Real-life impacts of olipudase alfa: The experience of patients and families taking an enzyme replacement therapy for acid sphingomyelinase deficiency.

BACKGROUND: Acid Sphingomyelinase Deficiency (ASMD) is an ultra-rare autosomal recessive lysosomal storage disorder characterized by intracellular lipid accumulation resulting from reduced function of acid sphingomyelinase. Olipudase alfa, an enzyme replacement therapy, was recently approved in several countries for the treatment of the non-neurologic manifestations of ASMD. Studies demonstrate improvement in organomegaly, pulmonary function and lipid profiles with olipudase alfa, yet little is known about its impact on quality of life (QoL) for patients and caregivers. The purpose of this study is to better understand the real-life impact of ASMD on patients and caregivers and assess how olipudase alfa impacts QoL for pediatric patients and their caregivers. METHODS: Caregivers of pediatric patients (≤ 18 years of age) with a confirmed diagnosis of ASMD that received olipudase alfa for at least 12 months were recruited in early 2022 through national patient organizations to participate in a global online questionnaire followed by semi-structured interviews. Ten caregivers of patients with ASMD who utilized olipudase alfa as an experimental therapy for pediatric patients participated in the study. Quantitative analysis of the results was undertaken, and qualitative data was analyzed using an inductive thematic approach. RESULTS: Ten eligible participants completed questionnaires, and 8 of the 10 went on to participate in structured interviews. Symptom burden of ASMD and impact on symptomatology and quality of life after olipudase alfa use are reported here. Five themes emerged from analysis: (1) ASMD is a systemic disease with a wide array of manifestations that significantly impact QoL; (2) Olipudase alfa was associated with improvements in all non-neurologic manifestations of ASMD; (3) Participants perceived the risk associated with olipudase alfa to be low and the benefits to greatly outweigh any risk or burden; (4) Participants reported an unmet need to treat the neurologic manifestations of the disease despite the benefits of olipudase alfa in the management of non-neurological symptoms; (5) Participants felt all patients with ASMD need access to olipudase alfa based on the life-changing experience they perceived. CONCLUSIONS: These findings highlight the sustained positive impact olipudase alfa had in many domains that are deemed important to patients and families living with ASMD and outline the extensive unmet need for patients and families living with ASMD.

Mortality in patients with alpha-mannosidosis: a review of patients' data and the literature.

BACKGROUND: Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) caused by reduced activity of alpha-mannosidase. Clinical manifestations include skeletal dysmorphism, mental impairment, hearing loss and recurrent infections. The severe type of the disease leads to early childhood death, while patients with milder forms can live into adulthood. There are no mortality studies to date. This study aimed to investigate the age at death and the causes of death of patients with alpha-mannosidosis who had not received disease-modifying treatment. METHODS: Clinicians and LSD patient organisations (POs) from 33 countries were invited to complete a questionnaire between April-May 2021. Cause of death and age at death was available for 15 patients. A literature review identified seven deceased patients that met the inclusion criteria. RESULTS: Median age at death for patients reported by clinicians/POs was 45 years (mean 40.3 ± 13.2, range 18-56, n = 15); 53% were female. One death occurred during the patient's second decade of life, and 14 out of 15 deaths (93.3%) during or after the patients' third decade, including four (26.7%) during their sixth decade. Median age at death for patients identified from the literature was 4.3 years (mean 15.7 ± 17.0, range 2.2-41, n = 7); two were female. Four of the seven patients (57.1%) died within the first decade of life. Seven of 15 deaths (46.7%) reported by clinicians/POs were recorded as pneumonia and three (20.0%) as cancer. Other causes of death included acute renal failure due to sepsis after intestinal perforation, decrease of red blood cells of unknown origin, kidney failure with systemic lupus erythematosus, aortic valve insufficiency leading to heart failure, and dehydration due to catatonia. Three out of seven causes of death (42.9%) reported in the literature were associated with septicaemia, two (28.6%) with respiratory failure and one to pneumonia following aspiration. CONCLUSIONS: This study suggests that pneumonia has been the primary cause of death during recent decades in untreated patients with alpha-mannosidosis, followed by cancer. Determining the causes of mortality and life expectancy in these patients is crucial to further improve our understanding of the natural history of alpha-mannosidosis.

Impact of the COVID-19 pandemic on access to the cerliponase alfa managed access agreement in England for CLN2 treatment.

BACKGROUND: Cerliponase alfa, an enzyme replacement therapy for neuronal ceroid lipofuscinosis type 2 (CLN2), is currently available in England through a managed access agreement (MAA). It is administered every 2 weeks via an intracerebroventricular device. Here we report qualitative research with families of children with CLN2 disease and healthcare professionals (HCPs) who run the MAA, to understand how access to cerliponase alfa via the MAA at Great Ormond Street Hospital (GOSH) in London, and the overall management of CLN2 disease, was affected during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Telephone interviews were conducted with nine families, representing 11 children with CLN2 disease, and two HCPs in November and December 2020. RESULTS: Children had received cerliponase alfa treatment for a mean (SD) of 23.1 ± 24.7 months (7.1 ± 4.6 months in the MAA). Families travelled 7-398 km for treatment (mean 210 ± 111 km). Treatment with cerliponase alfa was designated "essential" by GOSH and continued as normal during the pandemic but with extra safety precautions, and no children missed any treatments. Families were highly motivated to continue treatment, despite considerable anxiety about the risk of coronavirus infection from travelling and staying overnight but were reassured by communications from GOSH and the safety precautions put in place. Support therapy services were widely compromised, causing families concern about deterioration in their children's condition. Families were confused about COVID-19 testing and shielding, and were unclear whether children with CLN2 disease were vulnerable to COVID-19. CONCLUSIONS: Looking forward, advice for children with CLN2 disease should be specific and tailored, taking into account the family unit. Support therapies should be considered essential alongside cerliponase alfa treatment.

Gastrointestinal Manifestations in Mucopolysaccharidosis Type III: Review of Death Certificates and the Literature.

BACKGROUND: Mucopolysaccharidosis type III (MPS III, Sanfilippo disease) is a life-limiting recessive lysosomal storage disorder caused by a deficiency in the enzymes involved in degrading glycosaminoglycan heparan sulfate. MPS III is characterized by progressive deterioration of the central nervous system. Respiratory tract infections have been reported as frequent and as the most common cause of death, but gastrointestinal (GI) manifestations have not been acknowledged as a cause of concern. The aim of this study was to determine the incidence of GI problems as a primary cause of death and to review GI symptoms reported in published studies. METHODS: Causes of death from 221 UK death certificates (1957-2020) were reviewed and the literature was searched to ascertain reported GI symptoms. RESULTS: GI manifestations were listed in 5.9% (n = 13) of death certificates. Median (IQR) age at death was 16.7 (5.3) years. Causes of death included GI failure, GI bleed, haemorrhagic pancreatitis, perforation due to gastrostomies, paralytic ileus and emaciation. Twenty-one GI conditions were reported in 30 studies, mostly related to functional GI disorders, including diarrhoea, dysphagia, constipation, faecal incontinence, abdominal pain/distension and cachexia. CONCLUSIONS: GI manifestations may be an under-recognized but important clinical feature of MPS III. Early recognition of GI symptoms and timely interventions is an important part of the management of MPS III patients.

Theory-Based Digital Interventions to Improve Asthma Self-Management Outcomes: Systematic Review.

BACKGROUND: Asthma is a chronic disease requiring effective self-management to control it and prevent mortality. The use of theory-informed digital interventions promoting asthma self-management is increasing. However, there is limited knowledge concerning how and to what extent psychological theory has been applied to the development of digital interventions, or how using theory impacts outcomes. OBJECTIVE: The study aimed to examine the use and application of theory in the development of digital interventions to enhance asthma self-management and to evaluate the effectiveness of theory-based interventions in improving adherence, self-management, and clinical outcomes. METHODS: Electronic databases (CENTRAL, MEDLINE, EMBASE, and PsycINFO) were searched systematically using predetermined terms. Additional studies were identified by scanning references within relevant studies. Two researchers screened titles and abstracts against predefined inclusion criteria; a third resolved discrepancies. Full-text review was undertaken for relevant studies. Those meeting inclusion criteria were assessed for risk of bias using the Cochrane Collaboration tool. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Study outcomes were classified as medication adherence, self-management, asthma control, clinical markers of health, quality of life, other quality of life outcomes, and health care utilization. Effectiveness was calculated as an average outcome score based on the study's reported significance. The Theory Coding Scheme (TCS) was used to establish the extent to which each intervention had applied theory and which theoretical constructs or behavioral determinants were addressed. Associations between TCS scores and asthma outcomes were described within a narrative synthesis. RESULTS: Fourteen studies evaluating 14 different digital interventions were included in this review. The most commonly cited theories were Social Cognitive Theory, Health Belief Model, and Self-Efficacy Theory. A greater use of theory in the development of interventions was correlated with effective outcomes (r=.657; P=.01): only the 3 studies that met >60% of the different uses of theory assessed by the TCS were effective on all behavioral and clinical outcomes measured. None of the 11 studies that met ≤60% of the TCS criteria were fully effective; however, 3 interventions were partially effective (ie, the intervention had a significant impact on some, but not all, of the outcomes measured). Most studies lacked detail on the theoretical constructs and how they were applied to the development and application of the intervention. CONCLUSIONS: These findings suggest that greater use of theory in the development and application of digital self-management interventions for asthma may increase their effectiveness. The application of theory alone may not be enough to yield a successful intervention, and other factors (eg, the context in which the intervention is used) should be considered. A systematic approach to the use of theory to guide the design, selection, and application of intervention techniques is needed.

Treatment perceptions in patients with asthma: Synthesis of factors influencing adherence.

BACKGROUND: Non-adherence to asthma treatment is a contributing factor for poorly controlled asthma. AIM: The aim of this systematic review is to explore patients' perceptions of their inhaled asthma treatment, and how these relate to adherence, using both qualitative and quantitative data. METHODS: Pre-determined search terms and inclusion criteria were used to search electronic databases (The Cochrane Library, MEDLINE, EMBASE and PsycINFO). Two researchers screened titles and abstracts using the Rayyan web app and data were extracted in relation to psychological components (beliefs about, and attitudes towards, medicines) and adherence. RESULTS: Of 1638 papers, 36 met the inclusion criteria. Key themes were: Perceived need for treatment - all 12 studies using the BMQ to measure patients' perceived need for treatment found that patients' beliefs about their necessity for treatment were associated with adherence-; Concerns about treatment - immediate and long-term side effects (58%), worries about safety (19%), and potential addiction to asthma medication (31%)-; and Perceived social stigma - 22% of studies reported that embarrassment contributed to poor adherence. CONCLUSIONS: Acknowledging and addressing patient treatment beliefs and perceptual barriers to adherence is integral to designing adherence interventions for asthma patients. Further research is needed to better our understanding of the relationship between treatment perceptions and adherence.