Search

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM)—a debilitating, fatal disease resulting from the deposition of transthyretin (TTR) amyloid fibrils—can be hereditary due to mutations in the TTR gene (ATTRm) or wild type (ATTRwt). The global prevalence of ATTR-CM is largely unknown, although likely underestimated, with no formal epidemiological prevalence studies in Japan. This study aimed to estimate the prevalence of ATTR-CM in a large in-hospital database in Japan. Methods: This was a retrospective, observational, cross-sectional study which utilized data from all adult patients (aged ≥ 20 years) in the hospital-based Japan Medical Data Vision (MDV) database from January 2010 to September 2018 to estimate the number of currently diagnosed ATTR-CM patients and describe their demographic and clinical characteristics and diagnostic modalities. ATTR-CM patients (ATTRwt and ATTRm) were identified using a range of diagnosis codes that were applied to create broad and narrow definitions of the disease. Results: Over the 9 years of this study, there were 3255 (155.8 per million adult patients in the MDV database) to 3992 (191.1 per million) diagnoses of ATTRwt and 67 (3.2 per million) to 106 (5.1 per million) diagnoses of ATTRm in the MDV database (based on the narrow and broad definitions, respectively). There were 444 (21.2 per million) diagnoses of amyloid light-chain (AL) amyloidosis. Considering only those patients who were also diagnosed with heart failure, there were 1468 (70.3 per million) to 1798 (86.1 per million) diagnoses of ATTRwt and 50 (2.4 per million) to 61 (2.9 per million) diagnoses of ATTRm. Most ATTRwt patients (~ 90%) did not have a record of endomyocardial or abdominal wall biopsy, or of scintigram. Conclusion: This retrospective study provides an estimate of the number of patients diagnosed with ATTR-CM in a large in-hospital database in Japan over a period of 9 years. Improving awareness of disease prevalence may improve diagnosis and treatment. Funding: Pfizer. [ABSTRACT FROM AUTHOR]

Gene therapy will potentially provide people affected by haemophilia with the possibility to manage their disorder without regular factor infusions. Keywords: adeno-associated virus; clinical trials; immunogenicity; neutralizing antibodies; safety EN adeno-associated virus clinical trials immunogenicity neutralizing antibodies safety e628 e629 2 09/16/21 20210901 NES 210901 In the recent commentary by Pierce et al. titled 'Gene therapy to cure haemophilia: Is robust scientific inquiry the missing factor?. [Extracted from the article]

The cytoprotective properties of carbon monoxide ( CO) gas and CO-releasing molecules ( CORMs) are well established. Despite promising pre-clinical results, little attention has been paid to the toxicological profile of CORMs. The effects of CORM-2 and its CO-depleted molecule (i CORM-2) (20-400 μM) were compared in primary rat cardiomyocytes and two cell lines [human embryonic kidney ( HeK) and Madine-Darby canine kidney Cells ( MDCK)]. Cells were assessed for cell viability, apoptosis, necrosis, cytology, mitochondrial energetics, oxidative stress and cell cycle arrest markers. In separate experiments, the anti-apoptotic effects of CORM-2 and i- CORM-2 treatment were compared against CO gas treatment in HeK and MDCK lines. H2O2-induced cellular damage, measured by lactate dehydrogenase ( LDH) release from primary cardiomyocytes, was reduced by 20 μM CORM-2; LDH activity, however, was directly inhibited by 400 μM CORM-2. Both CORM-2/i CORM-2 and CO gas decreased cisplatin-induced caspase-3 activity in MDCK and HeK cells suggesting an anti-apoptotic effect. Conversely, both CORM-2 and i CORM-2 induced significant cellular toxicity in the form of decreased cell viability, abnormal cell cytology, increased apoptosis and necrosis, cell cycle arrest and reduced mitochondrial enzyme activity. Comparison of these markers after CO gas administration to MDCK cells found significantly less cellular toxicity than in 100 μ M CORM-2/i CORM-2-treated cells. CO gas did not have an adverse effect on mitochondrial energetics and integrity. Release of CO by low concentrations of intact CORM-2 molecules provides cytoprotective effects. These results show, however, that the ruthenium-based CORM by-product, i CORM-2, is cytotoxic and suggest that the accumulation of i CORM-2 would seriously limit any clinical application of the ruthenium-based CORMs. [ABSTRACT FROM AUTHOR]

Introduction: Until extended half-life (EHL) factor IX (FIX) concentrates became available in Japan in 2010, patients with hemophilia B received intravenous FIX replacement therapy with standard half-life (SHL) FIX concentrates. Purpose: To investigate the amount of factor dispensed and the associated medical expenditures for the treatment of hemophilia B in the real-world clinical setting in Japan. Methods: This retrospective study comprised patients with hemophilia B (N=197) who had filled prescriptions for FIX concentrates reported in Japan's Medical Data Vision database from 2015 to 2019. Patients were included if they had 2 or more prescriptions for the same FIX concentrates within the first 6 months of the study period and the interval between prescriptions was at least 2 weeks. Results: Since 2015, there was a decrease in the proportion of patients using SHL FIX concentrates and a corresponding increase in international units of dispensed EHL FIX concentrates. Median annualized dispensed dosages (IU/kg body weight) of EHL FIX concentrates were lower than for SHL concentrates for outpatient use only. Annual total health care expenditures per patient and annual expenditures for prescribed FIX concentrates increased each year during the study period. Following a switch from an SHL to an EHL concentrate, the median amount of prescribed FIX concentrate decreased slightly, although median total health care expenditures and FIX concentrate expenditures increased. Conclusion: In the real-world setting in Japan, medical expenditures and the proportion of patients prescribed EHL FIX concentrates for the treatment of hemophilia B have increased. [ABSTRACT FROM AUTHOR]

Background: Haemophilia A carries a substantial healthcare burden, affecting health-related quality of life (HRQoL). The Cost of Haemophilia in Men: a Socioeconomic Survey II (CHESS II), a retrospective real-world study, characterised the burden of haemophilia and its impact on HRQoL and work productivity. The current analysis explored the impact of bleeding events on HRQoL and work productivity in Europe. This analysis focused on data collected from males aged 18 to 64 years with haemophilia A without inhibitors who were receiving replacement factor products or a monoclonal antibody and were not participating in a clinical trial at the time of study recruitment. Descriptive statistics were analysed using scores from EuroQoL's EQ-5D-5L index and EQ-VAS analogue scale and the Work Productivity and Activity Index Specific Health Problem (WPAI:SHP) percentage scores stratified by the number of annual bleeding events (ABs) 0, 1, 2, 3–4, or ≥ 5. Results: Of 918 males with haemophilia A in CHESS II, 318 met inclusion criteria and had data available for HRQoL measures; mean age (SD) was 33.8 (12.1) years and 96% were White. Mean (SD) ABs of 2.7 (2.9) occurred over the preceding 12 months: 20% had 3 or 4 ABs; 17% had ≥ 5 ABs. Mean EQ-5D-5L index scores for patients with 0, 1, 2, 3–4, or ≥ 5 ABs were 0.92, 0.76, 0.76, 0.71, and 0.56, respectively. Mean (SD) EQ-VAS scores were 86.9 (13.6), with 0 ABs versus 69.5 (19.1) for 3 or 4 ABs and 61.2 (17.2) for ≥ 5 ABs. Mean percentage of overall work productivity loss on the WPAI:SHP questionnaire ranged from 9.70 to 0 ABs to 47.65 for ≥ 5 ABs. Conclusions: In this European sample of adult men with haemophilia A, HRQoL and work productivity scores were lower among those reporting more AB events. Bleeding burden appears to affect HRQoL and productivity; however, this cross-sectional analysis limits the ability to draw firm conclusions on causality. [ABSTRACT FROM AUTHOR]

Background: Patients with haemophilia experience recurring hemarthroses, mainly involving knees, elbows and ankles, which lead to haemophilic arthropathy, the major chronic complication of haemophilia. With new approaches to haemophilia treatment leading to fewer joint bleeds and, in some cases, no bleeding events, assessing whether current outcome assessment tools provide adequate sensitivity and specificity for management and care of patients with haemophilia is needed. Methods: An overview of current imaging tools for monitoring joint health, novel osteochondral damage and synovial proliferation biomarkers, and the relationship between assessments for functionality and imaging modalities is provided. Usefulness and sensitivity of point‐of‐care ultrasound (POCUS) to complement other assessments and use of ultrasound to monitor haemophilic arthropathy are also examined. Results: This review provides rationale for haemophilia teams to move beyond traditional outcomes in joint imaging, as well as guidance and evidence on assessment of joint health for potential new treatment modalities, such as gene therapy. The role of POCUS in the existing paradigm for haemophilia care and management along with the use of ultrasound as a complement to other outcome assessment tools are also discussed. Finally, the clinical effects of subclinical bleeding on joint function are described, to motivate screening for synovial proliferation. Conclusion: POCUS can facilitate the early detection of joint damage and can monitor disease progression while providing insights into the efficacy of treatment regimens, and should be considered as an essential assessment tool for managing the care of patients with haemophilia. [ABSTRACT FROM AUTHOR]

Introduction: With the development of gene therapy for people with haemophilia (PWH), it is important to understand how people impacted by haemophilia (PIH) and clinicians prioritise haemophilia treatment attributes to support informed treatment decisions. Objective: To examine the treatment attribute preferences of PIH and clinical experts in the United Kingdom (UK) and to develop a profile of gene therapy characteristics fit for use in future discrete choice experiments (DCEs). Methods: Semi‐structured interviews were conducted with PIH (n = 14) and clinical experts (n = 6) who ranked pre‐defined treatment attributes by importance. Framework analysis was conducted to identify key themes and treatment attributes; points were allocated based on the rankings. Synthesis of results by a multidisciplinary group informed development of a profile of gene therapy characteristics for use in future research. Results: Key themes identified by PIH and clinical experts included patient relevant features and the importance of 'informed decision making'. The six top‐ranked treatment attributes were 'effect on factor level' (79 points), 'uncertainty regarding long‐term risks' (57 points), 'impact on daily life' (41 points), 'frequency of monitoring' (33 points), 'impact on ability to participate in physical activity' (29 points), and 'uncertainty regarding long‐term benefits' (28 points). The final treatment characteristics were categorised as therapeutic option, treatment effectiveness, safety concerns, impact on self‐management and quality of life (role limitations). Conclusion: We identified several gene therapy characteristics important to PIH and clinicians in the UK. These characteristics will be used in a future DCE to further investigate patient preferences for gene therapy. [ABSTRACT FROM AUTHOR]