Publications by authors named "Sandra M Sirrs"

10 Publications

  • Page 1 of 1

Independent Registries Are Cost-Effective Tools to Provide Mandatory Postauthorization Surveillance for Orphan Medicinal Products.

Value Health 2021 02 19;24(2):268-273. Epub 2020 Nov 19.

Division of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Objectives: Orphan medicinal products (OMPs) often receive market authorization under conditions imposed by regulators for ongoing postauthorization surveillance (PAS) to answer questions that remain at the time of market entry. This surveillance may be provided through industry-funded registries (IFRs). Nevertheless, data in these registries may not be of sufficient quality to answer these questions and may not always be accessible for regulatory review. We propose that a mandatory independent registry is an efficient and cost-effective tool for PAS for OMPs.

Methods: Using data from the Canadian Fabry Disease Initiative, we reviewed costs per unique patient from sites participating in both the independent national registry and IFRs for Fabry disease and compared data completeness from the Canadian Fabry Disease Initiative to that in published documents from IFRs.

Results: The costs of data collection through the independent registry were 17% to 36% (depending on site) lower than costs to collect data in the IFRs, and completeness of data collected through the independent registry was higher than that through the IFRs. Data from the independent registry were reviewed annually to guide indications for publicly funded Fabry disease therapy. Even when enrollment ceased to be a requirement to receive therapy, 77% of patients continued to enroll in the registry, suggesting the structure was acceptable to patients.

Conclusions: Independent registries are cost-effective and efficient tools and should be mandated by regulatory agencies as the preferred tool for PAS for OMPs. Countries with publicly funded health systems should consider investment in registry infrastructure for OMPs.
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http://dx.doi.org/10.1016/j.jval.2020.10.006DOI Listing
February 2021

Brain MRI features and scoring of leukodystrophy in adult-onset Krabbe disease.

Neurology 2019 08 23;93(7):e647-e652. Epub 2019 Jul 23.

From the Department of Neurology, Reference Center for Lysosomal Diseases, UF Neuro-Genetics and Metabolism (L.C., R.D., Y.N.), and Department of Neuroradiology (B.L.-Y., N.P., D.L.), Pitié-Salpêtrière Hospital, Paris; Service de Biochimie et Biologie Moléculaire Grand Est (R.F., M.P.), Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron; UMR 5305 CNRS/UCBL (R.F.), Lyon, France; Department of Medicine, Surgery and Neurosciences (A.F., S.S.), Unit of Neurology and Neurometabolic Diseases, Medical School, University of Siena; Neuroradiology Unit (A.C.), Azienda Ospedaliera Universitaria Senese, Siena, Italy; Department of Neurology (M.C.M., J.D.), Coimbra Hospital and University Centre, Portugal; Department of Neurology (S.H.K.), College of Medicine, Hanyang University, Seoul, Korea; Division of Neurology (H.A.), Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan; Department of Neurology (B.A.), La Timone Hospital; Aix-Marseille University (B.A.), CNRS, CRMBM UMR, Marseille; Department of Neurology (X.A.), Montpellier University Hospital, France; Department of Neurology (Y.D.), Xuan Wu Hospital, Capital Medical University, Beijing, China; Department of Neurology (R.H.), Royal Brisbane Hospital, Brisbane, Australia; Laboratory of Neurogenetics of Motion and Department of Neuroradiology (R.L.P.), Montréal Neurological Institute and Hospital, McGill University, Montréal; Department of Radiology (C.L.), Department of Pathology and Laboratory Medicine (C.L.), International Collaboration on Repair Discoveries (ICORD) (C.L.), Department of Physics and Astronomy (C.L.), and Division of Endocrinology, Department of Medicine (S.M.S.), University of British Columbia, Vancouver, Canada; Department of Neurology (K.N.), Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; Department of Radiology (R.R.), Uppsala University, Sweden; Department of Neurology and Hertie-Institute for Clinical Brain Research (L.S.), Eberhard-Karls-University; German Center of Neurodegenerative Diseases (DZNE) (L.S.), Tübingen, Germany; Department of Neurology (F.V.), Caen-Normandie University Hospital, Caen; Inserm U1077 (F.V.), EPHE, Caen-Normandie University, Caen, France; and Department of Neurology and Stroke (K.J.), Medical University of Lodz, Poland.

Objective: To perform a systematic analysis and scoring of brain MRI white matter hyperintensities (WMH) in adult-onset Krabbe disease.

Methods: We retrospectively collected basic clinical data and the first available brain MRI from patients with confirmed Krabbe disease with first clinical manifestations beyond 10 years of age. Data were obtained from our reference center for lysosomal diseases (n = 6) and from contacted authors of published articles describing patients with adult-onset Krabbe disease (n = 15). T2-weighted fluid-attenuated inversion recovery images of each patient were analyzed and scored using a radiologic score of WMH in a single center.

Results: The corticospinal tract was always affected by WMH (100% of patients), however, with some distinctions along the tract: the precentral gyrus (100%), corona radiata (95%), and posterior internal capsule (81%) were highly abnormal, whereas the mesencephalon (57%), pons (52%), and medulla oblongata (5%) were less affected. WMH were also frequently present in the posterior lateral periventricular white matter (95%), optic radiations (86%), postcentral gyrus (71%), medial lemniscus (62%), and corpus callosum, especially in the isthmus (71%), whereas the genu was always normal. A few patients did not have the classical MRI pattern but extensive hyperintensities (n = 3), or patchy distribution of hyperintensities mimicking an acquired etiology (n = 2), or very subtle hyperintensities of the corticospinal tract (n = 1).

Conclusions: We specified the main locations of WMH, which were observed in the earliest stages of the disease and were also present in patients with atypical MRI pattern, highlighting the importance of radiologic features to guide the diagnosis.
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http://dx.doi.org/10.1212/WNL.0000000000007943DOI Listing
August 2019

Lessons from lung transplantation: Cause for redefining the pathophysiology of pulmonary hypertension in gaucher disease.

Respir Med Case Rep 2019 29;28:100893. Epub 2019 Jun 29.

Division of Respiratory Medicine, Department of Medicine, University of British Columbia, 2775 Laurel Street, 7th Floor, Vancouver, BC, V5Z 1M9, Canada.

Background: Gaucher disease type 1 (GD1) is a lysosomal storage disease rarely resulting in end stage pulmonary hypertension (PH) and interstitial lung disease. There have only been two previous case reports of patients with GD1 receiving lung transplants.

Case Presentation: We report a case of successful bilateral sequential lung transplantation in a patient with end-stage GD1-related PH. Prior to transplant, the patient was on enzyme replacement therapy with imiglucerase and pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol. The patient had pre-transplant comorbidities of prior splenectomy and osteopenia. She underwent bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction. Her explanted lungs demonstrated severe pulmonary arterial hypertensive changes, but no Gaucher cells. She was maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant. Her post-transplant course was complicated by hemorrhagic shock, prolonged support with extracorporeal membrane oxygenation, and acute renal failure requiring dialysis. Despite these complications, the patient was discharged and is doing well nine months post-transplantation.

Conclusions: This is one of only three reported cases of lung transplantation in patients with GD1. Each case has involved previously splenectomised, female patients with GD1. This is the first to report transplantation in a patient with severe PH and no pulmonary parenchymal disease. As evidenced in our patient, long term treatment with imiglucerase may eliminate the Gaucher cells in the lungs. The PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 PH.
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http://dx.doi.org/10.1016/j.rmcr.2019.100893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624456PMC
June 2019

Hematopoietic Stem Cell Transplantation in Late-Onset Krabbe Disease: No Evidence of Worsening Demyelination and Axonal Loss 4 Years Post-allograft.

J Neuroimaging 2018 05 26;28(3):252-255. Epub 2018 Feb 26.

Department of Medicine (Endocrinology), University of British Columbia, Vancouver, Canada.

Background And Purpose: Late-onset adult Krabbe disease is a very rare demyelinating leukodystrophy, affecting less than 1 in a million people. Hematopoietic stem cell transplantation (HSCT) strategies can stop the accumulation of toxic metabolites that damage myelin-producing cells. We used quantitative advanced imaging metrics to longitudinally assess the impact of HSCT on brain abnormalities in adult-onset Krabbe disease.

Methods: A 42-year-old female with late-onset Krabbe disease and an age/sex-matched healthy control underwent annual 3T MRI (baseline was immediately prior to HSCT for the Krabbe subject). Imaging included conventional scans, myelin water imaging, diffusion tensor imaging, and magnetic resonance spectroscopy.

Results: Brain abnormalities far beyond those visible on conventional imaging were detected, suggesting a global pathological process occurs in Krabbe disease with adult-onset etiology, with myelin being more affected than axons, and evidence of wide-spread gliosis. After HSCT, our patient showed clinical stability in all measures, as well as improvement in gait, dysarthria, and pseudobulbar affect at 7.5 years post-transplant. No MRI evidence of worsening demyelination and axonal loss was observed up to 4 years post-allograft.

Conclusions: Clinical evidence and stability of advanced MR measures related to myelin and axons supports HSCT as an effective treatment strategy for stopping progression associated with late-onset Krabbe disease.
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http://dx.doi.org/10.1111/jon.12502DOI Listing
May 2018

Phenylketonuria Scientific Review Conference: state of the science and future research needs.

Mol Genet Metab 2014 Jun 6;112(2):87-122. Epub 2014 Mar 6.

Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20982, USA. Electronic address:

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.
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http://dx.doi.org/10.1016/j.ymgme.2014.02.013DOI Listing
June 2014

Subcutaneous versus intraperitoneal insulin for patients with diabetes mellitus on continuous ambulatory peritoneal dialysis: meta-analysis of non-randomized clinical trials.

Clin Invest Med 2012 Jun 1;35(3):E132-43. Epub 2012 Jun 1.

Department of Endocrinology and Metabolism, UBC, Vancouver, British Columbia, Canada.

Background: Diabetes mellitus is one of the leading causes of end stage renal disease. Use of intraperitoneal (IP) nsulin in diabetic patients on peritoneal dialysis (PD) can restore glucose control to near normal values. The safety and efficacy of this method is unclear.

Methods: We performed a meta-analysis to study the safety and efficacy of IP insulin administration in diabetic patients on PD. The primary outcome measures is glycemic control: secondary outcome measures were plasma lipids, insulin dose requirement/day and the risk of peritonitis and hepatic subcapsular steatosis. Medline, EMBASE, Cochrane Central Register of Controlled Trials, and reference lists of eligible studies were searched. Eligible studies included randomized and non-randomized controlled trials that allocated adult PD diabetic patients to IP insulin and subcutaneous (SC) insulin.

Results: Twenty one citations were identified and three met the eligibility criteria. Glycemic control with IP insulin, as assessed with HbA1C, was equal to or better than that obtained with SC insulin: weighted mean difference was -1.49 % (95% CI: -2.17 to - 0.27, p=0.0001). The insulin dose required was more than two-fold higher in the IP treatment. Serum HDL-cholesterol decreased during IP insulin therapy while serum triglyceride (TG) concentration tended to increase, in comparison with levels seen in patients treated with SC insulin.

Conclusions: Use of IP insulin provides adequate glycemic control, which appears superior to that seen following treatment with conventional SC insulin. The plasma lipids are adversely affected by IP insulin, possibly contributing to increased cardiovascular risk. Data are limited and further studies are needed to assess for the long-term safety of this approach.
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http://dx.doi.org/10.25011/cim.v35i3.16589DOI Listing
June 2012

MR evidence of long T2 water in pathological white matter.

J Magn Reson Imaging 2007 Oct;26(4):1117-21

Department of Radiology, University of British Columbia, Vancouver, BC, Canada.

Purpose: To describe what, if any, specific long T(2)-related abnormalities occur in the white matter of subjects with either phenylketonuria (PKU) or multiple sclerosis (MS).

Materials And Methods: The 48-echo T(2) relaxation data (maximum TE = 1.12 sec) were acquired from 15 PKU subjects, 20 MS subjects, and 15 healthy volunteers. Regions of interest were drawn in diffuse white matter hyperintensities (DiffWM), lesions, normal-appearing white matter (NAWM), and normal white matter. Long T(2) maps (200 msec < T(2) < 800 msec) were created for each subject.

Results: A new water reservoir with a markedly prolonged T(2) peak was identified in DiffWM and NAWM in 12 out of 15 subjects with PKU and a long T(2) signal was also seen in 23/97 lesions in 50% of subjects with MS. Additionally, a long T(2) component was observed in the corticospinal tracts of 10 healthy volunteers. The characteristics of the long T(2) signal were unique for each subject group. Potential sources of this signal include vacuolation and increases in extracellular water.

Conclusion: This study supports the usefulness of increasing the data acquisition window of the multiecho T(2) relaxation sequence to better characterize the T(2) decay from pathological brain.
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http://dx.doi.org/10.1002/jmri.21132DOI Listing
October 2007

Agalsidase alfa therapy for Fabry disease.

Expert Rev Endocrinol Metab 2007 Mar;2(2):147-154

b Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8; Centre Hospitalier Universitaire de Sherbrooke, 3001 12e ave Nord, Sherbrooke, Québec, Canada J1H 5N4.

Fabry disease is a lysosomal storage disorder that results in neuropathic pain, progressive renal dysfunction, cardiomyopathy and stroke in affected individuals. The disease is caused by mutations in the GLA gene coding for α galactosidase A. The resulting deficiency of this enzyme causes accumulation of neutral glycosphingolipids in various tissues. Recombinant human agalsidase alfa has been developed to treat patients with Fabry disease. Preliminary data on this form of enzyme replacement therapy suggest that it improves pain, stabilizes renal function and improves cardiac hypertrophy in some patients. More data are needed on the ability of this therapy to prevent cardiac events, stroke and death.
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http://dx.doi.org/10.1586/17446651.2.2.147DOI Listing
March 2007

Normal-appearing white matter in patients with phenylketonuria: water content, myelin water fraction, and metabolite concentrations.

Radiology 2007 Jan;242(1):236-43

Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: To prospectively assess relative water content (RWC), myelin water fraction (MWF), and hydrogen 1 magnetic resonance (MR) spectroscopy findings in the white matter (WM) of patients with phenylketonuria (PKU).

Materials And Methods: This study was approved by the institution's investigational review board, and informed consent was obtained. T2 water relaxation data were acquired by using a 48-echo measurement in a transverse plane through the genu and splenium of the corpus callosum in 16 patients (six men, 10 women; age range, 18-40 years) with PKU and 16 age- and sex-matched control subjects. MR spectroscopy was performed in a voxel (94x70x15 mm) above the ventricles. WM in control subjects (defined as normal WM) was compared with normal-appearing WM (NAWM) and diffuse WM lesions in patients with PKU by using a Student t test.

Results: Patients with PKU had two forms of NAWM: (a) areas that looked normal on intermediate-weighted (IW) and T2-weighted MR images and long T2 maps and (b) areas that looked normal on IW and T2-weighted MR images but were hyperintense on long T2 maps. Both forms of NAWM showed increased RWC (up to 2.5%, P<.001) and reduced MWF (up to 56%, P<.001) relative to normal WM; these changes paralleled those seen in diffuse WM lesions. Approximately 9% of the water in diffuse WM lesions was in a reservoir with a long T2 time of 200-800 msec. Myoinositol concentrations were reduced by 14% (P=.003) in patients with PKU.

Conclusion: In patients with PKU, NAWM and diffuse WM lesions have altered RWC and MWF relative to normal WM, and diffuse WM lesions show a redistribution of water into an extracellular reservoir with a long T2 time.
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http://dx.doi.org/10.1148/radiol.2421051758DOI Listing
January 2007

Post-liver transplantation diabetes mellitus: an association with hepatitis C.

Liver Transpl 2002 Apr;8(4):356-61

Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.

A retrospective study was performed on all liver transplant recipients from British Columbia from 1989 to March 2000 to determine the prevalence and predictive factors of diabetes mellitus (DM) post-liver transplantation. DM was defined as hyperglycemia requiring treatment with insulin or oral hypoglycemic agents. Patient characteristics, cause of liver disease at transplantation, and immunosuppression regimen were considered. Both univariate and multiple logistic regression analyses were performed. Posttransplantation DM (PTDM) occurred in 43 of 177 transplant recipients (24%). Of these, 13 transplant recipients had DM pretransplantation, whereas 30 patients developed de novo PTDM. The majority of patients were treated with insulin (80%). In univariate analysis, transplantation for hepatitis C virus (HCV) liver disease was associated with a greater incidence of PTDM (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.46 to 6.23) and de novo PTDM (OR, 5.20; 95% CI, 2.25 to 11.99). Patients administered tacrolimus had a greater incidence of PTDM (OR, 2.04; 95% CI, 1.01 to 4.13), and there was a trend toward increased PTDM in older patients (mean age, 49 years). Recipient sex, steroid dosage, and acute rejection were not predictive of PTDM. The incidence of graft loss and death rates were similar between the two groups. On logistic regression, HCV was the only independent predictor of PTDM (OR, 4.12; 95% CI, 1.91 to 8.90) and de novo PTDM (OR, 6.02; 95% CI, 2.55 to 14.20). In conclusion, DM post-liver transplantation is a common occurrence and is associated with HCV.
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http://dx.doi.org/10.1053/jlts.2002.31745DOI Listing
April 2002