Gout: Diagnosis and management

Gout is a chronic inflammatory process that requires lifelong treatment and is associated with an increased burden of cardiovascular co-morbidities and higher mortality

Gout is the most common form of inflammatory arthritis. Earliest descriptions of gout date back to the fifth Century BC. It used to be known as ‘the disease of kings’ due to its association with certain foods and alcohol.

The prevalence of gout is highly variable among different ethnic groups, suggesting that both genetic and environmental factors play a role in its pathogenesis. Based on North American, European, and Asian studies, the prevalence ranges between <1-and-6.8 per cent in adults.¹

The highest prevalence is reported in Oceania – up to 13.9 per cent of Pacific people living in New Zealand have gout.²

Gout is more common in men than women; with a male-to-female ratio of 2:1-to-4:1.³ Testosterone inhibits, while oestrogen promotes, urate excretion by the kidneys. It is therefore uncommon for women to develop gout before menopause. However, with increasing age, the male-to-female ratio decreases.⁴

Gouty arthritis is correlated with many co-morbidities. Various epidemiological studies have shown that it is associated with hypertension, hyperlipidaemia, chronic kidney disease (CKD), and increased cardiovascular risk.⁵ Thus, perhaps unsurprisingly, it is associated with increased mortality, probably due to the burden of co-morbidities.⁶

Risk factors

There is a proven correlation related relationship between the levels of uric acid and the risk of gout. Interestingly, other animals do not develop hyperuricaemia due to an enzyme called uricase that converts uric acid to soluble allantoin, which is then easily excreted. Humans and other primates have lost this enzyme during our evolution; thus, our species is prone to gout.⁷

Uric acid is a breakdown product of purines (DNA, ATP turnover). Thus, its levels can be increased in conditions with high cellular production of purines or high purine oral intake. Serum uric acid levels will also be high in conditions with decreased uric acid excretion. One-third of uric acid is excreted by the gut, and two-thirds by the kidneys.

One-third of uric acid is excreted by the gut, and two-thirds by the kidneys

High cellular production of purines can be found in disease processes that result in rapid cell turnover, such as malignancy, psoriasis, or tumour lysis syndrome. Likewise, high ATP turnover will result in increased uric acid levels in sepsis, myocardial infarction, or seizures.

High purine intake can also result in increased uric acid levels. Meat and seafood have a high purine content.

There are other mechanisms by which food can increase serum uric acid levels. For instance, consuming sugary drinks high in fructose will lead to increased ATP turnover and hyperuricaemia.

Alcohol increases uric acid levels in the body by several means, including increased ATP turnover and decreased uric acid excretion by the kidneys. Also, some types of alcohol (eg, beer) have high purine content.⁸

Despite all the above, the role of diet in the development of gout is controversial – studies have found that the type of diet has little effect on the serum urate concentration levels in healthy populations.⁹

Clinical signs and symptoms

The renowned English physician, Thomas Sydenham, gave an accurate description of an acute gout flare based on his own experience: “The victim goes to bed and sleeps in good health. About 2 o’clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle or instep. The pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them. Then follows chills and shiver with a little fever. The pain, which was first moderate, becomes more intense.”

Indeed, gout flares typically occur between midnight and 5am. They are characteristically acute and very painful, with erythema, swelling, and tenderness of the affected joints. The first metatarsophalangeal (MTP) joint is the most common site, being involved in 50 per cent of the first acute flares. Other common sites include the ankles, knees, and toes.¹⁰ Acute attacks are self-limiting and last anything from one-to-two weeks. They can be associated with a fever, especially if more than one joint is affected.

Untreated persistent hyperuricaemia can lead to more frequent and severe attacks, which can become polyarticular. Interestingly, gout initially presents as a polyarticular attack in 10 per cent of cases.¹¹

Tophaceous gout is characterised by tophi formation – these are depositions of monosodium urate crystals in joints and soft tissues. They typically affect olecranon bursa, fingers, toes, Achilles tendon, or even the helix of the ear. They are composed of gouty crystals surrounded by inflammatory cells. Tophi are particularly difficult to treat, as they constitute a reservoir of urate in the body. Lowering serum uric acid levels will lead to a shift in the equilibrium of the total body urate burden and release of more uric acid from the tophi reservoir.

Tophi are associated with bone and joint damage. Deposition of urate crystals lead to chronic inflammatory response with local production of pro-inflammatory interleukins and metalloproteinases together with an activation of synovial fibroblasts and osteoclasts. This leads to tissue damage and remodelling resulting in bone destruction. In addition, the mass effect of the tophus itself can lead to joint damage.¹² This can be seen on plain x-ray as the characteristic ‘punched out lesions’.

Differential diagnosis

There are many gout mimics that physicians should be aware of. Septic arthritis also presents with acute swelling, erythema, and tenderness. Ideally, fluid aspirate should be examined for crystals as well as for fluid white cell count and gram stain.

Acute calcium pyrophosphate (CPP) deposition disease (‘pseudogout’) can clinically resemble gout. However, it is associated with a different joint involvement pattern with wrists and knees being commonly affected. Plain x-rays can reveal chondrocalcinosis. Synovial fluid examination will reveal CPP crystals. Monosodium urate (MSU) and CPP crystals can co-exist.

Gout diagnosis – clinical investigations

The gold standard of diagnosis is the microscopic analysis of synovial fluid or tophi. MSU crystals are needle shaped and negatively birefringent under polarised light. Synovial fluid should be sent for cell count, culture and sensitivity and gram stain, as gout and septic arthritis can co-exist. However, if the fluid examination is not possible, there are certain diagnostic criteria that can be used. The Acute Gout Diagnosis Rule was developed to stratify the risk for gouty arthritis. These criteria include certain features that are more likely to be attributed to gout (Table 1).¹³

Serum urate concentrations can be normal in a flare due to increased renal excretion, and thus can represent a negative acute phase reactant. Hyperuricaemia occurs in 20 per cent of males and 4 per cent of females in the general population and on its own is insufficient for a diagnosis of gout.¹⁴ Inflammatory markers, such as C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), will be elevated during an acute flare, however, these are non-specific findings.

Recently, the role of fibrinogen in monitoring disease activity in patients with gout has been supported by several studies. Fibrinogen was found to be a more specific marker of an acute flare than other conventional inflammatory indicators. It is believed that increased levels of fibrinogen are caused by activation of the coagulation system following damage to vascular endothelial cells during a flare.¹⁵

Ultrasonography and dual-energy CT scans aid in diagnosis of gout.^16,17 Ultrasonographic findings include ‘double contour sign’ (MSU crystal deposition on the surface of hyaline articular cartilage) and intra-articular tophi. Nevertheless, absence of MSU crystal deposition on ultrasound or dual aspect CT does not exclude gout, especially in the early phase of the disease. X-rays can reveal punched out lesions with sclerotic margins and overhanging edges. Plain radiographs are also normal at the time of initial diagnosis.

Treatment

Treatment of gout can be divided into treatment of acute flares and chronic management.

The goal of treatment of an acute flare is pain control and suppression of inflammation. This can be achieved with either prednisolone, NSAIDs, or colchicine. Studies have shown equivalent efficacy of oral agents and thus treatment choice depends on patient preferences, co-morbidities, and costs.^18,19

For instance, NSAIDs are not recommended in the setting of peptic ulcer disease, kidney or cardiac disease, or anticoagulant use. High-dose steroids should be avoided in infection or diabetes. Colchicine toxicity can occur with kidney or liver disease. Moreover, use of other medications such as ketoconazole, cyclosporin or clarithromycin can potentiate colchicine toxicity.²⁰ The most common side-effect of colchicine is diarrhoea.

Recent trials have found that the use of colchicine may decrease the rate of cardiovascular events in high-risk populations.^21,22 The 2021 European Society of Cardiology guidelines recommend the use of low-dose colchicine (0.5mg daily) as secondary prevention of cardiovascular disease in this patient group if other risk factors are not controlled.²³

Serum urate concentrations can be normal in a flare due to increased renal excretion, and thus can represent a negative acute phase reactant

Interleukin-1 plays a central role in the inflammatory process driving gouty arthritis. Indeed, IL-1 inhibitors have been found to be useful in acute gout management. Anakinra, an IL-1 inhibitor which is delivered via the subcutaneous route, has been found to have a similar safety profile and efficacy to other therapies for acute flares.²⁴

Long-term management of gout

It is important to highlight to all patients presenting with an acute gout flare that long-term urate lowering therapy (ULT) prevents future flares and joint damage. There are three different classes of urate-lowering drugs. Xanthine oxidase inhibitors (allopurinol, febuxostat) hinder uric acid production. Uricosurics (probenecid, lesinurad) promote uric acid excretion by the kidneys. Recombinant uricases (pegloticase) convert uric acid to soluble allantoin.

ULT is generally recommended to individuals with two or more acute flares, or one or more flare in the presence of co-morbidities (CKD, urolithiasis, very high serum urate levels).

ULT can be started during the attack if the inflammation is adequately treated. Treatment should not be discontinued during an acute attack. Flares tend to occur at an increased frequency following initiation of ULT, and thus anti-inflammatory agents, such as colchicine or NSAIDs, should be continued for at least three-to-six months to prevent further attacks.²⁵

Long-term treatment of gout is guided by the ‘treat to target’ approach. Typically, the initial dose of allopurinol is 100mg/day or 50mg/day in CKD. The dose can be slowly titrated based on the uric acid level up to a maximum 900mg/day. Serum uric acid target levels should be below 360umol/L for most patients, but less then 300umol/L in tophaceous gout. If allopurinol is not tolerated or serum target urate levels are not achieved, other agents should be considered.

Allopurinol-associated rash requiring withdrawal of the drug occurs in 1-to-2 per cent of patients. Allopurinol hypersensitivity syndrome, which occurs in the first few months after treatment initiation, is a rare, life-threatening reaction that involves widespread cutaneous changes and acute kidney injury in the presence of eosinophilia.²⁶ Patients of South East Asian descent are at higher risk, and the condition is associated with HLA-B*58:01 allele.²⁵ Other risk factors include CKD and high initial doses of allopurinol.²⁷

Febuxostat, a potent non-purine xanthine oxidase inhibitor, received a black box warning by the US Food and Drug Administration for an increased risk of cardiovascular events. This move, however, has been controversial. A 2020 European Medicines Agency study showed no evidence of an increased risk of major cardiovascular events with febuxostat compared to allopurinol.²⁸

Conclusions

Gout is not only a disease of the joints; it is a chronic inflammatory process that requires lifelong treatment and is associated with an increased burden of cardiovascular co-morbidities and higher mortality overall. Fortunately, we have effective treatments for both acute flares and long-term management. It is imperative to educate our patients and their healthcare providers about the potential long-term complications of gout and highlight the role of lifelong ULT.

Dr Anna Witkowska, Rheumatology Registrar, Mater Misericordiae University Hospital, Dublin; and
Prof Geraldine M McCarthy, Full Clinical Professor of Medicine, School of Medicine and Medical Science, University College Dublin, and Consultant Rheumatologist, Mater Misericordiae University Hospital, Dublin