Combined Point of Care Tools Are Able to Improve Treatment Adherence and Health-Related Quality of Life in Patients with Severe Hemophilia: An Observational Prospective Study

Introduction: Ultrasound (US) assessment of joints is an evolving point of care tool for the detection of early joint arthropathy (Napolitano M, Kessler CM. Hemophilia A and B. Consultative Hemostasis and Thrombosis, Kitchens, 4th edition); population pharmacokinetic (pop-PK) studies are adopted as a useful instrument to set the prophylaxis regimen for patients with hemophilia, they may improve adherence (Nagao A.et al. Thromb Res. 2019 Jan; 173:79-84) and reduce the annual bleeding rate (ABR). Adherence to continuous intravenous administrations of factor VIII or Factor IX products is challenging, thus patients may experience breakthrough bleedings while on prophylaxis. Repeated US examinations of joint status have recently been advocated to attempt to remedy sub-optimal medication adherence (Di Minno A et al., Blood Rev. 2019 Jan;33:106-116). Aim of the current prospective analysis was to evaluate the impact of combined US assessment and pop-PK study on adherence to treatment and health related quality of life in patients with severe hemophilia A(HA) and B (HB) under regular prophylaxis. Material and methods: This prospective observational study was performed at a single tertiary center from January 2017 to June 2019. Research was conducted following the Helsinki Declaration. All patients included in the study provided a written informed consent for study participation. Patients with severe HA and HB routinely underwent, as part of regular 12-months follow-up visits, the following: US joints evaluation of elbows, knees and ankles using the HEAD-US protocol, treatment adherence evaluation by VERITAS-Pro questionnaire, health –related quality of life assessment by the standardized EQ-5D,EQ-VAS and pop-PK study (WAPPS-Hemo, McMaster University) as needed (i.e.in case of changes in life style, planned treatment switch); each patient visualised US and his estimated PK profile during medial encounters. Compliance to the prescribed treatment was also determined by analysis of patient diaries with infusion logs. Statistical analysis was performed using the SPSS software version 25.0 (SPSS Chicago, IL). Statistical tests were 2-sided, with a significance threshold of 0.05. Results: Twenty consecutive males with severe haemophilia were included in the current analysis, 13 with severe HA, 2 with HA with previous inhibitors and 5 HB, with a median age of 30 (range 14- 56) years and a median ABR of 5 (range:0-12). Nine patients were under primary prophylaxis, 8 under secondary prophylaxis and 3 under tertiary prophylaxis, they all self-infused at home. Four patients had one target joint and 3 patients had multiple target joints. For each enrolled subject, HEAD-US score, VERITAS-pro, EQ5D and EQ-VAS score were assessed at enrolment (T0) and at 12 (T12) and 24 (T24) months follow-up visits, respectively. Pop-PK was assessed in 11 patients: in 7 (5 HA,2 HB) it was assessed twice, before and after treatment switch to extended half-life (EHL) products, in 4 it was assessed once to modify prophylaxis treatment schedules for a more active life-style (N=2) or weight changes (N=2). Median ABR was 4 at T12 and 3.8 at T24. Reported breakthrough bleeds at T12 were 14, mainly trauma-related (N= 8) or affecting target joints (N=4), they were not reported at T24 in patients with PK-driven modified schedules (N=4) and in 4 patients under EHL treatments. Mean HEAD-US score at T0 resulted 8 (range:0-16), at T24 it was 6 (range:0-16). Mean Veritas-Pro score values were 42.7 at TO, 40.1 at T12 and 38.7 at T24. At T0, EQ-5D mean utility score was 0.82 (range: 0.68-1), at T24, the mean was 0.87 (range:0.72-1). In detail, at 24 months follow-up, there was a statistically significant (p<0.05) improvement in adherence to treatment with particular reference to the dimensions of communication and skipped doses. A tendency toward improved HEAD-US score, higher adherence and better quality of life scores, was observed in particular in patients switched to EHL products at T24, at a mean of 10 months after switching (range: 6-22 months). Conclusion: Several combined measures of haemophilia treatment monitoring, allowing visual assessment of joints status and PK profile estimates by patients have here shown to improve treatment adherence and quality of life in patients with HA and HB, this may be not only related to new available treatments but also to an increased awareness and education of patients

Voxel-based morphometry and task functional magnetic resonance imaging in essential tremor: evidence for a disrupted brain network

The pathophysiology of essential tremor (ET) is controversial and might be further elucidated by advanced neuroimaging. Focusing on homogenous ET patients diagnosed according to the 2018 consensus criteria, this study aimed to: (1) investigate whether task functional MRI (fMRI) can identify networks of activated and deactivated brain areas, (2) characterize morphometric and functional modulations, relative to healthy controls (HC). Ten ET patients and ten HC underwent fMRI while performing two motor tasks with their upper limb: (1) maintaining a posture (both groups); (2) simulating tremor (HC only). Activations/deactivations were obtained from General Linear Model and compared across groups/tasks. Voxel-based morphometry and linear regressions between clinical and fMRI data were also performed. Few cerebellar clusters of gray matter loss were found in ET. Conversely, widespread fMRI alterations were shown. Tremor in ET (task 1) was associated with extensive deactivations mainly involving the cerebellum, sensory-motor cortex, and basal ganglia compared to both tasks in HC, and was negatively correlated with clinical tremor scales. Homogeneous ET patients demonstrated deactivation patterns during tasks triggering tremor, encompassing a network of cortical and subcortical regions. Our results point towards a marked cerebellar involvement in ET pathophysiology and the presence of an impaired cerebello-thalamo-cortical tremor network

Tailoring haemophilia A prophylaxis with BAY 81-8973: A case series

BAY 81-8973 is an unmodified, full-length third generation recombinant factor VIII (rFVIII) which offers a more favorable pharmacokinetic (PK) profile, compared to its predecessor sucrose-formulated rFVIII (rFVIII-FS). We here report on a retrospective case series of nine patients affected by hemophilia A (HA), with variable disease severity, bleeding phenotype and comorbidities, to underline our clinical practice on prophylaxis with a recently introduced standard hall-life recombinant Factor VIII. The current case series highlights how the current clinical management of hemophilia is able to personalize treatment in several specific conditions like concomitant illnesses with thrombotic risk and allergic reactions

Laying the foundations for gene therapy in Italy for patients with haemophilia A: A Delphi consensus study

IntroductionCurrent treatment for haemophilia A involves factor VIII replacement or non-replacement (emicizumab) therapies, neither of which permanently normalise factor VIII levels. Gene therapy using adeno-associated viral (AAV) vectors is an emerging long-term treatment strategy for people with severe haemophilia A (PwSHA) that is likely to be available for clinical use in the near future. AimThis article proposes practical guidelines for the assessment, treatment, and follow-up of potential PwSHA candidates for AAV-based gene therapy. MethodUsing the Delphi method, a working group of Italian stakeholders with expertise in and knowledge of the care of adults with haemophilia A analysed literature for AAV-based gene therapy and drafted a list of statements that were circulated to a panel of Italian peers. During two rounds of voting, panel members voted on their agreement with each statement to reach a consensus. ResultsThe Delphi process yielded 40 statements regarding haemophilia A gene therapy, across five topics: (1) organisational model; (2) multidisciplinary team; (3) patient engagement; (4) laboratory surveillance; and (5) patient follow-up and gene therapy outcomes. The consensus was reached for all 40 statements, with the second round of voting needed for five statements. ConclusionUse of the hub-and-spoke organisational model and multidisciplinary teams are expected to optimise patient selection for gene therapy, as well as the management of dosing and patient follow-up, patient engagement, laboratory surveillance, and patient expectations regarding outcomes. This approach should allow the benefits of AAV-based gene therapy for haemophilia A to be maximised

Transcription Factor EB Controls Metabolic Flexibility during Exercise

The transcription factor EB (TFEB) is an essential component of lysosomal biogenesis and autophagy for the adaptive response to food deprivation. To address the physiological function of TFEB in skeletal muscle, we have used muscle-specific gain- and loss-of-function approaches. Here, we show that TFEB controls metabolic flexibility in muscle during exercise and that this action is independent of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Indeed, TFEB translocates into the myonuclei during physical activity and regulates glucose uptake and glycogen content by controlling expression of glucose transporters, glycolytic enzymes, and pathways related to glucose homeostasis. In addition, TFEB induces the expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation. This coordinated action optimizes mitochondrial substrate utilization, thus enhancing ATP production and exercise capacity. These findings identify TFEB as a critical mediator of the beneficial effects of exercise on metabolism