Iorio, Raffaele

Abstract Anti-IgLON5 disease is an autoimmune encephalitis that presents with a heterogenous clinical phenotype, including sleep disorders, movement abnormalities and bulbar involvement. It is characterized by autoantibodies against IgLON5, 85% association with HLA-DQB1*05:∼ and a brainstem-dominant tauopathy. Cellular and murine models report pathogenic effects of the autoantibodies, and neurodegenerative factors suggest progressive atrophy as a common sequela. However, evidence from in vivo patient data and long-term follow-up is limited, and the degree of progression remains elusive. In this multicentre study, clinical and brain MRI data were collected from 127 patients across 12 countries to investigate the relationships between clinical presentations and the development of distinct brain atrophy patterns. Our data show that most patients develop a complex multisystem phenotype as the disease progresses; however, neuromuscular manifestations rarely emerge at later disease stages. By comparison to healthy controls, this disease presents with severe substructure-specific atrophy, especially affecting the hypothalamus, brainstem, accumbens and basal ganglia, which, in age-independent analyses, show significant ventricular enlargement and also suggest progression of brainstem atrophy over the disease course. Moreover, the focality of atrophy was functionally linked to specific symptoms, with more severe involvement of the basal ganglia in patients with movement disorders, and greater atrophy in the hippocampus and thalamus in patients with cognitive impairment. Taken together, our results provide evidence of distinct atrophy patterns in anti-IgLON5 disease, which closely mirror sites of pathophysiologic processes, including autoantibody binding and tau deposition. Our data emphasize the brainstem as the pathophysiological hub of the disease and provide normative data for the incorporation of atrophy measurements into routine clinical assessments and future treatment studies to monitor disease trajectory and evaluate future treatment strategies.

ABSTRACTBackground:Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC.Methods:We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam‐Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c‐statistic.Results:Model fit was good at 1 year (c‐statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam‐Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam‐Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over‐weighting of AST in these patients accounted for the observed versus predicted survival discrepancy.Conclusions:All 3 models offered good short‐term discrimination of outcomes but only fair long‐term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric‐specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long‐term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event‐free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver‐related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5‐year event‐free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5‐year event‐free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5‐year event‐free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5‐year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long‐term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long‐term outcome. We identified 781 patients, median age 12 years, with 4,277 person‐years of follow‐up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event‐free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC–inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5‐0.9, and 0.7, 95% confidence interval 0.5‐0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long‐term outcome. Conclusion: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC–inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518–527).