martes, 28 de diciembre de 2010

Hyperuricaemia and gout: state of the art and future perspectives, REVIEW 2010

Nicola Dalbeth 1, Alexander So 21Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand2Service of Rheumatology, Department of Musculoskeletal Medicine, University Hospital of Lausanne, Lausanne, Switzerland

Correspondence toProfessor Alexander So, Service de Rhumatologie, CHUV, 1011 Lausanne, Switzerland; alexanderkai-lik.so@chuv.ch

Major advances in understanding the pathogenesis and treatment of gout have been made in the past decade. Key highlights include identification of the genetic and environmental risk factors for gout, recognition that gout is an important risk factor for cardiovascular disease (CVD), elucidation of the pathways regulating the acute gout attack and the development of novel therapeutic agents to treat both the acute and chronic phases of the disease.
Here, we discuss these advances and future implications for research and clinical practice.

Novel therapeutic agents
One of the major challenges in the treatment of gout and hyperuricaemia is the appropriate use of urate-lowering drugs in conjunction with effective patient education (in particular lifestyle and dietary recommendations).
The European League Against Rheumatism guidelines for the management of this condition recommend that ULT should target a serum urate level of 360 mmol/l (6 mg/l), a level that is achieved in less than 50% of patients taking standard doses of allopurinol. A further concern is how to manage the patient who has an acute attack of gout, and has comorbid conditions such as renal and cardiac insufficiency. Recent advances in treatment of hyperuricaemia and acute gout give some hope for the future.

For over 40 years, the mainstay of treatment of hyperuricaemia has been allopurinol. Although moderately effective, it is not universally tolerated and a pharmacological alternative is potentially of great clinical importance. Recent trials have confirmed that febuxostat, a non-purine selective inhibitor of xanthine oxidase, is effective in lowering hyperuricaemia. In these clinical trials, 80 mg and 120 mg a day of febuxostat reduced urate levels more effectively that a fixed dose of allopurinol (300 mg a day). The allopurinol dose in that trial was not adjusted to achieve target urate levels, a point that has been emphasised by other experts. Patients with mild renal impairment responded well and demonstrated no signs of increased toxicity. The safety profile was judged to be comparable to that of allopurinol, although it was noted that some patients on febuxostat developed liver function abnormalities. These results are encouraging and suggest that febuxostat could be an alternative hypouricaemic drug in patients who cannot tolerate or are allergic to allopurinol.

Another approach to reduce a patient's urate levels is by the administration of recombinant uricase, an enzyme that breaks uric acid down to allantoin. The enzyme, normally absent in humans and high primates, reduces serum urate levels rapidly and dramatically after intravenous administration. However, because of its short half-life, administration needs to be repeated to have a sustained effect. As it is a ‘foreign’ protein, its administration can also provoke allergic side-effects, particularly on repeated administration. In order to overcome some of these drawbacks, a pegylated form of uricase has been developed (pegloticase) that has a longer half-life (10–12 days instead of 10 h). Its efficacy in lowering urate levels and reducing tophus size was demonstrated in clinical studies.

Rapid lowering of the urate concentration is associated with gout flares. In the febuxostat study, over 60% of patients had flares of gout during the treatment period of 1 year (frequencies were similar between febuxostat and allopurinol), and in the pegloticase study, 88% of patients. In the febuxostat study, patients were given either naproxen or colchicine as prophylaxis for flare during the first 8 weeks, and the flare rate was approximately 10%. Indeed, the duration of prophylaxis when initiating ULT has not been ascertained in controlled trials, but is likely to be significantly longer than 8 weeks. As flares was one of the main reasons that patients discontinued the study, it is clear that effective prophylaxis for acute gout flare is essential to obtain the maximum benefit from the new urate-lowering agents.

The discovery of the inflammasome has provided impetus to investigate the efficacy of IL-1 inhibition in acute gout. Three inhibitors have been studied to date, canakinumab (anti-IL-1 monoclonal antibody), kineret (IL-1Ra) and rilonacept (IL-1 Trap). Both kineret and rilonacept inhibit IL-1 signalling by binding to bioactive IL-1 (both α and β forms), thereby inhibiting its binding to the IL-1 receptor. Canakinumab is highly specific for IL-1β, thereby blocking its interaction with the IL-1 receptor. In terms of clinical studies in humans, no controlled studies have been performed with kineret. In a small case series of 10 patients with acute gout and who presented either intolerance or contraindications to non-steroidal anti-inflammatory drugs and colchicine, the investigators observed a rapid clinical response in all 10 patients. No adverse effects were observed. Since then, other case reports have confirmed this favourable effect. Rilonacept was compared with placebo in a small study of 10 patients with chronic gout, and again showed significant benefit in terms of pain relief and reduction of signs of inflammation. Finally, the results of a controlled study comparing different doses of canakinumab with triamcinalone in the treatment of acute gout reported significantly better relief of pain with canakinumab have been reported Interestingly, in patients treated with canakinumab, a striking reduction of gout flares was seen, superior to that seen with triamcinalone. These studies indicate that IL-1 inhibition is likely to be effective in acute gout, although we await the results of controlled trials to be able to assess the overall effects of this mode of treatment, and to decide which patients would most benefit from targeted therapy.

Fuente: Ann Rheum Dis 2010;69:1738-1743 doi:10.1136/ard.2010.136218
http://www.epocrates.com/dacc/1011/goutBMJ1011.pdf

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