IL-1 blockade with canakinumab helps reduce gout flares

Elvira Manzano
29 Jun 2018
IL-1 blockade with canakinumab helps reduce gout flares

Treatment with the immunomodulatory agent canakinumab reduces the risk of gout flares by more than half in patients with atherosclerosis, according to the post hoc analysis of the CANTOS* trial.

The hazard ratios for gout flares were 0.40 (95 percent CI, 0.22–0.73) for patients with normal baseline serum urate, 0.48 (95 percent CI, 0.31–0.74) for those with elevated serum urate, and 0.45 (95 percent CI, 0.28–0.72) for those with very elevated urate in the secondary analysis of the CANTOS trial. Normal urate levels were defined as <6.9 mg/dL, elevated levels as 6.9 to 8.9 mg/dL, and very elevated levels at 9 mg/dL or higher. [EULAR 2018, abstract OP0014]

“This is very important as a proof of concept,” said investigator Dr Daniel Solomon from the Harvard Medical School in Boston, Massachusetts, US.

CANTOS included 10,061 patients who had previous myocardial infarction and serum C-reactive protein (CRP) of 2 mg/L or higher. Patients median age was 61 years. Median body mass index was 29.8 kg/m2 whereas median baseline serum urate was 6.1 mg/dL. Three-quarters of the patients were male.

The study sought to investigate the cardiovascular benefits of canakinumab, and by extension, the inflammation hypothesis of cardiovascular disease. The data included records of gout diagnoses and attacks which became the basis for the secondary analysis.

“Gout inflammation depends on interleukin [IL]-1β release …  IL-1β is known to be an important mediator of acute cardiovascular events,” Solomon said.

The focus of current gout treatments is on lowering the serum urate. Targeting IL-1β represents a different mechanism of action.

Patients in the CANTOS study were randomized to receive placebo or canakinumab in 50 mg, 150 mg, or 300 mg doses subcutaneously every 3 months. Serum urate and high sensitivity CRP were measured every 3 months during the first year and then yearly.

Median baseline urate levels were 5.5 percent in the normal urate group, 7.6 percent in the elevated urate group, and 9.8 percent in the very elevated group. Median baseline CRP across the groups was 4–5 mg/L. Five to 20 percent had a history of gout.

The cumulative incidence of gout flares was 1–3 percent over 5 years of follow-up. Across the three canakinumab arms, the risk of acute gout was reduced by 50–60 percent, with no difference among doses. However, there was a much higher incidence among those with known gout at 10 –15 percent.

Rates of gout flares in the normal, elevated, and very elevated urate groups were 0.28, 1.36, and 5.94/100 person-years. Rates of major adverse cardiovascular events were 4.1, 5.3, and 5.6/100, respectively.

CRP levels dropped “dramatically” whereas urate remained stable. In a stratified analysis, there were no interactions found between gout flares and gender, age, aspirin or diuretic use, or body mass index.

The strengths of the secondary analysis were that it originated from a double-blind, placebo-controlled trial and had longitudinal CRP and urate measurements, Solomon said.  The limitation was that gout attacks were not adjudicated.

“The analysis showed an intriguing relative risk reduction, but the absolute risk reduction was about 1– 2 percent for a number needed to treat of 5,200,” said session moderator Dr Robert Landewé from the University of Amsterdam. To which Solomon said, “I’m not suggesting that canakinumab is a substitute for urate-lowering therapy – it has a different mechanism of action and ain’t ready for primetime.”

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