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What is the evidence to support the use of canakinumab or anakinra to treat refractory arthritic gout?

by Melissa Moriarty, PharmD Candidate, University of Illinois at Chicago; Bill Budris, BS Pharm, Drug Information Pharmacist, Northwestern Memorial Hospital

Question

What is the evidence to support the use of canakinumab or anakinra to treat refractory arthritic gout?

Introduction

Prior to calling the drug information group, the physician attempted to obtain prior authorization for canakinumab for a patient with refractory arthritic gout. However, the request was denied. She requested the available evidence for the off-label use of canakinumab or anakinra to make a case and obtain approval. This drug information consultation will review the current evidence on the off-label use of canakinumab and anakinra for arthritic gout.

Methodology

On January 4, 2016, a systematic search was performed beginning with the tertiary database UpToDate, the Food and Drug Administration (FDA)-approved labeling, Health Canada documents, and the European Medicines Agency (EMA) materials for Ilaris® (canakinumab) and Kineret® (anakinra). The tertiary database was searched with the terms “canakinumab,” “anakinra,” and “gout.” PubMed was searched with the terms ”gout,” “canakinumab,” “anakinra,” “canakinumab AND gout,” and “anakinra AND gout.” ClinicalTrials.Gov and a Google Power Search were performed with the same terms. PubMed and Google were also searched for guidelines by searching “gout guidelines” and “arthritis guidelines.”

Results

According to the Centers for Disease Control and Prevention, acute gout is characterized by sudden flare-ups of a hot, painful and swollen joint.¹ If a patient experiences recurrent flare-ups, a chronic form, known as gouty arthritis, can develop. However, the terms “acute gout” and “gouty arthritis” are often used interchangeably.

Neither canakinumab (Ilaris®) nor anakinra (Kineret®) are approved by the FDA or Health Canada for the treatment of gout or gouty arthritis.^2,3,4,5 However, the EMA approved canakinumab at a dose of 150 mg subcutaneously for the management of patients with gouty arthritis in whom other medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are not tolerated or were ineffective.⁶

The 2012 American College of Rheumatology (ACR) Guidelines for the Management of Gout indicate that an interleukin-1 (IL-1) inhibitor such as anakinra 100 mg subcutaneously daily for 3 consecutive days or canakinumab 150 mg subcutaneously is an option for severe acute gouty arthritis attacks that are refractory to other medications.⁷ However, it is noted that the use of IL-1 inhibitors for acute gout is uncertain due to a lack of randomized controlled trials (RCTs) evaluating anakinra and the unclear risk-benefit ratio for canakinumab.

The use of anakinra for gouty arthritis has been documented in several case reports.^8,9,10 However, there are no RCTs documenting its use, efficacy, or safety for the treatment of gout or gouty arthritis. Additionally, the results of the case reports varied. Although effective in treating flare-ups, relapses were common.

The use of canakinumab for the treatment of gout and gouty arthritis was addressed in two RCTs - the ß-RELIEVED and ß-RELIEVED-II trials.¹¹ In these two trials, canakinumab 150 mg was compared to triamcinolone acetonide 40 mg. The authors concluded that canakinumab was more effective than the comparator in reducing pain (p<0.0001), tenderness and swelling (p≤0.01), and the risk of new flares (p≤0.0001). Notably, there was a higher rate of both adverse events (AEs) (66.2% vs. 52.8%) and serious AEs (8% vs. 3.5%) in the pooled data for the canakinumab groups compared to the triamcinolone groups. Specifically, infectious AEs were 20.4% in the canakinumab groups and 12.2% in the triamcinolone groups. However, significance was not reported.

A retrospective analysis of data from the two trials reported superior efficacy compared to triamcinolone in patients who were intolerant or unresponsive to NSAIDs and colchicine.¹² Specifically, the percentage of patients who responded to therapy was greater in the canakinumab group for 8 of 12 variables (p<0.05), and the canakinumab groups met a greater percentage of response criteria compared to the triamcinolone groups (65% vs. 49%, p<0.001). A 2014 Cochrane Review assessed IL-1 inhibitors for the treatment of acute gout.¹³ The systematic review found 4 studies, 3 of which compared canakinumab to triamcinolone to treat acute gout flares. The authors concluded that there is moderate-quality evidence to suggest canakinumab likely provides better pain and swelling relief compared to triamcinolone in patients experiencing an acute gout flare. However, there may be an increased risk of adverse events, and the cost is significantly higher.

Multiple review articles discuss the role of IL-1 inhibitors, including canakinumab and anakinra, to manage gout, specifically in patients who cannot tolerate or have failed other therapies such as NSAIDs, colchicine, and steroids.^{14,15,16,17,18,19} These reviews described the efficacy of canakinumab for acute gout attacks in patients who are refractory to or have contraindications to other therapies, but some note the toxicity profile, as noted above, may limit its use. Anakinra was noted to have limited data for the indication of gout.

Multiple presentations at the Annual Scientific Meetings of the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) summarized safety and efficacy data for the use of canakinumab and anakinra in patients with gout.^20,21,22 Data presented in 2009 provided evidence that canakinumab could provide faster and stronger pain relief compared to triamcinolone for patients with refractory gout.²⁰

In June 2011, an FDA advisory committee reviewed canakinumab for the indication of gouty arthritis in patients with inadequate response to NSAIDs or colchicine.²³ The majority of committee members believed there was a lack of long-term safety data and minimal data in high risk patients. The committee noted that although the drug had been shown to be effective, additional studies are necessary for high risk patients and patients who are refractory to NSAIDs, colchicine, and corticosteroids.

Conclusion

Canakinumab and anakinra are IL-1 inhibitors that have been investigated for the treatment of acute gout and gouty arthritis in patients who are intolerant or refractory to standard therapy. There are minimal data for the efficacy of anakinra, which is limited to case reports, but more data, including 2 RCTs, support the efficacy of canakinumab. However, the FDA rejected canakinumab’s indication for the treatment of gouty arthritis attacks in 2011. From the available evidence, canakinumab 150 mg subcutaneously is likely effective to treat patients with refractory gouty arthritis. However, the costs, benefits, and risks (including the increased risk of infection) should be weighed prior to starting therapy.

References

Centers for Disease Control and Prevention. Gout (October 2015). http://www.cdc.gov/arthritis/basics/gout.html (accessed 30 Mar 2016).
Ilaris (canakinumab) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2009. Revised 2014 Oct.
Kineret (anakinra) package insert. Stockholm, Sweden: Swedish Orphan Biovitrum AB; 2001. Revised 2013 Oct.
Health Canada. Summary basis of decision: Ilaris (February 2010). http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2010_ilaris_131009-eng.php (accessed 2016 Jan 4).
Health Canada. Details for: Kineret (November 2015). https://hpr-rps.hres.ca/details.php?drugproductid=869&query=anakinra (accessed 2016 Jan 4).
European Medicines Agency. Ilaris: canakinumab (December 2009). http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001109/human_med_000826.jsp&mid=WC0b01ac058001d124 (accessed 2016 Jan 4).
Khanna D, Khanna PP, Fitzgerald JD et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res. 2012;64(10):1447-1461.
So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9:R28.
Chen K, Fields T, Mancuso CA et al. Anakinra’s efficacy is variable in refractory gout: report of ten cases. Semin Arthritis Rheum. 2010;40:210-214.
Singh D, Huston KK. IL-1 inhibition with anakinra in a patient with refractory gout. J Clin Rheumatol. 2009;15(7):366.
Schlesinger N, Alten RE, Bardin T et al. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis. 2012;71:1839-1848.
Hirsch JD, Gnanasakthy A, Lale R et al. Efficacy of canakinumab vs. triamcinolone acetonide according to multiple gouty arthritis-related health outcomes measures. Int J Clin Pract. 2014;68(12):1503-1507.
Sivera F, Wechalekar MD, Andrés M et al. Interleukin-1 inhibitors for acute gout. Cochrane Database Syst Rev. 2014;9:CD009993.
Tran TH, Pham JT, Shafeeq H, et al. Role of interleukin-1 inhibitors in the management of gout. Pharmacotherapy. 2013;33(7):744-753.
Cavagna L, Taylor WJ. The emerging role of biotechnological drugs in the treatment of gout. Biomed Res Int. 2014;2014:264859.
Avram A, Duarte C, Santos MJ et al. Identifying patient candidates for IL-1 Inhibition: lessons from real-world cases. Joint Bone Spine. 2015;82(suppl 1):eS17-eS29.
Khanna PP, Gladue HS, Singh MK et al. Treatment of acute gout: a systematic review. Semin Arthritis Rheum. 2014;44(1):31-38.
Bardin T. Canakinumab for the patient with difficult-to-treat gouty arthritis: review of the clinical evidence. Joint Bone Spine. 2015;82(suppl 1):eS9-eS16.
Perez-Ruiz F, Chinchilla SP, Herrero-Beites AM. Canakinumab for gout: a specific, patient-profiled indication. Expert Rev Clin Immunol. 2014;10(3):339-347.
So A, De Meulemeester M, Shamim T et al. Canakinumab (ACZ885) vs. triamcinolone acetonide for treatment of acute flares and prevention of recurrent flares in gouty arthritis patients refractory to or contraindicated to NSAIDs and/or colchicine. Presented at the ACR/ARHP Annual Scientific Meeting. Philadelphia, PA; 2009 Oct.
Perez-Ruiz F, Herrero-Beites AM, de Miguel M et al. Low-dose anakinra is effective for the prophylaxis of acute episodes of inflammation in severe tophaceous gout. Abstract presentation at the ACR/ARHP Annual Scientific Meeting. San Diego, CA; 2013 Sept.
Schlesinger N, Bardin T, Bloch M et al. A 3-Year follow-up study of canakinumab in frequently flaring gouty arthritis patients, contraindicated, intolerant, or unresponsive to nonsteroidal anti-inflammatory drugs and/or colchicine. Presented at the ACR/ARHP Annual Scientific Meeting. San Francisco, CA; 2015 Sept.
Food and Drug Administration. Summary minutes of the arthritis advisory committee meeting (July 2011). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM267388.pdf (accessed 2016 Jan 4).