Latest evidence on gout management: what the clinician needs to know

Abstract

Until recently, the last drug approved for the treatment of gout by the United States Food and Drug Administration was allopurinol in 1966. Since 2008, two new drugs for the treatment of gout, febuxostat and pegloticase, have been approved in the US. Febuxostat has been approved in the EU and pegloticase approval is anticipated. A new single-ingredient colchicine preparation is available in the US, and the treatment recommendations for the use of colchicine in acute gout have evolved, now favoring a low-dose regimen. Several other exciting drugs are in development. Herein, we review some of basic principles in the diagnosis and staging of gout. We then examine current treatment principles, with particular attention to febuxostat and pegloticase, offering suggestions as to where they might fit into a modern therapeutic algorithm for gout treatment. We then present available data on several exciting new agents in development, including interleukin-1 inhibitors, and relate them to advances in our understanding of gout pathogenesis. We conclude with some important nonpharmacologic principles for optimal management of this ancient and eminently treatable disease. Dedicated gout research, going on quietly in the background of other breathtaking advances in rheumatology, is now paying off. This comes at a time when the number of patients affected by gout continues to rise, mainly due to an epidemic of obesity. An effort to improve lifestyle choices as a society and better management of the disease by clinicians should have a positive impact on gout incidence and outcome in our lifetimes.

Keywords: febuxostat; gout; hyperuricemia; inflammasome; interleukin-1; pegloticase; uric acid.

Figure 1.

The clinical diagnosis of gout. (A) Podagra, or acute monoarticular inflammatory arthritis of the first metatarsophalangeal (MTP) joint. Reproduced from Jelley, MJ; Wortmann, R.: Practical steps in the diagnosis and management of gout. BioDrugs 2000 14: 2: 99-107, with permission from Springer International Publishing AG (© 2000, all rights reserved). B) A gout patient with numerous subcutaneous tophi on the palmar aspect of the fingers. (C) Monosodium urate crystals viewed under the polarizing microscope. (D) X-ray demonstrating typical gouty erosions at the first MTP joint, with well-demarcated erosions, away from the joint line, some with overhanging edges, and adjacent hazy tophaceous material. (Courtesy of Dr Douglas Goodwin, Dartmouth Hitchcock Medical Center, Lebanon, NH.) (E) Ultrasound images showing the double contour sign of gout in a first MTP joint (arrow) with a heterogeneous, hyperechoic tophus (beneath asterisk) within a hypoechoic effusion (dark area). (F) A cluster of tophi (arrow) in the olecranon bursa of a gout patient. (Images in E and F Courtesy of Dr John Yost, Dartmouth Hitchcock Clinic, Manchester, NH.)

Figure 2.

Initiation of the inflammatory response to monosodium urate crystals (MSU) by the innate immune system. MSU are recognized as danger-associated molecular patterns (DAMPs) by innate immune receptors, including Toll-like receptors (TLRs), on monocytes. A dual signaling process begins. One pathway, involving the adapter protein used by TLRs, MyD88 (myeloid differentiation primary response gene 88), leads to translocation of activated NFκ-β (nuclear factor κ-β) to the nucleus where it activates transcription of pro-IL-1β. Simultaneously, phagocytosis of MSU and processing by the phagosome and lysosome results in assembly and activation of the NLRP3 inflammasome in a cathepsin-B and K+ flux dependent fashion. As a result, pro-caspase-1 is cleaved to active caspase-1, which in turn cleaves the nascent pro-IL-1β to its active form, which is secreted into the cellular milieu. (IL-18 is released in a similar fashion.) Binding of IL-1β to its receptors on local macrophages and synoviocytes activates a signaling pathway that includes MyD88 and IRAK-4 (ILR1-receptor associated kinase), resulting in NFκ-β activation and translocation to the nucleus. There, NFκ-β mediates transcription of multiple inflammatory cytokines and chemokines, thus greatly amplifying the original danger signal. Other cells are recruited to the area, including neutrophils, and a full blown attack of gout ensues. ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase recruitment domain.