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Background: Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and progression in real-world clinical practice. Initiated in 2010, the Gaucher Outcome Survey (GOS) is an ongoing, international, multicenter, observational registry (ClinicalTrials.gov Identifier: NCT03291223) for patients with a diagnosis of Gaucher disease (GD), irrespective of treatment type or status, with a primary objective to monitor safety and long-term effectiveness of velaglucerase alfa. Methods: Here, we evaluated the GOS population 12 years after the registry initiation. Results: As of 25 February 2023, 2084 patients enrolled in the GOS and 1643 received GD-specific treatment. Patients exhibited broad heterogeneity at baseline: age of diagnosis (0 to 85.3 years), hemoglobin concentrations (<80.0 g/L to >150 g/L), platelet counts (<50 × 109/L to >450 × 109/L), and liver and spleen volumes. Most patients treated with enzyme replacement therapy or substrate reduction therapy reported improvements in clinical parameters within 1 year of treatment initiation, maintained over the course of treatment up to 12 years, whereas untreated patients had baseline values closer to standard reference thresholds and showed stability over time. Conclusion: The 12-year data from the GOS confirm the impact of long-term treatment with GD-specific agents and offer insights into disease progression and outcomes in a real-world setting.
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Gaucher disease is one of the most common lysosomal storage disorders. Osteonecrosis is a principal clinical manifestation of Gaucher disease and often leads to joint collapse and fractures. T1-weighted (T1w) modality in MRI is widely used to monitor bone involvement in Gaucher disease and to diagnose osteonecrosis. However, objective and quantitative methods for characterizing osteonecrosis are still limited. In this work, we present a deep learning-based quantification approach for the segmentation of osteonecrosis and the extraction of characteristic parameters. We first constructed two independent U-net models to segment the osteonecrosis and bone marrow unaffected by osteonecrosis (UBM) in spine and femur respectively, based on T1w images from patients in the UK national Gaucherite study database. We manually delineated parcellation maps including osteonecrosis and UBM from 364 T1w images (176 for spine, 188 for femur) as the training datasets, and the trained models were subsequently applied to all the 917 T1w images in the database. To quantify the segmentation, we calculated morphological parameters including the volume of osteonecrosis, the volume of UBM, and the fraction of total marrow occupied by osteonecrosis. Then, we examined the correlation between calculated features and the bone marrow burden score for marrow infiltration of the corresponding image, and no strong correlation was found. In addition, we analyzed the influence of splenectomy and the interval between the age at first symptom and the age of onset of treatment on the quantitative measurements of osteonecrosis. The results are consistent with previous studies, showing that prior splenectomy is closely associated with the fractional volume of osteonecrosis, and there is a positive relationship between the duration of untreated disease and the quantifications of osteonecrosis. We propose this technique as an efficient and reliable tool for assessing the extent of osteonecrosis in MR images of patients and improving prediction of clinically important adverse events.
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Aprendizado Profundo , Doença de Gaucher , Imageamento por Ressonância Magnética , Osteonecrose , Doença de Gaucher/diagnóstico por imagem , Doença de Gaucher/patologia , Humanos , Osteonecrose/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Feminino , Adulto , Fêmur/diagnóstico por imagem , Fêmur/patologia , Pessoa de Meia-Idade , Processamento de Imagem Assistida por Computador/métodos , Adolescente , Adulto Jovem , Medula Óssea/diagnóstico por imagem , Medula Óssea/patologiaRESUMO
Background: Gaucher disease (GD) is a rare, autosomal, recessive condition characterized by hepatosplenomegaly, thrombocytopenia, anemia, and bone abnormalities, often requiring life-long treatment. Velaglucerase alfa has improved hematologic and visceral parameters in clinical trials; however, limited long-term efficacy and safety data are available. Methods: The Gaucher Outcome Survey (GOS), a structured and validated international registry for patients with confirmed GD, provides an opportunity to evaluate long-term data from patients receiving velaglucerase alfa. Results: This analysis included 376 treatment-naïve children and adults with GD enrolled in GOS, including 20 with type 3 GD, who initiated velaglucerase alfa through participation in clinical trials or as part of their clinical management and continued treatment for a mean (range) time of 6.6 (0.003-18.6) years. Initial improvements in hematologic and visceral parameters and the biomarkers glucosylsphingosine (lyso-GL1) and chitotriosidase were observed after one year of treatment and were maintained throughout the follow-up period. Of 129 (34.3%) patients who developed adverse events during the follow-up period, events were considered related to treatment in 33 (8.8%). None led to treatment discontinuation. There were 21 deaths overall, none of which were considered related to treatment. Conclusions: This analysis of data from the GOS registry supports the safety and efficacy of velaglucerase alfa in patients with GD.
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BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for ≥1 year. METHODS: Patients were randomly assigned 2:1 to receive 1 mg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5 mL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36 mL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676.
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BACKGROUND: Fabry disease is a rare, X-linked inherited lysosomal storage disorder, that manifests as a heterogeneous disease with renal, cardiac and nervous system involvement. The most common pain experienced by people with Fabry disease are episodes of neuropathic pain reported in up to 80% of classical hemizygous male patients and up to 65% of heterozygous female patients. No clear consensus exists within UK clinical practice for the assessment and management of pain in Fabry disease based on agreed clinical practice and clinical experience. Here we describe a modified Delphi initiative to establish expert consensus on management of pain in Fabry disease in the UK clinical setting. METHODS: Delphi panel members were identified based on their demonstrated expertise in managing adult or paediatric patients with Fabry disease in the UK and recruited by an independent third-party administrator. Ten expert panellists agreed to participate in two survey rounds, during which they remained anonymous to each other. Circulation of the questionnaires, and collection and processing of the panel's responses were conducted between September 2021 and December 2021. All questions required an answer. RESULTS: The Delphi panel reached a consensus on 21 out of 41 aspects of pain assessment and management of pain in Fabry disease. These encompassed steps in the care pathway from the goals of therapy through to holistic support, including the use of gabapentin and carbamazepine as first-line analgesic medications for the treatment of neuropathic pain in Fabry disease, as well as the proactive management of symptoms of anxiety and/or depression associated with Fabry pain. CONCLUSIONS: The consensus panel outcomes reported here have highlighted strengths in current UK clinical practice, along with unmet needs for further research and agreement. This consensus is intended to prompt the next steps towards developing clinical guidelines.
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Doença de Fabry , Neuralgia , Adulto , Humanos , Feminino , Masculino , Criança , Doença de Fabry/diagnóstico , Doença de Fabry/tratamento farmacológico , Consenso , Neuralgia/diagnóstico , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Rim , Reino UnidoRESUMO
Thank you for allowing us the opportunity to respond to the commentary from Mistry and colleagues (Comment: The two substrate reduction therapies for type 1 Gaucher disease are not equivalent) [...].
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Classical homocystinuria (HCU) is caused by cystathionine ß-synthase deficiency leading to impaired homocysteine transsulfuration and accumulation of homocysteine and methionine. Patients present with a wide spectrum of manifestations including ocular, skeletal, neuropsychiatric, and vascular manifestations. We report a 48-year-old female with pyridoxine-unresponsive HCU treated with betaine, cyanocobalamin, and folate. Her diet was non-restricted due to intolerance of low-methionine diet. She was admitted to hospital following a fall, with multiple fractures and subsequently developed acute liver failure with encephalopathy. Shock, sepsis, and liver ischaemia/thrombosis were excluded. In the context of glutathione depletion expected in HCU, hepatic dysfunction was presumed to be due to iatrogenic paracetamol toxicity, despite paracetamol intake at conventional therapeutic dose, with role of hypermethioninemia as a contributing factor being uncertain. Betaine was discontinued on hospital admission. N-Acetylcysteine (NAC) infusion was initiated. Plasma total homocysteine (tHcy) was 3.4 µmol/L 9 days following initiation of NAC treatment with a markedly elevated plasma methionine of 1278 µmol/L. tHcy concentration returned to pre-admission baseline after NAC was discontinued. Recovery following this episode was slow with a prolonged cholestatic phase and gradual improvement in jaundice and coagulopathy. We recommend that paracetamol should be administered cautiously in HCU patients due to underlying glutathione depletion and risk of toxicity even at therapeutic doses. NAC is clearly effective in lowering tHcy in classical HCU in the short-term however further research is required to assess clinical efficacy and use as a potential therapy in classical HCU.
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Background Patients with Gaucher disease (GD) have a high risk of fragility fractures. Routine evaluation of bone involvement in these patients includes radiography and repeated dual-energy x-ray absorptiometry (DXA). However, osteonecrosis and bone fracture may affect the accuracy of DXA. Purpose To assess the utility of DXA and radiographic femoral cortical thickness measurements as predictors of fragility fracture in patients with GD with long-term follow-up (up to 30 years). Materials and Methods Patients with GD age 16 years and older with a detailed medical history, at least one bone image (DXA and/or radiographs), and minimum 2 years follow-up were retrospectively identified using three merged UK-based registries (Gaucherite study, enrollment 2015-2017; Clinical Bone Registry, enrollment 2003-2006; and Mortality Registry, enrollment 1993-2019). Cortical thickness index (CTI) and canal-to-calcar ratio (CCR) were measured by two independent observers, and inter- and intraobserver reliability was calculated. The fracture-predictive value of DXA, CTI, CCR, and cutoff values were calculated using receiver operating characteristic curves. Statistical differences were assessed using univariable and multivariable analysis. Results Bone imaging in 247 patients (123 men, 124 women; baseline median age, 39 years; IQR, 27-50 years) was reviewed. The median follow-up period was 11 years (IQR, 7-19 years; range, 2-30 years). Thirty-five patients had fractures before or at first bone imaging, 23 patients had fractures after first bone imaging, and 189 patients remained fracture-free. Inter- and intraobserver reproducibility for CTI/CCR measurements was substantial (range, 0.96-0.98). In the 212 patients with no baseline fracture, CTI (cutoff, ≤0.50) predicted future fractures with higher sensitivity and specificity (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI: 0.84, 0.99; sensitivity, 92%; specificity, 96%) than DXA T-score at total hip (AUC, 0.78; 95% CI: 0.51, 0.91; sensitivity, 64%; specificity, 93%), femoral neck (AUC, 0.73; 95% CI: 0.50, 0.86; sensitivity, 64%; specificity, 73%), lumbar spine (AUC, 0.69; 95% CI: 0.49, 0.82; sensitivity, 57%; specificity, 63%), and forearm (AUC, 0.78; 95% CI: 0.59, 0.89; sensitivity, 70%; specificity, 70%). Conclusion Radiographic cortical thickness index of 0.50 or less was a reliable independent predictor of fracture risk in Gaucher disease. Clinical trial registration no. NCT03240653 © RSNA, 2022 Supplemental material is available for this article.
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Fraturas Ósseas , Doença de Gaucher , Fraturas por Osteoporose , Adolescente , Adulto , Feminino , Humanos , Masculino , Absorciometria de Fóton , Densidade Óssea , Fraturas Ósseas/diagnóstico por imagem , Doença de Gaucher/complicações , Doença de Gaucher/diagnóstico por imagem , Reprodutibilidade dos Testes , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodosRESUMO
Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18-37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were - 0.06 (0.03) (p = 0.0010) and - 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety.
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Doença de Fabry , Humanos , Masculino , Adulto , Adolescente , Adulto Jovem , Doença de Fabry/patologia , alfa-Galactosidase/uso terapêutico , GlucosiltransferasesRESUMO
Switching between enzyme replacement therapies (ERT) and substrate reduction therapies (SRT) in patients with type 1 Gaucher disease (GD1) is not uncommon; however, the reasons for switchng treatments have not been explored in detail. Data from the Gaucher Outcome Survey (GOS), an international registry for patients with confirmed GD, were used to evaluate the reasons for, and consequences of, switching between these treatment types. Of the 1843 patients enrolled in GOS on 25 February 2020, 245 had undergone a treatment switch: 222 from initial ERT to SRT (of whom 88 later switched back to ERT) and 23 from initial SRT to ERT. The most common reasons for ERT-SRT switching were duration of infusion (25.4%), drug shortage (22.0%), and adverse events (AEs; 11.9%), and for SRT-ERT switching, AEs (63.6%), lack of beneficial effect (16.4%), and participation in a clinical trial (9.1%). Bodyweight and hematologic parameters largely remained stable before and after switching between ERT and SRT, although with substantial variation between patients. These findings contribute to understanding why treatment switching occurs in patients with GD, and may help physicians recognize the real-world impact of treatment switching between ERT and SRT for patients with GD.
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BACKGROUND: Disease-specific patient-reported outcome measures (PROMs) are fundamental to understanding the impact on, and expectations of, patients with genetic disorders, and can facilitate constructive and educated conversations about treatments and outcomes. However, generic PROMs may fail to capture disease-specific concerns. Here we report the development and validation of a Gaucher disease (GD)-specific PROM for patients with type 1 Gaucher disease (GD1) a lysosomal storage disorder characterized by hepatosplenomegaly, thrombocytopenia, anemia, bruising, bone disease, and fatigue. RESULTS AND DISCUSSION: The questionnaire was initially developed with input from 85 patients or parents of patients with GD1 or GD3 in Israel. Owing to few participating patients with GD3, content validity was assessed for patients with GD1 only. Content validity of the revised questionnaire was assessed in 33 patients in the US, France, and Israel according to US Food and Drug Administration standards, with input from a panel of six GD experts and one patient advocate representative. Concept elicitation interviews explored patient experience of symptoms and treatments, and a cognitive debriefing exercise explored patients' understanding and relevance of instructions, items, response scales, and recall period. Two versions of the questionnaire were subsequently developed: a 24-item version for routine monitoring in clinical practice (rmGD1-PROM), and a 17-item version for use in clinical trials (ctGD1-PROM). Psychometric validation of the ctGD1-PROM was assessed in 46 adult patients with GD1 and re-administered two weeks later to examine test-retest reliability. Findings from the psychometric validation study revealed excellent internal consistency and strong evidence of convergent validity of the ctGD1-PROM based on correlations with the 36-item Short Form Health Survey. Most items were found to show moderate, good, or excellent test-retest reliability. CONCLUSIONS: Development of the ctGD1-PROM represents an important step forward for researchers measuring the impact of GD and its respective treatment.
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Doença de Gaucher , Medidas de Resultados Relatados pelo Paciente , Inquéritos e Questionários/normas , Adulto , Humanos , Psicometria , Qualidade de Vida/psicologia , Reprodutibilidade dos TestesRESUMO
Mesenteric panniculitis is a rare disease caused by idiopathic inflammation of adipose tissue, most commonly affecting the mesentery of the small bowel. We present a unique case of mesenteric panniculitis in a patient with Tangier disease; a rare genetic disorder caused by mutations in the ABCA1 gene, leading to deficiency of high-density lipoprotein in the blood and accumulation of cholesterol esters within various tissues. The accumulation of cholesterol esters in body tissues in patients with Tangier disease may contribute to the pathogenesis of mesenteric panniculitis; although there is limited evidence to support this hypothesis due to the rarity of concurrent disease.
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Paniculite Peritoneal , Doença de Tangier , Abdome , Ésteres do Colesterol , Humanos , Lipoproteínas HDL , Paniculite Peritoneal/complicações , Paniculite Peritoneal/diagnóstico , Doença de Tangier/complicações , Doença de Tangier/diagnóstico , Doença de Tangier/genéticaRESUMO
BACKGROUND AND PURPOSE: Sandhoff disease is a rare type of hereditary (autosomal recessive) GM2-gangliosidosis, which is caused by mutation of the HEXB gene. Disruption of the ß subunit of the hexosaminidase (Hex) enzyme affects the function of both the Hex-A and Hex-B isoforms. The severity and the age of onset of the disease (infantile or classic; juvenile; adult) depends on the residual activity of the enzyme. The late-onset form is characterized by diverse symptomatology, comprising motor neuron disease, ataxia, tremor, dystonia, psychiatric symptoms and neuropathy. METHODS: A 36-year-old female patient has been presenting progressive, symmetrical lower limb weakness for 9 years. Detailed neurological examination revealed mild symmetrical weakness in the hip flexors without the involvement of other muscle groups. The patellar reflex was decreased on both sides. Laboratory tests showed no relevant alteration and routine electroencephalography and brain MRI were normal. Nerve conduction studies and electromyography revealed alterations corresponding to sensory neuropathy. Muscle biopsy demonstrated signs of mild neurogenic lesion. Her younger brother (32-year-old) was observed with similar symptoms. RESULTS: Detailed genetic study detected a known pathogenic missense mutation and a 15,088 base pair long known pathogenic deletion in the HEXB gene (NM_000521.4:c.1417G>A; NM_000521:c.-376-5836_669+1473del; double heterozygous state). Segregation analysis and hexosaminidase enzyme assay of the family further confirmed the diagnosis of late-onset Sandhoff disease. CONCLUSION: The purpose of this case report is to draw attention to the significance of late-onset Sandhoff disease amongst disorders presenting with proximal predominant symmetric lower limb muscle weakness in adulthood.
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Doença dos Neurônios Motores , Doença de Sandhoff , Adulto , Feminino , Hexosaminidase A/genética , Hexosaminidase B/genética , Humanos , Masculino , Mutação , Doença de Sandhoff/diagnóstico , Doença de Sandhoff/genéticaRESUMO
BACKGROUND: The Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study. RESULTS: At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery. CONCLUSION: Gaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability.
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Doença de Gaucher , Doenças do Sistema Nervoso , Estudos de Coortes , Doença de Gaucher/diagnóstico , Doença de Gaucher/genética , Glucosilceramidase/genética , Humanos , Estudos Prospectivos , Estudos RetrospectivosRESUMO
BACKGROUND: Fractures in Gaucher disease type 1 (GD1) patients cause significant morbidity. Fracture risk may be decreased by enzyme replacement therapy (ERT) but not eliminated. When considering initiation of treatment, it is useful to know to what extent fixed patient-specific factors determine risk for future fractures beyond standard risk factors that change with time and treatment, such as decreased bone mineral density. We developed a tool called the GRAF score (Gaucher Risk Assessment for Fracture) that applies 5 widely available characteristics (sex, age at treatment initiation [ATI], time interval between diagnosis and treatment initiation, splenectomy status, history of pre-treatment bone crisis) and provides a practical method to assess future fracture risk when imiglucerase ERT is initiated. METHODS: Inclusion criteria: GD1 patients in the International Collaborative Gaucher Group Gaucher Registry as of September 2019 initially treated with alglucerase/imiglucerase; known splenectomy status; at least one skeletal assessment on treatment (3216 of 6422 patients). Data were analyzed by ATI group (< 18, ≥ 18 to < 50, or ≥ 50 years of age) using Cox proportional hazards regression with all 5 risk factors included in the multivariable model. A composite risk score was calculated by summing the contribution of each parameter weighted by the strength of its association (regression coefficient) with fracture risk. RESULTS: Patients were followed from the date of treatment initiation (or age 18 years for patients if treatment started earlier) to the date of first adult fracture (n = 288 first fracture endpoints), death, or end of follow-up. The GRAF score for each ATI group was associated with a 2.7-fold increased risk of adult fracture for each one-point increase (p < 0.02 for < 18 ATI, p < 0.0001 for ≥ 18 to < 50 ATI and ≥ 50 ATI). CONCLUSIONS: The GRAF score is a tool to be used with bone density and other modifiable, non-GD-specific risk factors (e.g. smoking, alcohol intake, frailty) to inform physicians and previously untreated GD1 patients about risk for a future fracture after starting imiglucerase regardless of whether there is an eventual switch to an alternative ERT or to substrate reduction therapy. GRAF can also help predict the extent that fracture risk increases if initiation of treatment is further delayed.
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Doença de Gaucher , Adolescente , Adulto , Terapia de Reposição de Enzimas , Doença de Gaucher/complicações , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Humanos , Medição de Risco , Fatores de RiscoRESUMO
Chitotriosidase activity and CCL18 concentration are interchangeably used for monitoring Gaucher disease (GD) activity, together with clinical assessment. However, comparative studies of these two biomarkers are scarce and of limited sample size. The aim of this systematic review with meta-analysis of individual participant data (IPD) was to compare the accuracy of chitotriosidase activity and CCL18 concentration for assessing type I GD severity. We identified cross-sectional and prospective cohort studies by searching Medline, EMBASE, and CENTRAL from 1995 to June 2017, and by contacting research groups. The primary outcome was a composite of liver volume >1.25 multiple of normal (MN), spleen volume >5 MN, hemoglobin concentration <11 g/dL, and platelet count <100x109/L. Overall, IPD included 1109 observations from 334 patients enrolled in nine primary studies, after excluding 111 patients with undocumented values and 18 patients with deficient chitotriosidase activity. IPD were unavailable for 14 eligible primary studies. The primary outcome was associated with a 5.3-fold (95% confidence interval [CI], 4.2 to 6.6) and 3.0-fold (95% CI, 2.6 to 3.6) increase of the geometric mean for chitotriosidase activity and CCL18 concentration, respectively. The corresponding areas under the receiver operating characteristics curves were 0.82 and 0.84 (summary difference, 0.02, 95% CI, -0.02 to 0.05). The addition of chitotriosidase activity did not improve the accuracy of CCL18 concentration. Estimates remained robust in the sensitivity analysis and consistent across subgroups. Neither chitotriosidase activity nor CCL18 concentration varied significantly according to a recent history of bone events among 97 patients. In conclusion, CCL18 concentration is as accurate as chitotriosidase activity in assessing hematological and visceral parameters of GD severity and can be measured in all GD patients. This meta-analysis supports the use of CCL18 rather than chitotriosidase activity for monitoring GD activity in routine practice.
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Doença de Gaucher , Biomarcadores , Quimiocinas CC , Estudos Transversais , Doença de Gaucher/diagnóstico , Hexosaminidases , Humanos , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
The Erlenmeyer flask deformity is a common skeletal modeling deformity, but current classification systems are binary and may restrict its utility as a predictor of associated skeletal conditions. A quantifiable 3-point system of severity classification could improve its predictive potential in disease. Ratios were derived from volumes of regions of interests drawn in 50 Gaucher's disease patients. ROIs were drawn from the distal physis to 2 cm proximal, 2 cm to 4 cm, and 4 cm to 6 cm. Width was also measured at each of these boundaries. Two readers rated these 100 femurs using a 3-point scale of severity classification. Weighted kappa indicated reliability and one-way analysis of variance characterized ratio differences across the severity scale. Accuracy analyses allowed determination of clinical cutoffs for each ratio. Pearson's correlations assessed the associations of volume and width with a shape-based concavity metric of the femur. The volume ratio incorporating the metaphyseal region from 0 to 2 cm and the diametaphyseal region at 4-6 cm was most accurate at distinguishing femurs on the 3-point scale. Receiver operating characteristic curves for this ratio indicated areas of 0.95 to distinguish normal and mild femurs and 0.93 to distinguish mild and severe femurs. Volume was moderately associated with the degree of femur concavity. The proposed volume ratio method is an objective, proficient method at distinguishing severities of the Erlenmeyer flask deformity with the potential for automation. This may have application across diseases associated with the deformity and deficient osteoclast-mediated modeling of growing bone.
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Fêmur , Lâmina de Crescimento , Osso e Ossos , Fêmur/diagnóstico por imagem , Humanos , Radiografia , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. DESIGN AND SETTING: Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists' free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. RESULTS: A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. CONCLUSIONS: PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.
Assuntos
Doença de Fabry , Consenso , Técnica Delphi , Progressão da Doença , Doença de Fabry/diagnóstico , Doença de Fabry/tratamento farmacológico , Humanos , Inquéritos e QuestionáriosRESUMO
Niemann-Pick disease type C (NPC) and Tangier disease are genetically and clinically distinct rare inborn errors of metabolism. NPC is caused by defects in either NPC1 or NPC2; whereas Tangier disease is caused by a defect in ABCA1. Tangier disease is currently without therapy, whereas NPC can be treated with miglustat, a small molecule inhibitor of glycosphingolipid biosynthesis that slows the neurological course of the disease. When a Tangier disease patient was misdiagnosed with NPC and treated with miglustat, her symptoms improved. This prompted us to consider whether there is mechanistic convergence between these two apparently unrelated rare inherited metabolic diseases. In this study, we found that when ABCA1 is defective (Tangier disease) there is secondary inhibition of the NPC disease pathway, linking these two diseases at the level of cellular pathophysiology. In addition, this study further supports the hypothesis that miglustat, as well as other substrate reduction therapies, may be potential therapeutic agents for treating Tangier disease as fibroblasts from multiple Tangier patients were corrected by miglustat treatment.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Transportador 1 de Cassete de Ligação de ATP/genética , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Doença de Niemann-Pick Tipo C/genética , 1-Desoxinojirimicina/uso terapêutico , Adulto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Pessoa de Meia-Idade , Proteína C1 de Niemann-Pick , Resultado do TratamentoRESUMO
BACKGROUND: Fabry disease is a treatable X-linked condition leading to progressive cardiomyopathy, arrhythmia and premature death. Atrial and ventricular arrhythmias contribute significantly to adverse prognosis; however, guidance to determine which patients require cardiovascular implantable electronic devices (CIEDs) is sparse. We aimed to evaluate indications for implantation practice in the UK and quantify device utilisation. METHODS: In this retrospective study, we included demographic, clinical and imaging data from patients in four of the largest UK Fabry centres. Ninety patients with Fabry disease were identified with CIEDs implanted between June 2001 and February 2018 (FD-CIED group). To investigate differences in clinical and imaging markers between those with and without devices, these patients were compared with 276 patients without a CIED (FD-control). RESULTS: In the FD-CIED group, 92% of patients with permanent pacemakers but only 28% with implantable cardioverter-defibrillators had a class 1 indication for implantation. A further 44% of patients had defibrillators inserted for primary prevention outside of current guidance. The burden of arrhythmia requiring treatment in the FD-CIED group was high (asymptomatic atrial fibrillation:29%; non-sustained ventricular tachycardia requiring medical therapy alone: 26%; sustained ventricular tachycardia needing anti-tachycardia pacing/defibrillation: 28%). Those with devices were older, had greater LV mass, more scar tissue and larger atrial size. CONCLUSIONS: Arrhythmias are common in Fabry patients. Those with cardiac devices had high rates of atrial fibrillation requiring anticoagulation and ventricular arrhythmia needing device treatment. These are as high as those in hypertrophic cardiomyopathy, supporting the need for Fabry-specific indications for device implantation.