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Spring 2021 (Volume 31, Number 1)

Treat to Target in Gout

By Abhijeet Danve, MD, FACP; and Tuhina Neogi, MD, PhD

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Gout is the most common inflammatory arthritis affecting 42 million adults worldwide.1 Despite the well understood pathophysiology and availability of effective medications, gout care remains suboptimal and adherence to therapy is poor. The central strategy in gout management is to reduce serum urate (sUA) to below the saturation threshold (6.8mg/dL= 408 μMol/L) to prevent monosodium urate crystallization, thereby reducing risk of gout flares and tophi. Because of this understanding of the biology of gout, a treat-to-target (T2T) strategy has been advocated by rheumatology societies, though this recommendation has not been accepted by all organizations.2 A T2T strategy involves management of the index condition with frequent monitoring of disease activity while escalating treatment to achieve a pre-specified quantifiable therapeutic target, in contrast to using symptoms alone as a gauge. A T2T strategy is used in a number of chronic conditions including hypertension, diabetes, and rheumatoid arthritis.3-5

A criticism of T2T in gout has been whether sUA is an adequate marker of clinical disease manifestations of flare and tophi, but at least three randomized clinical trials (RCTs) to date have provided insights into the effects of lowering sUA to <6mg/dL (360 μMol/L) on clinically relevant outcomes.6-8 A UK trial of nurse-led care that involved specific use of a T2T strategy with dose titration compared with usual care by general practitioners demonstrated lower sUA, which was accompanied by decreased severity and frequency of flares, reduction in tophi and improved medication adherence.8 In a RCT carried out in participants with early gout, there was a greater proportion achieving sUA <6mg/dL (360 μMol/L) along with a greater decrease in overall flare incidence in the febuxostat arm compared with placebo.7 Similarly, Sundy et al. demonstrated that use of pegloticase resulted in significantly more participants achieving sUA <6mg/dL (360 μMol/L), as well as a greater proportion with reduction in tophi and flares compared with placebo.6 It is a fair concern that the specific threshold of <6mg/dL (360 μMol/L) has not been directly assessed in a RCT as being better than <6.8mg/dL (408 μMol/L) or <5mg/dL (300 μMol/L), for example. Nonetheless, these trials do provide support for lowering sUA to sufficiently below the saturation threshold to achieve improvements in the clinical outcomes of flares and tophi.

With consideration of these and other data in the comprehensive evidence report, the American College of Rheumatology (ACR) 2020 gout guidelines strongly recommended a T2T strategy with urate-lowering therapy (ULT) dose titration guided by serial sUA levels to achieve a target of <6 mg/dL (360 μMol/L). It also recommended that ULT titration should occur over a reasonable time frame to prevent treatment inertia.9 The 2016 European League Against Rheumatism (EULAR) recommendations for the management of gout also supported use of a T2T strategy with a goal sUA of <6mg/dL (360 μMol/L).10

In summary, there is now high-quality data available combined with good understanding of gout’s pathophysiology, and treatment guidelines to support T2T in gout. Thus, rather than practicing “reactive” health care, a proactive T2T approach can mitigate and prevent the longterm sequelae of inadequately managed gout.

Abhijeet Danve, MD, FACP
Assistant Professor of Medicine,
Yale School of Medicine
New Haven, Connecticut

Tuhina Neogi, MD, PhD
Professor of Medicine,
Boston University School of Medicine
Boston, Massachusetts

References:

1. Safiri S, Kolahi AA, Cross M, et al. Prevalence, incidence, and years lived with disability due to gout and its attributable risk factors for 195 countries and territories 1990-2017: A systematic analysis of the global burden of disease study 2017. Arthritis Rheumatol. 2020; 72(11):1916-27.

2. Qaseem A, Harris RP, Forciea MA, Clinical Guidelines Committee of the American College of Physicians. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2017; 166(1):58-68.

3. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014; 311(5):507-20.

4. Yki-Jarvinen H, Kauppila M, Kujansuu E, et al. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med.1992; 327(20):1426-33.

5. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004; 364(9430):263-9.

6. Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011; 306(7):711-20.

7. Dalbeth N, Saag KG, Palmer WE, et al. Effects of febuxostat in early gout: a randomized, double- blind, placebo-controlled study. Arthritis Rheumatol. 2017; 69(12):2386-95.

8. Doherty M, Jenkins W, Richardson H, et al. Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial. Lancet. 2018; 392(10156):1403-12.

9. FitzGerald JD, Dalbeth N, Mikuls, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Rheumatol. 2020; 72(6):879-95.

10. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017; 76(1):29-42.



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