Gout: A Prevalent Disease and an Unmet Medical Need
Gout afflicts up to 10 million people in the U.S. alone (1). Worldwide, the incidence of gout has doubled in the past 10 years and is expected to re-double in the next decade (2). Despite the prevalence of the disorder, its treatment resembles a throwback to the 1960s when Gertrude Elion and George Hitchings (future Nobel Prize winners) first synthesized allopurinol (3) in the Burroughs Wellcome laboratories as a drug that might improve clinical activity of the anti-leukemia drug, 6-mercaptopurine. More than 50 years later, allopurinol remains the established first-line, single-agent treatment for gout. Historical significance notwithstanding, fewer than half of patients treated with allopurinol actually achieve a clinical “target level” that is believed to be beneficial, and the drug has numerous side-effects, in particular serious allergic reactions.
Causes and Complications of Gout
Gout is associated with a sustained elevation of uric acid in blood. Found in all mammals, uric acid is produced by the breakdown of natural substances found in normal tissues and foods. As it accumulates, uric acid is normally filtered by the kidney and excreted in urine, although the human kidney can reabsorb a large quantity of the filtered amount back into the bloodstream. Thus, there exists a natural balance between the production of uric acid and its excretion. In patients with gout, this balance is altered, such that uric acid increases to abnormally high levels in blood – a condition known as “hyperuricemia”.
As a disease, gout occurs when this excessive uric acid begins to fall out of solution and form crystals. A classic gout attack is characterized by the onset of progressively more severe discomfort in one or more joints, leading to an excruciatingly painful attack of arthritis (or “flare”). These attacks are caused by formation of uric acid crystals in joints and other tissues. Thus, in addition to immediately trying to relieve pain and reduce inflammation, gout treatment involves longer-term measures to reduce the risk of recurrent flares (4).
Gout tends to be a chronic, lifelong condition. Without treatment of hyperuricemia, flares related to crystallized uric acid can recur and lead to a destructive and deforming arthritis. These crystals can deposit in the kidney, leading to renal failure as well as painful stones comprised of crystalline uric acid. Accelerated cardiovascular disease has also been linked to sustained hyperuricemia.
Treatment of Gout: General Concepts
Patient treatment focuses on two major areas: relief of pain and acute inflammation (“acute gout”) and prevention of recurrent attacks and complications (“chronic gout”). Acute gout is managed with pain-killers and standard anti-inflammatory drugs (such as ibuprofen, colchicine, etc.). Several new anti-inflammatory drugs are also being investigated. Management of chronic gout focuses on reducing uric acid in blood, with a goal of reducing the overall body content of uric acid, so that the risks of future attacks and complications are minimized. In general, drugs for chronic gout work by one of two general mechanisms: either reducing uric acid production or increasing its excretion(5).
Recent advances in molecular biology and genetics, nucleotide and proteomic profiling, and metabolomics (understanding the complexity of metabolic interactions and pathways) (6) have led to rapid advances in our understanding of heretofore highly complex disorders. The Relburn Gout Program is focused on the discovery and development of novel drugs that alter both sides of the urate production/excretion equilibrium.
1. Dubchak N, Falasca GF.: New and improved strategies for the treatment of gout. Int J Nephrol Cardiovasc Dis. 3:145-66, 2010. doi: 10.2147/IJNRD.S6048.
2. Zhu Y, Pandya BJ, Choi HK: Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arth Rheum. 63:3136-41, 2011. doi: 10.1002/art.30520. http://onlinelibrary.wiley.com/doi/10.1002/art.30520/abstract;jsessionid=8A2DBBA138AF7D05EB73186EC2165271.f01t03
3. Rundles RW, Wyngarden JB, Hitchings GH, et al.: Effects of a xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia, and gout. Trans Am Assoc Physicians 76:126-40, 1963.
4. VanItallie TB: Gout: epitome of painful arthritis. Metabolism Clinical and Experimental 59 (Suppl 1);S32–S36, 2010. http://www.metabolismjournal.com/article/S0026-0495(10)00229-5/abstract
5. Khanna D, FitzGerald JD, Khanna PP, et al.: 2012 American College of Rheumatology Guidelines for Management of Gout Part I: Systematic Non-pharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 64:1431–46, 2012. doi:10.1002/acr.21772.
6. Suhre K, Shin SY, Petersen AK, et al.: Human metabolic individuality in biomedical and pharmaceutical research. Nature 477:54-60, 2011. doi: 10.1038/nature10354.