Elsevier

The Lancet

Volume 397, Issue 10287, 15–21 May 2021, Pages 1843-1855
The Lancet

Seminar
Gout

https://doi.org/10.1016/S0140-6736(21)00569-9Get rights and content

Summary

Gout is a common and treatable disease caused by the deposition of monosodium urate crystals in articular and non-articular structures. Increased concentration of serum urate (hyperuricaemia) is the most important risk factor for the development of gout. Serum urate is regulated by urate transporters in the kidney and gut, particularly GLUT9 (SLC2A9), URAT1 (SLC22A12), and ABCG2. Activation of the NLRP3 inflammasome by monosodium urate crystals with release of IL-1β plays a major role in the initiation of the gout flare; aggregated neutrophil extracellular traps are important in the resolution phase. Although presenting as an intermittent flaring condition, gout is a chronic disease. Long-term urate lowering therapy (eg, allopurinol) leads to the dissolution of monosodium urate crystals, ultimately resulting in the prevention of gout flares and tophi and in improved quality of life. Strategies such as nurse-led care are effective in delivering high-quality gout care and lead to major improvements in patient outcomes.

Introduction

Gout is a common condition caused by the deposition of monosodium urate crystals in articular and non-articular structures. A high serum urate concentration is the most important risk factor for the development of gout. In clinical practice and research, hyperuricaemia (blood urate concentration over the saturation threshold) is typically reported when serum urate is higher or equal to 0·42 mmol/L (7 mg/dL). Gout presents as intermittent episodes of severely painful arthritis (gout flares) caused by the innate immune response to deposited monosodium urate crystals. The central strategy for effective management of gout is long-term urate-lowering therapy to reverse hyperuricaemia, which leads to the dissolution of monosodium urate crystals and long-term prevention of gout flares. In this Seminar, we provide an update on the clinical features, pathophysiology, and treatment of gout. Key terms and definitions are provided on appendix p 1.

Section snippets

Clinical presentation of gout

The typical first presentation of gout is an intensely painful acute inflammatory arthritis (gout flare) affecting a lower limb joint.1 In the absence of treatment, the gout flare is typically self-limiting over a period of 7–14 days. After resolution, there is a pain-free asymptomatic period (intercritical gout), until another gout flare occurs. Over time, some people with persistent hyperuricaemia also develop tophi, chronic gouty arthritis (persistent joint inflammation induced by monosodium

Incidence and prevalence

Population-based studies from Asia, Europe, and North America have reported incidence ranges between 0·6 and 2·9 per 1000 person-years, and prevalence ranges between 0·68% and 3·90% in adults.17, 18, 23, 24, 25, 26 The prevalence of gout increased steadily in the 20th century, probably due to the changing age structure of populations and to the growing rates of metabolic syndrome and its associated pathologies. However, the prevalence of gout appears to have stabilised in high-income countries.

Pathophysiology

The progression of hyperuricaemia and gout can be considered to take place over four pathophysiological stages: development of hyperuricaemia, deposition of monosodium urate crystals, clinical presentation of gout flares due to an acute inflammatory response to deposited crystals, and clinical presentation of advanced disease characterised by tophi.39 Some patients present with advanced disease without previous gout flares.

Differential diagnosis

The most important differential diagnosis in the acute clinical setting is soft tissue or musculoskeletal infection (eg, cellulitis, septic bursitis, septic arthritis, or osteomyelitis). Similarly to gout, soft tissue or musculoskeletal infections affect individuals more frequently as they age, or if they have multiple comorbidities, or are transplant recipients. Fever and leukocytosis can be reported in both severe gout flare and infection. Importantly, gout and infection can coexist. Sampling

Clinical investigations

Microscopic confirmation of monosodium urate crystals in synovial fluid or tophi is considered the gold standard for gout diagnosis. Monosodium urate crystals appear needle-shaped and negatively birefringent under polarising light microscopy (figure 3). In synovial fluid, crystals range in length from 1 μm to 20 μm, but can measure up to 40 μm in tophi.85

Gout can also be diagnosed with a high level of certainty and without recourse to joint aspiration in the presence of typical signs and

Management of the gout flare

The major priorities in the management of the gout flare are pain control and suppression of joint inflammation. Early administration of anti-inflammatory treatment (table 1) is recommended to rapidly suppress joint pain and inflammation. Head-to-head clinical trials comparing oral agents with different mechanisms of action have shown equivalent efficacy between oral prednisolone, non-steroidal anti-inflammatory drugs (non-selective or COX-2-selective), and low-dose colchicine for gout flare

Principles of management

Table 2 outlines the principles of long-term management, with specific examples of treatment. The central strategy for effective, long-term gout management is continuous urate-lowering therapy prescribed at a dose that achieves monosodium urate crystal dissolution, using a treat-to-serum urate target approach.97, 103 For most people with gout, the target serum urate is under 0·36 mmol/L (6 mg/dL), but for those with high urate burden (such as tophaceous gout), a lower serum urate target, of

Primary prevention of incident gout

Primary prevention of gout should be considered for those with asymptomatic hyperuricaemia, the most important risk factor for the development of gout. Medications indicated for related cardiometabolic conditions such as losartan, fenofibrate, and SGLT2 inhibitors have modest urate-lowering effects and also reduce incident gout.135, 136, 137 Similarly, substantial weight loss (particularly in the context of bariatric surgery138) and the Dietary Approaches to Stop Hypertension diet reduce serum

Outcomes

Despite the high population burden of gout, treatment of this disease remains suboptimal worldwide.24, 26, 29, 142, 143 Many patients have recurrent gout flares and do not receive regular urate-lowering therapy, which leads to poor health-related quality of life.143 In the USA, only a third of people with gout are prescribed urate-lowering therapy.26 In Australia, a concentration of serum urate under 0·36 mmol/L was documented in 22·4% of all people with gout over a 5 year period.142 Even when

Controversies and uncertainties

Although the underlying cause of gout (monosodium urate crystal deposition) is well documented and effective therapies are available, there are various uncertainties. For centuries, the dominant narrative about the cause of gout and its treatment has focused on dietary management.148 However, some research suggests that diet plays only a small role in regulation of serum urate in the healthy population;38 it is unknown whether these findings are also true for gout. Furthermore, randomised

Conclusion

Gout is a common and treatable rheumatic disease, caused by deposition of monosodium urate crystals in people with hyperuricaemia. Although presenting as an intermittent flaring condition, gout is a chronic disease. For patients with recurrent flares or tophaceous gout, long-term urate-lowering therapy with medications such as allopurinol leads to dissolution of monosodium urate crystals, ultimately resulting in prevention of gout flares and improved quality of life. Despite the availability of

Search strategy and selection criteria

We searched MEDLINE for publications dated Jan 1, 1946, to Dec 31, 2020, in English language exclusively, using the search term “gout”. We largely selected publications from the past 5 years, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identified through this search strategy and selected those we judged relevant. Review articles are cited to provide readers with more details and more references than this

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