In Gaucher disease (GD), biallelic mutations in GBA1 result in defective lysosomal glucocerebrosidase and the cellular accumulation of glucosylceramide (GlcCer) and its downstream metabolite, glucosylsphingosine (GlcSph) (Mistry et al., 2015; van Dussen et al., 2014). These lipids accumulate classically in tissue macrophages and trigger a cascade of myeloid cell activation and chronic metabolic inflammation (Orvisky et al., 2002; Rigante et al., 2017; Nair et al., 2015; Nair et al., 2016).

Classical disease manifestations of GD include hepatosplenomegaly, cytopenia, and complex skeletal disease involving marrow infiltration, bone pain, osteopenia, fragility fractures, and recurrent avascular osteonecrosis (AVN) (Hughes et al., 2019; Grabowski et al., 2019; Yeh et al., 2009). In the neuronopathic forms of the disease (GD type 2 and type 3), there is additionally childhood onset of neurodegeneration, spinal deformity, pectus carinatum, and pulmonary involvement. Remarkably, severely disabling skeletal manifestations, would a priori, will be expected to be associated with commensurate severe involvement of other disease compartment, but no such relationship can be discerned (Khan et al., 2012). In a large study from the International Gaucher Registry (ICGG, ClinicalTrials.gov: NCT00358943), occurrence of AVN did not correlate with severity of hepatosplenomegaly, genotype, thrombocytopenia, or extent of elevation of the disease biomarker, chitotriosidase. Only low hemoglobin and previous splenectomy were correlated with risk of AVN (Khan et al., 2012). Therefore, clinicians and patients must remain vigilant of risk of AVN whether or not receiving treatment. Fortunately, there has been a reduction in the incidence of AVN since enzyme replacement therapy (ERT) with macrophage mannose receptor (MMR)-targeted imiglucerase became the standard of care in 1990s (Mistry et al., 2009b). The incidence of osteonecrosis in untreated GD patients was reported to be 22.8 per 1000 person years (95% CI, 20.2–25.7) of follow-up. In small single center studies, AVN was reported in as many as half of GD patients (Desnick et al., 1981; Deegan et al., 2011). The introduction of ERT in the 1990s led to reduction in the incidence of AVN to 13.8 per 1000 years of follow-up. Studies have also shown striking reduction in reports of bone pain and bone crisis in the era of therapeutics (van Dussen et al., 2014; Mistry et al., 2017). Since 2010, two other MMR-targeted ERTs have become available: velaglucerase and taliglucerase (Cox, 2013; Zimran et al., 2013; Gonzalez et al., 2013). Specific impact of newer ERTs on risk of AVN is not known. A recent introduction to first-line therapies for GD1 includes substrate reduction therapy (SRT), using eliglustat, a potent inhibitor of GlcCer synthase. In the extensive clinical trial program spanning more than 10 years, only few episodes of AVN were reported (Cox et al., 2023). In the placebo-controlled ENGAGE trial, there was only one case of AVN, which occurred in a patient receiving placebo (Mistry et al., 2021).

Despite the success of ERT in reducing the risk of AVN, there are occasional reports of AVN occurring in patients receiving ERT (Goker-Alpan, 2011; Potnis et al., 2019; de Fost et al., 2008). Therefore, it becomes important to understand whether there are identifiable risk factors for AVN, despite receiving GD-specific therapy. Knowledge of such factors will guide physicians in more comprehensive monitoring of patients beyond hematological and visceral disease as well as potentially advance understanding of underlying mechanisms. Prompted by AVN occurring in two pediatric patients despite ERT, we conducted an analysis of longitudinally followed patients at our tertiary national referral center to identify risk factors for AVN among patients receiving GD-specific therapy. We found patients with compound heterozygous p.Asn409Ser/other genotype, compared to p.Asn409Ser homozygous genotype, were at higher risk of AVN. Other risk factors included history of prior AVN before treatment initiation, type of ERT, and serum level of GlcSph, a validated biomarker of GD. GlcSph is downstream metabolite produced by deacylation of GlcCer via acid ceramidase. GlcSph is a relevant biomarker to study inflammatory manifestations of GD including AVN, as it is known to trigger immune activation and osteoblast dysfunction (Nair et al., 2015; Dekker et al., 2011; Murugesan et al., 2016; Saville et al., 2020).

AVN is one of the most devastating and life-altering manifestations of GD that results in chronic disability and need for orthopedic surgeries (Marcucci et al., 2014). The underlying mechanism(s) of osteonecrosis in GD is not understood. Several mechanisms have been proposed, including disruption of microcirculation by lipid-laden Gaucher macrophages, abnormal red cell morphology leading to ischemia, and osteocyte death (Mikosch and Hughes, 2010). Bone marrow cells in GD exhibit abnormal secretome and osteoblast dysfunction in GD has been linked with accumulating bioactive Gaucher lipid, GlcSph (Mistry et al., 2010; Campeau et al., 2009). There is also evidence of aberrant osteoclast-osteoblast coupling via reduced sphingosine-1-phosphate in GD (Ryu et al., 2006; Ishii et al., 2009). Another emerging player in bone cellular pathology of GD is the damage-associated molecular patterns released by necrotic osteocytes via macrophage-inducible C-type lectin (Mincle), which is known to induce osteoclastogenesis and bone loss (Andreev et al., 2020). In patients with osteonecrosis, Mincle was highly expressed at skeletal sites of osteocyte death and correlated with strong osteoclastic activity (Andreev et al., 2020). GlcCer is a ligand for Mincle, which underscores the complex bone marrow-bone microenvironment in GD and need for optimal therapeutic targeting to prevent disabling AVN.

While AVN occurred frequently in GD in the pre-ERT era (Mistry et al., 2017), introduction of ERT since 1991 has reduced its incidence (Mistry et al., 2009b; Mistry et al., 2009a). However, there are occasional reports of AVN among GD patients receiving ERT (Goker-Alpan, 2011; Potnis et al., 2019; de Fost et al., 2008). Therefore, despite multiplicity of proposed mechanisms underlying AVN in GD, the final pathway likely involves the pathogenic lipids, metabolic inflammation, and lipid-laden Gaucher macrophages. These aberrant pathways are expected to be ameliorated by ERTs and eliglustat SRT but their tissue distribution may have a differential effect (Mistry et al., 2021; Weinreb et al., 2021), for example small molecule SRT vs recombinant MMR-targeted recombinant ERT.

Our study is the first to critically examine outcomes with respect to types (imiglucerase and velaglucerase) and mode of therapy (eliglustat SRT). In experience garnered over 20 years at a single tertiary referral center involving 1382 cumulative years of GD-specific treatments, we found no episode of AVN among eliglustat SRT-treated patients but there were several episodes among patients receiving imiglucerase and velaglucerase ERT. Unexpectedly, we found compared to imiglucerase ERT, patients receiving velaglucerase ERT had 4.7 odds ratio of AVN (95% CI, 1.67–13.07, p=0.003). The basis for this apparent differential effectiveness to prevent AVN is not known. It should be kept in mind that imiglucerase and velaglucerase are not bioidentical. They differ in glycan residues and have minor amino acid changes. Gene expression analysis in mice infused with these enzymes result in different transcriptional profiles (Dasgupta et al., 2013). Moreover, velaglucerase have greater number of mannose residues compared to imiglucerase (Tekoah, 2013). Theoretically, greater clearance by the liver and spleen via mannose receptors in macrophages of these organs could result in less delivery to the bone marrow. Additionally, imiglucerase have been shown to reverse osteoblast defect in cell cultures even though osteoblasts do not exhibit mannose receptors (Panicker et al., 2018). Our findings underscore the need for investigation of this topic in registry setting such as the Gaucher Outcomes Survey (GOS) that monitor long-term outcomes of velaglucerase ERT (ClinicalTrials.gov: NCT03291223). A phase 4 study on bone outcomes was recently completed, and its results will be relevant (ClinicalTrials.gov: NCT02574286) although the primary end-point for the trial appears to be bone density only. During our study, we did not have any episodes of AVN among patients treated with eliglustat SRT. This is in keeping with strikingly low episodes of AVN in extensive clinical trials (Cox et al., 2023). In the ENGAGE placebo-controlled trial, only one episode of AVN occurred in patient on placebo (Mistry et al., 2021; Cox et al., 2023).

Our results advance optimal management of patients with GD based on their biomarker profile. We found that other significant predictors of AVN while receiving treatment included patients with history of AVN prior to initiation of therapy, p.Ser409Asp/other GBA genotype and serum GlcSph level. We did not find any association of splenectomy with occurrence of AVN while on treatment. Some studies have suggested association of AVN with splenectomy (Mistry et al., 2009b) but studies in longitudinally followed patients in UK showed AVN occurrence frequently preceded splenectomy suggesting that both AVN and need for splenectomy in pre-ERT era were indicators of severe disease (Deegan et al., 2011).

In our cohort, GBA genotype had a significant effect on the risk for developing osteonecrosis during treatment. Patients who were heteroallelic for p.Asp409Ser were 10 times more likely than p.Asp409Ser homozygous patients to develop osteonecrosis during treatment. In contrast, p.Asp409Ser/p.Asp409Ser appears to be protective against developing osteonecrosis, underscored by the fact that 51% of our cohort were homozygous for p.Asp409Ser mutation, among whom only one patient developed AVN during treatment. Another significant risk factor for developing AVN on treatment was previous history of AVN prior to treatment initiation.

The biomarkers of GD, chitotriosidase and GlcSph, are reduced by ERT and eliglustat SRT (Murugesan et al., 2016). Of the therapies we examined, we found eliglustat to be most effective in reducing serum GlcSph compared to ERTs (imiglucerase>velaglucerase). We did not find any association of residual chitotriosidase and AVN. This is in keeping with other reports (Khan et al., 2012). In our study we found residual serum GlcSph to be significantly associated with risk of AVN. Residual GlcSph level refers to serum concentration measured in sample taken at close proximity to the onset of AVN (but not levels prior to initiation of treatment). For the first time, our data demonstrate the significance of residual biomarker level which should aid patient stratification for risk of AVN among patients receiving treatment. We used a dual cut-off strategy for serum level of GlcSph to stratify patients for the risk of AVN while receiving treatment in GD patients. There were no episodes of AVN when GlcSph level was less than 21.7 ng/ml with a sensitivity of 100% (95% CI, 79.4–100%) and specificity 24.6%. In contrast, GlcSph level of 77.64 ng/ml has sensitivity of 81.2% (95% CI, 54.4–96%) and specificity of 82.8% (95% CI, 80.7–84.8%) for association with AVN in GD patients receiving treatment. Therefore, our findings permit AVN risk stratification based on GlcSph levels into three groups (Table 4): patients with low risk: GlcSph<21.7 ng/ml, patients with intermediate risk: 21.8 ng/ml<GlcSph<77.64 ng/ml, and patients at high risk: GlcSph>77.64 ng/ml.

These findings suggest that it is prudent to aim to achieve GlcSph levels <21.8 ng/ml as a therapeutic goal, that is, <21.8-fold above normal. In practice, the significance of considering these GlcSph levels is greatly enhanced by considering its context of use regarding other risk factors. For example, as shown in Figure 2B, in patients with at least one of delineated risk factors in our study that is compound heterozygosity for p.Asn409Ser, history of AVN prior to treatment or velaglucerase ERT, sensitivity for GlcSph level at 77.64 ng/ml increases to 87.5% (Figure 2B). In patients who harbor at least two of these risk factors, GlcSph level of 77.14 ng/ml has sensitivity of 92.9% and specificity of 78.8% to rule in the probability of AVN on ERT (Figure 2C). In patients with all three risk factors, GlcSph level of 71.8 ng/ml is 100% sensitive to support the probability of AVN with specificity of 82.4% (Figure 2D).

Our findings are not an indication to change ERTs, as we recognize many patients are benefiting from both imiglucerase and velaglucerase. However, our experience suggests that it is unwise for empirical changes in types of ERTs by third parties (Barranger et al., 2014). Rather, our findings help to elevate optimal management of GD from prevalent practice of monitoring blood counts with or without biomarkers and occasional imaging to a higher level of risk stratification to identify high-risk patients who would benefit from closer monitoring and treatment optimization. Our study is not without limitations. First, it is a single center study, however, the uniform protocol for comprehensive evaluation and long-term follow-up of individual patients are significant strengths. Second, our center is a tertiary referral center, and a referral bias could have enriched patients with AVN, however, this potential bias would apply across our entire patient population. It will be important to examine the GOS which captures data on outcomes of velaglucerase ERT. Hitherto, reports from GOS have iteratively reported only hematological and visceral outcomes, frequently conflating outcomes from multiple ERTs under a generic term ERT (Hughes et al., 2022). It behooves on the investigators to build incremental evidence of efficacy, instead of iterative reports of end-points used in primary trials. It should be noted that in 2014, a study was initiated to assess bone outcomes on velaglucerase ERT (ClinicalTrials.gov: Identifier: NCT02574286), however, there are no reports to date from this study and end-points do not include reduction of AVN incidence.

In conclusion, our study demonstrates residual risk of AVN on GD patients receiving therapy. Independent risk factors for AVN while patients were receiving therapy were pAsp409Ser/other GBA mutation, pre-ERT history of AVN, serum GlcSph level, and velaglucerase ERT. Our results will aid optimal monitoring of GD patients, help enrich clinical trials of rare heterogeneous GD, and stimulate comparative effectiveness analysis in the era of multiple therapies.

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

1. Mohsen Basiri

   Department of Internal Medicine, Yale University, New Haven, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9592-4059

2. Mohammad E Ghaffari

   Department of ENT, Head and Neck Surgery, Guilan University of Medical Sciences, Rasht, Islamic Republic of Iran

   Contribution

   Conceptualization, Formal analysis, Validation, Visualization, Methodology, Writing - original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Jiapeng Ruan

   Department of Internal Medicine, Yale University, New Haven, United States

   Contribution

   Resources, Data curation, Methodology, Writing - original draft, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

4. Vagishwari Murugesan

   Department of Rheumatology, University of Toronto, Toronto, Canada

   Contribution

   Data curation, Validation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

5. Nathaniel Kleytman

   Department of Internal Medicine, Yale University, New Haven, United States

   Contribution

   Data curation, Methodology, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

6. Glenn Belinsky

   Department of Internal Medicine, Yale University, New Haven, United States

   Contribution

   Data curation, Validation, Methodology, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

7. Amir Akhavan

   Department of Computer and Information Science, University of Massachusetts Dartmouth, Dartmout, United States

   Contribution

   Conceptualization, Formal analysis, Validation, Visualization, Methodology, Writing - original draft, Writing – review and editing

   Competing interests

   No competing interests declared

8. Andrew Lischuk

   Department of Radiology and Biomedical Imaging, Yale University, New Haven, United States

   Contribution

   Resources, Data curation, Validation, Visualization, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

9. Lilu Guo

   Translational Sciences, Sanofi, Framingham, United States

   Contribution

   Resources, Methodology, Writing – review and editing

   Competing interests

   is an employee of Sanofi and may hold stocks

10. Katherine Klinger

    Translational Sciences, Sanofi, Framingham, United States

    Contribution

    Resources, Methodology, Writing – review and editing

    Competing interests

    is an employee of Sanofi and may hold stocks

11. Pramod K Mistry

    Department of Internal Medicine, Yale University, New Haven, United States

    Contribution

    Conceptualization, Resources, Data curation, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing – review and editing

    For correspondence

    pramod.mistry@yale.edu

    Competing interests

    Reviewing editor, eLife

    "This ORCID iD identifies the author of this article:" 0000-0003-3447-6421

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