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Gaucher disease: Review, epidemiology and modelling of the biological and clinical markers evolution

Defense Thèse de privat-docent : Univ. Genève, 2016
Abstract Gaucher disease (GD) is a rare genetic lysosomal disorder which is sometimes complicated by bone events (BEs) such as avascular necrosis, bone infarct or pathological fracture. It modifies a number of biomarkers (increased chitotriosidase, angiotensin converting enzyme, ferritin and tartrate-resistant acid phosphatase, and decreased platelets levels). Specific treatments are available. In 2009, we established a French Gaucher Disease Registry (FGDR). An epidemiological analysis of all cases of GD in France identified 562 patients, registering 378 with follow-up (including 90 deaths and 46 monoclonal gammopathies) and 283 undergoing follow-up. BE occurred before treatment (130 BE in 67 patients), but also during it (60 BEs in 41 patients), with frequencies at 10 years (95% CI) of 20.3% (14.1%–26.5%) and 19.8% (13.5%–26.1%), respectively after diagnosis and treatment onset. The present work focused particularly on ferritin, showing that other iron-based parameters remained normal (in 72 patients), and it is the first to describe (decreased) glycosylated ferritin in 25 patients with GD. An analysis of 62 patients showed that BEs occurred before and during treatment; biomarkers were modelled (using mixed models) and the impact of slope and values at treatment onset were tested on BEs. In 2009, a worldwide shortage in the supply of imiglucerase led to treatment modifications or interruptions for patients with GD type 1. We describe the shortage’s impact on therapeutic management and the disease’s course in French patients. We report on the first dynamic model of how biomarkers evolve during the course of GD. This model enabled us to estimate that 95% of biomarkers response to enzyme replacement therapy (ERT) was achieved in 2 years. We also found that by using the current treatment, about 65% of patients should experience a normalisation of chitotriosidase and ferritin. We used a frailty model to analyse the occurrence of repeated BEs in Gaucher patients after treatment initiation. In the discussion, we developed the use of joint models for analysing repeated longitudinal data (biomarkers) and survival time (BEs) in GD. Further studies should continue to use biomarker modelling with the patient registry in order to try to predict BE and other complications before treatment.
Keywords Gaucher diseaseLysosomal disorderAvascular necrosisBone infarctChitotriosidaseFerritinRegistryMixed modelsFrailty modelJoint modelImiglucerase
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STIRNEMANN, Jérôme. Gaucher disease: Review, epidemiology and modelling of the biological and clinical markers evolution. Université de Genève. Thèse de privat-docent, 2016. https://archive-ouverte.unige.ch/unige:85560

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Deposited on : 2016-07-29

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