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.

Gout Flares and Mortality After Sodium-Glucose Cotransporter-2 Inhibitor Treatment for Gout and Type 2 Diabetes

“…When colchicine is prescribed for a discrete episode, it is more often to patients who experienced gout flares . In addition, we demonstrated that the risk of gout flares increased during the first 3 months after initiating allopurinol and then leveled off, which is comparable to the findings of the previous randomized clinical trials . All this evidence suggests a reasonable level of ascertainment for gout flares.…”

“… 10 , 44 In addition, we demonstrated that the risk of gout flares increased during the first 3 months after initiating allopurinol and then leveled off, which is comparable to the findings of the previous randomized clinical trials. 45 All this evidence suggests a reasonable level of ascertainment for gout flares. Furthermore, if gout flares were misclassified, such misclassification is likely nondifferential and biases the results toward the null.…”

Not Only Excruciating Pain: Might a Gout Flare Episode Lead to Pulmonary Embolism?

“…Another related question is whether the risk of VTE would still be increased in the presence of flares paradoxically induced by introduction of urate-lowering therapy (15). These types of flares tend to be worse with more effective urate-lowering, which is the goal of standard gout care.…”