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Interleukin-1 (IL-1) inhibitors are under extensive review for the treatment of gout. While this form of therapy holds great potential, data is currently limited and more studies are underway to investigate their efficacy.

Gout is characterized as an inflammatory disease of the joints, accounting for 5% of all forms of arthritis. Common symptoms include joint pain and swelling (especially in the big toe), inability to move the joints, and chronic pain. Gout is caused by an increase in uric acid levels in the blood. Crystallized uric acid can deposit in the joints, ultimately resulting in inflammation, pain, and swelling. Over time, deposits may accumulate in the joints, resulting in permanent deformity and an inability to move the joint. Attacks of gout can last anywhere from 3-10 days, and may become more frequent over time, lasting for longer periods. Moreover, gout can increasingly affect more joints in the body as time progresses.

Current therapies aim to reduce or eliminate pain associated with gout flares and prevent future attacks. Conventional therapy for gout flares are non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and colchicine. Additionally, some lifestyle alterations are encouraged to prevent gout flares. There are patients who are unable to take these drugs due to intolerance or contraindications. In addition, a subset of patients experience breakthrough gout flares during long-term therapy. These patients therefore require more treatment options.

An important mediator of the inflammatory response triggered by crystallized uric acid deposits in the joints is IL-1β. For this reason, IL-1β activity has become a key target for the treatment of gout flares. The IL-1 inhibitors currently under extensive clinical investigation for gout include: canakinumab, anakinra, and rilonacept. While anakinra and rilonacept block both IL-1β and IL-1α, canakinumab specifically blocks only IL-1β.

Canakinumab (Ilaris)

Canakinumab is a human monoclonal anti-human IL-1β antibody, which binds to and blocks the interaction of IL-1β with its receptor, thereby preventing its activity. Canakinumab is currently used for the treatment of the Cryoprin-Associated Syndromes and Systemic Juvenile Idiopathic Arthritis, and is now in clinical trials for the treatment of Gout. Preliminary data show an improvement in symptoms with canakinumab treatment; however, some serious adverse events have been reported. This has prompted the FDA to request further testing and long-term studies assessing safety and efficacy of canakinumab for gout. One advantage of canakinumab is the low dose required to see an improvement in symptoms, making it a potential alternative for those patients who are unresponsive to or unable to tolerate, conventional therapy. Follow up studies by Novartis are underway worldwide to assess the long-term safety and efficacy of canakinumab as well as its ability to relieve gout flares and prevent recurrence in patients with hard to treat gout.

Anakinra (Kineret)

Anakinra, a human IL-1 receptor antagonist, inhibits the action of both IL-1β and IL-1α. It is currently used for the treatment of rheumatoid arthritis. The only data available for anakinra use for gout comes from a few case studies and a pilot study consisting of ten patients. The patient population treated with anakinra has consisted of patients who are unable to tolerate, or have conditions that contraindicate, current therapies for gout. Also included have been patients whose conditions were not improved following treatment with current therapies. Collectively, the results show a reduction in pain and inflammation with anakinra treatment, with no adverse events reported. These results are promising and suggest a need for clinical trials to assess the role of anakinra as a potential therapy for gout. There are currently no clinical trials registered for anakinra in the treatment of gout.

Rilonacept

Rilonacept is a fusion protein that inhibits the binding of IL-1α and IL-1β to the IL-1 receptor, thereby preventing its activation. Rilonacept has previously been used for the treatment of inflammatory Cryopyrin-associated autoinflammatory syndrome and is now also under review as a potential therapy for gout. In three studies, rilonacept showed a significant reduction in gout flares; however, the FDA requires further data, specifically long-term safety and efficacy studies, before rilonacept will be approved as a treatment for gout. Five trials were recently completed by Regeneron Pharmaceuticals in study centers worldwide to assess the effectiveness of rilonacept in the treatment of gout.

Albeit in preliminary stages, IL-1 inhibitors are a promising new mode of therapy for patients suffering from gout. Adding this drug class to the repertoire of gout therapies will allow more options for patients with difficult to treat gout that are unable to tolerate existing therapies.

 

 

Clinicaltrials.gov “Safety & Efficacy of Canakinumab (ACZ885) in Patients With Frequent Flares for Whom Nonsterodial Anti-Inflammatory Drug (NSAIDs) and/ or Colchicine Are Contraindicated, Not Tolerated or Ineffective” Available from: http://clinicaltrials.gov/ct2/show/NCT01362608?term=Safety+%26+Efficacy+of+Canakinumab+%28ACZ885%29+in+Patients+With+Frequent+Flares+for+Whom+Nonsterodial+Anti-Inflammatory+Drug+%28NSAIDs% Last Accessed: January 15, 2014.

Clinicaltrials.gov “Long-Term Safety and Tolerability of Canakinumab Prefilled Syringes in Frequently Flaring Acute Gouty Arthritis Patients” Available from: http://clinicaltrials.gov/ct2/show/NCT01431638?term=Long-Term+Safety+and+Tolerability+of+Canakinumab+Prefilled+Syringes+in+Frequently+Flaring+Acute+Gouty+Arthritis+Patients&rank=1 Last Accessed: January 15, 2014.

Clinicaltrials.gov “Study of the Safety and Effectiveness of Rilonacept for the Prevention of Gout Flares” Available from: http://clinicaltrials.gov/ct2/show/NCT00610363?term=Study+of+the+Safety+and+Effectiveness+of+Rilonacept+for+the+Prevention+of+Gout+Flares&rank=1 Last Accessed: January 15, 2014.

Clinicaltrials.gov “Review of Safety Using Rilonacept in Preventing Gout Exacerbations (RE-SURGE)” Available from: http://clinicaltrials.gov/ct2/show/NCT00856206?term=Review+of+Safety+Using+Rilonacept+in+Preventing+Gout+Exacerbations+%28RE-SURGE%29&rank=1 Last Accessed: January 15, 2014.

Clinicaltrials.gov “PREventative Study Against URate-Lowering Drug-Induced Gout Exacerbations (PRE-SURGE 2)” Available from: http://clinicaltrials.gov/ct2/show/NCT00958438?term=PREventative+Study+Against+URate-lowering+Drug-induced+Gout+Exacerbations+1&rank=2 Last Accessed: January 15, 2014.

Clinicaltrials.gov “PREventative Study Against URate-lowering Drug-induced Gout Exacerbations 1” Available from: http://clinicaltrials.gov/ct2/show/NCT00829829?term=PREventative+Study+Against+URate-lowering+Drug-induced+Gout+Exacerbations+1&rank=1 Last Accessed: January 15, 2014.

Clinicaltrials.gov “Study Utilizing Rilonacept in Gout Exacerbations” Available from:  http://clinicaltrials.gov/ct2/show/NCT00855920?term=nct00855920&rank=1 Last Accessed: January 15, 2014.

Tran, T.H., Pham J.T., Shafeeq, H., Manigault, K.R., Arya, V. “Role of Interleukin-1 Inhibitors in the Management of Gout” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 33 (7): 744–753, July 2013.

Schlesinger NAlten REBardin TSchumacher HRBloch MGimona AKrammer GMurphy VRichard DSo AK. “Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomized, multicentre, active-controlled, double-blind trials and their extensions.” Ann Rheum Dis. 71(11):183948, November 2012.

So, A., De Meulemeester, M., Pikhlak, A., Yücel, A.E., Richard, D., Murphy, V., Arulmani, U., Sallstig, P., Schlesinger, N. “Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study.” Arthritis & Rheumatism.

62 (10):  3064–3076, October 2010.

 

 

Written by Deborah Tallarigo, PhD

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