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.
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.
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.
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.
Fabry disease is an X-linked disorder caused by a deficiency of α-galactosidase A. This leads to a progressive accumulation of globotriaosylceramide in tissues throughout the body. Cardiac, renal and ...neurological manifestations are common and life expectancy is significantly reduced relative to the general population. Management of Fabry disease involves the administration of intravenous enzyme replacement therapy (ERT). Two forms – agalsidase alfa and agalsidase beta – have been licensed in certain jurisdictions and are generally well tolerated; however, some patients develop antibodies to the infused enzyme, which may impair the efficacy and safety of treatment. Agalsidase alfa and agalsidase beta are produced in different systems; this leads to certain differences in post-translational modification that may affect immunogenicity. Immunoglobulin (Ig) G antibodies have frequently been reported in patients with Fabry disease receiving ERT; IgG responses are reported in a greater proportion of patients receiving agalsidase beta than in patients receiving agalsidase alfa. IgE antibodies are less common than IgG antibodies, and have not been observed in patients receiving agalsidase alfa. However, these data are difficult to interpret due to methodological differences in the assessment of seropositivity, and in the doses of enzyme used. The clinical impact of the development of IgG antibodies to ERT in patients with Fabry disease remains unclear, due to lack of data and to the marked heterogeneity of patients both in terms of disease manifestations and response to therapy. Further studies that examine the development of antibodies in patients with Fabry disease and the potential impact of such antibodies on the outcome of ERT are necessary.
Clinical Features of Lysosomal Acid Lipase Deficiency Burton, Barbara K.; Deegan, Patrick B.; Enns, Gregory M. ...
Journal of pediatric gastroenterology and nutrition,
2015-December, Letnik:
61, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Objective:
The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults.
Methods:
Investigators reviewed medical records of ...LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset.
Results:
A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease‐related abnormality was 9.0 years (range 0–42); mean age at diagnosis was 15.2 years (range 1–46). Twenty‐nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low‐density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid‐lowering therapies, and 44% had high‐density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ~1.15 multiples of normal (MN) and median spleen volume was ~2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9–43.5 years).
Conclusion:
This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.
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.
Enzyme replacement therapy (ERT) for Gaucher disease with mannose-terminated glucocerebrosidase has proved its therapeutic position with salutary effects on hematologic abnormalities, visceral ...infiltration, and quality of life. The frequency of new bone complications is reduced but not eliminated. Established osteonecrosis is beyond salvage. A systematic description of the burden of bone manifestations, persisting despite ERT, should inform future remedial strategies. Thus, we conducted this study to quantify the burden of residual skeletal disease and to explore putative relationships between clinical, radiologic, and biochemical factors and bone sequelae associated with disability.Consecutive adult patients attending 3 referral centers in the United Kingdom were invited to participate. A representative group of 100 patients agreed to a structured interview, clinical examination, radiologic review, and completion of questionnaires. Osteonecrosis was evident in 43%, Erlenmeyer flask deformity in 59%, fragility fracture in 28%, osteomyelitis in 6%, and lytic lesions in 4%. Mobility was impaired in 32% of patients, while 15% experienced significant pain. The EuroQol 5D (EQ5D) quality of life summary measure was reduced and was associated with osteonecrosis and fragility fracture. Eight patients experienced new osteonecrosis after the start of ERT, though the presentation and evolution were often atypical. Nine patients had been treated from childhood and had an excellent outcome. Osteonecrosis was associated with age of presentation and with splenectomy-indeed, we observed a strong temporal association between splenectomy and incidence of osteonecrosis.The biomarkers PARC/CCL18 and chitotriosidase were associated with prevalent osteonecrosis, and, in particular, with osteonecrosis occurring despite treatment. This study documents significant residual skeletal pathology and disability in patients in the mature phase of their treatment in a developed region. The temporal association between splenectomy and osteonecrosis implies causation. The relationship between clinical and biochemical markers and existing bone complications sets the scene for future prospective studies that will focus on management strategies informed by credible assessment of risk.
Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since ...administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD.
A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement.
For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped.
The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.
Cholesteryl ester storage disease (CESD), an inherited deficiency of lysosomal acid lipase (LAL), is an underappreciated cause of progressive liver disease with no approved therapy. Presenting ...features include dyslipidemia, elevated transaminases, and hepatomegaly. To assess the clinical effects and safety of the recombinant human LAL, sebelipase alfa, nine patients received four once‐weekly infusions (0.35, 1, or 3 mg·kg−1) in LAL‐CL01, which is the first human study of this investigational agent. Patients completing LAL‐CL01 were eligible to enroll in the extension study (LAL‐CL04) in which they again received four once‐weekly infusions of sebelipase alfa (0.35, 1, or 3 mg·kg−1) before transitioning to long‐term every‐other‐week infusions (1 or 3 mg·kg−1). Sebelipase alfa was well tolerated, with mostly mild adverse events unrelated to sebelipase alfa. No antidrug antibodies were detected. Transaminases decreased in patients in LAL‐CL01 and increased between studies. In seven patients receiving ongoing sebelipase alfa treatment in LAL‐CL04, the mean ± standard deviation (SD) decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL‐CL01 were 46 ± 21 U/L (−52%) and 21 ± 14 U/L (−36%), respectively (P ≤ 0.05). Through week 12 of LAL‐CL04, these seven patients also showed mean decreases from baseline in total cholesterol of 44 ± 41 mg/dL (−22%; P = 0.047), low density lipoprotein‐cholesterol of 29 ± 31 mg/dL (−27%; P = 0.078), and triglycerides of 50 ± 38 mg/dL (−28%, P = 0.016) and increases in high density lipoprotein‐cholesterol of 5 mg/dL (15%; P = 0.016). Conclusion: These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with CESD is well tolerated, rapidly decreases serum transaminases, and that these improvements are sustained with long‐term dosing and are accompanied by improvements in serum lipid profile. (HEPATOLOGY 2013;58:950–957)
BackgroundPegunigalsidase 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.MethodsPatients 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.ResultsSeventy-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.ConclusionsBased 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.
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.
•Substantial pharmacodynamic effects of venglustat in adult males with Fabry disease.•Adverse events were mostly mild (73%) and unrelated to study drug (70%).•No deaths or treatment-related life-threatening adverse events.•Nine serious and 11 severe treatment-emergent adverse events.•Exploratory efficacy justifies further clinical evaluation in patients with Fabry disease.
ObjectivesThe 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 settingAnonymous 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.ResultsA 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.ConclusionsPREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.
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