Gout management in 2024 – pearls and pitfalls

Reference: June 2024 | Issue 6 | Vol 10 | Page 58

While most doctors in primary care and medical specialties are experienced in the management of uncomplicated gout, initiation of urate-lowering therapy (ULT) and adoption of a treat-to-target approach (with respect to serum urate levels) remains low.¹ Its differential diagnoses (septic arthritis, inflammatory arthritis) and an increasingly comorbid, elderly population present challenges that can undermine confidence in managing this common disorder.

Furthermore, emerging diagnostic and therapeutic strategies can lead to confusion as to the best way to proceed for a given patient, as can both physician (eg, attitude to guidelines) and patient factors (eg, attitude to taking medications).² Despite these trends, ULT remains a safe and effective option for reducing the burden of morbidity associated with gout. In this article, we reiterate some of what we know about the diagnosis and management of the condition, and where special care should be taken.

Epidemiology

Worldwide, gout is the commonest of the inflammatory arthritides, with over nine million new cases reported in 2019.³ In Europe, between 1 and 4 per cent of the general population are affected.⁴ Risk factors for the development of gout include: Male sex; purine-rich diet; family history; diuretic use; hypertension; cardiovascular disease; cerebrovascular disease; type 2 diabetes mellitus; obesity; psoriasis; sickle cell disease; anaemia; and chronic kidney disease (CKD).⁵

A cross-sectional study of adult patients with CKD treated at specialist nephrology clinics in Ireland found a gout prevalence rate ranging from 7.5 per cent in patients with estimated glomerular filtration rate (eGFR) >60ml/min to 22.8 per cent in patients with eGFR <30ml/min.⁶

More recently, gout has been associated with atrial fibrillation, venous thromboembolism, and erectile dysfunction. Interestingly, obstructive sleep apnoea has also been associated with gout, with hypoxia-mediated purine turnover proposed as a potential mechanism.⁴

Clinical course and complications

Untreated, gout progresses through a series of stages:⁸

1. Asymptomatic hyperuricaemia: Uric acid is a product of purine metabolism, hence its association with high-turnover states in which DNA and adenosine triphosphate (ATP) are produced and denatured. Metabolism of alcohol by the liver is an ATP-dependent process, with degradation of ATP to adenosine monophosphate resulting in higher circulating urate. Similarly, fructose, used as a sweetener in soft drinks, is phosphorylated in an ATP-dependent manner, driving urate production.

High-purine foods including seafood and red meat also contribute to hyperuricaemia. Urate is predominantly excreted by the kidneys, and in high concentrations can also contribute to the production of kidney stones. In the presence of therapeutic uricase, urate is metabolised to allantoin, which is more efficiently excreted in the urine. Urate is also excreted from the intestine, and in this manner intestinal diseases such as acute gastroenteritis can contribute to gout flares.

2. Monosodium urate crystal deposition: Once the serum urate concentration exceeds a saturation threshold, either through under-excretion or, less frequently, over-production of urate, monosodium urate (MSU) precipitates as crystals. MSU crystals are preferentially deposited at the first metatarsophalangeal joint, joints of the midfoot, and the Achilles tendon, though they may occur in any joint.

3. Acute gout flare: MSU crystals are ingested by monocytes and neutrophils, with consequent release of pro-inflammatory cytokines (primarily interleukin (IL)-1B). Immune cells are recruited to the joint with consequent release of tissue-destructive enzymes (such as matrix metalloproteinases). This inflammatory cascade results in the classical clinical appearance of podagra, with exquisite pain, heat, redness, and swelling noted at the affected joint or joints. Untreated, the flare will self-resolve after seven-to-10 days. 

4. Tophaceous gout and joint damage: The tophus is a macroscopically visible, subcutaneous, organised structure comprised of MSU crystals and host immune cells/granulomata. Chronic inflammation around the tophus is associated with stimulation of osteoclasts and downregulation of osteocytes, while MSU crystals themselves are toxic to osteoblasts. This environment drives bone resorption, with permanent, potentially disabling joint erosions developing.

Gout has been implicated in the development of cardiovascular disease and the deterioration of co-existing CKD. A 2017 meta-analysis of 16 studies and 1211 patients with CKD revealed that uric-acid lowering therapy was associated with a 55 per cent relative reduction in the risk of kidney failure events and a 60 per cent reduction in cardiovascular events.⁹

ULT is effective at preventing recurrent gout flares and driving recession of tophi. However, with recent evidence supporting its role in reducing incident cardiovascular complications, its initiation should not be unduly delayed.  

Diagnosing gout

Ideally, gout should be diagnosed based on polarised light microscopic examination of synovial fluid aspirated from an affected joint. However, this resource is unavailable to the majority of providers seeing patients with gout. Gout may be diagnosed clinically. It should be suspected when there is rapid onset of severe pain, redness, and swelling in one or both of the metatarsophalangeal joints, midfoot, ankle, knee, hand, wrist, or elbow. The presence of tophi is helpful in reaching a diagnosis.

The clinical suspicion of gout is confirmed with a serum urate level of >360umol/L or >6mg/dL.10 It should be noted, however, that a serum urate level of <360umol/L may be seen during an acute flare due to increased renal excretion and sequestration of crystals into the joint so that the presence of hyperuricaemia is best assessed between gout flares. Diagnosis can be further supported with ultrasound scanning. 

Management of acute gout

The key consideration before initiating treatment is ruling out septic arthritis. This should be suspected if the flare is atypical for the patient already known to have gout, the patient has had a penetrating injury to the affected joint, or the patient is immunocompromised. If septic arthritis is considered at least as likely as gout, the patient should be assessed in the emergency setting with arthrocentesis and joint fluid analysis.

Otherwise, acute gout flares may be managed with the administration of colchicine, non-steroidal anti-inflammatory drugs (NSAIDS), or prednisolone, either alone, or in combination if the patient has an inadequate response to monotherapy. While each approach is equally effective, treatment choice should reflect patient factors (Table 2). An intra-articular injection with methylprednisolone acetate may alternatively be administered, at a dose of 20mg for small joints, 40mg for medium-sized joints, and 80mg for a large joint. This strategy reduces the risks associated with systemic steroid therapy.

During a flare, ULT should be continued. If a patient is not already receiving ULT, this may be started while the flare is ongoing, so long as the flare is being actively treated.

Colchicine is the modern derivative of the ancient medicinal plants Colchicum autumnale and Gloriosa superba.¹⁴ It is widely-used in the management of crystal arthropathies, familial Mediterranean fever, and pericarditis, among other conditions. Its therapeutic effects are mediated by microtubule disruption and NLRP3 inflammasome inhibition.¹⁵

There is justifiable concern about its use among those inexperienced in its application – it has a narrow therapeutic window, and in toxic doses it may rarely be associated with mortality. However, historically the worst cases of toxicity were associated with intravenous administration and colchicine is generally well-tolerated with only mild side-effects reported. Of these, the most prevalent is gastrointestinal disturbances. Myopathy may infrequently occur in patients receiving statins.

The risk of toxicity is elevated in patients with impaired hepatic or renal function, and those taking CYP3A4 inhibitors, as well as medications that inhibit P-glycoprotein (such as clarithromycin and ciclosporin). While clinical guidelines have not (yet) specified dose modifications for colchicine in at-risk groups, the US Food and Drug Administration has done so in its summary of product characteristics.¹⁶

It recommends reduced starting doses and/or frequency of administration, with close monitoring for toxicity whenever dose changes occur. In patients with a combination of renal or hepatic impairment and an interacting drug, alternatives to colchicine should be considered.

Long-term management of gout

Patient education is at the core of long-term management of gout, as with any chronic disease. Many patients are motivated to make dietary modifications; however, alone this is not as effective in the management of gout as ULT.

A ‘treat-to-target’ approach is the gold standard for the management of gout, with a target serum urate level of <360umol/L recommended by the National Institutes of Health and Care Excellence in the UK, and by the European Alliance of Associations for Rheumatology. A lower target of <300umol/L may be used for patients with severe gout (ie, those with tophi, frequent attacks, or chronic arthropathy).¹³ These targets should be maintained lifelong, and for most patients this will necessitate long-term treatment as cessation of ULT is ultimately associated with relapse.

ULT should be offered at the first presentation of gout for patients with one or more comorbidities, high urate levels (>480umol/L) or age of onset <40 years.^10,13 While guidelines recommend initiation two-to-four weeks after a flare, ULT may be initiated concurrently with acute flare management. Either allopurinol or febuxostat may be offered first-line. Febuxostat may be preferable in patients of East Asian origin, in whom the prevalence of the HLA-B*5801 allele is higher than other ethnic groups.

This mutation confers a significant risk of allopurinol hypersensitivity syndrome, which may present as severe cutaneous adverse reactions with renal and/or hepatic injury, fever, eosinophilia, and leukocytosis. Genetic screening should be considered before starting allopurinol in patients in these groups.⁸ Of note, this complication is also likelier in patients with severe renal impairment, and a lower maximum dose of allopurinol is suggested. Allopurinol was historically preferred in patients with established cardiovascular disease,^10,17 however, a large prospective randomised controlled trial has since shown that febuxostat has non-inferior cardiovascular outcomes to allopurinol.¹⁸

The dose of allopurinol should be increased in 100mg intervals, to a maximum dose of 900mg once-daily, every two-to-four weeks until the target serum urate level is achieved. Alternatively, febuxostat at a starting dose of 80mg once-daily may be increased to 120mg once daily after two-to-four weeks if the urate target has not been achieved.

On initiation, ULT is paradoxically associated with an increased risk of acute gout flares. This is a potential complication about which patients should be counselled to support adherence, and it should not be a reason for discontinuation of ULT. Instead, it is recommended to start ULT at a low dose, and to co-prescribe prophylactic colchicine or low-dose NSAIDs for the first three-to-six months of ULT.¹³ The ULT agent should be changed if there is intolerance.

Referral to a rheumatologist should be considered if the diagnosis of gout is uncertain, if the patient has received an organ transplant, or if they have CKD stage 3-5. A rheumatologist should also be consulted if the patient has not responded to two different ULT agents, or if the patient has flares that do not respond to conventional agents such as NSAIDs, colchicine, or glucocorticoids. In this latter situation, it may be appropriate to treat with the biologic IL-1 antagonist, anakinra.

Summary

Gout remains a common and potentially disabling condition. Early initiation of an appropriate urate-lowering agent can improve long-term patient outcomes. There is no ‘one-size-fits-all’ approach to managing acute or chronic gout however, and patient factors should be taken into consideration to avoid complications from therapy. For more complicated patients, especially those with comorbid hepatic or renal impairment, consult a rheumatologist.