| 1. |
- Bastard, Paul, et al.
(författare)
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Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.
- 2021
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Ingår i: The Journal of experimental medicine. - 1540-9538. ; 218:7
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Tidskriftsartikel (refereegranskat)abstract
- Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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| 2. |
- Mughal, M. Zulf, et al.
(författare)
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Burosumab for X-linked hypophosphatemia in children and adolescents : Opinion based on early experience in seven European countries
- 2022
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 13
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Forskningsöversikt (refereegranskat)abstract
- Given the relatively recent introduction of burosumab in the management of X-linked hypophosphatemia (XLH), there is limited real-world data to guide its use in clinical practice. As a group of European physicians experienced with burosumab treatment in clinical practice, we convened with the objective of sharing these practice-based insights on the use of burosumab in children and adolescents with XLH. We attended two virtual meetings, then discussed key questions via Within3, a virtual online platform. Points of discussion related to patient selection criteria, burosumab starting dose, dose titration and treatment monitoring. Our discussions revealed that criteria for selecting children with XLH varied across Europe from all children above 1 year to only children with overt rickets despite conventional treatment being eligible. We initiated burosumab dosing according to guidance in the Summary of Product Characteristics, an international consensus statement from 2019 and local country guidelines. Dose titration was primarily guided by serum phosphate levels, with some centers also using the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR). We monitored response to burosumab treatment clinically (growth, deformities, bone pain and physical functioning), radiologically (rickets and deformities) and biochemically (serum phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, urine calcium-creatinine ratio and TmP/GFR). Key suggestions made by our group were initiation of burosumab treatment in children as early as possible, from the age of 1 year, particularly in those with profound rickets, and a need for clinical studies on continuation of burosumab throughout adolescence and into adulthood.
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| 3. |
- Padidela, Raja, et al.
(författare)
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BUR-CL207 : An Open-label, Multicenter, Non-randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Burosumab in Pediatric Patients from Birth to Less than 1 Year of Age with XLH
- 2021
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Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:Suppl. 1, s. 226-226
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: X-linked hypophosphatemia (XLH) is caused by mutations in PHEX which increases serum Fibroblast Growth Factor 23 (FGF23) concentrations leading to phosphate wast-ing and osteomalacia. Burosumab is a recombinant fully human IgG1 monoclonal antibody which selectively inhibits the activity of FGF23. In clinical trials burosumab demonstrated significant clinical improvements in radiological rickets severity, growth, and biochemistry among XLH children aged 1-12 years compared to those continuing on conventional therapy (Imel 2019). Buro-sumab is licensed by the European Medicines Agency for manage-ment of XLH in children >1 year. Early initiation of treatment in XLH improves height (Makitie 2003) and effective and sustained treatment improves dental and musculoskeletal outcomes. Study BUR-CL207 has been designed to evaluate the safety, tolerability, pharmacology and efficacy of burosumab in pediatric patients <12 months.Methods: This study is enrolling and will include approxi-mately 20 XLH infants (<12 months old) with a confirmed PHEXmutation. Baseline fasted serum phosphate below the age-adjusted normal range is required for inclusion. Infants receiving conven-tional therapy will discontinue medications >1 week before com-mencing burosumab treatment and for the duration of study. This study comprises three cohorts with a total treatment period of up to 48 weeks. Subjects will be enrolled into a cohort dependent on their age. Cohorts 1 and 2 for subjects aged: ≥6 months to <12 months, and cohort 3 for subjects <6 months. Burosumab starting doses of 0.4 mg/kg (Cohorts 1 and 3) and 0.8 mg/kg (Cohort 2), administered every two weeks, will be studied in each subgroup in a staggered manner with up to 3 subjects per cohort (final num-ber per cohort will depend on age of eligible patients as enrolled). Burosumab dose adjustments will be determined by serum phos-phate levels. A Data Safety Monitoring Board will review data accrued in each cohort.Outcome Measurements: The primary endpoint is the safety of burosumab in pediatric patients <12 months. The secondary endpoints include: PK assessments and change from baseline in serum phosphate and 1,25(OH)2D, the clinical effects of buro-sumab on growth and prevention and/or healing of rickets and skeletal deformities. Exploratory endpoints include presence and appearance of bone and skeletal XLH related abnormalities in pediatric subjects starting treatment <12 months, anthropometric and motor development in pediatric subjects with XLH and char-acterizing the immunogenicity of burosumab following adminis-tration to pediatric subjects with XLH.BUR-CL207 is conducted in Austria, France, Germany, Italy, Spain, Sweden, UK.
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