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

Abstract

BackgroundGaucher 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.MethodsChanges 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.ResultsAn 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.ConclusionWe 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.

Evaluation of disease burden and response to treatment in adults with type 1 gaucher disease using a validated disease severity scoring system (DS3)

“…The observed serial changes in DS3 scores and transitions in GD1 health states (mild, moderate, marked) further demonstrate not only the short-term and longer-term effectiveness of ERT for reversing and controlling common GD1 manifestations but also reveal some of its limitations. In that significant improvement in DS3 scores is largely confined to the first 5 years from inception of treatment followed by a 5-20 year plateau, our findings mirror earlier reports that are more narrowly concentrated than the composite DS3 score on hematological and visceral responses or on changes in surrogate biomarkers such as serum ferritin and chitotriosidase [ 34 – 37 ]. However, the DS3 methodology may be insufficiently sensitive to reflect changes in manifestations that respond relatively slowly to ERT such as bone mineral density [ 38 ].…”

Effect of velaglucerase alfa enzyme replacement therapy on red blood cell properties in Gaucher disease

“…As expected, the response to ERT decreased the sizes of the spleen and the liver and increased Hb and Hematocrit (Hct) values as well as platelet counts. 5 GD ERT patients also exhibited lower chitotriosidase activity and CC chemokine ligand 18 (CCL18) levels as compared with GD UT patients. Surprisingly, ERT neither reduced the RBC adhesiveness to laminin nor the expression of Lu/BCAM (see Table 1).…”

“…We analyzed the relationship between hospital teaching status and clinical outcomes among adult patients with a primary discharge diagnosis of AML using the National Inpatient Sample (NIS) from 2008 to 2013. The NIS is part of the Healthcare Cost and Utilization Project (HCUP) that is sponsored by the Agency for Healthcare Research and Quality 5. Each year of the NIS includes over seven million inpatient stays from U.S. hospitals and represents more than 95% of the U.S. On unadjusted analyses, patients at non-teaching hospitals were older (mean age 67.1 years vs. 58.1 years, P < .0001) and had a higher Charlson comorbidity index (CCI) (mean 3.05 vs. 2.78, P < .0001).…”

The prognostic value of the serum ferritin in a southern Brazilian cohort of patients with Gaucher disease

“…The first study to report hyperferritinemia over the course of GD was published by Morgan et al (1983) , and since then these findings have been replicated in different cohorts worldwide ( Poll et al , 2002 ; Grosbois et al , 2009 ; Saadi et al , 2010 ; Stein et al , 2010 ; Stirnemann et al , 2010 ; Stirnemann et al , 2011 ; Mekinian et al , 2012 ). The reduction in SF exhibited by patients with GD undergoing ERT could be indicative of a positive clinical outcome ( Stirnemann et al , 2010 ; Vigan et al , 2014 ), although no studies to date have identified a clear association between SF levels and GD severity. In Brazilian patients, these findings have yet to be replicated.…”