Anakinra for the Treatment of Acute Gout Flares

A Randomized, Double-Blind, Placebo-Controlled, Active-Comparator, Non-Inferiority Trial

Carly A. Janssen; Martijn A. H. Oude Voshaar; Harald E. Vonkeman; Tim L. Th. A. Jansen; Matthijs Janssen; Marc R. Kok; Bea Radovits; Caroline van Durme; Hetty Baan; Mart A. F. J. van de Laar

Disclosures

Rheumatology. 2019;58(8):1344-1352. 

In This Article

Discussion

In this study we set out to determine the clinical efficacy and safety of anakinra for the treatment of acute, crystal-proven, gout flares in a randomized, active-comparator, NI trial. A daily subcutaneous injection of anakinra was compared with oral treatments administered according to the standard of care, using optimal dosages as recommended in gout guidelines. As far as we know, this is the first double-blind, randomized controlled trial to evaluate the use of anakinra in an acute gouty arthritis population.

The results presented here show at least NI of anakinra compared with conventional therapies for the treatment of acute gout flares, supported by the additional finding that patients in both treatment arms achieved a significant reduction of their gout-related symptoms over the course of one week. Additionally, evaluation of the reported AE did not reveal any severe, uncommon or unexpected safety outcomes. These findings suggest that anakinra might be a viable treatment option for gout flares.

To date, various non-randomized, uncontrolled, observational studies have reported on the clinical efficacy of anakinra for treating gout, mostly reporting promising outcomes on the numbers or percentages of patients who responded well to anakinra within the first days of treatment.[15–25,40–43] However, the absence of a control group in these studies hampers the interpretation of such results, as the observed improved clinical status of patients might merely reflect the self-limiting natural course of acute gout.[44] In our present study, anakinra was compared with treatment in accordance with current gout management guidelines, using several anti-inflammatory agents with previously established effectiveness in treating gout flares.[5,45] The results showed that the efficacy of anakinra in treating gout flares was consistently numerically superior to standard of care treatment across the primary and secondary study outcomes. However, the direct comparison of anakinra with standard of care does not by itself allow for conclusions about the effectiveness of either treatment in gout, as no placebo arm was included. By relating the results to a NI margin that was estimated using the imputed placebo method, our results indirectly support the efficacy of anakinra in gout. However, this conclusion is based on the assumption that the relative effectiveness of standard of care treatment compared with placebo would have been the same as the relative effectiveness of NSAID compared with placebo that was observed in the study used for estimating the NI margin.[32,46,47]

Data from our study builds on previous clinical trials that have reported varying efficacies of IL-1 inhibitors in gout patients. Terkeltaub et al.[32] reported on rilonacept, in which treatment with rilonacept plus NSAID did not significantly improve pain levels compared with NSAID monotherapy, and rilonacept monotherapy was shown to be inferior to NSAID monotherapy over a 72-h follow-up period. This difference in efficacy compared with our study might be attributed to differences in study designs, but also to pharmacokinetic differences between the IL-1 inhibiting drugs. The authors reflect that rilonacept reaches its maximum plasma concentration after 48–72 h, which could potentially have led to insufficient drug concentrations during the period of the primary outcome assessment. For anakinra, maximum plasma concentrations are reached within 3–7 h . This rapid increase in drug plasma concentrations may explain why the results in our study seem more promising 72 h after baseline, than those seen with rilonacept. Canakinumab is currently the only IL-1 inhibitor for which effectiveness during an acute gout exacerbation has been demonstrated in a randomized study.[36,48] Schlesinger et al.[49] reported that a single subcutaneous injection of canakinumab 150 mg was superior to a single intramuscular injection of triamcinolone acetonide 40 mg, in relieving pain after 72 h. The mean VAS (0–100 mm) pain score at that moment was 25 mm for the canakinumab arm. Although it is difficult to compare these outcomes with our results, because of differences in study design and populations, results from our study reveal similar pain scores after 72 h in the anakinra group on a 0–10 NRS (i.e. score = 2.4).

Considering the high costs of canakinumab treatment, anakinra therefore seems to be a cost-effective alternative for gout patients seen in daily practice who are difficult to treat with conventional therapies, in case they meet the local reimbursement criteria. Importantly, anakinra could possibly allow a larger proportion of the difficult to treat gout population to be treated with an IL-1 inhibitor, including patients having comorbidities as diabetes mellitus, renal disorders or cardiovascular disease. In this respect it should be noted that patients with severe renal impairment were excluded from participation in our study. However, favourable outcomes have previously been described in a retrospective case-series of 31 patients with either a renal transplantation or stage 4 or stage 5 chronic kidney disease, that signs and symptoms of gout flares subsided after admission of treatment with anakinra.[50] Moreover, a current ongoing feasibility study, designed as a double-blind, double-dummy, randomized controlled trial, will contribute to developing a definite clinical trial wherein the efficacy and tolerability of anakinra to corticosteroids in patients with chronic kidney disease will be compared.[29]

The multicentre, randomized, placebo-controlled, double-blinded nature of our study, as well as the inclusion of only patients with MSU crystal-proven gout, the diagnostic gold-standard, are strengths of our study. However, the present study was not without limitations. First, the total number of patients included was lower than initially calculated in the power analyses for the primary efficacy analyses. However, in contrast to the a priori power calculation that assumed no difference between the treatment arms in ΔPain, we found a difference in favour of anakinra in both the PP and ITT analyses, with on average 0.155 points on a five-point rating scale. Therefore, and having the other assumptions remain constant, a smaller sample size would have sufficed to demonstrate NI of anakinra compared with imputed placebo. Within the limitations of a small clinical trial, relatively few data on the safety of anakinra in gout was obtained. However, the long-term treatment experience of anakinra in rheumatoid arthritis already provides a sound safety profile. Nevertheless, additional short-term safety data for anakinra in gout is desired. Finally, the study was carried out in a hospital-based setting, possibly making our results less generalizable to a primary care setting, in which other types of acute gout patients may be treated.

In conclusion, in our study anakinra was shown to be non-inferior to registered treatment as usual for the treatment of acute gout flares. Our results suggest that anakinra is an effective treatment alternative for the treatment of acute gout flares.

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