To quantify the value of early suppression of high sensitivity C-reactive protein (hsCRP) as a biomarker of the protective role of canakinumab against future gout flares.
We conducted a post-hoc causal mediation analysis of the Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) for gout flares. The 3-month change in the log hsCRP was the mediator of interest. We used linear regression for the hsCRP mediator and Cox or Weibull regression for gout flare outcomes, combining them in causal mediation analysis. We examined the cohort overall as well as stratified by prevalent gout at baseline.
We analyzed 9,221 patients without prevalent gout and 747 with prevalent gout. The Cox regression hazard ratio (HR) for a gout flare was 0.50 [95% confidence interval (CI) 0.37, 0.68] comparing canakinumab to placebo, of which 6% was explained by the mediated effect through hsCRP reduction in the first three months. In the prevalent-gout subgroup, the HR was 0.58 [95% CI 0.36, 0.95], of which 31% was explained by the mediated effect through hsCRP reduction. The Weibull analysis gave a proportion mediated estimate of 47%. The indirect effect via hsCRP reductions was unclear in the subgroup without prevalent gout.
The first 3-month reduction in hsCRP was not a good biomarker for canakinumab's protective effect on future gout flares in the overall cohort. Among prevalent gout patients, there may be a potential role for early hsCRP reduction as a biomarker for IL-1β inhibitors' future gout flare benefit.