Gout Flare Risk Varies By Urate-Lowering Therapy Dosing, Prophylactic Measures

Findings from a recent study are providing insight into the management of gout flares during the initiation or escalation of urate-lowering therapy (ULT), underscoring the importance of considering different drugs, dosing schedules, and prophylactic measures for minimizing the risk of flares.¹

Results from the systematic review and network meta-analysis showed greater fixed doses of febuxostat and febuxostat in combination with lesinurad were generally associated with a greater risk of flares, whereas prophylaxis with colchicine or rilonacept significantly reduced the incidence of flares.¹

A form of inflammatory arthritis causing pain and swelling in the joints, gout is caused by a buildup of excess uric acid – thus, management often involves a combination of ULT and prophylaxis for flares, including nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids. Although gradual ULT dose escalation strategies without prophylaxis have demonstrated comparable flare rates to standard dose ULT with prophylaxis, the need for prophylactic measures is not well understood.^1,2

“This systematic review represents the most comprehensive data synthesis regarding the relative risk of gout flares when initiating or escalating ULT. It is the first NMA investigating the relative risk of gout flares with different ULT drugs, ULT dosing schedules and prophylaxis, and the AEs with prophylaxis,” wrote Michael Wiese, PhD, associate professor in pharmacotherapeutics at the University of South Australia, and colleagues.¹

To determine the relative risk of gout flares associated with different ULT drugs and dosing strategies, evaluate the impact of flare prophylaxis on flare incidence, assess the adverse event rates related to prophylaxis, and investigate the optimal duration of flare prophylaxis, investigators searched Medline, Embase, Web of Science, Cochrane database and clinical trial registries from inception to November 10, 2021, for trials investigating adults with gout initiating or escalating ULT. Searches included terms relating to gout, ULT, and flare prophylaxis.¹

Randomized controlled clinical trials (RCTs) or prospective controlled clinical trials including adults with confirmed gout either initiating ULT or escalating subtherapeutic ULT and reporting on the frequency of flares or flare prophylaxis-related adverse events were included in the present study. The primary outcomes of interest were flare rates and prophylaxis-related AE frequencies. Secondary outcomes were flare severity, pain scores, flare duration, and health-related quality of life.¹

Of 3775 screened publications, 29 publications reporting on 27 RCTs were included in the study. Of these, 19 trials randomized ULT, 7 randomized prophylaxis, and 1 randomized both. Trials were predominately based in North America or China, > 90% of participants were male, and the mean age was approximately 50 years. Of note, 61% and 45% of publications were labeled as high-risk or had concerns regarding bias due to missing outcome data, and 64% and 73% of publications were labeled as high-risk or had concerns regarding bias in the selection of the reported results.¹

When compared to placebo with prophylaxis, the risk ratio (RR) of flares ranged from 1.08 (95% CI, 0.87-1.33) for febuxostat 40mg with prophylaxis to 2.65 (95% CI, 1.58-4.45) for febuxostat 80mg with lesinurad 400mg and prophylaxis. Although investigators noted the data were too limited to make definite conclusions about optimal ULT drug and/or dosing strategies, they pointed out greater fixed doses of febuxostat and febuxostat in combination with lesinurad were generally associated with greater flare risk, whereas prophylaxis with either colchicine or rilonacept significantly reduced the incidence of flares.¹

Indeed, ULT plus prophylaxis had a lower RR of flares compared to ULT without any prophylaxis. Compared to ULT alone, the risk ratio of flares was lower for ULT with rilonacept 160mg (RR, 0.35; 95% CI, 0.25-0.50), ULT with rilonacept 80mg (RR, 0.43; 95% CI, 0.31-0.60), and ULT with colchicine (RR, 0.50; 95% CI, 0.35-0.72).¹

Compared to ULT without prophylaxis, there were no statistically significant differences in withdrawals due to AEs, total AEs, or serious AEs with prophylaxis, and no statistically significant difference was observed between the different prophylactic drugs. Of note, there was insufficient evidence regarding gradual up-titration strategies, NSAIDs and corticosteroids as prophylaxis, and the optimal duration of prophylaxis.¹

Investigators described several potential limitations to these findings, including the high risk of bias for both primary outcomes across most publications, restrictions imposed by trial reporting, a disproportionality high number of trials with fixed ULT dosing compared to the newer gradual up-titrated dosing, and exclusion of some available therapies.¹

Investigators concluded, “High fixed doses of ULT were associated with a greater risk of flares, but since most treatment guidelines have shifted to a gradual ULT up-titration approach, coupled with the reductions in flare risk noted with prophylaxis, there should be a greater emphasis on the need for future studies to compare gradual up-titration approaches against the prophylactic therapies currently used in clinical practice (i.e., colchicine, NSAIDs and/or corticosteroids) and to define the optimal duration of prophylaxis.”

References:

1. ^{Maher D, Reeve E, Hopkins A, et al. Comparative risk of gout flares when initiating or escalating various urate-lowering therapy: a systematic review with network meta-analysis. Arthritis Care & Research. https://doi.org/10.1002/acr.25309}
2. ^{Cleveland Clinic. Gout. Diseases & Conditions. February 19, 2023. Accessed February 21, 2024. https://my.clevelandclinic.org/health/diseases/4755-gout}