When underlying biology threatens the randomization principle - initial gout flares of urate-lowering therapy

Abstract

Flare is the dominant feature of gout and occurs because of inflammatory response to monosodium urate crystals; prevention of gout flares should be the major goal of gout care. However, a paradoxical increase in the risk of flare following initiation of urate-lowering therapy presents considerable challenges for proving the expected long-term benefits of flare prevention in clinical trials. Nevertheless, excluding from enumeration flares that occur in the initial post-randomization period (which can last several months to 1 year) can threaten the core benefits of randomization: the characteristics of the remaining participants can differ from those who were randomized, introducing potential bias from confounding (both measured and unmeasured); participants who drop out or die are excluded from the analysis, introducing potential selection bias; and, finally, ignoring initial flares underestimates participants' experience during the trial. This Perspective discusses these issues and recommends measures that will allow for high-level evidence that preserves the randomization principle, to satisfy methodological scrutiny and generate robust evidence-based guidelines for gout care.

Fig. 1. Gout flare trends after initiation of a potent urate-lowering agent in a hypothetical placebo-controlled randomized controlled trial.

The risk of flares in the urate-lowering drug group increases after the initial anti-inflammatory prophylaxis phase of the trial (for example, 3 months) dissipates. This paradoxical worsening is followed by a substantially lower risk of flares over time. By contrast, the placebo group is expected to have a similar (or higher) level of flares over time, once the initial anti-inflammatory prophylaxis effect discontinues.