SNOWMASS, COLO. – Pegloticase (Krystexxa) is a gout drug that’s expensive, inconveniently administered by intravenous infusion every 2 weeks, and saddled with a substantial rate of immunogenicity, with infusion reactions that can include anaphylaxis.
So why does gout authority Dr. Michael H. Pillinger call pegloticase "a greatly underestimated and underutilized drug"? And why do the current American College of Rheumatology gout guidelines recommend pegloticase for refractory gout?
"Nothing else we have will get rid of tophi the way this drug gets rid of tophi," Dr. Pillinger explained at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
"Why do we care about that? Because tophi are erosive, they’re damaging, and also because they’re much more extensive than we think they are," said Dr. Pillinger, a rheumatologist and director of the crystal diseases study group at New York University.
Besides, the safety concern regarding this powerhouse urate-lowering drug has been resolved. The infusion reactions are readily avoidable. Pegloticase is not a drug rheumatologists should be scared of, he emphasized.
Dr. Michael H. Pillinger
Dr. Pillinger cited an eye-opening study that demonstrated just how much larger gout patients’ total body urate burden actually is compared with what’s apparent clinically. Investigators at the University of British Columbia, Vancouver, used dual-energy CT to assess urate deposits in 20 consecutive patients with tophaceous gout and 10 controls with other arthritic conditions. Physical evaluation of the gout patients turned up 111 areas of urate deposition; dual-energy CT revealed 440 such areas. The mean total urate volume was a hefty 40.2 cm3 (Ann. Rheum. Dis. 2009;68:1609-12).
"There’s a lot more tophi under the surface," Dr. Pillinger commented.
Pegloticase is a recombinant porcine uricase that’s modified with a baboon N-terminus. It’s pegylated to reduce immunogenicity to the uricase and increase stability and half-life. Paradoxically, the drug is still quite immunogenic because many patients develop antibodies to the polyethylene glycol used in pegylation.
The drug’s urate-lowering effect is unmatched. Within 12-24 hours of the first dose, the plasma uric acid level plummets to almost nothing.
"What happens is that very, very quickly these patients are going to split into two groups. For one group this is the greatest drug in the world; their uric acid remains almost undetectable – and that’s in our sickest refractory patients. And then there’s another group that starts to fail. It’s in the neighborhood of 30%-40% of patients, so it’s a real problem. We know they’re failing because their uric acid level starts rising. They’re making antibodies and inactivating the drug every time it’s given. And they’re the ones who get bad infusion reactions," the rheumatologist explained.
The solution to using pegloticase safely is to routinely measure serum urate 1-2 days before each infusion. If the serum urate climbs to 6 mg/dL on one or two occasions, it’s time to discontinue the drug.
"For everybody else, they’re going to do really, really well," Dr. Pillinger said.
A key point emphasized in the 2012 ACR gout guidelines (Arthritis Care Res. 2012;64:1431-46; 1447-61) is that when patients go on pegloticase, all other urate-lowering therapies must be stopped as a matter of safety. Otherwise, it’s impossible to use the pre-infusion plasma urate measurement to determine if pegloticase has stopped working.
The ACR guidelines recommend pegloticase as third-line urate-lowering therapy in patients who are not at target despite maximum-dose therapy with a xanthine oxidase inhibitor plus second-line therapy with probenecid, losartan, or fenofibrate.
Dr. Pillinger reported having received research grants from Savient, which markets pegloticase, and Takeda.