Lowering serum uric acid in the management of gout

Gout is nowadays considered a curable disease.¹ It is a consequence of monosodium urate (MSU) crystal deposition resulting from hyperuricaemia, which precedes the initial attack2 that signals its presence. If hyperuricaemia persists, it can develop at other sites. MSU crystals form at the surface of the joint cartilage, inside tendons, ligaments and at other sites, forming large aggregates known as tophi. The mechanisms of MSU crystal formation are starting to be defined.³ Tophi growing in the joints result in radiological erosions and may lead to joint damage and decreased function. The disease is characterised by acute and generally very painful attacks of arthritis. These attacks are self-limiting and resolve within two to three weeks, except occasionally in advanced or severe cases.

Hyperuricaemia is often of renal origin, especially if linked to excessive dietary habits, metabolic syndrome, and also the concurrent use of diuretics. Uric acid is filtered by the glomeruli but the majority is reabsorbed at the proximal tubule, and in those circumstances serum uric acid (SUA) reabsorption reduces its renal clearance, thereby raising the serum levels.

Urate crystals are recognised by the innate immune system, resulting in interleukin-1 (IL-1) triggered inflammation. This causes both gout attacks and persistent subclinical inflammation during the intercritical periods.^4,5 Crystal deposition is far from innocuous, and gout, through the acute and subclinical inflammation, is associated with a increased risk of cardiovascular disease and other arteriosclerotic consequences.^6,7

Although arthritis at the 1st metatarsophalangeal joint is considered characteristic, the disease very often affects other joints and can be easily mistaken for other conditions. A definite diagnosis can be made through identification of MSU crystals in synovial fluid (Figure 1); sonography allows a closer diagnosis by identifying different crystal deposits. Clinical manifestations can frequently be uncharacteristic and reliance on them for diagnosis can be misleading. Although crystals in the joint and other places are always present in untreated/poorly treated cases, the disease is often asymptomatic during intercritical periods

Fig 1: Monosodium urate crystals as seen with a simple polarised microscope (filters slightly uncrossed to allow background detail). This finding establishes the diagnosis of gout.

Reduction of serum urate levels to normal values results in dissolution and elimination of the crystals, so gout is currently considered a curable disease. Although results are still preliminary, the cardiovascular risk is likely to normalise sometime after the start of treatment.⁸

The main aim of gout treatment is to fully dissolve the urate crystals. Secondary aims include: 1) preventing the attacks; 2) treating them if they occur; and 3) recognising and treating associated conditions. Patient counselling about the disease, its treatment and prevention is important to encourage compliance⁹ where medication is prescribed. This is an important part of patient care in a disease so frequently poorly treated.¹⁰

Dissolving MSU crystals is achieved by reducing SUA levels to normal values (<6mg/dl). Although this value has been considered as the target to reach, lower values result in faster dissolution and earlier disappearance of the crystals.¹¹ It is now established that MSU crystal deposition precedes clinical presentation of gout. The 2016 EULAR guidelines now take this into account and suggest lower values when crystal deposits are heavy, as seen in chronic gout, cases where multiple joints are affected, tophaceous gout, or in cases of early onset gout.¹

Prolonged values below 3mg/dl are currently not recommended because some studies have suggested that uric acid might protect against various neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease or amyotrophic lateral sclerosis.¹ A known trigger for gout attacks is the lowering of SUA levels, and the initiation of SUA-lowering drugs may result in gout attacks. This is generally avoided by the co-administration of prophylaxis – usually with colchicine. When attacks in this setting occur, patients consider that the treatment has failed and mistake the gout flare as a side effect or a consequence of inadequate treatment, tending then to abandon the medication – when such flares are in fact a consequence of the efficacy of the SUA-lowering drug.

The sharper the lowering of SUA levels, the greater the possibility of flares. Disappearance of the crystals from the joint is reasonably rapid¹² provided that SUA levels are reduced to low values. We lack standardised means of determining complete dissolution of MSU crystals and up to three to four years of treatment may be necessary in cases of substantial MSU crystal deposits⁹; sonography may be of use to ascertain when sizeable deposits are no longer present. When total elimination is considered to have occurred, SUA levels should be maintained indefinitely below 6mg/dl to prevent any new formation of crystals, and return of gout. Proper dietary modifications, especially if SUA levels were only mildly elevated, can bring SUA levels to a reasonable value without medication.

Allopurinol, a purine competitive xanthine oxidase inhibitor (XO) is the mainstay of reducing hyperuricaemia. Because severe toxicity has been linked to the starting dose, it is recommended to start with 50 or 100mg daily and gradually increase to the optimal dose.¹³ Allopurinol is frequently under-dosed at the most frequently prescribed dose of 300mg daily, but this fails to achieve SUA levels below 6mg/dl in approximately 25% of patients, and even 600mg daily is insufficient for a considerable percentage of patients.¹⁴ In these cases, higher doses of up to 800–900mg daily (depending local regulations) provided that renal function is normal may be required – especially if lower SUA levels are desired.

This gradual increase also reduces the flares that may occur at the start of serum uric acid lowering treatment by reducing the sharp drops in the SUA levels. Febuxostat, also a XO inhibitor, is highly effective and is indicated in patients intolerant to allopurinol or those with renal failure, because its hepatic metabolism poses fewer problems, and for whom achieving a particularly low uricaemia appears appropriate. The doses marketed in Europe – 80mg and 120mg tablets (in the US, 40mg and 80mg) usually produce a sharp reduction in SUA levels, and commonly trigger attacks, so effective prophylaxis should be co-administered. Although it is used in cases of intolerance to allopurinol, similar adverse reactions have been observed despite the difference in molecular structure and the more selective mechanism of inhibition of XO.

Uricosurics work by reducing the renal tubular reabsorption of uric acid, thereby increasing its renal clearance. Benzbromarone was withdrawn from the market because of rare, severe liver toxicity, but in some European countries it remains available as a special prescription. If given alone, it can produce uric acid renal calculi, which are possibly reduced by alkalinising the urine. The weaker probenecid is an alternative that can be obtained through specialist clinicians. They are the treatment of choice in patients intolerant to both XO inhibitors. Uricosurics are useful in combination with XO inhibitors in difficult cases where maximum doses of XO inhibitors are insufficient⁸; in those patients, uric acid production is reduced by the XO inhibitor while its excretion is enhanced by the uricosuric.

Pegloticase and rasburicase metabolise uric acid into the more soluble allantoin, resulting in very low uricaemia and rapid dissolution of the crystals. Though only a limited number of doses can be given, they might have a role in the initiation of treatment of very severe and difficult gout.

Prophylaxis (prevention) of attacks is especially necessary at the initiation of SUA reducing treatment that commonly triggers attacks as a result of the drop in uricaemia. After a desired uricaemia has been achieved, gout attacks become less frequent.¹⁵ Prophylaxis is achieved by reducing the subclinical inflammation linked to the urate crystals making it more stable. Colchicine 0.5–1mg daily is the usual approach. If colchicine is not tolerated, NSAIDs can be tried (as 500mg daily of naproxen). If inappropriate because of the frequent gout comorbidities, a small dose of prednisone (5–15mg daily) until stable target uricaemia is achieved can be given.

Treatment of gout attacks is the usual reason for seeking medical attention, and should be started as early as possible. Effective drugs include colchicine at doses of 1.2–1.6 mg the first 24 hours, followed by 1–1.2mg daily.^1,16 Most NSAIDs at maximum tolerated dose are effective, but should be prescribed with caution in patients with comorbidities. Corticosteroids are frequently used, for example, a short course of oral prednisone (as 30mg initially to be tapered after four to six days) is a rapidly acting option with fewer side effects. If accompanied by colchicine in prophylactic doses (0.5–1mg daily) at the start of treatment, gout attacks that can occur if duration of treatment is too short can be prevented. Finally IL-1 inhibitors – especially anakinra – are increasingly utilised in this context and result in prompt resolution of the attack.

Management of this condition, along with its treatment, should take into account careful consideration of commonly occurring comorbidities. Lifestyle modifications and patient education about the treatment and its aims, and the role of the different drugs should not be forgotten to encourage compliance with the treatment.

• Besides painful acute attacks due to persistent monosodium urate (MSU) crystal-linked inflammation, gout facilitates arteriosclerosis and comorbidities, particularly coronary vascular disease.
• MSU crystal deposits result from hyperuricaemia, but it is reversible and crystals dissolve when serum urate levels are normalised. The main aim of gout treatment is total crystal dissolution and gout is currently considered a curable disease.
• Allopurinol remains the mainstay serum uric acid (SUA)-lowering drug. Febuxostat is useful in patients with poor renal function and in those experiencing side effects of allopurinol treatment. Uricosurics still have a place in treatment of gout.
• The start of SUA-lowering treatment without prophylaxis of attacks frequently results in a gout attack, and patients sometimes (improperly) discontinue medication.
• Patient counselling and education on the disease, its curability and the role of different drugs is important to assure compliance with medication. Lifestyle modifications are also advisable.

 

References

1. Richette P et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis 2016;Jul 25 [Epub ahead of print].
2. De Miguel E et al. Diagnosis of gout in patients with asymptomatic hyperuricaemia: a pilot ultrasound study. Ann Rheum Dis 2012;71:157–8.
3. Pascual E et al. Mechanisms of crystal formation in gout-a structural approach. Nat Rev Rheumatol 2015;11:725–30.
4. Pascual E. Persistence of monosodium urate crystals and lowgrade inflammation in the synovial fluid of patients with untreated gout. Arthritis Rheum 1991;34:141–5.
5. Dalbeth N et al. Cellular characterization of the gouty tophus: a quantitative analysis. Arthritis Rheum 2010;62(5):1549–56.
6. Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation 2007;116:894–900.
7. Andrés M et al. Silent monosodium urate crystal deposits are associated with severe coronary calcification in asymptomatic hyperuricemia: An exploratory study. Arthritis Rheumatol 2016;68:1531–9.
8. Chen JH et al. Effect of urate-lowering therapy on all-cause and cardiovascular mortality in hyperuricemic patients without gout: A case-matched cohort study. PLoS One 2015;10(12):e0145193.
9. Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative treatment if informed appropriately: proof-of-concept observational study. Ann Rheum Dis 2013;72:826–30.
10. Pascual E, Sivera F. Why is gout so poorly managed? Ann Rheum Dis 2007;66:1269–70.
11. Perez-Ruiz F et al. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum 2002;47:356–60.
12. Pascual E, Sivera F. The time required for disappearance of urate crystals from synovial fluid after successful hypouricemic treatment relates to the duration of gout. Ann Rheum Dis 2007;66:1056–8.
13. Stamp LK et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum 2012;64:2529–36.
14. Reinders MK et al. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day in patients with gout. Ann Rheum Dis 2009;68:892–7.
15. Sarawate CA et al. Serum urate levels and gout flares: analysis from managed care data. J Clin Rheumatol 2006;12:61–5.
16. Terkeltaub RA et al. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010;62:1060–8.