Abstract
Introduction
Patients with chronic refractory gout face a considerable burden of disease due to unexpected flares characterized by severe and debilitating pain, which can lead to chronic pain and joint damage. This study aimed to understand the symptoms and impacts of chronic refractory gout on health-related quality of life (HRQoL).
Methods
A targeted literature review was conducted to identify and review key articles describing the symptoms and impacts of gout, and articles examining the psychometric performance of the Medical Outcomes Survey Short Form-36 (SF-36) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in gout. Qualitative interviews were conducted with 20 participants with chronic refractory gout. The results were used to develop the conceptual model and determine the appropriateness of the SF-36 and HAQ-DI in evaluating HRQoL in this population.
Results
Most frequently reported symptoms included bodily pain (n = 18, 90.0%), joint swelling (n = 18, 90.0%), joint tenderness (n = 18, 90.0%), and joint pain (n = 16, 80.0%). Most frequently reported impacts were difficulties climbing a flight (n = 20, 100.0%) or several flights of stairs (n = 20, 100.0%), climbing five steps (n = 19, 95.0%), completing chores (n = 19, 95.0%), and running errands and shopping (n = 19, 95.0%). All assessed items from SF-36 and HAQ-DI were reported by ≥ 25% (n = 5) of participants and mapped sufficiently to concepts elicited by participants.
Conclusions
Patients with chronic refractory gout report symptoms and impacts that are highly bothersome and burdensome to everyday life. Items included in the HAQ-DI and SF-36 mapped directly to these symptoms and impacts and are relevant to understand the burden of disease of chronic refractory gout.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40744-024-00697-8.
Keywords: Chronic disease, Disease burden, Drug resistance, Gout, Health-related quality of life, Patient-reported outcomes
Key Summary Points
| Why carry out this study? | |
| Refractory gout, resulting from long-term mismanagement of the disease and/or treatment resistance, is associated with negative impacts on physical function and health-related quality of life (HRQoL) of patients. | |
| This study aimed to better understand patient-specific experiences with chronic refractory gout and determine if the patient-reported outcome tools studied include items conceptually relevant and applicable for evaluating patient experience with the disease, through a targeted literature review and interviews used to inform the development of a conceptional model. | |
| What was learned from the study? | |
| Patients with chronic refractory gout experience symptoms and impacts that are highly bothersome and burdensome to their everyday lives, and the domains and concepts included in the final conceptual model mapped directly to all assessed items in the 36-Item Short Form Survey (SF-36) and Health Assessment Questionnaire-Disability Index (HAQ-DI). | |
| HAQ-DI and SF-36 are relevant to understand the burden of disease of chronic refractory gout, and the conceptual model highlights concepts of relevance and offers a better understanding of the experiences of these patients. | |
| As this was a qualitative study, future studies should be conducted to psychometrically validate the measures within the chronic refractory gout population, in addition to conducting studies to understand the burden of chronic refractory gout and HRQoL in comparison with the healthy population. |
Introduction
Gout is among the most common inflammatory rheumatic diseases and is caused by the deposition of monosodium urate crystals in and around joints [1–3]. An increasing prevalence and incidence has been observed in developed countries [4]. In the United States of America (USA), the overall prevalence was 3.9% among adults in 2015–2016, with higher prevalence in men (5.2%) than women (2.7%) [5]. Furthermore, there is a greater incidence and prevalence among racial/ethnic minorities, with a higher prevalence of gout noted in the non-Hispanic Black or African-American population compared with non-Hispanic white population [4, 6, 7]. Incidence of gout has been observed to increase between and after ages 50–59 [6].
Persistently elevated serum urate (sUA) levels result in an acute inflammatory response manifesting as gout flares that are associated with severe joint pain, swelling, and tenderness [1]. Guidelines for gout management recommend target sUA levels below 6 mg/dl, as a sustained reduction of sUA concentrations results in dissolution of monosodium urate crystals, reduced gout flares, and resolution of tophi [8–10]. Patients face a considerable burden of disease due to chronic pain, decreased mobility, and concerns for unexpected gout flares [11]. Comorbidities such as hypertension and chronic kidney disease (CKD) pose significant challenges in disease management, which can improve with better treatment of gout [6]. There are multiple challenges in gout management, such as poor patient–physician communication, disease and treatment misperceptions, and low/suboptimal treatment adherence [1, 12]. Patient education is an overarching principle of gout treatment with behavioral interventions increasing patient adherence to urate lowering therapies and improving clinical outcomes [10, 12, 13].
Long-term mismanagement of gout and/or resistance to treatment leads to refractory gout, which has been defined as a condition where target sUA levels below 6 mg/dl are not adequately sustained [14]. Painful arthritis, destructive tophi, and negative impacts on physical function and health-related quality of life (HRQoL) are observed in refractory gout [15]. Given this, the assessment and monitoring of the impact of gout from the patient perspective is critical. The Outcome Measures in Rheumatology Clinical Trials (OMERACT) endorses Medical Outcomes Survey Short Form-36 (SF-36) and Health Assessment Questionnaire-Disability Index (HAQ-DI) as validated instruments to measure HRQoL and physical function in patients with gout [16]. The content validity and relevance of the HAQ-DI has been studied previously [2, 17]. It was noted that as impacts on fine motor movements and physical functioning in the upper extremities are assessed by most items in HAQ-D1, rather than the lower extremities and gross motor movements, this patient-reported outcome (PRO) tool is more relevant to patients with tophaceous gout [2]. These findings support previous literature, and to some extent the OMERACT guidance, to use the HAQ-DI and SF-36 for assessing physical impacts of chronic refractory gout only, as these measures may lack sensitivity to capture the impacts of gout in those with less severe disease.
The impact of frequent gout flares on physical HRQoL has been found comparable to that observed with other chronic health conditions [18]. Several qualitative studies have evaluated HRQoL in gout [2, 16, 19–21], with an increase in gout flares associated with decreased SF-36 scores in all domains except physical functioning and general health [22]. However, for those patients without flares or without a change in flare rate, no substantial differences in HRQoL were reported [22]. In the C0405 and C0406 trials, 85 patients with chronic refractory gout treated with pegloticase biweekly experienced improvements in HRQoL, with SF-36 scores approaching age- and sex-matched normative values in five of eight domains [23]. Improvements were more pronounced in the physical domains; however, a multifactorial improvement was observed in fatigue, emotional status, and social interactions [23]. Also, in a study of patients with gouty arthritis flares treated with 150 mg canakinumab (n = 27), after 8 weeks the SF-36 scores for physical functioning and bodily pain approached general United States (US) population norms [24].
This study adds to this evidence by developing a conceptual model that offers insights into the understanding of patient-specific experiences with chronic refractory gout in the USA, following a brief literature review and qualitative participant interviews. Although the term chronic refractory gout is used in this manuscript, the condition is also known as refractory gout or uncontrolled gout. This study aimed to understand the burden of chronic refractory gout from the patient’s perspective, along with unmet treatment needs, and determine if the HAQ-DI and SF-36 PRO tools include items conceptually relevant and applicable for evaluating patient experience with the disease.
Methods
Targeted Literature Review
A targeted review of the literature was conducted in July 2021 using Boolean operators to identify signs, symptoms, and impacts of chronic refractory gout using MEDLINE® and ClinicalTrials.gov. Inclusion criteria for key symptoms and impacts included abstracts specifically discussing chronic refractory gout or gout in general terms and articles discussing symptom presentation and/or general impacts and HRQoL. The search terms and progression for key symptoms and impacts of gout were: 1. Article Title: Gout; 2. Article Title: Symptom; 3. Article Title: Impact; 4. Article Title: Quality of Life; 5. 1 AND 2; 6. 1 AND 3; and 7. 1 AND 4. Abstract selection for psychometric performance and clinically meaningful changes in existing clinical outcome assessments included those discussing SF-36 and/or HAQ-DI in gout. The search terms and progression for studies that report on the psychometric performance/meaningful change of existing clinical outcome assessments were: 1. Article Title: Gout; 2. Article Title and Abstract: SF-36; 3. Article Title and Abstract: HAQ-DI; 4. 1 AND 2; and 5. 1 AND 3. The literature review was used to inform the preliminary hypothesized conceptual model, which was developed according to the US Food and Drug Administration Guidance for Industry on PROs [25], and which was further refined following the participant concept elicitation interviews.
Participants and Ethical Considerations
The study, conducted between July 2021–March 2022, included US-based participants aged ≥ 18 years with a history of symptomatic gout (defined as: at least three gout flares within 18 months of screening; or a presence of at least one gout tophus; or current diagnosis of gouty arthritis [defined as joint damage due to gout]) and chronic refractory gout (defined as having failed to normalize sUA and whose signs and symptoms are inadequately controlled with any of the xanthine oxidase inhibitors [allopurinol and/or febuxostat at medically appropriate doses], or for whom these drugs are contraindicated [9, 26]). Participants with any other arthritic conditions that could make it difficult to describe experiences specifically with gout (e.g., rheumatoid or psoriatic arthritis, infected joint [septic arthritis], pseudogout, bacterial skin infection [cellulitis], or stress fracture) were excluded.
The study received approval from the Western International Review Board-Copernicus Group Institutional Review Board (IRB Protocol #20215052) and participants were recruited through clinical sites (Family Care Research, Investigators Research Group) and patient advocacy groups (Rare Patient Voice). The investigator and research personnel conducted this study in accordance with ethical principles outlined in the Declaration of Helsinki. All subjects provided informed consent to participate in the study. The clinicians, recruitment agency, and/or their coordinators were trained to screen and enroll participants in accordance with the process overview presented in Supplemental Fig. 1.
Interview Conduct
Interviews, conducted from October–December 2021 over a video conferencing platform (i.e., Zoom) or via telephone, were audio-recorded with participant consent, and lasted approximately 90 min. Following interview completion, participants were compensated for their time.
The concept elicitation interview guide included open-ended questions to encourage spontaneous responses and good qualitative data. Topics, questions, and probes were designed to understand signs and symptoms of chronic refractory gout, as well as impacts and experiences related to it from the participant perspective. Interviews were designed in line with the concepts and domains included in SF-36 [27] and HAQ-DI [28, 29], as well as broad and probing questions to determine their relevance to and experiences of participants with chronic refractory gout.
Data Analysis
Audio-recordings of the interviews were transcribed verbatim and anonymized. Each transcript was considered a unit of analysis, and data from all transcripts were aggregated following coding. An initial coding scheme was developed based on the targeted literature review results, preliminary hypothesized conceptual model, interview guide, and research objectives. The coding scheme catalogued concepts that were reported by participants spontaneously or after direct questioning from the interviewer. Codes were applied to specific text within each transcript and then queried for frequency across transcripts using ATLAS.ti version 8.0 or higher (ATLAS.ti GmbH, Berlin [30]).
Individual cases were identified and formed broader categories, which helped to identify patterns and relationships within the data set (a conceptual framework) [31, 32].
Intercoder reliability was evaluated using percent agreement, based on benchmarks outlined in the literature (70–94%) [33], with ≥ 90% agreement among all coders.
Results
Targeted Literature Review
The search strategy yielded 135 abstracts; based on the inclusion and exclusion criteria 41 were selected for in-depth review (Fig. 1).
Fig. 1.
Targeted literature review. aExclusion criteria for key symptoms and impacts of gout: abstract is about a different type of gout and does not discuss gout generally; discusses gout as it related to a pediatric population; and research search term(s) are included in the title and/or abstract but are not the main focus of article. Exclusion criteria to identify and review studies that report on the psychometric performance/meaningful change of existing clinical outcome assessments employed in the current phase 3 trial: abstract does not discuss validation of SF-36 or HAQ-DI in gout; does not discuss SF-36 or HAQ-DI meaningful change scores in relation to gout; or is related to a pediatric population. HAQ-DI Health Assessment Questionnaire-Disability Index; SF-36 36-Item Short Form Survey
Participant Demographics and Health Status
Table 1 presents demographic data and participant-reported health information. The mean age was 55.9 years (standard deviation [SD] = 12.1 years), a majority of whom self-identified as male (n = 14, 70.0%) and non-Hispanic white (n = 11, 55.0%). Twelve participants (60.0%) reported severe gout flares (defined as more than three flares in ≤ 6 months) and tophi severity was reported as severe (more than three tophi in ≤ 6 months) by seven participants (35.0%).
Table 1.
Participant-reported demographic information and health information
| Characteristic | Total sample (N = 20) |
|---|---|
| Mean (SD) age (years) | 55.9 (12.1) |
| Gender, n (%) | |
| Male | 14 (70.0%) |
| Female | 6 (30.0%) |
| Race, n (%) | |
| White | 13 (65.0%) |
| Black or African American | 7 (35.0%) |
| Ethnicity, n (%) | |
| Hispanic/Latino | 2 (10.0%) |
| Highest level of education, n (%) | |
| High school graduate (or equivalent) | 4 (20.0%) |
| Some college (no degree) | 8 (40.0%) |
| Associate’s degree | 4 (20.0%) |
| Bachelor’s degree | 3 (15.0%) |
| Master’s degree | 1 (5.0%) |
| Work status, n (%) | |
| Full-time | 8 (40.0%) |
| On disability | 5 (25.0%) |
| Retired | 4 (20.0%) |
| Unemployed | 3 (15.0%) |
| Part-time | 2 (10.0%) |
| Living status, n (%) | |
| With family or friends | 15 (75.0%) |
| Alone | 3 (15.0%) |
| With caregiver | 1 (5.0%) |
| In hotel | 1 (5.0%) |
| Health status, n (%) | |
| Excellent | 1 (5.0%) |
| Very good | 2 (10.0%) |
| Good | 9 (45.0%) |
| Fair | 6 (30.0%) |
| Poor | 2 (10.0%) |
| Gout flare severity in the past 6 months, n (%) | |
| Severe (> 3 flares in ≤ 6 months) | 12 (60.0%) |
| Moderate (1–3 flares in ≤ 6 months) | 8 (40.0%) |
| Tophi severity in hands in the past 6 months, n (%) | |
| 0 | 12 (60.0%) |
| 1–3 | 6 (30.0%) |
| 4 or more | 2 (10.0%) |
| Tophi severity in feet in the past 6 months, n (%) | |
| 0 | 7 (35.0%) |
| 1–3 | 9 (45.0%) |
| 4 or more | 4 (20.0%) |
| Tophi severity overall in the past 6 months, n (%) | |
| Severe (> 3 tophi in ≤ 6 months) | 7 (35.0%) |
| Moderate (1–3 tophi in ≤ 6 months) | 9 (45.0%) |
| None | 4 (20.0%) |
| Tophi in other parts of the body, n (%) | |
| Elbows | 5 (25.0%) |
| Knees | 4 (20.0%) |
| Wrists | 2 (10.0%) |
| Ankles | 1 (5.0%) |
SD standard deviation
Symptoms
Signs and symptoms reported by the participants are presented in Fig. 2a and Supplemental Table 1. Bodily pain (n = 18, 90.0%), joint swelling (n = 18, 90.0%), joint tenderness (n = 18, 90.0%), and joint pain (n = 16, 80.0%) were most frequently reported. When describing bodily pain, participants remarked how pain repeatedly impeded their mobility and ability to do certain things, such as get out of bed and walk.
Fig. 2.
a Signs and symptoms reported by participants with their b mean bothersome ratings c order of most important to treat and d meaningful change ratings (N = 20). a Participant-reported signs and symptoms. b Mean bothersome rating of signs and symptoms. c Most important sign or symptom to treata. aParticipants were able to provide multiple answers to the question: “Of all the symptoms that you experience [list signs/symptoms] which are the most important to treat? Why?”. d Meaningful change ratingb. bNot all participants provided meaningful change data for each symptom they reported; this was due to either comprehension issues or interview time constraints
Joint pain and joint tenderness were the most bothersome symptoms (Fig. 2b and Supplemental Table 1). One participant likened their joint pain to “someone putting a knife through your joint when you’re taking a step”, while another reported that it felt like they are “walking on nails and glass”. Four participants (20.0%) noted that joint tenderness prevented them from falling asleep “as even a bedsheet could cause pain”.
Most important to treat Participants were asked which signs/symptoms they felt were the most important to treat and eight (40.0%) responded with more than one sign or symptom. Bodily pain was most frequently reported as important to treat (n = 14, 70.0%) (Fig. 2c). One participant reported that one symptom often caused another: “… the tophi thing is probably the cause of everything, though, I would guess. I mean, because if you didn’t have that, then this wouldn’t be happening…”.
Meaningful changes in signs or symptoms of chronic refractory gout Participants were asked what improvement in each sign/symptom would be considered to be meaningful (defined to participants during interviews as “…an improvement in your health where you feel better, but it does not necessarily mean that your [symptom] is completely cured”) (Fig. 2d and Supplemental Table 1). Participant quotes included “the pain and the discomfort (associated with joint swelling) would need to improve” and “I think it would have to at least alleviate joint pain from being a daily thing. You know what I mean? If it was maybe once or twice a week, I think it could possibly be more tolerable”.
Impacts of Chronic Refractory Gout
Figures 3a, b, and Supplemental Table 2 present the impacts of chronic refractory gout and related bothersome ratings. Due to interview time constraints, bothersome ratings were not collected for emotional impacts, use of aids and devices, activities that participants required assistance from others, and work-related impacts.
Fig. 3.
Participant-reported a impacts with their b mean bothersome ratings and c meaningful change ratings. a Participant-reported impacts (N = 20). aThe majority of participants (n = 14, 70.0%) were asked directly about climbing a flight of stairs. Some participants (n = 6, 30.0%) were not asked about climbing a flight of stairs, because it was determined they would be affected given they reported having difficulty climbing five steps. bThe majority of participants (n = 13, 65.0%) were asked directly about climbing several flights of stairs. Some participants (n = 7, 35.0%) were not asked about climbing several flights of stairs, because it was determined they would be affected given they reported difficulty climbing five steps. b Mean bothersome ratings of impacts. c Meaningful change rating (N = 20)c. cSome participants endorsed more than one way in which a meaningful change could occur
Difficulty completing chores (n = 19, 95.0%) and running errands and shopping (n = 19, 95.0%) were the most frequently reported impacts to daily activities (Fig. 3a and Supplemental Table 2). Participants also reported difficulties with eating and drinking activities, such as gripping and twisting objects (n = 12, 60.0%) and opening previously opened jars (n = 12, 60.0%). Exemplifying the difficulty completing chores, a participant noted that “when I wash dishes, that hurts to stand there on it”.
All participants reported an impact on their ability to climb a flight of stairs (100.0%) and several flights of stairs (100.0%; Fig. 3a and Supplemental Table 2). The average bothersome rating was 8.6 (Fig. 3b and Supplemental Table 2). One participant with difficulty climbing a flight of stairs reported that “… it seems like you’ll end up crawling upstairs. And then not put any pressure on your foot, you are pretty much on your hands and knees going upstairs”.
When asked about activities related to bathing and bathroom use, the ability to shower/wash/dry (n = 16, 80.0%) was the most frequently reported impact (Fig. 3a and Supplemental Table 2). One participant noted, “…when I have a gout flare-up, it affects me getting into the shower. As far as like pivoting and moving my feet to get stable to get into the shower, that affects me”.
When describing their use of aids and devices for support, participants most commonly reported using canes (n = 12, 60.0%; Fig. 4). When detailing their support needs from others, participants most often reported needing assistance with errands and chores (n = 15, 75.0%; Fig. 4). Emotional impacts, which were reported by 19 participants (95.0%), included feeling worn out (n = 16, 80%). Participants also reported impact on their sex life (n = 8, 40.0%) and their ability to work (n = 17, 85.0%; Fig. 4). More than half of the participants (n = 12, 60.0%) reported work impacts related to symptoms of their chronic refractory gout; however, some (n = 3, 15.0%) reported that these impacts were due to emotional hardship, such as feeling sad or anxious. Eighteen participants (90.0%) reported impact on sleep because of chronic refractory gout (Fig. 3a and Supplemental Table 2).
Fig. 4.
Impacts of chronic refractory gout: impacts on work and professional life, activities requiring assistance from others, and use of aids and devices
Meaningful changes in impacts of chronic refractory gout Fig. 3c and Supplemental Table 2 present participants’ responses when asked what would need to improve with each impact in order to consider the change or improvement to be meaningful (e.g., improvements in frequency, bothersomeness, and/or difficulty in doing the activity). Participant quotes included “I would say that while I’m walking and stuff, it just—it is not a normal gait” and “You don’t want to be around nobody [sic]. And you don’t want nobody [sic] around you when you have gout. You want to separate yourself”.
Data Saturation
Conceptual saturation for all spontaneously reported signs/symptoms and impacts are summarized and presented in Fig. 5. Conceptual saturation was assessed for the 12 unique signs/symptoms and 24 impacts spontaneously reported by participants. No new signs/symptoms were introduced in the last five (25.0%) interviews; three new impacts were introduced, which were sex life, bending, and ability to get in/out of car. It should be noted that the new concepts were all probed separately in the interviews.
Fig. 5.
Saturation graph for the signs/symptoms and impacts of chronic refractory gout (N = 20)
Conceptual Mapping of the HAQ-DI to Concept Elicitation Data
Figure 6 shows that all 20 items of HAQ-DI [28, 29] mapped to impacts reported by participants during interviews, and each were endorsed by at least five (25.0%) participants. Most highly endorsed domains included arising and walking; and most highly endorsed concepts were the ability to climb up five steps, walk outdoors on flat ground, run errands and shop, and do chores such as vacuuming or yard work (n = 19, 95.0% for all).
Fig. 6.
Concept mapping HAQ-DI [28, 29] to concept elicitation data. a‘Bathing/hygiene’ was not included in the preliminary hypothesized conceptual model but was frequently reported during interviews. b‘Arising’ was not included in the preliminary hypothesized conceptual model; however, difficulty arising (e.g., getting in and out of bed, standing up from a chair) was reported by the majority of participants as an impact of chronic refractory gout. c‘Feeding oneself’ was not included in the preliminary hypothesized conceptual model, but was frequently reported during interviews. HAQ-DI Health Assessment Questionnaire-Disability Index
The least commonly endorsed domains were eating and grip; however, all items within both were endorsed at higher rates by participants who reported hand, elbow, and/or wrist tophi compared with participants who only experienced chronic refractory gout in their feet, ankles, or knees. One participant remarked, “It affects it a whole bunch. Like I said, you don’t want to move your fingers, you don’t want to bend them at all. [Regarding jars and bottles], even if it’s already open, you just take the lid off, it’s hard”.
Conceptual Mapping of the SF-36 to Concept Elicitation Data
Figure 7 shows all the concept elicitation data mapped to items of the SF-36 [27]; all concepts assessed in the concept elicitation interviews were endorsed by at least five participants (25.0%) and 55% or more for the majority. Participants most frequently endorsed lifting or carrying groceries, walking more than a mile, and walking several hundred yards (n = 18, 90.0% for all). Nineteen participants (95.0%) endorsed at least one negative emotional impact.
Fig. 7.
Concept mapping SF-36 [27] to concept elicitation data. aItem 4a and 5a use identical language. bItem 4b and 5b use identical language. SF-36 36-Item Short Form Survey
Conceptual Model
Results of the qualitative interviews were used to further refine the conceptual model (Fig. 8); six additional symptoms were added. Nine participants (45.0%) reported experiencing muscle weakness due to their chronic refractory gout. Itching, cramps, difficulty breathing, kidney stones, and loss of finger movement were each spontaneously reported by one participant (5.0%).
Fig. 8.
Conceptual model for symptoms and impacts of chronic refractory gout. Bolded indicates reported by at least 50.0% of participants in interviews; Italics indicates identified in the literature review.
Reproduced from POS0528 Patient Experiences With Chronic Refractory Gout and its Impact On Health-Related Quality Of Life, Annals of the Rheumatic Diseases, Oladapo A, Strand V, Kragh N, Johnson N, Yousefian C, Brooks D, Sharp H, Kim C, Pillinger M, 82, 527–528, 2023 with permission from BMJ Publishing Group Ltd
Discussion
The conceptual model was developed to identify and characterize symptoms and impacts of chronic refractory gout. Concepts included in the conceptual model align with what can be found in similar qualitative work [2, 20, 34, 35]. The observations of the current study add to evidence from a previous study that showed that disease-associated impairments in HRQoL are more prevalent in patients with chronic refractory gout than those with less severe symptoms (no tophi, monoarticular disease, and fewer attacks) [36].
Overall, the symptoms and impacts experienced by participants align closely to those identified in the targeted literature review [2, 19, 34, 35]. Highlighted symptoms included pain, tenderness, cramping, swelling, heat, joint stiffness, shortness of breath, and itching (a side effect of allopurinol [13]); highlighted impacts were difficulty gripping, walking, climbing steps, driving, tolerating bed sheets, as well as emotional hardship [2]. Consistent with a previous study that noted the HRQoL impact of the unpredictable nature of gout flares and location of joint pain and swelling [34], participants in this study also rated joint pain as the most bothersome symptom; and bodily pain the most important symptom to treat. Similarly, many of the commonly reported impacts in the literature (anxiety, depression, daily functioning, limited mobility, and concern) are consistent with the most commonly reported impacts reported by participants (climbing steps, walking outdoors, emotional impacts, running errands/shopping, putting on shoes, and the ability to do chores) [2, 20, 21, 34, 37]. Moreover, symptoms and impacts varied depending on the joint locations where participants experienced their gout flares and/or tophi. Joint swelling was one of the three most frequently reported symptoms (90.0%), and the second most spontaneously reported symptom; swelling in feet, ankles, knees, and hands was most reported. Tophi and frequent gout flares have been identified to have a considerable impact on HRQoL, as well as work productivity impairment [21]; these impacts are confirmed in the present study.
The domains and concepts included in the final conceptual model mapped directly to all assessed items in SF-36 and HAQ-DI, providing evidence that these PRO measures are relevant to people living with chronic refractory gout. Although the targeted literature review did note that both measures are likely to have high ceiling effects when administered to people with severe disease, it also suggested that both measures included items that are correlated with symptoms and impacts of gout. Results of these analyses also indicate that the impacts reported by participants varied depending on where the participant experienced their symptoms, as well as the presence or absence of tophi. Therefore, the driver of bothersome symptoms is the refractory nature of the chronic gout that results in frequent and unpredictable flares.
There are certain drawbacks of using generic instruments such as HAQ-DI and SF-36, such as the scoring of the impact of comorbidities instead of the specific disease, an example being the impact of osteoarthritis on bodily pain and activity limitation; and lack of disease-specific sensitivity [38–40], but disease-specific tools such as the Gout Impact Scale (GIS) pose other challenges, including the inability to compare between disease states [19, 41]. GIS has yet to receive an endorsement by OMERACT as a fully validated HRQoL measure in chronic gout [16]. Both HAQ-DI and SF-36 offer age- and sex-matched normative values from healthy populations. In the present study, items in the physical component of SF-36 were endorsed at higher rates. Of all items assessed, an average of 16 participants (80.0%) endorsed each physical health item and an average of 13 participants (65.0%) endorsed each mental health item from the SF-36 (Fig. 7).
Following a robust methodology to elicit and confirm concepts with interview participants, this study provided an insight on treatment and disease burden by evaluating the perceptions and experiences of patients with chronic refractory gout. To do so, this study aimed to include a representative sample of people living with chronic refractory gout. Recruitment targets were established to include participants who had different disease experiences related to flare severity (i.e., moderate and severe) and appearance of tophi, as well as demographic characteristics including race, gender, age, ethnicity, and highest level of educational attainment. The conceptual model of symptoms and impacts on HRQoL highlighted concepts of relevance and offered a better understanding of the specific experiences of patients with chronic refractory gout in the USA.
The study has a few limitations that should be noted. The study sample did not meet all race/ethnicity targets and, therefore, results may not be completely representative of all participant experiences with chronic refractory gout. This was strictly a qualitative study; as such, it did not include psychometric evidence. Future studies should be conducted to psychometrically validate the measures within the chronic refractory gout population. In addition, studies should be conducted to understand the burden of chronic refractory gout and HRQoL in comparison with the healthy population. As this study was conducted in the USA, results may not be generalizable to individuals with chronic refractory gout in other countries. During interviews, interviewers probed for the impacts that were included in the SF-36 and HAQ-DI; probed endorsement of these impacts may overestimate their prevalence among the chronic refractory gout population. The potential impact of probing should be considered, as the absence of probed questions from an interviewer could limit the instruments’ sensitivity, especially in situations when questionnaires are completed online. Nonetheless, patients may appreciate the flexibility of being able to complete these questionnaires online, rather than in the clinic. Furthermore, physical component summary and mental component summary scores of SF-36 are composite scores that are difficult to interpret except to allow statistical analysis of the individual domains of SF-36. Debriefing the instruments in a chronic refractory gout population for relevance could provide more insight on the relevance of these impacts in the population. Moreover, bothersome ratings were not collected for all impacts of chronic refractory gout due to interview time constraints.
Conclusions
The targeted literature review and qualitative interviews demonstrate that patients with chronic refractory gout experience symptoms and impacts that are highly bothersome and burdensome to their everyday lives, impacting both their physical and emotional health. Both HAQ-DI and SF-36 mapped directly to symptoms and impacts experienced by participants interviewed in this study, thereby confirming the final conceptual model.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
Medical Writing, Editorial, and Other Assistance
Medical writing support was provided by Ritika Banerjee and Hayley Owen of Bioscript Group, Macclesfield, UK, funded by Sobi, based on the authors’ input and direction, and in accordance with Good Publication Practice (GPP) 2022 guidelines (https://www.ismpp.org/gpp-2022).
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for their contribution to this article, take responsibility for the integrity of the work as a whole, and approved the manuscript for submission.
Author Contributions
Vibeke Strand, Michael H. Pillinger, Abiola Oladapo, Charis Yousefian, Dani Brooks, and Nana Kragh read, provided critical feedback on intellectual content, and approved the final manuscript. Vibeke Strand, Michael H. Pillinger, Abiola Oladapo, Charis Yousefian, Dani Brooks, and Nana Kragh were involved in drafting the manuscript and analysis or interpretation of data.
Funding
The study and the publication, including the journal's Rapid Service Fee, were funded by Sobi. Sobi reviewed and provided feedback on the manuscript.
Data Availability
The data that support the findings of this study are available within the article and its supplementary information files or from the corresponding author upon reasonable request.
Declarations
Conflict of Interest
Vibeke Strand declares consulting fees from AbbVie, Alumis, Amgen, AstraZeneca, Atom Biosciences, Bayer, Blackrock, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Citryll, Equillium, Ermium, Fortress Biotech, Genentech/Roche, Gilead, GSK, Horizon, Inmedix, Janssen, Kiniksa, Eli Lilly, Merck, Novartis, Omeros, Pfizer, R-Pharm, RAPT, Regeneron, Samsung, Sandoz, Sanofi, Scipher, Setpoint, Sobi, Sorrento, Spherix, and Urica, and participation on a data safety monitoring board or advisory board for AbbVie and AstraZeneca. Michael H. Pillinger declares investigator-initiated research grants paid to institution from Hikma Pharmaceuticals; consulting fees from Sobi, Amgen, Federation Bio, Scilex and Fortress Biotech; and participation on a data safety monitoring board for Horizon Therapeutics. Abiola Oladapo and Nana Kragh are employees of Sobi. Nana Kragh may hold stock/stock options in Sobi. Charis Yousefian and Dani Brooks declare consulting fees to Endpoint Outcomes from Sobi. Current affiliation of Charis Yousefian is Vector Psychometric Group, LLC, Chapel Hill, NC, USA; current affiliation of Dani Brooks is Boston Medical Center, Boston, MA, USA.
Ethical Approval
The study received approval from the Western International Review Board-Copernicus Group Institutional Review Board (IRB Protocol #20215052). The investigator and research personnel conducted this study in accordance with ethical principles outlined in the Declaration of Helsinki. All subjects provided informed consent to participate in the study.
Footnotes
Prior Presentation: Data included within this manuscript were presented as poster presentations at the European Alliance of Associations for Rheumatology (EULAR) 2023 European Congress of Rheumatology held in Milan, Italy (May 31–June 3, 2023; abstract/poster number: POS0528), and The Professional Society for Health Economics and Outcomes Research (ISPOR) 2023 held in Boston, Massachusetts, USA (May 7–10, 2023; abstract/poster number: PCR87). The corresponding abstracts have been published in a supplement of the Annals of the Rheumatic Diseases and Value in Health, respectively. Data within the manuscript have also been included in an encore presentation at the Academy of Managed Care Pharmacy (AMCP) 2024 held in New Orleans, Los Angeles, USA (April 15–18, 2024; poster number: M7).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available within the article and its supplementary information files or from the corresponding author upon reasonable request.