Givosiran in acute intermittent porphyria: A personalized medicine approach.

BACKGROUND: In patients with acute intermittent porphyria (AIP), induction of delta aminolevulinic acid synthase 1 (ALAS1) leads to haem precursor accumulation that may cause recurring acute attacks. In a recent phase III trial, givosiran significantly reduced the attack rate in severe AIP patients. Frequent adverse events were injection-site reaction, fatigue, nausea, chronic kidney disease and increased alanine aminotransferase. OBJECTIVES: To describe the efficacy and safety of givosiran based on a personalized medical approach. METHODS: We conducted a retrospective patient file study in 25 severe AIP patients treated with givosiran in France. We collected data on clinical and biochemical efficacy along with reports of adverse events. RESULTS: Givosiran drastically reduced the attack rate in our cohort, as 96% were attack-free at the time of the study. The sustained efficacy of givosiran in most patients allowed us to personalize dosing frequency. In 42%, givosiran was only given when haem precursor levels were increasing. Our data suggest that givosiran is most effective when given early in the disease course. We confirmed a high prevalence of adverse events. One patient discontinued treatment due to acute pancreatitis. All patients had hyperhomocysteinemia, and all patients with initial homocysteine levels available showed an increase under treatment. In this context, one patient was diagnosed with pulmonary embolism. CONCLUSION: The sustained effect of givosiran allowed a decrease in dosing frequency without compromising treatment efficacy. The high prevalence of adverse events emphasizes the importance of restricting the treatment to severe AIP and administering the minimum effective dose for each patient.

Clinical and microbiological characteristics of the infections in patients treated with rituximab for autoimmune and/or malignant hematological disorders.

INTRODUCTION: Rituximab is commonly used for the treatment of hematological malignancies and autoimmune diseases. Despite a reputation for good tolerance, case-series and registries reported rituximab-related infections of variable severity including opportunistic infections. We aimed at describing the natural history of infectious events (IE) after treatment by rituximab providing clinical and microbiological features and outcome. PATIENTS AND METHODS: We retrospectively analyzed the medical records of patients treated with rituximab in an internal medicine department of a tertiary hospital between 2007 and 2015, and identified all IE after this therapy. Events' severity was assessed using the Common Terminological Criteria of Adverse Events (version 4.3) definitions. RESULTS: Among 101 patients treated with rituximab, we identified 228 IE in 74 (73.3%) of these patients (median follow-up 30.4months). Indication for rituximab was either autoimmune disease (AID) (52.5% of patients), or monoclonal hematological disease (MHD) (47.5%). Patients received an overall median number of 5 rituximab infusions [interquartile range: 4-8], representing a cumulative dose of 4340mg [2620-6160]. After last rituximab infusion, IE occurred after 3.1months [0.7-9.4]. Respectively, IE were severe in 28.1% of cases in patients treated for AID vs 58.0% in patients treated for MHD (p<0.001), due to opportunistic pathogens in 7.8% vs 11.0% (p=0.49) and fatal in 4.7% vs 13.0% (p=0.044). Factor associated with mortality were polymicrobial infection (p<0.001), monoclonal hematological disease (p=0.035), use of steroids over 10mg/d within the last two weeks (p=0.003), and rituximab cumulative dose (p<0.001). We identified a group of 10 patients (9.9%) showing life-threatening, polymicrobial, and opportunistic infections constituting a 'catastrophic infectious syndrome', which was lethal in 7 cases. CONCLUSION: IE after treatment by rituximab can be extremely severe, especially in patients immunocompromised by several other drugs. Further studies should focus on the group with life-threatening polymicrobial infections.

[Impact of mobile intensive care units on treating stroke within the 3-hour time window in a semi-rural area]. / Intérêt d'une médicalisation préhospitalière des accidents vasculaires cérébraux de moins de 3 heures en milieu semi-rural.

OBJECTIVES: We tested the hypothesis that calling emergency medical services ("15", French equivalent of 911 or 999 calls) and response by a mobile intensive care unit staffed by emergency physicians (MICU) reduces the time to treatment to within the 3-hour time window required for administration of recombinant tissue plasminogen activator. METHODS: This study compared the time from symptom onset to admission (prehospital time), from admission to treatment (imaging and treatment delays, hospital time), and total time from symptom onset to treatment in an observational cohort of 53 consecutive patients, according to how they reached the hospital (Group 1: MICU and group 2: standard emergency ambulance dispatched by EMS center [2a] or direct admission [2b]). RESULTS: The study included 52 patients (1 was excluded because hospitalized at the time of the stroke): 27 (51.9%) in group 1, 16 (30.8%) in group 2a, and 9 (17.3%) in group 2b. Calling "15" shortened total home-to-needle time by 24 minutes (p=0.034). The mean total time was not significantly shorter in group 1 (152 versus 162 min; p=0.27) but MICUs were used for patients farther away (mean distance 25 versus 11 km; p=0.02). The average prehospital time was thus higher in group 1 (86 versus 69 min; p=0.044), but was compensated by a reduction in the average hospital time (66 versus 93 min; p=0.0001), due mainly to shorter waits for imaging (22 versus 45 min; p=0.0001). CONCLUSION: Calling the emergency services number reduces mean total time. MICUs were associated with a longer prehospital time, mainly due to greater distances, but they facilitated in-hospital management.