“A pox of this gout! or a gout of this pox! for the one or the other plays the rogue with my great toe.” – Falstaff, Henry IV
Gout was once called “the king of diseases and the disease of kings.” Thanks to that proximity to power, gout has been well documented through history, from the Egyptians to the Greeks to 17th century England, when physician Thomas Sydenham described an outbreak as “The night is passed in torture.” But today, gout has been democratized, afflicting roughly 6 million people in the United States and connected with obesity, heart disease, and alcohol abuse. Fortunately, treatments for gout have kept pace with its numbers, and in this week’s Journal of the American Medical Association, another option has been added to the physician’s arsenal against the rheumatic disorder.
The new treatment, pegloticase, has its origins in an unlikely place for a “royal” disease: an enzyme from the common swine. Unlike humans, most animals can avoid gout thanks to an enzyme called uricase that converts uric acid (high levels of which cause gout) to the harmless and excretable allantoin. Duke University chemists spent decades modifying pig uricase for therapeutic use in humans, adding a protective coating that can keep the enzyme active for days instead of hours. Perfected at last, the treatment showed positive results in its first two major clinical trials, run by researchers at the Medical Center.
“This represents the first effective therapy for a group of patients who previously had no options at all,” said the study’s senior author, Michael Becker, professor of medicine at the University of Chicago. “This is for patients with severe gout, including major disabilities and high levels of pain. Many of these people had dramatic responses within months…as well as reduced levels of pain and disability. The rapidity of these outcomes is unheard of.”
Gout is caused by the gradual accumulation of uric acid, either from over-production or inadequate removal. When levels exceed the saturation point, uric acid forms tiny urate crystals, like thousands of little needles, that deposit in the lining of joints and other tissues. The crystals can cause inflammation, swelling and intense pain, including painful swollen joint nodules known as tophi.
Many patients are treated with medications that block the synthesis of uric acid or help the kidneys remove it. But not everyone with gout finds relief from these medications, or can tolerate their side effects. Three percent of gout patients – about 120,000 to 180,000 Americans – have chronic, disabling disease with no effective therapy.
Those types of patients made up the two parallel trials of pegloticase, conducted at over 50 rheumatology clinics across North America. Patients in the treatment groups were given an intravenous infusion of pegloticase once every two weeks or once every month, and monitored for six months to see if their uric acid levels fell and their symptoms resolved. The results showed an interesting split: although uric acid levels dropped in all patients given the drug, only 42 percent (in the every-two-weeks group) sustained those decreased levels over the entire six months.
Still, helping two out of five patients without any other treatment option is a significant clinical achievement. And in those patients where the drug worked, the magnitude of relief was great, resolving at least one tophi and improving quality of life and physical function. The drug, brought to market under the name Krystexxa, is expected to cost about $60,000 a year.
“People are dramatically helped by the drug,” said rheumatologist John Sundy, director of the Duke Clinical Research Unit and lead author of the study. The drug’s response among patients who have failed common therapies is typically an “all-or-nothing result,” he added, “providing marked relief for those who benefit.”
“This is a group of people for whom there has not been another option for a long time,” Sundy added.
Pegloticase treatment, like most therapies, is not without its side effects. Many patients experienced “gout flares” (brief attacks of pain or inflammation), while a quarter of patients suffered an infusion-related immune response to the drug. In fact, most patients generated antibodies against the drug, suggesting that it may not be a viable treatment long-term. But even temporary relief of severe gout symptoms is beneficial in the big picture of a patient’s fight against the chronic disease, Becker said.
“It’s not curative, but it resets the clock, moving the hands back on a patient’s struggle with a progressive disease,” Becker said. “This is an advance – a significant advance.”
Sundy, J., Baraf, H., Yood, R., Edwards, N., Gutierrez-Urena, S., Treadwell, E., Vazquez-Mellado, J., White, W., Lipsky, P., Horowitz, Z., Huang, W., Maroli, A., Waltrip, R., Hamburger, S., & Becker, M. (2011). Efficacy and Tolerability of Pegloticase for the Treatment of Chronic Gout in Patients Refractory to Conventional Treatment: Two Randomized Controlled Trials JAMA: The Journal of the American Medical Association, 306 (7), 711-720 DOI: 10.1001/jama.2011.1169