This story was originally published June 14, 2018. As part of MedPage Today’s year-end review of 2018’s top stories, we are republishing it along with an update on what has happened since with interleukin-1 as a treatment target in gout.
AMSTERDAM — Treatment with canakinumab (Ilaris) reduced the risk of gout flares by more than half among patients with a history of myocardial infarction (MI), according to a post-hoc analysis of trial data presented here.
In a secondary analysis of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), the hazard ratios for gout flares were 0.40 (95% CI 0.22-0.73) for patients with normal baseline serum urate, 0.48 (95% CI 0.31-0.74) for those with elevated serum urate, and 0.45 (95% CI 0.28-0.72) for those with very elevated urate, reported Daniel Solomon, MD, of Harvard Medical School in Boston.
“I think this is really important as a proof of concept,” Solomon said during the opening plenary abstract session at the European Congress of Rheumatology annual meeting, sponsored by the European League Against Rheumatism (EULAR).
Normal urate levels were defined as below 6.9 mg/dL, elevated levels were 6.9 to 8.9 mg/dL, and very elevated levels were ≥9 mg/dL.
CANTOS enrolled 10,061 patients who had previously had an MI, and whose serum C-reactive protein (CRP) was ≥2 mg/L. Their median age was 61, median BMI was 29.8, and median baseline serum urate was 6.1 mg/dL. Three-quarters were men.
The study’s main purpose, as reported at the 2017 European Society of Cardiology annual meeting and in the New England Journal of Medicine, was to test the cardiovascular benefits of canakinumab and, by extension, the so-called inflammation hypothesis of cardiovascular disease. However, the data included records of gout diagnoses and attacks, forming a basis for the current secondary analysis.
“As we all know, gout inflammation depends on interleukin (IL)-1β release from a variety of cells. IL-1β is also known to be an important mediator of acute cardiovascular events,” Solomon said.
Current gout treatments focus on lowering serum urate, and targeting IL-1β represents a different mechanism of action.
Patients were randomized to receive placebo or canakinumab in doses of 50 mg, 150 mg, or 300 mg subcutaneously every 3 months. Serum urate and high sensitivity CRP were measured every 3 months during the first year and then annually.
Median baseline urate levels were 5.5% in the normal urate group, 7.6% in the elevated urate group, and 9.8% in the very elevated group. Median baseline CRP across the groups was approximately 4 to 5 mg/L, and 5% to 20% had a history of gout.
Over 5 years of follow-up, the cumulative incidence of gout flares was 1% to 3%, and across the three canakinumab arms, the risk of acute gout was reduced by 50% to 60%, with no difference according to dose. There was a much higher incidence, however, at 10% to 15%, among those with known gout.
Rates of gout flares in the normal, elevated, and very elevated urate groups were 0.28, 1.36, and 5.94/100 person-years, and rates of major adverse cardiovascular events were 4.1, 5.3, and 5.6/100, respectively.
Levels of CRP dropped “dramatically,” but urate remained stable. In a stratified analysis, there were no interactions detected between gout flares and gender, age, aspirin or diuretic use, or BMI.
Strengths of this secondary analysis were that it originated in a double-blind, placebo-controlled trial and had longitudinal CRP and urate measurements, but a major limitation was that gout attacks were not adjudicated, according to Solomon.
EULAR session moderator Robert Landewé, MD, PhD, of the University of Amsterdam, commented that this analysis found “an intriguing relative risk reduction, but the absolute risk reduction was about 1% to 2%, for a number needed to treat of 5,200.” He posed the question to Solomon, “Do you think this will at any time be found a feasible therapy?”
“Currently in the U.S. the price tag for canakinumab is very high, and it is used very sparingly, mostly in orphan diseases,” Solomon replied. “But there are a number of IL-1 blocking agents in development, some of which are small molecules. I’m not suggesting that this is a substitute for urate-lowering therapy — it’s a different mechanism of action.”
Solomon added, “But, it is not ready for prime time.”