis.

Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia: A Randomized Clinical Trial

BACKGROUND Epistaxis is the most frequent and disabling manifestation of hereditary hemorrhagic telangiectasia (HHT). The efficacy of intravenous bevacizumab (an anti-vascular endothelial growth factor monoclonal antibody) for epistaxis has been shown. However, the efficacy of intranasal bevacizumab has yet to be evaluated. OBJECTIVE To evaluate the efficacy of 3 different doses of bevacizumab administered as a nasal spray in a repeated manner for the duration of nosebleeds in patients with HHT. DESIGN, SETTING, AND PARTICIPANTS Randomized, multicenter, placebo-controlled, phase 2/3 clinical trial with dose selection at an intermediate analysis and prespecified stopping rules (nonbinding stopping for futility). Patients aged 18 years or older with a diagnosis of HHT were recruited from 5 French centers from April 2014 to January 2015 with a 6-month follow-up after the end of treatment. Participants had a history of self-reported nosebleeds with a monthly duration of more than 20 minutes in at least the 3 months prior to inclusion corroborated by epistaxis grids completed during the same preinclusion period. INTERVENTIONS Eighty consecutive HHT patients were randomized and treated in the phase 2 study, with 4 parallel groups in a 1:1:1:1 ratio. One group received placebo (n = 21); the other 3 received bevacizumab nasal spray. Each bevacizumab group received a different dose of the drug (25 mg [n = 20], 50 mg [n = 20], or 75 mg [n = 19] per treatment) in 3 doses 14 days apart for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, and 225 mg in each treatment group. MAIN OUTCOMES AND MEASURES Mean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment. RESULTS Of the 80 patients who were randomized (mean age, 60.47 [SD, 10.61] years; 37 women [46.25%]), 75 completed the study. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 59 patients receiving bevacizumab in comparison with the placebo group (P = .57) or between the bevacizumab groups. The mean monthly epistaxis duration was 259.2 minutes (95% CI, 82.1-436.3 minutes) in the 25-mg group, 244.0 minutes (95% CI, 81.8-406.2 minutes) in the 50-mg group, 215.0 minutes (95% CI, 102.8-327.2 minutes) in the 75-mg group, and 200.4 minutes (95% CI, 109.3-291.5 minutes) in the placebo group. Toxicity was low and no severe adverse events were reported. This study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee. CONCLUSIONS AND RELEVANCE In patients with HHT, a bevacizumab nasal spray treatment of 3 administrations at 14-day intervals with doses of 25 mg, 50 mg, or 75 mg per spray, compared with a placebo, did not reduce monthly epistaxis duration in the 3 consecutive months immediately after the end of treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02106520.

Localized Cutaneous Leishmaniasis due to Leishmania infantum in a Patient Treated with Infliximab

We report the first case of cutaneous leishmaniasis in a patient treated with infliximab. The species was Leishmania infantum, agent of both cutaneous leishmaniasis and visceral leishmaniasis. Cutaneous leishmaniasis occurred after the 9th infusion of infliximab in a patient who was suffering from ankylosing spondylitis.

Dose – response relationship of bevacizumab in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder associated with epistaxis and hepatic shunts, is responsible for high-output cardiac failure in rare cases. Bevacizumab, which targets vascular endothelial growth factor, was shown to decrease both cardiac index (CI) and epistaxis duration in HHT patients with severe liver involvement. The relationship between its serum concentration and change in both CI and epistaxis duration was investigated to design the bevacizumab maintenance dosing regimen of future therapeutic studies. Twenty-five HHT patients with dyspnea and high CI were included in a prospective non-comparative study. They received bevacizumab at a dose of 5 mg/kg per infusion every 14 days for a total of 6 injections. The relationships between bevacizumab serum concentration and both CI and epistaxis duration were described using transit compartments and direct inhibition pharmacokinetic-pharmacodynamic models. The performances of different maintenance regimens were evaluated using simulation. Infusions every 3, 2 and one months were predicted to maintain 41%, 45% and 50% of patients with CI <4 L/min/m2 at 24 months, respectively. The fraction of patients with <20 min epistaxis per month was predicted to be 34%, 43% and 60%, with infusion every 3, 2 or one months, respectively. Simulations of the effects of different maintenance dosing regimens predict that monthly 5 mg/kg infusions of bevacizumab should allow sustained control of both cardiac index and epistaxis.

Comment améliorer la rentabilité diagnostique des biopsies de la sphère oto-rhino-laryngée dans la maladie de Wegener : analyse anatomo-clinique de 49 biopsies chez 21 patients

Resume Les biopsies de la sphere oto-rhino-laryngee (ORL) et conjonctivales sont classiquement rapportees comme peu contributives dans le diagnostic de la maladie de Wegener (MW). A partir de 49 biopsies ORL ou conjonctivales (fosses nasales 29, sinus 7, cavite buccale 4, larynx 4, conjonctive 3, oreille externe 2) realisees lors du diagnostic chez 21 patients atteints de MW, nous avons decrit les lesions histologiques evocatrices et etudie la rentabilite diagnostique de ces prelevements en fonction : de la presence de lesions macroscopiques, du site anatomique biopsie, des modalites d’obtention (anesthesie generale ou locale), de leur taille et du nombre de recoupes realisees. L’association de lesions granulomateuses (cellules geantes isolees (28,5 % des biopsies), granulomes epithelioides (28,5 %)), de lesions necrosantes (micro-abces a polynucleaires neutrophiles (16,3 %), foyers de necrose du tissu conjonctif (18,3 %)) et d’une vascularite (necrosante (12 %), leucocytoclasique (10 %), granulomateuse (6 %)) permettant d’affirmer le diagnostic n’etait presente que dans 18,3 % des biopsies (28,5 % des patients). Il nous a paru licite de proposer le diagnostic « compatible avec une MW » lorsqu’une ou deux de ces lesions histologiques etaient presentes (24,5 % des biopsies, 26 % des patients). Nos resultats montrent qu’il etait toujours preferable de biopsier les lesions macroscopiques lorsqu’elles existaient. En leur absence, il valait mieux s’orienter vers un prelevement de muqueuse sinusienne sous anesthesie generale. En effet, les nombreuses biopsies systematiques des fosses nasales realisees sous AL etaient non contributives dans 90 % des cas. Enfin, nous avons montre que la realisation de deux recoupes permettait d’augmenter la sensibilite de l’examen histologique de 7 %.

Inflammatory bowel diseases in anti-neutrophil cytoplasmic antibody–associated vasculitides: 11 retrospective cases from the French Vasculitis Study Group

OBJECTIVE Coexistence of ANCA-associated vasculitis (AAV) and IBD is a rare condition that is rarely described in the literature. The aim of the study was to describe the main characteristics of patients presenting with both IBD and AAV. METHODS A retrospective study of AAV patients in the French Vasculitis Study Group cohort who also had a diagnosis of IBD was conducted. We reviewed the medical records and outcomes of these patients. RESULTS We identified 11 patients with AAV and IBD. Four patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss) also had ulcerative colitis and seven patients with granulomatosis with polyangiitis (GPA) had Crohns disease. No Crohns disease was observed in eosinophilic GPA and no ulcerative colitis in GPA. IBD started before AAV manifestations in six cases, simultaneously in two cases and after AAV manifestations in three cases. CONCLUSION Coexistence of IBD and AAV is a rare condition. The therapeutic management of these patients includes corticosteroids in all cases and immunosuppressive drugs in some patients. Coexistence of IBD and AAV might be explained by common underlying inflammatory responses and cytokine profiles polarized towards either Th1 or Th2. Finally, in the presence of digestive manifestations in the context of AAV, the hypothesis of IBD should be assessed.