Imaging as an Outcome Measure in Gout Studies: Report from the OMERACT Gout Working Group

Urate Deposition

MSU crystal deposition is the central pathogenic cause of gout. The usual primary outcome for interventional studies of patients with chronic gout is change in serum urate over time⁴, with urate deposition being as yet an unmeasured outcome. US, MRI, and CT can all identify nodular masses in subcutaneous tissue, joints, and tendons that have appearances recognizable as tophi. In US, for example, masses identified as tophi are usually hyperechoic with a heterogenous appearance, which may be calcified. These are often grouped together, have a poorly defined border, and may show postacoustic shadowing⁵. This appearance reflects the histological composition of tophi, which is of MSU crystals together with fibrovascular tissue and inflammatory cells⁶. DECT, in contrast, specifically identifies the MSU crystal component of the tophus. Plain film cannot directly identify tophi, but their presence is suggested by erosions or soft tissue opacities attributed to tophi. Thus US, MRI, CT, and DECT can potentially be used for measurement of urate deposition. US, MRI, and DECT all fulfill the truth components of the OMERACT filter, including the important direct confirmation of MSU crystals from structures identified as tophi on imaging^7,8,9,10,11. These modalities also largely fulfill the discrimination components of the filter, although more data on sensitivity-to-change data are required for DECT and are lacking for MRI. High interreader reliability has been demonstrated for US across numerous anatomical locations.

Measurement of whole body urate deposition, by any modality, is not a feasible option in clinical studies. An alternative is quantification of tophus burden (as a surrogate for MSU crystal deposition), which could be measured in a single, representative area (joints and/or soft tissue) or a predetermined set of joints. US assessment of intraarticular and periarticular tophi has been demonstrated to have good intrareader and interreader reliability and sensitivity to change with successful urate-lowering over 12 months, discriminating between responders and nonresponders to urate-lowering therapies⁸. Therefore, US has the potential to quantify tophi in superficial areas and include both joints and relevant periarticular and subcutaneous locations; its setup costs are low, although operator cost and patient time are significant. MRI has the potential for repeat assessments, but access to facilities, high cost, and demands on patient time are significant barriers. In contrast, DECT provides a direct measure of MSU deposition. However, the issue of where to measure remains unclear because repeated imaging of multiple locations probably carries unacceptable radiation exposure for the clinical trial setting, and there may be limited access to DECT in many research centers. Overall, US and DECT appear to have most potential for measurement of urate burden. It is uncertain how the host tissue response and MSU crystal components of tophi interrelate and whether these components all respond similarly to ULT in most patients and at most locations, which may influence the use of US. Advantageously, DECT directly measures urate crystal deposition, but the ability to measure change over time in response to treatment has not yet been demonstrated.

US is also able to identify small amounts of MSU deposited on articular cartilage in the form of the double contour sign (DCS). This appearance can also be observed in individuals with asymptomatic hyperuricemia⁵. Some observers have reported that the DCS resolves with successful ULT¹²; however, this requires further systematic assessment. It is relevant to remember that the domain initially identified was tophus burden, which may be a different concept for this low level of MSU deposition.

Some key areas identified for future research on use of US and DECT in determining urate burden were responsiveness to ULT (in particular, detection of between-group differences in a randomized controlled trial setting), areas for assessment (a single joint vs a set and whether to include soft tissue tophi or a target tophus), and development of scoring systems to quantitate urate burden. The DCS may be most relevant in patient groups with less advanced gout, where large tophaceous deposits may not be present. Assessment of patient acceptability must also be addressed in future studies that aim to develop imaging modalities for use in clinical trials, especially where measurement of multiple sites is used.

Inflammation

Intermittent attacks of acute gout occur in intercritical and chronic gout; however, the periods between attacks appear to be characterized by ongoing inflammation as evidenced by hyperactive inflammatory cells, elevated systemic inflammatory proteins, and imaging evidence of inflammation^{1,2,3,13,14,15,16}. This is identified in the discretionary domain of joint inflammation, for which no clinician-assessed outcome tools have been validated for chronic gout studies. Identification of inflammation using imaging is possible with US and MRI. MRI studies in patients with tophaceous gout have reported joint effusions, synovitis, tenosynovitis, and tophus with surrounding soft tissue or mild bone marrow edema (BME) and synovial enhancement after contrast^{4,5,16,17,18,19,20}. MRI synovitis and BME have face validity as indicators of joint inflammation although construct validity data (MSU crystal identification and histological or biochemical evidence of local inflammation) are lacking, as are data to address discrimination. US can potentially identify evidence of inflammation in gout that includes joint effusion, synovial hypertrophy, power Doppler signal, and soft tissue edema. US-demonstrated synovitis has face validity for inflammation, yet it lacks construct validity data and discrimination data. When the 2 modalities are directly compared, MRI appears more sensitive but less specific than US for findings, suggesting inflammation^6,16. This is especially important when considering the patients in chronic gout studies, who could range from patients with intercritical gout with no clinical inflammation between attacks, through to those with high tophi load and chronic indolent inflammation. Data systematically quantifying degree of imaging-identified inflammation in these differing stages of gout are not yet available, but such findings will be important in informing potential sites for assessment and sensitivity to change over time or with ULT, and these issues are import foci for future research.

Structural Damage

Chronic gout features typical radiographic changes of articular damage^5,8,12,21,22, which are caused by tophi²³. Most common findings on plain film are bone erosions, new bone formation, and joint space narrowing (JSN). These features are also identified by CT, DECT, and MRI, with US identifying only erosions and cartilage damage. A scoring system for XR based on the Sharp-van der Heijde method for rheumatoid arthritis shows excellent interobserver and intraobserver reliability and high correlation with expert opinion on the extent of joint damage. Extent of joint damage required only erosions and JSN to be scored. However, the rate of change in radiographic scores and the responsiveness of radiographic scores to therapy are largely unknown²⁴. Erosion and cartilage damage assessment have intuitive face validity for XR, CT, DECT, MRI, and US; however, other aspects of the truth criterion are only partially fulfilled for erosions and cartilage damage for DECT, CT, and MRI while discrimination data, particularly for sensitivity to change, requires further data across all modalities. Because the concept of resolution or retardation of structural damage is analogous to “disease-modification,” it would seem that addressing these gaps in current knowledge, particularly sensitivity to change, is critical in developing imaging measurements of structural damage. Engaging with industry to ensure imaging modalities are included in the protocol of future interventional studies was considered a high priority, along with longitudinal observation data in gout cohorts.

Conclusion

The working group attendees concluded that multiple imaging modalities need to be further developed for use as outcome measures in chronic gout because different modalities have relevance and potential for different domains. The prioritization of modalities with the most potential for each of the relevant domains and the key considerations for research agenda are summarized in Figure 1. More than 1 modality may need to be developed for each domain, to give flexibility in design of clinical trials, depending on the underlying research question. Inflammation in chronic gout has been underappreciated, and future therapeutic agents may have dual targets of urate lowering and control of inflammation, requiring more than 1 imaging modality to accurately assess changes in these domains. Further, the study population has a critical influence on the choice of imaging modality for an outcome measure. XR changes of chronic gout occur late, but US evidence of structural damage is identified earlier. Ideally, imaging outcome instruments will need to have similar performance characteristics at different stages of disease.

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Figure 1.

Gout working group prioritization of imaging modalities with most potential for development in each of the 3 relevant domains (highest priority indicated as unshaded, possible modalities indicated in grey, and modalities not recommended for further development as black). Critical considerations for research agenda across all domains are indicated in lower panel. LOS: longitudinal observational study; RCT: randomized controlled trial; DECT: dual-energy computed tomography; CT: conventional computed tomography; MRI: magnetic resonance imaging.

It will not be feasible to image all potentially affected joints with any imaging modality. A data-driven strategy for choice of joints is required while assessment of a standard set of commonly affected joints versus symptomatic index joint(s) are options to be explored. The patient acceptability of different modalities also remains unclear, with duration and timing of imaging and radiation doses all likely to be important considerations. A description of the research agenda is shown in Table 2.