OP0184 The frequency of flares in subjects with chronic refractory gout treated with pegloticase is related to variation in the level of plasma urate
Authors: L. Calabrese, T. Fields, A. Yeo, P. Lipsky
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Lowering plasma urate in subjects with gout is associated with an increase in flares because of an altered equilibrium between soluble urate and uric acid crystals.<sup>1</sup> Details of the relationship between plasma urate lowering and gout flares have not been fully delineated. Pegloticase is a mammalian recombinant uricase conjugated to polyethylene glycol approved for the treatment of chronic gout refractory to conventional oral urate lowering therapy.<sup>2–4</sup> Results from the two 6 month randomised clinical trials (RCTs) of pegloticase showed that during months 1–3, there was an increase in pegloticase-treated subjects experiencing gout flares vs those receiving placebo. However, the reported analysis did not separate results for subjects who did and did not respond to pegloticase with a sustained reduction in plasma urate levels or relate flares to plasma urate levels. <h3>Objectives</h3> To determine factors associated with the occurrence of flares in subjects who did and did not respond to pegloticase in the two RCTs for this therapy. <h3>Methods</h3> This analysis used results from 2 pivotal RCTs<sup>2</sup> of pegloticase (8 mg every 2 weeks [q2] or every 4 weeks [q4]) vs placebo in subjects with chronic refractory gout. A responder was defined as a subject with plasma urate &lt;6.0 mg/dL≥80% of the time from the week-9 infusion to just prior to the week-13 infusion and from the week-21 infusion to the week-25 final study visit. Gout flares were defined as acute joint pain and swelling requiring treatment. Gout flare prophylaxis (colchicine, 0.6 mg once or twice daily, or a NSAID) was initiated 1 week before the first infusion and continued throughout the study. <h3>Results</h3> There were increases in the frequency of subjects experiencing flares and the mean flare frequency in the pegloticase group vs placebo during the first 3 months of the trial (figure 1A). In contrast, there were marked reductions in both outcomes during months 3–6 (figure 1B). The increase in flares in the first 3 months was most evident (p=0.0006) and the decrease during the second 3 months was least marked (p=0.0006) in subjects receiving q4 pegloticase. Previous analysis indicated that q2 pegloticase caused persistently lowered plasma urate in responders, whereas q4 administration resulted in a more saw tooth pattern.<sup>5</sup> Multivariate linear regression analysis indicated that the only variable associated with flares in the treated subjects was the absolute change in plasma urate prior to these events. Assessment of plasma urate at both 2 weeks and immediately before flares indicated that larger differences between these two values were associated with increased flare occurrence (p=0.002). <h3>Conclusions</h3> Flares associated with pegloticase treatment in subjects with chronic refractory gout were increased most markedly in responders to monthly administration and were significantly associated with fluctuations in plasma urate levels. Such fluctuations are much more common with monthly administration of pegloticase vs the recommended biweekly treatment regimen. <h3>References</h3> [1] Wortmann RL, et al. Clin Ther2010;32:2386. [2] Sundy JS, et al. JAMA2011;306:711. [3] Mandell BF, et al. <i>Arthritis Rheumatol</i>2016;68(suppl 10):212. [4] Mandell BF, et al. <i>Arthritis Rheumatol</i>2017; 69(suppl 10):2054. [5] Lipsky PE, et al. Arthritis Res Ther2014;16:R60. <h3>Disclosure of Interest</h3> L. Calabrese: None declared, T. Fields Consultant for: Horizon Pharma, Takeda, Ironwood, Speakers bureau: Horizon Pharma, Takeda, Ironwood, A. Yeo Consultant for: Horizon Pharma, P. Lipsky Consultant for: Horizon Pharma