Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Pegloticase Therapy Does Not Increase Oxidative Stress Status
Hershfield1, Michael S., Roberts II2, L. Jackson, Ganson1, Nancy J., Kelly1, Susan J., Sundy3, John S., Scarlett4, Edna, Jaggers5, Denise A.
Pegloticase, a pegylated recombinant mammalian urate oxidase, can rapidly lower plasma urate (PUA) to <2 mg/dL. Since urate is postulated to be an important free radical scavenger, and urate oxidation generates hydrogen peroxide, it has been suggested that pegloticase therapy might increase oxidative stress. To address this concern, we examined plasma concentration of F2-Isoprostanes (IsoP) in a phase 2 trial of pegloticase in 21 patients with refractory gout. IsoP result solely from free radical attack on membrane-associated arachidonic acid, and plasma IsoP is well validated as a biomarker of oxidative stress status.
Plasma IsoP was measured by GC-MS, and PUA by HPLC. The clinical protocol called for 5 infusions of pegloticase (8 mg) at 3 week intervals. PUA and IsoP were assessed at baseline and 2, 48, and 168 h after infusion #1, at 7 d after the final infusion, and at a follow-up visit about 7 weeks later.
At baseline, mean PUA was 10.8 +/- 1.3 mg/dL, and mean plasma IsoP was 69 +/- 40 pg/mL (normal, 35 +/- 6 pg/mL). After pegloticase infusion #1, PUA fell to 7.0 mg/dL within 2 h, and to <1 mg/dL at 48 and 168 h in all 21 subjects. In 15 subjects, mean PUA remained <1 mg/dL at 7 d after the final infusion, and was 6.3 mg/dL at follow-up. In 6 subjects who developed clearing antibodies to pegloticase, mean PUA in the final 2 samples had returned to baseline. Overall, plasma IsoP showed no relationship to PUA (R2= 0.01). As a change from baseline, mean plasma IsoP (all 21 patients) decreased by 7% by d 7 after infusion #1, and by 12% at 7 d after the last infusion of pegloticase in the 15 persistently hypouricemic patients.
Elevated baseline plasma IsoP suggests that hyperuricemia in refractory gout is associated with high oxidative stress. Sustained hypouricemia induced by IV pegloticase therapy was associated with a slight, but non-significant decrease in plasma IsoP, and over a wide concentration range there was no correlation between plasma urate and IsoP levels. These findings indicate that pegloticase therapy does not increase oxidative stress status, and they raise questions about the importance of urate as a free radical scavenger.
To cite this abstract, please use the following information:
Hershfield, Michael S., Roberts II, L. Jackson, Ganson, Nancy J., Kelly, Susan J., Sundy, John S., Scarlett, Edna, et al; Pegloticase Therapy Does Not Increase Oxidative Stress Status [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1100