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T. Raskovalova et al.
GD severity. Additionally, chitotriosidase activity has limited incremental value in improving CCL18 concentra- tion accuracy, as reflected by the unchanged AUC-ROC curve estimate.
Our meta-analysis demonstrates that chitotriosidase activity and CCL18 concentration relate to visceral and hematological parameters that can be easily monitored in the routine practice. Hence, additional studies are needed to further investigate the usefulness of these two biomar-kers. In the current practice, they are used to monitor an early response to treatment although their value for initiating specific treatment or adjusting treatment dosage remains questioned. Only prospective patient management studies or randomized controlled trials can establish the effective- ness of biomarker-guided therapy. The lack of robust data and measurement heterogeneity may also explain why some of the GD severity scores do not include biomarkers.58 Lastly, the relationships between GD biomarkers and patient-centered outcomes, including quality of life, fatigue, chronic pain, and restriction of daily activities should be evaluated.55,59
This meta-analysis analyzed IPD from nine primary stud- ies that were completed since 2004, summarizing the most recent available evidence on the accuracy of chitotriosidase activity and CCL18 concentration in assessing type 1 GD severity. All studies included in this meta-analysis evaluated both biomarkers in the same patients, providing uncon- founded comparative accuracy estimates.60 Moreover, our findings have strong generali-zability because we combined primary studies that enrolled various populations of patients worldwide.60
However, our meta-analysis also has a few caveats that must be considered. First, the finding interpretation is inevitably limited by the unavailability of IPD from the other 14 potentially eligible primary studies. Second, there was substantial between-study heterogeneity in chitotriosi- dase activity and, to a lesser extent, in CCL18 concentra- tion. The lack of assay standardization may have con- tributed to this heterogeneity, although chitotriosidase activity and CCL18 concentration were measured at a sin- gle central core laboratory in five clinical trials. Therefore, we used mixed-effect regressions to account for this hete- rogeneity and performed sensitivity and subgroup analyses that supported the robustness of the summary estimates.
In conclusion, CCL18 concentration is as accurate as chi- totriosidase activity in assessing hematological and visceral parameters of GD activity and can be measured in patients
who are homozygous for null chitotriosidase variants. However, the observed between-study heterogeneity and the limitations of this meta-analysis should encourage the international community to i) implement a strategy of homogenization and standardization of dosage techniques, more than 15 years after their implementation in clinical practice and ii) set up a prospective large-scale study to eval- uate GD biomarkers, including glucosyl-sphingosine. This latter biomarker seems interesting from a pathophysiologi- cal perspective, but its superiority over chitotriosidase activ- ity and CCL18 concentration remains to be documented.
Disclosures
PD received speaker and board membership fees from Takeda and consulting fees from Sanofi Corporation; PM received research grant, lecture fee honoraria, and travel support from Sanofi- Genzyme; AZ received consulting fees from Shire and Prevail Therapeutics, honoraria from Shire Corporation and Pfizer, he is an employee at the Gaucher Clinic, Shaare Zedek Medical Center, Israel, which received research grants from Shire Corporation, Centogene and Pfizer, and support from Shire Corporation, Pfizer and Sanofi-Genzyme for participation in their respective registries (GOS, TALIAS and ICGG). MGB received speaker fees and unrestricted research grants from Sanofi- Genzyme and Shire Corporation. The other authors have no con- flict of interest relevant to this study.
Contributions
TR contributed to the study design, data acquisition, interpreta- tion of the results, and manuscript preparation; PD, EP, PM, RY, AZ, JB, CB contributed to data acquisition and manuscript prepa- ration; BP and JL contributed to the study design, data acquisition, data management, statistical analysis, interpretation of the results, and manuscript preparation; MB provided project leadership, con- tributed to the interpretation of the results, and manuscript prepa- ration. All authors approved the final version of the manuscript.
Acknowledgments
The authors are indebted to the investigators of all primary studies for their contributions that allowed carrying out this secondary analysis. They are also grateful to Zoya Panahloo, Farid Merazi, Hak-Myung Lee, Bjorn Mellgard, Michael Craig, and Hartmann Wellhoefer from Shire, Lexington, MA, for sharing individual participant data from clinical trials and facilitating the pooled analysis. Statistical analysis was per- formed within the framework of the Grenoble Alpes Data Institute (ANR-15-IDEX-02).
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