INTRODUCTION/AIMS:Facioscapulohumeral muscular dystrophy (FSHD) is characterized by relentlessly progressive muscular weakness, impacting patients' daily functioning, health-related quality of life (HRQoL), and activities of daily living (ADLs), particularly those that require upper extremity (UE) function. Reachable workspace (RWS) is a performance outcome (PerfO) measure for UE function in FSHD. This study aimed to explore the reliability and validity of RWS average (for both arms) Total relative surface area (RSA) Q1-Q5 with 500 g wrist weight score ("Total Q1-Q5 RSA score") in FSHD. METHODS:Data were sourced from the Phase 2 ReDUX4 clinical trial. Test-retest reliability and convergent validity of the Total Q1-Q5 RSA score were evaluated. The following outcome measures were included in the analyses: Timed up and go (TUG) and FSHD TUG, manual dynamometry, FSHD-health index, patient's global impression of change, Ricci Clinical Severity Scale (CSS), and musculoskeletal magnetic resonance imaging (MRI). RESULTS:Almost perfect test-retest reliability (ICC = 0.98) and good convergent validity with moderate (|r| ≥ 0.3) correlations with most ADL items, clinical severity and UE muscle strength were shown. DISCUSSION:Psychometric evidence supports the reliability and validity of the Total RSA Q1-Q5 score as a measure of UE function in FSHD and contributes to the evidence for its use as an outcome in clinical trials of FSHD. Additional study is required to explore responsiveness to change.

Tuberous sclerosis complex (TSC)-associated seizures result in a significant burden for caregivers. To quantify time spent and describe activities undertaken by caregivers of individuals with TSC-associated seizures in Sweden, primary caregivers participated in a cross-sectional, non-interventional online survey. Questions comprised patient/caregiver characteristics, care provision, time, and activities associated with generalized seizures or non-seizure-related care. Twenty-three primary caregivers participated; 96 % parents, 100 % female. Median number of caregivers per individual was three. In the last month, median (interquartile range [IQR]) hours for caregiving per week was 52.0 (25.7-100.0; n = 21); median (IQR) hours for non-seizure-related care was 46.7 (20.0-93.3; n = 21) and for generalized seizure-related care was 4.7 (1.7-15.8; n = 12). Beyond the last month, hours/week of generalized seizure-related care varied from 1.9 (0-8.8) to 14.0 (0.5-77.0). Professional/ paid carers contributed 99.2 (73.5-127.5) hours/week of care. Non-seizure-related care activities included assisting with routine medical care (n = 22, 96 %) and daily activities (n = 22, 96 %). Activities relating to generalized seizures included assessing the need for (n = 16, 84 %) and giving (n = 17, 89 %) rescue medication, providing physical support (n = 16, 84 %), and clearing the individual's environment during generalized seizures (n = 13, 68 %). During generalized seizure recovery, activities included taking the individual to bed (n = 18, 95 %), emotional support (n = 14, 74 %), and managing behavioral issues (n = 14, 74 %). In Sweden, despite contributions of paid caregivers, individuals with TSC-associated seizures require substantial time from unpaid primary caregivers, including seizure- and non-seizure-related care. Generalized seizures have a considerable impact on time spent caregiving and the care activities undertaken.

Topic: 32. Platelet disorders Background: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by hemolytic anemia, thrombocytopenia and organ damage. Ravulizumab (RAV) and eculizumab (ECU) are complement C5 inhibitors (C5i) approved for the treatment of aHUS. There is limited consensus on treatment duration of C5i and appropriate monitoring after discontinuation for patients with aHUS. Aims: To understand real-world clinical practice of healthcare professionals (HCPs) regarding the discontinuation and re-initiation of C5i for patients with aHUS. Methods: A double-blind cross-sectional online survey (Institutional Review Board-approved) was conducted across Europe, North America and Oceania in 2022. HCPs were eligible if they had ≥6 months experience with C5i for the treatment of patients with aHUS. Survey questions were developed from targeted literature review findings on the personalized treatment of aHUS with RAV and ECU. This survey focused on decisions regarding discontinuation and re-initiation of these C5i treatments. Results: In total, 145 HCPs were surveyed (n=74, 51% with experience prescribing both RAV and ECU), including hematologists (n=83, 57%) and nephrologists (n=52, 36%). The median number of newly diagnosed patients that HCPs treated with C5i within the last two years was 6.0 (interquartile range: 17.0). HCPs provided the estimated proportion of patients with aHUS who were treated with (median [range] 70% [1–100%]) or discontinued (19% [0–100%]) C5i. Those who re-initiated C5i after discontinuation was estimated by hematologists (50% [0–100%]; n=65) and nephrologists (25% [0–100%]; n=37). In addition, 45 HCPs (31%) endorsed the statement ‘I recommend discontinuing treatment and discuss this with the patient’. Most HCPs (n=44/74, 59%) with experience prescribing both RAV and ECU agreed that the important factors to consider when discontinuing C5i differ between RAV and ECU; the Table shows the top five factors from surveyed HCPs when making the decision to discontinue C5i. More than two-thirds of HCPs surveyed ‘often’ or ‘always’ used all markers and tests relating to thrombotic microangiopathy response, hemolysis and kidney function when considering discontinuation of C5i treatment. In addition, 43 HCPs (31%) reported that the minimum treatment duration of C5i should be lifetime. When monitoring patients after C5i discontinuation 102 HCPs (86%) discussed with patients about actions to take when signs, symptoms or triggers occur, monitoring potential triggers (n=89, 75%) and monitoring test results (n=83, 70%). The most common post-discontinuation monitoring tests were serum creatinine, platelet count, hemoglobin and lactate dehydrogenase. To improve C5i discontinuation decision making, HCPs indicated they needed more clinical study data (n=105, 72%), treatment discontinuation guidelines (n=99, 68%), post-discontinuation monitoring guidelines (n=87, 60%), information on relapse risk factors (n=86, 59%) and treatment re-initiation guidelines (n=77, 53%). Summary/Conclusion: Assessment of known aHUS relapse risk factors is essential for decisions on treatment duration and discontinuation. Our findings indicate that there is some commonality among HCPs regarding key factors when considering C5i discontinuation, including kidney function and comorbidities, and their monitoring practice. HCPs need more clinical data and guidance on C5i discontinuation and monitoring, to help with the development of robust personalized treatment strategies for patients with aHUS. Study/medical writing support funder: Alexion, AstraZeneca Rare Disease.Keywords: Monitor, Treatment, Thrombotic microangiopathy, Health care

Background Hereditary transthyretin amyloidosis (ATTRv) is an ultra-rare, life-shortening disease with a high unmet need. This study examined ATTRv caregiver health-related quality of life (HRQoL) and productivity. Methods A cross-sectional online survey, including EQ-5D-3L, Hospital anxiety and depression scale (HADS), and caregiver and patient characteristics questions, was developed to assess ATTRv caregiver burden. A companion general population survey collected EQ-5D-3L, HADS and chronic health conditions data. Caregiver-control group differences in HRQoL were assessed using t-tests and chi-square tests. Ordinary Least Squares regression was used to estimate the disutility of being a caregiver compared to controls stratified by patient ambulatory status. Results Thirty-six caregivers and matched controls completed the survey (n = 72). The disease severity of patients they cared for was varied: 33% required no assistance walking, 58% required assistance with walking and 9% required a wheelchair/were bedridden. On average, caregivers spent 6 h daily on practical care and 4 h daily on emotional support. Fifty-six percent indicated that they had changed their employment due to providing ATTRv care. Caregivers reported lower HRQoL, as indicated by lower EQ-5D 3L utility scores (M = 0.772, SD = 0.178 vs. M = 0.849, SD = 0.218) and higher HADS anxiety (9.3 vs. 6.1, p < 0.01) and depression (7.6 vs. 4.4, p < 0.01) scores, compared with matched controls. Caregivers were also more likely to report sleep problems (33% vs. 8%, p < 0.01) and stress (42% vs. 0%, p < 0.001) as chronic conditions than controls. Conclusions The study results indicate that caring for a person with ATTRv can have a considerable negative impact on caregivers’ HRQoL and productivity. The study findings provide important information for economic evaluations of ATTRv treatments.

Tuberous sclerosis complex (TSC) is a rare multisystem genetic condition characterised by benign tumours; prevalent manifestations include epilepsy and neuropsychiatric disorders. This study examined the burden of TSC for primary caregivers and families, exploring the impact of characteristics such as seizures. Primary caregivers of individuals with TSC in the United Kingdom participated in an online survey, comprising the Pediatric Quality of Life Inventory™ Family Impact Module, Hospital Anxiety and Depression Scale (HADS), and TSC-specific items. Responses were analysed using descriptive and regression analysis statistics (closed-ended) or qualitative content analysis (open-ended). Seventy-three participants partially completed and 59 fully completed the survey; 95

Background Tuberous sclerosis complex (TSC) is a rare genetic condition commonly accompanied by neurological and neuropsychological disorders, resulting in a high burden of illness for individuals and a substantial impact on their caregivers. Due to the diversity and complexity of clinical manifestations, patients with TSC need aligned multidisciplinary healthcare services starting in childhood through to adulthood. However, patients and caregivers are sometimes dissatisfied with the care provided, for which one of the most common reasons is a lack of involvement in clinical decision-making. Shared decision-making, whereby clinicians make clinical management decisions together with patients and their caregivers, is advocated for in the management of epilepsy, but evidence of its benefit in managing TSC is currently lacking. In this cross-sectional, UK-based analysis we used an online survey to capture the experiences of primary caregivers for individuals with TSC, including the impact on work productivity, clinical shared decision-making, satisfaction with care, and the impact of the coronavirus disease 2019 (COVID-19) pandemic. Results In total, 73 eligible caregivers provided consent (analysis set), with 14 completing the survey partially and 59 completing the full survey. Many caregivers (72%) reported receiving recommendations about new treatments from their doctor and discussing the treatment together, with a high proportion (89%) preferring that treatment was initiated at a low dose. Most caregivers (69%) were satisfied or extremely satisfied with pediatric TSC healthcare services, but only 25% were satisfied or extremely satisfied with the transition to adult TSC healthcare services. Several (n = 30) caregivers specified the impact of caring on their work productivity and career in optional open-ended survey responses. Finally, 80% of caregivers indicated that the COVID-19 pandemic had a “large” or “very large” impact on their caring activities, negatively affecting the emotional wellbeing and behavior of individuals with TSC, and caregivers’ ability to work and arrange medical appointments. Conclusions Caregivers largely feel involved in treatment decisions, and the majority were satisfied with healthcare services for children with TSC. However, many highlighted the need for an improved transition from pediatric to adult healthcare services. The survey also showed that COVID-19 has considerably affected caregivers and individuals with TSC.

The gastrointestinal immune system consists of immune cells in organized gut-associated lymphoreticular tissues (GALT) and diffuse lamina propria, which give rise to mucosal secretory IgA antibody responses. A recent study showed that the retinoic acid produced by GALT dendritic cells (DCs) imprints B cells for gut homing. Surprisingly, GALT DCs, together with interleukin-5 (IL-5) and IL-6, also provided a milieu for both B cell switching to IgA and IgA synthesis.

Abstract Background Previous research has extensively documented the impact of migraine episodes (‘ictal’) on patients’ health-related quality of life. Few studies have looked at the impact of migraine on migraine-free days (‘interictal’). This study was designed to describe interictal burden of migraine in a mixed group of people affected by migraine and to explore patient characteristics associated with interictal burden. Methods People with migraine in the United States (US) and Germany were recruited for a cross-sectional online survey, including a subgroup treated with calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb). The survey included the Migraine Interictal Burden Scale (MIBS-4), Headache Impact Test (HIT-6), and items measuring patient demographics, clinical and treatment background. Data were analyzed using descriptive statistics and linear regression. Results Five hundred six people with migraine completed the survey (US: n = 257; Germany: n = 249), of whom 195 had taken a CGRP mAb for three or more months. Participants had a mean of 8.5 (SD = 6.4) Monthly Migraine Days (MMD) and 10.4 (SD = 7.1) Monthly Headache Days (MHD). The mean MIBS-4 score was 6.3 (SD = 3.4), with 67% reporting severe interictal burden (MIBS-4: ≥5). The mean HIT-6 score was 65.3 (SD = 6.0), with 86% reporting severe migraine impact (HIT-6: ≥60). MIBS-4 was correlated with the HIT-6 (r = 0.37), MMD and MHD (both r = 0.27). The HIT-6, MMD, MHD, CGRP mAb treatment, and depression all had an independent positive association with the MIBS-4. Conclusion Two-thirds of the study sample reported substantial interictal burden. Whilst interictal burden was associated with migraine frequency and impact of migraine attacks, study results also show it represented a distinct aspect of the overall disease burden. Study findings further indicate unique associations between interictal burden and depression. A unique positive association between interictal burden and CGRP mAb treatment suggests a remaining unmet need among people affected by migraine treated with CGRP mAb.

Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disease. The study objective was to evaluate patient and caregiver preferences for treatment attributes in Type 2 and non-ambulatory Type 3 SMA across five European countries using a stated preference survey. A total of sixty-five adult patients (n=42) and caregivers of patients (n=23) with Type 2 and non-ambulatory Type 3 SMA from Portugal (n=18), the Netherlands (n=17), Finland (n=12), Ireland (n=11) and Belgium (n=7) were recruited via patient associations to take part in an online discrete choice experiment (DCE) survey. Participants completed a survey version in their local language. Attribute selection and attribute descriptions were based on an earlier DCE study and updated using recent literature on SMA treatments. Five attributes, each with 3 attribute levels, were included: motor function, breathing function, treatment administration, treatment risks and side effects (diarrhoea and rash risk vs. fever, headache, vomiting and/or body pain vs. liver injury risk with fatigue, headache and nausea), and treatment evidence in different SMA populations. A conditional logit model with clustering by respondent was used to estimate strength of preference for each attribute. The model results indicated that participants placed most value on motor function, followed by breathing function. Participants also made choices to avoid intrathecal injections, liver injury risk with fatigue, headache and nausea, and treatments with evidence in Type 1 SMA only (i.e. no demonstrated effectiveness in Type 2 or 3 SMA). Patients and caregivers of patients with Type 2 and non-ambulatory Type 3 SMA place great value on motor function, followed by breathing function. The study results show the considerable value of improvement as well as stabilisation of function to patient and caregivers. The pooled study data from five small- and medium-sized European countries could inform national decision making in this rare disease.

BACKGROUND:The debilitating nature of migraine attacks is widely established; however, less is known about how the interictal burden (i.e., how patients are affected in-between migraine episodes) of migraine impacts on patients' health-related quality of life (HRQL). Acute and preventive treatments may lift the burden of the disease, but they often have unwanted side effects and limited effectiveness. The objective of this study was to understand the interictal burden of migraines, from the patient perspective, and to explore patient experience with migraine treatments.METHODS:Participants (n=35) with a self-reported diagnosis of migraine were recruited in the US, UK and Canada, including a subgroup of patients who had taken calcitonin gene-related peptide monoclonal antibody (CGRP mAb) treatment for at least three months. Participants completed a background questionnaire, followed by a semi-structured interview via telephone or video call. The interviews explored patients' migraine symptoms, perception of interictal burden and treatment experience. The interview transcripts were analysed using thematic analysis.RESULTS:The most reported migraine symptom was migraine pain, followed by aura, sensory sensitivity and nausea. Most participants reported interictal impact on HRQL, lifestyle changes they made to avoid triggers or in anticipation of an attack, impacts on work, career, daily activities and relationships. Emotional impacts were reported by all participants, including anger, depression, anxiety and hopelessness. Many participants who took preventive treatments reported improvements in HRQL and functioning but still experienced breakthrough attacks. Among patients who took CGRP mAbs, participants noted varying consistency of treatment effectiveness between treatment administrations.CONCLUSION:This study detailed the additional HRQL impact of migraine in-between migraine attacks and described the unmet need for effective treatment options to prevent and mitigate migraine attacks.

PurposeLennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are rare, treatment-resistant forms of epilepsy characterized by childhood onset of seizures. Cost-effectiveness analysis for new antiseizure medications typically requires health state utilities (HSUs) that reflect the patient and caregiver burden of the relevant conditions. This study aimed to estimate HSUs for LGS and DS. Focus was placed on valuing the impact of seizure frequency and seizure-free days on health-related quality of life (HRQL) for patients and caregivers.MethodsHealth state vignettes that described the experience of living with and caring for a child with LGS or DS were developed based on a targeted literature review and feedback from interviews with LGS and DS clinical experts and DS caregivers. Vignettes varied by the number of seizures and seizure-free days per month. Twenty-four vignettes were developed that described patient HRQL (6 per condition) and caregiver HRQL (6 per condition) for LGS or DS. Vignettes were evaluated via interviews from the general population in the United Kingdom and Sweden using a visual analog scale and time trade-off (TTO) method. Participants were recruited by interviewers based in different regions of the United Kingdom and Sweden using convenience sampling.FindingsTwo hundred interviews were conducted by video call from March to April 2020. One hundred participants evaluated each of the 6 patient and 6 caregiver vignettes for LGS; a different 100 participants evaluated each of the DS vignettes. The estimated utility values vary consistently according to seizure frequency and number of seizure-free days. Patient TTO utility values range from −0.186 (highest seizure frequency and fewest seizure-free days) to 0.754 (seizure-free state) for LGS and from 0.171 to 0.778 for DS. The caregiver TTO utility values range from 0.032 to 0.810 and 0.510 to 0.881 for LGS and DS, respectively. Fewer seizures and additional seizure-free days are associated with better patient and caregiver HRQL.ImplicationsThis study estimated utility values for patients with LGS or DS and their caregivers using visual analog scale and TTO valuation among a general public sample. These utility values can be used in cost-effectiveness assessments of new antiseizure medications. The findings indicate the importance of seizure-free days as well as seizure frequency in patient and caregiver HRQL, which may inform the design of future clinical trials.

Tuberous sclerosis complex (TSC) is a rare multisystem disorder often associated with treatment-resistant epilepsy. Cost-effectiveness analysis for new antiseizure medications typically requires health state utilities (HSUs) that reflect the burden of a given condition. This study aimed to estimate HSUs, with a focus on valuing the impact of seizure type and seizure frequency on health-related quality of life (HRQL) for patients with TSC and their caregivers. A targeted literature review and qualitative research with healthcare professionals and caregivers informed the development of health state vignettes describing the experience of living with TSC or caring for a child with TSC. Vignettes were evaluated in interviews with the UK general population using the time trade-off (TTO) method. Sixteen vignettes were developed describing patient HRQL (n = 8) and caregiver HRQL (n = 8). Two hundred interviews were conducted via online video calls due to COVID-19 pandemic restrictions. Two hundred participants evaluated the patient (n = 100) and caregiver (n = 100) health state vignettes. Estimated utility scores varied consistently according to seizure type and seizure frequency. Patient TTO utility scores ranged between −0.234 (highest seizure frequency and multiple seizure types) and 0.725 (seizure-free state). Caregiver TTO utility scores ranged from 0.221 to 0.905. Findings highlight the substantial burden of living with TSC and caring for a child with TSC. Patient and caregiver burden was greater for generalised versus focal seizures. The burden was greatest for a combination of both seizure types and worsened with increasing seizure frequency.

Spinal muscular atrophy (SMA) is a rare neuromuscular disease that affects motor neurons, resulting in progressive skeletal muscle weakness and atrophy. The aim was to understand the value patients with SMA and caregivers place on treatment attributes and to estimate health utilities for SMA treatment outcomes from a general public sample. Two discrete choice experiments were designed to elicit treatment preferences and health utilities, respectively. Patients with Type 2 and non-ambulatory Type 3 SMA, caregivers of patients with SMA and a general public sample in the UK completed the surveys. Patients and caregiver participants were recruited through patient associations. General public participants were recruited via a survey recruitment panel. Attributes included motor function, breathing function, treatment administration, treatment reactions, eyesight monitoring, contraception (patients only) and overall survival (general public only). Clustered conditional logit models were used to estimate treatment preferences, and marginal rates of substitution were used to estimate disutilities. Adult patients (n = 84) were twice as likely to choose a treatment with improved (vs. stable) motor and breathing function and four to five times less likely to choose a treatment with deteriorated (vs. stable) motor and breathing function as a treatment outcome. Caregivers (n = 83) were three to nine times more likely to choose improved and two to four times less likely to choose deteriorated (vs. stable) motor and breathing function. Both patients and caregivers preferred oral over intrathecal treatment. Treatment reactions, eyesight monitoring or contraception had no significant effect on patient choices. Conversely, caregivers preferred avoidance of treatment reactions. General public data (n = 506) yielded disutilities for unable to sit (− 0.408), need for > 16 h daily mechanical breathing support (− 0.304) and intrathecal therapy (− 0.071). Study results show the importance of motor and breathing function to patients and caregivers, and an oral treatment preference. Disutilities (decrements to utility) were substantial for SMA disease outcomes and care aspects.

Hereditary angioedema (HAE) is an inherited chronic rare disease characterised by recurrent swelling attacks that are associated with significant physical and psychological burden. There is limited understanding of the effect of attack location on this burden and of caregiver burden. Our objective was to capture the relative burden of HAE health and caregiver states, including different attack locations, through a time trade-off (TTO) analysis involving participants from the general public. Qualitative interviews were undertaken to inform vignette development for the TTO study, including vignettes for abdominal, facial, hand and laryngeal attack health states, and an attack-free and caregiver state. Members of the general public in England rated vignettes in TTO interviews, which included a visual analogue scale (VAS) component. For the development of the health state vignettes, qualitative interviews with 15 patients, 5 caregivers and 1 clinical expert were performed. TTO analysis was based on vignette valuation completed by 100 members of the general public. The TTO values were as follows: attack-free, 0.783 (standard deviation [SD] 0.316); hand: 0.582 (SD 0.380); facial: 0.483 (SD 0.448); abdominal: 0.345 (SD 0.458); and laryngeal: 0.128 (SD 0.529). The caregiver rating was 0.762 (SD 0.303). V′ scores were similar and consistent with TTO values. TTO utility values demonstrate that HAE places a significant burden on patients, which is influenced by attack location, and on caregivers. These utility weights can provide important information on quality of life for future economic evaluations of treatments.

The present study aimed to explore patient preferences for attributes of advanced hepatocellular carcinoma (HCC) treatments. A stated preference survey was completed by 150 patients with HCC living in Europe. Overall survival (OS) was the most important attribute, closely followed by risk of diarrhea and hypertension, and other adverse event (AE) risks. Patients were willing to trade OS to reduce AE risks. While less important than OS and AEs, patients also preferred shorter waiting times, and one-off administration of selective internal radiation therapy and oral tablets over intravenous infusions. Although patients placed the most value on extending OS, they were willing to forego OS to avoid risk of treatment-related AEs, to maintain their quality of life. Lay abstract This study aimed to understand patient preferences for characteristics of advanced hepatocellular carcinoma (HCC) treatments. A total of 150 people with HCC in Europe were presented a series of questions asking them to choose between two hypothetical treatments. Overall, length of life was the most important issue for patients, followed by avoiding diarrhea and hypertension, and then other side effects and treatment risks. Patients were willing to forego some months of life to avoid side effects or risks. Patients preferred to be given their treatment via a single minimally invasive hospital procedure or oral daily tablets compared with intravenous drips. In conclusion, although patients placed the most value on overall length of life, side effects and treatment risks were also important.