What Outcomes are Important for Gout Patients? In-Depth Qualitative Research into the Gout Patient Experience to Determine Optimal Endpoints for Evaluating Therapeutic Interventions

Gout is among the most common inflammatory rheumatic diseases of adulthood, affecting approximately 1–2 % of adults in Western Europe [1] and 3.9 % of adults in the USA [2]. With a higher incidence in men than women (3:1) [2], the prevalence of gout is also rapidly increasing, with an increase of 4 % per year reported in the UK alone [3]. Gout results from elevated or excess serum uric acid (SUA) levels in the body [4], leading to the formation and deposition of monosodium urate (MSU) crystals in the synovial fluid and lining of joints and soft tissue [5, 6]. Shedding of crystals into the synovial fluid of a peripheral joint (typically the first metatarsophalangeal joint, or ‘big toe’) typically triggers the first episode or ‘flare’ [7]. Other commonly affected joints include the mid-tarsal joints, ankles, knees, fingers, wrists, and elbows [5].

Flares are characterized by sudden onset of severe pain, swelling, erythema, and tenderness to touch in the joint [8]. Without treatment, or through poor clinical management, chronic tophaceous gout can develop, characterized by chronic pain and stiffness, joint damage, and visibly evident subcutaneous nodular deposits of MSU crystals (tophi) [5]. Only 10 % of the overall gout patient population are currently estimated to progress to chronic tophaceous gout [9].

While there is evidence that the symptoms experienced during flares can substantially impact the health-related quality of life of patients with gout [8], qualitative research documenting the patient experience in depth is limited [10, 11]. Gout has been reported to impact on mobility (especially walking and climbing stairs), activities of daily living (such as gardening and doing housework), emotional functioning, sleep, and diet [12, 13], as well as work productivity [10, 14]. A number of studies have demonstrated that individuals with gout have lower physical functioning than normative populations and study controls [8]. However, those existing studies are limited by the use of mostly generic instruments to measure HRQoL, which arguably lack the sensitivity to capture the full impact of the condition, particularly in those with less severe gout [8].

Qualitative research can help provide a better understanding of the patient experience and overall health burden of gout. Furthermore, the subsequent development of a conceptual model detailing the experience from the patient perspective could provide a starting point to aid selection of appropriate clinical study endpoints or guide the development of a new disease-specific measure. The ability to effectively measure HRQoL is crucial for evaluating the effects of the disease and treatment, as well as helping to better understand the best approach to managing gout [15].

OMERACT (Outcome Measures in Rheumatology Clinical Trials) recently published a report summarizing the appropriateness of patient-reported outcomes (PROs) in measuring impacts of chronic gout [16], based on assessments of the OMERACT filters of truth (face, content, construct and criterion validity), discrimination (reliability, responsiveness), and feasibility (how easily the measure can be applied given constraints of time, money, and interpretability) [16]. Based on these criteria, OMERACT endorsed the Health Assessment Questionnaire-Disability Index (HAQ-DI) for use in assessing the physical impacts of chronic gout [17]. Conversely, a gout-specific QoL measure (Gout Assessment Questionnaire [GAQ]-v2.0) [18] was not deemed appropriate because of several concerns, including low internal consistency and construct validity [17]. Following publication of the OMERACT guidance, the Tophus Impact Questionnaire (TIQ-20) was developed using qualitative interviews to assess tophi burden; its content validity and psychometric validity have been established [19]. These existing measures are either gout-specific or have been used in gout populations. Nevertheless, it is essential to ensure all concepts that are relevant and important to patients are captured. The core domains relevant to assess in acute gout, as identified by OMERACT, include pain, joint swelling, joint tenderness, patient global assessment, and activity limitations. For chronic gout, the core domains identified are serum urate, acute gout attacks, tophus burden, HRQoL, activity limitations, pain, and patient global assessment [12].

This study aimed to gain a strong understanding of gout patients’ experiences of symptoms, flares, tophi burden, and the broader impact of gout using a patient-centred approach to inform development of a conceptual model. Supplementary to traditional patient interviews, the study employed novel digital methods to collect real-time qualitative data. Additionally, the content validity of three existing PROs in the specific context of use in gout populations was assessed in accordance with the criteria outlined in the US FDA PRO guidance [20].

Throughout, a ‘patient-centric’ approach was taken. As well as conducting patient interviews in a rigorous and ethical fashion, this also involved two patient advisors providing input and guidance as research partners rather than being interviewed as ‘subjects’ [19, 21].

This study employed a patient-centered approach [19, 21] to support the development of a conceptual model of gout patients’ experiences of symptoms, management of gout attacks (flares), tophi burden, and the broader impact of gout. This was followed by evaluation of the adequacy of existing PROs for measuring impacts from gout.

Consistent with the literature [8, 19, 36, 37], CE activities (both patient and clinician interviews and qualitative digital ethnography) identified pain as being the cardinal, defining symptom of gout, leading to a range of impacts on QoL. In particular, this study found that patients discussed severe debilitating flares of pain causing an inability to weight bear and an impact on physical functioning (e.g., difficulty walking), sleep, daily activities, and work (e.g., productivity) and social activities (e.g., missing/cancelling plans). Such findings support a previous qualitative interview study whereby pain, isolation, and work disability were described as key impacts of gout [10]. Furthermore, the findings are consistent with previous work that specifically demonstrated the impact of gout on work and productivity [10, 14]. The relationship between pain and sleep, and the subsequent impact on QoL, is also well documented in other pain conditions [38‐40]. Interestingly, despite being mentioned by almost all patients in this study and as a key outcome identified in other qualitative studies, sleep disturbance did not make it into OMERACT’s core outcome domains for studies of acute and chronic gout [12]. Tophi were not considered generally bothersome, but were painful when knocked and impacted footwear choice.

The resulting conceptual model illustrates that the vast majority of symptoms elicited from patients with tophaceous gout were also reported by those with non-tophaceous gout, aside from those specifically related to tophi, such as skin damage. A model based on qualitative evidence is of value to aid selection of the optimal outcomes for monitoring, both in general clinical care and in clinical research, and evaluating treatment efficacy. The added value of digital RTQD should be considered in conjunction with traditional patient interview methods when designing future qualitative research [41]. While traditional patient interviews remain the gold standard in exploring the patient experience, qualitative data collected in real-time arguably have stronger ecological validity and provide valuable additional insights into the patient experience of non-tophaceous gout; specifically the severity of symptoms and impacts discussed. However, not all patients experienced flares during the period of digital data collection, therefore some concepts only emerged from the interviews.

CD findings and feedback from expert clinicians indicated that the HAQ-DI lacks relevance in the non-tophaceous gout sample, predominantly because most items assess impacts on physical functioning in the upper extremities and fine motor movements as opposed to lower extremities and gross motor movements. The HAQ-DI was more relevant to the patients with tophaceous gout, who were more likely to experience symptoms in the upper extremities. These findings support previous literature [8] and to some extent the OMERACT guidance to use the HAQ-DI for assessing physical impacts of chronic gout only, as the measure lacks sensitivity to capture the impact of gout in those with less severe disease. However, the findings also suggest potential value in developing a measure of functioning specific to gout and relevant to both patient groups that is less focused on the impact on upper extremities/fine motor skills and has greater focus on the lower extremities. The ability to effectively measure HRQoL is critical for assessing treatment benefit in terms of change over time and determining the best approach to managing gout [15].

The majority of concepts captured in the GAQ domain were reported to be too severe for patients with non-tophaceous gout, suggesting the domain will have limited value and is likely to have floor effects. The domain may have value in a population of patients with poorer control over their gout and who therefore potentially experience stronger emotional impacts—but the responsiveness of the instrument would need careful exploration.

CD findings for the TIQ-20 demonstrated conceptual comprehensiveness in capturing impacts on functioning specific to tophi. To capture the full impact of all gout symptoms (and not just tophi-specific burden), it is recommended the measure is used in conjunction with an instrument capturing wider functional impacts of gout. Additionally, in terms of measuring a treatment intervention, it may be useful to employ a response scale capturing severity from 0 to 10 to clearly capture improvement rather than an attitudinal scale (agree/disagree), and to clarify the recall period.

While the patient advisors supported a ‘patient-centric’ approach [19, 21], only two advisors were engaged, the views of whom may not represent the diversity of views among the gout patient population. To capture a greater breadth of experience, future research could include more patient advisors. It is also important to note that, while quantitative data have been reported in terms of the frequency of concepts reported, the data are based on a small number of patients, therefore limiting the generalizability of the findings. Finally, it is acknowledged that real-time data capture was only employed in the sample of patients with non-tophaceous gout because of logistical challenges, and future research could explore the added value of utilizing this novel method in a sample of patients with tophaceous gout.

In this qualitative interview study, a patient-centric approach combined expert clinical input with patient interviews and novel digital methods of qualitative data collection to increase patient engagement and the ecological validity of the data. The findings provide evidence that the instruments evaluated have some value for the assessment of patients with gout but also some limitations. These shortcomings could be overcome with modifications or through the development of a new measure capturing all functional impacts in both populations as guided by the conceptual model.