Modeling changes in biomarkers in Gaucher disease patients receiving enzyme replacement therapy using a pathophysiological model

Orphanet Journal of Rare Diseases

France Mentré⁵  Nadia Belmatoug¹  Bruno Fantin¹  Anne Boutten⁶  Roseline Froissart³  Catherine Caillaud⁴  Jérôme Stirnemann²  Marie Vigan⁵ 

[1] Service de Médecine Interne, Hôpital Beaujon, AP–HP, Clichy, France;Division of General Internal Medicine, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland;Laboratoire des Maladies Héréditaires du Métabolisme, Centre de Biologie Est, Hospices Civils de Lyon, Bron, France;Laboratoire de Biochimie, Métabolomique et Protéomique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France;Univ Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France;Laboratoire de Biochimie, Hôpital Bichat, Paris, France

关键词: Model;    Platelets;    Hemoglobin;    Chitotriosidase;    Ferritin;    Glucosylceramide;    Imiglucerase;    Enzyme replacement therapy;    French registry;    Gaucher disease;   

Others  :  861465
DOI  :  10.1186/1750-1172-9-95

 received in 2014-03-07, accepted in 2014-06-20,  发布年份 2014

【 摘 要 】

Background

Gaucher disease (GD) is a rare recessively inherited disorder caused by deficiency of a lysosomal enzyme, glucocerebrosidase. Accumulation of glucosylceramide or glucosylsphingosine in macrophages leads to increased production of ferritin and chitotriosidase and to decreases in hemoglobin concentration and platelet count, which are used as blood biomarkers. GD is treated by enzyme replacement therapy (ERT) or, sometimes by substrate reduction therapy. However, no physiological model for analysis of biomarkers change during ERT has been proposed. We aimed to develop a pathophysiological model to analyze biomarker’s response to ERT and several covariates impact.

Methods

Changes in blood ferritin, chitotriosidase, hemoglobin and platelets were analyzed in French GD Registry patients receiving imiglucerase/alglucerase as ERT. We used simplified exponential pathophysiological model, with initial concentration, biomarkers amplitude of variation and rate constant of normalization during ERT. Changes in four biomarkers were analyzed separately and then all four together from initiation to discontinuation of ERT, or until the end of follow-up. Several covariates were tested, including age at ERT initiation, splenectomy, sex, genotype (N370S/N370S), and ERT dose.

Results

An exponential model gave a good data fit. The four biomarkers analysis showed that the rate of nomalization was the same for all biomarkers, with a half-life of 0.5 years. Predicted values of biomarkers at ERT’s steady state were 40% and 10% of initial concentrations, for ferritin and chitotriosidase, respectively, and 120% and 200% for hemoglobin and platelets, respectively. We found that 3 covariates had an effect on initial concentration or on amplitude of variation in ferritin, hemoglobin and platelets: women and patients under 15 years of age had lower ferritin and hemoglobin concentrations, and patients under 15 years of age had higher platelet count. Splenectomized patients had higher ferritin concentrations and platelet count and lower amplitude of variation of hemoglobin.

Conclusion

We report the first dynamic model of biomarker changes in GD. It enabled us to estimate that 95% of biomarker response to ERT was achieved in 2 years, but with high inter-patient variability. We also found that with the current treatment, normalization of chitotriosidase and ferritin will occur in about 65% of patients.

【 授权许可】

   
2014 Vigan et al.; licensee BioMed Central Ltd.

【 图 表 】

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