Attendees were welcomed to the virtual meeting by chairpersons Professor Johannes Aerts (University of Leiden, Leiden, The Netherlands) and Professor Derralyn Hughes (Royal Free Hospital, London, UK). The meeting covered key topics in the field of Gaucher disease, including: outcomes for untreated patients; novel or investigational therapies; GBA1-associated parkinsonism; risk for malignancy; and bone metabolism and pathophysiology. Clinical considerations and laboratory sessions were also presented, in addition to an introduction to the Young Researchers Network and presentations from the International Gaucher Alliance (IGA).
Day 1 of EWGGD 2020 began with Professor Ari Zimran (Gaucher Unit Shaare Zedek Medical Center, Jerusalem, Israel) explaining that the natural history of untreated Gaucher disease is important for understanding its management. Even though treatments for Gaucher disease were unavailable before 1991, the natural history of the untreated disease had received little attention. Furthermore, support was lacking for the assumption that Gaucher disease followed a progressive course. Professor Zimran and colleagues investigated the disease course through a follow-up of 53 patients and observed patient stabilisation over time, mainly during adulthood.1 However, Professor Zimran emphasised that while the observation of patient stabilisation over time is important for our understanding of the disease, it does not mean that not treating patients with Gaucher disease is advised.
Professor Zimran went on to explain that there are several predictors of severe disease course, for example: early onset of symptoms; particular episodes of bone crisis; “bad genotypes”; family history of an older sibling with severe Gaucher disease; splenectomy; and biomarkers.2-9 In more detail, he explained that it has been observed that the younger the patient who presents with symptoms, the greater the severity of Gaucher disease.2 Therefore, in Professor Zimran’s opinion, all young patients reporting with symptoms must receive treatment. Additionally, particular episodes of bone crisis are also associated with increased severity of disease.3 “Bad genotypes” referred to the predictive relationship between GBA1 mutation and Gaucher disease type.4 Professor Zimran suggested an implication of this finding could be close monitoring of patients with “bad genotypes” for early treatment intervention. For example, as outlined by Elstein and colleagues, a patient presenting with “a family history in a sibling with a rapid acceleration in the course of the disease” was the number one criterion in 1994 for treatment initiation in Israel.5 Professor Zimran observed that the most predictive independent risk factor for late complications, such as avascular necrosis, is splenectomy.6 For biomarkers, Professor Zimran acknowledged that there are some good, specific, predictive biomarkers, such as glucosylsphingosine (lyso-Gb1)7,8 and Dixon quantitative chemical shift imaging (Dixon-QCSI), which is a magnetic resonance imaging technique to measure displacement of fatty marrow by Gaucher cells.9 However, Professor Zimran noted that QCSI is not commonly available.
Since not enough is yet known about Gaucher disease, Professor Zimran explained that further research is required to investigate other clinical aspects of Gaucher disease, for example: which patients are at risk of developing skeletal complications during adulthood; which patients will suffer a severe phenotype despite “good genotypes”, emphasising the need for biomarkers when genotypes alone are not enough; and which patients are at risk of comorbidities such as Parkinson’s disease and cancer.
The second part of this keynote lecture concerned those patients with Gaucher disease who are mildly affected or asymptomatic and never treated. In 1995, at the National Institute of Health conference on Gaucher disease: current issues in diagnosis and treatment, Professor McCabe, who chaired the committee, summarised that “the value of treatment for asymptomatic patients has not been determined”.10 Nearly 25 years later, a paper published in 2019 addressed this topic through a long-term follow-up of 103 mildly affected patients with Gaucher disease Type 1 who had never received enzyme replacement therapy or substrate reduction therapy. They observed that no patients developed clinical bone disease and most had mild hepatosplenomegaly, with nine patients splenectomised. Furthermore, the median lyso-Gb1 level, measured since 2014, was 108.5 ng/mL at the last visit.11 This paper confirmed that mildly affected patients may remain stable for many years without Gaucher disease-specific therapy. Another study of never-treated and non-splenectomised patients with Gaucher disease Type 1, identified in the French registry, found that a more heterozygous patient population (median age [range] at diagnosis, 24.8 years [0.1–72.1]; median [range] time between diagnosis and last evaluation, 7.8 years [0.4–32.4]) still had stable clinical parameters over many years.12 Gaucher disease Type 1 did not worsen in 75% of these patients and some parameters improved (fatigue and haemoglobin concentration) from diagnosis to last evaluation. Professor Zimran summarised the presented research with the following points: that mildly affected patients may remain stable for many years without Gaucher disease-specific therapy; that some untreated non-splenectomised patients with Gaucher disease Type 1 may improve spontaneously; and that the future challenge is to set indications for early, pre-symptomatic therapy.
Next, the speaker discussed the results at a single site in Israel (14:12 males to females) who were mildly affected or asymptomatic. These patients had received treatment but experienced a ‘drug holiday’, such as during the 2009‒2011 global shortage of the enzyme replacement therapy imiglucerase, and reported no incidents of bone crisis, pathological fractures, avascular necrosis or any other clinically significant deterioration. Moreover, key clinical parameters in these patients did not return to pre-enzyme replacement therapy levels.13 Another study performed during this ‘drug holiday’ also suggested that patients with Gaucher disease may have short-term treatment holidays or delayed infusions without experiencing short-term adverse effects.14 However, Professor Zimran emphasised that this could still be reflective of the natural history of the disease instead. He then introduced a recently published paper that used machine learning as a technique to identify risk factors for late complications in Gaucher disease, from which the researchers found that delayed diagnosis and therapy were associated with the most severe, and a higher risk of, complications.15 In Professor Zimran’s opinion, this finding highlights the importance of early diagnosis and therapy for patients with Gaucher disease.
The audience were reminded that there are some symptomatic patients with Gaucher disease who cannot get access to treatment, such as those in ‘under-developed’ countries; thus, he concluded that there is a great need to expand the supply of treatment.
The final part of Professor Zimran’s presentation concerned the recruitment of treatment-naïve patients with Gaucher disease in clinical trials. He listed four challenges, in his opinion, which comprised (1) finding patients with severe phenotypes to allow some comparison with existing therapies; (2) severely affected untreated patients are hard to find in ‘developed’ countries; (3) after finding these patients, success also depends on retaining them for the duration of the trial16; and (4) recruiting untreated patients from ‘under-developed’ countries is associated with significant ethical and logistic considerations. Professor Zimran concluded his presentation by stating that, in his opinion, recruitment into clinical trials can be life changing for patients with Gaucher disease from ‘under-developed’ countries and can improve their lives with otherwise unavailable treatment.
Professor Derralyn Hughes (Royal Free Hospital, London, UK) introduced this session with her observation that there is a need for new and sufficient treatments of Gaucher disease for patients who cannot be appropriately treated with currently available therapies. Professor Hughes emphasised that in her experience, many patients with Gaucher disease have been successfully managed with enzyme replacement therapy or substrate reduction therapy, thus improving their lives. However, she noted that the optimal management of the brain, bones, and in some cases, lymph nodes in patients with Gaucher disease requires further treatment exploration. Should new treatment options be developed, different methods of measuring outcomes and understanding the success of those therapies may be required. She indicated that this was particularly important for areas of research that have not conventionally been studied in Gaucher disease. Professor Hughes concluded her introduction by emphasising that novel or investigational treatments for Gaucher disease are important. In the first session, presenters discussed unpublished novel or investigational treatments that are currently being investigated for Gaucher disease.
The second session of EWGGD 2020 included presentations on the clinical manifestations of Gaucher disease, many of which contained presently unpublished data. The topics of liver steatosis and parkinsonism in patients with Gaucher disease included published data and are highlighted below.
Liver steatosis is associated with metabolic risk factors and liver fibrosis in adult patients with Gaucher disease Type 1
Professor Francesca Carubbi (University of Modena and Reggio Emilia, Emilia-Romagna, Italy) presented the results of a multicentre, prospective, observational study, which aimed to assess the prevalence and predictors of significant liver fibrosis in 37 adult patients with Gaucher disease Type 1.17 Baseline demographics were as follows: median age (range) of 46 (18‒78) years; 57% of patients were male; and 30% of patients had moderate-marked Gaucher disease severity. Additionally, 27% were splenectomised and 95% of patients had received enzyme replacement therapy (median duration [range] of 98 [0‒294] months). The median liver stiffness value (range) was 4.6 (3‒15.1) kPa, with seven patients (19%) showing a significant fibrosis as a Fibroscan® liver stiffness ≥7 kPa.
The speaker then listed the following factors associated with liver stiffness: severity of Gaucher disease according to the disease severity scoring system (DS3); number of factors of metabolic syndrome; angiotensin-converting enzyme; and low levels of high-density lipoprotein cholesterol. Professor Carubbi went on to explain that to assess the importance of the length of enzyme replacement therapy on liver stiffness, a sensitivity analysis was performed. Results from the study showed that the variables associated with significant fibrosis among the 29 patients who had received enzyme replacement therapy for ≥24 months were: a past history of splenectomy (p=0.009); having moderate-marked Gaucher disease according to the DS3 (p=0.004) and severity score index (p<0.001); and two non-N370S mutations (GBA1 variants) [p<0.001]. Furthermore, liver stiffness was significantly associated with diastolic blood pressure (rho=0.424, p=0.022); body mass index (BMI) (rho=0.419, p=0.024) and the number of factors of metabolic syndrome (rho=0.417, p=0.025). The finding that liver stiffness increased across all BMI categories (p=0.026), raises the question of liver steatosis (abnormal retention of fat).16
Professor Carubbi ended her talk voicing her opinion that, despite the current available therapies for Gaucher disease, the adoption of an unhealthy lifestyle in some patients is leading to metabolic dysfunction-associated fatty liver disease. Therefore, advice on ensuring a healthy lifestyle should be given to all patients with Gaucher disease.
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Cognitive decline and depressive symptoms; early non-motor presentations of parkinsonism among Egyptian Gaucher patients
Professor Amira Adly (Ain Shams University, Cairo, Egypt) presented results of a cross-sectional study in Egyptian patients with Gaucher disease Type 1, that investigated correlations of parkinsonian features with genotype, phenotype, severity scoring index (SSI), cognitive function and the presence of depressive symptoms.18 Between October 2018 and September 2019, 24 patients with Gaucher disease Types 1 and 3 attended the haematology/oncology clinic in Ain Shams University and were enrolled in the study. Patients with severe neurological affection and other central nervous system diseases were excluded.18
It was explained that patients' family history of parkinsonian manifestations, neurological symptoms and haematological manifestations were recorded. Patients also received a complete physical evaluation, and abdominal and neurological examinations. Gaucher disease severity was assessed using the SSI. Neuropsychiatric evaluations included the Unified Parkinson’s Disease Rating Scale (UPDRS), the Beck Depression Inventory (BDI) and the Wechsler Intelligence Scale. A movement-disorder specialist reassessed the nature of the tremors observed. Laboratory and radiological investigations comprised the following: complete blood count; examination of peripheral blood-stained smears; glucocerebrosidase enzyme activity; plasma chitotriosidase; molecular analysis of the GBA1 gene; and abdominal ultrasonography to assess the volume of the liver and spleen.18
Summarising the results, the speaker stated that none of the 24 patients with Gaucher disease included in the study had a family history of parkinsonism; however, 16 patients had positive parkinsonian features, with a male-to-female ratio of 1:1; 13 had an L483P mutation. Patients with parkinsonian features had higher SSI compared with those without parkinsonian features (p<0.001). The most common motor manifestations were bradykinesia (75%), rigidity (16.6%) and resting tremors (12.5%). The median modified Hoehn and Yahr staging of those with Gaucher disease and parkinsonian features was 2; the median UPDRS for mentation behaviour and mood was 3. Mild memory loss (43.75%), depression (37.5%) and loss of initiative to non-routine activities (25%) were the most common findings.18
Professor Adly went on to explain that patients with parkinsonian features had significantly lower cognitive function (p=0.007) and significantly higher depressive symptoms (p=0.031) than those without parkinsonian features. A total of 10 patients with positive parkinsonian features had depressive symptoms, of whom four had mild depression, three had moderate depression and three had severe depression. Logistic regression analysis indicated that Gaucher disease genotype, Gaucher disease type and cognitive deficit were the only significant independent factors associated with the development of parkinsonian features among patients with Gaucher disease in this cohort (p=0.003, p=0.006 and p=0.03, respectively).18
In Professor Adly's opinion, an increased lifespan and improved somatic manifestations of Gaucher disease on enzyme replacement therapy may lead to patients developing parkinsonism. Additionally, based on the evidence presented, patients with Gaucher disease Type 3 are more likely to develop parkinsonism than patients with Gaucher disease Type 1, and patients with GBA1 genotype L483P may manifest parkinsonism more frequently than other benign genotypes. It was suggested that the manifestation of parkinsonism as depression and cognitive impairment could be used as early predictors for the development of parkinsonism in Gaucher disease.18 Professor Adly emphasised that more research is needed to explore this link between GBA1 mutations and parkinsonism, as well as to address the unresolved long-term complications of patients with Gaucher disease on enzyme replacement therapy.
Retinal thinning in adolescents and young adults with Gaucher disease; relation to parkinsonian features
Professor Adly then introduced a second study, which assessed ganglion cell complex (GCC) thickness variations among 48 adolescents and young adults aged 11‒29 years with Gaucher disease Types 1 and 3 in relation to the presence of parkinsonian features. The aim of this cross-sectional, case-control study was to correlate GCC thickness with Gaucher disease phenotype, genotype, clinical prodromal markers of parkinsonism, and clinical and laboratory severity markers).19 Patients were split into three groups: Group 1 included 11 patients with Gaucher disease and parkinsonian features; Group 2 included 37 patients with Gaucher disease without parkinsonian features; and Group 3 included 48 age- and sex-matched healthy individuals as a control.19
A similar methodology to the study described above was used, including the UPDRS, BDI and SSI assessments. Additional assessments included screening for sleep disorders, the olfactory dysfunction scale, ophthalmological examination, macula map scan and retinal-thickness measurements. Laboratory and radiological investigations included quantitative measurement of lyso-Gb1, and abdominal ultrasound to assess liver and spleen volume; electroencephalogram was performed on those patients with Gaucher disease Type 3.19
In Group 1, the most noted parkinsonian features were bradykinesia (72.7%), rigidity (36.4%) and resting tremors (27.3%). Group 1 patients had significantly higher lyso-Gb1 than Group 2 (p=0.035), and significantly lower height (p=0.003) and IQ (p=0.004) versus Group 2 or 3. GCC was significantly thinner in Group 1 than in Groups 2 or 3 (p=0.001 and p=0.004, respectively), but there was no significant difference between Groups 2 and 3 (p=0.977). No anterior or posterior segment pathologies were observed in any of the patients, except for one patient who had visually insignificant vitreous opacities and two who had undergone previous strabismus surgeries. The mean GCC thickness was significantly lower in patients with Gaucher disease than in the control group (93.14 vs 8.63, respectively; p=0.023). No significant difference in mean GCC thickness was observed between patients with Gaucher disease Type 1 versus Type 3 (p=0.85). A multivariate logistic regression analysis for predictors of GCC thinning in patients with Gaucher disease found the highest correlation with lyso-Gb1 (p=0.008).19
The presentation was concluded by highlighting that significant GCC thinning was seen in patients with Gaucher disease and parkinsonian features versus those with Gaucher disease without parkinsonian features, and versus control individuals. She suggested that GCC thinning starts in early adolescence in patients with Gaucher disease Types 1 and 3, irrespective of disease severity or genotype. Professor Adly suggested that GCC thinning may be a promising biomarker for central nervous system neurodegeneration, with the potential to monitor not only retinal but also cerebral involvement. She ended her presentation by emphasising that caution should be taken in investigating cases where patients with Gaucher disease are suspected to have glaucoma, due to confounding pre-existing GCC thinning.19
The Young Researchers session was chaired by Professor Marc Berger (Auvergne University, Clermont-Ferrand, France) and Dr Andrea Dardis (University Hospital of Udine, Udine, Italy). One of the main aims of the EWGGD is to provide training and education for the new generation of young physicians and researchers in the field of Gaucher disease. Consequently, the Young Researchers Network was developed to provide a platform where young researchers can discuss ideas and propose activities based on their own needs. The purpose of this session was to introduce members of the Young Researchers Network and provide an overview of the aims of the network, which include:
- Enhancement of the research productivity of the new generation of experts in Gaucher disease
- Incorporation of the knowledge of advanced researchers in other countries
- Creation of programmes, seminars and workshops
- Greater involvement in the Gaucher disease community.
The members of the Young Researchers Network defined a young researcher as: (1) a person with a young spirit; (2) a newcomer to the field; and (3) a person eager to learn about Gaucher disease. The needs of the Young Researchers Network include background education on Gaucher disease, workshops on Gaucher disease, research grants and funding, and interactions with experts in the field.
During the presentation, the following benefits and contributions of the Young Researchers Network were outlined:
- Involvement in the working groups of the EWGGD
- The opportunity to present in large forums on Gaucher disease
- Advertisement of new career opportunities
- Collaboration with young representatives from the International Gaucher Alliance
- Collaboration of young researchers with different experts in the field.
Members of the Young Researchers Network then discussed the plans of the network for the near future, which included: the first Young Researchers Network workshop at EWGGD 2021; an e-Conference for young researchers; development of a young researchers’ forum within the EWGGD website; participation in exchange programmes; and visibility on social media.
To conclude Day 1 of EWGGD 2020, Dr Ellen Sidransky (National Institutes of Health, Bethesda, MD, USA) began her presentation on the advances and challenges of understanding GBA1-associated Parkinson’s disease. Dr Sidransky began her presentation with the following quote, “I live in a very small house, but my windows look out on a very large world”. She stated that, in her opinion, this is relatable to the field of rare diseases, and that what we know about Gaucher disease is helping inform knowledge of a seemingly unrelated disorder, Parkinson’s disease. The audience were reminded of the vast clinical heterogeneity associated with Gaucher disease, and that the GBA1 gene encodes glucocerebrosidase. She then highlighted the clinical and pathological features leading to a diagnosis of Parkinson’s disease according to the UK Parkinson’s Disease Society Brain Bank Criteria.20 She also noted that ‘parkinsonism’ is a term describing the motor features of Parkinson’s disease and that disorders with parkinsonism features are referred to as Lewy body disorders or synucleinopathies. Dr Sidransky highlighted that α-synuclein is a protein that aggregates and is found in Lewy bodies. Autopsies have shown that these aggregates are found in brain samples from patients with parkinsonism, including those with Gaucher disease.21
Development of Parkinson’s disease is a result of a combination of genetic and environmental factors; Dr Sidransky noted that she liked to think of Parkinson’s disease as having a ‘genetic tapestry’, where genes can have a large or small effect size and the allele frequency can range from very rare to very common. For example, she stated that rare alleles may cause Mendelian disorders that can have a large effect size compared with very common disorders that may have a small effect size. Dr Sidransky highlighted that many genes associated with Parkinson’s disease have been identified, which range from very rare to very common. She noted that mutations in the GBA1 gene related to Parkinson’s disease occur at a low frequency but have a moderate effect size. In this keynote lecture, it was noted that it was important to identify disease-causing genes, as this can provide more information on pathogenesis.
Dr Sidransky then discussed how she became involved in GBA1-associated parkinsonism, and highlighted a study, published in 2003, of 17 patients with both Gaucher disease and Parkinson’s disease.22 She then presented data from an international multicentre study, which showed that patients with Parkinson’s disease were 5.43-fold more likely to have mutations in the GBA1 gene. Carriers of GBA1 mutations were also more likely to develop an earlier onset of Parkinson’s disease and exhibit more cognitive deficits.23 A separate multicentre study was then described, which also demonstrated that carriers of GBA1 mutations were more likely to exhibit earlier-onset dementia with Lewy bodies (odds ratio 8.28 [95% confidence interval [CI] 4.78–14.88]).24 In Dr Sidransky’s opinion, these findings have directed attention to the role of the lysosome in neurodegeneration.
The speaker then discussed her clinical experience of studying the following groups:
- Patients with Gaucher disease and Parkinson’s disease
- Carriers of GBA1 mutations with Parkinson’s disease
- Patients with Gaucher disease and a family history of Parkinson’s disease
- Carriers of GBA1 mutations with a family history of Parkinson’s disease.
Then, published data from a longitudinal study that investigated the clinical course and prognosis of 19 patients with Gaucher disease and parkinsonism were presented. A broad spectrum of systemic manifestations related to Gaucher disease was observed in these patients, and the majority of patients had at least one N370S (c.1226A>G; p.Asp409Ser) allele in the GBA1 gene. Only one patient was diagnosed with Gaucher disease Type 3. The mean age at onset of parkinsonism symptoms was 49.7 years; olfactory and cognitive impairments were also observed in this patient population. Dr Sidransky also noted that a positive response to dopaminergic therapy was evident in the 15 patients who received treatment.25 Additionally, she indicated that her research group also found that patients with Gaucher disease Type 3 can develop Parkinson’s disease.26 Dr Sidransky emphasised that, in her opinion, GBA1 genotypes should not be used to predict the clinical course of Parkinson’s disease in patients with Gaucher disease and carriers of GBA1 mutations.
Next, Dr Sidransky presented data from a longitudinal positron emission tomography study of 57 homozygous or heterozygous carriers of GBA1 mutations, of whom 15 had parkinsonism. Levels of [18F]-fluorodopa (a measurement of dopamine synthesis) within the striatum revealed that carriers of GBA1 mutations with parkinsonism had reduced levels comparable with idiopathic Parkinson’s disease. However, [18F]-fluorodopa levels in carriers of GBA1 mutations without parkinsonism were comparable with the unaffected healthy control group (n=98). It was highlighted that these findings suggest that not all carriers of GBA1 mutations, who are considered at risk for Parkinson’s disease, will develop parkinsonism.27 She then noted that her research group are also interested in sibling pairs with Gaucher disease, where only one individual also has Parkinson’s disease. A prospective, longitudinal study of nine sibling pairs has, at present, shown there is no relationship between treatments for Gaucher disease, genotype or splenectomy with Parkinson’s disease. Further longitudinal evaluation may help identify risk factors or protective alleles for Parkinson’s disease.28 The speaker then reiterated that mutations in the GBA1 gene are considered a risk factor for Parkinson’s disease, and that a combination of clinical evaluations and genomic approaches may aid the identification of factors or genes that increase or decrease the risk for Parkinson’s disease. Data from patients with and without GBA1 mutations gathered from the International Parkinson’s Disease Genomics Consortium and the UK Biobank have been published.29 Dr Sidransky shared her view from a Gaucher disease perspective, that combining samples of patients with Gaucher disease with and without Parkinson’s disease, via the establishment of an international consortium, will be important given the rarity of the disease. A publication by Tayebi and colleagues was then highlighted, which proposed a network that links Gaucher disease and Parkinson’s disease. This publication suggested that alterations in the progranulin, pro-cathepsin and prosaposin network, and associated receptors, may modify lysosomal functioning, thus impacting on both α-synuclein degradation and glucocerebrosidase activity. Exploration of this network and protein interactions may identify secondary risk factors for parkinsonism, and may lead to the development of novel therapeutic targets.30
The third session of EWGGD 2020, which commenced Day 2 of the virtual meeting, consisted of unpublished laboratory studies related to Gaucher disease. Next, a dedicated session on updates and plans for the future from the IGA were presented. The IGA is an umbrella organisation that represents 57 patient associations for Gaucher disease worldwide.
Professor Carla Hollak (Academic Medical Centre, Amsterdam, The Netherlands) began her presentation by outlining case studies of patients with Gaucher disease who had developed malignancies. She then highlighted that one early study indicated that patients with Gaucher disease Type 1 have a 3.6-fold increase in the relative risk of cancer (95% CI 1.7‒7.5). In this study, the relative risk of cancer of haematopoietic origin was also higher in patients with Gaucher disease (n=48) compared with unaffected healthy controls (n=511): relative risk, 14.7 (95% CI 5.2‒41.7).31 Conversely, a separate single-centre study suggested that patients with Gaucher disease (n=500) had no relative increased risk for cancer. However, of the 20 patients who did develop cancer in this study, two incidences of multiple myeloma were observed.32 In line with these data, evidence from the Gaucher Registry of 2742 patients suggests that the relative risk of cancer in patients with Gaucher disease is 0.79 (95% CI 0.67‒0.94); however, the risk of multiple myeloma is higher (relative risk, 5.9 [95% CI 2.8‒10.8]).33 Finally, Professor Hollak presented data from her own research, which suggested that patients with Gaucher disease (n=131) have a 2.5-fold higher risk for developing cancer (95% CI 1.1‒4.7) and an increased risk of haematological cancer (relative risk, 12.7 [95% CI 2.6‒37.0]), particularly multiple myeloma and hepatocellular carcinoma in the absence of pre-existing cirrhosis.34 Professor Hollak indicated that a 2020 update on the malignancy outcome of patients enrolled in this study is in the pipeline. The speaker concluded this section of her presentation by showing data from a systematic review of the prevalence of monoclonal gammopathies and malignancies in patients with Gaucher disease. The findings from this review suggest that patients with Gaucher disease are at an increased risk for35:
- Cancer in general: relative risk, 1.7 (95% CI 1.27–2.31)
- Multiple myeloma: estimated risk between 25.0 and 51.1
- Haematological malignancies: estimated risk between 3.5 and 12.7.
The possible pathophysiology that may underlie the increased risk for malignancy in patients with Gaucher disease was next discussed. Professor Hollak indicated that the direct effect of sphingolipids and the presence of classically versus alternatively activated macrophages may lead to tumour development in patients with Gaucher disease.36,37 Gaucher cells resemble alternatively activated macrophages, and it is possible that accumulation of glucosylceramide in macrophages causes Gaucher cells to play a pro-tumoural role within the tumour microenvironment. Expression of programmed cell death protein 1 (PD-1) on macrophages affects survival of cancer cells by binding programmed-death ligand 1 (PD-L1) on the tumour cell. Production of cytokines may then promote the invasiveness of cancer cells, support angiogenesis and cytokine-induced metastasis in patients with Gaucher disease. In addition, impairments in ceramide functioning due to enzymatic blockade promote cancer-cell survival signals.38 In line with this hypothesis, tumour-associated macrophages have also been implicated in the development of haematological malignancies, such as leukaemia, lymphoma and myeloma.39 It was also noted that immune activation by glycosphingolipids may lead to continuous antibody production culminating in cancer-cell formation.40-42 Professor Hollak mentioned that other lysosomal storage diseases have been linked to increased risk of cancer; for example, one study reported a possible increased risk of melanoma, urological malignancies and meningiomas in patients with Fabry disease.43
In this keynote lecture, it was then stated that there have been some suggestions that enzyme replacement therapy may have a beneficial effect on the occurrence or risk of malignancy in patients with Gaucher disease. One study modelled the course of Gaucher disease to investigate the effects of enzyme replacement therapy on long-term complications in 66 patients with Gaucher disease, and a ‘natural history’ cohort of historical data on 90 patients before enzyme replacement therapy was available. This study demonstrated that early initiation of enzyme replacement therapy, in the absence of multiple complications, reduces the risk of malignancy in patients with Gaucher disease. In this study, of the three patients with Gaucher disease Type 1 who developed hepatocellular carcinoma, all were splenectomised.44 Professor Hollak noted that some patients with Gaucher disease may still develop malignancy despite long-term treatment with enzyme replacement therapy. She stated that the presence of focal Gaucher lesions, known as Gaucheroma, in the spleen of patients is strongly correlated with serum ferritin levels. Patients with Gaucher disease Type 1 with hyperferritinaemia, with increased levels of iron in the liver and bone marrow, may have an increased risk for liver fibrosis and cancer.45 It is recommended that splenectomised patients or those with iron overload be evaluated for signs of liver fibrosis and, if found, should be monitored for the development of hepatocellular carcinoma.46
In the speaker's experience, there is no reason to treat patients with Gaucher disease with cancer differently. Moreover, in her opinion, cases of hepatocellular carcinoma, liver transplantation may be feasible. Professor Hollak expressed her opinion that timely initiation of enzyme replacement therapy or substrate reduction therapy may prevent irreversible disease in patients with Gaucher disease and may reduce the risk of malignancy. She noted that screening for monoclonal abnormalities should occur at baseline, with follow-on monitoring once every 2 years in patients aged <50 years and once a year in patients aged >50 years.47 It was also highlighted that patients with Gaucher disease with ≥1 of the following risk factors should be monitored for the development of hepatocellular carcinoma every 6 months46:
- Splenectomised patients
- Presence of liver fibrosis or cirrhosis
- Persistent hyperferritinaemia (>2 times upper limit of normal) despite adequate Gaucher disease-specific treatment in combination with transferrin saturation >45%
- Carriers of chronic hepatitis B/C.
The final keynote lecture of EWGGD 2020 was presented by Professor Richard Eastell (University of Sheffield, Sheffield, UK), who began by providing the conceptual definition of osteoporosis. He indicated that osteoporosis is recognised as “a disease characterised by low bone mass and micro-architectural deterioration of bone tissue”, leading to enhanced bone fragility and a consequent increase in fracture risk.48 Osteoporosis is operationally defined on the basis of bone mineral density (BMD) assessment. The most widely validated technique to measure BMD is dual-energy X-ray absorptiometry (DXA), with diagnostic criteria based on the T-score for BMD.49 In Professor Eastell’s opinion, the benefits of measuring BMD using DXA include: it is a strong predictor of fracture risk; the dose of radiation used is low; and it enables assessment of skeletal sites clinically relevant to Gaucher disease (e.g. hip, forearm and spine). According to the World Health Organization criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations (SD) or more below the average value for a healthy young female (a T-score of less than ‒2.5 SD). He also noted that, according to these criteria, a T-score of between ‒1.0 SD and ‒2.5 SD below the average value for a healthy young adult female is defined as osteopaenia.49 Professor Eastell presented data which showed that risk of fracture becomes more frequent with age, particularly in females.50 In addition, the speaker noted that the risk of fracture and BMD score varies according to age, with older individuals exhibiting a lower BMD score and thus a higher risk of fractures.51
In this keynote lecture, it was stated that osteoporosis is a result of bone loss due to an imbalance between bone resorption and formation. Deficiency in oestrogen is central to bone loss in both males and females.48 Professor Eastell next presented a diagnostic algorithm developed for the management of post-menopausal osteoporosis.52 He also provided his own clinical approach to managing patients with osteoporosis, which includes pain relief, falls prevention (e.g. exercise), nutrition (e.g. avoid low body weight and ensure 1200 mg/day calcium and 800 IU/day vitamin D) and drug therapy. It was noted that treatment with bisphosphonates can reduce the risk of fracture in post-menopausal osteoporosis.53 The speaker then indicated that following therapy for osteoporosis, patient response can be monitored by measuring bone turnover markers, such as serum C-terminal cross-linking telopeptide or procollagen type 1 N-terminal propeptide.53 Professor Eastell then presented data from a study that examined levels of bone turnover markers in response to treatment with bisphosphonates, where non-responders to therapy had smaller increases in BMD.54
Professor Eastell next described a coupling mechanism during bone remodelling, whereby osteoclasts modulate the activity of osteoblasts and vice versa. Of note, he mentioned that one of the key signals from osteoclasts to osteoblasts is sphingosine-1-phosphate.55,56 Clinical recommendations were then highlighted, which include best practice and unmet needs related to the skeletal features of Gaucher disease. He noted that patients with Gaucher disease may have a complex bone symptomatology, including bone marrow infiltration from Gaucher cells, modelling and remodelling defects of trabecular and cortical bone, and medullary bone infarction (for example, osteonecrosis and osteosclerosis).57
Professor Eastell concluded his presentation by providing his lessons from metabolic diseases for management of bone symptoms in patients with Gaucher disease:
- Osteonecrosis may be due to osteocyte apoptosis rather than ischaemia, and treatment with bisphosphonates may be effective.
- Sphingosine-1-phosphate is a key regulator of osteoclast activity and may be a key biomarker worth evaluating in patients with Gaucher disease.
Closing remarks of the 14th EWGGD virtual meeting 2020 were provided by chairpersons Professor Johannes Aerts and Professor Derralyn Hughes, who thanked the presenters, organisers and attendees for an insightful meeting. Professor Hughes noted that she hoped the 15th EWGGD meeting would take place as a face-to-face meeting in Leiden, The Netherlands on 7‒10 June 2021, with a Young Investigator meeting on 6 June 2021.
Disclaimer: The views expressed here are the views of the presenting physicians. The content presented in this report is not reviewed, approved, or endorsed by the European Working Group on Gaucher Disease (EWGGD), or any of its employees, agents, or contractors. No speakers or staff were interviewed directly or involved in the development of this report. Unofficial content. Official content is available only to registered attendees of EWGGD 2020.
C-ANPROM/INT/GAUD/0002; Date of preparation: January 2021
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