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T. Raskovalova et al.
Introduction
Gaucher disease (GD; OMIM#230800) is a recessively inherited lysosomal sto-rage disorder caused by biallelic mutations in the GBA1 gene that encodes the lysosomal acid β-glucosidase.1 The metabolic defect in GD results in bone marrow and visceral organ infiltration by Gaucher cells (i.e., glucosylceramide-laden macrophages), leading to anemia, thrombocytopenia, hepatosplenomegaly, and skeletal manifestations.2-4 Three main GD types (I, II and III) have been described, on the basis of the clinical fea- tures and age of onset. Type I (i.e., non-neuropathic) GD is predominant (85-94%).5
GD natural course is rather unpredictable, even within subgroups of patients with the same GBA1 mutation.6 Therefore, evaluating the disease severity and prognosis is challenging for clinicians. In this context, a surrogate blood biochemical marker is highly desirable for assessing GD severity and helping decision-making for specific ther- apy initiation or adjustment.7 Several biomarkers have been identified, including chitotriosidase, CCL18, and glu- cosylsphingosine.8-10
Chitotriosidase, the human analogue of the non-verte- brate chitinase, is directly secreted by Gaucher cells and is considered an indicator of the overall Gaucher cell burden.11 In patients with GD, chitotriosidase activity is about 1,000-fold higher than the normal values, and its level correlates with liver and spleen volume, hemoglobin concentration, platelet count, and some bone manifesta- tions.12,13 Plasma chitotriosidase activity decreases dramat- ically after initiation of enzyme replacement therapy (ERT) and rises again when the treatment is stopped.14 However, plasma chitotriosidase activity has major limita- tions for monitoring GD activity. Indeed, measuring plas- ma chitotriosidase activity is technically complex and not standardized across laboratories.15 Moreover, 6% of the general population is homozygous for a chitotriosidase variant harboring a 24-base pair duplication in the CHIT1 gene and is deficient in chitotriosidase activity.16 In addi- tion, 35% of the general population is heterozygous for this chitotriosidase variant, and displays about half of the activity observed in people with wild-type CHIT1. Finally, other CHIT1 gene polymorphisms have been reported that slightly impair the enzyme activity.11
CC chemokine ligand 18 (CCL18), originally named pulmonary and activation-regulated chemokine (PARC), is also directly secreted by Gaucher cells and is considered an indicator of the overall Gaucher cell burden.8 Plasma CCL18 concentration in GD patient is 10- to 50-fold high- er than in healthy subjects.8 CCL18 concentration corre- lates with the liver and spleen volume, platelet count, his- tory of osteonecrosis, and number of anatomical sites of osteonecrosis.12,17 Importantly, the CCL18 concentration is not subject to genetic variation and can be measured in all patients, including those with deficient chitotriosidase activity.8
Hitherto, both chitotriosidase activity and CCL18 con- centration are used for monitoring GD activity and assessing response to treatment, based on the findings from single-center studies of relatively limited sample size. The lack of large scale, multicenter, head-to-head comparison studies have hindered full validation of these biomarkers and formulation of context of use in the clini- cal practice. We hypothesized that evidence on the com- parative accuracy of these two biomarkers could be
strengthened by the secondary analysis of individual par- ticipant data (IPD) from primary studies on patients with GD. Therefore, our primary objective was to compare the accuracy of CCL18 concentration and chitotriosidase activity for assessing hematological and visceral parame- ters of type I GD severity. The secondary objective was to compare the accuracy of these two biomarkers for dis- criminating type I GD patients with symptomatic bone events.
Methods
This systematic review with IPD meta-analysis was performed according to current guidelines18,19 and complied with the Preferred Reporting Items for Systematic review and Meta- Analysis (PRISMA)-IPD statement.20 The rationale and methods were pre-specified and reported in a protocol21 registered at PROS- PERO (CRD42015027243). This meta-analysis was carried out on data from primary studies for which ethical approval had been obtained by the investigators. The Comité de Protection des Personnes Sud Est 6, Clermont-Ferrand, France (IRB 00008526) reviewed the protocol and considered that it did not qualify for biomedical research requiring patient informed consent, provided that no supplementary data would be collected from the partici- pants enrolled in primary studies.21
Eligibility criteria
Eligible studies included cross-sectional and cohort studies that measured both chitotriosidase activity and CCL18 concentration at baseline and/or at follow-up in consecutive patients with type I GD (Online Supplementary Materials and Methods). Studies with fewer than 10 participants were excluded from this systematic review.
Information sources
Studies were identified by searching Medline, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from January 1995 to June 2017. Our electronic search was supplemen- ted by scanning the reference lists of the retrieved articles and by contacting research groups.
Search strategy
The search concepts included chitotriosidase activity, CCL18, biological markers, ERT, and GD (Online Supplementary Appendices S1-3). No restriction of document type and language was applied, and no methodology filter was used.
Study selection
Two review authors (TR and JL) assessed potentially relevant full-text articles against pre-specified eligibility criteria.
Data collection
Information on primary studies were collected using a standar- dized data extraction form. Where possible, IPD were extracted from published articles. Otherwise, the corresponding authors or principal investigators were invited to collaborate in this system- atic review project by supplying de-identified IPD.21 The requested IPD included baseline characteristics and pre-specified outcomes.21 Organ volumes were expressed as multiples of normal (MN) adjusted for body weight.
Outcomes
The primary outcome was a composite of hemoglobin concen- tration <11 g/dL (<10 g/dL for patients aged 12-59 months of age),
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