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The Journal of Pediatrics Jan 2023The objective of this study was to assess the impact of treatment response to the ileal bile acid transporter inhibitor maralixibat on health-related quality of life... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The objective of this study was to assess the impact of treatment response to the ileal bile acid transporter inhibitor maralixibat on health-related quality of life (HRQoL) in children with Alagille syndrome.
STUDY DESIGN
This analysis used data from the ICONIC trial, a phase 2 study with a 4-week double-blind, placebo-controlled, randomized drug withdrawal period in children with Alagille syndrome with moderate-to-severe pruritus. Clinically meaningful treatment response to maralixibat was defined a priori as a ≥1-point reduction in the Itch-Reported Outcome (Observer) score, from baseline to week 48. HRQoL was assessed using the Pediatric Quality of Life Inventory Generic Core, Family Impact, and Multidimensional Fatigue scale scores, which were collected via the caregiver. The minimal clinically important difference for HRQoL ranged from 4 to 5 points, depending on the scale.
RESULTS
Twenty of the 27 patients (74%) included in this analysis achieved an Itch-Reported Outcome (Observer) treatment response at week 48. The mean (SD) change in Multidimensional Fatigue score was +25.8 (23.0) for responders vs -3.1 (19.8) for nonresponders (P = .03). Smaller and non-statistically significant mean changes were observed for the Pediatric Quality of Life Inventory Generic Core and Family Impact scores. Controlling for baseline Family Impact score, responders' Family Impact scores increased an average of 16.9 points over 48 weeks compared with non-responders (P = .05). Smaller and non-statistically significant point estimates were observed for the Pediatric Quality of Life Inventory Generic Core and Multidimensional Fatigue scores.
CONCLUSION
The significant improvements in pruritus seen with maralixibat at week 48 of the ICONIC study are clinically meaningful and are associated with improved HRQoL.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT02160782.
Topics: Child; Humans; Quality of Life; Alagille Syndrome; Fatigue; Pruritus
PubMed: 36096175
DOI: 10.1016/j.jpeds.2022.09.001 -
Annales de Biologie Clinique Dec 2018We report the case of an infant hospitalized for neonatal anoxic ischemia in whom the diagnosis of Alagille syndrome (SAG ; MIM # 118450) was suspected in the presence...
We report the case of an infant hospitalized for neonatal anoxic ischemia in whom the diagnosis of Alagille syndrome (SAG ; MIM # 118450) was suspected in the presence of major cholestasis, cardiac malformations, suggestive facial dysmorphia, and vertebral and ocular abnormalities. This diagnosis was later confirmed by the detection of a heterozygous pathogenic variant in the gene JAG1, i.e. the gene predominantly responsible for this syndrome with autosomal dominant transmission, which affects about 1 in 30 000 births. The purpose of this presentation is to highlight this relatively unknown syndrome, both from the diagnostic and physiopathological points of view. This clinical case is also an opportunity to discuss pseudo-bisalbuminemia, accidentally discovered in the patient during the exploration of serum proteins by capillary electrophoresis. In total, the medical biologist is directly concerned by the multidisciplinary management of this syndrome, which involves biological perturbances in multiple organs.
Topics: Alagille Syndrome; Clinical Laboratory Techniques; Humans; Infant, Newborn; Male; Neonatal Screening
PubMed: 30543192
DOI: 10.1684/abc.2018.1399 -
The Journal of Pediatrics Feb 1999
Topics: Alagille Syndrome; Calcium-Binding Proteins; Humans; Intercellular Signaling Peptides and Proteins; Membrane Proteins; Mutation; Proteins; Receptors, Notch; Serrate-Jagged Proteins
PubMed: 9931516
DOI: 10.1016/s0022-3476(99)70403-8 -
Journal of Pediatric Gastroenterology... Mar 2024Maralixibat, an ileal bile acid transporter inhibitor, is the first drug approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in... (Review)
Review
OBJECTIVE
Maralixibat, an ileal bile acid transporter inhibitor, is the first drug approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients aged ≥3 months with Alagille syndrome (ALGS). Approval was based on reductions in pruritus from the pivotal ICONIC trial, information from two additional trials (ITCH and IMAGO), and long-term extension studies. Although participants in these trials met strict inclusion and exclusion criteria, patients have received maralixibat under broader circumstances as part of an expanded access program or commercially. The expanded access and postapproval settings inform a real-world understanding of effectiveness and safety. The objective was to report on the use of maralixibat in the real-world setting in eight patients who otherwise would not have met entrance criteria for the clinical trials, providing unique insights into its effectiveness in the management of ALGS.
METHODS
We reviewed records of patients with ALGS who received maralixibat but would have been excluded from trials due to surgical biliary diversion, reduction of antipruritic/cholestatic concomitant medications, administration of medication through a gastrostomy or nasogastric tube, or use in patients under consideration for transplantation.
RESULTS
Maralixibat appeared to be effective with reductions in pruritus compared to baseline. Consistent with clinical trials, maralixibat was well tolerated without appreciable gastrointestinal complications. Liver enzyme elevations were observed but were interpreted as consistent with normal fluctuations observed in ALGS, with no increases in bilirubin.
CONCLUSION
Maralixibat may be effective and well tolerated in patients with ALGS in broader clinical contexts than previously reported.
Topics: Humans; Alagille Syndrome; Benzothiepins; Cholestasis; Longitudinal Studies; Pruritus; Clinical Trials as Topic; Infant
PubMed: 38334237
DOI: 10.1002/jpn3.12101 -
The Journal of Pediatrics Mar 2020We describe 10 children with Alagille syndrome and inflammatory arthritis. In our centers, the prevalence of chronic arthritis in patients with Alagille syndrome is...
We describe 10 children with Alagille syndrome and inflammatory arthritis. In our centers, the prevalence of chronic arthritis in patients with Alagille syndrome is approximately 50 times higher compared with the general population. Arthritis was refractory to most treatment. Patients with Alagille syndrome should routinely be screened for musculoskeletal symptoms.
Topics: Adolescent; Alagille Syndrome; Arthritis, Juvenile; Child; Child, Preschool; Chronic Disease; Contrast Media; Female; Humans; Inflammation; Liver Transplantation; Magnetic Resonance Imaging; Male; Pediatrics; Retrospective Studies; Rheumatology; Surveys and Questionnaires; Wrist
PubMed: 31748120
DOI: 10.1016/j.jpeds.2019.10.042 -
The Journal of Extra-corporeal... Dec 2022Alagille syndrome is an autosomal dominant disorder that is caused by heterozygous mutation of JAG1 or NOTCH2 gene that impacts several multisystem organs including but...
Alagille syndrome is an autosomal dominant disorder that is caused by heterozygous mutation of JAG1 or NOTCH2 gene that impacts several multisystem organs including but may not be limited to the liver, heart, musculoskeletal, skin, and the eyes. The most common congenital heart defect associated with Alagille syndrome is multilevel right ventricular outflow tract obstruction with multiple central and peripheral branch pulmonary arterial stenoses occurring in up to two-thirds of these patients. We report two cases of Alagille syndrome who underwent extensive pulmonary arterial branch rehabilitation and experienced unusual oxygenator failure during cardiopulmonary bypass (CPB). We present lessons learned from these two cases and the changes that we implemented in our practice that facilitated smooth conduct of CPB in other cases that we performed subsequently.
Topics: Humans; Alagille Syndrome; Cardiopulmonary Bypass; Hypertension, Pulmonary; Heart Defects, Congenital; Oxygenators
PubMed: 36742021
DOI: 10.1182/ject-2200022 -
Gastroenterology Mar 2018
Topics: Alagille Syndrome; Animals; Jagged-1 Protein; Mice; Mutation, Missense
PubMed: 29425927
DOI: 10.1053/j.gastro.2018.02.007 -
PloS One 2015Alagille syndrome may mimic biliary atresia in early infancy. Since mutations in JAG1 typical for Alagille syndrome type 1 have also been found in biliary atresia, we...
Alagille syndrome may mimic biliary atresia in early infancy. Since mutations in JAG1 typical for Alagille syndrome type 1 have also been found in biliary atresia, we aimed to identify JAG1 mutations in newborns with proven biliary atresia (n = 72). Five biliary atresia patients with cholestasis, one additional characteristic feature of Alagille syndrome and ambiguous liver histology were single heterozygotes for nonsense or frameshift mutations in JAG1. No mutations were found in the remaining 67 patients. All "biliary atresia" carriers of JAG1 null mutations developed typical Alagille syndrome at the age of three years. Our data do not support association of biliary atresia with JAG1 mutations, at least in Czech patients. Rapid testing for JAG1 mutations could prevent misdiagnosis of Alagille syndrome in early infancy and improve their outcome.
Topics: Alagille Syndrome; Biliary Atresia; Calcium-Binding Proteins; Codon, Nonsense; Czech Republic; Diagnosis, Differential; Female; Frameshift Mutation; Humans; Infant, Newborn; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Male; Membrane Proteins; Mutation; Serrate-Jagged Proteins
PubMed: 26618708
DOI: 10.1371/journal.pone.0143939 -
Fetal and Pediatric Pathology Aug 2014Alagille syndrome is a rare autosomal dominant disorder with characteristic findings of paucity of intrahepatic bile ducts, congenital heart disease, and vertebral,... (Review)
Review
Alagille syndrome is a rare autosomal dominant disorder with characteristic findings of paucity of intrahepatic bile ducts, congenital heart disease, and vertebral, ocular, and renal abnormalities. We present a unique autopsy case of an 18-year-old female with Alagille syndrome and splenic hamartomas. Autopsy findings included growth restriction, Tetralogy of Fallot, paucity of intrahepatic bile ducts, end-stage renal disease with mesangiolipidosis, and splenomegaly with two well-circumscribed, splenic tumors. Histologic findings of the splenic tumors revealed disorganized vascular channels lined by cells without cytologic atypia. Immunohistochemical analysis demonstrated CD8(+)CD31(+) endothelial cells, consistent with splenic hamartomas. In summary, Alagille syndrome is a rare genetic disorder characterized by JAG1 mutations and disrupted Notch signaling. Review of the literature highlights the importance of Notch signaling in vascular development and disorders. However, to our knowledge this is the first description of splenic hamartomas in Alagille syndrome.
Topics: Adolescent; Alagille Syndrome; Calcium-Binding Proteins; Female; Hamartoma; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Mutation; Neovascularization, Pathologic; Receptors, Notch; Serrate-Jagged Proteins; Signal Transduction; Splenic Diseases
PubMed: 24865822
DOI: 10.3109/15513815.2014.913748 -
The Journal of Pediatrics Feb 2023To assess and characterize health care resource utilization (HRU) in children with the rare, genetic, multisystem disorder, Alagille syndrome.
OBJECTIVE
To assess and characterize health care resource utilization (HRU) in children with the rare, genetic, multisystem disorder, Alagille syndrome.
STUDY DESIGN
This retrospective analysis reviewed commercially insured and Medicaid-insured claims from October 1, 2015 to December 31, 2019 to assess HRU in patients with Alagille syndrome. As there is no specific International Classification ofDiseases-10 code for Alagille syndrome, patients were identified using the following algorithm: ≥1 claim with diagnosis code Q44.7 (other congenital malformations of the liver); <18 years of age, with no history of biliary atresia (International Classification ofDiseases-10 code: Q44.2); and ≥6 months of insurance eligibility prior to diagnosis. HRU was summarized per patient per year over all available claims postdiagnosis.
RESULTS
A total of 171 commercially insured and 215 Medicaid-insured patients with Alagille syndrome were available for analysis. Annually, commercially insured and Medicaid-insured patients averaged 31 medical visits (range, 1.5-237) and 48 medical visits (range, 0.7-690), respectively. The most common visits were outpatient with the majority encompassing lab/imaging and primary care visits (commercially insured: 21 [range, 0.0-183]; Medicaid-insured: 26 [range, 0.0-609]). Inpatient visits were the highest driver of costs in both the commercial and Medicaid populations.
CONCLUSIONS
Patients with Alagille syndrome have a substantial HRU burden driven largely by numerous outpatient visits and costly inpatient stays. Given the complexity and variability of Alagille syndrome presentation, patients may benefit from multidisciplinary and subspecialized care.
Topics: Child; United States; Humans; Health Care Costs; Retrospective Studies; Alagille Syndrome; Delivery of Health Care; Patient Acceptance of Health Care; Medicaid; Insurance, Health
PubMed: 36179890
DOI: 10.1016/j.jpeds.2022.09.033