Gout: optimizing treatment to achieve a disease cure

Abstract

Gout is one of the most common inflammatory arthritides. The disease is due to the deposition of monosodium urate crystals. These deposits are reversible with proper treatment, suggesting that gout is a curable disease. The main aim in gout is to lower serum uric acid levels to a pre-established target; there are different urate-lowering drugs (xanthine oxidase inhibitors, uricosurics and uricases) through which this can be achieved. Proper treatment of gout also involves correct management of acute flares and their prevention. To ensure treatment adherence it is necessary to explain to the patient what the objectives are.

Introduction

Gout is the most prevalent cause of arthritis in developed countries [Roddy and Choi, 2014], and it is due to the deposition of monosodium urate (MSU) crystals in joints and soft tissues. Maintained hyperuricemia is required for MSU crystal formation but not all subjects with hyperuricemia will develop gout [Campion et al. 1987]. MSU crystals are found in inflamed joints of patients with gout, but also in previously inflamed joints during intercritical stages in untreated patients or in treated patients before its disappearance [Pascual et al. 1999].

Despite significant advances in the knowledge of the pathophysiology of gout and the availability of effective treatments, gout continues to be poorly managed [Roddy et al. 2007; Pascual and Sivera, 2007b]. In fact, inappropriate management by the physicians may lead gout, which is currently considered as a curable disease [Zhang et al. 2006], to become a chronic condition. Another common problem is the low patient adherence to lowering serum uric acid (SUA) therapies. The low compliance is mostly due to lack of understanding of the aim of gout therapy by the physicians and patients. It is worthwhile to explain to patients the objective of the treatment [Riedel et al. 2004; Harrold et al. 2009; Rees et al. 2013]. Patients must understand that the main objective is to dissolve urate crystals and that the risk of flares will disappear if they are compliant.

The aim of the treatment is to dissolve MSU crystal stores by normalizing SUA levels. Moreover, SUA should continue to be maintained below saturation levels in order to avoid the formation of new crystals. Until crystal clearance is achieved, prevention and proper management of acute episodes of arthritis (flares) is essential. In this review we will discuss current gout management in three areas: lowering SUA therapies, prophylaxis and treatment of acute inflammation with a focus on achieving optimal management that results in the cure of the disease.

Urate-lowering therapies

The uric acid saturation threshold is around 7 mg/dl (0.42 mmol/liter), although it is widely recommended to aim for SUA levels under 6 mg/dl (0.35 mmol/liter) in patients with gout in order to deplete MSU deposits [Zhang et al. 2006; Khanna et al. 2012; Sivera et al. 2014a] as this cutoff level has been proven effective [Li-Yu et al. 2001]. However, lower SUA levels result in a faster reduction of MSU crystal deposits, as has been shown in tophaceous gout [Pérez-Ruiz et al. 2002b]. It therefore appears reasonable to aim for a lower SUA level, especially in severe gout [Pascual et al. 2013]. Ideally, target SUA levels should be tailored according to the crystal load of the patients. Unfortunately, no instrument is currently available to assess it, although the presence of a longer history or tophaceous disease can be used as surrogate markers of the extent of deposits [Pascual and Sivera, 2007a]. It is interesting to note that reduction of SUA has been found to improve renal function in patients with renal impairment, in both patients without gout [Siu et al. 2006] and those with the condition [Pérez-Ruiz et al. 2000].

Three main urate-lowering therapy (ULT) groups are available: xanthine oxidase inhibitors (allopurinol and febuxostat), uricosuric drugs and recombinant uricases.

Xanthine oxidase inhibitors

Allopurinol

Allopurinol is the most widely used drug to decrease SUA levels. As a purine analogue, it inhibits the xanthine oxidase enzyme which is responsible for the transformation of xanthine and hypoxanthine into uric acid. Allopurinol has a good oral bioavailability and it is rapidly metabolized to oxypurinol; moreover the hypouricemic effect of allopurinol is largely due to oxypurinol [Day et al. 2007].

According to the drug label the maximum dose is 800–900 mg daily [FDA, 2003]. In clinical practice 300 mg daily is a widely used dose, but this is often insufficient, as shown in several clinical trials. In one study only 53% of patients with gout attained SUA less than 6 mg/dl (0.36 mmol/liter) with 300 mg daily of allopurinol, but when allopurinol was increased to 450–600 mg daily all subjects achieved the target SUA [Pérez-Ruiz et al. 1998]. In another study, SUA levels below 6 mg/dl (0.36 mmol/liter) were achieved by 26% of patients treated with 300 mg daily, and 78% of patients reached the target levels with 600 mg daily [Reinders et al. 2009a]. In a third trial that compares probenecid with benzbromarone after allopurinol failure, only 24% of subjects reached the target level (<5 mg/dl or 0.3 mmol/liter) after 2 months of treatment with 300 mg daily of allopurinol [Reinders et al. 2009b]. Thus, a standard dose of 300 mg is often insufficient to achieve the target. Correct allopurinol dosage must be tailored based on SUA levels and renal function to reach the objective [Jennings et al. 2014].

Allopurinol dose needs to be adjusted according to renal function because oxypurinol is excreted by the kidneys [Emmerson et al. 1987]. Dose adjustment rules based on creatinine clearance have been proposed [Hande et al. 1984] but often fail to achieve SUA target [Dalbeth et al. 2006]. In order to prevent toxicity, starting at a low daily dose, 50–100 mg daily and further slow uptitration seems to be effective and safe [Sivera et al. 2014a]. Slow uptitration also reduces the probability of an acute attack after ULT onset [Zhang et al. 2006]. An example of slow titration is proposed by the European League Against Rheumatism (EULAR) recommendations: start allopurinol at 100 mg daily and then increase by 100 mg increments every few weeks (in our experience weekly increases are safe) until the desired SUA levels are achieved [Zhang et al. 2006]. It is generally recommended that allopurinol should not be started or stopped during a flare as it has been suggested that these situations may worsen the attack and make the recovery longer. Recent data, albeit of two small studies, suggest that these fears might be misplaced [Hill et al. 2015; Taylor et al. 2012]; but in any case there is no reason to stop the SUA lowering treatment during a flare.

Hypersensitivity syndrome may occur with allopurinol and remains the main safety concern. Symptoms usually begin 2–6 weeks after the initiation and can be distinguished from other drug hypersensitivity syndromes because there is usually no lymphadenopathy and renal involvement is more common. This situation can potentially be lethal. The risk of a hypersensitivity reaction seems to be reduced by adjusting the initial allopurinol dose to the renal function and slowly uptitrating the dosage [Gutiérrez-Macías et al. 2005], as indicated in the EULAR and American College of Rheumatology (ACR) recommendations [Zhang et al. 2006; Khanna et al. 2012].

Febuxostat

Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase. The metabolism is predominantly hepatic and this is an advantage for patients with gout and chronic kidney disease (CKD), a common comorbidity that affects around 10% of patients [Richette et al. 2015]. Short-term pharmacokinetic studies performed in subjects without gout with mildly impaired renal function [Mayer et al. 2005] suggest that dose adjustment of febuxostat may not be required in these patients. However, in clinical trials patients with severe CKD have been excluded [Schumacher et al. 2008] and caution is advised in patients with a severely reduced estimated glomerular filtration rate (below 30 ml/min/1.73 m²) [EMA, 2015a].

Febuxostat in doses of 80 or 120 mg daily reduced SUA levels to below 6 mg/dl (0.36 mmol/l) in 62% of patients [Becker et al. 2005]. In another clinical trial, that included 1072 patients with gout, patients were randomized to febuxostat (80, 120 or 240 mg daily), allopurinol (100 or 300 mg daily) or placebo. At all doses febuxostat showed more effectiveness in keeping SUA levels below 6 mg/dl (0.36 mmol/liter) compared with allopurinol at 100–300 mg daily [Schumacher et al. 2008]. In a more recent retrospective study that compared effectiveness of febuxostat and allopurinol, febuxostat (40 or 80 mg daily) was more effective than allopurinol (300 mg daily or lower) in lowering SUA and was quicker in achieving the SUA goals [Singh et al. 2015]. Thus, these data suggest that febuxostat is superior to allopurinol in achieving the SUA target. However, this should be taken with caution as the use of allopurinol in those studies was not optimized.

Regarding safety, adverse events were similar with febuxostat and allopurinol [Schumacher et al. 2008; Huang et al. 2014; Tausche et al. 2014]. The reasons for withdrawal were similar across groups except gout flares, which were more frequent with febuxostat than with allopurinol (probably as a consequence of a deeper and swifter SUA reduction by the relatively higher doses available). Febuxostat is an option for patients with prior rash or hypersensitivity reaction to allopurinol [Chohan, 2011], remembering that a hypersensitivity reaction to febuxostat can occur [Abeles, 2012].

Uricosurics drugs

In the majority of patients, hyperuricemia is due to a reduced renal clearance of uric acid [Pérez-Ruiz et al. 2002a]. Hence it is reasonable to use drugs that increase urate renal excretion. Due to the low availability of specific drugs in many countries and safety concerns (especially with benzbromarone), uricosuric therapy is usually an option when the target SUA levels are not achieved or toxicity issues with XOI arise. In addition, in difficult-to-manage patients it is possible to combine a uricosuric drug with allopurinol or febuxostat to enhance SUA reduction [Reinders et al. 2007]. Due to the increase in urate renal excretion, caution with the use of uricosuric drugs in patients with a history of renal calculi is advisable and alkalinization of the urine is recommended to avoid renal calculi formation. Also, when the uricosuric is combined with a XOI the amount of uric acid excreted by kidneys is reduced by the effect of the latter, thus lessening the chances of developing renal stones.

Benzbromarone is the most widely used uricosuric drug in Europe but it is unavailable in America. In 2003 it was withdrawn from the market after several cases of lethal liver toxicity were reported, but it remains available for restricted use in several European countries. It has afterwards been shown that benzbromarone has no more toxicity than allopurinol or colchicine [Lee et al. 2008; Jansen et al. 2004] and the withdrawal of benzbromarone from the market may have been unnecessary. In clinical trials [Reinders et al. 2009a; Pérez-Ruiz et al. 1999] no relevant differences have been found between benzbromarone and allopurinol in their ability to achieve SUA normalization, and no differences were found in withdrawals due to adverse events. Benzbromarone starting dose is 50 mg daily, to be increased in steps of 50 mg until the required maintenance dose is reached (maximum dose of benzbromarone is 200 mg daily). Benzbromarone can be used in patients with renal impairment at advanced stages of the disease [Pérez-Ruiz et al. 1999], and it is a valid option for transplanted patients using azathioprine or cyclosporine which limits the use of XOI due to drug interactions [Zürcher et al. 1994].

There are other uricosuric drugs like probenecid and sulfinpyrazone. Probenecid is recommended by ACR guidelines [Khanna et al. 2012] and is available in America. In patients whose condition fails to respond to allopurinol the addition of probenecid has been shown to be effective [Reinders et al. 2007]. Probenecid is started at 500 mg daily, increasing to 1500–2000 mg daily to achieve target SUA. Benzbromarone is probably more effective than probenecid in attaining SUA normalization and a study showed fewer withdrawals due to adverse events with benzbromarone [Reinders et al. 2009b].

Lesinurad is a phase III drug which inhibits the uric acid transporter 1, like benzbromarone, which is located in the proximal tubule, blocking the uric acid reabsorption and acting as a uricosuric drug. Lesinurad in combination with allopurinol increases the number of patients achieving the SUA target when it is compared with placebo plus allopurinol [Saag et al. 2015; Bardin et al. 2015]. It has also been combined with febuxostat versus febuxostat alone in tophaceous gout. The combination treatment increased the proportion of patients achieving the target SUA [Dalbeth et al. 2015]. Thus, lesinurad is a promising drug for the management of severe gout cases with an insufficient SUA reduction by XOI agents alone.

Uricase

Unlike most mammals, upper primates and humans do not have a functional uricase. This enzyme degrades uric acid into allantoin, a more soluble molecule, easily eliminated through the kidney. With uricase treatment it is possible to achieve an immediate, significant reduction of SUA levels [Goldman et al. 2001]. Rasburicase is a recombinant uricase licensed for the treatment and prevention of tumour lysis syndrome which has been used in selected patients with severe gout [Richette et al. 2007]. A monthly dose of rasburicase seems to be an effective option, but its short half life and the possible appearance of antibodies against the drug with repeated doses (in the authors’ experience after fifth to sixth infusion) that reduces the drug effect and encourages hypersensitivity reactions should be noted. In addition, the sharp SUA reductions often result in severe gouty attacks in these patients, requiring intense prophylaxis schemes (such as prednisone 30 mg daily for 5 days).

Pegloticase is a pegylated uricase developed in an attempt to avoid immunogenicity issues and increase the half life of the drug. The effectiveness of this drug has been proved in severe cases of gout [Sundy et al. 2011; Becker et al. 2013], defined as ‘three or more self-reported gout flares in the previous 18 months, 1 or more tophi, or gouty arthropathy’. Pegloticase is used intravenously 8 mg every 2 or 4 weeks. Preinfusion SUA level monitoring is recommended in order to reveal a loss of effectiveness, which should be suspected if SUA levels are higher than 6 mg/dl (0.36 mmol/liter). In this situation pegloticase should be discontinued as the SUA increase is associated with the development of pegloticase antibodies and an increased risk of infusion reactions. Its role in gout treatment has yet to be properly defined, and may have a place in those situations in which it is desirable to achieve a rapid reduction of urate crystal deposits [Pascual et al. 2013].

Other drugs

There are other drugs which can be useful in gout, but their effect seems mild and collateral. For example, losartan has shown a uricosuric effect [Puig et al. 1999] and in one clinical trial fenofibrate has demonstrated uricosuric and SUA lowering effects [Bastow et al. 1988]. Losartan and fibrates can be useful in combination with the previously mentioned drugs when the patient also has hypertension or hypertriglyceridaemia [Takahashi et al. 2003].

Prophylaxis

Gout is characterized by recurrent acute inflammatory attacks. Patients continue to be at risk of acute inflammatory episodes even after initiation of ULT, as long as MSU deposits are not cleared. At this point it is very important to ensure treatment adherence as an inflammatory episode can negatively impact patient compliance. The patient should understand that attacks may result as a consequence of effective SUA treatment, and the importance of prophylaxis. Thus the patient will benefit from receiving prophylaxis, ideally beginning 1–2 weeks prior to the start of ULT. The optimal duration of prophylaxis is unclear and should be decided together with the patient and based on individual factors. A period of 6 months after ULT initiation has been recommended, as after prolonged successful SUA-lowering therapy the risk of gouty attacks is lower [Beutler et al. 2001].

During intercritical periods a subclinical inflammation persists in joints induced by the presence of MSU crystals. Daily colchicine reduces the synovial fluid white cell count [Pascual and Castellano, 1992] and works by settling the subclinical inflammation and making it more stable. Colchicine is the most widely used drug for flare prophylaxis. Two clinical trials have shown the effectiveness of low-dose colchicine (0.6–1.5 mg daily) in preventing flares and their severity [Borstad et al. 2004; Paulus et al. 1974]. A common side effect is diarrhoea but at low doses (0.5–0.6 mg daily or every other day), colchicine is generally well tolerated. In our experience an alternative is a daily low-dose nonsteroidal anti-inflammatory drug (NSAID), that is, naproxen 250 mg daily or, in severe and constantly flaring gout, prednisone (5–7.5 mg daily) [Sivera et al. 2014a] or even anti-interleukin (IL)-1β therapies, as discussed later, but these strategies have not been properly tested.

Treatment of acute inflammation

Gouty attacks probably result from a disturbance of the equilibrium attained between cells and crystals in the joint cavity during intercritical periods. The flares have been traditionally treated with NSAIDs, corticosteroids or colchicine, with generally good results in the majority of patients; however, patients with gouty attacks often have multiple comorbidities that often limit the use of these therapies. A relatively recent systematic review suggests that NSAIDs [including selective cyclooxygenase 2 (COX2) inhibitors], corticosteroids (oral and intramuscular), adrenocorticotropic hormone (ACTH), colchicine and canakinumab (IL-1β inhibitor) are all effective therapies for acute attacks [Khanna et al. 2014]. It is advisable to educate patients about treatment of acute attacks if they occur.

NSAIDs

NSAIDs are widely used in gout, and they are considered a convenient and well accepted therapeutic option [Zhang et al. 2006]. They should be used at maximal doses, which can be reduced when symptoms start to subside. NSAIDs should be started as soon as symptoms develop. The choice of the specific NSAID is largely a matter of personal preference. Both selective COX2 inhibitors and traditional NSAIDs are effective in treating acute flares. A recent systematic review that includes six trials (851 patients) shows a similar effectiveness of etoricoxib (120 mg administered orally once daily) to indomethacin and diclofenac in acute gout, with a better gastrointestinal tolerance [Zhang et al. 2015]. Another selective COX2 inhibitor, celecoxib, is comparable to indomethacin in the treatment of moderate to extreme pain in patients with acute gouty arthritis [Schumacher et al. 2012]. A systematic review concluded that NSAIDs and selective COX2 inhibitors produced similar benefits in terms of pain, swelling and global improvement, but traditional NSAIDs were associated with more withdrawals due to adverse events [Van Durme et al. 2014].

Side effects of these drugs (gastrointestinal, cardiovascular and renal) are the major limitation for the use of NSAIDs in acute gouty arthritis, which often involves older patients in whom comorbidities are prevalent. This fact should be taken into account when considering NSAIDs for gout flares treatment.

Colchicine

Colchicine has been used for the treatment of acute gout for many decades. Some trials, and daily practice, suggested that colchicine resulted in very frequent gastrointestinal side effects [Ahern et al. 1987]; however, the doses used were higher than those generally used nowadays. A large multicentral trial in patients with gout with normal renal function has shown equivalent efficacy of acute low-dose colchicine (1.8 mg: 1.2 mg followed by 0.6 mg in 1 h) and high-dose colchicine (4.8 mg: 1.2 mg followed by 0.6 mg every hour, for 6), with significantly less gastrointestinal toxicity in the lower dose group [Terkeltaub et al. 2010]. High-dose schemes of colchicine for acute gout flares must therefore be avoided.

Colchicine toxicity and drug interactions remain a concern [Terkeltaub, 2009]. Toxicity commonly appears as an acute gastrointestinal effect but myelotoxicity or myotoxicity after prolonged use has been described, often in older patients with comorbidities [Debie et al. 2003]. In the presence of renal or hepatic impairment colchicine doses must be reduced or alternative therapies should be considered.

Corticosteroids

Corticosteroids can be used through a parenteral, oral or even intraarticular route. They are an excellent option in case of contraindications for colchicine or NSAID use, but also for the average patient. A short course of systemic glucocorticoids [Janssens et al. 2008a, 2008b; Man et al. 2007] or ACTH [Daoussis et al. 2014] has been found to be effective. An example could be oral prednisone 30 mg for 2–4 days, followed by a rapid tapering to zero. Intramuscular corticosteroids are as effective as indomethacin [Alloway et al. 1993] and are a good option for cases with polyarticular joint involvement. Short courses of corticosteroids may be followed by a rebound attack; this situation can be prevented if prophylaxis with low-dose colchicine is initiated simultaneously.

In our experience intraarticular glucocorticoids are a quick and effective option for acute attacks, even at small doses [Fernández et al. 1999]. Joint infection should be ruled out before intraarticular glucocorticoids are administered.

Anti-IL-1

IL-1β is the main proinflammatory cytokine responsible for crystal-induced inflammation. IL-1β inhibitors have been appraised for the treatment of different inflammatory conditions, including patients with refractory gouty flares or who are intolerant to conventional therapies. Data about three IL-1β inhibitors are available in gout so far: canakinumab, rilonacept and anakinra [Tran et al. 2013].

All three IL-1β inhibitors are generally well tolerated, but several potential harms deriving from IL-1β inhibition must be noted. Safety issues with IL-1β blockade use, especially infection, should be kept in mind [Sivera et al. 2014b]. As for many subcutaneous drugs, there is also a possibility of injection site reactions.

Canakinumab

Canakinumab is an anti-IL-1β monoclonal antibody with a plasma half life of 3–4 weeks. In two randomized trials a single subcutaneous dose of 150 mg of canakinumab was more effective than a single intramuscular triamcinolone acetonide (40 mg) in pain relief and swelling improvement during a gout flare [Schlesinger et al. 2012]. However, safety concerns with canakinumab led the US Food and Drug Administration (FDA) to reject approval for gout flares [FDA, 2015]. In 2013, the European Medicines Agency (EMA) approved canakinumab in restricted situations (patients with more than three flares per year in which the use of NSAIDs and colchicine is limited and repeated corticosteroid courses are not appropriate) [EMA, 2015b].

Rilonacept

Rilonacept is a fully human soluble receptor of IL-1. A single clinical trial compared rilonacept and indomethacin in monotherapy and the combination of rilonacept plus indomethacin in patients with an acute gout flare. Neither rilonacept arms (monotherapy and combination) were more effective at reducing pain at 72 h compared with indomethacin alone [Terkeltaub et al. 2013]; the rate of adverse events was similar. This drug is currently not licensed for gout.

Anakinra

Anakinra is an IL-1 receptor antagonist that inhibits the activity of IL-1α and IL-1β. Several case series show patient improvement of acute gout flares in terms of both pain and inflammation [So et al. 2007]. There are no controlled clinical trials of anakinra in acute gout. Anakinra is relatively well tolerated for short-term use, and in the authors’ experience could be a relevant option for treating a gouty attack and to prevent flares when ULT is started; long-term use may be limited by infectious complications [Ottaviani et al. 2013].

Lifestyle

Lifestyle and dietary habits are related to the remarkable increase of hyperuricemia and gout in recent decades in many countries [Miao et al. 2008]. The relationship between gout and metabolic syndrome should be noted [Choi et al. 2007], and a diagnoses of gout must be followed by an evaluation of cardiovascular risk factors. There is no evidence to recommend a specific diet [Lee et al. 2006], but a low-fat diet in patients with obesity has shown an increase in urate clearance [Tinahones et al. 1997]. Guidelines recommend limiting the consumption of purine-rich meat, seafood, alcohol and fructose-based beverages.

Conclusion

The concept of gout as a crystal deposition disease remains essential in order to plan an appropriate disease management strategy. The main aim is to lower SUA levels to target, commonly established at less than 6 mg/dl (0.36 mmol/liter), but which should be lower in selected patients and those with severe gout to hasten crystal dissolution. ULT drugs must be titrated up to achieve the target SUA. When the SUA target has not been achieved, drug doses should be increased or drug combinations should be considered. When ULT is prescribed, a prophylaxis scheme should be established concomitantly in order to avoid gout flares as these impact negatively on patients and on their adherence. Explanation to the patient of the aim of the different drugs used is essential. The result of poor management is for gout to become a chronic condition. However, MSU deposition is reversible and gout therefore curable.