A retrospective and prospective observational study of MRI changes in bone in patients with type 1 Gaucher disease treated with velaglucerase alfa: the EIROS study.

A retrospective and prospective observational study of MRI changes in bone in patients with type 1 Gaucher disease treated with velaglucerase alfa: the EIROS study. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A retrospective and prospective observational study of MRI changes in bone in patients with type 1 Gaucher disease treated with velaglucerase alfa: the EIROS study. Monia Bengherbia, Marc Berger, Benedicte Hivert, Florian Rigaudier, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3694934/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Gaucher disease type 1 (GD1) is a rare autosomal recessive disorder characterized by hepatosplenomegaly, thrombocytopenia, and disabling bone manifestations that require regular MRI monitoring to assess disease progression and treatment responses. Velaglucerase alfa therapy results in long-term improvements in hematologic and visceral manifestations, but more real-world data on its impact on bone manifestations are needed. The EIROS study aimed to address this knowledge gap by using MRI data collected in daily practice in France to assess the impact of velaglucerase alfa on GD1 bone disease. Methods Patients with GD1 and bone MRI data from around the time of velaglucerase alfa initiation were eligible for inclusion. All MRIs collected retrospectively from treatment initiation and prospectively to the end of follow-up (12 months) were analyzed centrally by a blinded expert radiologist to evaluate bone infiltration using the Bone Marrow Burden (BMB) score and a qualitative method (scored for the spine and femur: stable, improved or worsened). Abdominal MRIs were also centrally analyzed to assess hepatosplenomegaly. Reports from bone MRIs, X-rays, and abdominal ultrasounds made by local radiologists were also collected. Clinical (acute and chronic bone pain) and biological parameters were analyzed from medical records. Results MRI data were available for 20 patients from 9 hospital centers: 6 treatment-naive patients and 14 patients who switched to velaglucerase alfa from another GD treatment. Readable MRIs for BMB scoring were only available for 7 patients for the spine and 1 patient for the femur. Qualitative assessments, performed for 18 patients, revealed stability in spine and femur infiltration in 100.0% and 84.6% of treatment-switched patients (n = 13), respectively, and improvements in 80.0% and 60.0% of treatment-naive patients, respectively; no worsening of bone infiltration was observed. Liver, spleen and hematologic parameters improved in treatment-naive patients and remained stable in treatment-switched patients. Conclusions This study provided real-world evidence suggesting the long-term effectiveness of velaglucerase alfa treatment in GD1, including bone manifestations. The data indicate that if MRI assessment by a radiologist with experience of GD bone manifestations is not possible, a simplified qualitative assessment provides sufficient evidence in clinical practice for monitoring bone disease progression and treatment response. Gaucher disease lysosomal storage disorder bone marrow infiltration hepatosplenomegaly thrombocytopenia real-world data enzyme replacement therapy velaglucerase alfa magnetic resonance imaging. Figures Figure 1 Figure 2 Figure 3 Introduction Gaucher disease (GD) is a rare, autosomal recessive, metabolic disorder caused by pathological variants in the GBA1 gene leading to deficiency in the activity of the lysosomal enzyme glucocerebrosidase. The disease is characterized by the progressive accumulation of glucosylceramide and glucosylsphingosine in the lysosomes of macrophages (named Gaucher cells)—particularly in the liver, spleen, and bone marrow—resulting in multisystemic disease and heterogenous clinical manifestations. Three main clinical forms of GD have been described [ 1 ]. GD Type 1 (GD1) is characterized by hepatosplenomegaly, thrombocytopenia, and bone involvement with the severity and age of onset of disease ranging from severe during childhood to patients who remain asymptomatic throughout life. Type 2 is an acute neuronopathic disease with hepatosplenomegaly and very early onset with death during in infancy. Type 3 is a chronic neuronopathic form associated with onset in childhood or adolescence, and systemic symptoms similar to those observed in GD1 [ 1 ]. The estimated prevalence of GD has been reported to range from 1 to 2 per 100 000 in the general population, but is much higher (118 in 100 000) in the Ashkenazi Jewish population [ 2 ]. GD1 is the most common form, accounting for around 94% of GD cases in Western countries [ 2 ]. As a chronic illness, GD1 can lead to significant morbidity and can have a major impact on patient quality of life. In particular, the highly prevalent bone manifestations in GD1—which include bone marrow infiltration, Erlenmeyer flask-shaped deformation, bone infarcts, avascular osteonecrosis, osteopenia, osteoporosis, osteolytic lesions, fractures, secondary osteoarthritis, and osteosyntheses—are the main cause of pain and disability [ 3 , 4 ]. There are currently two therapeutic strategies for the treatment of GD: enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). ERT is widely used as the first-line treatment and two intravenously administered ERTs have received marketing authorization in the EU, imiglucerase (Cerezyme®) [ 5 ] and velaglucerase alfa (VPRIV®) [ 6 ]. Both substances have been shown to be safe and effective, leading to improvements in the hematologic and visceral manifestations of GD [ 7 – 12 ]. Although ERT cannot reverse pre-existing permanent bone damage, long-term ERT is associated with a reduction in bone crises and bone pain, and improvements in bone mineral density and bone marrow burden (BMB) scores [ 9 , 12 – 18 ]. Various recommendations for the overall management of patients with GD being treated with ERT have been published based on evaluations by international and national working groups [ 19 – 25 ], but there has been little consensus when it comes to defining treatment algorithms and monitoring protocols. However, management protocols have been proposed by national healthcare providers, and clear short-term and long-term treatment goals have been defined [ 26 – 28 ]. In addition, analyses of data collected by national [ 29 – 31 ] and international registries [ 4 , 32 ] have provided valuable insights into disease outcomes and improved understanding of the natural history of GD. Despite these advances, the impact of ERT on the bone pathophysiology associated with GD remains poorly understood, prompting the publication of detailed expert recommendations for the monitoring of bone alterations with the aim of improving the management and follow-up of bone disease [ 3 , 33 ]. These practical recommendations highlighted the complexity of bone involvement in GD and the need for radiologists experienced in GD to be included in the multidisciplinary management team. The key recommendations for evaluating bone involvement included the use of MRI as the gold standard for assessing bone marrow infiltration in the lumbar spine and lower extremities, with semiquantitative analyses using either the Düsseldorf Gaucher or bone marrow burden (BMB) scores for clinical studies involving adults, and for monitoring avascular osteonecrosis and bone infarcts. X-rays were recommended for identifying specific lesions, cortical thinning, lytic lesions, fractures, osteosyntheses, and osteoarthritis. Standardized regular dual-energy x-ray absorptiometry (DXA) assessments of bone mineral density were recommended to evaluate osteopenia and osteoporosis [ 3 ]. In France, patients with GD are managed according to a National Protocol for Diagnosis and Care (PNDS [ 28 ]) by a network of specialized referral centers for lysosomal diseases and data are collected in a national GD registry [ 29 , 30 ], all of which is facilitated by a multidisciplinary committee for the evaluation and treatment of GD (Comité d’Évaluation du Traitement de la maladie de Gaucher; CETG) [ 34 ]. The PNDS contains guidelines for the monitoring of bone involvement and refers to detailed procedures developed for radiologists carrying out abdominal and bone MRIs in patients with GD [ 35 ]. This current real-world observational study (EIROS) was carried out in response to the ongoing evaluation by the French national health authority ( Haute Autorité de Santé; HAS) to gain a better understanding of the evolution and outcomes of bone disease in patients with GD1 being treated with velaglucerase alfa. Thus, the main objective of this study was to evaluate the progression of bone disease in these patients using MRI data obtained by individual radiologists in real-world practice. Given the complexity of bone imaging in patients with GD and the high level of expertise required to interpret the data, the MRIs were transferred to a specialized center and a standardized evaluation and analysis by an expert radiologist was conducted for the purpose of the study. Other objectives included the evaluation of changes in other key disease characteristics including organomegaly, clinical manifestations (acute and chronic bone pain), and biological parameters. Methods Study design and patients This observational study of patients with GD1 treated with velaglucerase alfa was conducted using data collected retrospectively and prospectively in everyday clinical practice. The study was conducted between March 2017 and August 2019. French hospital centers involved in the management of more than one patient with GD1 being treated with velaglucerase alfa were invited to participate in the study. Participating centers were asked to provide data collected from patient medical records for all patients with a confirmed diagnosis of GD1, who were being treated with velaglucerase alfa, and who had available digital MRI data from an examination conducted within the 5 years preceding velaglucerase alfa initiation, or within the 3 months following treatment initiation. The MRIs could have been conducted in either a private or hospital radiology center. Prior to starting velaglucerase alfa treatment, patients could either be treatment naive or have been treated previously with any other GD treatment. Patients participating in an ongoing blinded clinical trial were excluded. All patients, or their parents or legal representative, provided written informed consent before being included in the study. Data collection All data analyzed in this study were collected from patient medical records on routine imaging, clinical examinations and biological analyses that were part of the standard medical care and systematic follow up of patients with GD1 by the physicians responsible for their management. A summary of the study design and data collected is shown in Fig. 1 . For the retrospective analysis, data were analyzed for each patient from the date of the MRI closest to the initiation of velaglucerase alfa (reference MRI) to the date of inclusion in the study. The reference MRI was defined as the MRI conducted within the 5 years preceding velaglucerase alfa initiation, or within the 3 months following treatment initiation. In the prospective analysis, data were analyzed from all visits from inclusion until the date of last MRI before the end of the study follow-up period (12 months after inclusion). Analysis of imaging data All available digital MRI data (bone MRIs and abdominal MRIs) were collected, anonymized, transferred to a central imaging lab (Clario, formerly known as Bioclinica), and then analyzed by a single radiologist with experience in GD. This central radiologist was blinded to all clinical and demographic data but had access to data from all available MRI visits and sequences, in chronological order of acquisition. The bone MRIs were used to determine BMB scores (as described previously [ 36 ]). For the abdominal MRIs, liver and spleen volumes were semi-automatically measured by trained and experienced MRI technicians (Clario), based on axial T1-weighted and T2-weighted sequences respectively, or on the most suitable available MRI sequence if these were missing or of poor quality. Boundaries of both organs were carefully reviewed on each MRI slice, when visible, and the corresponding volumes were automatically derived in mm 3 based on image resolution, and then expressed as multiples of normal (MN) based on 25 mL/kg of body weight for the liver and 2 mL/kg of body weight for the spleen, as described previously [ 27 ]. Reports of imaging investigations (abdominal MRI for monitoring of hepatosplenomegaly and standard X-rays or MRI for bone lesions) written by local radiologists at each visit were collected from medical records. Analysis of demographic, clinical, and biological data Data concerning patient demographics and disease and treatment history were collected at inclusion. Data were also collected on the dose, frequency, and duration of velaglucerase alfa treatment, the use of concomitant treatments, and the occurrence of any adverse events during the study period. The time between visits was also recorded for each variable. Both retrospective and prospective clinical and biological data were analyzed from patient medical records of examinations and analyses performed within three months of each MRI and at velaglucerase alfa initiation (Fig. 1 ). The clinical data included body mass index (BMI), and the occurrence of acute and chronic bone pain, and clinical assessments of hepatomegaly and splenomegaly. For the biological analyses, all available data were collected and data concerning hemoglobin concentrations, platelet counts and chitotriosidase activity were analyzed relative to published reference standards. For hemoglobin, normal levels were defined as ≥ 12.0 g/dL for men and ≥ 11.0 g/dL for women and children (≤ 12 years of age) [ 32 ]. Thrombocytopenia was classified as normal or mild (not clinically significant) for platelet counts > 120.0 ×10 9 /L; as moderate for counts < 120.0 ×10 9 /L to ≥ 60 ×10 9 /L, and as severe for counts < 60 ×10 9 /L [ 32 ]. The upper limit for chitotriosidase activity, an established marker for GD [ 37 ], was compared to the median levels reported in individuals without GD (median [range]: 20 [4‒76] nmol/mL/h) [ 38 ]. Study endpoints The primary endpoint was the change in BMB score between the reference MRI and the last follow-up MRI determined by the centralized analysis. The secondary endpoints included the change between the reference visit and the last follow-up examination for the following variables: the presence of bone infiltration according to imaging reports written by local radiologists; the occurrence of hepatosplenomegaly and of acute and chronic bone pain according to clinical records; spleen and liver volumes determined by centralized analysis of abdominal MRIs; and biological parameters according to medical records. Bone lesions, bone pain, treatment duration, changes in liver and spleen volumes and biological parameters, as well as the slope of these changes, were also assessed according to treatment history (i.e., in treatment naive patients compared to those switching to velaglucerase alfa from another GD treatment). Statistical methods Descriptive data were described as means (± standard deviation) for quantitative variables and as numbers and percentages (n %) for qualitative variables. After analysis of the distribution of all variables, changes in BMB scores and in MRI liver and spleen volumes between MRIs were analyzed using the Wilcoxon rank test. Between-visit changes in clinical characteristics and MRI bone characteristics were analyzed using the McNemar chi-square test. For biological analyses, between-visit changes and differences in values between treatment-naive and treatment-switched patients were analyzed using the t test or the Wilcoxon rank test. Missing data were treated as such, and no imputation of missing values was performed. Only variables for which data were available for more than 25% of the patients were included in the analysis. P values < 0.05 were considered significant. All statistical analyses were carried out using SAS® software (version 9.4). Post-hoc analysis A post-hoc analysis was performed by the central radiologist to qualitatively assess the change in bone infiltration from the first to last available MRIs. Changes were rated as stable, improved, or worsened and were scored for the spine and femur separately. The presence of emerging new spine and femur events was also documented. The changes were analyzed for the whole population and according to treatment history (treatment naive patients versus treatment-switched patients), time between the first and last MRI, and duration of treatment (velaglucerase alfa alone and velaglucerase alfa plus any prior treatment). Differences in the proportion of treatment-naive patients and treatment-switched patients with improved, stable or worsened characteristics were analyzed using the Fisher test, all other post-hoc analyses were analyzed using descriptive statistics. Results Study population A total of 20 patients (17 adults and 3 children) managed at nine hospital centers were included in the study between March 01, 2017, and December 27, 2018. The first retrospective MRI took place on March 17, 2006, and the last prospective follow-up visit took place on August 16, 2019. One patient was excluded from the MRI analyses due to technical problems with the storage and transfer of the MRI data (Fig. 2 ). Demographic and clinical characteristics The demographic, bone imaging, and clinical characteristics of the patients are shown in Table 1 . The mean age of the adult patients at inclusion was 52 ± 12 years (range 28–75 years) and the ages of the three children at inclusion were 8, 10 and 15 years. Three patients had undergone splenectomy before the start of the study. Biological data are also listed in Table 1 . Table 1 Demographic, clinical and MRI characteristics of the patients. Patient demographics and disease history at inclusion N (%) or Mean ± SD (min–max) Age (years) 46.0 ± 18.7 (8.0–75.0) Gender (M/F) 11 (55) / 9 (45) Age of diagnosis of Gaucher disease (years) 22.3 ± 15.3 (1.0–52.0) Family history of Gaucher disease (Y/N) 7 (35.0)/13 (65.0) Splenectomy 3 (15)/ 17 (85) Treatment patterns N = 20 Time between diagnosis and velaglucerase alfa initiation (years) 16.6 ± 14.6 (0.0–59.0) Use of treatment for Gaucher disease prior to velaglucerase alfa (Y/N) 14 (70) / 6 (30) Duration of use of prior treatment for Gaucher disease (years) 11.3 ± 5.5 (1.2–19.3) Treatment before switching to velaglucerase alfa N = 14 Imiglucerase 13 Miglustat 1 Clinical characteristics at velaglucerase alfa initiation N = 20 BMI (kg/m²), n = 14 20.7 ± 4.1 (14.2–27.1) Chronic pain in bone (Y/N) 6 (37.5) / 10 (62.5) Acute bone pain (Y/N) 2 (15.4) / 11 (84.6) Clinical signs of hepatomegaly (Y/N) 3 (50.0) / 3 (50.0) Clinical signs of splenomegaly (Y/N) 5 (62.5) / 3 (37.5) Biological analyses at velaglucerase alfa initiation N = 20 Hemoglobin concentration (g/dL), n = 16 13.3 ± 2.5 (7.9–17.1) Platelets (×10 9 /L), n = 16 133.6 ± 91.9 (26.0–356.0) Ferritin (µg/L), n = 10 480.2 ± 579.4 (77.0–1894.0) Chitotriosidase activity (nmol/mL/h), n = 10 8663.3 ± 14370 (968.0–48750.0) Monoclonal gammopathy (Y/N) 2 (11.8) /15 (88.2) Disease imaging characteristics at the time of the reference MRI a N = 19 a Presence of bone lesions (Y/N) b 17 (89.5) / 2 (10.5) Hepatomegaly (Y/N) 7 (70) / 3 (30) Estimated liver volume (mL), n = 7 1691.2 ± 809.2 Estimated liver volume, multiples of normal c 1.3 ± 3.8 (0.7–3.0) Splenomegaly (Y/N) 10 (83.3) / 2 (16.7) Estimated spleen volume (mL), n = 7 843.0 ± 1206.3 Estimated spleen volume, multiples of normal c 9.9 ± 53.1 (1.2–38.7) a The reference MRI was defined as the MRI conducted within the 5 years preceding velaglucerase alfa initiation, or within the 3 months following treatment initiation. b Bone lesions included Erlenmeyer flask-shaped deformation, bone infiltration, cortical thinning, lytic lesions, avascular osteonecrosis (defined as an infarct located in epiphysis) and bone infarct (defined as an infarct located in long bone: metaphysis or diaphysis, or flat bone), vertebral collapse, fracture, secondary osteoarthritis, and osteosynthesis. C For multiples of normal, the normal liver volume was 25 mL/kg of body weight, and the normal spleen volume was 2 mL/kg of body weight. Abbreviations : BMI, body mass index; F, female; M, male; min–max: minimum and maximum values; n, number of patients with available data; SD, standard deviation. Treatment patterns and exposure The mean duration of velaglucerase alfa treatment, from initiation to the last study follow-up visit, was 5.2 ± 2.6 years (n = 19). Six of the patients included in the study (3 children and 3 adults) were naive to GD treatment before velaglucerase alfa initiation. The mean time between GD1 diagnosis and treatment initiation for these patients was 2.6 ± 4.3 years and the mean duration of treatment with velaglucerase alfa was 2.6 ± 1.4 years. Among the 14 patients who switched to velaglucerase alfa, 93% switched from another ERT (imiglucerase) and one patient switched from an SRT (miglustat). The mean time between GD1 diagnosis and initiation of treatment with any type of GD therapy for these patients was 9.9 ± 10.9 years and the mean duration of velaglucerase alfa treatment was 6.4 ± 2.1 years. The mean dose of velaglucerase alfa administered during the study was 56.8 ± 12.7 U/kg (n = 19). Analysis of dose frequency showed that most patients (n = 14) received the treatment fortnightly (every 14 or 15 days), as recommended [ 6 ]; whereas the remaining patients received treatment every 17 days (n = 1), every 21 days (n = 3) or monthly (n = 1). Minor modifications to the dose and/or frequency of velaglucerase alfa administration were made for nine patients. One patient temporarily stopped treatment with velaglucerase alfa (for 112 days), and then later switched to an oral treatment (eliglustat). The total duration of velaglucerase alfa treatment in this patient was 6.3 years. No adverse events were reported during the study period. Overall, 13 patients (65%) were prescribed a concomitant treatment during the study period, including analgesics (6/20), vitamin D supplements (6/20) and treatment for osteoporosis (3/20). Evolution of bone marrow burden scores according to the centralized analysis A total of 71 digital MRI records (58 collected retrospectively and 13 collected prospectively), with an average of around 4 MRIs per patient (range: 2–7), were available for centralized analysis. However, the number of optimal or interpretable MRIs for assessment of the BMB score was limited (Fig. 2 ). Seven of the MRIs (five collected retrospectively and two collected prospectively) were excluded from the BMB analysis because they were from examinations conducted on children, for whom calculation of the BMB score has previously been found to be unreliable [ 3 ]. Out of the remaining 64 MRIs analyzed, 23 (35.9%) were deemed uninterpretable for evaluation of the BMB spine score and 55 (85.9%) were deemed uninterpretable for evaluation of the femur BMB score. The most common causes for the insufficient quality of the MRIs were the use of incorrect scanning parameters (acquisition of T1- and T2-weighted sequences with fat suppression preventing proper comparison of MRI signal intensity with that of subcutaneous fat (femur) and non-diseased intervertebral discs (spine), as originally required for BMB scoring) and/or incomplete imaging of the required anatomical region (particularly the absence or incomplete imaging of the distal femur). In total, only seven patients had interpretable data for BMB spine scoring from both the reference MRI (mean score: 3.6 ± 2.1) and a follow-up MRI (mean score: 2.9 ± 1.1). The average time between the reference MRI visit and last MRI visit for calculation of the BMB score was 4.3 years ± 2.9 years. No significant change in the mean BMB spine score was observed between these reference and last MRIs (Δ -0.7 ± 1.5; P = 0.25). Only one patient had interpretable data for BMB femur scoring from both the reference MRI and a follow-up visit. As a result, no calculation could be performed for the change in femur BMB score or total BMB score for the whole population. As an alternative, a post-hoc qualitative assessment of the change in bone infiltration in the spine and femur from the first to last MRI data was performed by the central radiologist. Post-hoc qualitative analysis of the evolution of bone infiltration in the spine and femur Overall, 18 patients (5 treatment-naive patients and 13 treatment-switched patients) had interpretable MRIs for the post-hoc qualitative evaluation of the change in spine or femur infiltration (Fig. 2 ). Improvements in spine and femur infiltration were observed for 22.2% (n = 4/18) and 27.8% (n = 5/18) of patients, respectively, and stability was observed for 77.8% (n = 14/18) and 72.2% (n = 13/18) of patients, respectively. None of the patients had worsening spine or femur infiltration between the first and last MRIs (Fig. 3 ). Significant differences in the proportion of patients who had improved or stable spine and femur infiltration between the first and last MRIs were observed for treatment-naive patients compared to treatment-switched patients ( P < 0.001 for the spine and P < 0.05 for the femur). The proportion of patients with an improvement in infiltration was highest among treatment-naive patients: improvements in spine infiltration were observed for 80.0%, (n = 4/5) of these patients and improvements in femur infiltration were observed for 60.0% (n = 3/5). In contrast, spine infiltration remained stable for all patients (n = 13) who had switched to velaglucerase alfa from another GD treatment. An improvement in femur infiltration was observed for two of the treatment-switched patients (15.4%), with femur characteristics in the 11 remaining patients (84.6%) remaining stable between MRIs (Fig. 3 ; P values for between-group differences in the proportion of patients in each class < 0.05). The change in spine and femur infiltration also varied depending on the duration of velaglucerase alfa treatment and of velaglucerase alfa and any prior treatments (Table 2 ). The mean duration of treatment was shorter for patients who had an improvement in spine infiltration (3.5 ± 0.3 years both for velaglucerase alfa alone and for velaglucerase alfa and prior treatment) than for patients with stable spine infiltration (6.0 ± 2.5 years for velaglucerase alfa alone and 17.0 ± 7.2 years for velaglucerase alfa and prior treatment). The same trend was observed for the change in femur characteristics: mean treatment duration for patients with an improvement in femur characteristics was 4.7 ± 1.7 for velaglucerase alfa alone and 10.1 ± 9.2 for velaglucerase alfa and prior treatment, compared to 5.7 ± 2.6 for velaglucerase alfa alone and 15.5 ± 8.2 for velaglucerase alfa and prior treatment for patients with stable femur characteristics (Table 2 ). Table 2 Change in spine and femur infiltration between the first and last available MRIs according to the time between MRIs, duration of velaglucerase alfa treatment, and the duration of all treatments for Gaucher disease (velaglucerase alfa and any prior treatment). N = 19 a Time (years ± SD) Spine infiltration Improved n = 4 Stable n = 14 Worsened n = 0 Time between first and last MRI 3.7 ± 0.7 5.2 ± 3.0 0 Treatment duration: Velaglucerase alfa alone 3.5 ± 0.3 6.0 ± 2.5 0 Velaglucerase alfa plus prior GD treatment 3.5 ± 0.3 17.0 ± 7.2 0 Femur infiltration Improved n = 5 Stable n = 13 Worsened n = 0 Time between first and last MRI 6.3 ± 3.7 4.5 ± 2.6 0 Treatment duration: Velaglucerase alfa alone 4.7 ± 1.7 5.7 ± 2.6 0 Velaglucerase alfa plus prior GD treatment 10.1 ± 9.2 15.5 ± 8.2 0 a MRI data were uninterpretable for one patient Abbreviations: GD, Gaucher disease; SD, standard deviation Review of bone imaging data and clinical bone manifestations according to medical records Collection of bone imaging reports written by local radiologists indicated that 17 of the 19 patients had bone lesions assessed by standard X-Rays and MRI at the reference visit and at the last visit (Table 3 ). One new case of bone infiltration (in a treatment-naive patient) was reported by local radiologists at the last visit compared to the reference visit. This new case of bone infiltration occurred in the patient for whom the data were deemed uninterpretable for the post-hoc centralized analysis. One case of bone infiltration present at the reference MRI was reported as absent at the last MRI. However, bone infiltration in this patient (a treatment-naive patient aged 15 years) was noted as present at the last visit by the central radiologist. Other bone lesions deemed unlikely to be related to GD were reported in 12 patients (63%), with the most common lesions including vertebral hemangiomas and degenerative disc disease (each present in two patients; 10.5% of the study population). Table 3 Review of bone imaging and clinical characteristics from local imaging and clinical records between the reference visit and the last available follow-up visit Bone imaging characteristics a , N = 19 Reference visit d n (%) Last available visit n (%) P value f change reference to last Change reference to last (n ↑↓) g Treatment-naive patients (N = 6) Treatment-switched patients (N = 14) Presence of bone lesions b (Y/N) 17 (89.5) / 2 (10.5) 17 (89.5) / 2 (10.5) N/A ↔ ↔ Bone infiltration (Y/N) 11 (57.9) / 8 (42.1) 11 (57.9) / 8 (42.1) 1.0 ↑1 h ↓1 ↔ Clinical bone characteristics c , N = 20 Reference visit e n (%) Last available visit n (%) P value d change reference–last Treatment-naive patients (N = 6) Treatment-switched patients (N = 14) Chronic bone pain (Y/N), n = 16 8 (50) / 8 (50) 6 (37.5) / 10 (62.5) 0.5 ↑1 ↓1 ↑2 ↓4 Acute bone pain (Y/N), n-14 2 (14.3) / 12 (85.7) 0 (0) / 14 (100) N/A ↑0 ↓1 ↑0 ↓1 a Average time between the reference visit and last visit for bone imaging: 6.6 years ± 3.4 years. b Bone lesions included Erlenmeyer flask-shaped deformation, bone infiltration, cortical thinning, lytic lesions, avascular osteonecrosis (defined as an infarct located in epiphysis) and bone infarct (defined as an infarct located in long bone: metaphysis or diaphysis, or flat bone), vertebral collapse, fracture, secondary osteoarthritis, and osteosynthesis. c Average time between the reference clinical examination and last clinical examination: 6.7 years ± 3.4 for chronic bone pain and 5.9 years ± 3.2 for acute bone pain. d For imaging analyses, the reference visit was either the reference MRI (conducted within 5 years before or 3 months after velaglucerase alfa initiation) or other bone imaging modality conducted within 3 months of the reference MRI. e For the clinical analyses, the reference visit was the clinical examination performed within 3 months of the reference MRI. f P values were calculated using the McNemar chi-square test. g ↑ number of patients with a change from the reported absence of this lesion at the reference visit to the reported presence of this lesion at the last visit. ↓ number of patients with a change from the reported presence of the lesion at the reference visit to the reported absence of this lesion at the last visit. ↔ no change for all patients. h For the patient in which bone infiltration was reported to be absent at the first MRI but present at the last MRI by local radiologists, the MRIs were deemed uninterpretable by the central radiologist. Abbreviations : N, number of patients in whole population; n, number of patients with data available for both visits; N/A; P value not available. In the clinical examinations, no statistically significant changes in the overall number of patients with acute or chronic bone pain were reported (Table 3 ). No new occurrences of acute bone pain were reported during the study and neither of the two patients with mild (n = 1) or moderate (n = 1) acute bone pain at the reference visit reported having acute bone pain at the last visit. Data on the change in severity of chronic bone pain were available for six patients, all of whom had mild or moderate pain at the reference visit. Four of these patients had no chronic bone pain at the last visit, and the mild (n = 1) and moderate (n = 1) pain in the remaining patients remained stable. Evolution of liver and spleen parameters The number of patients in the whole population with hepatosplenomegaly, evaluated by MRI and/or by clinical examination, did not change significantly over the course of the study (Table 4 ). Table 4 Change in liver and spleen parameters over the course of the study Hepatosplenomegaly a,b c Reference visit n (%) Last visit n (%) Change between reference and last visit n (% total Y/N) e P value f Hepatomegaly on clinical examination (Y/N), n = 12 4 (33.3) / 8 (66.7) 3 (25.0) / 9 (75.0) ↑ 1 (33.3) ↓ 2 (22.2) 0.2 Hepatomegaly by MRI (Y/N), n = 7 4 (57.1) / 3 (42.9) 3 (42.9) / 4 (57.1) ↑ 0 (0) ↓ 1 () 0.3 Splenomegaly on clinical examination (Y/N), n = 11 6 (54.5) / 5 (45.5) 1 (9.1) / 10 (90.9) ↑ 1 (100.0) ↓ 6 (60.0) 0.5 Splenomegaly by MRI (Y/N), n = 9 7 (77.8) / 2 (22.2) 5 (55.6) / 4 (44.4) ↑ 0 (0.0) / ↓ 2 (50.0) 0.2 Estimated liver volume, centralized analysis d First MRI Mean ± SD Last MRI Mean ± SD Change first and last MRI Mean ± SD P value g Whole population, n = 12 mL 1617.8 ± 644.8 1523.4 ± 376.2 -94.4 ± 440.6 0.5 MN 1.09 ± 0.63 0.93 ± 0.23 0.17 ± 0.5 Treatment-naive patients, n = 3 mL 2061.1 ± 1166.2 1498.5 ± 395 -562.6 ± 777.0 0.1 MN 1.8 ± 1.1 1.2 ± 0.23 -0.6 ± 0.8 Treatment-switched patients, n = 9 mL 1470.0 ± 365.2 1531.7 ± 394.0 61.7 ± 79.7 MN 0.9 ± 0.2 0.8 ± 0.1 0.1 ± 0.1 Estimated spleen volume, centralized analysis d First MRI Mean ± SD Last MRI Mean ± SD Change first and last MRI Mean ± SD P value g Whole population, n = 10 e mL 776.6 ± 992.7 385.9 ± 199.6 -390.7 ± 863.9 0.001 MN 16.3 ± 19.8 3.9 ± 2.8 -12.4 ± 17.4 Treatment-naive patients, n = 3 mL 1497.7 ± 1764.6 398.1 ± 296.1 -1099.6 ± 1497.4 0.3 MN 16.3 ± 19.8 3.9 ± 2.8 -12.4 ± 17.4 Treatment-switched patients, n = 7 mL 467.5 ± 262.4 380.7 ± 174.5 -86.9 ± 114.6 MN 3.2 ± 1.4 2.6 ± 1.0 -0.7 ± 0.7 a Three patients had undergone splenectomy. b Mean time between the reference clinical examination and the last available clinical examination: 5.8 years ± 3.9 for hepatomegaly and 6.2 ± 3.8 for splenomegaly. c Mean time between the reference MRI and the last available MRI: 5.9 ± 4.2 for hepatomegaly and 6.6 ± 4.1 for splenomegaly. d Mean time between the first available MRI and the last available MRI for volume estimates: 5.6 years ± 2.9 for liver measurements and 5.6 years ± 3.1 for spleen measurements. e ↑ change from the reported absence of this manifestation at the reference visit to the reported presence of this manifestation at the last visit. ↓ change from the reported presence of this manifestation at the reference visit to the reported absence of this manifestation at the last visit. f P values calculated using the McNemar chi-square test. g P values calculated using the Wilcoxon rank test. Abbreviations : MN, multiples of normal (25 mL/kg of body weight for the liver 2 mL/kg of body weight for the spleen); n, number of patients with data available for both visits; SD, standard deviation. A total of 38 abdominal MRIs were conducted during the study period and all these MRIs contained interpretable data: 33 (86.8%) and 31 (81.6%) of the MRIs were deemed optimal for liver and spleen volume measurements, whereas 7 (18.4%) and 5 (13.2%) of the MRIs were deemed suboptimal but interpretable, mainly due to motion artifacts or suboptimal anatomical coverage. As abdominal MRIs had only been conducted for a limited number of patients at both a reference visit and follow-up visit (liver: 7 patients; spleen; 6 patients), the centralized analysis of the evolution of spleen and liver volume was evaluated from the first available MRI to the last MRI. The mean time between the first and last visits was 5.6 ± 2.9 years for the liver analysis and 5.6 ± 3.1 years for the spleen analysis (compared to mean times of 5.6 years ± 3.7 for liver analysis and 5.4 years ± 4.0 for spleen analysis between the reference and last MRIs). The mean estimated liver and spleen volumes at the first and last MRIs for the whole population and according to treatment history are shown in Table 4 . The mean liver volume in patients who had switched from a prior treatment (n = 9) was 0.9 ± 0.2 MN at the reference MRI and remained stable at the last MRI (mean: 0.8 ± 0.1 MN; Δ + 61.7 ± 79.7 mL). Similarly, spleen volumes remained largely stable in the treatment-switched patients: 3.2 ± 1.4 MN at the reference MRI and 2.6 ± 1.0 MN at the last visit (Δ -86.9 ± 114.6 mL). In the treatment-naive patients (n = 3), liver volumes were on average 1.8 ± 1.1 MN at the reference MRI, but decreased by -562.6 ± 777.0 mL to 1.2 ± 0.23 MN at the last visit. Spleen volumes in these patients were considerably above normal at the reference MRI (mean: 16.3 ± 19.8 MN) but decreased by the last MRI (Δ -1099.6 ± 1497.4 mL) to 3.9 ± 2.8 MN. Evolution of biological parameters The mean changes in hemoglobin and concentrations, and in platelet counts and chitotriosidase activity for the whole population between the first and last analyses are shown in Table 5 . Table 5 Change in biological parameters over the course of the study Parameter (N = 20) Reference analysis Mean ± SD Last analysis Mean ± SD Change between reference and last Mean ± SD Slope units/year P value (Δ Ref to Last) c Hemoglobin concentration (g/dL) a All patients, n = 19 13.2 ± 2.2 13.8 ± 1.6 0.6 ± 1.5 0.3 ± 0.9 0.08 Treatment-naive patients, n = 6 10.8 ± 1.7 12.8 ± 1.0 2.0 ± 1.3 1.1 ± 1.3 -- Treatment-switched patients, n = 13 14.3 ± 1.3 14.3 ± 1.6 0 ± 1.2 -0.1 ± 0.4 P value (naive–non-naive patients at each analysis) b < 0.0001 0.05 0.005 0.007 -- Platelet counts (×10 9 /L) a All patients, n = 18 139.1 ± 76.5 185.2 ± 77.6 46.1 ± 42.7 14.1 ± 25.3 0.0003 Treatment-naive patients, n = 6 123.8 ± 119.3 215.7 ± 126.8 91.8 ± 28.2 40.6 ± 26.1 -- Treatment-switched patients, n = 12 146.8 ± 48.8 169.9 ± 35.2 23.2 ± 27.3 0.76 ± 10.2 P value (naive–treatment switched patients) b 0.6 0.3 0.0001 0.0002 -- Chitotriosidase activity (nmol/mL/h) a All patients, n = 13 9084.0 ± 16039.5 2442.9 ± 5031.8 -6641.1 ± 16831.2 -2.3 ± 16.6 0.02 Treatment-naive patients, n = 4 25688.3 ± 22224.4 6284.5 ± 8408.2 -19403.8 ± 28604.8 -2397.5 ± 11939.5 -- Treatment-switched patients, n = 9 1704.3 ± 1248.7 735.6 ± 898.9 -968.8 ± 677.4 -160.5 ± 138.7 P value (naive–treatment-switched patients) b 0.007 0.14 0.19 0.19 -- a Mean time between the reference biological analysis and the last available biological analysis: 6.6 ± 3.6 for measurement of hemoglobin, 6.1 ± 3.4 years for platelet counts, 5.9 ± 3.4 for chitotriosidase activity. b P values for the difference between values obtained for treatment-naive and treatment-switched patients at each analysis and for the slope were obtained using the t test for hemoglobin concentration and platelet counts, and the Wilcoxon rank test for chitotriosidase activity. c P values for the difference in values at the reference and last analysis obtained using the t test for hemoglobin concentration and platelet counts and the Wilcoxon rank test for chitotriosidase activity. Abbreviations : n, number of patients with data available for both visits; Ref, reference analysis; SD, standard deviation. The hemoglobin concentration in patients that had switched from a prior treatment was in the normal range (≥ 11.0–12.0 g/dL depending on age and gender) for all patients at the reference analysis, and remained stable with no significant change being observed between analyses (mean: 14.3 g/dL at both visits; slope: − 0.1 g/dL/year; Table 5 ). In contrast, the mean hemoglobin concentration in treatment-naive patients was slightly below normal at the reference visit (mean: 10.8 g/dL), but increased to within the normal range for all patients at the last visit (mean: 12.8 g/dL; slope: 11 g/L per year; Table 5 ). Among the treatment-switched patients (n = 12), platelet counts at the reference analysis were within the normal/mild range (≥ 120 ×10 9 /L) for eight patients but moderate thrombocytopenia (platelet counts ≤ 120 ×10 9 /L but ≥ 60 ×10 9 /L) was present in four patients. Platelet counts increased or remained stable at the last analysis for all the patients who switched treatments (mean: 169.9 ± 35.2 ×10 9 /L; Δ: + 23.2 ± 27.3 ×10 9 /L), although the moderate thrombocytopenia persisted in one patient. For treatment-naive patients (n = 6), platelet counts at the reference analysis were in the normal/mild range for two patients, whereas the remaining four patients had either moderate (n = 2) or severe (n = 2; platelet counts ≤ 60 ×10 9 /L) thrombocytopenia. Platelet counts had increased (Δ: + 40.6 ± 26.1) for all the treatment-naive patients at the last analysis, with all patients having platelet counts within the normal range (mean count: 215.7 ± 126.8 ×10 9 /L). As expected, the mean levels of chitotriosidase activity reported in the study population were much higher than those reported in individuals without GD in all analyses, but did decrease over the course of the study. Chitotriosidase activity levels decreased in both patient groups, with, as expected, a greater decrease among the treatment-naive patients (Δ -19403.8 nmol/mL; slope: -2397.5 nmol/mL/h per year) than among the treatment-switched patients (Δ -968.8 nmol/mL; slope: -160.5 nmol/mL/h per year). Discussion This retrospective–prospective study using real-world data to assess the evolution of bone disease in patients with GD1 being treated with velaglucerase alfa provided valuable insights into the impact of the treatment, and into the quality and effectiveness of patient monitoring in clinical practice in France. Despite the publication of a detailed protocol for the monitoring of bone disease in patients with GD, we found that the quality of bone MRI data collected in clinical practice was often insufficient to allow for semiquantitative assessments of treatment responses through calculation of BMB scores. However, the centralized qualitative assessment of real-world MRI data used in this study provided evidence of the positive impact of velaglucerase alfa on bone disease, with improvements in bone infiltration being observed in treatment-naive patients and stabilization of bone infiltration being observed in treatment-switched patients. Furthermore, reductions in acute and chronic bone pain, and improvements or stabilization of hematologic parameters, and visceral manifestations were observed, providing further evidence from clinical practice of the effectiveness of velaglucerase alfa in allowing patients to achieve and maintain the well-established goals for GD treatment. Assessing the extent of bone marrow infiltration in patients with GD is essential for evaluating the extent of bone involvement, monitoring patient responses to ERT, and for guiding therapeutic decision making and optimizing treatment regimens [ 3 , 39 ]. The BMB score, which provides an MRI-based semiquantitative evaluation of bone marrow infiltration based on the distribution of lesions and the change in signal intensity, is one of the most widely used methods in clinical studies [ 3 , 40 ]. This method has the advantage of being more reflective of whole-body bone marrow involvement because it includes assessment of the spine and the femur, and is simpler to use and more widely accessible than Dixon quantitative chemical shift imaging (QCSI) assessments of the bone marrow fat fraction because it uses conventional MRI imaging [ 14 , 17 , 36 , 39 , 41 ]. However, the interobserver agreement of BMB scores has been questioned, even between experienced radiologists [ 42 ]. In addition, BMB scoring has been found to be less reliable for assessing bone infiltration in younger patients with GD, due to potential masking of the true extent of bone infiltration by the higher proportion of red bone marrow normally present in children and young adults [ 3 , 43 , 44 ]. The findings from the current study have highlighted the problems associated with the use of the BMB scoring for monitoring bone involvement in GD in real-world clinical practice. Longitudinal assessments of BMB scores rely on the collection of high-quality sequential MRI data according to a rather strict protocol to ensure consistency between device settings and scanning parameters during follow up. The MRIs used in this study were conducted by local radiologists using a range of MRI machine models from multiple centers and varied scanning parameters, resulting in large technical variations in the quality of the images obtained. Despite the availability of detailed procedures for conducting bone MRIs in patients with GD [ 35 ], the centralized analysis of the MRI data revealed that in many cases these good practice guidelines were not followed, particularly the recommendations to collect image sequences of both the distal and proximal femur and to acquire T1- and T2-weighted sequences without fat-suppressed imaging to allow optimal comparison of the relative changes in signal intensity between healthy and diseased bone areas. These findings indicate that more specialized training needs to be provided to local radiologists on the acquisition and interpretation of data for calculating BMB scores. In countries where resources permit, this may need to be combined with centralized analysis through a national reference platform to limit interobserver variability in BMB scoring, or alternatively, the development of semi-automated techniques could be investigated to improve consistency. As a result of the technical limitations associated with data acquisition, only one of the 17 adult patients included in the current study had interpretable data for femur BMB scoring, and only seven patients had interpretable data for spine BMB scoring. This absence of adequate data for the assessment of total BMB score led us to explore whether a subjective qualitive assessment of the change in bone infiltration (classified as worsened, improved or stabilized) would provide a more feasible method for analyzing the response to velaglucerase alfa treatment in clinical practice. The results of the centralized analysis indicated that this qualitative method could indeed be used to monitor changes in bone infiltration in the spine and femur over time, and to identify statistically significant differences between treatment groups. In addition, qualitative analysis by the centralized radiologist also appeared to provide valuable information about the change in bone infiltration in the three children included in the study cohort. Although the normal developmental changes in red marrow made it more challenging to assess improvements in bone infiltration in these younger patients compared to in the adults with GD, the masking effect of bone marrow maturation was not considered to have prevented the visualization of significant worsening of bone infiltration during qualitative assessment. Thus, although larger validation studies are needed, our findings suggest that the qualitative bone infiltration analysis used in this study could provide an alternative, less stringent, and easier-to-interpret method that could be used by local radiologists to assess bone disease in patients with GD, particularly in countries or regions where medical resources are scarce and access to GD expert radiologists is extremely limited. The results of the qualitative analysis provided valuable real-world insights into the impact of velaglucerase alfa treatment on bone involvement in patients with GD, with treatment-naive patients and those with shorter treatment durations (3.5 years on average) tending to show improvements in femur and spine infiltration, and patients who switched treatments and treatment-naive patients with longer treatment durations (6 years on average) generally having stable bone disease. Importantly, none of the patients showed signs of worsening bone disease during velaglucerase alfa treatment. Our results are therefore consistent with findings of previous clinical studies in which assessment of BMB scores showed that velaglucerase alfa treatment led to a significant reduction in bone infiltration [ 14 ], with largest reductions being observed during the first 5 years of ERT, followed by long-term stabilization after 5 years [ 16 , 17 ]. As pointed out in these studies [ 16 , 17 ], the stabilization of bone infiltration after 5 years of treatment suggests the need to revise current bone MRI monitoring protocols, perhaps increasing the interval between MRI evaluations for bone infiltration in patients who are adherent to treatment and have stable bone disease. Indeed, the current PNDS guidelines recommend bone MRI at treatment initiation, after 1 year, and then every 2 years once the disease has stabilized [ 28 ]. Improving adherence to the PNDS guidelines and ensuring that patients are monitored by MRI, particularly when initiating ERT or switching between therapies, is essential to allow for meaningful evaluation of treatment responses and for evidence-based updates of current monitoring recommendations. In addition to improving bone infiltration, reducing bone pain is one of the key therapeutic goals in patients with GD [ 26 , 28 ]. Our analysis of clinical medical records indicated that this goal was met in our cohort: no new cases of acute bone pain were reported during velaglucerase alfa treatment and the resolution of acute bone pain was reported in two patients. Although available data on pain severity were limited, the velaglucerase alfa treatment also seemed to lead to a reduction or stabilization of chronic bone pain. Similar findings have been reported previously in several studies examining the impact of the alternative ERT, imiglucerase, on bone pain in patients with GD [ 9 , 13 , 18 ]. Based on the analysis of bone imaging records written by local radiologists, the large majority of patients in our cohort had existing bone lesions before the initiation of velaglucerase alfa therapy. As noted in previous studies, ERT cannot reverse all of the existing bone manifestations of GD, most notably avascular osteonecrosis and disease-related complications such as secondary osteoarthritis and fracture deformities [ 3 ], and thus the goal of therapy is to prevent bone infiltration and the occurrence of new lesions [ 26 , 28 ]. Velaglucerase alfa treatment appeared to allow all of the patients included in our study to achieve this goal. However, the occurrence of bone lesions in patients receiving ERT has been reported in previous studies [ 45 – 48 ], particularly in patients that initiated ERT more than 2 years after GD diagnosis [ 49 ]. Indeed, in our study the mean time between diagnosis and initiation of any form of GD treatment was 2.6 years in treatment-naive patients and 9.9 years in patients switching treatments. Thus, the early detection of new lesions and surveillance of the severity of existing lesions remains essential for patients receiving ERT, not only for guiding the adjustment and optimization of velaglucerase alfa treatment, but also to allow timely intervention with supportive therapies and interventions such as prosthetic replacement to maintain or improve patient mobility and quality of life. In addition, other bone complications, not specifically related to GD were reported in over 50% of the patients in our study. Clearly, there is a need to ensure that these nonspecific bone lesions are not overlooked during monitoring of the complex bone manifestations of GD and that correct diagnosis and appropriate management are provided. Hepatomegaly and splenomegaly are hallmark manifestations of GD1, present in between 60% and 90% and more than 90% of cases, respectively [ 1 ]. The PNDS recommends regular monitoring of liver and spleen volumes every 6 months during the first year of treatment and then biannually after stabilization of organ volumes, by either abdominal MRI or ultrasound [ 28 ]. Although ultrasound has the advantage of being more accessible and affordable than other imaging modalities, it provides a less comprehensive assessment of organ involvement than MRI [ 44 ]. In contrast, MRI data can be analyzed using semi-automated methods for measuring organ volumes, improving measurement accuracy and reproducibility [ 50 ]. In our study, less than half of the patients had available abdominal MRI data collected around the time of initiation of velaglucerase alfa treatment and only around half of the patients had longitudinal abdominal MRI data. However, contrary to the bone MRIs, all of the abdominal MRIs conducted provided interpretable, although not always optimal, cross-sectional data for the centralized analysis of organ volumes, demonstrating that the semi-automated method used in this study was sufficiently robust to overcome the variations in scanning parameters and sequence types associated with MRI data collected in clinical practice. Thus, while clinical examination and ultrasound maybe sufficient for routine long-term management when MRI facilities are scarce, when MRI is widely available, this technique could be used in clinical practice to monitor visceral disease severity and treatment responses. The treatment goals for the visceral complications in GD1 are to reduce (within the first two years of treatment) and then stabilize organ volumes [ 28 ], ideally to within less than 1.0 to 1.5 MN for the liver and 2 to 8 MN for the spleen [ 26 ]. The centralized analysis of liver and spleen volumes demonstrated that these goals were met in our patient cohort, with treatment-naive patients showing decreases in liver and spleen volumes by the last visit to achieve average volumes of 1.2 MN and 3.9 MN, respectively, and treatment-switched patients showing stabilization of organ volumes (0.8 MN for the liver and 2.6 MN for the spleen at the last visit). These findings are therefore consistent with those of previous studies showing that velaglucerase alfa treatment leads to near-normalization of hepatomegaly and major reductions in splenomegaly within around 4 years of initiating treatment [ 12 , 51 , 52 ]. The same pattern of improvement in treatment-naive patients and stabilization in patients switching to velaglucerase alfa was observed for hemoglobin concentrations and platelet counts during the study. All patients had normalization or stabilization of hemoglobin and platelet counts at the last visit. Such normalization and maintenance of hematologic parameters in the 4 years after initiating treatment has been reported previously in patients receiving velaglucerase alfa [ 12 ], and has often been observed within the first 2 years post treatment initiation [ 51 ]. These findings are consistent with those of previous studies clearly demonstrating the effectiveness of velaglucerase alfa treatment in allowing patients to achieve the therapeutic goals of preventing anemia and reducing bleeding tendency, as well as the complications related to these hematologic manifestations [ 26 , 28 , 52 ]. Finally, monitoring of chitotriosidase activity, a well-established biomarker of GD severity and treatment responses [ 47 , 53 , 54 ], revealed decreases in activity both in the treatment-naive patients and treatment-switched patients. The real-world ambispective design of the current study allowed the long-term impact of velaglucerase alfa treatment in GD1 to be assessed in clinical practice, in a patient population that was homogeneous in terms of the dose and frequency of velaglucerase alfa treatment received, and in both treatment-naive patients and those who had switched treatment. However, this real-world approach led to several study limitations. First, the amount and quality of the MRI data collected in clinical practice were insufficient to allow assessment of the primary study endpoint (i.e., the change in BMB scores). However, this lack of available data led us to explore the potential of an alternative and less stringent qualitative method for assessing bone marrow involvement. Future studies would allow us to further evaluate the suitability of this method for monitoring the bone marrow response to ERT in real-world clinical practice, and to more closely examine the suitability of the method for use in younger patients. Second, the size of study population was small and limited the power of the study to detect statistically significant between-visit differences and between-parameter correlations for some measures, most notably in the occurrence of bone pain. The small size of the study population was associated with several factors. GD is a rare disease with an estimated prevalence of 1 in 140 000 in France [ 29 ]. According to the CETG registry, there were 97 patients with GD living in France who had received at least one dose of velaglucerase alfa at the time of the study. Among the centers managing these patients, only those treating more than one patient were invited to participate and only patients with GD1 and digital records of MRIs conducted within the 5 years preceding velaglucerase alfa initiation, or within the 3 months following treatment initiation, were eligible for study inclusion. Future studies involving larger populations would help to further clarify the extent to which ERT can prevent bone infiltration, and allow more detailed characterization of patients who are at highest risk of bone disease progression despite treatment. Ideally, a more organized, well-funded, international approach is required, perhaps using a purpose-designed platform for data collection. However, to allow pooling of all the collected data it is important that consensus is reached on MRI monitoring protocols and on the terminology used to describe the bone lesions, with the terms osteonecrosis, avascular necrosis, aseptic osteonecrosis and bone infarct often being used interchangeably in the literature, regardless of the anatomical location of the lesion. The size of the population also did not allow for a separate evaluation of disease evolution in patients that had undergone splenectomy, although the impact of this intervention on treatment responses has been reported previously [ 12 ]. Due to the retrospective nature of part of the study, the only GD marker with a sufficient amount of data available for longitudinal analysis was chitotriosidase, as more recently validated markers, such as glucosylsphingosine (lyso-Gb1) [ 55 ], were not commonly used in clinical practice at time when many of the patients included in study initiated velaglucerase alfa treatment. Finally, the duration of the interval between the first and last available measure varied for each variable, reflecting the monitoring regimen of individual patients. Conclusions This study provided useful data indicating the long-term real-word effectiveness of velaglucerase alfa for the treatment of GD1 bone manifestations in treatment-naive and switched patients. Our findings also highlighted the difficulties associated with using BMB scores for monitoring bone treatment responses in routine clinical practice. Specialized training for local radiologists and/or a centralized analysis reference platform may improve bone monitoring. The simplified qualitative bone infiltration analysis method used in the current study indicated that bone infiltration improved in treatment-naive patients and remained stable for treatment-switched patients. In addition, improvements in bone infiltration were observed in patients with shorter treatment durations ( 6 years) bone infiltration remained stable. These results therefore support those of previous studies suggesting that the interval between MRI evaluations can be increased to every 5 years in patients with long-term stabilization of bone infiltration. Although larger validation studies are needed, our findings suggest that when a GD expert radiologist is not available, an easier qualitative analysis method could be a valuable tool for routine bone monitoring in clinical practice. Evaluation of the clinical characteristics of the patients suggested that velaglucerase alfa treatment also appeared to be associated with a reduction in bone pain. Similar patterns of improvement and stabilization were observed in the two groups for the reduction in liver and spleen volumes and hematologic parameters. Declarations Funding source(s): This study was funded by Takeda Pharmaceutical Company Limited, France. Ethics approval and consent to participate This study (trial registration number: NCT03333447) was performed in accordance with Good Clinical Practice guidelines and all patients, or their legally authorized representative, provided signed consent before being enrolled in the study. In accordance with French law, approval for the processing of personal data was obtained from the French data protection agency (Commission Nationale de l'Informatique et des Libertés; CNIL ) and the study methodology was approved by the French advisory committee on information processing in healthcare research ( Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé; CCTIRS ). Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests N. Belmatoug received travel grants and honoraria for consultancy, and as a board participant and speaker from Sanofi and Takeda. Her institution received funds for clinical trials and research grants from Sanofi and Takeda. M. Berger received honoraria for interventions in scientific boards and has received financial support for conference participation from Takeda, Sanofi, Pfizer, and Novartis. M. Bengherbia joined Takeda after study completion, and M Maric, and M. Malcles are employees of Takeda France SAS. None of the authors have stocks or shares in this organization. L. Bracoud and O. Vaeterlein are employees of Clario (formerly Bioclinica). F. Rigaudier is an employee of CEN Biotech. B. Hivert and K. Yousfi have no conflicts of interest to declare. Funding Funding for the study, and for medical writing assistance (supplied by Santé Active Edition - Synergy Pharm), was provided by Takeda France SAS. The sponsor played no role in the design of the study or the collection, analysis or interpretation of the data. Authors' contributions M. Bengherbia and N. Belmatoug were responsible for the design of the study and the acquisition, analysis and interpretation of the data. F. Rigaudier made substantial contributions to the analysis and interpretation of the data, and M. Berger, K. Yousfi and B. Hivert made substantial contributions to data acquisition and analysis. L. Bracoud and O. Vaeterlein were responsible for the analysis and interpretation of the MRI data. N. Belmatoug, and M. Malcles made major contributions to writing the first draft of the paper, and all authors made substantial contributions to revising and reviewing subsequent drafts. All authors approved the final version of the manuscript. Acknowledgments The authors would like to thank Drs Pascal Hutin (hôpital Laënnec–Site de Quimper), Vanessa Leguy-Seguin (CHU Dijon Bourgogne), Yves-Marie Pers (Hôpital Lapeyronie), Clara Mariette (CHU Michallon), Claire Gay (CHU Saint Etienne), and Valerie Li Thiao Te (CHU Amiens) for their participation in the study, together with Cinira Lefèvre (RWE strategy lead) for help reviewing the statistical methodology and analysis. We would also like to thank Drs Emma Pilling and Marielle Romet (Santé Active Edition - Synergy Pharm) for medical writing assistance. References Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, Serratrice J, Brassier A et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci 2017;18. Nalysnyk L, Rotella P, Simeone JC, Hamed A, Weinreb N. Gaucher disease epidemiology and natural history: a comprehensive review of the literature. Hematology. 2017;22:65–73. 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Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials. Am J Hematol. 2015;90:584–91. Zimran A, Elstein D, Gonzalez DE, Lukina EA, Qin Y, Dinh Q, Turkia HB. Treatment-naive Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4 years in phase 3 trials. Blood Cells Mol Dis. 2018;68:153–9. Sims KB, Pastores GM, Weinreb NJ, Barranger J, Rosenbloom BE, Packman S, Kaplan P, Mankin H, Xavier R, Angell J, et al. Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study. Clin Genet. 2008;73:430–40. Elstein D, Haims AH, Zahrieh D, Cohn GM, Zimran A. Impact of velaglucerase alfa on bone marrow burden score in adult patients with type 1 Gaucher disease: 7-year follow-up. Blood Cells Mol Dis. 2014;53:56–60. Elstein D, Foldes AJ, Zahrieh D, Cohn GM, Djordjevic M, Brutaru C, Zimran A. Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, including dose reduction. Blood Cells Mol Dis. 2011;47:56–61. Paskulin LD, Starosta RT, Bertholdo D, Vairo FP, Vedolin L, Schwartz IVD. Bone marrow burden score is not useful as a follow-up parameter in stable patients with type 1 Gaucher disease after 5 years of treatment. Blood Cells Mol Dis. 2021;90:102591. Fedida B, Touraine S, Stirnemann J, Belmatoug N, Laredo JD, Petrover D. Bone marrow involvement in Gaucher disease at MRI: what long-term evolution can we expect under enzyme replacement therapy? Eur Radiol. 2015;25:2969–75. Charrow J, Dulisse B, Grabowski GA, Weinreb NJ. The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease. Clin Genet. 2007;71:205–11. Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E, Fuller M, Revel-Vilk S, Hughes D, Cox T, et al. Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1. Orphanet J Rare Dis. 2022;17:442. Giraldo P, Andrade-Campos M, Morales M, Group S. Recommendations on the follow-up of patients with Gaucher disease in Spain: Results from a Delphi survey. JIMD Rep. 2023;64:90–103. Kaplan P, Baris H, De Meirleir L, Di Rocco M, El-Beshlawy A, Huemer M, Martins AM, Nascu I, Rohrbach M, Steinbach L, et al. Revised recommendations for the management of Gaucher disease in children. Eur J Pediatr. 2013;172:447–58. Martins AM, Valadares ER, Porta G, Coelho J, Semionato Filho J, Pianovski MA, Kerstenetzky MS, Montoril Mde F, Aranda PC, Pires RF, et al. Recommendations on diagnosis, treatment, and monitoring for Gaucher disease. J Pediatr. 2009;155:10–8. Revel-Vilk S, Szer J, Mehta A, Zimran A. How we manage Gaucher Disease in the era of choices. Br J Haematol. 2018;182:467–80. Kishnani PS, Al-Hertani W, Balwani M, Goker-Alpan O, Lau HA, Wasserstein M, Weinreb NJ, Grabowski G. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus. Mol Genet Metab. 2022;135:154–62. Weinreb NJ, Aggio MC, Andersson HC, Andria G, Charrow J, Clarke JT, Erikson A, Giraldo P, Goldblatt J, Hollak C, et al. Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients. Semin Hematol. 2004;41:15–22. Biegstraaten M, Cox TM, Belmatoug N, Berger MG, Collin-Histed T, Vom Dahl S, Di Rocco M, Fraga C, Giona F, Giraldo P, et al. Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease. Blood Cells Mol Dis. 2018;68:203–8. Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M, Grabowski GA, Mistry PK, Tylki-Szymanska A. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004;41:4–14. PNDS: Protocole National de Diagnostic et de Soins (PNDS): Maladie de Gaucher. (2015, last reviewed and updated 2022). https://www.has-sante.fr/upload/docs/application/pdf/2022-05/pnds_maladie_de_gaucher_cetg_avril_2022.pdf . Accessed 01 November 2022. Stirnemann J, Vigan M, Hamroun D, Heraoui D, Rossi-Semerano L, Berger MG, Rose C, Camou F, de Roux-Serratrice C, Grosbois B, et al. The French Gaucher's disease registry: clinical characteristics, complications and treatment of 562 patients. Orphanet J Rare Dis. 2012;7:77. Stirnemann J, Hamroun D, Bengherbia M, Yousfi K, Fantin B, Belmatoug N. Registre français de la maladie de Gaucher – Épidémiologie en 2015. La Revue de Médecine Interne. 2015;36:A31. Giraldo P, Pocovi M, Perez-Calvo J, Rubio-Felix D, Giralt M. Report of the Spanish Gaucher's disease registry: clinical and genetic characteristics. Haematologica. 2000;85:792–9. Zimran A, Belmatoug N, Bembi B, Deegan P, Elstein D, Fernandez-Sasso D, Giraldo P, Goker-Alpan O, Lau H, Lukina E, et al. Demographics and patient characteristics of 1209 patients with Gaucher disease: Descriptive analysis from the Gaucher Outcome Survey (GOS). Am J Hematol. 2018;93:205–12. Vom Dahl S, Poll L, Di Rocco M, Ciana G, Denes C, Mariani G, Maas M. Evidence-based recommendations for monitoring bone disease and the response to enzyme replacement therapy in Gaucher patients. Curr Med Res Opin. 2006;22:1045–64. Stirnemann J, de Villemeur TB, Belmatoug N. [Organization of Gaucher disease management in France]. Rev Med Interne. 2007;28(Suppl 2):198–201. CETG: Procédure pour la réalisation des IRM dans la maladie de Gaucher. (2012). http://cetl.net/maladies-lysosomales/cetg-maladie-de-gaucher/documents-d-aide-a-la-prise-en/documents-d-information-pour-les/article/procedure-pour-la-realisaiton-des . Accessed 01 February 2023. Maas M, van Kuijk C, Stoker J, Hollak CE, Akkerman EM, Aerts JF, den Heeten GJ. Quantification of bone involvement in Gaucher disease: MR imaging bone marrow burden score as an alternative to Dixon quantitative chemical shift MR imaging–initial experience. Radiology. 2003;229:554–61. Aerts JM, Kallemeijn WW, Wegdam W, Joao Ferraz M, van Breemen MJ, Dekker N, Kramer G, Poorthuis BJ, Groener JE, Cox-Brinkman J, et al. Biomarkers in the diagnosis of lysosomal storage disorders: proteins, lipids, and inhibodies. J Inherit Metab Dis. 2011;34:605–19. Gaucher Institute. : Diagnosis of Gaucher disease: Chitotriosidase. Last updated December 2022. https://gaucher-institute.com/differential-diagnosis/diagnosis-of-gaucher-disease/chitotriosidase . Accessed 01 February 2022. Robertson PL, Maas M, Goldblatt J. Semiquantitative assessment of skeletal response to enzyme replacement therapy for Gaucher's disease using the bone marrow burden score. Am J Roentgenol. 2007;188:1521–8. Zimran A, Dinur T, Revel-Vilk S, Akkerman EM, van Dussen L, Hollak CEM, Maayan H, Altarescu G, Chertkoff R, Maas M. Improvement in bone marrow infiltration in patients with type I Gaucher disease treated with taliglucerase alfa. J Inherit Metab Dis. 2018;41:1259–65. de Mello RA, Mello MB, Pessanha LB. Magnetic resonance imaging and BMB score in the evaluation of bone involvement in Gaucher's disease patients. Radiol Bras. 2015;48:216–9. Lai JKC, Robertson PL, Goh C, Szer J. Intraobserver and interobserver variability of the bone marrow burden (BMB) score for the assessment of disease severity in Gaucher disease. Possible impact of reporting experience. Blood Cells Mol Dis. 2018;68:121–5. Laudemann K, Moos L, Mengel KE, Lollert A, Reinke J, Brixius-Huth M, Wagner D, Düber C, Staatz G. Evaluation of Bone Marrow Infiltration in Non-Neuropathic Gaucher Disease Patients with Use of Whole-Body MRI–A Retrospective Data Analysis. Rofo. 2015;187:1093–8. Degnan AJ, Ho-Fung VM, Ahrens-Nicklas RC, Barrera CA, Serai SD, Wang DJ, Ficicioglu C. Imaging of non-neuronopathic Gaucher disease: recent advances in quantitative imaging and comprehensive assessment of disease involvement. Insights Imaging. 2019;10:70. Deegan PB, Pavlova E, Tindall J, Stein PE, Bearcroft P, Mehta A, Hughes D, Wraith JE, Cox TM. Osseous Manifestations of Adult Gaucher Disease in the Era of Enzyme Replacement Therapy. Medicine. 2011;90:52–60. van Dussen L, Biegstraaten M, Dijkgraaf MG, Hollak CE. Modelling Gaucher disease progression: long-term enzyme replacement therapy reduces the incidence of splenectomy and bone complications. Orphanet J Rare Dis. 2014;9:112. Stirnemann J, Belmatoug N, Vincent C, Fain O, Fantin B, Mentré F. Bone events and evolution of biologic markers in Gaucher disease before and during treatment. Arthritis Res Ther. 2010;12:R156. de Fost M, van Noesel CJ, Aerts JM, Maas M, Pöll RG, Hollak CE. Persistent bone disease in adult type 1 Gaucher disease despite increasing doses of enzyme replacement therapy. Haematologica. 2008;93:1119–20. Mistry PK, Deegan P, Vellodi A, Cole JA, Yeh M, Weinreb NJ. Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis. Br J Haematol. 2009;147:561–70. Bracoud L, Ahmad H, Brill-Almon E, Chertkoff R. Improving the accuracy of MRI spleen and liver volume measurements: a phase III Gaucher disease clinical trial setting as a model. Blood Cells Mol Dis. 2011;46:47–52. Zimran A, Wang N, Ogg C, Crombez E, Cohn GM, Elstein D. Seven-year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 G aucher disease. Am J Hematol. 2015;90:577–83. Elstein D, Cohn GM, Wang N, Djordjevic M, Brutaru C, Zimran A. Early achievement and maintenance of the therapeutic goals using velaglucerase alfa in type 1 Gaucher disease. Blood Cells Mol Dis. 2011;46:119–23. Van Dussen L, Hendriks E, Groener J, Boot R, Hollak C, Aerts J. Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy. J Inherit Metab Dis. 2014;37:991–1001. Raskovalova T, Deegan PB, Mistry PK, Pavlova E, Yang R, Zimran A, Berger J, Bourgne C, Pereira B, Labarère J, et al. Accuracy of chitotriosidase activity and CCL18 concentration in assessing type I Gaucher disease severity. A systematic review with meta-analysis of individual participant data. Haematologica. 2021;106:437–45. Revel-Vilk S, Fuller M, Zimran A. Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review. Int J Mol Sci 2020;21. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3694934","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":271584527,"identity":"83c17a38-80d8-4dab-b066-182c83b1ff5a","order_by":0,"name":"Monia Bengherbia","email":"","orcid":"","institution":"Takeda France SAS","correspondingAuthor":false,"prefix":"","firstName":"Monia","middleName":"","lastName":"Bengherbia","suffix":""},{"id":271584528,"identity":"ec0157ce-0fb8-4cc4-ac86-6627d0c9318b","order_by":1,"name":"Marc Berger","email":"","orcid":"","institution":"CHU Clermont-Ferrand: Centre Hospitalier Universitaire de Clermont-Ferrand","correspondingAuthor":false,"prefix":"","firstName":"Marc","middleName":"","lastName":"Berger","suffix":""},{"id":271584529,"identity":"446cec0a-ecc0-499b-952c-b9d409e7115c","order_by":2,"name":"Benedicte Hivert","email":"","orcid":"","institution":"Saint Vincent de Paul Hospital, Lille","correspondingAuthor":false,"prefix":"","firstName":"Benedicte","middleName":"","lastName":"Hivert","suffix":""},{"id":271584530,"identity":"27d54cc7-5a28-41eb-ac7f-4a656753ee9c","order_by":3,"name":"Florian Rigaudier","email":"","orcid":"","institution":"CEN Biotech, Dijon","correspondingAuthor":false,"prefix":"","firstName":"Florian","middleName":"","lastName":"Rigaudier","suffix":""},{"id":271584531,"identity":"40d1e634-70fd-46be-ad09-41dbf25aa3cc","order_by":4,"name":"Luc Bracoud","email":"","orcid":"","institution":"Clario Inc","correspondingAuthor":false,"prefix":"","firstName":"Luc","middleName":"","lastName":"Bracoud","suffix":""},{"id":271584532,"identity":"076787e7-09b2-4e82-a74e-f15b8034f92d","order_by":5,"name":"Ole Vaeterlein","email":"","orcid":"","institution":"Clario Inc, Germany","correspondingAuthor":false,"prefix":"","firstName":"Ole","middleName":"","lastName":"Vaeterlein","suffix":""},{"id":271584533,"identity":"3819a6ae-6c02-43e5-b08f-84f399e16df6","order_by":6,"name":"Karima Yousfi","email":"","orcid":"","institution":"Assistance Publique Hopitaux de Paris: Assistance Publique - Hopitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Karima","middleName":"","lastName":"Yousfi","suffix":""},{"id":271584534,"identity":"19534b3f-a909-4d22-8639-8bbae8db1770","order_by":7,"name":"Michele Maric","email":"","orcid":"","institution":"Takeda france SAS","correspondingAuthor":false,"prefix":"","firstName":"Michele","middleName":"","lastName":"Maric","suffix":""},{"id":271584535,"identity":"0d8a76c0-27a9-42b8-807e-253555c90c8c","order_by":8,"name":"Marie Malcles","email":"","orcid":"","institution":"Takeda France SAS","correspondingAuthor":false,"prefix":"","firstName":"Marie","middleName":"","lastName":"Malcles","suffix":""},{"id":271584536,"identity":"816f21ac-4dea-4503-a48d-88c06cc610cb","order_by":9,"name":"Nadia Belmatoug","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYHACgwMMDAcY+KA8OQYGHiBlQ4QWNgYGxgYgzxiiJQ2/FgZkLYkNhLSYsx/eeOAHwx05NrHDzx98bKtN75/de+wBQ8I9nFose9IKDvYwPDNmk04zbJzZdjx3xp1z6QYMCcV4PJJjcICH4XBim3SCYTNv27Hchhs5ZhKMPxJwazn/xuDgH4bD9W3S6R9BWtLlQVoYEvBouZFjcBhoSwKbdA7IlpoEA8JanhUcljF4ZtgmnVM4c8a5A4Yb75wxN0jAp+V88uaPbyruyPNLp2/48KGsTl7udo/Zgw94tEA1wlmHGRgkgHFESAMyqINoGQWjYBSMglGABAAzj1y4TzUbigAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7917-741X","institution":"Assistance Publique - Hopitaux de Paris","correspondingAuthor":true,"prefix":"","firstName":"Nadia","middleName":"","lastName":"Belmatoug","suffix":""}],"badges":[],"createdAt":"2023-12-02 01:11:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3694934/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3694934/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51009180,"identity":"a1724aa6-864b-43d8-b300-c819beab6768","added_by":"auto","created_at":"2024-02-12 16:10:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":22229,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of the study design. The reference MRI was defined as the MRI conducted in the five years preceding the start of treatment or in the three months following velaglucerase alfa initiation. In France, MRIs are recommended to be performed at treatment initiation, 1 year after initiation and then every 2 years; thus, the last MRI may have been performed in the year before inclusion or during the 12-month follow-up period. Clinical and biological data were collected for examinations performed either three months before or three months after each MRI, and at velaglucerase alfa initiation.\u003c/p\u003e","description":"","filename":"Figure1studydesignVF.png","url":"https://assets-eu.researchsquare.com/files/rs-3694934/v1/c85a88da11a076037156f02a.png"},{"id":51009181,"identity":"9a567d64-17d6-4027-9f82-1c64ad0318f5","added_by":"auto","created_at":"2024-02-12 16:10:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44687,"visible":true,"origin":"","legend":"\u003cp\u003ePatient flow through the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations: \u003c/strong\u003eBMB score, bone marrow burden score. *The main reasons for MRIs being uninterpretable were the use of incorrect scanning parameters (acquisition of T1- and T2-weighted sequences with fat suppression) and/or incomplete imaging of the required anatomical region (particularly the absence or incomplete imaging of the distal femur).\u003c/p\u003e","description":"","filename":"Figure2StudyprofileVF.png","url":"https://assets-eu.researchsquare.com/files/rs-3694934/v1/c9bb387de1a51707ec7150ea.png"},{"id":51009182,"identity":"a6bda868-2249-4bd4-bad1-1703350906db","added_by":"auto","created_at":"2024-02-12 16:10:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":142709,"visible":true,"origin":"","legend":"\u003cp\u003eEvaluation of the qualitative change in spine and femur infiltration between the first and last available MRIs for the whole population (n=18) and according to treatment patterns. MRI data were uninterpretable for one of the treatment-naive patients. Mean times between the first and last MRIs were 4.9 years ± 2.6 for the whole population (n=18), 3.6 ± 1.4 for treatment-naive patients (n=5), and 5.5 ± 2.9 for patients who switched to velaglucerase alfa from another Gaucher disease treatment (n=13). No patients showed worsening of spine or femur infiltration.\u003c/p\u003e","description":"","filename":"Figure3VF.png","url":"https://assets-eu.researchsquare.com/files/rs-3694934/v1/acfd1349b53192ea6ede4ce2.png"},{"id":51911844,"identity":"afa5f424-182b-40d0-b9e8-713c9d0ebb07","added_by":"auto","created_at":"2024-03-03 10:21:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1101256,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3694934/v1/07908033-14a1-4596-97ba-e0731e4a7f11.pdf"}],"financialInterests":"","formattedTitle":"A retrospective and prospective observational study of MRI changes in bone in patients with type 1 Gaucher disease treated with velaglucerase alfa: the EIROS study.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGaucher disease (GD) is a rare, autosomal recessive, metabolic disorder caused by pathological variants in the \u003cem\u003eGBA1\u003c/em\u003e gene leading to deficiency in the activity of the lysosomal enzyme glucocerebrosidase. The disease is characterized by the progressive accumulation of glucosylceramide and glucosylsphingosine in the lysosomes of macrophages (named Gaucher cells)\u0026mdash;particularly in the liver, spleen, and bone marrow\u0026mdash;resulting in multisystemic disease and heterogenous clinical manifestations. Three main clinical forms of GD have been described [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. GD Type 1 (GD1) is characterized by hepatosplenomegaly, thrombocytopenia, and bone involvement with the severity and age of onset of disease ranging from severe during childhood to patients who remain asymptomatic throughout life. Type 2 is an acute neuronopathic disease with hepatosplenomegaly and very early onset with death during in infancy. Type 3 is a chronic neuronopathic form associated with onset in childhood or adolescence, and systemic symptoms similar to those observed in GD1 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe estimated prevalence of GD has been reported to range from 1 to 2 per 100 000 in the general population, but is much higher (118 in 100 000) in the Ashkenazi Jewish population [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. GD1 is the most common form, accounting for around 94% of GD cases in Western countries [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. As a chronic illness, GD1 can lead to significant morbidity and can have a major impact on patient quality of life. In particular, the highly prevalent bone manifestations in GD1\u0026mdash;which include bone marrow infiltration, Erlenmeyer flask-shaped deformation, bone infarcts, avascular osteonecrosis, osteopenia, osteoporosis, osteolytic lesions, fractures, secondary osteoarthritis, and osteosyntheses\u0026mdash;are the main cause of pain and disability [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are currently two therapeutic strategies for the treatment of GD: enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). ERT is widely used as the first-line treatment and two intravenously administered ERTs have received marketing authorization in the EU, imiglucerase (Cerezyme\u0026reg;) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and velaglucerase alfa (VPRIV\u0026reg;) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Both substances have been shown to be safe and effective, leading to improvements in the hematologic and visceral manifestations of GD [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although ERT cannot reverse pre-existing permanent bone damage, long-term ERT is associated with a reduction in bone crises and bone pain, and improvements in bone mineral density and bone marrow burden (BMB) scores [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVarious recommendations for the overall management of patients with GD being treated with ERT have been published based on evaluations by international and national working groups [\u003cspan additionalcitationids=\"CR20 CR21 CR22 CR23 CR24\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], but there has been little consensus when it comes to defining treatment algorithms and monitoring protocols. However, management protocols have been proposed by national healthcare providers, and clear short-term and long-term treatment goals have been defined [\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In addition, analyses of data collected by national [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and international registries [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] have provided valuable insights into disease outcomes and improved understanding of the natural history of GD. Despite these advances, the impact of ERT on the bone pathophysiology associated with GD remains poorly understood, prompting the publication of detailed expert recommendations for the monitoring of bone alterations with the aim of improving the management and follow-up of bone disease [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. These practical recommendations highlighted the complexity of bone involvement in GD and the need for radiologists experienced in GD to be included in the multidisciplinary management team. The key recommendations for evaluating bone involvement included the use of MRI as the gold standard for assessing bone marrow infiltration in the lumbar spine and lower extremities, with semiquantitative analyses using either the D\u0026uuml;sseldorf Gaucher or bone marrow burden (BMB) scores for clinical studies involving adults, and for monitoring avascular osteonecrosis and bone infarcts. X-rays were recommended for identifying specific lesions, cortical thinning, lytic lesions, fractures, osteosyntheses, and osteoarthritis. Standardized regular dual-energy x-ray absorptiometry (DXA) assessments of bone mineral density were recommended to evaluate osteopenia and osteoporosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn France, patients with GD are managed according to a National Protocol for Diagnosis and Care (PNDS [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]) by a network of specialized referral centers for lysosomal diseases and data are collected in a national GD registry [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], all of which is facilitated by a multidisciplinary committee for the evaluation and treatment of GD (Comit\u0026eacute; d\u0026rsquo;\u0026Eacute;valuation du Traitement de la maladie de Gaucher; CETG) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The PNDS contains guidelines for the monitoring of bone involvement and refers to detailed procedures developed for radiologists carrying out abdominal and bone MRIs in patients with GD [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis current real-world observational study (EIROS) was carried out in response to the ongoing evaluation by the French national health authority (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHaute Autorit\u0026eacute; de Sant\u0026eacute;; HAS)\u003c/span\u003e to gain a better understanding of the evolution and outcomes of bone disease in patients with GD1 being treated with velaglucerase alfa. Thus, the main objective of this study was to evaluate the progression of bone disease in these patients using MRI data obtained by individual radiologists in real-world practice. Given the complexity of bone imaging in patients with GD and the high level of expertise required to interpret the data, the MRIs were transferred to a specialized center and a standardized evaluation and analysis by an expert radiologist was conducted for the purpose of the study. Other objectives included the evaluation of changes in other key disease characteristics including organomegaly, clinical manifestations (acute and chronic bone pain), and biological parameters.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis observational study of patients with GD1 treated with velaglucerase alfa was conducted using data collected retrospectively and prospectively in everyday clinical practice. The study was conducted between March 2017 and August 2019. French hospital centers involved in the management of more than one patient with GD1 being treated with velaglucerase alfa were invited to participate in the study. Participating centers were asked to provide data collected from patient medical records for all patients with a confirmed diagnosis of GD1, who were being treated with velaglucerase alfa, and who had available digital MRI data from an examination conducted within the 5 years preceding velaglucerase alfa initiation, or within the 3 months following treatment initiation. The MRIs could have been conducted in either a private or hospital radiology center. Prior to starting velaglucerase alfa treatment, patients could either be treatment naive or have been treated previously with any other GD treatment. Patients participating in an ongoing blinded clinical trial were excluded. All patients, or their parents or legal representative, provided written informed consent before being included in the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eAll data analyzed in this study were collected from patient medical records on routine imaging, clinical examinations and biological analyses that were part of the standard medical care and systematic follow up of patients with GD1 by the physicians responsible for their management. A summary of the study design and data collected is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. For the retrospective analysis, data were analyzed for each patient from the date of the MRI closest to the initiation of velaglucerase alfa (reference MRI) to the date of inclusion in the study. The reference MRI was defined as the MRI conducted within the 5 years preceding velaglucerase alfa initiation, or within the 3 months following treatment initiation. In the prospective analysis, data were analyzed from all visits from inclusion until the date of last MRI before the end of the study follow-up period (12 months after inclusion).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis of imaging data\u003c/h2\u003e \u003cp\u003eAll available digital MRI data (bone MRIs and abdominal MRIs) were collected, anonymized, transferred to a central imaging lab (Clario, formerly known as Bioclinica), and then analyzed by a single radiologist with experience in GD. This central radiologist was blinded to all clinical and demographic data but had access to data from all available MRI visits and sequences, in chronological order of acquisition. The bone MRIs were used to determine BMB scores (as described previously [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]). For the abdominal MRIs, liver and spleen volumes were semi-automatically measured by trained and experienced MRI technicians (Clario), based on axial T1-weighted and T2-weighted sequences respectively, or on the most suitable available MRI sequence if these were missing or of poor quality. Boundaries of both organs were carefully reviewed on each MRI slice, when visible, and the corresponding volumes were automatically derived in mm\u003csup\u003e3\u003c/sup\u003e based on image resolution, and then expressed as multiples of normal (MN) based on 25 mL/kg of body weight for the liver and 2 mL/kg of body weight for the spleen, as described previously [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eReports of imaging investigations (abdominal MRI for monitoring of hepatosplenomegaly and standard X-rays or MRI for bone lesions) written by local radiologists at each visit were collected from medical records.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis of demographic, clinical, and biological data\u003c/h2\u003e \u003cp\u003eData concerning patient demographics and disease and treatment history were collected at inclusion. Data were also collected on the dose, frequency, and duration of velaglucerase alfa treatment, the use of concomitant treatments, and the occurrence of any adverse events during the study period. The time between visits was also recorded for each variable.\u003c/p\u003e \u003cp\u003eBoth retrospective and prospective clinical and biological data were analyzed from patient medical records of examinations and analyses performed within three months of each MRI and at velaglucerase alfa initiation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The clinical data included body mass index (BMI), and the occurrence of acute and chronic bone pain, and clinical assessments of hepatomegaly and splenomegaly. For the biological analyses, all available data were collected and data concerning hemoglobin concentrations, platelet counts and chitotriosidase activity were analyzed relative to published reference standards. For hemoglobin, normal levels were defined as \u0026ge;\u0026thinsp;12.0 g/dL for men and \u0026ge;\u0026thinsp;11.0 g/dL for women and children (\u0026le;\u0026thinsp;12 years of age) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Thrombocytopenia was classified as normal or mild (not clinically significant) for platelet counts\u0026thinsp;\u0026gt;\u0026thinsp;120.0 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L; as moderate for counts\u0026thinsp;\u0026lt;\u0026thinsp;120.0 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L to \u0026ge;\u0026thinsp;60 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, and as severe for counts\u0026thinsp;\u0026lt;\u0026thinsp;60 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The upper limit for chitotriosidase activity, an established marker for GD [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], was compared to the median levels reported in individuals without GD (median [range]: 20 [4‒76] nmol/mL/h) [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStudy endpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoint was the change in BMB score between the reference MRI and the last follow-up MRI determined by the centralized analysis. The secondary endpoints included the change between the reference visit and the last follow-up examination for the following variables: the presence of bone infiltration according to imaging reports written by local radiologists; the occurrence of hepatosplenomegaly and of acute and chronic bone pain according to clinical records; spleen and liver volumes determined by centralized analysis of abdominal MRIs; and biological parameters according to medical records. Bone lesions, bone pain, treatment duration, changes in liver and spleen volumes and biological parameters, as well as the slope of these changes, were also assessed according to treatment history (i.e., in treatment naive patients compared to those switching to velaglucerase alfa from another GD treatment).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eDescriptive data were described as means (\u0026plusmn;\u0026thinsp;standard deviation) for quantitative variables and as numbers and percentages (n %) for qualitative variables. After analysis of the distribution of all variables, changes in BMB scores and in MRI liver and spleen volumes between MRIs were analyzed using the Wilcoxon rank test. Between-visit changes in clinical characteristics and MRI bone characteristics were analyzed using the McNemar chi-square test. For biological analyses, between-visit changes and differences in values between treatment-naive and treatment-switched patients were analyzed using the \u003cem\u003et\u003c/em\u003e test or the Wilcoxon rank test. Missing data were treated as such, and no imputation of missing values was performed. Only variables for which data were available for more than 25% of the patients were included in the analysis. \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant. All statistical analyses were carried out using SAS\u0026reg; software (version 9.4).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePost-hoc analysis\u003c/h2\u003e \u003cp\u003eA post-hoc analysis was performed by the central radiologist to qualitatively assess the change in bone infiltration from the first to last available MRIs. Changes were rated as stable, improved, or worsened and were scored for the spine and femur separately. The presence of emerging new spine and femur events was also documented. The changes were analyzed for the whole population and according to treatment history (treatment naive patients versus treatment-switched patients), time between the first and last MRI, and duration of treatment (velaglucerase alfa alone and velaglucerase alfa plus any prior treatment). Differences in the proportion of treatment-naive patients and treatment-switched patients with improved, stable or worsened characteristics were analyzed using the Fisher test, all other post-hoc analyses were analyzed using descriptive statistics.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eA total of 20 patients (17 adults and 3 children) managed at nine hospital centers were included in the study between March 01, 2017, and December 27, 2018. The first retrospective MRI took place on March 17, 2006, and the last prospective follow-up visit took place on August 16, 2019. One patient was excluded from the MRI analyses due to technical problems with the storage and transfer of the MRI data (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDemographic and clinical characteristics\u003c/h2\u003e \u003cp\u003eThe demographic, bone imaging, and clinical characteristics of the patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age of the adult patients at inclusion was 52\u0026thinsp;\u0026plusmn;\u0026thinsp;12 years (range 28\u0026ndash;75 years) and the ages of the three children at inclusion were 8, 10 and 15 years. Three patients had undergone splenectomy before the start of the study. Biological data are also listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic, clinical and MRI characteristics of the patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient demographics and disease history at inclusion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN (%) or Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (min\u0026ndash;max)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7 (8.0\u0026ndash;75.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (M/F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (55) / 9 (45)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge of diagnosis of Gaucher disease (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3 (1.0\u0026ndash;52.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history of Gaucher disease (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (35.0)/13 (65.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSplenectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (15)/ 17 (85)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment patterns\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime between diagnosis and velaglucerase alfa initiation (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6 (0.0\u0026ndash;59.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of treatment for Gaucher disease prior to velaglucerase alfa (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (70) / 6 (30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of use of prior treatment for Gaucher disease (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5 (1.2\u0026ndash;19.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment before switching to velaglucerase alfa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN\u0026thinsp;=\u0026thinsp;14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImiglucerase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiglustat\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical characteristics at velaglucerase alfa initiation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u0026sup2;), \u003cem\u003en\u0026thinsp;=\u0026thinsp;14\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 (14.2\u0026ndash;27.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic pain in bone (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (37.5) / 10 (62.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute bone pain (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (15.4) / 11 (84.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical signs of hepatomegaly (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (50.0) / 3 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical signs of splenomegaly (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (62.5) / 3 (37.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBiological analyses at velaglucerase alfa initiation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin concentration (g/dL), \u003cem\u003en\u0026thinsp;=\u0026thinsp;16\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5 (7.9\u0026ndash;17.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), \u003cem\u003en\u0026thinsp;=\u0026thinsp;16\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e133.6\u0026thinsp;\u0026plusmn;\u0026thinsp;91.9 (26.0\u0026ndash;356.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin (\u0026micro;g/L), \u003cem\u003en\u0026thinsp;=\u0026thinsp;10\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e480.2\u0026thinsp;\u0026plusmn;\u0026thinsp;579.4 (77.0\u0026ndash;1894.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChitotriosidase activity (nmol/mL/h), \u003cem\u003en\u0026thinsp;=\u0026thinsp;10\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8663.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14370 (968.0\u0026ndash;48750.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonoclonal gammopathy (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (11.8) /15 (88.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDisease imaging characteristics at the time of the reference MRI\u003c/b\u003e \u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eN\u0026thinsp;=\u0026thinsp;19\u003c/b\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of bone lesions (Y/N) \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (89.5) / 2 (10.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatomegaly (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (70) / 3 (30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated liver volume (mL), n\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1691.2\u0026thinsp;\u0026plusmn;\u0026thinsp;809.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated liver volume, multiples of normal \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 (0.7\u0026ndash;3.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSplenomegaly (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (83.3) / 2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated spleen volume (mL), n\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e843.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1206.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated spleen volume, multiples of normal \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.9\u0026thinsp;\u0026plusmn;\u0026thinsp;53.1 (1.2\u0026ndash;38.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e The reference MRI was defined as the MRI conducted within the 5 years preceding velaglucerase alfa initiation, or within the 3 months following treatment initiation. \u003csup\u003eb\u003c/sup\u003e Bone lesions included Erlenmeyer flask-shaped deformation, bone infiltration, cortical thinning, lytic lesions, avascular osteonecrosis (defined as an infarct located in epiphysis) and bone infarct (defined as an infarct located in long bone: metaphysis or diaphysis, or flat bone), vertebral collapse, fracture, secondary osteoarthritis, and osteosynthesis. \u003csup\u003eC\u003c/sup\u003e For multiples of normal, the normal liver volume was 25 mL/kg of body weight, and the normal spleen volume was 2 mL/kg of body weight.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: BMI, body mass index; F, female; M, male; min\u0026ndash;max: minimum and maximum values; n, number of patients with available data; SD, standard deviation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eTreatment patterns and exposure\u003c/h2\u003e \u003cp\u003eThe mean duration of velaglucerase alfa treatment, from initiation to the last study follow-up visit, was 5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6 years (n\u0026thinsp;=\u0026thinsp;19). Six of the patients included in the study (3 children and 3 adults) were naive to GD treatment before velaglucerase alfa initiation. The mean time between GD1 diagnosis and treatment initiation for these patients was 2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 years and the mean duration of treatment with velaglucerase alfa was 2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 years. Among the 14 patients who switched to velaglucerase alfa, 93% switched from another ERT (imiglucerase) and one patient switched from an SRT (miglustat). The mean time between GD1 diagnosis and initiation of treatment with any type of GD therapy for these patients was 9.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9 years and the mean duration of velaglucerase alfa treatment was 6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 years.\u003c/p\u003e \u003cp\u003eThe mean dose of velaglucerase alfa administered during the study was 56.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7 U/kg (n\u0026thinsp;=\u0026thinsp;19). Analysis of dose frequency showed that most patients (n\u0026thinsp;=\u0026thinsp;14) received the treatment fortnightly (every 14 or 15 days), as recommended [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]; whereas the remaining patients received treatment every 17 days (n\u0026thinsp;=\u0026thinsp;1), every 21 days (n\u0026thinsp;=\u0026thinsp;3) or monthly (n\u0026thinsp;=\u0026thinsp;1). Minor modifications to the dose and/or frequency of velaglucerase alfa administration were made for nine patients. One patient temporarily stopped treatment with velaglucerase alfa (for 112 days), and then later switched to an oral treatment (eliglustat). The total duration of velaglucerase alfa treatment in this patient was 6.3 years. No adverse events were reported during the study period.\u003c/p\u003e \u003cp\u003eOverall, 13 patients (65%) were prescribed a concomitant treatment during the study period, including analgesics (6/20), vitamin D supplements (6/20) and treatment for osteoporosis (3/20).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eEvolution of bone marrow burden scores according to the centralized analysis\u003c/h2\u003e \u003cp\u003eA total of 71 digital MRI records (58 collected retrospectively and 13 collected prospectively), with an average of around 4 MRIs per patient (range: 2\u0026ndash;7), were available for centralized analysis. However, the number of optimal or interpretable MRIs for assessment of the BMB score was limited (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Seven of the MRIs (five collected retrospectively and two collected prospectively) were excluded from the BMB analysis because they were from examinations conducted on children, for whom calculation of the BMB score has previously been found to be unreliable [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Out of the remaining 64 MRIs analyzed, 23 (35.9%) were deemed uninterpretable for evaluation of the BMB spine score and 55 (85.9%) were deemed uninterpretable for evaluation of the femur BMB score. The most common causes for the insufficient quality of the MRIs were the use of incorrect scanning parameters (acquisition of T1- and T2-weighted sequences with fat suppression preventing proper comparison of MRI signal intensity with that of subcutaneous fat (femur) and non-diseased intervertebral discs (spine), as originally required for BMB scoring) and/or incomplete imaging of the required anatomical region (particularly the absence or incomplete imaging of the distal femur). In total, only seven patients had interpretable data for BMB spine scoring from both the reference MRI (mean score: 3.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1) and a follow-up MRI (mean score: 2.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1). The average time between the reference MRI visit and last MRI visit for calculation of the BMB score was 4.3 years\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9 years. No significant change in the mean BMB spine score was observed between these reference and last MRIs (Δ -0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.25). Only one patient had interpretable data for BMB femur scoring from both the reference MRI and a follow-up visit. As a result, no calculation could be performed for the change in femur BMB score or total BMB score for the whole population. As an alternative, a \u003cem\u003epost-hoc\u003c/em\u003e qualitative assessment of the change in bone infiltration in the spine and femur from the first to last MRI data was performed by the central radiologist.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003ePost-hoc qualitative analysis of the evolution of bone infiltration in the spine and femur\u003c/h2\u003e \u003cp\u003eOverall, 18 patients (5 treatment-naive patients and 13 treatment-switched patients) had interpretable MRIs for the \u003cem\u003epost-hoc\u003c/em\u003e qualitative evaluation of the change in spine or femur infiltration (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Improvements in spine and femur infiltration were observed for 22.2% (n\u0026thinsp;=\u0026thinsp;4/18) and 27.8% (n\u0026thinsp;=\u0026thinsp;5/18) of patients, respectively, and stability was observed for 77.8% (n\u0026thinsp;=\u0026thinsp;14/18) and 72.2% (n\u0026thinsp;=\u0026thinsp;13/18) of patients, respectively. None of the patients had worsening spine or femur infiltration between the first and last MRIs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSignificant differences in the proportion of patients who had improved or stable spine and femur infiltration between the first and last MRIs were observed for treatment-naive patients compared to treatment-switched patients (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for the spine and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for the femur). The proportion of patients with an improvement in infiltration was highest among treatment-naive patients: improvements in spine infiltration were observed for 80.0%, (n\u0026thinsp;=\u0026thinsp;4/5) of these patients and improvements in femur infiltration were observed for 60.0% (n\u0026thinsp;=\u0026thinsp;3/5). In contrast, spine infiltration remained stable for all patients (n\u0026thinsp;=\u0026thinsp;13) who had switched to velaglucerase alfa from another GD treatment. An improvement in femur infiltration was observed for two of the treatment-switched patients (15.4%), with femur characteristics in the 11 remaining patients (84.6%) remaining stable between MRIs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; \u003cem\u003eP\u003c/em\u003e values for between-group differences in the proportion of patients in each class\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eThe change in spine and femur infiltration also varied depending on the duration of velaglucerase alfa treatment and of velaglucerase alfa and any prior treatments (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The mean duration of treatment was shorter for patients who had an improvement in spine infiltration (3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 years both for velaglucerase alfa alone and for velaglucerase alfa and prior treatment) than for patients with stable spine infiltration (6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5 years for velaglucerase alfa alone and 17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 years for velaglucerase alfa and prior treatment). The same trend was observed for the change in femur characteristics: mean treatment duration for patients with an improvement in femur characteristics was 4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 for velaglucerase alfa alone and 10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2 for velaglucerase alfa and prior treatment, compared to 5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6 for velaglucerase alfa alone and 15.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 for velaglucerase alfa and prior treatment for patients with stable femur characteristics (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChange in spine and femur infiltration between the first and last available MRIs according to the time between MRIs, duration of velaglucerase alfa treatment, and the duration of all treatments for Gaucher disease (velaglucerase alfa and any prior treatment).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;19\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eTime (years\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpine infiltration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImproved\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStable\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;14\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWorsened\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;0\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime between first and last MRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment duration:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVelaglucerase alfa alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVelaglucerase alfa plus prior GD treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemur infiltration\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eImproved\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en\u0026thinsp;=\u0026thinsp;5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eStable\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en\u0026thinsp;=\u0026thinsp;13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eWorsened\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en\u0026thinsp;=\u0026thinsp;0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime between first and last MRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment duration:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVelaglucerase alfa alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVelaglucerase alfa plus prior GD treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e MRI data were uninterpretable for one patient\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAbbreviations:\u0026nbsp;\u003c/strong\u003eGD, Gaucher disease; SD, standard deviation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eReview of bone imaging data and clinical bone manifestations according to medical records\u003c/h2\u003e \u003cp\u003eCollection of bone imaging reports written by local radiologists indicated that 17 of the 19 patients had bone lesions assessed by standard X-Rays and MRI at the reference visit and at the last visit (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). One new case of bone infiltration (in a treatment-naive patient) was reported by local radiologists at the last visit compared to the reference visit. This new case of bone infiltration occurred in the patient for whom the data were deemed uninterpretable for the \u003cem\u003epost-hoc\u003c/em\u003e centralized analysis. One case of bone infiltration present at the reference MRI was reported as absent at the last MRI. However, bone infiltration in this patient (a treatment-naive patient aged 15 years) was noted as present at the last visit by the central radiologist. Other bone lesions deemed unlikely to be related to GD were reported in 12 patients (63%), with the most common lesions including vertebral hemangiomas and degenerative disc disease (each present in two patients; 10.5% of the study population).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eReview of bone imaging and clinical characteristics from local imaging and clinical records between the reference visit and the last available follow-up visit\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBone imaging characteristics \u003csup\u003ea\u003c/sup\u003e, N\u0026thinsp;=\u0026thinsp;19\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eReference visit \u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eLast available visit\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value \u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003cp\u003echange reference to last\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eChange reference to last (n \u0026uarr;\u0026darr;) \u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eTreatment-naive patients (N\u0026thinsp;=\u0026thinsp;6)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eTreatment-switched patients (N\u0026thinsp;=\u0026thinsp;14)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of bone lesions \u003csup\u003eb\u003c/sup\u003e (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (89.5) / 2 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (89.5) / 2 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eN/A\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026harr;\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026harr;\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone infiltration (Y/N)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (57.9) / 8 (42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (57.9) / 8 (42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026uarr;1 \u003csup\u003eh\u003c/sup\u003e \u0026darr;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026harr;\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical bone characteristics\u003c/b\u003e \u003csup\u003e\u003cb\u003ec\u003c/b\u003e\u003c/sup\u003e, \u003cb\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eReference visit\u003c/b\u003e \u003csup\u003e\u003cb\u003ee\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eLast available visit\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e \u003cb\u003evalue\u003c/b\u003e \u003csup\u003e\u003cb\u003ed\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003echange reference\u0026ndash;last\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eTreatment-naive patients (N\u0026thinsp;=\u0026thinsp;6)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eTreatment-switched patients (N\u0026thinsp;=\u0026thinsp;14)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic bone pain (Y/N), n\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (50) / 8 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (37.5) / 10 (62.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026uarr;1 \u0026darr;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026uarr;2 \u0026darr;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute bone pain (Y/N), n-14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (14.3) / 12 (85.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0) / 14 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026uarr;0 \u0026darr;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026uarr;0 \u0026darr;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Average time between the reference visit and last visit for bone imaging: 6.6 years\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4 years. \u003csup\u003eb\u003c/sup\u003e Bone lesions included Erlenmeyer flask-shaped deformation, bone infiltration, cortical thinning, lytic lesions, avascular osteonecrosis (defined as an infarct located in epiphysis) and bone infarct (defined as an infarct located in long bone: metaphysis or diaphysis, or flat bone), vertebral collapse, fracture, secondary osteoarthritis, and osteosynthesis. \u003csup\u003ec\u003c/sup\u003e Average time between the reference clinical examination and last clinical examination: 6.7 years\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4 for chronic bone pain and 5.9 years\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2 for acute bone pain. \u003csup\u003ed\u003c/sup\u003e For imaging analyses, the reference visit was either the reference MRI (conducted within 5 years before or 3 months after velaglucerase alfa initiation) or other bone imaging modality conducted within 3 months of the reference MRI. \u003csup\u003ee\u003c/sup\u003e For the clinical analyses, the reference visit was the clinical examination performed within 3 months of the reference MRI. \u003csup\u003ef\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e values were calculated using the McNemar chi-square test. \u003csup\u003eg\u003c/sup\u003e \u0026uarr; number of patients with a change from the reported absence of this lesion at the reference visit to the reported presence of this lesion at the last visit. \u0026darr; number of patients with a change from the reported presence of the lesion at the reference visit to the reported absence of this lesion at the last visit. \u003cb\u003e\u0026harr;\u003c/b\u003e no change for all patients. \u003csup\u003eh\u003c/sup\u003e For the patient in which bone infiltration was reported to be absent at the first MRI but present at the last MRI by local radiologists, the MRIs were deemed uninterpretable by the central radiologist.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e: N, number of patients in whole population; n, number of patients with data available for both visits; N/A; \u003cem\u003eP\u003c/em\u003e value not available.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn the clinical examinations, no statistically significant changes in the overall number of patients with acute or chronic bone pain were reported (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). No new occurrences of acute bone pain were reported during the study and neither of the two patients with mild (n\u0026thinsp;=\u0026thinsp;1) or moderate (n\u0026thinsp;=\u0026thinsp;1) acute bone pain at the reference visit reported having acute bone pain at the last visit. Data on the change in severity of chronic bone pain were available for six patients, all of whom had mild or moderate pain at the reference visit. Four of these patients had no chronic bone pain at the last visit, and the mild (n\u0026thinsp;=\u0026thinsp;1) and moderate (n\u0026thinsp;=\u0026thinsp;1) pain in the remaining patients remained stable.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eEvolution of liver and spleen parameters\u003c/h2\u003e \u003cp\u003eThe number of patients in the whole population with hepatosplenomegaly, evaluated by MRI and/or by clinical examination, did not change significantly over the course of the study (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChange in liver and spleen parameters over the course of the study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHepatosplenomegaly \u003csup\u003ea,b c\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference visit\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLast visit\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChange between reference and last visit\u003c/p\u003e \u003cp\u003en (% total Y/N) \u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value \u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHepatomegaly on clinical examination (Y/N), \u003cem\u003en\u0026thinsp;=\u0026thinsp;12\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (33.3) / 8 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (25.0) / 9 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026uarr;\u003c/b\u003e 1 (33.3) \u003cb\u003e\u0026darr;\u003c/b\u003e 2 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eHepatomegaly by MRI (Y/N), \u003cem\u003en\u0026thinsp;=\u0026thinsp;7\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (57.1) / 3 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (42.9) / 4 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026uarr;\u003c/b\u003e 0 (0) \u003cb\u003e\u0026darr;\u003c/b\u003e 1 ()\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSplenomegaly on clinical examination (Y/N), \u003cem\u003en\u0026thinsp;=\u0026thinsp;11\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (54.5) / 5 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (9.1) / 10 (90.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026uarr;\u003c/b\u003e 1 (100.0) \u0026darr; 6 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSplenomegaly by MRI (Y/N), \u003cem\u003en\u0026thinsp;=\u0026thinsp;9\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (77.8) / 2 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (55.6) / 4 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026uarr;\u003c/b\u003e 0 (0.0) / \u0026darr; 2 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEstimated liver volume, centralized analysis\u003c/b\u003e \u003csup\u003e\u003cb\u003ed\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFirst MRI\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eLast MRI\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eChange first and last MRI\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e \u003cb\u003evalue\u003c/b\u003e \u003csup\u003e\u003cb\u003eg\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eWhole population, \u003cem\u003en\u0026thinsp;=\u0026thinsp;12\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1617.8\u0026thinsp;\u0026plusmn;\u0026thinsp;644.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1523.4\u0026thinsp;\u0026plusmn;\u0026thinsp;376.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-94.4\u0026thinsp;\u0026plusmn;\u0026thinsp;440.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTreatment-naive patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2061.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1166.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1498.5\u0026thinsp;\u0026plusmn;\u0026thinsp;395\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-562.6\u0026thinsp;\u0026plusmn;\u0026thinsp;777.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTreatment-switched patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;9\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1470.0\u0026thinsp;\u0026plusmn;\u0026thinsp;365.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1531.7\u0026thinsp;\u0026plusmn;\u0026thinsp;394.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61.7\u0026thinsp;\u0026plusmn;\u0026thinsp;79.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEstimated spleen volume, centralized analysis\u003c/b\u003e \u003csup\u003e\u003cb\u003ed\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFirst MRI\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eLast MRI\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eChange first and last MRI\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e \u003cb\u003evalue\u003c/b\u003e \u003csup\u003e\u003cb\u003eg\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eWhole population, \u003cem\u003en\u0026thinsp;=\u0026thinsp;10\u003c/em\u003e \u003csup\u003e\u003cem\u003ee\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e776.6\u0026thinsp;\u0026plusmn;\u0026thinsp;992.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e385.9\u0026thinsp;\u0026plusmn;\u0026thinsp;199.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-390.7\u0026thinsp;\u0026plusmn;\u0026thinsp;863.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.3\u0026thinsp;\u0026plusmn;\u0026thinsp;19.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-12.4\u0026thinsp;\u0026plusmn;\u0026thinsp;17.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTreatment-naive patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;3\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1497.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1764.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e398.1\u0026thinsp;\u0026plusmn;\u0026thinsp;296.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-1099.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1497.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.3\u0026thinsp;\u0026plusmn;\u0026thinsp;19.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-12.4\u0026thinsp;\u0026plusmn;\u0026thinsp;17.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTreatment-switched patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;7\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e467.5\u0026thinsp;\u0026plusmn;\u0026thinsp;262.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e380.7\u0026thinsp;\u0026plusmn;\u0026thinsp;174.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-86.9\u0026thinsp;\u0026plusmn;\u0026thinsp;114.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Three patients had undergone splenectomy. \u003csup\u003eb\u003c/sup\u003e Mean time between the reference clinical examination and the last available clinical examination: 5.8 years\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9 for hepatomegaly and 6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 for splenomegaly. \u003csup\u003ec\u003c/sup\u003e Mean time between the reference MRI and the last available MRI: 5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 for hepatomegaly and 6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1 for splenomegaly. \u003csup\u003ed\u003c/sup\u003e Mean time between the first available MRI and the last available MRI for volume estimates: 5.6 years\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9 for liver measurements and 5.6 years\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 for spleen measurements. \u003csup\u003ee\u003c/sup\u003e \u0026uarr; change from the reported absence of this manifestation at the reference visit to the reported presence of this manifestation at the last visit. \u0026darr; change from the reported presence of this manifestation at the reference visit to the reported absence of this manifestation at the last visit. \u003csup\u003ef\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e values calculated using the McNemar chi-square test. \u003csup\u003eg\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e values calculated using the Wilcoxon rank test.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e: MN, multiples of normal (25 mL/kg of body weight for the liver 2 mL/kg of body weight for the spleen); n, number of patients with data available for both visits; SD, standard deviation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA total of 38 abdominal MRIs were conducted during the study period and all these MRIs contained interpretable data: 33 (86.8%) and 31 (81.6%) of the MRIs were deemed optimal for liver and spleen volume measurements, whereas 7 (18.4%) and 5 (13.2%) of the MRIs were deemed suboptimal but interpretable, mainly due to motion artifacts or suboptimal anatomical coverage. As abdominal MRIs had only been conducted for a limited number of patients at both a reference visit and follow-up visit (liver: 7 patients; spleen; 6 patients), the centralized analysis of the evolution of spleen and liver volume was evaluated from the first available MRI to the last MRI. The mean time between the first and last visits was 5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9 years for the liver analysis and 5.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 years for the spleen analysis (compared to mean times of 5.6 years\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7 for liver analysis and 5.4 years\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0 for spleen analysis between the reference and last MRIs). The mean estimated liver and spleen volumes at the first and last MRIs for the whole population and according to treatment history are shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe mean liver volume in patients who had switched from a prior treatment (n\u0026thinsp;=\u0026thinsp;9) was 0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2 MN at the reference MRI and remained stable at the last MRI (mean: 0.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1 MN; Δ\u0026thinsp;+\u0026thinsp;61.7\u0026thinsp;\u0026plusmn;\u0026thinsp;79.7 mL). Similarly, spleen volumes remained largely stable in the treatment-switched patients: 3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 MN at the reference MRI and 2.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 MN at the last visit (Δ -86.9\u0026thinsp;\u0026plusmn;\u0026thinsp;114.6 mL).\u003c/p\u003e \u003cp\u003eIn the treatment-naive patients (n\u0026thinsp;=\u0026thinsp;3), liver volumes were on average 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1 MN at the reference MRI, but decreased by -562.6\u0026thinsp;\u0026plusmn;\u0026thinsp;777.0 mL to 1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23 MN at the last visit. Spleen volumes in these patients were considerably above normal at the reference MRI (mean: 16.3\u0026thinsp;\u0026plusmn;\u0026thinsp;19.8 MN) but decreased by the last MRI (Δ -1099.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1497.4 mL) to 3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8 MN.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eEvolution of biological parameters\u003c/h2\u003e \u003cp\u003eThe mean changes in hemoglobin and concentrations, and in platelet counts and chitotriosidase activity for the whole population between the first and last analyses are shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChange in biological parameters over the course of the study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter (N\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference analysis\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLast analysis\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eChange between reference and last\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSlope\u003c/p\u003e \u003cp\u003eunits/year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003cp\u003e(Δ Ref to Last) \u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHemoglobin concentration (g/dL)\u003c/b\u003e \u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAll patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;19\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-naive patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;6\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-switched patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;13\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 \u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e \u003cb\u003evalue (naive\u0026ndash;non-naive patients at each analysis)\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePlatelet counts (\u0026times;10\u003c/b\u003e\u003csup\u003e\u003cb\u003e9\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e/L)\u003c/b\u003e \u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAll patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;18\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e139.1\u0026thinsp;\u0026plusmn;\u0026thinsp;76.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185.2\u0026thinsp;\u0026plusmn;\u0026thinsp;77.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46.1\u0026thinsp;\u0026plusmn;\u0026thinsp;42.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.1\u0026thinsp;\u0026plusmn;\u0026thinsp;25.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-naive patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;6\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e123.8\u0026thinsp;\u0026plusmn;\u0026thinsp;119.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e215.7\u0026thinsp;\u0026plusmn;\u0026thinsp;126.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91.8\u0026thinsp;\u0026plusmn;\u0026thinsp;28.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40.6\u0026thinsp;\u0026plusmn;\u0026thinsp;26.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-switched patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;12\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e146.8\u0026thinsp;\u0026plusmn;\u0026thinsp;48.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e169.9\u0026thinsp;\u0026plusmn;\u0026thinsp;35.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;27.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.76\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e \u003cb\u003evalue (naive\u0026ndash;treatment switched patients)\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChitotriosidase activity (nmol/mL/h)\u003c/b\u003e \u003csup\u003e\u003cb\u003ea\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAll patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;13\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9084.0\u0026thinsp;\u0026plusmn;\u0026thinsp;16039.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2442.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5031.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-6641.1\u0026thinsp;\u0026plusmn;\u0026thinsp;16831.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;16.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-naive patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;4\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25688.3\u0026thinsp;\u0026plusmn;\u0026thinsp;22224.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6284.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8408.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-19403.8\u0026thinsp;\u0026plusmn;\u0026thinsp;28604.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-2397.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11939.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-switched patients, \u003cem\u003en\u0026thinsp;=\u0026thinsp;9\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1704.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1248.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e735.6\u0026thinsp;\u0026plusmn;\u0026thinsp;898.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-968.8\u0026thinsp;\u0026plusmn;\u0026thinsp;677.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-160.5\u0026thinsp;\u0026plusmn;\u0026thinsp;138.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eP\u003c/b\u003e \u003cb\u003evalue (naive\u0026ndash;treatment-switched patients)\u003c/b\u003e \u003csup\u003e\u003cb\u003eb\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Mean time between the reference biological analysis and the last available biological analysis: 6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6 for measurement of hemoglobin, 6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4 years for platelet counts, 5.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4 for chitotriosidase activity. \u003csup\u003eb\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e values for the difference between values obtained for treatment-naive and treatment-switched patients at each analysis and for the slope were obtained using the \u003cem\u003et\u003c/em\u003e test for hemoglobin concentration and platelet counts, and the Wilcoxon rank test for chitotriosidase activity. \u003csup\u003ec\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e values for the difference in values at the reference and last analysis obtained using the \u003cem\u003et\u003c/em\u003e test for hemoglobin concentration and platelet counts and the Wilcoxon rank test for chitotriosidase activity.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e: n, number of patients with data available for both visits; Ref, reference analysis; SD, standard deviation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe hemoglobin concentration in patients that had switched from a prior treatment was in the normal range (\u0026ge;\u0026thinsp;11.0\u0026ndash;12.0 g/dL depending on age and gender) for all patients at the reference analysis, and remained stable with no significant change being observed between analyses (mean: 14.3 g/dL at both visits; slope: \u0026minus;\u0026thinsp;0.1 g/dL/year; Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). In contrast, the mean hemoglobin concentration in treatment-naive patients was slightly below normal at the reference visit (mean: 10.8 g/dL), but increased to within the normal range for all patients at the last visit (mean: 12.8 g/dL; slope: 11 g/L per year; Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAmong the treatment-switched patients (n\u0026thinsp;=\u0026thinsp;12), platelet counts at the reference analysis were within the normal/mild range (\u0026ge;\u0026thinsp;120 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) for eight patients but moderate thrombocytopenia (platelet counts\u0026thinsp;\u0026le;\u0026thinsp;120 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L but \u0026ge;\u0026thinsp;60 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) was present in four patients. Platelet counts increased or remained stable at the last analysis for all the patients who switched treatments (mean: 169.9\u0026thinsp;\u0026plusmn;\u0026thinsp;35.2 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L; Δ: + 23.2\u0026thinsp;\u0026plusmn;\u0026thinsp;27.3 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), although the moderate thrombocytopenia persisted in one patient. For treatment-naive patients (n\u0026thinsp;=\u0026thinsp;6), platelet counts at the reference analysis were in the normal/mild range for two patients, whereas the remaining four patients had either moderate (n\u0026thinsp;=\u0026thinsp;2) or severe (n\u0026thinsp;=\u0026thinsp;2; platelet counts\u0026thinsp;\u0026le;\u0026thinsp;60 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) thrombocytopenia. Platelet counts had increased (Δ: + 40.6\u0026thinsp;\u0026plusmn;\u0026thinsp;26.1) for all the treatment-naive patients at the last analysis, with all patients having platelet counts within the normal range (mean count: 215.7\u0026thinsp;\u0026plusmn;\u0026thinsp;126.8 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L).\u003c/p\u003e \u003cp\u003eAs expected, the mean levels of chitotriosidase activity reported in the study population were much higher than those reported in individuals without GD in all analyses, but did decrease over the course of the study. Chitotriosidase activity levels decreased in both patient groups, with, as expected, a greater decrease among the treatment-naive patients (Δ -19403.8 nmol/mL; slope: -2397.5 nmol/mL/h per year) than among the treatment-switched patients (Δ -968.8 nmol/mL; slope: -160.5 nmol/mL/h per year).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e This retrospective\u0026ndash;prospective study using real-world data to assess the evolution of bone disease in patients with GD1 being treated with velaglucerase alfa provided valuable insights into the impact of the treatment, and into the quality and effectiveness of patient monitoring in clinical practice in France. Despite the publication of a detailed protocol for the monitoring of bone disease in patients with GD, we found that the quality of bone MRI data collected in clinical practice was often insufficient to allow for semiquantitative assessments of treatment responses through calculation of BMB scores. However, the centralized qualitative assessment of real-world MRI data used in this study provided evidence of the positive impact of velaglucerase alfa on bone disease, with improvements in bone infiltration being observed in treatment-naive patients and stabilization of bone infiltration being observed in treatment-switched patients. Furthermore, reductions in acute and chronic bone pain, and improvements or stabilization of hematologic parameters, and visceral manifestations were observed, providing further evidence from clinical practice of the effectiveness of velaglucerase alfa in allowing patients to achieve and maintain the well-established goals for GD treatment.\u003c/p\u003e \u003cp\u003eAssessing the extent of bone marrow infiltration in patients with GD is essential for evaluating the extent of bone involvement, monitoring patient responses to ERT, and for guiding therapeutic decision making and optimizing treatment regimens [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The BMB score, which provides an MRI-based semiquantitative evaluation of bone marrow infiltration based on the distribution of lesions and the change in signal intensity, is one of the most widely used methods in clinical studies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. This method has the advantage of being more reflective of whole-body bone marrow involvement because it includes assessment of the spine and the femur, and is simpler to use and more widely accessible than Dixon quantitative chemical shift imaging (QCSI) assessments of the bone marrow fat fraction because it uses conventional MRI imaging [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. However, the interobserver agreement of BMB scores has been questioned, even between experienced radiologists [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. In addition, BMB scoring has been found to be less reliable for assessing bone infiltration in younger patients with GD, due to potential masking of the true extent of bone infiltration by the higher proportion of red bone marrow normally present in children and young adults [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. The findings from the current study have highlighted the problems associated with the use of the BMB scoring for monitoring bone involvement in GD in real-world clinical practice. Longitudinal assessments of BMB scores rely on the collection of high-quality sequential MRI data according to a rather strict protocol to ensure consistency between device settings and scanning parameters during follow up. The MRIs used in this study were conducted by local radiologists using a range of MRI machine models from multiple centers and varied scanning parameters, resulting in large technical variations in the quality of the images obtained. Despite the availability of detailed procedures for conducting bone MRIs in patients with GD [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], the centralized analysis of the MRI data revealed that in many cases these good practice guidelines were not followed, particularly the recommendations to collect image sequences of both the distal and proximal femur and to acquire T1- and T2-weighted sequences without fat-suppressed imaging to allow optimal comparison of the relative changes in signal intensity between healthy and diseased bone areas. These findings indicate that more specialized training needs to be provided to local radiologists on the acquisition and interpretation of data for calculating BMB scores. In countries where resources permit, this may need to be combined with centralized analysis through a national reference platform to limit interobserver variability in BMB scoring, or alternatively, the development of semi-automated techniques could be investigated to improve consistency.\u003c/p\u003e \u003cp\u003eAs a result of the technical limitations associated with data acquisition, only one of the 17 adult patients included in the current study had interpretable data for femur BMB scoring, and only seven patients had interpretable data for spine BMB scoring. This absence of adequate data for the assessment of total BMB score led us to explore whether a subjective qualitive assessment of the change in bone infiltration (classified as worsened, improved or stabilized) would provide a more feasible method for analyzing the response to velaglucerase alfa treatment in clinical practice. The results of the centralized analysis indicated that this qualitative method could indeed be used to monitor changes in bone infiltration in the spine and femur over time, and to identify statistically significant differences between treatment groups. In addition, qualitative analysis by the centralized radiologist also appeared to provide valuable information about the change in bone infiltration in the three children included in the study cohort. Although the normal developmental changes in red marrow made it more challenging to assess improvements in bone infiltration in these younger patients compared to in the adults with GD, the masking effect of bone marrow maturation was not considered to have prevented the visualization of significant worsening of bone infiltration during qualitative assessment. Thus, although larger validation studies are needed, our findings suggest that the qualitative bone infiltration analysis used in this study could provide an alternative, less stringent, and easier-to-interpret method that could be used by local radiologists to assess bone disease in patients with GD, particularly in countries or regions where medical resources are scarce and access to GD expert radiologists is extremely limited.\u003c/p\u003e \u003cp\u003eThe results of the qualitative analysis provided valuable real-world insights into the impact of velaglucerase alfa treatment on bone involvement in patients with GD, with treatment-naive patients and those with shorter treatment durations (3.5 years on average) tending to show improvements in femur and spine infiltration, and patients who switched treatments and treatment-naive patients with longer treatment durations (6 years on average) generally having stable bone disease. Importantly, none of the patients showed signs of worsening bone disease during velaglucerase alfa treatment. Our results are therefore consistent with findings of previous clinical studies in which assessment of BMB scores showed that velaglucerase alfa treatment led to a significant reduction in bone infiltration [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], with largest reductions being observed during the first 5 years of ERT, followed by long-term stabilization after 5 years [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. As pointed out in these studies [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], the stabilization of bone infiltration after 5 years of treatment suggests the need to revise current bone MRI monitoring protocols, perhaps increasing the interval between MRI evaluations for bone infiltration in patients who are adherent to treatment and have stable bone disease. Indeed, the current PNDS guidelines recommend bone MRI at treatment initiation, after 1 year, and then every 2 years once the disease has stabilized [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Improving adherence to the PNDS guidelines and ensuring that patients are monitored by MRI, particularly when initiating ERT or switching between therapies, is essential to allow for meaningful evaluation of treatment responses and for evidence-based updates of current monitoring recommendations.\u003c/p\u003e \u003cp\u003eIn addition to improving bone infiltration, reducing bone pain is one of the key therapeutic goals in patients with GD [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Our analysis of clinical medical records indicated that this goal was met in our cohort: no new cases of acute bone pain were reported during velaglucerase alfa treatment and the resolution of acute bone pain was reported in two patients. Although available data on pain severity were limited, the velaglucerase alfa treatment also seemed to lead to a reduction or stabilization of chronic bone pain. Similar findings have been reported previously in several studies examining the impact of the alternative ERT, imiglucerase, on bone pain in patients with GD [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on the analysis of bone imaging records written by local radiologists, the large majority of patients in our cohort had existing bone lesions before the initiation of velaglucerase alfa therapy. As noted in previous studies, ERT cannot reverse all of the existing bone manifestations of GD, most notably avascular osteonecrosis and disease-related complications such as secondary osteoarthritis and fracture deformities [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and thus the goal of therapy is to prevent bone infiltration and the occurrence of new lesions [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Velaglucerase alfa treatment appeared to allow all of the patients included in our study to achieve this goal. However, the occurrence of bone lesions in patients receiving ERT has been reported in previous studies [\u003cspan additionalcitationids=\"CR46 CR47\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e], particularly in patients that initiated ERT more than 2 years after GD diagnosis [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Indeed, in our study the mean time between diagnosis and initiation of any form of GD treatment was 2.6 years in treatment-naive patients and 9.9 years in patients switching treatments. Thus, the early detection of new lesions and surveillance of the severity of existing lesions remains essential for patients receiving ERT, not only for guiding the adjustment and optimization of velaglucerase alfa treatment, but also to allow timely intervention with supportive therapies and interventions such as prosthetic replacement to maintain or improve patient mobility and quality of life. In addition, other bone complications, not specifically related to GD were reported in over 50% of the patients in our study. Clearly, there is a need to ensure that these nonspecific bone lesions are not overlooked during monitoring of the complex bone manifestations of GD and that correct diagnosis and appropriate management are provided.\u003c/p\u003e \u003cp\u003eHepatomegaly and splenomegaly are hallmark manifestations of GD1, present in between 60% and 90% and more than 90% of cases, respectively [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The PNDS recommends regular monitoring of liver and spleen volumes every 6 months during the first year of treatment and then biannually after stabilization of organ volumes, by either abdominal MRI or ultrasound [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Although ultrasound has the advantage of being more accessible and affordable than other imaging modalities, it provides a less comprehensive assessment of organ involvement than MRI [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In contrast, MRI data can be analyzed using semi-automated methods for measuring organ volumes, improving measurement accuracy and reproducibility [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. In our study, less than half of the patients had available abdominal MRI data collected around the time of initiation of velaglucerase alfa treatment and only around half of the patients had longitudinal abdominal MRI data. However, contrary to the bone MRIs, all of the abdominal MRIs conducted provided interpretable, although not always optimal, cross-sectional data for the centralized analysis of organ volumes, demonstrating that the semi-automated method used in this study was sufficiently robust to overcome the variations in scanning parameters and sequence types associated with MRI data collected in clinical practice. Thus, while clinical examination and ultrasound maybe sufficient for routine long-term management when MRI facilities are scarce, when MRI is widely available, this technique could be used in clinical practice to monitor visceral disease severity and treatment responses.\u003c/p\u003e \u003cp\u003eThe treatment goals for the visceral complications in GD1 are to reduce (within the first two years of treatment) and then stabilize organ volumes [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], ideally to within less than 1.0 to 1.5 MN for the liver and 2 to 8 MN for the spleen [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The centralized analysis of liver and spleen volumes demonstrated that these goals were met in our patient cohort, with treatment-naive patients showing decreases in liver and spleen volumes by the last visit to achieve average volumes of 1.2 MN and 3.9 MN, respectively, and treatment-switched patients showing stabilization of organ volumes (0.8 MN for the liver and 2.6 MN for the spleen at the last visit). These findings are therefore consistent with those of previous studies showing that velaglucerase alfa treatment leads to near-normalization of hepatomegaly and major reductions in splenomegaly within around 4 years of initiating treatment [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe same pattern of improvement in treatment-naive patients and stabilization in patients switching to velaglucerase alfa was observed for hemoglobin concentrations and platelet counts during the study. All patients had normalization or stabilization of hemoglobin and platelet counts at the last visit. Such normalization and maintenance of hematologic parameters in the 4 years after initiating treatment has been reported previously in patients receiving velaglucerase alfa [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and has often been observed within the first 2 years post treatment initiation [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. These findings are consistent with those of previous studies clearly demonstrating the effectiveness of velaglucerase alfa treatment in allowing patients to achieve the therapeutic goals of preventing anemia and reducing bleeding tendency, as well as the complications related to these hematologic manifestations [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Finally, monitoring of chitotriosidase activity, a well-established biomarker of GD severity and treatment responses [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e], revealed decreases in activity both in the treatment-naive patients and treatment-switched patients.\u003c/p\u003e \u003cp\u003eThe real-world ambispective design of the current study allowed the long-term impact of velaglucerase alfa treatment in GD1 to be assessed in clinical practice, in a patient population that was homogeneous in terms of the dose and frequency of velaglucerase alfa treatment received, and in both treatment-naive patients and those who had switched treatment. However, this real-world approach led to several study limitations. First, the amount and quality of the MRI data collected in clinical practice were insufficient to allow assessment of the primary study endpoint (i.e., the change in BMB scores). However, this lack of available data led us to explore the potential of an alternative and less stringent qualitative method for assessing bone marrow involvement. Future studies would allow us to further evaluate the suitability of this method for monitoring the bone marrow response to ERT in real-world clinical practice, and to more closely examine the suitability of the method for use in younger patients. Second, the size of study population was small and limited the power of the study to detect statistically significant between-visit differences and between-parameter correlations for some measures, most notably in the occurrence of bone pain. The small size of the study population was associated with several factors. GD is a rare disease with an estimated prevalence of 1 in 140 000 in France [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. According to the CETG registry, there were 97 patients with GD living in France who had received at least one dose of velaglucerase alfa at the time of the study. Among the centers managing these patients, only those treating more than one patient were invited to participate and only patients with GD1 and digital records of MRIs conducted within the 5 years preceding velaglucerase alfa initiation, or within the 3 months following treatment initiation, were eligible for study inclusion. Future studies involving larger populations would help to further clarify the extent to which ERT can prevent bone infiltration, and allow more detailed characterization of patients who are at highest risk of bone disease progression despite treatment. Ideally, a more organized, well-funded, international approach is required, perhaps using a purpose-designed platform for data collection. However, to allow pooling of all the collected data it is important that consensus is reached on MRI monitoring protocols and on the terminology used to describe the bone lesions, with the terms osteonecrosis, avascular necrosis, aseptic osteonecrosis and bone infarct often being used interchangeably in the literature, regardless of the anatomical location of the lesion. The size of the population also did not allow for a separate evaluation of disease evolution in patients that had undergone splenectomy, although the impact of this intervention on treatment responses has been reported previously [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Due to the retrospective nature of part of the study, the only GD marker with a sufficient amount of data available for longitudinal analysis was chitotriosidase, as more recently validated markers, such as glucosylsphingosine (lyso-Gb1) [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e], were not commonly used in clinical practice at time when many of the patients included in study initiated velaglucerase alfa treatment. Finally, the duration of the interval between the first and last available measure varied for each variable, reflecting the monitoring regimen of individual patients.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study provided useful data indicating the long-term real-word effectiveness of velaglucerase alfa for the treatment of GD1 bone manifestations in treatment-naive and switched patients. Our findings also highlighted the difficulties associated with using BMB scores for monitoring bone treatment responses in routine clinical practice. Specialized training for local radiologists and/or a centralized analysis reference platform may improve bone monitoring. The simplified qualitative bone infiltration analysis method used in the current study indicated that bone infiltration improved in treatment-naive patients and remained stable for treatment-switched patients. In addition, improvements in bone infiltration were observed in patients with shorter treatment durations (\u0026lt;\u0026thinsp;3.5 years with velaglucerase alfa alone or velaglucerase alfa plus a prior GD treatment), whereas for patients with longer treatment durations (\u0026gt;\u0026thinsp;6 years) bone infiltration remained stable. These results therefore support those of previous studies suggesting that the interval between MRI evaluations can be increased to every 5 years in patients with long-term stabilization of bone infiltration. Although larger validation studies are needed, our findings suggest that when a GD expert radiologist is not available, an easier qualitative analysis method could be a valuable tool for routine bone monitoring in clinical practice. Evaluation of the clinical characteristics of the patients suggested that velaglucerase alfa treatment also appeared to be associated with a reduction in bone pain. Similar patterns of improvement and stabilization were observed in the two groups for the reduction in liver and spleen volumes and hematologic parameters.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding source(s):\u003c/p\u003e\n\u003cp\u003eThis study was funded by Takeda Pharmaceutical Company Limited, France.\u003c/p\u003e\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study (trial registration number: NCT03333447)\u0026nbsp;was performed in accordance with Good Clinical Practice guidelines\u0026nbsp;and all patients, or their legally authorized representative, provided signed consent before being enrolled in the study. In accordance with French law, approval for the processing of personal data was obtained from the French data protection agency \u003cem\u003e(Commission Nationale de l\u0026apos;Informatique et des Libert\u0026eacute;s; CNIL\u003c/em\u003e) and the study methodology was approved by the French advisory committee on information processing in healthcare research (\u003cem\u003eComit\u0026eacute; Consultatif sur le Traitement de l\u0026apos;Information en mati\u0026egrave;re de Recherche dans le domaine de la Sant\u0026eacute;; CCTIRS\u003c/em\u003e).\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eN. Belmatoug received travel grants and honoraria for consultancy, and as a board participant and speaker from Sanofi and Takeda. Her institution received funds for clinical trials and research grants from Sanofi and Takeda. M. Berger received honoraria for interventions in scientific boards and has received financial support for conference participation from Takeda, Sanofi, Pfizer, and Novartis. M. Bengherbia joined Takeda after study completion, and M Maric, and M. Malcles are employees of Takeda France SAS. None of the authors have\u0026nbsp;stocks or shares in this organization. L. Bracoud and O. Vaeterlein are employees of Clario (formerly Bioclinica). F. Rigaudier is an employee of CEN Biotech. B. Hivert and K. Yousfi have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eFunding for the study, and for medical writing assistance (supplied by\u0026nbsp;Sant\u0026eacute; Active Edition\u0026nbsp;- Synergy Pharm), was provided by Takeda France SAS. The sponsor played no role in the design of the study or the collection, analysis or interpretation of the data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eM. Bengherbia and N. Belmatoug were responsible for the design of the study and the\u0026nbsp;acquisition, analysis and interpretation of the data. F. Rigaudier made substantial contributions to the analysis and interpretation of the data, and M. Berger, K. Yousfi and B. Hivert\u003csup\u003e\u0026nbsp;\u003c/sup\u003emade substantial contributions to data acquisition and analysis. L. Bracoud and O. Vaeterlein were responsible for the analysis and interpretation of the MRI data. N. Belmatoug, and M. Malcles made major contributions to writing the first draft of the paper, and all authors made substantial contributions to revising and reviewing subsequent drafts. All authors approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Drs Pascal Hutin (h\u0026ocirc;pital La\u0026euml;nnec\u0026ndash;Site de Quimper), Vanessa Leguy-Seguin (CHU Dijon Bourgogne), Yves-Marie Pers (H\u0026ocirc;pital Lapeyronie), Clara Mariette (CHU Michallon), Claire Gay (CHU Saint Etienne), and Valerie Li Thiao Te (CHU Amiens) for their participation in the study, together with Cinira Lef\u0026egrave;vre (RWE strategy lead) for help reviewing the statistical methodology and analysis. We would also like to thank Drs Emma Pilling and Marielle Romet (Sant\u0026eacute; Active Edition - Synergy Pharm) for medical writing assistance. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, Serratrice J, Brassier A et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci 2017;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNalysnyk L, Rotella P, Simeone JC, Hamed A, Weinreb N. Gaucher disease epidemiology and natural history: a comprehensive review of the literature. Hematology. 2017;22:65\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHughes D, Mikosch P, Belmatoug N, Carubbi F, Cox T, Goker-Alpan O, Kindmark A, Mistry P, Poll L, Weinreb N, et al. Gaucher Disease in Bone: From Pathophysiology to Practice. 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Intraobserver and interobserver variability of the bone marrow burden (BMB) score for the assessment of disease severity in Gaucher disease. Possible impact of reporting experience. Blood Cells Mol Dis. 2018;68:121\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaudemann K, Moos L, Mengel KE, Lollert A, Reinke J, Brixius-Huth M, Wagner D, D\u0026uuml;ber C, Staatz G. Evaluation of Bone Marrow Infiltration in Non-Neuropathic Gaucher Disease Patients with Use of Whole-Body MRI\u0026ndash;A Retrospective Data Analysis. Rofo. 2015;187:1093\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDegnan AJ, Ho-Fung VM, Ahrens-Nicklas RC, Barrera CA, Serai SD, Wang DJ, Ficicioglu C. Imaging of non-neuronopathic Gaucher disease: recent advances in quantitative imaging and comprehensive assessment of disease involvement. Insights Imaging. 2019;10:70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeegan PB, Pavlova E, Tindall J, Stein PE, Bearcroft P, Mehta A, Hughes D, Wraith JE, Cox TM. Osseous Manifestations of Adult Gaucher Disease in the Era of Enzyme Replacement Therapy. Medicine. 2011;90:52\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Dussen L, Biegstraaten M, Dijkgraaf MG, Hollak CE. Modelling Gaucher disease progression: long-term enzyme replacement therapy reduces the incidence of splenectomy and bone complications. Orphanet J Rare Dis. 2014;9:112.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStirnemann J, Belmatoug N, Vincent C, Fain O, Fantin B, Mentr\u0026eacute; F. Bone events and evolution of biologic markers in Gaucher disease before and during treatment. Arthritis Res Ther. 2010;12:R156.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Fost M, van Noesel CJ, Aerts JM, Maas M, P\u0026ouml;ll RG, Hollak CE. Persistent bone disease in adult type 1 Gaucher disease despite increasing doses of enzyme replacement therapy. Haematologica. 2008;93:1119\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMistry PK, Deegan P, Vellodi A, Cole JA, Yeh M, Weinreb NJ. Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis. Br J Haematol. 2009;147:561\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBracoud L, Ahmad H, Brill-Almon E, Chertkoff R. Improving the accuracy of MRI spleen and liver volume measurements: a phase III Gaucher disease clinical trial setting as a model. Blood Cells Mol Dis. 2011;46:47\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZimran A, Wang N, Ogg C, Crombez E, Cohn GM, Elstein D. Seven-year safety and efficacy with velaglucerase alfa for treatment‐na\u0026iuml;ve adult patients with type 1 G aucher disease. Am J Hematol. 2015;90:577\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElstein D, Cohn GM, Wang N, Djordjevic M, Brutaru C, Zimran A. Early achievement and maintenance of the therapeutic goals using velaglucerase alfa in type 1 Gaucher disease. Blood Cells Mol Dis. 2011;46:119\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Dussen L, Hendriks E, Groener J, Boot R, Hollak C, Aerts J. Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy. J Inherit Metab Dis. 2014;37:991\u0026ndash;1001.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaskovalova T, Deegan PB, Mistry PK, Pavlova E, Yang R, Zimran A, Berger J, Bourgne C, Pereira B, Labar\u0026egrave;re J, et al. Accuracy of chitotriosidase activity and CCL18 concentration in assessing type I Gaucher disease severity. A systematic review with meta-analysis of individual participant data. Haematologica. 2021;106:437\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRevel-Vilk S, Fuller M, Zimran A. Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review. Int J Mol Sci 2020;21.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gaucher disease, lysosomal storage disorder, bone marrow infiltration, hepatosplenomegaly, thrombocytopenia, real-world data, enzyme replacement therapy, velaglucerase alfa, magnetic resonance imaging.","lastPublishedDoi":"10.21203/rs.3.rs-3694934/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3694934/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eGaucher disease type 1 (GD1) is a rare autosomal recessive disorder characterized by hepatosplenomegaly, thrombocytopenia, and disabling bone manifestations that require regular MRI monitoring to assess disease progression and treatment responses. Velaglucerase alfa therapy results in long-term improvements in hematologic and visceral manifestations, but more real-world data on its impact on bone manifestations are needed. The EIROS study aimed to address this knowledge gap by using MRI data collected in daily practice in France to assess the impact of velaglucerase alfa on GD1 bone disease.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients with GD1 and bone MRI data from around the time of velaglucerase alfa initiation were eligible for inclusion. All MRIs collected retrospectively from treatment initiation and prospectively to the end of follow-up (12 months) were analyzed centrally by a blinded expert radiologist to evaluate bone infiltration using the Bone Marrow Burden (BMB) score and a qualitative method (scored for the spine and femur: stable, improved or worsened). Abdominal MRIs were also centrally analyzed to assess hepatosplenomegaly. Reports from bone MRIs, X-rays, and abdominal ultrasounds made by local radiologists were also collected. Clinical (acute and chronic bone pain) and biological parameters were analyzed from medical records.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMRI data were available for 20 patients from 9 hospital centers: 6 treatment-naive patients and 14 patients who switched to velaglucerase alfa from another GD treatment. Readable MRIs for BMB scoring were only available for 7 patients for the spine and 1 patient for the femur. Qualitative assessments, performed for 18 patients, revealed stability in spine and femur infiltration in 100.0% and 84.6% of treatment-switched patients (n\u0026thinsp;=\u0026thinsp;13), respectively, and improvements in 80.0% and 60.0% of treatment-naive patients, respectively; no worsening of bone infiltration was observed. Liver, spleen and hematologic parameters improved in treatment-naive patients and remained stable in treatment-switched patients.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis study provided real-world evidence suggesting the long-term effectiveness of velaglucerase alfa treatment in GD1, including bone manifestations. The data indicate that if MRI assessment by a radiologist with experience of GD bone manifestations is not possible, a simplified qualitative assessment provides sufficient evidence in clinical practice for monitoring bone disease progression and treatment response.\u003c/p\u003e","manuscriptTitle":"A retrospective and prospective observational study of MRI changes in bone in patients with type 1 Gaucher disease treated with velaglucerase alfa: the EIROS study.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-12 16:10:12","doi":"10.21203/rs.3.rs-3694934/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"847e701a-3640-4ed3-82d4-fbe91752cb7d","owner":[],"postedDate":"February 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-03T10:13:46+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-12 16:10:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3694934","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3694934","identity":"rs-3694934","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}