Toward a holistic tophus assessment in gout clinical trials: What lies beyond tophus count and size?

Tophus burden is a crucial outcome domain in gout, the most prevalent inflammatory joint disease in adults worldwide, characterized by the continuous deposition of monosodium urate (MSU) crystals.1 Individuals with gout typically experience recurrent episodes of arthritis (gout flares) during the earlier phase of the disease. Without proper treatment, many individuals will develop signs and symptoms of advanced gout, including tophus formation, joint destruction, or chronic arthritis.2 Subcutaneous tophi are nodules detectable by physical examination, formed as a result of MSU crystal accumulation combined with an associated host tissue response.3 In individuals diagnosed with gout, the presence of tophi is the most tangible indicator of an excess burden of MSU crystals in the soft tissues and joints. Tophi typically develop after several years of hyperuricemia and MSU crystal buildups, causing peri-tophaceous inflammation, joint destruction, and joint deformity.2 The number of tophi correlates with a greater impairment in physical activities, lower work productivity, and decreased health-related quality of life in individuals with gout.4 Tophaceous gout is also associated with a greater risk of mortality, particularly from cardiovascular causes.5 Uncontrolled gout has also been linked to increased healthcare cost and healthcare resource utilization.6 The long-term treatment of gout aims to continually lower serum urate levels to below 6 mg/dL (0.36 mmol/L) in order to facilitate the dissolution of deposited MSU crystals and subsequently the resolution of tophus.7 For individuals with tophaceous gout, a lower target serum urate level of 5 mg/dL (0.30 mmol/L) has been recommended by the European Alliance of Associations for Rheumatology (EULAR) because it was associated with greater velocity of tophus regression.8, 9 Therefore, tophus burden is one of the OMERACT-endorsed mandatory outcome domains for long-term studies of gout.10 Several measurements of tophus burden have been employed in past clinical trials of urate-lowering therapy (ULT), with most focusing on assessing the physical attributes of subcutaneous tophi. The Febuxostat versus Allopurinol Controlled Trial (FACT) used the number of tophi and tape-measured areas of the index tophus as tophus-specific outcomes.11 In a pegloticase clinical trial, the subcutaneous tophus area was measured using software-assisted digital photography.12 Digital Vernier calipers were alternatively used to measure the size of up to five target tophi in a randomized trial of the uricosuric agent, lesinurad (CLEAR-2 study).13 These methods are relatively simple, requiring no or little training or advanced equipment. However, it is crucial to note that the apparent resolution of visible tophi does not necessarily equate to the complete removal of urate deposits in the joints and surrounding tissues. The observed size and appearance of subcutaneous nodules may not accurately reflect the actual volume of MSU crystal deposits because subcutaneous tophi comprise not only MSU crystals but also associated granulomatous formation and fibrosis.14 Ultrasonography (US) is sensitive in detecting and measuring the size of intra-articular tophi as well as subcutaneous tophi not identified by physical examination.15 However, US has not been widely utilized in clinical trials of long-term gout therapy due to the limited availability of qualified sonographers and sonography machines. More recently, MSU crystal volume was quantified using dual-energy computed tomography (DECT) in a study comparing treat-to-target allopurinol dosing to conventional allopurinol dosing.16 While these measurements are highly accurate, they primarily focus on the physical aspects of tophi, emphasizing the disease itself rather than the impact on the patient's well-being. In 2015, the Tophus Impact Questionnaire (TIQ-20) was developed, utilizing data from multiethnic individuals diagnosed with chronic tophaceous gout in Aotearoa/New Zealand.17 The questionnaire comprises 20 items covering several aspects of patients' lived experience related to tophaceous gout: functional impairment, social impact, psychological stress, and healthcare utilization.17 It is easily understandable by English-speaking individuals with tophaceous gout and demonstrates high feasibility and reproducibility. Furthermore, the questions require only a yes or no answer, making it easily implementable in a clinical setting, requiring minimal guidance or additional time from participants. A recent study from the same research group from Aotearoa/New Zealand demonstrated that the TIQ-20 was also responsive to changes in the physical and radiographic indicators of tophus burden in individuals with gout during treat-to-target ULT.18 Specifically, the TIQ-20 score showed improvement over 2 years of treat-to-target therapy with allopurinol. This is a noteworthy finding because the resolution rate of tophus size is typically slow, with reduction rates of less than 1 cm per year for those taking allopurinol.9 It is therefore encouraging to see that even such a small reduction can lead to measurable improvements in patients' well-being. Another notable finding was the correlation between the TIQ-20 score and physical tophus size (measured with Vernier caliper) as well as MSU crystal volume (measured by DECT) at various time points during the 2-year allopurinol treatment. This implies that the improvement of patient-reported outcomes is at least partially linked to the resolution of MSU crystal, the primary goal of long-term gout management. These observations provide strong support for the use of TIQ-20 as an instrument for measuring tophus burden in addition to the physical and radiological instruments in long-term studies of gout (Figure 1). Despite the progress in imaging techniques for tophus burden assessment and the emergence of tophus-specific patient-reported outcome measures, several challenges persist. While US and DECT are highly accurate for measuring tophus size and volume, their application in large-scale clinical trials of long-term gout therapy is likely to be cost-prohibitive at the current time. Quality control for the interpretation and operation of advanced imaging techniques can also pose a significant challenge. Although the questions in the TIQ-20 appeared to be universal, both its development and recent test of responsiveness to ULT were conducted in cohorts from Aotearoa/New Zealand. It would be prudent to validate the TIQ-20 in other populations, preferably those with different socioeconomic and cultural backgrounds, as these factors strongly contribute to the characteristics, treatment outcomes, and healthcare access for individuals living with gout.19 The high prevalence of gout in Aotearoa/New Zealand may have influenced disease perception and response to the questionnaire due to the population's greater familiarity with the concept of gout compared to areas with lower gout prevalence.20 Despite the TIQ-20 being responsive to changes during treat-to-target ULT, it is worth noting that the degree of reduction in the TIQ-20 score that is considered clinically significant remains unknown. Furthermore, it would be valuable to explore whether the TIQ-20 correlates with broader composite quality-of-life assessments, such as the SF-36 questionnaire and the Gout Assessment Questionnaire (GAQ).21 How will these new developments in tophus burden assessment affect the pursuit of gout remission? Although the debate is far from settled, the current understanding of gout remission, among other criteria, necessitates the resolution of subcutaneous tophi based on physical examination.22 The arrival of tophus burden assessment using advanced imaging techniques may lead to the adoption of the most stringent definition of gout remission, requiring the complete disappearance of MSU crystal deposition detectable by DECT. Conversely, the presence of tophus-specific patient-reported outcome measures may allow for a less stringent definition of remission. In this context, remission could be achieved when patients are no longer troubled by their tophi, even in the presence of detectable tophus burden. For example, a small tophus at the ear pinna that does not adversely affect the individual's quality of life may be considered compatible with remission. Clinical trials, especially those related to long-term gout treatment such as ULT, are encouraged to adopt a holistic approach when assessing tophus burden as one of the outcome domains. Such an approach may comprise a combination of physical measurement (tophus number and size measured by caliper) and patient-report instruments (TIQ-20), with additional assessment of urate volume by DECT where resources allow (Figure 1). This would not only ensure that the treatment of interest can induce the dissolution of tophus but also ensure that such improvement is also reflected on the patients' lives. Not applicable. No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article. The author declares no conflict of interest. Not applicable. Data sharing is not applicable to this article as no new data were created or analyzed in this study.