Efficacy and Safety of Gout Flare Prophylaxis and Therapy Use in People With Chronic Kidney Disease

A Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN)-Initiated Literature Review

Huai Leng Pisaniello; Mark C. Fisher; Hamish Farquhar; Ana Beatriz Vargas-Santos; Catherine L. Hill; Lisa K. Stamp; Angelo L. Gaffo

Disclosures

Arthritis Res Ther. 2021;23(130) 

In This Article

Results

An overview for all included studies was outlined in Table 1. Herein, results for each gout flare prophylaxis/therapy with efficacy and safety outcome data stratified by renal function were presented in the main text and were summarised in Table 2. Specifically, the details for drug indication and drug dosage were reported in Table 2. For studies with outcome data reported without any renal function stratification, these were summarised separately in the Supplementary Materials.

Colchicine

A total of 2325 studies of colchicine use were identified, as summarised in a PRISMA flowchart of the literature search (Supplementary Figure 1), and a final total of 49 studies were eligible for data extraction.[9–57] Twenty of these 49 studies, which were mostly case series or case reports, described the efficacy and/or safety outcomes of colchicine use stratified by renal function, as summarised in Table 2 and Table 3, respectively.[17,18,20,22,24,28,29,31–33,35–37,39,44,46,49,53,55,57] The remaining 29 studies reported efficacy and/or safety outcomes of colchicine use without renal function stratification, as summarised in Supplementary Table 2 and Supplementary Table 3, respectively.[9–16,19,21,23,25–27,30,34,38,40–43,45,47,48,50–52,54,56]

Studies of Colchicine use With Analyses Stratified by Renal Function. These 20 studies included 1 single-centre audit, 3 case series, and 16 case reports, with a total of 43 study participants. Varying patterns in colchicine dosing amount and frequency as well as varying routes of drug administration were seen across these studies. Only 5 studies reported efficacy outcome data stratified by renal function, although no definitive conclusion could be drawn due to their heterogenous study characteristics and the quality of the evidence was low.[18,33,44,53,55]

For the safety outcome, all studies reported varying level of transient change in renal function during colchicine use as well as after drug cessation. Fifteen studies reported colchicine-induced neuromyopathy and rhabdomyolysis.[18,20,24,29,31,32,35–37,39,44,46,49,53,55] Nine studies reported colchicine toxicity secondary to drug-drug interaction with statin, cyclosporin, clarithromycin, and hepatitis C treatments (i.e. sofosbuvir/ledipasvir).[17,18,28,29,31,32,36,46,49] It was unclear from these studies if the reported adverse events were directly attributed to the colchicine use.

Studies of Colchicine use Without Analyses Stratified by Renal Function. These 29 studies included 2 single-centre randomised controlled trials (RCTs), 1 post hoc analysis of 3 different ULT-related RCTs, 1 post hoc analysis of a cross-sectional study, one case-control study, 2 retrospective observational studies, 4 audits, 8 case series, and 10 case reports. All studies included study participants with varying degree of baseline renal impairment, and only pooled efficacy and safety outcome data were presented, without any renal function stratification in the outcome reporting. Furthermore, in studies using colchicine as gout flare prophylaxis, study participants with eGFR of < 30 mL/min/1.73 m2 were excluded, as evident in the RCT by Borstad and colleagues and the post hoc study of 3 different ULT-related RCTs.[10,11]

IL-1 Inhibitors

A total of 1067 studies of IL-1 inhibitor use were identified, as summarised in a PRISMA flowchart of the literature search (Supplementary Figure 2), and a final total of 26 studies were eligible for data extraction.[58–83] Eight of these 26 studies, which were mostly case series or case reports, described the efficacy and/or safety outcomes of IL-1 inhibitor use stratified by renal function, as summarised in Table 2 and Table 3, respectively.[67–69,71,76,77,81,83] The remaining 18 studies reported efficacy and/or safety outcomes of IL-1 inhibitor use without renal function stratification, as summarised in Supplementary Table 2 and Supplementary Table 3 respectively.[58–66,70,72–75,78–80,82] Overall, there were 17 studies of anakinra use, 7 studies of canakinumab use, and 2 studies of rilonacept use.

Studies of IL-1 Inhibitor use With Analyses Stratified by Renal Function. These 8 studies of IL-1 inhibitor use as gout flare therapy included 4 case series and 3 case reports of anakinra use, and 1 case report of canakinumab use. A standard 100-mg dosing was routinely observed in studies of anakinra use, albeit varying dose frequency and duration in the context of varying degree of renal impairment and the duration of gout flare. Six out of 7 studies of anakinra use demonstrated stable renal function during treatment irrespective of pre-existing CKD.[67–69,76,81,83] One case report of anakinra use described a decline in renal function.[71] In terms of anakinra's safety profile, 4 studies reported non-fatal infection-related adverse events.[68,71,76,81] The case report on canakinumab use described good efficacy in treating gout flare without any compromise in renal function or in safety signal.[77] No definitive conclusion on IL-1 inhibitor use in CKD could be drawn due to the low quality of evidence for these studies.

Studies of IL-1 Inhibitor use Without Analyses Stratified by Renal Function. There were 10 studies of anakinra use (1 single-centre open-label clinical trial, 4 case series, and 5 case reports).[60,70,72–75,78–80,82] In the open-label clinical trial of anakinra use by So and colleagues, study participants with advanced CKD (i.e. eGFR of < 30 mL/min/1.73 m2) were excluded from the study and the efficacy and/or safety outcomes for CKD subgroups were not presented, as only pooled results were reported.[60]

All RCTs of canakinumab use, described in 6 different published articles, excluded individuals with advanced CKD (i.e. eGFR of < 30 mL/min/1.73 m2).[58,59,61–64] These studies included a multi-centre phase 2 trial evaluating the efficacy of canakinumab of varying doses (with the initial study results reported by So and colleagues, followed by the remaining study results reported by Schlesinger and colleagues),[58,61] and the β-RELIEVED and β-RELIEVED II randomised trials (with study results reported in 3 separate published articles).[59,62,63] In the β-RELIEVED and β-RELIEVED II randomised trials, although the analyses were performed on a subgroup of participants with CKD ≥ stage 3, pooled outcome results were presented.[59,62,63] Similarly, for the β-RELIEVED and β-RELIEVED II randomised trials looking at different canakinumab formulations, pooled outcome results for CKD subgroup were presented.[64]

Two clinical trials of rilonacept use (1 crossover trial and 1 post hoc analysis of PRE-SURGE 1, PRE-SURGE 2, and RE-SURGE clinical trials) also similarly excluded study participants with CKD ≥ stage 3 and only pooled outcome results were presented.[65,66]

NSAIDs

Using the search terms as outlined in Supplementary Table 1, 1835 studies of NSAID use were initially identified, as summarised in a PRISMA flowchart summary (Supplementary Figure 3). After a sequential review of the title, abstract, and full-text, a final total of 4 studies of NSAID use were included for data extraction, with 3 studies reported efficacy and/or safety outcomes stratified by renal function and the remaining 1 study had study outcomes reported without renal function stratification.[57,84–86] These 4 studies largely aimed at showcasing the potential risk for nephrotoxicity with NSAID use as gout flare prophylaxis and therapy in patients with CKD.

Studies of NSAID use With Analyses Stratified by Renal Function. There were 1 case series and 2 case reports of NSAID use reporting study outcomes based on renal function (Table 2 and Table 3).[57,84,86] Of note, these studies documented the onset of acute kidney injury (AKI) with NSAID use in patients with gout flare and concomitant CKD. However, despite the eligibility for data extraction, these studies had insufficient number of patients and information to accurately ascertain the efficacy or toxicity of NSAID use in managing gout flares in patients with CKD.

Studies of NSAID use Without Analyses Stratified by Renal Function. One case series, although without outcome results documented by renal function stratification, described an association between NSAID use and risk of developing AKI (Supplementary Table 2 and Supplementary Table 3).[85]

Glucocorticoids

Using the search terms as outlined in Supplementary Table 1, 1678 studies of glucocorticoid use were initially identified, as summarised in a PRISMA flowchart summary (Supplementary Figure 4). After a sequential review of the title, abstract and full-text, a final total of 12 studies were included for data extraction.[57,64,87–96] Eleven out of these 12 studies were of case reports (n = 10) and of case series (n = 1).[57,87–96] Therefore, the evidence provided from these limited data did not allow any accurate conclusion drawn on the efficacy and/or safety of glucocorticoid use in gout flare and concomitant CKD. Only 2 studies reported efficacy and/or safety outcomes stratified by renal function and the remaining 10 study had study outcomes reported without renal function stratification.

Studies of Glucocorticoid use With Analyses Stratified by Renal Function. Two case reports had outcome results stratified by renal function, but further conclusion could not be drawn due to the low level of evidence for these studies (Table 2 and Table 3).[57,95]

Studies of Glucocorticoid use Without Analyses Stratified by Renal Function. Ten studies of glucocorticoid use described outcome results without renal function stratification (Supplementary Table 2 and Supplementary Table 3).[64,87–94,96] One single-centre case series by Bajaj and colleagues described a cohort of 10 lupus patients with gout flare, of which 8 of them were on varying doses of prednisone as gout flare therapy.[87]

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