A key determinant of outcomes for individuals with gout is the promptness of diagnosis and initiation of treatment. Prompt diagnosis and treatment are challenging, however, because the cutoff serum uric acid (sUA) concentration that defines hyperuricemia is poorly defined, and the recommended sUA target varies from one guideline to the next.1-3 When to start urate-lowering pharmacological treatment and the prognostic indicators to monitor treatment effectiveness are also ill-defined. Furthermore, the available guidelines lack consistency in their recommendations for the treatment of asymptomatic and symptomatic hyperuricemia. For example, guidelines from the American College of Rheumatology (ACR) recommended that pharmacologic urate-lowering therapy (ULT) may be started during an acute gout attack, with a goal of achieving a sUA target of <6 mg/dL at a minimum.3,4 Early initiation of ULT is also advocated by the 2016 updated European League Against Rheumatism(EULAR) recommendations for the treatment of acute gout flares, particularly for patients with comorbidities or sUA level >8 mg/dL,2 whereas a consensus statement on the management of hyperuricemia and gout suggested that the adoption of pharmacological ULT in asymptomatic patients should be dependent on cardiovascular risks and serum uric acid level.1

Irrespective of the guideline recommendations, the benefits of ULT have been documented. At a sUA level of 0 to 4.0 mg/dL, the effect of pharmacological treatment is a potential resolution of tophi with faster reduction of the urate burden; at 4.1 to 5.9 mg/dL, the effect is a slow dissolution of visible and nonvisible tophi; and at 6.0 to 6.8 mg/dL, the effect is a slowing of gout progression.5 Therefore, tools for accurate measurement of sUA level, particularly at low levels, are essential for early diagnosis, prompt treatment initiation, and monitoring of treatment effectiveness.

Obtaining synovial fluid during acute gout flare can be difficult, and accurate detection of urate crystals can be challenging, as it requires a polarizing microscope and a trained operator, which may not be available in the primary care or in the rheumatologic settings. Furthermore, differentiating gout from other conditions, such as pseudogout, septic arthritis, or trauma, that have similar presentations can be difficult, and may result in considerable diagnostic delay, and suboptimal treatment.6,7 The 2017 guidelines from the American College of Physicians acknowledge that alternatives to the analysis of synovial fluid for the diagnosis of gout are needed; however, the ACP’s review of the alternatives, specifically, ultrasonography and dual-energy computed tomography (DECT), concluded that the limited low-quality studies were insufficient to determine their clinical usefulness.8 The ACP recommend that “clinicians use synovial fluid analysis when clinical judgment indicates that diagnostic testing is necessary for patients with possible acute gout. (Grade: weak recommendation, low-quality evidence).”8

The studies evaluated by the ACP for the diagnostic utility of DECT and ultrasonography were indeed limited by study design and the technology available at the time of the studies; however, the updated gout classification criteria, published jointly in 2015 by the ACR and EULAR, recognized the potential utility of DECT and ultrasonography for gout classification.9 The application of imaging studies to accurately detect monosodium urate crystals in asymptomatic individuals prompted the recommendation by the ACR/EULAR for a more accurate classification of gout, acknowledging the limitations of the previously published criteria that were developed at a time when limited evidence from advanced imaging modalities was available.9

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Imaging has been shown to be able to detect a wide range of abnormalities in gout, and therefore may be applied to its diagnosis, clinical monitoring, and management.10 However, compared with ultrasonography, DECT has been shown to have a lower sensitivity for the detection of serum urate crystals.6 Accumulating evidence supports the versatility and considerable potential of ultrasonography because of its capacity to detect urate crystal deposits on the surface of cartilage in joints and in soft tissues (such as in tophi), and can visualize both synovitis and bone erosion.6 On the basis of available studies, ultrasonography can potentially detect urate deposits in clinically asymptomatic individuals with hyperuricemia, as well as in patients with gout and no visible tophi,11 demonstrating good correlation with synovial fluid analysis in detecting crystal deposition.12 Furthermore, ultrasonography has been used to confirm reduction in urate deposition after ULT, which correlated with decreased serum urate level, confirming its potential utility for disease monitoring.13 Ogdie and colleagues concluded from their study of 824 participants (416 cases of gout and 408 control patients) that musculoskeletal ultrasound features of monosodium urate crystal deposition had high specificity for the diagnosis of gout among subjects with at least 1 swollen joint consistent with gout, and the specificity remained high for patients with early disease and with no clinical signs of tophi.14 Ultrasonography may be a useful adjunct in the differential diagnosis of acute gout in patients presenting with acute arthritis, particularly when specialized microscopic techniques are not available.15

Given the evidence that early treatment of hyperuricemia is beneficial in asymptomatic individuals, ultrasonography may potentially be the most useful in establishing a diagnosis of hyperuricemia in individuals with high clinical suspicion of gout despite asymptomatic presentation or difficult-to-diagnose gout.14

The accumulating evidence for the clinical utility of ultrasonography for early diagnosis of hyperuricemia and monitoring of acute gout potentially offers an alternative tool to synovial fluid analysis. Ultrasonography may also be useful in the reclassification of hyperuricemia to include asymptomatic gout that should be considered for ULT to resolve urate deposits. The potential utility of ultrasonography is significant, but should be approached with caution, according to Mark Greenberg, MD, associate professor of medicine in the Division of Rheumatology at the University of South Carolina School of Medicine in Columbia. In his review of the study by Ogdie and colleagues,14 Dr Greenberg commented that several caveats should be noted, including the need to evaluate the performance of ultrasonography in different populations with a higher or lower gout prevalence than the almost 50% prevalence in the study by Ogdie and colleagues.16

Other unknowns must also be resolved before ultrasonography can be recommended for routine clinical use; for example, the duration and intensity of ULT required to demonstrate resolution of gout or to define disease remission on the ultrasonography, as well as the required clinical expertise of the physician to operate and interpret ultrasonographic results. Clearly, further studies are needed. The ACR-updated guideline for the management of gout is currently in development, with anticipated publication in late 2019 or early 2020. The hope is that new and updated evidence related to improvement in hyperuricemia classification, diagnosis, treatment, and monitoring will be reflected in the updated guideline recommendations.

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References

  1. Li Q, Li X, Kwong JS, et al. Diagnosis and treatment for hyperuricaemia and gout: a protocol for a systematic review of clinical practice guidelines and consensus statements. BMJ Open. 2017;7(6):e014928.
  2. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76:29-42.
  3. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64(10):1447-1461.
  4. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431-1446.
  5. KRYSTEXXA® (pegloticase) Guidelines for sUA reduction. https://www.krystexxahcp.com/guidelines-for-sua-reduction/. Accessed November 15, 2018.
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  9. Neogi T, Jansen TL, Dalbeth N, et al. 2015 gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol. 2015;67(10):2557-2568.
  10. Scirocco C, Rutigliano IM, Finucci A, Iagnocco A. Musculoskeletal ultrasonography in gout. Med Ultrason. 2015;17(4):535-540.
  11. Puig JG, Beltrán LM, Mejía-Chew C, Tevar D, Torres RJ. Ultrasonography in the diagnosis of asymptomatic hyperuricemia and gout. Nucleosides Nucleotides Nucleic Acids. 2016;35(10-12):517-523.
  12. Wang Y, Deng X, Xu Y, Ji L, Zhang Z. Detection of uric acid crystal deposition by ultrasonography and dual-energy computed tomography: A cross-sectional study in patients with clinically diagnosed gout. Medicine (Baltimore). 2018;97(42):e12834.
  13. Ebstein E, Forien M, Norkuviene E, et al. Ultrasound evaluation in follow-up of urate-lowering therapy in gout: the USEFUL study [published online October 4, 2018]. Rheumatology (Oxford). doi:10.1093/rheumatology/key303
  14. Ogdie A, Taylor WJ, Neogi T, et al. Performance of ultrasound in the diagnosis of gout in a multicenter study: comparison with monosodium urate monohydrate crystal analysis as the gold standard. Arthritis Rheumatol. 2017;69(2):429-438.
  15. Pattamapaspong N, Vuthiwong W, Kanthawang T, Louthrenoo W. Value of ultrasonography in the diagnosis of gout in patients presenting with acute arthritis. Skeletal Radiol. 2017;46(6):759-767.
  16. Greenberg M. NEJM Journal Watch. Can ultrasonography help diagnose gout? https://www.jwatch.org/na43632/2017/03/16/can-ultrasonography-help-diagnose-gout. Published March 16, 2017. Accessed November 15, 2018.