Burden of Wilson Disease among patients and care partners in the United States: results from a cross-sectional survey

Abstract

Objective

This study assessed the burden of Wilson Disease (WD) among patients and care partners (WD-CPs) in the US and compared it to a US general population of adults (GPs) and care partners (GP-CPs).

Methods

This cross-sectional, self-reported survey included patients with WD and WD-CPs aged ≥18 years recruited through the Wilson Disease Association (WDA), while data for GPs and GP-CPs were obtained from the 2022 National Health and Wellness Survey. GPs and GP-CPs were propensity score matched (3:1) with WD patients and WD-CPs for demographics and health characteristics. Bivariate analysis evaluated differences in comorbidity burden and health-related outcomes of the WD cohorts compared to matched GP cohorts.

Results

Thirty-seven patients with WD and 53 WD-CPs completed the survey. Most patients reported some treatment burden (73.3%), experienced sleep problems (60%), and visited a healthcare provider (HCP) in the past 6 months (91.9%). Compared with matched GPs, patients with WD had a significantly higher mortality risk (p < .001) and reported greater rates of chronic liver disease, cirrhosis (both, p < .001), migraines (p = .032), non-alcoholic steatohepatitis (p = .004), sleep problems (p = .009) and HCP visits (p = .002). Most WD-CPs (75.5%) reported high burden of caring (mean ZBI-12 score, 26.5) and more negative impact on esteem than GP-CPs.

Conclusion

This study highlights the burden of WD experienced by patients and WD-CPs, with patients experiencing high treatment burden, comorbidity burden and healthcare resource utilization, and WD-CPs experiencing high impact of caring, including impact on employment and self-esteem.

PLAIN LANGUAGE SUMMARY

Wilson Disease (WD) is a rare genetic disorder that results from copper building up in the liver and the central nervous system. The management of WD has been consistent for the past 50 years. We surveyed patients with WD and family members of patients with WD (“care partners,” hereby referred to as WD-CPs) residing in the US, to understand the burden of WD. We also used data from the 2022 National Health and Wellness Survey to compare patients with and WD-CPs to a sample of adults and care partners of adults in the general population (hereby referred to as GP and GP-CPs). The study found that the majority of the patients with WD reported some treatment burden (73.3%), experienced sleep problems (60.0%), and visited a healthcare provider (HCP) in the past 6 months (91.9%). Compared to GPs, patients with WD had a significantly higher risk of dying in the next 10 years and reported greater rates of other health conditions (chronic liver disease, cirrhosis, migraines, and non-alcoholic steatohepatitis), sleep problems, and visits to healthcare providers in the last 6 months. The majority of WD-CPs (75.5%) reported high burden of caring and more negative impact on their self-esteem than GP-CPs. Overall, this study highlights the burden of WD and suggests the need for more effective treatments that can reduce this burden.

Keywords:

• Burden of disease
• burden of illness
• caregiver burden
• cross-sectional survey
• patient reported outcome measures
• united states
• wilson disease

Introduction

Wilson Disease (WD) is a rare, autosomal recessive disorder¹ caused by mutations in the ATP7B gene, which results in loss of function of the copper transporting ATPase and deleterious accumulation of copper initially in the liver and then central nervous system^2–4. The clinical hallmark of WD is characterized by the presence of liver disease, neurological and psychiatric symptoms, and Kayser-Fleischer rings^4,5. Hepatic symptoms include asymptomatic elevated liver enzymes (aminotransferases) and fibrosis, chronic hepatitis, cirrhosis, and acute liver failure^5,6. Neurological manifestations appear in the second or third decade and include dysarthria, parkinsonism, tremor, chorea, and ataxia as well as cognitive, depressive, behavioral, and psychiatric changes^1,7. The prevalence of WD was estimated to be 1:29,000 to 40,000 globally and between 1:30,000 to 50,000 in the United States (US)⁸.

WD can be successfully managed if diagnosed and treated early; however, a delay in diagnosis, inadequate treatment, non-adherence, or non-persistence may result in worsening of symptoms and/or may even become fatal^9–11. Current management options include pharmacological therapies and liver transplantation. Clinical outcomes of WD improved with chelating agents (penicillamine, trientine, sodium dimercaptopropane sulfonate, and ammonium tetrathiomolybdate) and zinc salts by reducing the copper levels^12,13. Management of WD has been consistent for the past 50 years¹⁴, but there remains an unmet need to diagnose patients earlier in the course of their disease and monitor treatment response and disease progression^15,16.

Research suggests that WD imposes a substantial burden on affected individuals^17,18. For example, a recent survey in the US and Canada found that the patients reported that WD had a negative impact on their overall quality of life (QoL), ranking their emotional state as the most negatively affected aspect of their life, followed by their ability to perform physical activity, work, or school, and their social life². Additionally, medication regimen and financial burden were reported as the most bothersome aspects of WD². Research suggests that patients with WD experience daily difficulties due to motor impairment, a wide range of social limitations, and psychiatric comorbidity even after early diagnosis and appropriate chronic therapy^19–21. A large case-control study using claims data reported higher healthcare resource utilization (HCRU) and associated costs in patients with WD compared with matched chronic liver disease without WD controls¹⁸.

However, our current understanding of the burden of WD is limited in several ways. First, much of the research examining the burden of WD has been either conducted outside of the US or combined the data collected in the US with other regions^2,7,21,22. Given the differences in the US payer landscape and access to healthcare in general²³, it is important to understand the burden of WD in the US population. Few studies have examined the burden experienced among patients with WD compared to individuals in the general population^14,24,25. Finally, very limited research has included the perspective of the caregiver^,26,27. As informal caregiving for a person with physical and mental disability is stressful and can result in physical, emotional, social, and financial strain, and thereby lead to enhanced morbidity and mortality^,28,29, it is important to understand the impact of caring for a patient with WD. Indeed, a study examining the burden of caring for patients with neurologic WD in a Chinese population reported moderate caregiver burden, directly associated with the duration of WD, and indirectly associated with cognitive impairment, depression, anxiety, and functional problems in patients with WD²⁶. To address these limitations, the aim of the present study was to characterize the burden of WD in patients and their care partners in the US. We also aimed to compare the burden of WD in patients and care partners to the general population of adults and care partners in the US, thus putting the burden of WD in context.

Methods

Study design and data source

This retrospective, observational study employed a cross-sectional online, self-reported survey of adults with WD and care partners of patients with WD (WD-CPs) in the US. Participants who completed the online survey were paid a nominal, fair market value, remuneration.

Prior to the administration of the online survey, the survey was pre-tested with five patients with WD and three WD-CPs. This qualitative phase was conducted to assess the interpretation of the questions and to ensure that the survey instrument accurately measured the intended design. The qualitative interviews were conducted via telephone and a computer screen-sharing program and lasted 45–60 min. The participants were paid a fair value incentive for their time and contribution.

All study participants were recruited from the Wilson Disease Association (WDA), a patient advocacy group for patients and care partners of patients with WD. The WDA distributed information about the survey and the survey link to patients via email, social media, and its website.

In addition, a matched sample of adults from the general population [herein referred to as GP], as well as a matched sample of care partners in the general population [herein referred to as GP-CP], were selected from the 2022 US National Health and Wellness Survey (NHWS), in order to compare the burden of disease in terms of work productivity and activity impairment (WPAI) and QoL. The NHWS is a self-administered, internet-based survey of a representative sample of US adults, which has been validated and weighted against reliable sources, including government agencies’ health statistics and unaffiliated third parties^30–32. Quota sampling with strata by age, gender, and race is implemented within the survey panel to ensure demographically accurate representativeness of the US adult population.

The study protocol was reviewed and granted an exemption from full review by the Pearl Institutional Review Board according to FDA 21 CFR 56.104 and 45CFR46.104(b)(2): (2) Tests, Surveys, Interviews on 8 June 2021 (IRB Protocol #21-KANT-259). The 2022 US NHWS Patient Centered Research Program was also reviewed and determined by the Pearl Institutional Review Board to be Exempt according to the same criteria on 11 April 2022. All participants completed informed consent electronically.

Study participants

Patients were included in the current study if they were aged ≥18 years, resided in the US, self-reported a diagnosis of WD, and could read and understand the survey in English. Patients were excluded if they were participating in a clinical trial.

Care partners were included if they were aged ≥18 years, resided in the US, lived with a person diagnosed with WD, devoted at least 5 h/week to their care, could read and understand the survey in English, and the patient they cared for was ≥13 years of age. Care partners were excluded if they or their family member with WD was participating in a clinical trial or if they were paid, professional caretakers/partners.

The comparison groups (GP and GP-CPs) included participants of the NHWS 2022 survey who were aged ≥18 years, resided in the US, and could read and understand the survey in English or Spanish; care partners also had to report being a caregiver for an adult or child with a chronic health condition.

Measures

Study measures are described below. Supplemental Table 1 contains a crosswalk of the study measures to the groups who completed them (patients with WD, WD-CPs, GP, GP-CPs).

Sociodemographic and health characteristics

Sociodemographic and health characteristics data on age, gender, employment status, body mass index (BMI), and patient insurance coverage were collected for both patients with WD and WD-CPs. Patients with WD were also asked about sources for support in managing WD. WD-CPs also provided data on patient age and the number of hours they spend caring for the patient each week.

Diagnostic, clinical, and treatment characteristics

Patient clinical and treatment characteristics measured in this study included age at first symptom related to WD led to seeking medical help/treatment, age at diagnosis, duration of WD, time from symptom onset to diagnosis, type of physician who diagnosed WD, symptoms prompting consultation with a healthcare provider (HCP), medications ever taken for WD, current medication taken for WD, and time from diagnosis to start of WD treatment.

Treatment burden

Patients’ self-reported data related to WD treatment burden, including rating of the burden of taking WD medications, treatment switches, treatment dose/frequency reductions, reasons for treatment discontinuation or adjustment, polypharmacy, diet modifications, the burden of dietary restrictions, and severity of WD treatment side effects, were collected. Data on treatment burden, including polypharmacy, diet modifications, and severity of WD treatment side effects were provided by WD-CPs.

Comorbidity burden

Comorbidity burden was assessed using the Charlson Comorbidity Index (CCI)³³, which produces a weighted summary score of several conditions that contribute to mortality risk. Higher index scores indicate greater comorbidity burden. Data on other diagnosed comorbidities were also collected, including diabetes, high blood pressure, high cholesterol, and migraine. Data on sleep conditions experienced in the past 12 months were also collected.

Humanistic outcomes

The 9-item Patient Health Questionnaire (PHQ-9) was used to measure the frequency of depression symptoms experienced in the past 2 weeks, with items rated on a 4-point scale (0 = not at all to 3 = nearly every day). Items were summed into a total score (range: 0–27); a score of ≥10 suggests the presence of major depressive disorder. Scores of 5, 10, 15, and 20 represent cut-offs for mild, moderate, moderately severe, and severe depression, respectively^34,35.

The 7-item Generalized Anxiety Disorder Assessment (GAD-7) measured the degree of anxiety symptoms experienced in the past 2 weeks, with items rated on a 4-point scale (0 = not at all to 3 = nearly every day). Items were summed into a total score (range: 0-21). Scores of 5, 10, and 15 represent cut-offs for mild, moderate, and severe anxiety, respectively³⁶.

The 5-Level EQ-5D version (EQ-5D-5L) measures economic preferences for health states and consists of a descriptive system and a visual analogue scale (EQ VAS). The EQ-5D descriptive system comprises five dimensions; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. EQ-5D index scores range from <0 to 1 (0, health state equivalent to death; 1, health state equivalent to perfect health). The EQ VAS asks respondents to indicate on a 0-100 line their self-rated health with the endpoints of the line being “best imaginable health state” and “worst imaginable health state”³⁷.

The Unified Wilson’s Disease Rating Scale-Part II (UWDRS II) is a clinical rating scale for WD and part 2 consists of a historical review based on the Barthel scale that evaluates activities of daily living. The scale has 10 items and ranges from 0 (completely independent) to 40 (completely dependent), with higher values reflecting worse clinical outcomes³⁸.

Adherence was assessed with the Medication Adherence Reasons-Scale (MAR-Scale) consisting of 20 items − 1 global item assessing the amount of adherence in the past week (with higher scores indicating better adherence) and 19 specific reasons for medication non-adherence, rated on an 8-point scale (0-7). The resulting composite score is the sum of the 19 reasons with a range of 0-133 with higher scores indicating higher complexity of non-adherence³⁹.

Caregiver burden was measured with Caregiver Reaction Assessment (CRA) and Zarit Burden Interview – Short Form (ZBI-12). The CRA is a 24-item scale that assessed caregiver burden. Responses were measured on a 5-point Likert-type scale (strongly disagree to strongly agree) and assessed 5 domains: impact on health (4 items, range: 4 to 20), caregiver’s esteem (7 items, range: 7 to 35), impact on schedule (5 items, range: 5 to 25), impact on finances (3 items, range: 3 to 15), and lack of family support (5 items, range: 5 to 25). Items for each subscale are summed to form a total subscale score. Higher scores indicate a greater burden on all subscales except the caregiver’s esteem scale, where higher scores indicate less burden^40,41.

The ZBI-12 is comprised of 12 items in two domains– personal strain and role strain. Each question was scored on a 5-point Likert scale from 0 to 4 (never to almost always); items were summed to form a total scale (range: 0–48). Higher scores indicate greater perceived caregiver burden, and scores of 0–10, 10–20, and >20 are indicative of no to mild burden, mild to moderate burden, and high burden, respectively.

Economic outcomes

HCRU outcomes included the self-reported number of traditional HCP visits, number of emergency room (ER) visits, and number of hospitalizations in the past 6 months. The proportion of patients with HCP visits, ER visits, and hospitalizations in the past 6 months was also reported.

The broad category of traditional HCP included dieticians, general practitioners, gastroenterologists, gynecologists/obstetricians, hepatologists, movement disorder specialists, neurologists, occupational therapists, ophthalmologists, physical therapists, psychiatrists/psychologists/counselors, social workers, speech therapists, and others.

The Work Productivity and Activity Impairment (WPAI) scale is a validated instrument used to quantify impairments in work productivity and daily activities due to one’s personal health problem(s). The scale consists of 4 metrics: absenteeism, presenteeism, overall work impairment, and activity impairment. The WPAI + classroom impairment questionnaire: allergic specific (WPAI + CIQ: AS)⁴² was adapted for use among patients with WD (questions were worded to reference Wilson Disease rather than allergies). Care partners completed the WPAI: general health v2.0 version of the questionnaire⁴³. Only respondents who reported being employed provided data for absenteeism, presenteeism, and overall work impairment, and only patients who were students completed measures of classroom impairment. The impact of WD on schooling/education (patient with WD) and employment (WD-CPs) were also assessed.

Statistical analysis

The responses of patients with WD and WD-CPs were analyzed descriptively. Means and standard deviations (SD) were provided for continuous variables and counts and percentages for categorical variables. The analyses were conducted separately for patients and WD-CPs. Sensitivity analyses were conducted among WD-CPs to qualitatively compare outcomes by age of the patient cared for (13-17 years vs ≥18 years).

An unmatched bivariate analysis between WD and GP cohorts was carried out to identify covariates for matching using the chi-square test and t-test for categorical and continuous variables, respectively. To minimize the possible bias due to differences in demographics and health characteristics, the comparison cohorts (GP and GP-CPs) were matched in a ratio of 3:1 to the WD cohorts using propensity score matching methodology. The propensity scores were estimated using a multivariable logistic regression model with WD status as a dependent variable. Age, sex, region, education level, marital status, children living in the household, and BMI category (for patients only) were included as explanatory variables in the model after reviewing the unmatched bivariate results. The propensity scores were further used to match each WD patient/WD-CP to 3 NHWS GP/GP-CPs with a similar propensity score using a greedy-matching algorithm. The new cohorts were compared on the covariates of interest to confirm a successful match. A successful match was indicated when the p-values were ≥ .2⁴⁴.

Bivariate analyses were then conducted to compare WD cohorts to the respective matched cohorts on the sociodemographic and health characteristics, and humanistic and economic outcomes that were available in both datasets.

Results

A total of 37 patients with WD and 53 WD-CPs completed the online survey. After 3:1 propensity score matching, the comparison groups included 111 GP respondents and 159 GP-CP respondents from the 2022 US NHWS.

Sociodemographic and health characteristics

The mean age of patients with WD was 44.7 years; the majority were female (67.6%), employed (48.6%), had a normal weight (73.0%), and were privately insured (70.3%). Participants in the WD-CP cohort had a mean age of 44.6 years. Similar to the patient cohort most of the WD-CPs were female (67.9%) and employed (81.1%). However, 84.9% of WD-CPs declined to provide their height or weight. At the time of the study, the majority of the patients in care had health insurance through a private insurer (67.9%) (Table 1). Nearly 35% of patients with WD reported receiving healthcare support from a spouse/partner and 37.8% from their parents, while 40.5% of patients reported having no support for managing their disease (Data not shown).

Table 1. Sociodemographic and health characteristics among survey participants (patients with WD and WD-CPs) and matched NHWS general population cohorts.

Characteristics	Patients with WD n = 37	Matched GP (NHWS)^a n = 111	WD-CPs n = 53	Matched GP-CPs (NHWS)^a n = 159
Age, years
Mean (SD)	44.7 (17.4)	45.4 (16.6)	44.6 (9.2)	45.0 (10.7)
Median (min-max)	45.0 (18.0-75.0)	45.0 (19.0-75.0)	42.0 (35.0-78.0)	42.0 (21.0-80.0)
Gender, n (%)^b
Female	25 (67.6)	73 (65.8)	36 (67.9)	108 (67.9)
Employment status, n (%)
Employed	18 (48.6)	75 (67.6)	43 (81.1)	113 (71.1)
Retired	8 (21.6)	17 (15.3)	2 (3.8)	12 (7.5)
Not employed	11 (29.7)	19 (17.1)	8 (15.1)	34 (21.4)
BMI, n (%)
Underweight (<18.5 kg/m^2)	0	2 (1.8)	0	18 (11.3)
Normal weight (18.5-24.9 kg/m^2)	27 (73.0)	77 (69.4)	6 (11.3)	42 (26.4)
Overweight (25.0-29.9 kg/m^2)	7 (18.9)	22 (19.8)	1 (1.9)	36 (22.6)
Obese (≥30.0 kg/m^2)	1 (2.7)	4 (3.6)	1 (1.9)	50 (31.4)
Decline to provide height or weight	2 (5.4)	6 (5.4)	45 (84.9)	13 (8.2)
Patient’s insurance status, n (%)
Private insurer	26 (70.3)	67 (60.4)	36 (67.9)	–
Public insurer^c	11 (29.7)	26 (23.4)	17 (32.1)	–
Not sure	0	1 (0.9)	0	–
Not insured	0	17 (15.3)	0	–

Abbreviations. BMI, body mass index; GP, general population; GP-CPs, general population care partners; NHWS, National Health and Wellness Survey; SD, standard deviation; WD, Wilson disease; WD-CPs, Wilson disease care partners.

^a Note: NHWS cohorts were matched in a ratio of 3:1 to WD cohorts using propensity scoring. The multivariable logistic regression model used to estimate propensity scores included age, sex, region, education level, marital status, children living in households, and BMI category (for patients only) as explanatory variables.

^b One WD-CP declined to report their gender.

^c Public insurance includes: Medicaid, Medicare, Veterans Affairs (VA)/CHAMPVA, CHAMPUS/TRICARE.

The majority of WD-CPs were providing care for their child. The average age of patients in care was 18.2 years (SD = 9.79, median = 15); 67.9% were under 18 years old. WD-CPs reported devoting an average of 101.3 (SD: 52.6; range: 7 to 168) hours per week caring for their family member with WD.

After matching, the covariates (age, sex, education, marital status, children living in household, region of residence, and BMI category) were well-balanced between the patients with WD versus the matched GP cohort, and WD-CP versus the matched GP-CP cohort (all p > .05).

Diagnostic, clinical, and treatment characteristics

The first symptoms of WD that led patients with WD to seek help from an HCP occurred at the mean (SD) age of 20.0 (11.3) years, while patients of WD-CPs experienced the first WD manifestations at a mean age of 8.8 (3.9) years (Table 2). Mean age at the date diagnosed for patients in the patient and WD-CP samples, was 20.9 (12.4) years and 11.6 (4.4) years, respectively. More than half the patients received a WD diagnosis before the age of 18 years (52.9%) or 26 years (64.7%). For patients with WD, the mean (SD) time from diagnosis to survey administration was 25.1 (14.9) years (n = 34), and a diagnosis was received within 12.9 (31.7) months (n = 26).

Table 2. Diagnostic, clinical, and treatment characteristics of patients with WD and patients of WD-CPs.

Characteristic	Patients with WD	WD-CPs
Age at the date of onset of first symptoms related to WD^a, years	n = 37	n = 6
Mean (SD)	20.0 (11.3)	8.8 (3.9)
Median (min–max)	18.0 (5.0-47.0)	9.0 (2.0-13.0)
Age at date diagnosed with WD by physician, years^a	n = 34	n = 7
Mean (SD)	20.9 (12.4)	11.6 (4.4)
Median (min–max)	18.0 (4.0-49.0)	10.0 (7.0-20.0)
Age at date diagnosed with WD by physician, split at 18^a, n (%)	n = 34	–
<18 years	18 (52.9)	–
≥18 years	16 (47.1)	–
Age at date diagnosed with WD by physician, split at 26^a, n (%)	n = 34	–
<26 years	22 (64.7)	–
≥26 years	12 (35.3)	–
Years since diagnosed with WD by physician^b	n = 34	–
Mean (SD)	25.1 (14.9)	–
Median (min-max)	21.5 (3.0-53.0)
Months between the date of first symptoms leading to seek medical help/treatment and date diagnosed with WD by physician^b	n = 26	–
Mean (SD)	12.9 (31.7)	–
Median (min-max)	2.5 (0.0-161.0)	–
Type of physician that diagnosed WD, n (%)	n = 37	n = 53
Gastroenterologist	15 (40.5)	6 (11.3)
Hepatologist	8 (21.6)	31 (58.5)
Medical geneticist	3 (8.1)	11 (20.8)
General practitioner	3 (8.1)	2 (3.8)
Others^c	7 (18.9)	0
Not sure	1 (2.7)	3 (5.7)
Medications ever taken for WD, n (%)	n = 37	n = 53
Penicillamine	25 (67.6)	46 (86.8)
Trientine	21 (56.8)	45 (84.9)
Zinc acetate, Rx	26 (70.3)	49 (92.5)
Zinc acetate, OTC	17 (45.9)	23 (43.4)
Others	2 (5.4)	0
Not sure	0	2 (3.8)
Medications currently taken for WD, n (%)	n = 37	–
Penicillamine	8 (21.6)	–
Trientine	11 (29.7)	–
Zinc acetate, Rx	14 (37.8)	–
Zinc acetate, OTC	9 (24.3)	–
Others	2 (5.4)	–
None	1 (2.7)	–
Time from WD diagnosis to date started prescription medication, months^b	–	n = 7
Mean (SD)	–	0.1 (0.4)
Median (min–max)	–	0.0 (0.0–1.0)
Time from WD diagnosis to date started penicillamine, months^d	n = 15	–
Mean (SD)	12.5 (47.2)	–
Median (min-max)	0.0 (0.0–183.0)	–
Time from WD diagnosis to date started trientine, months^d	n = 11	–
Mean (SD)	47 (103.8)	–
Median (min-max)	3.0 (0.0–323.0)
Time from WD diagnosis to date started zinc, months^d	n = 17	–
Mean (SD)	100.1 (139.5)	–
Median (minmax)	5.0 (0.0-371.0)	–

Abbreviations. OTC, over-the-counter; Rx, prescription; SD, standard deviation; WD, Wilson disease; WD-CPs, Wilson disease care partners.

^a Patients with WD were asked about the date they first begin experiencing symptoms related to their Wilson disease that made them want to seek medical help/treatment, and WD-CPs were asked about the date when the person they care for first began to show signs and symptoms of WD.

^b Data provided for 34 WD (3 unsure) and/or 7 WD-CP (46 unsure).

^c Patients with WD: Other diagnosing physicians included neurologist (n = 2), opthamologist (n = 2), and ‘other’ category (n = 3).

^d Data missing due to being unsure for 2, 3, and 6 patients with WD for pencillamine, trientine, and, zinc, respectively.

In the patient cohort, WD was predominantly diagnosed by gastroenterologists (40.5%), followed by hepatologists (21.6%), and less frequently by medical geneticists, general practitioners, or other specialists. In the WD-CP cohort, WD was diagnosed primarily by hepatologists (58.5%), followed by medical geneticists (20.8%) and gastroenterologists (11.3%) (Table 2). In the WD-CP cohort, the most frequently reported symptoms that prompted the decision to consult an HCP were elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels (34.0%) and cirrhosis of the liver (28.3%). In contrast, fewer patients in the patient cohort reported that these symptoms prompted their decision to consult an HCP (elevated AST/ALT levels: 13.5%; cirrhosis of the liver: 10.8%).

In the patient and WD-CP cohorts, the most common treatments ever used by patients for WD were prescribed zinc acetate (70.3% and 92.5%), followed by penicillamine (67.6% and 86.8%), trientine (56.8% and 84.9%), and zinc purchased over the counter (OTC) (45.9% and 43.4%). At the time of the study, the most frequently used medication by patients with WD was prescribed zinc acetate (37.8%) and the least used was penicillamine (21.6%). In the patient cohort, on average, treatment for WD with penicillamine began within ∼13 months (12.5 [47.2] months; n = 15) of diagnosis, whereas treatment with trientine and treatment with zinc began within 4 years (47.0 [103.8] months; n = 11), and within 9 years (100.1 [139.5] months; n = 17) of receiving WD diagnosis, respectively (Table 2).

Treatment burden

The majority of patients with WD reported at least some burden of taking their WD medications (73.3%), with 23.3% reporting moderate or extreme burden, and experienced a treatment switch (78.4%). Over one-fourth of respondents (27.8%) reported ever reducing the frequency (19.4%) or dose (8.3%) of their medication (Supplemental Table 2). Penicillamine treatment changes (n = 18) were most frequently attributed to side effects (61.1%), doctor’s recommendation (55.6%), and pregnancy attempts among female patients (23.1%; n = 13). The top 3 reasons for trientine treatment discontinuation or adjustment (n = 14) were related to the medication cost or the doctor’s recommendation (both, 28.6%) and forgetfulness (21.4%). The most common reasons for changes in treatment with prescribed zinc acetate (n = 15) were related to tolerability (40.0%), forgetfulness (33.3%), and the inconvenience of treatment administration (20.0%). Regarding the changes in treatment with OTC zinc (n = 8), more than one-third of patients with WD reported forgetfulness (37.5%), and a quarter of them invoked the cost of medication, tolerability, inconvenience of treatment administration, and doctor’s recommendation (all, 25.0%). As reported by patients and WD-CPs, respectively, patients took an average of 3.2 (3.2) and 2.6 (0.8) prescription medications daily to manage their health conditions (n = 35 and n = 42), of which 1.2 (0.9) and 2.1 (0.6) prescription medications, respectively, were used to treat WD (Supplemental Tables 2 and 3). Among patients, penicillamine and trientine were more likely taken twice daily (57.1% and 70.0%, respectively), while Rx or OTC zinc was more likely to be taken 3 times a day (44.4%).

Table 3. Comorbidity and humanistic burden among patients with WD and WD-CPs and matched NHWS general population cohorts.

Characteristic	Patients with WD n = 37	Matched GP (NHWS) n = 111	WD-CPs n = 53	Matched GP-CPs (NHWS) n = 159
CCI score, mean (SD)	1.5 (2.0)**	0.3 (0.7)	0.2 (0.7)**	0.8 (1.2)
CCI score, n (%)
0	18 (48.6)**	87 (78.4)	49 (92.5)**	97 (61.0)
1	6 (16.2)**	18 (16.2)	1 (1.9)**	41 (25.8)
2	3 (8.1)**	3 (2.7)	2 (3.8)**	9 (5.7)
≥3	10 (27.0)**	3 (2.7)	1 (1.9)**	12 (7.5)
Comorbidities, n (%)
Chronic liver disease	10 (27.0)**	0	–	–
Cirrhosis	10 (27.0)**	0	–	–
Migraine	8 (21.6)*	8 (7.2)	–	–
High cholesterol	7 (18.9)	24 (21.6)	–	–
High blood pressure	7 (18.9)	13 (11.7)	–	–
Depression	6 (16.2)	20 (18.0)	–	–
NASH	5 (13.5)**	1 (0.9)	–	–
Sleep conditions experienced in past 12 months, n (%)
Any sleep problem	22 (59.5)**	37 (33.3)	20 (37.7)	–
Insomnia	10 (27.0)	17 (15.3)	3 (5.7)	–
Idiopathic hypersomnia	1 (2.7)	3 (2.7)	–	–
Narcolepsy	1 (2.7)	3 (2.7)	–	–
Sleep apnea	2 (5.4)	4 (3.6)	–	–
Sleep difficulties (others)^a	13 (35.1)*	17 (15.3)	18 (34.0)	–
PHQ-9 score, mean (SD)	5.1 (5.7)	6.6 (7.9)	3.0 (3.2)**	9.6 (8.0)
PHQ-9 score segment, n (%)
0–4, none-minimal depression	22 (59.5)	59 (53.2)	37 (69.8)**	56 (35.2)
5–9, mild depression	11 (29.7)	21 (18.9)	15 (28.3)**	30 (18.9)
10–14, moderate depression	1 (2.7)	11 (9.9)	1 (1.9)**	30 (18.9)
15–19, moderately severe depression	1 (2.7)	8 (7.2)	0	22 (13.8)
20–27, severe depression	2 (5.4)	12 (10.8)	0	21 (13.2)
GAD-7, mean (SD)	4.4 (5.6)	5.1 (5.8)	3.7 (3.9)**	8.2 (6.2)
GAD-7 score segment, n (%)
0–4, none-minimal anxiety	24 (64.9)	60 (54.1)	34 (64.2)**	56 (35.2)
5–9, mild anxiety	7 (18.9)	29 (26.1)	14 (26.4)**	32 (20.1)
10–14, moderate anxiety	2 (5.4)	11 (9.9)	5 (9.4)**	45 (28.3)
15–21, severe anxiety	4 (10.8)	11 (9.9)	0	26 (16.4)
EQ-5D index score, mean (SD)	0.845 (0.146)	0.806 (0.195)	0.886 (0.086)**	0.705 (0.235)
EQ VAS, mean (SD)	75.5 (17.8)	76.5 (22.6)	68.0 (12.9)	64.7 (28.6)
EQ-5D-5L, n (%)
Mobility, any problems	7 (18.9)	25 (22.5)	2 (3.8)**	77 (48.4)
Self-care, any problems	4 (10.8)	12 (10.8)	0	56 (35.2)
Usual activities, any problems	14 (37.8)	35 (31.5)	2 (3.8)**	79 (49.7)
Pain/discomfort, yes	18 (48.6)	63 (56.7)	15 (28.3)**	123 (77.4)
Anxiety/depression, yes	15 (40.5)	62 (55.8)	30 (56.6)*	105 (66.0)
CRA^b, mean (SD), n (%)
Impact on health subscale	–	–	11.2 (1.8)	10.8 (2.5)
Caregiver’s esteem subscale	–	–	23 (3.3)**	25.7 (5.1)
Impact on schedule subscale	–	–	15.8 (3.9)	17.21 (5.0)
Impact on finance subscale	–	–	10 (1.9)	9.5 (2.5)
Lack of family support subscale	–	–	14.4 (3.5)	15.5 (4.3)

Abbreviations. CCI, Charlson Comorbidity Index; CRA, Caregiver Reaction Assessment; EQ-5D-5L, 5-Level EQ-5D version; GAD-7, 7-item Generalized Anxiety Disorder Assessment; GP, general population; GP-CPs, general population care partners; NASH, non-alcoholic steatohepatitis; NHWS, National Health & Wellness Survey; PHQ-9, 9-item Patient Health Questionnaire; SD, standard deviation; VAS, Visual Analog Scale; WD, Wilson disease; WD-CPs, Wilson disease care partners.

^a “Sleep difficulties (others)” category for patients with WD and matched NHWS GP included difficulties other than insomnia, idiopathic hypersomnia, narcolepsy, and sleep apnea; for WD-CPs it included difficulties other than insomnia, narcolepsy and apnea.

^b CRA was reported only for n = 71 matched NHWS GP-CPs because the NHWS respondents only took the CRA if the respondent was a caregiver of an adult relative with Alzheimer’s disease, autism, bipolar disorder, cancer, Crohn’s disease, chronic kidney disease on dialysis, dementia, epilepsy, macular degeneration, multiple sclerosis, muscular dystrophy, osteoporosis, Parkinson’s disease, schizophrenia, or stroke.

* p < .05;

** p < .01.

all statistics reported relative to GP or GP-CP cohorts, for patients and WD-CP analyses, respectively.

Most of the patients (83.8%) and WD-CPs (98.1%) reported that patients followed a modified diet to avoid food with copper (Supplemental Tables 2 and 3). Among the patient cohort, 90.3% reported this diet was burdensome, and 64.5% reported that they have eaten foods that should be avoided because they were tired of the restrictions or found the modifications too challenging to follow. For the attitude towards various aspects of treatment management (on a 5-point scale, ranging from 1, “disagree completely” to 5, “agree completely”), most patients who adjusted their diet (n = 31) disagreed (rating of 1 or 2) with statements saying that 1) as a result of their dietary restrictions dining out at restaurants was hard (83.9%), 2) they felt embarrassed when eating with friends/acquaintances (77.4%), and 3) they avoided dining out/sharing a meal with anyone outside their closest friends or family (90.3%) (Supplemental Table 2).

Among patients with WD who had experienced any side effects with penicillamine, the most commonly reported as very bothersome were nausea, diarrhea, loss of appetite, fatigue, and muscle spasms or weakness (all, 100.0%). With trientine treatment, for those who experienced any side effects, the most commonly reported as very bothersome were iron deficiency (100.0%), followed by fatigue (60.0%), and nausea (25.0%). The most commonly reported side effects with zinc as very bothersome were low white blood cell (WBC) count (100.0%), followed by fatigue (83.3%), loss of appetite (50.0%), stomach pain (42.9%), and diarrhea (40.0%) (Supplemental Table 4). Most of the WD-CPs (n = 43 [81.1%]) reported that within the month prior to survey administration, patients in their care experienced side effects to WD medication, predominantly with mild or moderate severity.

Comorbidity burden

Mean (SD) CCI score in patients with WD was 1.5 (2.0); over half (51.4%) of all WD patients had a CCI score of ≥1, with 27.0% having a score of ≥3. The majority of WD-CPs reported a low comorbidity burden overall (mean [SD] CCI score, 0.2 [0.7]) (Table 3). The highest prevalent comorbidities among patients with WD were chronic liver disease and cirrhosis (both, 27.0%) followed by migraine (21.6%). Nearly 60% of patients with WD reported experiencing a sleep problem in the past 12 months, with more than a third experiencing other sleep difficulties (35.1%), and over a quarter having insomnia (27.0%). A total of 37.7% of WD-CPs reported sleep problems, and 5.7% had insomnia (Table 3).

Compared with the GP cohort (mean CCI, 0.3 [0.7]), patients with WD reported a considerably higher mortality risk, as measured by CCI (p < .001). Also, a higher proportion of patients with WD reported having chronic liver disease (27.0% vs 0.0%; p < .001), cirrhosis (27.0% vs 0.0%; p < .001), migraines (21.6% vs 7.2%; p = .032), and non-alcoholic steatohepatitis (NASH; 13.5% vs 0.9%; p = .004) compared to the matched GP cohort. In addition, a higher proportion of patients with WD experienced sleep problems (59.5% vs 33.3%; p = .009) and other sleep difficulties (35.1% vs 15.3%; p = .018) than the matched GP cohort.

Humanistic outcomes

Among patients with WD, the mean PHQ-9 score was 5.1 (5.7) and the mean GAD-7 score was 4.4 (5.6), indicating a mild level of depression and no to mild anxiety, respectively. The WD-CP cohort reported a low level of depression (mean PHQ-9 score, 3.0 [3.2]) and anxiety (mean GAD-7 score, 3.7 [3.9]). In the patient cohort, 29.7% of participants indicated a mild level of depression and 35.1% reported mild, moderate, or severe anxiety (Table 3). Among WD-CPs, 30.2% reported a mild or moderate level of depression and 35.8% reported mild or moderate anxiety (Table 3).

QoL (EQ-5D-5L) measures showed that nearly half of the patients (48.6%) with WD experienced at least some pain/discomfort, 40.5% reported anxiety or depression, 37.8% experienced problems with usual activities, 18.9% had some mobility problems, and 10.8% reported problems with self-care. The mean EQ-5D index score was 0.845 (0.146) and the mean VAS score was 75.5 (17.8). At the time of survey administration, a majority of WD-CPs (56.6%) reported being anxious or depressed, and over a quarter (28.3%) experienced pain/discomfort. However, most of the WD-CPs (96.2%) reported no problems with mobility or usual activities, and none faced any problems with self-care. Their perceived health status overall was reflected by a mean EQ-5D index of 0.886 (0.086) and a mean EQ VAS score of 68.0 (12.9) (Table 3).

Patients with WD recorded a relatively high level of overall independence with a mean UWDRS II score of 2.4 (4.2). MAR-Scale results demonstrated a high level of adherence to WD treatment among patients with WD (mean score, 6.2 [1.7]); 64.9% of WD patients were perfectly adhering to their WD medications. Consistent with this finding, the mean composite score of 2.3 [5.0] on the MAR-Scale reflected a lower complexity of non-adherence (i.e. a higher score indicates higher complexity of non-adherence) (Data not shown).

Mean scores on the CRA subscales were indicative that WD-CPs experienced a negative impact of caregiving on their health (mean CRA score, 11.2 [1.8]), schedule (mean CRA score, 15.8 [3.9]), and finances (mean CRA score, 10.0 [1.9]), as well as family support (mean CRA score, 14.4 [3.5]) (Table 3). Additionally, 75.5% of WD-CPs reported a high burden of caring as measured by the ZBI-12 (mean ZBI-12 score, 26.5 [8.0]), and 24.5% of WD-CPs reported mild to moderate burden (Data not shown).

No significant differences were observed for humanistic outcomes of patients with WD and the matched GP group. Compared to the matched GP-CP cohort, WD-CPs reported significantly lower severity of depression, anxiety, and a better QoL (p < .001, for all). Regarding the EQ-5D-5L dimensions, WD-CPs reported statistically significant lower rates of functional impairment or pain (p < .001 for all measures) and were more likely to report mild or moderate levels of anxiety and depression (p = .016) compared with matched GP-CPs. However, WD-CPs had lower mean scores on the caregiver’s esteem subscale of the CRA than their counterparts in the GP-CP group (23.0 [3.3] vs 25.7 [5.1]; p < .001), indicating that the caregiving had a more positive impact on GP-CPs compared with WD-CPs.

Economic outcomes

In the past 6 months, 21.6% of patients reported all-cause ER visits, and 8.1% of patients reported hospitalization, while most WD-CPs (>80.0%) in this study did not report any ER visits, hospitalizations, or traditional HCP visits to address their own health conditions. Compared with the matched GP cohort, patients with WD were significantly more likely to have visited a traditional HCP (91.9% vs 64.0%; p = .002), including gastroenterologists (43.2% vs 4.5%) and hepatologists (32.4% vs 0.9%) (p < .001 for both), and ophthalmologists (16.2% vs 1.8%; p = .003) (Table 4). In addition, patients with WD had a higher number of mean traditional HCP visits (2.9 vs 1.6; p = .018), including appointments to gastroenterologists (0.6 vs 0.05), hepatologists (0.4 vs 0.01) (p < .001 for both), and ophthalmologists (0.2 vs 0.02; p = .032) in the past 6 months compared to the matched GP cohort. The majority of WD-CPs reported they did not know the number of times in the past 6 months they had a traditional HCP visit (84.9%), went to the ER (83.0%), or were hospitalized (83.0%) for their own health.

Table 4. Economic burden among patients with WD and WD-CPs and matched NHWS general population cohorts.

Characteristics	Patients with WD	Matched GP (NHWS)	WD-CPs	Matched GP-CPs (NHWS)
HCRU, visits in past 6 months, n (%)	n = 37	n = 111	n = 53^a	n = 159
ER visits	8 (21.6)	20 (18.0)	0	50 (31.5)
Hospitalizations	3 (8.1)	13 (11.7)	1 (1.9)**	53 (33.3)
Traditional HCP visits^b	34 (91.9)**	71 (64.0)	5 (9.4)**	134 (84.3)
HCP seen in past 6 months, n (%)	n = 37	n = 111	–	–
Gastroenterologist	16 (43.2)**	5 (4.5)	–	–
General practitioner/family practitioner/internist	24 (64.9)	57 (51.4)	–	–
Hepatologist	12 (32.4)**	1 (0.9)	–	–
Ophthalmologist	6 (16.2)**	2 (1.8)	–	–
None of the above	2 (5.4)**	38 (34.2)	–	–
HCRU, number of visits in past 6 months, mean (SD)	n = 36	n = 111	n = 9	n = 159
ER visits	0.3 (0.5)	0.3 (0.7)	0	0.8 (1.6)
Hospitalizations	0.2 (0.7)	0.2 (0.6)	0.1 (0.3)**	0.8 (1.7)
Traditional HCP visits^a	n = 37	n = 111	n = 8	n = 159
	2.9 (2.7)*	1.6 (3.1)	2 (2.1)*	4.2 (7.1)
	n = 37	n = 111	–	–
Gastroenterologist	0.6 (0.8)**	0.05 (0.2)	–	–
General practitioner/family practitioner/internist	1.1 (1.1)	0.70 (1.0)	–	–
Hepatologist	0.4 (0.6)**	0.01 (0.1)	–	–
Ophthalmologist	0.2 (0.5)*	0.02 (0.1)	–	–

Abbreviations. ER, emergency room; GP, general population; GP-CPs, general population care partners; HCP, healthcare provider; HCRU, healthcare resource utilization; NHWS, National Health & Wellness Survey; SD, standard deviation; WD, Wilson disease; WD-CPs, Wilson disease care partners.

^a N = 44 WD-CPs reported not being able to recall how many times they went to an ER or were hospitalized for their own medical conditions in the past 6 months, and N = 45 WD-CPs reported not being able to recall how many times they had an HCP visit in the past 6 months.

^b Traditional providers include gastroenterologists, general practitioners/family practitioners/internists, gynecologist/obstetricians, hepatologists, neurologists, ophthalmologists, psychiatrists/psychologists/counselors.

* p < .05;

** p < .01.

all statistics reported relative to GP or GP-CP cohorts, for patients and WD-CP analyses, respectively.

WPAI results are shown in Figure 1. Overall, the mean (%) for activity impairment due to illness in the patient population was 16.0%. Employed patients with WD (n = 18) reported a mean (%) overall work impairment of 11.1%, driven mainly by presenteeism 8.9% (Figure 1). Students with WD (n = 6) reported a mean overall classroom impairment of 20.0% due to presenteeism (data not shown). A total of 50.0% of students with WD reported having difficulty focusing in school, 33.3% reported a decline in grades, and 16.7% reported a negative impact on their relationship with fellow students or teachers, as well as a reduced ability to complete the classwork. WD-CPs reported a mean (%) activity impairment of 4.5% and employed WD-CPs (n = 42) reported 2.5% overall work impairment, driven mainly by presenteeism (2.4%) (Figure 1). Nearly half (49.1%) of all WD-CPs reported that their employment status has been affected by the demands of caregiving (data not shown).

Figure 1. WPAI among survey participants (patients with WD and WD-CPs) and matched NHWS general population cohorts GP, general population; GP-CPs, general population care partners; NHWS, National Health & wellness Survey; WD, Wilson disease; WD-CPs, Wilson disease care partners; WPAI, work productivity and activity impairment.

Although not statistically significant, the proportion of respondents who were employed (full-time, part-time, or self-employed) was lower among patients with WD (48.6%) than the matched GP cohort (67.6%; odds ratio: 0.45; p = .062). Compared to the matched GP cohort, patients with WD reported less productivity loss at work (11.1% vs 27.5%; p = .017) in terms of both absenteeism (p = .003) and presenteeism (p = .015), and a lower level of impairment in daily activities (p = .020). Employed WD-CPs reported statistically significant lower rates of work impairment in terms of both absenteeism and presenteeism (p < .001 for all) than the employed GP-CP cohort. WD-CPs also had a lower level of impairment in regular daily activities (p < .001) compared with the matched GP-CP cohort (Figure 1).

WD-CPs of children (13-17 years) versus WD-CPs of adults (≥18 years)

A total of 17 WD-CPs were caring for a child (age 13–17 years) with WD, and 36 WD-CPs were caring for an adult (age ≥18 years) with WD. Descriptive results showed higher comorbidity burden (CCI score ≥1: 23.5% vs 0.0%, respectively) and a propensity for emotional distress among WD-CPs caring for adult patients, compared with those caring for children with WD. Within the past 12 months at the time of survey administration, a higher proportion of WD-CPs caring for adults experienced depression (41.2% vs 16.7%) and insomnia (17.7% vs 0.0%), compared with those caring for children. Accordingly, a higher proportion of WD-CPs caring for adult patients had mild or moderate depression (47.1% vs 22.2%), according to the PHQ-9, and mild or moderate anxiety (47.1% vs 30.6%), according to the GAD-7, compared with those caring for children with WD (Supplemental Table 5).

Even though the EQ-5D index and VAS scores were comparable between WD-CP subgroups, a higher proportion of WD-CPs caring for adults reported experiencing pain/discomfort (53.0% vs 16.7%) compared to those caring for children. A higher proportion of WD-CPs caring for adults reported that caring for someone with WD has impacted their physical health (17.7% vs 2.8%), emotional health (35.3% vs 13.9%), and social health (23.5% vs 8.3%) greatly (rated very or extremely impactful) compared to those caring for children (Supplemental Table 5). WD-CPs caring for children were more inclined to report no impact on their relationship with the patient (“None of the above”: 58.8% vs 86.1%). While a higher proportion of WD-CPs caring for adults reported that the act of caring strengthened the bond between themselves and the patient in their care compared to WD-CPs caring for children (“We are growing stronger together”: 17.7% vs 2.8%) (Supplemental Table 5).

No WD-CPs of children reported activity impairment, but WD-CPs of adult patients reported an average of 14.1% activity impairment due to their own health problems. Whereas employed WD-CPs of children (n = 10) reported no work impairment, employed WD-CPs of adult patients (n = 32) reported on average 9.5% overall work impairment due to their own health problems. Additionally, a higher proportion of WD-CPs assisting adult patients reported that their employment status has been affected by the demands of caregiving (10/17, 58.8% vs 16/36, 44.4%). Specifically, while WD-CPs caring for children allocated more time telecommuting (0/10, 0.0% vs 3/16, 18.8%), WD-CPs caring for adults with WD were more inclined to quit their job (2/10, 20.0% vs 1/16, 6.3%), and thus they were more likely to report a decrease in income because of caregiving (4/7, 57.1% vs 2/9, 22.2%) (Supplemental Table 5).

Discussion

This real-world, quantitative study, utilizing validated patient-reported outcome measures, examined the burden associated with WD in patients and WD-CPs in the US and compared the findings to the general population. Overall, patients with WD and WD-CPs showed evidence for high burden of WD/caring for a patient with WD. Patients reported high treatment and comorbidity burden, and high HCRU. Pain and sleep-related problems, mild depression, and anxiety were experienced by both patients and WD-CPs. Compared with the matched GP cohort, patients with WD experienced greater comorbidity burden, including higher rates of sleep problems, and greater HCRU. WD-CPs reported a more negative impact of caregiving on their esteem than the matched GP-CP cohort. Patients with WD reported productivity loss, both at school and work, as well as impairments in activities of daily life. Almost half of the WD-CPs indicated the demands of caregiving affected their employment status. However, both patients and WD-CPs exhibited lesser work and daily activity impairment relative to their counterparts in the matched GP cohorts.

Whereas almost 60% of patients in the WD-CP cohort were diagnosed by a hepatologist, just 22% of patients in the patient cohort were diagnosed by a hepatologist. This discrepancy in diagnosing HCP between cohorts could be attributable to the symptoms that first prompted patients to see an HCP. While elevated AST/ALT levels and cirrhosis of the liver were the most frequently reported symptoms that prompted the decision to consult an HCP among WD-CPs, fewer patients reported these symptoms as prompting their decision to consult an HCP. This may have led WD-CPs to seek care from a hepatologist initially, whereas patients may have been more likely to consult a general practitioner or a different specialist initially. However, it is important to recognize that patients in our study were diagnosed, on average, 25 years ago. When taking this into consideration along with the knowledge that cognitive impairment is relatively common in patients with WD⁴⁵, it is quite possible that patients may have had difficulty in recalling the symptoms that prompted them to seek care and the specialty of the diagnosing HCP. Thus, results may need to be interpreted with caution.

In the current study, the majority of patients with WD reported a burden of WD treatment, which emphasizes the need for improvement in the current pharmacologic therapies. The majority of patients are taking more than one medication for their WD, with a majority taking their medication more than once a day. Over half of patients reported taking medications for other health conditions. The necessity to utilize multiple medications for various health conditions could further compound the burden of the disease. While dosage reduction may indicate clinical improvement, tolerability was one of the most common rationales for discontinuation or dose adjustments specified by the patients (range, 7.1% [trientine] to 61.1% [penicillamine]). Patients with WD may switch between therapies for various reasons including inability to tolerate due to side effects, ineffectiveness, patient chronic and emerging comorbidities, or costs. At least 78% of the patients in the current study switched medications. Transitioning regimens is often challenging specifically when on multiple medications, hence close monitoring is necessary⁴⁶. Most patients with WD followed a modified diet to avoid food with copper, and most perceived the modified diet as burdensome. Avoiding foods high in copper may be beneficial after diagnosis of WD and at the start of treatment. However, due to a lack of clear evidence for the advantages of a strict low copper diet, consistent adherence to drug therapy is more important than a modified diet⁴⁷.

Evaluation of the participants’ reported outcomes revealed that preoccupation with WD disrupted the physical and mental abilities of those affected directly or indirectly by this condition. Comorbidity burden was high among patients, suggesting that in adult patients, the burden of WD may be complicated by the presence of other comorbidities which are pervasive in this age group, hence making the disease management more difficult. A significantly higher mortality risk and higher rates of comorbidities such as chronic liver disease, cirrhosis, migraines, and NASH were noted among patients with WD compared to the matched NHWS GP cohort. Previous research demonstrates higher mortality in patients with WD compared to the general population, regardless of adherence, clinical symptoms, advancement of disease at diagnosis, or type of treatment^20,25,48. The significantly higher comorbidity burden of patients with WD raises concern about polypharmacy and drug-drug interactions and highlights the importance of patient-centered, rather than disease-centric care, especially as comprehensive medication management for WD can contribute to substantial cost savings. Sleep disorders are highly prevalent in patients with WD49. In our study, both patients with WD and WD-CPs experienced sleep problems; patients with WD had more sleep problems relative to the GP cohorts. This observation is consistent with previous research wherein patients with WD were more prone to sleep disturbances compared to healthy matched controls^50,51. Early detection and intervention for sleep disturbances can improve the QoL of the patients as well as care partners.

Both patients with WD and WD-CPs were currently experiencing pain, at least mild depression, and anxiety. In addition, more than three-quarters of WD-CPs associated their role with a high burden on the ZBI instrument. Previous studies demonstrated a negative impact of WD on the overall QoL (emotional [feeling depressed and anxious], physical, and daily living status) of patients with WD^{2,21,22,52,53}. Owing to the risk of mild, moderate, or major depression in patients with WD, active screening for depressive disorders should be considered in the management of WD^7,22. Additionally, developing depression is a risk in chronic diseases and is associated with increased disease burden, as well as reduced functionality and quality of life in patients with chronic disorders^54–57. Future research should assess the role of clinical factors, such as depression, in the burden of WD, which may help inform disease management and identify targets for clinical care that lead to improved outcomes in patients with WD. The burden of caring noted in the current study was comparable with the caregiver burden associated with Parkinson’s disease and psychogenic non-epileptic seizures, and higher than traumatic brain injury^58–60. Unavane et al. reported poorer QoL of parents of children with WD and their family functioning compared with controls. This highlights the negative impact of WD on the whole family, thereby emphasizing the need for support groups and coping strategies for caregivers as well²⁷. This is especially important given that the family’s involvement in WD care may continue well into adulthood. Indeed, our study found that although participants in the patient cohort were, on average, older (∼45 years), and considered themselves independent regarding their self-care ability, more than a third (∼38%) reported receiving support from their parents.

In this study, no significant differences were observed between patients with WD and the matched GP cohort on humanistic outcomes. WD-CPs reported significantly lower severity of depression and anxiety, and a better QoL compared to the matched GP-CP cohort. Similar/or better humanistic outcomes in the patient and WD-CP cohorts compared to the matched GP may be attributed to the recruitment of the survey participants via a patient advocacy group, WDA, which provides patient education and support for the management of WD. Hence, the present study participants may have had better health literacy and reflected a more engaged patient population who were taking care of themselves better than those not part of such support groups. Involvement in the patient advocacy group may also have increased the amount of perceived social support WD-CPs had. Past research has shown that high levels of perceived social support is associated with lower caregiver burden^61–63. Future research should examine the role of social support in caregivers of patients with WD. It is also important to note differences in the care partner samples. WD-CPs in this study were required to spend ≥5 h per week caring for a patient with WD who was ≥13 years of age, whereas the GP-CPs simply had to indicate they were caring for an adult relative with one of the listed health conditions. It may be that the GP-CPs spent more hours providing care and were caring for a sicker population. However, as data on these aspects was not collected for GP-CPs, hence such comparisons cannot be made in the current study. Nonetheless, caregiving had a significant negative impact on the self-esteem of WD-CPs compared with the GP-CPs, emphasizing a subtle aspect of disease burden, as a contributor to lack of confidence, which could lead to social withdrawal and unequal life opportunities^61,64,65.

Given the high comorbidity burden among patients with WD, it was not surprising that this cohort had significantly higher HCP visits, including gastroenterologists, hepatologists, and ophthalmologists compared to the matched GP cohort. Of note, most WD-CPs were not able to recall the last visit to their own HCP, suggesting a lack of health-seeking behavior, which could manifest in increased direct costs, if the neglect of receiving preventive care leads to health issues requiring ER visits and hospitalizations. Perhaps WD-CPs are focused on caring for the patient with WD at the neglect of their own healthcare.

In general, patients with WD had a 19% lower employment rate than the matched GP cohort. Activity impairment, a decline in competence to work, and a decrease in academic performance was also experienced by WD patients. Among WD-CPs, the adversities of caring were less apparent in terms of productivity loss at work and activities of daily life but were rather demonstrated by the influence of demands of caregiving on their employment status. The impairment of work/classroom and daily living activities noted in our study is in line with literature studies wherein the ability to perform physical activities and go to work/school were considered difficult^2,27. Cognitive deficits have long been recognized as hallmarks of WD, predominantly altering processing speed and daily function due to hand-eye discoordination, as well as the mental acuity of those affected by WD^66,67.

In the present study, significantly less work productivity and daily activity impairment were reported by both patients and WD-CPs relative to the respective matched GP cohorts. Previous studies comparing caregivers of patients with multiple sclerosis and schizophrenia to non-caregivers demonstrated a greater activity impairment among caregivers than the non-caregivers^68,69. Some divergences in the results of the current study could be generated by the recruitment of the survey participants from a patient advocacy group, which may indicate that the WD-CPs in our study are more engaged and have a support network that helps them navigate the treatment journey of their loved one with WD. In our study, patients and WD-CPs had similar/better health characteristics (depression, anxiety, mobility, and self-care) compared to the matched GP, which could have contributed to reduced work/activity impairments. However, it is worth noting that we measured work productivity and activity impairment in the context of the care partners’ own health problems, rather than in the context of caring for the patient with WD. Had we measured the impact of caring for a patient with WD on work productivity and activity impairment, we may have seen greater impairment. It is also possible that the extent of the WD-CP burden may be underestimated in our study as comparisons with non-caregivers were not included.

Finally, it is worth noting that over 40% of patients with WD reported not having support for managing their disease. This lack of support, whether from family, friends, or paid assistance, may exacerbate the burden experienced by patients as they manage the difficulties of WD alone.

Strengths and limitations

The present research is one of the largest US patient surveys to utilize various validated PRO instruments for assessing WD burden among patients with WD as well as WD-CPs. Few studies have utilized PROs to capture different dimensions of the impact of the disease on QoL^7,21,52. In addition, the use of propensity score-matching methodology in the present study adjusted for potential confounders and reduced the variance with minimal bias. This allowed for making comparisons with a US general population representative of our sample and provided better context to the burden actually experienced by patients with WD and WD-CPs.

Another strength of the current study was the study geography. Quality of care in the US is influenced by various factors including access to timely care, affordability of care, and use of evidence-based guidelines to drive treatment⁷⁰. Considering the disparities in the US payer landscape and access to healthcare^23,71 assessing the WD burden in the US population is crucial. The burden showcased in this population may help inform disease management and treatment development for this rare, understudied disease.

In addition to the selection bias that may have occurred by recruiting patients and care partners through a patient advocacy group, this study has other limitations. Respondents who were more interested in research, had internet access, or perhaps, who were healthy enough to participate, may be over-represented in the present study, which may reflect another source of selection bias. Due to the cross-sectional data collection, no causal associations can be made. With the use of self-reported data via an online survey, there may be a possibility of selection, recall, and self-presentation biases. Given the low prevalence of the disease in the general population, the sample used in this study was relatively small; hence robust quantitative analyses were limited.

Conclusions

The study findings demonstrate the burden of WD among patients and care partners. Patients with WD experience high treatment and comorbidity burden, sleep problems, and high HCRU; comorbidity burden, sleep problems, and HCRU was greater than the matched GP. All WD-CPs experienced at least mild burden in caring for patients with WD, with over three-fourths experiencing high burden, which impacted employment status for approximately half of WD-CPs. In comparison to matched GP-CPs, WD-CPs experienced a more negative impact of caregiving on their esteem. The study results indicate that an unmet need exists among patients with WD and their care partners. Our study highlights the need for more effective treatments that can reduce the burden of disease and improve the outcomes of WD.

Transparency

Author contributions

J.V. and M.K. contributed to the conception of the study. M.J.C.M. and H.C. were involved in data analysis. M.J.C.M. drafted the manuscript. All authors contributed to the design of the study, interpretation of the data and the critical review of the manuscript. All authors provided the final approval of the manuscript and agreed to be accountable for all aspects of the work.

Acknowledgements

The authors acknowledge Kyla Finlayson, ScM, of Oracle Life Sciences, for her assistance with statistical analysis and Neetu Menghani, PhD and Ramu Periyasamy, PhD, of Indegene Pvt. Ltd., India, for their assistance with medical writing.

Declaration of financial/other relationships

J.V. and M.K. declare being employees of Alexion, AstraZeneca Rare Disease. M.J.C.M and H.C. declare being employees of Oracle Corporation, Oracle Life Sciences division, which received funding from Alexion, AstraZeneca Rare Disease to conduct this study. M.J.C.M. also holds stock in Oracle Corporation.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

The participants of this study did not give written consent for their data to be shared publicly, so due to the sensitive nature of the research supporting data is not available.

Additional information

Funding

This study was sponsored by Alexion, AstraZeneca Rare Disease. Medical writing support was provided by Indegene Pvt. Ltd., India, in accordance with Good Publication Practice (GPP 2022) guidelines (http://ismpp.org/gpp-2022) and funded by Alexion, AstraZeneca Rare Disease.