The coadministration of methotrexate with pegloticase has greatly increased rates of urate-lowering efficacy. As more patients are being successfully treated with pegloticase, better understanding SU management following treatment is of increasing importance. The current study provides some of the first and much needed insights on post-pegloticase oral urate-lowering therapy use and efficacy and reports real-world data on how rheumatologists are using oral ULTs following a treatment course of pegloticase. Just over half (54.5%) of patients were prescribed an oral ULT after pegloticase discontinuation, with allopurinol most prescribed (67.0% of patients). Additionally, approximately two-thirds of patients who began an oral ULT agent did so within 30 days after last pegloticase infusion. Because the United Rheumatology database includes laboratory values, this study also examined the success of SU-lowering in patients with available laboratory data who were prescribed an oral ULT following pegloticase discontinuation, showing an overall efficacy (first SU < 6 mg/dL after oral ULT initiation) of 54.8%. However, patients who had received ≥ 12 pegloticase infusions, and presumably had a marked reduction in their deposited urate crystal burden [4, 5] had a significantly higher rate of oral urate-lowering efficacy than patients with a shorter treatment course (78.4% vs. 36.2%; p < 0.001). Further, among patients who underwent a longer treatment course, 88.9% (nearly 90%) had urate-lowering with an oral ULT if it had been initiated within 60 days of last pegloticase infusion (vs. 50.0% when initiated > 60 days after last infusion). In patients who did not receive an oral ULT following pegloticase discontinuation, SU rose to a mean of 7.9 mg/dL within a few months of discontinuing pegloticase. However, the sample size of patients with SU measurements was small in those who did not initiate an oral ULT after pegloticase (n = 13).

Pegloticase is indicated for patients who have uncontrolled gout that is refractory to oral ULTs. If oral ULTs were not effective prior to pegloticase treatment, the question arises as to what has changed to make them effective in some patients following pegloticase therapy. Patients without gout and patients with gout who do not have urate stores only have metabolic activity and dietary intake contributing to SU, with diet accounting for < 1% of variation in SU levels [15]. In patients with gout and monosodium urate crystal (MSU) deposits, dissolving MSU would also contribute to SU. Xanthine oxidase inhibitors (XOIs) act by slowing the conversion of purines to urate and can lower SU but do not directly act on urate that is already present. When a patient with MSU deposits and receiving an XOI has their SU fall below 6 mg/dL, MSU throughout the body begins to dissolve, which must still be removed from the body. When levels once again rise above 6 mg/dL, tophi and other urate deposits stop dissolving. In contrast, pegloticase rapidly converts serum urate to allantoin, which is highly water-soluble and readily excreted by the kidneys. Therefore, as MSU deposits dissolve, the new urate entering the serum immediately gets eliminated, SU remains near zero, and tophi and other urate deposits continue to dissolve. Dual-energy CT (DECT) imaging studies from clinical trials have shown that after 12 biweekly pegloticase infusions, MSU deposits were depleted by > 85% [4]. Theoretically, once urate deposits are fully depleted, slowing urate production with XOIs may be enough to lower and maintain SU below 6 mg/dL. In support of this idea, the current analysis showed that nearly 8 in 10 patients who received ≥ 12 pegloticase infusions and initiated a post-pegloticase oral ULT achieved an SU < 6 mg/dL. This increased to nearly 9 in 10 patients when the oral ULT was started within 60 days of last pegloticase infusion. In contrast, only 1 in 3 patients who received < 12 infusions were able to maintain SU < 6 mg/dL when administered an oral ULT after pegloticase discontinuation. Together, these new data suggest that, once urate deposits are depleted, a proactive vs. reactive approach with XOI SU management may be beneficial.

The current study had several limitations, largely inherent to retrospective analyses of existing databases. First, pegloticase treatment duration, timing of SU measurements, and follow-up time in the database were not uniform between patients. As a result, the number of pegloticase infusions may not be uniform, and some may be outliers likely leading to a non-normal distribution and a high standard deviation in the mean number of infusions. However, it should be noted that the median number of pegloticase infusions was not much different between patients with post-pegloticase oral ULT use [8 (range 3–16)] vs. those with no post-pegloticase oral ULT use [9 (range 4–18); p = 0.303; Table 1]. The second limitation was that we could only examine data that had been captured in the database; therefore, long-term post-pegloticase oral ULT efficacy could not be examined here. Third, although we were able to preliminarily examine post-pegloticase oral ULT efficacy with available SU data, the United Rheumatology database did not have reliable oral ULT dosing information. However, pegloticase is indicated for refractory gout making it likely that the majority of the patients who initiated a post-pegloticase oral ULT were refractory to oral ULTs prior to treatment. Fourth, even though results were statistically significant, patient numbers were small in some of the subgroup analyses. Considering the limitations due to missing or unavailable data on ULT dosing and long-term SU levels, as well as the retrospective nature of the study, these findings may be considered hypothesis-generating. Nevertheless, these data suggest the benefit of stable oral ULT use post pegloticase and also shed light on the relevance of longer pegloticase course and timing of oral ULT initiation post pegloticase. Further studies with larger datasets are needed to better understand these findings.