The Burden of Illness in Patients with Familial Chylomicronemia Syndrome (FCS) in the United Kingdom

Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder associated with a deficiency in lipoprotein lipase activity, which is characterized by severe hypertriglyceridemia, recurrent abdominal pain and episodes of acute pancreatitis. Investigation of Findings and Observations Captured in Burden of Illness Survey in FCS Patients (IN-FOCUS) assessed the impact of FCS on patient quality of life (QoL) and quantified the burden of illness attributable to FCS for 166 patients in 10 countries. Given the lack of data to support value-based treatment of FCS in the United Kingdom (UK), a prespecified sub analysis of respondents from the UK was performed to evaluate country-specific experiences for patients with FCS and any associated outcomes. Methods: A web-based survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions from adults living with FCS. Results: Twenty respondents from the UK completed the survey. Three-quarters indicated that FCS limits their life and significant time and energy is required to manage their FCS. Respondents reported moderate physical symptoms 1–3 times every 2 weeks, all respondents reported worrying about their FCS getting worse with age and 85% worrying about the long-term impact of FCS on their health. Only 3 respondents (15%) reported working full-time,53% of respondents reported that their diminished employment was largely or entirely due to FCS. Furthermore, 90% of respondents reported restricting their dietary fat consumption to an extreme degree and 75% reported using fasting to help manage the symptoms of FCS, suggesting a level of overcompensation. Only one of five women reported a pregnancy. The UK data was largely consistent with the overall study, except for an increased prevalence of worry and differences in disease management. Conclusions: FCS is associated with an ongoing physical and emotional burden that negatively impacts QoL for patients in the UK. Attempts to self-manage FCS may increase

). The most common cognitive symptoms experienced were difficulty concentrating (18%), brain fog (17%), forgetfulness (10%), impaired judgement (8%) and memory (8%). The emotional symptoms most commonly reported were constant worry about having pain or acute pancreatitis (34%), anxiety/fear/worry about their health (26%) and meal planning (20%), embarrassment due to always thinking about and planning food (20%) and feeling sad/down/blue/depressed (18%). Psychosocial symptoms reported were anxiety/fear/worry in social situations -food related (17%) and feelings of social withdrawal or isolation (13%). All these factors contribute to the decreased quality of life has made managing rare disorders a priority (Health DO, 2012), we conducted this pre-specified sub-analysis of IN-FOCUS to provide UK-specific data on the impact of FCS on QoL to inform future treatments for FCS patients in the UK.

Study design
A comprehensive description of the study methods has been previously published (Davidson et al. 2017)  Additionally, respondents had to satisfy one of the following: 1) a history of TG-induced acute pancreatitis or recurrent abdominal pain requiring emergency department visit/hospitalization due to high TG levels, in the absence of another cause; 3) a family history compatible with FCS or Fredrickson type I hyperlipoproteinemia, in the absence of another known cause; or 4) genetic diagnosis consistent with FCS.

Ethical approval was provided by National Health Services (NHS) Research Ethics
Committee for respondents in the UK.

Data analysis and presentation
Continuous variables, including rating scales, were analyzed descriptively and are presented either as means with standard deviations, or medians with ranges. Comparisons were made between UK patients and the overall IN-FOCUS survey population. Categorical variables were analyzed as frequencies and percentage of occurrence for each category.
IBM SPSS statistics 22 (Armonk, NY) was used to conduct all analyses.

Respondent demographics
Twenty respondents from the UK completed the survey. UK participants were predominately male (75%) with a median age of 32 years (range: 19-53 years) ( Table 1).
Patients reported the median age of FCS diagnosis was 8 years (range: 2-17 years) and 80% of respondents were diagnosed with FCS prior to age 10 years (Table 1). In agreement with the young age of diagnosis, respondents reported beginning to utilize dietary management strategies in adolescence. All but one respondent reported TG values greater than 8.4 mmol/L at the time of diagnosis and 35% had TG levels above this value at their most recent test, despite multiple management strategies.
Experience with health care professionals (HCPs) Participants reported seeing a mean of four HCPs regarding their symptoms prior to receiving a diagnosis of FCS (Table 1). Of the 12 respondents who could recall their diagnosing physician, pediatricians were the most common diagnosing HCP (Fig 1a), 7 followed by endocrinologists (n=3), and lipid specialists (n=2). Four respondents (20%) reported that their symptoms were initially misdiagnosed as either acute pancreatitis (n=2), stomach pain (n=1) or mental retardation (n=1). These misdiagnoses were by primary care physicians (n=2) and an ER doctor (n=1); the fourth patient could not recall this information.
Seventy percent of patients reported they were satisfied with current HCP management of their FCS (Figure 1c). Obtaining a knowledgeable and dependable HCP to manage their FCS is critical for these patients because 86% of patients reportedly receive information regarding FCS from their managing HCP.

Symptoms of FCS
Participants reported experiencing a median of four symptoms of FCS at any one time, regardless of the severity of their symptoms at the time ( Table 2). Physical symptoms of moderate severity, 1-3 times every 2 weeks, were reported as typical and included generalized abdominal pain, indigestion, fatigue and lack of appetite (Table 2). Emotional symptoms of FCS related to anxiety, fear and/or worry were reported by the respondents as typically occurring with moderate severity once or twice weekly, while other emotional symptoms may present once or twice monthly ( Table 2). The most pervasive emotional symptom was constant uncertainty regarding an attack of pain/acute pancreatitis at any time which was reported by five (25%) respondents each. Cognitive symptoms most frequently reported in both severe and typical periods was impaired judgment (n=3, 15%) During severe periods, patients reported similar symptoms to those experienced during typical periods, but slightly less frequent and of much greater severity (Table 2).
Comorbidities and Acute Pancreatitis 8 All respondents had been diagnosed with at least one FCS-related comorbidities ( Figure   2a,b), including nine respondents (45%) who had experienced FCS-related acute pancreatitis. Respondents reported an average of one episode of acute pancreatitis in the preceding 12 months and 13 episodes during their lifetime. All respondents who reported acute pancreatitis required hospitalization for at least one of their episodes and one patient was readmitted within 30 days of being discharged for acute pancreatitis. Amongst the nine patients hospitalized for acute pancreatitis, the mean length of stay was 4 nights, with one patient staying 8 nights. The second most reported comorbidity (n=6, 30%) was a physician diagnosed eating disorder and FCS-related diabetes was also reported by three (15%) respondents.

Management of FCS
Respondents reported that they employ a median of five strategies for managing symptoms of FCS ( Figure 3). Ninety percent (n=18) of respondents reported following an extremely low-fat diet, adhering to a maximum reported daily fat intake of 25g (mean = 22g). However, only 55% of respondents reported also reducing their consumption of carbohydrates and 50% completely abstain from consuming alcohol. Fifteen (75%) respondents reported using fasting to help manage the symptoms of FCS, seven of whom reported fasting routinely. Use of TG-lowering medications was reported by 40% of respondents. The strategies for managing FCS can be extremely challenging to maintain and may not alleviate symptoms. Three-quarters of respondents (n=15) reported that significant time and energy is required to manage their FCS and despite strict compliance to this rigid management strategy, 40% of respondents continue to experience symptoms ( Figure 4). Anxiety, fear, or worry due to health concerns and food preparation and management were also reported by 20% of respondents in varying degrees of severity (Table 2). Impact on Employment Status and Career Selection FCS impacted respondents' employment status, career selection, and work place productivity. Thirteen (65%) respondents reported being employed, but only three had a full-time position (15%) (Figure 5a). Of the 14 UK respondents who were unemployed, or employed part time, at least 50% reported it was largely due to their FCS and only 2 respondents reported that FCS had no impact on their employment status (Figure 5b).
Eighteen (90%) respondents believe that FCS has impacted their career choices ( Figure   5c). Respondents reported they cannot pursue a career that involves travel (83%) or that their ideal career is prohibitive to adhering to their strict diet (78%). Twelve (67%) of these respondents indicated they can only do their job effectively on "good days" and a feeling of forced under employment due to FCS was reported by seven out of the 13 (62%) respondents in paid employment. Nine out of 13 respondents (69%) in paid employment also reported requiring a mean 15 days off work in the preceding 12 months due to FCSrelated issues.

Impact on Outlook and Social Engagement
The extremely restrictive nature of the management strategies makes it difficult to interact socially with friends, colleagues, and family. Respondents reported that their current management strategy impacts their ability to entertain at their home, be spontaneous, or travel. Additionally, the unique nature of FCS and its management strategies causes stress for respondents' families and is challenging to explain to social and professional acquaintances. (Figure 6).
FCS had a negative impact on the emotional and mental well-being of many respondents.
FCS was considered to be a major stressor by 70% of respondents (Figure 7). Sixty five percent of respondents also reported that FCS has significant impact on their feeling of self-worth ( Figure 7). Combined, these factors severely detract from the mental well-being of patients with FCS as reported by 55% of respondents (Figure 7). Respondents in the UK had a higher prevalence of concern about the progression of their FCS with age, compared to the global study. All respondents reported worrying about their FCS getting worse with age and 85% worry about the long-term ramifications of FCS on their health (Figure 8). FCS also had an impact on the decision to have children, or how many to have, with 10 respondents reporting the decision was influenced by their FCS.
One of the five female respondents reported a pregnancy and even though she was diagnosed at the age of 2 was unaware of the complications associated with FCS.

Discussion
The UK subanalysis of the IN-FOCUS study was consistent with the findings of the global IN-FOCUS study analyses (Davidson et al. 2018), showing that patients with FCS face a vast array of physical, emotional and cognitive symptoms that impact healthcare resource utilization, while also uncovering unique, country-specific experiences and outcomes for patients in the UK. For example, respondents from the UK consulted a mean of four HCPs before obtaining a diagnosis of FCS and at a slightly lower age (median = 8 years) than reported in the overall study outcome, in which individuals reported an average of five physicians being consulted before diagnosis at a median age of 9 years (Davidson et al, 2018). UK respondents were also all diagnosed prior to the age of 18, while the global sample age of diagnosis ranged from 1 to 57. However, 90% of the global respondents were diagnosed prior to age of 18 as well. Pediatricians diagnosed a third of the cases of FCS in UK respondents, which corresponds to the young age of diagnosis, but is a much greater portion than the global analysis (10%) which may be due to differences in the pathway of care or healthcare systems. The frequent requirement for patients to be examined by multiple HCPs, from a variety of specialties, before a definitive diagnosis is Acute pancreatitis, the most severe clinical characteristic of FCS, was reported as a comorbidity due to FCS by 45% of UK respondents, which was slightly higher than the global analysis (40%). Respondents from both analyses experienced a mean of 10 events over their lifetime so far and they all required hospitalization for some of the events. Acute pancreatitis induced by high triglycerides, that patients the FCS experience, may have a more severe course (Nawaz et al. 2015), while also representing a substantial healthcare expense. Cost and outcome modeling has predicted that a 50% reduction in TGs could have substantial lowering effect on acute pancreatitis events, corresponding to a significant reduction in medical expenses while simultaneously contributing to improved patient QoL. (Lin F 8-12 November 2014) The effect of FCS experienced by patients extended far beyond symptom profiles. Notably, FCS is associated with a significant emotional burden related to anxiety, fear and worrying, which appears to translate into an increased burden relating to attempts to self-manage the condition and avoid symptoms. Notably, the prevalence of extreme dietary measures beyond those recommended in guidelines, such as fasting, amongst respondents in the UK, highlights the need for additional patient education surrounding the optimal management of FCS. Fasting, in particular, may carry a risk of this behavior becoming habitual and transitioning into an eating disorder (Stice et al. 2018), as well as potentially affecting the nutritional status of the patient. The percentage of UK respondents that reported utilizing fasting as a management strategy was higher than the global population and emphasized the importance of a collaborative approach between health care professionals to treat patients with FCS. Specifically, registered dieticians are critical as the diet is challenging to adhere to and each patient requires an individualized strategy to optimally manage their FCS (Williams et al, 2018). Despite, a potentially more efficient pathway to diagnosis and appropriate treating specialist for UK respondents, all of them still reported concern about their condition getting worse with age and 85% reported being worried about the long-term health consequence of their FCS. While these concerns were also expressed by many in the global analysis, 87% and 86% respectively, the near unanimous agreement on worry regarding long-term ramifications of FCS in UK respondents highlights the need for effective treatment options.
While more UK respondents reported being employed compared to the global study (60% vs 65%), only 15% of UK respondents were employed full time while 23% of the global study respondents reported full time employment. Additionally, 90% of respondents in both analyses reported that FCS impacted their ability to fulfill responsibilities at work and their career choice was influenced by their FCS. Professional time off taken due to FCS was reported in both analyses, with 69% of UK respondents reporting a mean of 15 days off and 60% of global respondents reporting 24 days. All of these factors, combined with the median age of UK respondents (32), demonstrate that FCS potentially has a 13 devastating impact on patients' lifetime earning potential.
Pregnancy is also an innately challenging prospect for women with FCS patients because is it accompanied by a natural increase in plasma TG levels and can trigger an episode of acute pancreatitis. (

Availability of data and material
All datasets used and/or analyzed during the IN-FOCUS study are available from the corresponding author on reasonable request. BI reported no relevant disclosures.

Funding
Akcea Therapeutics Inc. and Ionis Pharmaceuticals funded the completion of this study and analysis.  Comorbidities reported by respondents with FCS -Respondents reported the comorbidities that have been diagnosed by a physician due to FCS (a).
Respondents predominately had one comorbidity, but some had as many as 3 (b).
22 Figure 3 Strategies used by respondents to manage their FCS: Respondents reported the strategies they utilize to manage their FCS. Respondents could indicate more than one strategy, so percentages are for each strategy and will total more than 100. 23