The current widely used clinical staging system for hyperuricaemia and gout describes the symptomatology of gout, but does not capture key aspects of the pathological basis of the disease. We propose a new clinical staging system. Stage A: hyperuricaemia, but without evidence of monosodium urate (MSU) crystal deposition or symptoms of gout. Stage B: MSU crystal deposition by microscopy or advanced imaging, but without signs or symptoms of gout. Stage C: MSU crystal deposition with prior or current symptoms of acute gout flares. Stage D: advanced gout requiring specialist interventions. This proposed new staging system provides a clear focus on gout as a chronic disease of MSU crystal deposition, and provides a rational framework to test the role of screening and treatment of asymptomatic disease.
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The central pathogenetic cause of gout is monosodium urate (MSU) crystal deposition.1 Clinical features of gout occur as a result of the host response to MSU crystals deposited in joint structures, subcutaneous tissues and other sites.2 These clinical manifestations include recurrent acute flares of severe inflammatory arthritis and tendinobursitis, deposition of tophi, chronic gouty arthritis and destructive joint disease. The other well-defined clinical manifestation of chronic uric acid deposition is uric acid kidney stones. Although atherosclerotic disease, hypertension and chronic kidney disease are associated with elevated serum urate concentrations, the direct causal relationship between urate and these disorders is currently unproven.3 ,4
In prospective observational studies, elevated serum urate concentration (hyperuricaemia) is the central risk factor for development of incident gout.5–7 Development of gout is typically observed in patients with serum urate concentrations above the level at which MSU crystals form at physiological pH and temperature (6.8 mg/dL, 0.41 mmol/L).8 Additionally, the risk of developing gout increases with rising serum urate concentrations. However, even in those asymptomatic individuals with very high serum urate concentrations (≥9 mg/dL, 0.54 mmol/L), only 22% will develop symptomatic gout over a 5-year period.5 Thus, hyperuricaemia is required, but is not sufficient for the development of symptomatic gout.
As recently described by Bardin and Richette,9 several additional phases or checkpoints are required for development of gout in people with hyperuricaemia. The first of these checkpoints is formation of MSU crystals. A number of factors may contribute to the formation and growth of MSU crystals. These factors include pH, temperature, local joint factors that act as a nidus for crystal formation, and chemical factors that promote or inhibit crystal growth.8 ,10 The clinical gold standard for detection of MSU crystals is by polarising light microscopy. Recently, ultrasonography and dual-energy CT (DECT) have been shown to have high specificity for MSU crystals, and have the potential to allow non-invasive detection of these crystals. On ultrasonography, appearances of gout are the double contour sign and/or tophi,11 and DECT has the ability to detect the chemical composition of urate.12 In the last 5 years, a number of ultrasonography and DECT studies have demonstrated that the advanced imaging appearances of gout are present in people with asymptomatic hyperuricaemia (table 1). These studies demonstrate that in some hyperuricaemic individuals, deposition of MSU crystals can occur without symptomatic disease.13–17
The next key checkpoint in the development of gout is the host response to MSU crystals deposited in the joints and other tissues. In most patients, this presents as the gout flare; an episode of severe, acute inflammatory arthritis or tendinobursitis. This flare is typically self-resolving over 7–10 days. The molecular and cellular responses in the acute gout flare are well characterised and stereotyped, with the central initiation role of NLRP3 inflammasome activation and release of mature IL-1β by resident macrophages, with an amplification phase characterised by neutrophil chemotaxis and release of additional proinflammatory mediators.18 ,19 After presentation of the first gout flare, further flares frequently occur,20 and in the presence of untreated hyperuricaemia, these flares become more frequent, prolonged and polyarticular over time. In addition to the recurrent acute inflammatory flares, chronic gouty arthritis and gouty tophi may also develop, with risk of bone and joint damage.21 By contrast with the acute gout flares, gouty tophi are frequently painless without clinically apparent inflammation. Although usually a late manifestation of disease,22 tophi can occur early in the course of clinically apparent disease, and occasionally represent the first presentation of disease.23
Staging ‘defines discrete points in the course of individual diseases that are clinically detectable, reflect severity in terms of risk of death or residual impairment, and possess clinical significance for prognosis and choice of therapeutic modality’.24 Disease staging is important, as this can guide management with respect to screening and treatment. Traditionally, hyperuricaemia and gout has been considered to have four disease stages:25
Asymptomatic hyperuricaemia: the presence of high serum urate but no clinical symptoms.
Acute gouty arthritis: sustained hyperuricaemia leads to the deposition of MSU crystals in joints or periarticular tissues resulting in an intermittent self-limiting acute inflammatory arthritis.
Intercritical gout: defined as the period between acute attacks. The individual will remain hyperuricaemic and have further attacks without treatment.
Chronic tophaceous gout: usually occurs after gout has been present for many years and is associated with complications such as the presence of tophi and bone/joint damage.
Although this widely accepted staging system describes the symptomatology of gout, it does not capture key aspects of the pathological basis of the disease.9 As described above and in table 1, advanced imaging and microscopy studies have shown that MSU crystals are present in many people with hyperuricaemia with no history of flares and no clinical evidence of tophi. These individuals are not captured within the current staging system. Similarly, in people with prior acute flares and hyperuricaemia, MSU crystals may be present microscopically at joints that are not clinically inflamed and in joints that have never been affected by flares.26 ,27 These patients may have increasing MSU crystal deposition, but are considered to have ‘inter-critical’ disease. Furthermore, this staging system promotes the widely held concept that gout is a condition of recurrent flares, rather than a chronic disease of MSU crystal deposition. This concept is an important barrier to effective gout management for the practitioner and patient.28 ,29
A variety of systems are used for clinical staging chronic diseases in a diverse range of specialities including nephrology, haematology, hepatology and oncology. The American Heart Association heart failure guidelines provide a particularly useful template for revised hyperuricaemia and gout staging.30 As with gout, people with heart failure may have no symptoms despite structural disease, and symptoms may fluctuate over time. The heart failure staging system encompasses a spectrum from those people at risk for symptomatic heart failure (Stage A: at risk for heart failure, but without structural heart disease or symptoms of heart failure; Stage B: structural heart disease but without signs or symptoms of heart failure); to those with symptomatic heart failure (Stage C: structural heart disease with prior or current symptoms of heart failure; Stage D: refractory heart failure requiring specialised interventions). An analogous clinical staging system may be readily applied to hyperuricaemia and gout to capture the pathological phases of disease (figure 1), with Stage A: hyperuricaemia but without evidence of MSU crystal deposition or symptoms of gout; Stage B: MSU crystal deposition by microscopy or advanced imaging but without signs or symptoms of gout; Stage C: MSU crystal deposition with prior or current symptoms of acute gout flares; Stage D: advanced gout requiring specialist interventions (eg, tophaceous gout and chronic gouty arthropathy). As with heart failure, this progression is typically linear, but occasionally asymptomatic structural disease (MSU crystal deposition) may progress directly to advanced disease requiring specialist interventions, for example, in individuals who present with tophaceous gout as the first manifestation of symptomatic disease. It should be noted that this proposed staging system focuses on gout rather than the other manifestation of recognised chronic uric acid-associated disease (uric acid kidney stones) or putative urate-associated disease (such as cardiovascular disease, chronic kidney disease and hypertension).
Revision of the hyperuricaemia and gout clinical staging system would have a number of advantages. First, the revised system would provide a rational basis for testing the potential role for screening of asymptomatic disease, both serum urate concentrations in those at high risk of hyperuricaemia (eg, those with metabolic syndrome, chronic kidney disease and/or heart failure, those on diuretics, solid organ transplant recipients, and those with a family history of gout); and in those with severe hyperuricaemia, imaging methods to detect features of asymptomatic MSU crystal deposition. At present, the benefits of such screening are not certain, and research to examine the role of screening in asymptomatic disease is required. Furthermore, this proposed revision provides a clear focus on gout as a chronic disease of MSU crystal deposition, and emphasises the importance of targeting the underlying basis of disease in order to achieve dissolution of MSU crystals and ‘cure’ of gout. Finally, this staging system would allow assessment of the potential role of early intervention for presymptomatic disease, particularly those with Stage B disease (MSU crystal deposition but without signs or symptoms of gout).
Handling editor Tore K Kvien
Contributors Both authors conceived of the paper and drafted the manuscript.
Funding ND and LS are supported by the Health Research Council of New Zealand (grant numbers 10/414 and 12/111).
Competing interests ND has received consulting or speaker fees from Takeda, Savient, Menorini, AstraZeneca, Ardea, Novartis, Metabolex and Fonterra. LS has received consulting fees from AstraZeneca.
Provenance and peer review Not commissioned; externally peer reviewed.
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