Osteonecrosis in Gaucher Disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center
- Yale University, United States
- Guilan University of Medical Sciences, Islamic Republic of Iran
- University of Toronto, Canada
- University of Massachusetts Dartmouth, United States
- Sanofi, United States
Abstract
Background: A salutary effect of treatments for Gaucher disease (GD) has been reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT), and it is not known whether it is related to individual treatments, GBA genotypes, phenotypes, biomarkers of residual disease activity or anti-drug antibodies.
Objective: Prompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center.
Methods: Longitudinal follow-ups of 155 GD patients between 2001 and 2021, were analyzed for episodes of AVN on therapy, type of therapy, GBA1 genotype, spleen status, biomarkers, and other disease indicators. We applied mixed-effects logistic model to delineate the independent correlates of AVN while receiving treatment.
Results: The patients received cumulative 1382 years of treatment. There were 16 episodes of AVN in 14 patients, with two episodes, each occurring in two patients. Heteroallelic p.Asn409Ser GD1 patients were 10 times (95% CI,1.5 - 67.2) more likely than p.Asn409Ser homozygous patients to develop osteonecrosis during treatment. History of AVN prior to treatment initiation was associated with 4.8-fold increased risk of AVN on treatment (95% CI, 1.5-15.2). The risk of AVN among patients receiving velaglucerase ERT was 4.68 times higher compared to patients receiving imiglucerase ERT (95% CI,1.67-13). No patient receiving eliglustat SRT suffered AVN. There was a significant correlation between GlcSph levels and AVN. Together, these biomarkers reliably predicted risk of AVN during therapy (ROC AUC 0.894, p<0.001).
Conclusions: There is a low, but significant risk of AVN in GD in the era of ERT/SRT. We found increased risk of AVN was related to GBA genotype, history of AVN prior to treatment initiation, residual serum GlcSph level, and the type of ERT. No patient receiving SRT developed AVN. These findings exemplify a new approach to biomarker applications in a rare inborn error of metabolism to evaluate clinical outcomes in comprehensively followed patients and will aid identification of GD patients at higher risk of AVN who will benefit from closer monitoring and treatment optimization.
Funding: LSD Training Fellowship from Sanofi to MB.
Data availability
This observational study is approved by Yale University IRB and each patient provided informed consent. The patients have not provided consent to sharing their data with other investigators. Interested academic, non-commercial researchers can contact the Senior Corresponding author, Dr Pramod Mistry at Pramod.mistry@yale.edu to discuss the request to access original data. They do not need to apply or submit a project proposal. All statistical analyses were performed with SPSS version 28 (SPSS Inc., Chicago, IL, USA). MedCalc version 20.026 was used for ROC curve analysis and graphs were plotted by GraphPad Prism version 9.3.1.We do not have consent to share individual patient data. Even de-identified data risks identification through age and GBA genotype information, thus violating HIPPA patient confidentiality. Upon request to the Senior Corresponding author, the PI, we will share processed version of datasets.
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Author details
Funding
Sanofi Genzyme (LSD Training Fellowship from Sanofi to MB)
- Mohsen Basiri
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: All participants were enrolled in our observational studies approved by Yale's IRB. Patients also were provided with verbal explanations and their data were collected after signing consent forms.HIC#0209021074HIC#1005006783
Copyright
© 2023, Basiri et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Osteonecrosis in Gaucher Disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center
eLife 12:e87537.
https://doi.org/10.7554/eLife.87537
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