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

Discussion

This review explores the current literature on the efficacy and safety outcome data on the use of gout flare prophylaxis and therapy in people with CKD ≥ stage 3. Without limiting the publication date and study design, we were able to capture all of the efficacy and/or safety data for different anti-inflammatory therapy used for gout flare in people with underlying renal impairment. Using the best evidence synthesis approach, we then extracted and summarised the outcome data for each study based on the presence or absence of renal function stratification. Overarchingly, this review has highlighted the absence of conclusive data on efficacy or safety in gout flare prophylaxis and therapy use in patients with underlying advanced CKD.

Although colchicine has been used for many years and remains a first-line anti-inflammatory drug for gout flare prophylaxis and therapy, we currently have insufficient data to adequately inform us on the efficacy and safety of using colchicine in people with gout and concomitant CKD. For instance, there are only 2 single-centre RCTs and 1 post hoc analysis study of three RCTs reporting on colchicine prophylactic use in people with underlying CKD, although these clinical trials presented aggregated outcome results (i.e. without renal function stratification) for the efficacy and safety data on colchicine use in this subgroup, and these results are not necessarily informative for people with varying CKD stages. In addition, we have seen different results on the impact of gout flare treatment on renal function in case reports and case series. For instance, 12 studies reported deteriorated renal function with colchicine use,[17,20,22,24,32,33,35,39,44,53,55,57] whereas 7 other studies reported stable renal function with colchicine use.[18,28,29,31,36,46,53] As a result, given the underlying risk of bias on study quality for these studies, we cannot sufficiently conclude on the efficacy and/or safety outcomes on colchicine use for people with gout and concomitant CKD. In the AGREE clinical trial, low-dose colchicine use was as comparably effective as the high-dose colchicine in gout flare with minimal side effects, and therefore, low-dose colchicine has been recommended for use in gout flare prophylaxis and therapy.[97] The question remains, whether low-dose colchicine use remains effective and safe, for treatment of flares or flare prophylaxis, in those with advanced CKD. Similarly, we do not have adequate efficacy and safety outcome data for IL-1 inhibitor use in gout flare and CKD to inform clinicians if renally adjusted dosing is required when using these IL-1 inhibitors for different renal disease severity. The issue of IL-1 inhibition use for flare prophylaxis in patients with gout and advanced CKD remains essentially unexplored. Additionally, from the pharmacovigilance perspective, drug tolerance is an important consideration when using these anti-inflammatory medications in gout flare. For colchicine, increased drug toxicity is seen in individuals with CKD, due to increased drug half-life. In addition, the overall colchicine-related side effects secondary to drug retention are more noticeable when treating gout flare transiently in the clinical settings of concomitant CKD and acute illness such as dehydration and sepsis. It is also important to note that colchicine use in gout and advanced CKD can be hazardous when used in conjunction with some medications, such as statin therapies (CYP3A4 inhibitors), cyclosporin (both CYP3A4 and P-glycoprotein inhibitors), and macrolide antibiotic, such as clarithromycin (both CYP3A4 and P-glycoprotein inhibitors). Similarly, for anakinra, the dose should be renally adjusted in individuals with gout and advanced CKD due to the risk of increased drug half-life, and yet, this recommendation is seldom applied in the clinical practice.

In the case of NSAID use as gout flare prophylaxis and therapy, we did not expect to find any recent data to justify NSAID use in CKD, as all NSAIDs are widely known to be contraindicated in advanced CKD. Indeed, the included case series/reports of NSAID use in this review favourably justify the avoidance of any NSAID use in individuals with gout and renal failure. Almost all studies found were only aiming at highlighting the nephrotoxic risk of NSAID use in this high-risk comorbid population with gout flare. The question remains, however, as to whether NSAID use is equally effective and safe in patients with non-residual renal function compared with those with normal renal function but we did not find any published evidence to support or refute that hypothesis. In the case of glucocorticoid use, all studies found described either refractory or very severe gout flare cases, which are not necessarily reflecting the common clinical practice of gout flare management. We did not find studies exploring the question of whether low doses of glucocorticoids could be part of the prophylaxis of gout flares. Another question that remains is whether glucocorticoid use is equally effective and safe or if there is a potential risk of exacerbating tophaceous gout disease.

Furthermore, we found that all clinical trials reported pooled data on efficacy and/or safety outcomes, even with renal function stratified at baseline for all study participants. Pertinent to our review aims, it is evident that most clinical trials of gout flare prophylaxis and therapy excluded study participants with advanced CKD (i.e. CKD ≥ stage 3). This is likely explained by the strict regulations implemented in most clinical trial approval by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), of which these regulatory bodies restrict the inclusion of study participants with CKD ≥ stage 3. In terms of profiling drug safety in the management of gout flare, we identified certain side effects being reported in the studies, but unlikely to have any attribution to the underlying renal impairment. For example, infections were commonly reported for IL-1 inhibitors and glucocorticoid use, which would be likely due to the immunomodulatory effects from the drug use, rather than the effects of the underlying reduced renal function. This finding highlights the importance of profiling drug safety with the comparison between individuals with and without CKD in gout studies, where possible.

This review has highlighted the heterogenous patterns in efficacy and/or safety outcome reporting in all studies on gout flare management and prophylaxis, irrespective of the study designs. This observation is also echoed by a recent systematic review by Stewart and colleagues on gout flare reporting in clinical trials.[98] Besides the patient's self-reported gout flare resolution and other symptom reporting, objective assessments such as using the pain visual analogue score (VAS) and C-reactive protein (CRP) level are commonly implemented in the study protocols in evaluating treatment efficacy in most clinical trials and observational studies of gout flare management. Yet, these objective assessments are not necessarily standardised among clinical trials and the gout flare definition may differ between studies. Such issues can further complicate the interpretation of study findings when comparisons between studies are made collectively. A recent validation study in defining gout flare by Gaffo and colleagues has stressed the importance of having an accurate and validated definition and assessment of gout flare in all clinical studies of gout.[99] By incorporating standardised gout flare definition in future gout flare studies, comparisons in treatment outcomes across studies of different treatments used as gout flare prophylaxis and therapy can be performed fairly and efficiently. Ideally, the efficacy and safety of gout flare and urate-lowering treatments based on stratified renal function should be emphasised in all gout studies, as gout and CKD often co-exist. For example, an ongoing Veterans Affairs (VA) StopGOUT study in the USA is currently evaluating the 'treat-to-target' dose escalation of urate-lowering therapies (allopurinol versus febuxostat) in managing gout and with further observation in assessing the efficacy and safety of renally adjusted dosing in study participants with co-existing CKD.[100]

This review has some study limitations. We did not include non-English published studies or unpublished data, which could potentially lead to bias in the study inclusion and exclusion process. Specifically, relevant information on the use of IL-1 inhibitors may be missed, considering that anakinra is an off-label use for gout flare therapy in some countries and canakinumab is not widely indicated for gout flare therapy in some English-speaking countries. We did not have sufficient data for people with gout flare and underlying renal transplant, and therefore, the findings from this review may not reflect on this specific renal disease subgroup. Due to the heterogeneity nature of the study designs across all included studies, quantitative analysis such as meta-analysis could not be performed. In general, we propose that the overall findings and interpretations of this review using the best evidence synthesis approach is unlikely to differ despite our study limitations.

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