Treating to target: a strategy to cure gout

Rheumatology 2009;48:ii9–ii14 doi:10.1093/rheumatology/kep087 Treating to target: a strategy to cure gout Fernando Perez-Ruiz1 Acute gout attacks and the long-term complications of gout are associated with the deposition of monosodium urate (MSU) monohydrate crystals in the joints and soft tissues, causing acute and chronic inflammation. The aim of long-term treatment is to reduce the serum urate (sUA) level to 6 mg/dl (4360
mol/l), below the saturation point of MSU, so that new crystals cannot form and existing crystals are dissolved. Serial joint aspiration studies confirmed the disappearance of crystals with effective urate-lowering therapy. There is good evidence that achieving sUA <6 mg/dl (360
mol/l) results in freedom from acute gout attacks, and shrinkage and eventual disappearance of tophi. Gout patients must be informed about their diagnosis and educated about gout management including the importance of compliance with long-term treatment. Patients starting urate-lowering therapy need to understand the importance of prophylactic therapy with colchicine or NSAIDs to reduce the risk of ‘mobilization flares’ in the first few months. In the long term, reduction in the sUA below the target level will result in gout being effectively cured. KEY WORDS: Gout, Monosodium urate, Urate-lowering, Treatment target, Arthrocentesis, Crystals, Tophi, Cure. asymptomatic (intercritical) periods [5]. However, no correlation has been observed between the size, shape and numbers of crystals in the SF and the severity of inflammation—some patients with severe acute gout may have only a few crystals. Hence, other factors must affect the severity of the inflammatory response in gout [6]. Formation of crystals may initially start in the joint cartilage in an orderly way, suggesting epitaxial nucleation and growth [7]. Introduction As already discussed in the first paper in this supplement [1], gout is one of the most common inflammatory arthritic diseases. It is a true crystal deposition disease and both acute episodes of inflammation (the so-called gout flares or attacks) and the long-term sequelae due to chronic inflammation of gout are induced by monosodium urate (MSU) monohydrate crystals formed in the tissues. If there are no MSU crystals present, gout cannot occur. This means that if the tissue environment urate concentration is reduced sufficiently, existing crystals are dissolved and new crystals can no longer form, which essentially cures gout. This potential for cure with adequate long-term treatment makes gout a rewarding condition for clinicians to manage. This paper will discuss the role of MSU crystals in the pathogenesis of acute and chronic gout and the importance of targeting a low serum urate (sUA) level during the treatment of chronic gout, in order to achieve the clinical benefits of freedom from acute gout attacks, resolution of tophi and prevention of structural damage to joints and tissues. Practical aspects of the long-term management of gout patients are also reviewed. Acute gout flares Deposition of crystals may continue for months or years without causing symptoms [8], until shedding of crystals into the SF triggers the first episode of acute gout. Innate immunity (through toll-like receptors) may be involved in MSU-induced macrophage activation [9]. MSU crystals are intensely inflammatory and recent research has provided new insights into the inflammatory process. MSU crystals are phagocytosed by monocytes and macrophages, activating the NALP3 inflammasome and triggering the release of IL-1 and other cytokines. This leads to infiltration of neutrophils and the symptoms of an acute flare [10–12]. Acute gout attacks typically resolve spontaneously and differentiated macrophages, through secretion of TGF-, may exert a protective role to the joint [13]. Hyperuricaemia as the underlying cause It is clear that long-standing hyperuricaemia is the principal factor in the occurrence of gout, based not only on the epidemiological evidence, but also on physicochemical principles. Uric acid is a weak acid that is present in plasma as MSU. Numerous studies have shown that the solubility of MSU is strongly temperature dependent and that the saturation threshold at 378C is
6.8 mg/dl (408
mol/l) [2]. However, only a small proportion of patients with hyperuricaemia develop gout and hence other factors must determine whether crystal formation occurs. Several groups have shown that SF from gout patients enhances the formation of MSU crystals [3, 4]. In one study, the addition of SF from gout patients to super-saturated solutions of sodium urate under physiological conditions greatly enhanced crystal formation, whereas SF from OA patients had a modest effect and fluid from RA patients had little effect [3]. Crystals are present, and may be retrieved by aspirating the SF of gout patients during gout flares, but also during 1 Chronic gout Long-standing persistence of MSU crystals may also cause chronic neutrophilic inflammation [14], osteoclast activation [15] and chronic granulomatous infiltration of the synovium (Fig. 1). Micro-aggregates of MSU crystals occur in all patients with gout, but in some, macroscopic aggregates occur, manifested as tophus formation. Tophi are usually considered to be a late manifestation of gout. However, intra-articular tophi have been reported before an acute gout attack has occurred [16]. Recent imaging studies have highlighted the presence of asymptomatic tophi not apparent on physical examination [17]. In a recent ultrasound study of patients with asymptomatic hyperuricaemia, tophi were detected in the tendons, synovial membrane or soft tissues in 12 of the 35 examined (34%). Power Doppler showed evidence of inflammation in two-thirds of these [8]. As well as diagnosing tophi, ultrasound can also be useful to detect the deposition of urate crystals on the articular cartilage [18]. MRI and CT are also valuable for detecting asymptomatic tophi [17]. Rheumatology Division, Hospital de Cruces, Vizcaya, Spain. Submitted 18 December 2008; revised version accepted 18 March 2009. Correspondence to: Fernando Perez-Ruiz, Rheumatology Division, Hospital de Cruces, 48600 Baracaldo, Vizcaya, Spain. E-mail: ii9 ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: ii10 Fernando Perez-Ruiz FIG. 1. Synovial deposition of urate crystals and chronic inflammation: (a) synovial hypertrophy in an arthroscopic view; (b) MRI showing thickening of the synovial membrane mimicking villonodular pigmented synovitis; (c) ‘foreign body’ granulomatous synovitis in a patient with chronic gout. ßF. Perez-Ruiz 2008, with permission for this publication. FIG. 2. Reduction in sUA to <5 mg/dl (<300
mol/l) in the first 3 months of urate-lowering therapy (a) and corresponding reduction in crystals in the SF (b) [22]. (Reproduced from Ann Rheum Dis with (...truncated)