British Journal of Radiology 75 (2002),A25-A36 © 2002 The British Institute of Radiology
Response of Gaucher bone disease to enzyme replacement therapy
L W Poll, MD1,
M Maas, MD2,
M R Terk, MD3,
M Roca-Espiau, MD4,
B Bembi, MD5,
G Ciana, MD5 and
N J Weinreb, MD6
1 Institute of Diagnostic Radiology, Heinrich Heine University, Düsseldorf, Germany, 2 Department of Radiology, Academic Medical Centre, Amsterdam, The Netherlands, 3 Keck School of Medicine, University of Southern California, USA, 4 Department of Radiology, Musculoskeletal MRI Section, Miguel Servet Hospital, Zaragoza, Spain, 5 Burlo Garofolo Institute, Trieste, Italy and 6 University Gaucher Research Foundation Inc., University Gaucher Treatment Center, Tamarac, Florida, USA
Correspondence: Ludger W Poll, Institute of Diagnostic Radiology, Heinrich Heine University, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Tel. +49 211 81 17752; Fax +49 211 81 16145; email polll{at}uni-duesseldorf.de
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Abstract
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In Gaucher disease, enzyme replacement therapy usually reduces liver and spleen volumes and improves haematological abnormalities within 1 year. In contrast, skeletal manifestations of Gaucher disease are thought to respond more slowly. For example, decreased bone marrow glycolipid infiltration and increased bone mineral density have been reported to take up to 3–4 years of treatment. In this report, we present recent studies using T1- and T2-weighted MRI and quantitative chemical shift imaging that demonstrate decreases in abnormal glucocerebroside infiltration and increases in normal fat content of bone marrow within the first year of treatment. There was no obvious relationship between age, gender, splenectomy status or genotype and the response of bone marrow to therapy. Although the dose of enzyme replacement therapy may be related to bone marrow response, no significant relationship was demonstrated in this report. Long-term enzyme replacement therapy induces continued degradation of Gaucher cell deposits, reconversion of fat marrow and increased bone mineral density. This treatment is also associated with improved or non-progressive bone symptoms and functional status in most adult patients, and it prevents the new occurrence of bone pain and bone crisis in nearly all patients. The development of more sensitive, quantitative imaging methods will help to evaluate disease severity better and to assess the response to therapy.
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Introduction
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Gaucher disease is classified into three types based on the presence and nature of central nervous system involvement [1]. There is substantial clinical variability within all subtypes, particularly within type 1 [2]. Disease progression in type 1 and type 3 Gaucher disease is variable but type 2 Gaucher disease progresses rapidly and is usually fatal within 2 years.
Skeletal manifestations of Gaucher disease have a greater impact on the quality of life than haematological and visceral abnormalities. Accumulation of glucocerebroside in bone marrow is associated with substandard growth in childhood and adolescence, osteopenia, lytic lesions, pathological fractures, chronic bone pain, acute episodes of excruciating bone crisis, bone infarcts, osteonecrosis and skeletal deformities [3].
Until the advent of effective enzyme replacement therapy (ERT) with purified, macrophage-targeted, human ß-glucocerebrosidase derived either from human placenta (alglucerase) or from recombinant DNA production methods (imiglucerase), treatment of skeletal manifestations was largely restricted to relief of symptoms and to post facto management of orthopaedic complications. Improvements in haematological parameters and reductions in visceral organ volumes are observed within 6–12 months of ERT [4]. However, the skeletal response to ERT appears to take longer [5]. The severity, frequency and duration of painful bone crises may be reduced within the first year of ERT [6, 7], but other measures may not improve within the first 3 years of therapy, although this may be due to the relative insensitivity of the techniques applied to detecting improvement. Long-term treatment over 3–4 years improves marrow composition and bone mass [8]. Although local disease and generalized osteopenia respond well to ERT, success in treating existent focal disease in adults is less likely because of irreversible damage such as bone death.
In this paper, we present the most recent data on the long-term effects of ERT from various centres, with a particular focus on the response of skeletal aspects.
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German data
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Successful ERT in adult patients results in replacement of the glucocerebroside-laden Gaucher cells in marrow with triglyceride-rich adipocytes (yellow marrow). Thus, ERT-induced changes to bone marrow can be studied using MRI with subcutaneous fat as an internal standard [9]. At the Heinrich Heine University in Düsseldorf, Germany, a score of eight anatomical sites was used for evaluation of bone marrow abnormalities of the lower extremities. Using coronal T1- and T2-weighted spin echo MRI of the lower extremities, the response of skeletal disease to ERT in 30 patients with type 1 Gaucher disease was assessed (Table 1
) [10].
The baseline data for these 30 patients are shown in Table 2. The bone marrow response to ERT was analysed by dose, by genotype and by morphology (type A morphology is homogenous and type B morphology is non-homogenous as described in Poll et al [10]).
Non-skeletal aspects of Gaucher disease improved in all patients. After a median of 36 months of treatment (range 9–72 months), 63% of patients showed a bone marrow response, namely increased signal intensity on the follow-up MR examination owing to a partial reconversion of fat marrow (Table 3). This response was observed as early as 9 months after starting therapy (Figure 1). The median time on ERT was similar among responders (38 months (9–66 months)) and non-responders (32 months (9–72 months)) and gender did not influence response. The median score in the responder and non-responder groups was 6.5 and 5.8, respectively (non-significant difference). An intra-individual change in this score over the longest follow-up interval was not detectable.
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Table 3. German efficacy data on the effects of enzyme replacement therapy on skeletal aspects of Gaucher disease measured by MRI
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Figure 1. Coronal T1-weighted magnetic resonance images of the femurs, TR/TE 615/25, of a patient with Gaucher disease from a study conducted at Heinrich Heine University Düsseldorf: (a) before starting enzyme replacement therapy (ERT); (b) after 9 months of ERT (60 U/kg/2 weeks).
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In this sample, bone marrow response to ERT was not dependent on the dose of ERT, on whether patients were splenectomized or not, or on the morphology of bone disease (Table 3
). However, the small number of patients makes it difficult to detect any significant differences and certain biases exist. For example, there is a trend towards a greater response in more severely affected patients with type B morphology (Table 3), but all patients with type B morphology received the highest dose of ERT, which may have biased the response data.
Focal bone lesions surrounded by a low signal intensity rim were visible on MRI in 11 patients. These lesions were most frequent in patients with type B morphology (82%; p=0.0021) and in splenectomized patients (86%; p=0.0045), and did not respond to ERT, which suggests that the lesions were bone infarcts (Table 2).
In general, the skeletal response to ERT depended on the degree of bone marrow involvement, and delaying ERT may result in irreversible bone marrow changes.
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American data
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Bone marrow response to ERT has also been assessed using coronal T1-weighted MRI of femurs at The Keck School of Medicine of the University of Southern California (Table 1). In addition, correlation between marrow responses and reductions in liver and spleen volumes was assessed [11]. The T1-weighted images were analysed blindly.
Of 42 patients with Gaucher disease, 32 received ERT, of which 16 had an MRI assessment before starting ERT, and 10 patients did not receive ERT. Baseline characteristics are shown in Table 4.
Patients were treated with alglucerase or imiglucerase for a median of 34 months (range 12–56 months). Liver volumes were reduced in 81% (26/32) of treated patients and spleen volumes were reduced in 93% (28/30) of treated, non-splenectomized patients. Overall, 44% (14/32) of patients showed a marrow response. If only patients with pretreatment MRI assessments showing abnormal marrow are included, 67% (10/15) of patients responded. Two patients had increased bone marrow signal intensity after 13 months of treatment, and it is possible that earlier MRI assessment may have detected improvement within the first year of treatment.
Bone marrow response was not dependent on the length of time on ERT (mean follow-up 35 months (14–38 months) and 33.6 months (13–54 months) in the non-responding and responding groups, respectively), age or gender. Analysis of the effects of ERT dosage on skeletal response was not possible because the dosage of ERT varied during the course of this study. 2 (20%) of the 10 patients who had been splenectomized had a marrow response to treatment, whereas 12/22 (55%) non-splenectomized patients had a marrow response (p=0.55; 
2 test). One untreated patient showed an apparent marrow response, the reasons for which are not clear.
A subgroup of five patients had heterogenous signal increases on T1-weighted images. In some of these patients, non-responding focal lesions were not visible on pretreatment scans and became more conspicuous after treatment. Care must be taken not to mistake these for new lesions.
Changes in T1-weighted images correlated to reductions in liver and spleen volumes. The mean spleen volume reduction was 50% in patients with a marrow response and 4% in non-responders (p=0.00038; Student's t-test; Figure 2); the mean reduction in liver volume was 20% in patients with a marrow response but the volume increased by 6% in non-responders (p=0.005).
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Figure 2. Plot of changes in T1-weighted marrow images against spleen volume changes for patients studied at The Keck School of Medicine of the University of Southern California. Mean volumes are shown numerically. Reproduced from Skeletal Radiol 2000;291:563–71 [11] with permission of the International Skeletal Society.
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A quantitative method for detecting relative differences in the fat concentration in bone marrow has been tested [12]. Using bone marrow H1 spectroscopy, the ratio of the fat and water in bone marrow was determined for the metaphysis and epiphysis, and the ratio of these two values was calculated. The mean ratio in six patients with Gaucher disease significantly differed from the mean ratio in 12 normal volunteers.
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Spanish data
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Since 1993, all patients with Gaucher disease in Spain have been monitored in an anonymous database. By December 2000, the database included 178 patients, of whom 124 were receiving ERT. Significant improvements in haemoglobin and platelet counts and decreases in liver and spleen volume were observed in the 124 patients receiving ERT. 35 patients who received ERT for at least 4 years had an improved perception of their health.
A semiquantitative scoring system for Gaucher disease which reflects bone marrow involvement as well as other disease variables has been developed at the Miguel Servet Hospital in Zaragoza, Spain. The spine, pelvis and femur of 18 patients with type 1 Gaucher disease were assessed by MRI (Table 1). Three distinct patterns of bone marrow involvement were defined: no infiltration (N), non-homogenous morphology pattern of infiltration (NH) and homogenous morphology pattern of infiltration (H). The NH morphology was subclassified into reticular pattern (NHR), mottled pattern (NHM) and diffuse (NHD) (Figure 3). The score assigned to each pattern on MRI (H=4, NHD=3, NHM=2, NHR=1 and complications=4) was combined with the Zimran severity score index [13, 14] to give a total score for disease severity. Of the 18 patients, two had mild disease (score 0–10), 14 had moderate disease (score 11–25) and two had severe disease (score 26 and above) (Table 5). Although untested for measuring response to ERT, this scoring system may be useful.
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Figure 3. Patterns of bone marrow involvement on magnetic resonance images, TR/TE 600/20 from patients studied at Miguel Servet Hospital: (a) homogenous morphology or pattern of involvement on a sagittal T1-weighted MRI of the spine; (b) non-homogenous diffuse morphology on a sagittal T1-weighted magnetic resonance image of the spine; (c) non-homogenous mottled morphology on a coronal T1-weighted magnetic resonance image of the pelvis; (d) non-homogenous reticular morphology on a coronal T1-weighted magnetic resonance image of the femurs.
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Skeletal response to ERT (30 U/kg every 2 weeks) was measured in 6 patients using MRI. Quantification of the response was attempted by graphically representing the number of pixels on an MRI in a defined area of the lumbar spine (L3 and L4) before and after 2 years of therapy. The signal intensity increased in 3 patients, consistent with decreased bone marrow infiltration. The signal was unchanged in 2 patients. The bone marrow infiltration increased in one patient, for whom the dose of ERT was then increased to 60 U/kg every 2 weeks.
Quantitative use of MRI needs to be tested more thoroughly but may be useful in combination with other quantitative measures of bone marrow response.
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Dutch data
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Quantitative chemical shift imaging (QCSI), a very reproducible technique [15], can be used to measure the quantities of fat and water in bone marrow, because of the differences in the resonant frequencies of the protons in water and fat molecules [15, 16]. The relative fat signal on MRI is decreased in Gaucher disease because the total mass of lipid in bone marrow is less. A correlation between QCSI and Gaucher disease severity has been demonstrated [17], and a response to ERT has been detected using QCSI [8]. QCSI is being used at the Academic Medical Centre in Amsterdam, The Netherlands, to monitor the response to ERT in 58 patients with type 1 Gaucher disease. In this way the individualized dosing schemes are monitored and, if necessary, adjusted [18]. Axial bone marrow of the lumbar spine was assessed every year by QCSI and follow-up data have been collected for 24 patients (Figure 4). In 11/12 patients with follow-up data of at least 2 years, QCSI measured a marked elevation of the fat fraction indicating a bone marrow response [19]; a significant increase in the fat fraction after 1 year of treatment has already been reported [20].
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Figure 4. Colour representation of the change in the bone marrow fat fraction (as measured by QCSI every year) in the lumbar spine of a patient with Gaucher disease receiving ERT. The darker colours represent a lower fat fraction as shown on the scale.
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Alternative quantitative MRI methods are being tested in The Netherlands because QCSI is not widely available [21, 22]. One method, the vertebra-disk ratio (VDR) is calculated from T1-weighted spin echo MRI by dividing the signal intensity of the bone marrow of the lumbar spine L3 by the signal intensity of an adjacent healthy intravertebral disc (L3/L4). The VDR of a patient can then be compared with the normal range of healthy age-matched adults [31]. In most of the patients with Gaucher disease, ERT resulted in a normalization of the VDR within 1–2 years (Figure 5). The VDR correlated well with the QCSI measurements in the same patients (Vlieger et al, in preparation).
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Figure 5. Change with time in VDR score in patients with Gaucher disease: (a) untreated patients studied at the Academic Medical Centre in Amsterdam; (b) patients receiving enzyme replacement therapy.
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The bone marrow burden score [31] may also be useful for quantifying response of bone marrow to ERT. The bone marrow burden score is based on the signal intensity of T1- and T2-weighted images of the femurs and the lumbar spine, and on the sites of infiltration. Initial data suggest that response is detected later than with QCSI, but these data are still being analysed.
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Italian data
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Osteopenia in patients with Gaucher disease is associated with a significant reduction in lumbar bone mineral density (BMD) [23]. Dual-energy X-ray absorptiometry (DXA) can be used to measure BMD, and may be useful for measuring generalized osteopenia and its response to ERT in patients with Gaucher disease. DXA is being used at the Burlo Garofolo Institute in Trieste, Italy, to assess changes in lumbar BMD in patients with type 1 Gaucher disease receiving ERT.
The baseline characteristics of 24 patients are shown in Table 6. The mean follow-up and treatment period was 5.7 years (range 4–8.1 years); only data from patients who received ERT for 4 years or longer are presented here. In most patients, there was a subjective improvement in bone pain within the first year. This improvement came in the form of relief from mechanical pain due to osteonecrosis and was observed in approximately 50% of patients. This may suggest that ERT has an effect on pain associated with Gaucher cell infiltration, which may lead to physical compression of the intramedullary blood vessels and bone marrow tissue. However, focal bone lesions, monitored with plain radiography, did not show any morphological improvement. A worsening of femoral head deformation was evident after 6 years of treatment and two cases of progressive degenerative knee joint changes were observed owing to previous osteonecrosis of distal femur and tibial plateau, respectively. These data indicate that existing osteonecrosis and arthritic sequelae can evolve independently from treatment, and the "true bone pain" associated with such events have little chance of improving with ERT.
BMD measurements were taken in 10 of these patients at L1–L4 of the lumbar spine every 4–6 months for the first year then once every year. The mean BMD of these 10 patients increased within 6 months of starting ERT and continued to increase over the next 4 years (Table 7). However, the increase in the mean BMD was not significant until 4.5 years after starting ERT. The mean lumbar BMD Z score also increased significantly from -0.67 at baseline to -0.41 (p=0.004; Student's two sided t-test) at the last DXA assessment (mean 4.5 years). Although the mean BMD Z score increased significantly, the increase in some individuals was small. In children, improvements in BMD induced by ERT may appear more rapid and consistent than in adults [32], but this probably reflects an initially lower lumbar BMD in children, who generally have more diffuse skeletal involvement. Adult patients generally present with less severe generalized osteopenia but more pronounced focal involvement.
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Table 7. Change in mean bone mineral density in 10 patients with Gaucher disease treated with enzyme replacement therapy (measured by dual-energy X-ray absorptiometry) from the Italian study
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Measurement of BMD by DXA appears to be a useful indicator of the resolution of generalized osteopenia during ERT.
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Gaucher Registry data
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The Gaucher Registry is an international, observational, longitudinal registry established by The Genzyme Corporation in 1991. Over 2000 patients have been registered [33].
Baseline data for registered patients are shown in Table 8. Overall, ERT reduced bone pain. 89 (52%) of 172 patients who reported a history of bone pain when they started ERT had no bone pain in the second year of treatment; most of these patients (64) had no bone pain in the first or second year of treatment. Only 8 of 116 (7%) patients who had no history of bone pain at baseline reported bone pain in the second year of ERT. For patients with a history of bone crisis, 57 of 61 (93%) had no recurrence in the second year of ERT, and only 1 of 188 (0.5%) patients with no prior history had bone crisis in the second year of therapy.
Physicians providing data for the Gaucher Registry were asked to provide an overall assessment of the response of bone disease to ERT in their patients. In adults, after 3 years of treatment, 32% (12/37) were classified as improved, 57% (21/37) were classified as stable and 11% (4/37) were classified as worse. For an additional 25 patients with data after 4 years of treatment, 20% (5/25) were classified as improved, 76% (19/25) were classified as stable and 4% (1/25) were classified as worse.
Skeletal complications in Gaucher disease have a significant impact on the quality of life of patients and can severely impair the mobility of the patient. An important aim of ERT is therefore to improve the functional status of patients. Among patients on the Gaucher Registry with baseline data on mobility status, most patients with mobility problems improved or stabilized within the first year of receiving alglucerase/imiglucerase (Figure 6). 151 of 152 patients who were unrestricted at baseline remained unrestricted after 1 year of therapy; one patient had difficulty in walking.
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Figure 6. Change after 1 year of enzyme replacement therapy in the functional status of patients in the Gaucher Registry with restricted mobility at baseline.
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Discussion
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These recent data from America and Europe demonstrate the efficacy of ERT in the treatment of Gaucher disease. Improvements in haematological parameters and reductions in visceral volumes confirm previous studies [6, 24, 25], and several skeletal complications improved with treatment. However, most focal skeletal complications consist of irreversible lesions that would not be expected to respond to ERT.
The most striking results were those showing a rapid response of bone marrow to ERT. In some patients, improvement in bone marrow was detected with MRI within the first year of treatment [10]. Changes were detected in the femurs of one patient after 9 months of treatment, but the findings from The Netherlands suggest that bone marrow response may be detectable, with sensitive techniques, in the lumbar spine even sooner. The observed rapid improvements in bone marrow challenge the belief that bone responses to ERT develop more slowly than visceral responses. In support of this is the observation that rapid haematological responses occur in splenectomized patients, suggesting a direct effect of ERT on the bone marrow. The evidence from these reports suggests that, even in patients with a relatively rapid bone marrow response, the bone marrow continues to improve with several years of treatment and prolonged treatment is needed to achieve normalization.
The increase in the mean BMD was evident within the first year of ERT but this did not reach significance until 4.5 years after starting ERT. Although increases were rapid in some individuals, it remains to be seen whether these increases are maintained in the longer term. Those patients who showed only minor improvements in BMD (even after several years of therapy) may be candidates for investigative trials of adjunctive agents such as bisphosphonates.
The reduction in bone pain within the first year of treatment has been demonstrated previously [6, 7]. Results from the Gaucher Registry suggest that reductions in bone pain continue after the first year of therapy and that recurrence is infrequent. Bone pain in Gaucher disease takes many forms, and the causes of the different types of pain are often not well defined. The data collected so far indicate that generalized bone pain responds best to ERT whereas pain attributable to focal, irreversible lesions tends to be more resistant [10].
The faster than expected response of bone disease to ERT may be attributable to advances in imaging technology. The possibility that increased familiarity with ERT has resulted in better management of Gaucher disease should also be considered. However, no conclusions on the optimum ERT dosage can be offered on the basis of this report. The bone marrow response did not display statistically significant dose dependence in the one study in which this was investigated, possibly because the number of patients was small and doses varied. The heterogeneity of the disease, in terms of initial presentation and disease progression, supports an individualized approach to dosing.
The findings show that bone marrow response to ERT in adults with Gaucher disease should ideally be monitored with MRI, which is the most reliable method of assessing bone marrow changes. The results appear to be consistent across the different countries (for example the German and American results are similar) [10, 11]. Although these are qualitative assessments, the consistency increases our confidence in the results. Quantitative methods to measure the bone marrow response to ERT would be useful, and initial results with quantitative methods derived from MRI are promising.
QCSI is the most developed method for the quantitative assessment of bone marrow in Gaucher disease. The QCSI data presented here confirm that bone marrow fat content increases in the first year of ERT and continues to increase for at least 5–6 years. As long as this time- and resource-intensive method remains unavailable in many centres, alternative semiquantitative methods may be useful. VDR and bone marrow burden scores appear to correlate with QCSI but these methods may be less sensitive. Pixel counts of MRIs may help to confirm the qualitative assessments of these images but the accuracy of this method remains untested. MRI scoring may be useful for assessing disease stage and response to therapy. The value of these scoring systems is unclear until they are validated, and a consensus is reached on the relevance of the locations used for measurement.
DXA is the best quantitative method for the measurement of generalized osteopenia. Changes in bone density are slow, as they are probably dependent on normalization of bone marrow. Changes in DXA scores are therefore only seen after long term treatment. DXA is insensitive to local changes, and its usefulness is limited because the natural history of osteopenia in Gaucher disease is unknown. DXA is not useful in patients with avascular necrosis of the hip, collapse of vertebrae or sclerosis, because of erroneous high values for BMD.
In general, the lack of information on the natural history of bone complications in Gaucher disease makes analysis of the response of bone pain, bone crisis and bone marrow to ERT difficult. The long-term stabilization of bone disease by ERT is considered a success, but some authors have suggested that bone disease progresses slowly or not at all in untreated adults with Gaucher disease [7, 14]. In contrast, many more reports have demonstrated progression of the skeletal aspects of Gaucher disease in most non-Jewish, untreated, adult patients [26–29]. In a recent report, one adult patient showed deterioration of bone disease on MRI within 2 years of ERT cessation [30].
Despite the success of ERT for type 1 Gaucher disease, some of the patients in the American study had no measurable bone marrow response. These patients also have relatively minor reductions in liver and spleen volumes. Inadequate dosage of ERT may explain a suboptimal response. The lack of a sensitive method for measuring bone marrow response may also explain this, and emphasizes the need for sensitive tools to assess the extent of bone marrow involvement and to direct possible dose adjustments.
In conclusion, these new data confirm the efficacy of ERT for Gaucher disease. Visceral organ volumes are reduced, haematological parameters are improved and the incidence and severity of skeletal complications are reduced. The initial response of bone marrow may be as rapid as the reductions in liver and spleen volumes in some patients, but bone marrow responses are more difficult to quantify and a maximal response usually takes a long time to achieve. Changes in the mineral phase of the skeleton are slower because they are dependent on the marrow response. However, it is imperative to emphasize that bone destruction and related pain are irreversible. T1- and T2-weighted MRI is a good method for measuring bone marrow changes and quantitative methods of measuring these changes are being studied. BMD increases can be quantified using DXA. Delaying ERT may result in irreversible changes to bone and marrow, and lead to functional disability that could otherwise be prevented.
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Acknowledgments
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We would like to thank and acknowledge the invaluable input from P Giraldo (Spanish Gaucher Registry), J-A Koch (Germany), S vom Dahl (Germany), E M Akkerman (The Netherlands), J M F G Aerts (The Netherlands) and C E M Hollak (The Netherlands). In addition, we are grateful for the indispensable contribution to the Gaucher Registry of the hundreds of physicians worldwide in the International Collaborative Gaucher Group.
Received for publication November 2, 2001.
Revision received January 3, 2002.
Accepted for publication January 14, 2002.
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Abstract
Introduction
