Recent pharmacological advances in the management of gout

Recent pharmacological advances in the management of gout Abstract Gout is the most common cause of inflammatory arthritis worldwide, and reports show that despite availability of therapies, management is still suboptimal. The new EULAR 2016 recommendations for the treatment of gout highlight the huge development in gout therapies, and the number of drugs being trialled only continues to increase. A clinical review of the evidence that underlies the recommendations from EULAR can reveal possible gaps in the literature and avenues for future research into gout therapies. gout, management, EULAR, IL-1, allopurinol, canakinumab, anakinra, febuxostat, pharmacology, lesinurad Rheumatology key messages Canakinumab remains the only IL-1 agent approved to be used in acute gout flares. More trials are needed comparing anakinra with conventional gout treatment, after promising reports. Inclusion of gout patients with renal failure is needed when trialling urate-lowering therapies. Introduction Gout is the most common cause of inflammatory arthritis worldwide [1] and its prevalence is increasing [2]. Despite the availability of therapies for acute flare management of gout to lower urate levels, studies report that the management of gout is often suboptimal [2]. The EULAR 2016 recommendations for the treatment of gout [3] highlighted not only guidance on how to treat the condition, but also an insight into the research behind the drugs and the mechanisms of the newer drugs coming through. The development of Febuxostat has been heralded as a new era for gout treatment [4] as has the discovery of the role of IL-1 and the NLRP3 inflammasome [5]. There are several new drugs that are being developed for the control of hyperuricaemia that do not target xanthine oxidase. In light of the EULAR 2016 recommendations for the treatment of gout, this review aims to review the literature with regard to the newer therapies outlined by the guidance. This review will provide an update on current trials for the gout therapies outlined by the 2016 EULAR guidelines. Furthermore, this review will report the common doses and side effects for these newer medications to help non-expert clinicians identify them on the wards. Strategy This review focused on randomized control trials and case series for medications mentioned in the EULAR 2016 recommendations for the treatment of gout. The search engines used included Pubmed, Onesearch, the Cochrane library and Web of Science and was conducted in March 2017. Only papers written in English or those which included an English translation were accepted. There were no date restrictions placed when searching for trials. The search strategy resulted in 38 papers being identified (see Fig. 1) and they are the subject of this review article. The search results had their titles and abstracts reviewed. The citations from within these papers were also evaluated. Trials included all had the primary end point of serum uric acid (UA) of <6.0 mg/dl for urate lowering therapies (ULTs) and for the resolution of the flare in terms of pain for therapies for acute flare management. The following points were seen when evaluating the agents discussed: the populations included in the trials, renal disease, reported side effects and the efficacy of the agent. Fig. 1 View largeDownload slide Search strategy Fig. 1 View largeDownload slide Search strategy The IL-1 inhibitors—acute flare management IL-1 is a proinflammatory cytokine that has been shown to play an important role in gouty inflammation [5]. MSU crystals activate the NLRP3 inflammasome through a number of pathways after the MSU crystals are released into the synovial fluid, where they bind to toll-like receptors on macrophages leading to their phagocytosis [6]. The MSU crystals destabilise the phagolysosome. This is associated with the generation of reactive oxygen species, which activate the inflammasome leading to the activation of the important enzyme caspase-1, which leads to the generation of active IL-1β, resulting in an inflammatory response [5]. As a result of these findings, IL-1 has been a target for recent drug therapies. These include canakinumab, anakinra and rilonacept. Canakinumab Canakinumab is a fully human monoclonal anti-IL-1β antibody and was originally approved in 2009 in the USA for the treatment for children with cryopyrin-associated periodic syndromes. It has a 28-day half-life and is administered subcutaneously as a single 150 mg dose that may be repeated 12 weeks later if symptoms recur. Flare management Schlesinger et al. [7] conducted a trial, albeit single blind, on 200 patients who had acute gouty arthritis who could not take NSAIDs and/or colchicine. Patients were randomized to receive either subcutaneous canakinumab (doses ranging from 10 to 150 mg) or an i.m. 40 mg dose of triamcinolone acetonide (standard dose 40–100 mg [8]) and were followed up for 8 weeks. The results found that the 150 mg dose of canakinumab provided a significantly greater and faster reduction in the signs and symptoms of inflammation (tenderness and swelling) and pain compared with triamcinolone acetonide. Following the results from these previous two trials, two further trials were conducted using 150 mg of canakinumab compared with 40 mg of triamcinolone acetonide, using a larger pool of patients with difficult-to-treat gout. The two trials (B-RELIEVED and B-RELIEVED II) were double-blinded, phase III trials reported together in one paper [9]. The patients included in the B-RELIEVED trials had had an acute gout flare-up for <5 days and had a pain intensity of >50 on a 100-point visual analogue scale. The patients also had a contraindication, intolerance or not adequate response to NSAIDs and/or colchicine. A total of 225 patients received canakinumab 150 mg and 229 received triamcinolone acetonide 40 mg. The results showed that a single dose of canakinumab of 150 mg reduced the risk of new flares, provided fast and sustained pain relief and reduced the signs and symptoms of inflammation. Over the 24-week period of the trials the risk of subsequently gouty arthritic attacks was reduced by 56% with canakinumab compared with triamcinolone acetonide (P = 0.0001). While these findings are promising, the 40 mg dosage of triamcinolone acetonide is considered to be low by specialists and therefore may be a suboptimal comparator [10]. Furthermore, the significant findings for the reduction of pain have been considered to be of ‘borderline clinical significance’. Considering a 150 mg dose of canakinumab costs £9926.31 more than 40 mg of triamcinolone acetonide, the National Institute for Health and Care Excellence (NICE) advise that all treatments should be optimized before canakinumab is considered [10]. Flare prophylaxis Schlesinger et al. [11] conducted a double-blind trial with 432 patients with gouty arthritis who were initiating allopurinol treatment and divided them into groups to receive one of three treatments: (i) a single dose of canakinumab, with dosing ranging from 25 to 300 mg subcutaneously, (ii) 4 × 4 weekly doses of canakinumab or (iii) daily 0.5 mg of colchicine for 16 weeks. The results showed that patients treated with canakinumab experienced a 62–72% reduction in the mean number of flares for doses >50 mg compared with colchicine (P < 0.0083), and the number of patients experiencing more than one flare was significantly lower for all canakinumab doses compared with colchicine. Furthermore, there was a 64–72% reduction in the risk of experiencing more than one flare in patients taking >50 mg of canakinumab compared with colchicine. There was no difference in the number of adverse effects suffered by patients between any of the three groups. Adverse events Despite the positives, canakinumab is associated with an increased risk of infection. In the 24-week period of the B-RELIEVED trials, the infection rate was 20.4% in patients treated with canakinumab compared with 12.2% in those taking triamcinolone acetonide. In the development of canakinumab, hypersensitivity reactions have been reported, mainly ranging from mild to moderate [12], and this is reflected in the literature. During the B-RELIEVED trials, two participants receiving canakinumab injections reported mild or moderate reactions at the injection site. Furthermore, canakinumab should not be commenced in patients with active or latent tuberculosis or neutropenia, and patients should be monitored for the symptoms of both tuberculosis and the development of neutropenia [12]. Currently, canakinumab is approved for use in Europe for patients who have contraindication to NSAIDs, colchicine and steroids [3]. Anakinra Anakinra is an IL-1 receptor antagonist originally approved for use in treating RA. A small pilot study investigating its use for gout, conducted by So et al. [13], involved 10 patients who had failed standard therapies (NSAIDs, colchicine or steroids) or were otherwise contraindicated. The patients received 100 mg anakinra subcutaneously daily for 3 days. The results found all 10 patients responding rapidly to the drug, with the main response seen in the first 24 h; all patients had responded within 48 h. When the patients were examined clinically on day 3, 9/10 patients showed complete resolution of signs of arthritis. Despite these findings, there have been no further trials using anakinra for gout treatment [3], although there are a series of case reports highlighting its potential [14]. Small studies in which patients were given 100 mg subcutaneously for 3 days [15–19] showed a significant improvement in gout symptoms after treatment, usually within 24 h, as well as good tolerability. Reports using anakinra in hospitalized patients and critically ill patients [14, 17, 20] found that either the majority or all of their patients had a significant response to anakinra. So et al. reported no treatment-related side effects or relapses, similar to two case reports totalling 29 patients. One retrospective analysis of anakinra use in 10 patients notes that relapses occurred in 90% of patients within 3–45 days [15]. Furthermore, the largest retrospective analysis of anakinra used in 40 patients reported that 13 of their patients relapsed after a median time of 15 days [16]. Other side effects of anakinra include drug-site reactions and infection. Of the 40 patients analysed, seven infections were reported, with six of these infections occurring in patients with long-term continuation of anakinra (predominantly staphylococcal infections) [16]. Anakinra is not currently recommended for the treatment of gout, but formal clinical trials comparing it with conventional anti-inflammatories are proposed by EULAR [3]. There are concerns about the pharmacokinetics of anakinra, such as a short half-life [21]. A recent study suggested an additional anti-inflammatory mechanism of anakinra [22], although concerns remain about drug-site reactions with its use [23]. Rilonacept Rilonacept acts as a soluble decoy receptor for IL-1α and IL-1β [24]. A trial investigating its use recruited 225 patients compared across three groups: a rilonacept (320 mg) plus indometacin group (50 g, three times a day for 3 days), a rilonacept plus oral placebo group and a placebo s.c. injection plus indometacin group [25]. Patient-reported pain was recorded over 3 days. All groups improved over the 3 days, but there was no difference found between the indometacin only and the indometacin and rilonacept group. The rilonacept-only group was inferior to both the other groups. The theory behind its ineffectiveness concerned the time-scale by which rilonacept was administered (<48 h of symptoms onset). In comparison with both anakinra and canakinumab, rilonacept is the largest (∼250 kDa), and has the longest half-life, of all of the IL-1 inhibitors. Therefore the size of rilonacept may have limited its rate of distribution to target tissues during an acute attack. The long half-life of rilonacept means that its future may reside in preventing gout flares, as opposed to its use in acute flares, where it has been recently rejected by the US Food and Drug Administration (FDA) due to safety concerns [23]. Research looking at rilonacept has focused now on its role in flare prevention, as opposed to a treatment for the flare itself, where it has demonstrated significant reductions in gouty flares both with allopurinol [25] and against placebo [26]. The PRESURGE trial [25] compared three groups of patients (n = 82–84), all treated with allopurinol, with either 80 mg or 160 mg of rilonacept or placebo over 16 weeks. Allopurinol was titrated every 2 weeks in each group, as needed, to a maximum daily dose of 800 mg. They found that both rilonacept groups had significantly fewer gout glares, significantly longer median time to the first gout flare and significantly less pain compared with the placebo. When compared against placebo in patients currently taking or initiating ULT in the RESURGE trial [26], those treated with 160 mg of rilonacept were found to have significantly fewer gout flares per patient and flare days relative to placebo over the course of 16 weeks. Adverse reactions for rilonacept are generally classed as mild-to-moderate, with the most commonly reported being headaches, dizziness and injection site reactions [25–27]. Despite these effects, rilonacept has been considered to demonstrate an acceptable safety and tolerability profile [25], and its future use may be reserved for lower gout flares to cover those patients initiating ULTs, rather than to treat an acute flare alone. ULT Allopurinol is the current mainstay of treatment for hyperuricaemia, and two RCTs have confirmed its superior urate-lowering efficacy compared with placebo in the last 10 years [28, 29]. Furthermore, studies have reported the cost-effective protocol of dose-escalating allopurinol [30, 31]. Other ULTs include febuxostat, uricosuric agents and pegloticase. Febuxostat Febuxostat, currently second-line for the treatment of hyperuricaemia, is a non-purine analogue inhibitor of xanthine oxidase. It is currently approved at daily doses of 80–120 mg in Europe [3]; it is metabolized via the liver and its pharmacokinetics are not especially dependent on renal clearance, allowing it to be used in patients with moderate kidney failure [24]. Febuxostat has been the subject of four large trials and has been shown to have superior urate-lowering efficacy at 80 or 120 mg doses when compared directly with a standard fixed daily dose of allopurinol (300 mg, usual dose 300–600 mg [32]) (P < 0.001) [28, 33–35], although, two trials [33, 35] failed to include those with a serum creatinine >133 μmol/l, a patient group who would comprise a significant number of the patients receiving the drug. Febuxostat 40 mg/day was also shown to be non-inferior to allopurinol 200 or 300 mg/day. A large number of case reports have demonstrated the urate-lowering capabilities of febuxostat in either tophaneous or refractory gout resistant to other ULTs [14, 36–38]. The urate-lowering effect of febuxostat is unaltered in patients with renal impairment, and trials looking at patients with both gout and renal impairment (defined either as an estimated creatinine clearance of 60–89 ml/min [34] or a serum creatinine level of between 1.5 and 2.0 mg/dl [28]) have found febuxostat to be effective in lowering MSU levels. There are, however, no studies comparing the efficacy of febuxostat with allopurinol using a dose-escalation approach [3]. The antihyperuricaemic activity of febuxostat is largely dose dependent. Febuxostat 80 mg/day was found to be significantly more effective than 40 mg/day, and 120 mg/day was found to demonstrate greater urate-lowering efficacy than 80 mg/day, which simultaneously evaluated these doses. Febuxostat has been shown to be effective in reducing serum UA levels below 300 μmol/l and maintaining this level over long-term treatment [39, 40]. Furthermore, this sustained reduction in UA level was associated with reduced gout flares and preservation of renal function [41, 42]. A Cochrane review, however, found that patients taking febuxostat compared with allopurinol experienced more gout flare-ups during early treatment [43]. EULAR recommends that patients treated with allopurinol should be switched to febuxostat if there is failure to achieve the pre-determined serum UA target with allopurinol alone [3], or if there is a history of allergy to allopurinol. These findings were echoed in a recent review for the use of febuxostat in the UK [44]. Additionally, febuxostat has been reported to be a cost-effective second-line agent to allopurinol [45]. As febuxostat may become more common in the population, especially among those with renal failure, clinicians should be aware of its potential side effects. The most commonly reported adverse events with febuxostat are abnormal liver function tests, so it is recommended that these are performed prior to initiation. Rarely, allergy and hypersensitivity reactions occur in patients receiving febuxostat, so patients are closely monitored, especially during the early stages of treatment, as the majority of reactions occur within 1 month of starting febuxostat [46–48]. In the long-term clinical extension studies of febuxostat, there was an increase in investigator-reported cardiovascular events with febuxostat compared with allopurinol [49]. Although this observation was not significant, the European Union Risk Management Plan for febuxostat indicated that a study to evaluate the cardiovascular safety of the drug was to be conducted. The trials, FAST [49] and CARES [50], are ongoing prospective studies designed to evaluate the cardiovascular safety profile of both drugs. Uricosuric agents Uricosuric agents promote the renal excretion of UA. Compared with the 2006 EULAR recommendations, the 2016 recommendations highlight using the so-called uricosuric agents, either as an alternative to febuxostat or in combination with a xanthine oxidase inhibitor. Included in the recommendations were the more potent benzbromarone and the less potent probenecid. Both work by inhibiting organic anion transporters in the kidney. In an add-on trial with patients who were without proper control on allopurinol, daily benzbromarone 200 mg was shown to be more effective than daily probenecid 2 g with 92% of patients reaching an UA target of 0.30 mmol/L [51]. Another trial [52] used 100 mg benzbromarone vs 300 mg allopurinol (stage 1), or 200 mg benzbromarone vs 600 mg allopurinol (stage 2) if the target UA was not reached. In stage 1, 52% of patients in the benzbromarone group reached the target UA compared with 26% in the allopurinol group. In stage 2, however, 78% of each group reached the target. This led the authors to suggest that benzbromarone is more potent than allopurinol, but as they are titrated allopurinol becomes equally effective. These findings were also found in another trial comparing allopurinol vs benzbromarone at various dosages [53]. In the lower dosage group (100 mg benzbromarone vs 300 mg allopurinol), 100% of benzbromarone patients reached their UA target (6 mg/dl), whereas only 53% of patient on allopurinol reached theirs, although with up-titration 100% of the allopurinol group reached the UA target. Case reports on benzbromarone claim that, when used with other ULT, the combination therapy is able to lower MSU levels below the target of 6 mg/dl [36, 54]. However in one of these reports, with a patient receiving long-term benzbromarone who is started on allopurinol and febuxostat, the MSU levels were actually increasing, and reached a peak of 28.2 mg/dl, until the allopurinol treatment was initiated [36]. Probenecid is a less potent uricosuric agent. A trial involving probenecid 1000 mg as an add-on therapy to allopurinol 300 mg led to 65% of patients reaching their UA target of 0.30 mmol/l [51]. A case series looking at probenecid monotherapy (n = 30) compared with probenecid and allopurinol combination therapy (n = 27) found that 33 and 37% of patients reached their UA targets, respectively [55]. The recommendation for the usage of uricosuric agents comes from uncontrolled trials suggesting that combination therapies with uricosuric agents and allopurinol are more effective than allopurinol alone [55–58]. In terms of side effects, benzbromarone is associated with abnormal liver function tests, and probenecid is associated with impaired renal function [24]. Recently, the FDA approved a uricosuric agent called lesinurad, a selective UA resorption inhibitor. Clinical trials have demonstrated that, when used in combination with allopurinol, lesinurad reduces mean UA concentrations [6]. The results of two replicate RCTs, CLEAR-1 [59] and CLEAR-2 [60], have recently been published. Following a run-in period with allopurinol, participants were randomized into three groups, all with allopurinol plus either: lesinurad 200 mg, lesinurad 400 mg or placebo. In the CLEAR-2 study at 6 months, 66.5% of patients in the lesinurad 400 mg had reached the UA level of <6.0 mg/dl, compared with 55.4% in the lesinurad 200 mg and 23.3% in the allopurinol-alone group. The onset of UA reduction in the lesinurad groups was much higher than in the allopurinol-alone group, and significant differences were present from month 1. The study concluded that lesinurad was generally well tolerated, with adverse events occurring more often in the 400 mg group compared with the 200 mg and allopurinol-alone groups. The CLEAR-1 study published similar results, with the percentages who reached the UA target at 59.2, 54.2 and 27.9% for the 400, 200 mg and allopurinol-alone groups, respectively. Similar to other uricosuric agents, lesinurad is associated with the development of kidney stones [6]. Pegloticase Since the 2006 EULAR recommendations, the ULT pegloticase has emerged as a treatment for refractory gout. Pegloticase is a PEG-conjugated uricase that aims to convert urate to allantoin, a more soluble and easily excreted end product [61]. The drug is produced by a genetically modified strain of Escherichia coli [3]. Assessment of pegloticase has involved two replicate, 6-month trials in patients with severe gout [62, 63]. Patients either received 12 biweekly intravenous infusions of pegloticase 8 mg (biweekly treatment group), pegloticase alternating with placebo (monthly treatment group) or placebo. The primary end point was a plasma UA level of < 6.0 mg/dl, which was reached by 47% of the patients in the biweekly group, 20% in the monthly group and 0% of patients treated with placebo. Further trials have demonstrated that pegloticase has a statistically significant improvement on quality of life [64] and can reduce tophus burden in patients with refractory tophaceous gout [65]. Similar results were found in case reports using pegloticase for treatment in patients with tophaceous polyarticular gout [66–68], with two claiming reversal or resolution of gouty tophi, although one patient developed a severe reaction during treatment despite an initial improvement [66]. The main problem with pegloticase is that its efficacy can be limited by the development of antibodies, which may in turn lead to allergic reactions [69]. In a trial following 169 patients receiving pegloticase, 89% of patients generated measurable anti-pegloticase antibody, though only 41% developed a high enough titre to have the capacity to affect drug levels. Those who developed the high titre antibody were typically non-responders, whereas responders had a low titre of the antibody [69]. NICE published guidance in 2013 for the use of pegloticase [70]. NICE do not currently recommend pegloticase for people with severe gout with tophi (despite acknowledging that it had worked well), due to its high cost, and concluded that it does not provide enough benefit to justify its cost. NICE were also concerned at the risk of anaphylaxis with pegloticase treatment. EULAR’s updated guidance recommends the use of pegloticase for patients with ‘clinically severe’ gout that cannot be properly treated with a conventional ULT or a combination therapy. It comments that there was ‘no firm agreement’ for the duration of treatment with pegloticase, but there was a consensus to switch to an oral ULT once all tophi had disappeared [3]. Rasburicase Rasburicase, a recombinant uricase, is an agent that was originally approved for tumour lysis syndrome. Trials looking at this agent in the treatment of gout have found that it significantly reduces UA levels and acts faster than first-line allopurinol [71]. An exploratory study conducted by Richette et al. [72] evaluated the short-term safety of raburicase in two patient groups, both of whom had topaceous gout not treatable with allopurinol and who suffered with renal failure. The first group (n = 5) received an infusion each month for 6 months, whereas the second group (n = 5) received an infusion each day for 5 days. All patients were pre-medicated with 60 mg of methylprednisolone. The authors found that UA levels decreased significantly in the first group following their six infusions. The second group experienced a marked decrease in UA levels during treatment, but following completion of treatment, UA levels rose again to pre-treatment levels in all patients. When measured at 1 and 2 months following treatment, UA levels were not significantly lower than baseline. Eight of the 10 patients experienced an adverse event, the most common being an acute gout flare, despite prophylactic colchicine treatment. Furthermore, two of the patients in the second group experienced an allergic reaction (rash and bronchospasm) following their sixth infusion, prompting discontinuation of treatment. The long-term efficacy of rasburicase has been shown in a series of case reports in the literature [73–77]. Two out of the five patients reported acute gout flares following the infusions of rasburicase [74, 75], although all showed either an important reduction in tophi or complete disappearance of tophi. One of these reports [76], which used monthly infusions of rasburicase to accelerate the resolution of disabling tophi in a patient already using a combination of allopurinol, benzbromarone and colchicine, found that initiation of rasburicase reduced UA levels to undetectable levels for a period of time, although, rasburicase was discontinued following its fifth infusion because of flushing and urticarial development. Despite the significant, fast reduction in UA levels with rasburicase and evidence of tophi regression in responding patients, chronic treatment with it is not without risk, and more studies to assess its long-term safety are needed if it is to be considered as a treatment option. Discussion Overall, the management of gout has changed radically since the last EULAR guidelines, and there are a number of treatments now available for both acute flares and for lowering urate levels. While the number of drugs for the treatment of gout are increasing, with more in the pipeline [6], it would possibly be more useful for future research to validate the medications that we currently have at our disposal, such as anakinra [3] rather than pursuing new ventures. Considering the number of newer treatments available, clinicians, rheumatologists or otherwise, should be aware of the side-effects of these newer medications, and should be encouraged to report any such findings, beneficial or otherwise, of these newer medications. Such findings could help shape the already congested number of trials for gout treatments to help us identify which agents are worth pursuing. The EULAR 2016 guidelines, however, provide clinicians with easy-to-follow guidelines for both the acute treatment of gout and for ULTs. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: M.B. has been sponsored to attend national and international meetings by Union Chimique Belge (UCB) celltech, Roche/Chugai, Pfizer, Abbvie, Merck, Mennarini and Eli-lilly and has received honoraria for speaking and attended advisory boards with Bristol-Myers Squib, UCB Celltech, Roche/Chugai/Pfizer, Abbvie, Merck and Mennarini. The other author has declared no conflicts of interest. References 1 Roddy E, Doherty M. Epidemiology of gout. Arthritis Res Therapy  2010; 12: 223. Google Scholar CrossRef Search ADS   2 Kuo CF, Grainge MJ, Mallen C, Zhang W, Doherty M. Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann Rheum Dis  2015; 74: 661– 7. Google Scholar CrossRef Search ADS PubMed  3 Richette P, Doherty M, Pascual E et al.   2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis  2017; 76: 29– 42. Google Scholar CrossRef Search ADS PubMed  4 Burns CM, Wortmann RL. 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For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Recent pharmacological advances in the management of gout

Rheumatology , Volume Advance Article (6) – Sep 14, 2017

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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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Abstract

Abstract Gout is the most common cause of inflammatory arthritis worldwide, and reports show that despite availability of therapies, management is still suboptimal. The new EULAR 2016 recommendations for the treatment of gout highlight the huge development in gout therapies, and the number of drugs being trialled only continues to increase. A clinical review of the evidence that underlies the recommendations from EULAR can reveal possible gaps in the literature and avenues for future research into gout therapies. gout, management, EULAR, IL-1, allopurinol, canakinumab, anakinra, febuxostat, pharmacology, lesinurad Rheumatology key messages Canakinumab remains the only IL-1 agent approved to be used in acute gout flares. More trials are needed comparing anakinra with conventional gout treatment, after promising reports. Inclusion of gout patients with renal failure is needed when trialling urate-lowering therapies. Introduction Gout is the most common cause of inflammatory arthritis worldwide [1] and its prevalence is increasing [2]. Despite the availability of therapies for acute flare management of gout to lower urate levels, studies report that the management of gout is often suboptimal [2]. The EULAR 2016 recommendations for the treatment of gout [3] highlighted not only guidance on how to treat the condition, but also an insight into the research behind the drugs and the mechanisms of the newer drugs coming through. The development of Febuxostat has been heralded as a new era for gout treatment [4] as has the discovery of the role of IL-1 and the NLRP3 inflammasome [5]. There are several new drugs that are being developed for the control of hyperuricaemia that do not target xanthine oxidase. In light of the EULAR 2016 recommendations for the treatment of gout, this review aims to review the literature with regard to the newer therapies outlined by the guidance. This review will provide an update on current trials for the gout therapies outlined by the 2016 EULAR guidelines. Furthermore, this review will report the common doses and side effects for these newer medications to help non-expert clinicians identify them on the wards. Strategy This review focused on randomized control trials and case series for medications mentioned in the EULAR 2016 recommendations for the treatment of gout. The search engines used included Pubmed, Onesearch, the Cochrane library and Web of Science and was conducted in March 2017. Only papers written in English or those which included an English translation were accepted. There were no date restrictions placed when searching for trials. The search strategy resulted in 38 papers being identified (see Fig. 1) and they are the subject of this review article. The search results had their titles and abstracts reviewed. The citations from within these papers were also evaluated. Trials included all had the primary end point of serum uric acid (UA) of <6.0 mg/dl for urate lowering therapies (ULTs) and for the resolution of the flare in terms of pain for therapies for acute flare management. The following points were seen when evaluating the agents discussed: the populations included in the trials, renal disease, reported side effects and the efficacy of the agent. Fig. 1 View largeDownload slide Search strategy Fig. 1 View largeDownload slide Search strategy The IL-1 inhibitors—acute flare management IL-1 is a proinflammatory cytokine that has been shown to play an important role in gouty inflammation [5]. MSU crystals activate the NLRP3 inflammasome through a number of pathways after the MSU crystals are released into the synovial fluid, where they bind to toll-like receptors on macrophages leading to their phagocytosis [6]. The MSU crystals destabilise the phagolysosome. This is associated with the generation of reactive oxygen species, which activate the inflammasome leading to the activation of the important enzyme caspase-1, which leads to the generation of active IL-1β, resulting in an inflammatory response [5]. As a result of these findings, IL-1 has been a target for recent drug therapies. These include canakinumab, anakinra and rilonacept. Canakinumab Canakinumab is a fully human monoclonal anti-IL-1β antibody and was originally approved in 2009 in the USA for the treatment for children with cryopyrin-associated periodic syndromes. It has a 28-day half-life and is administered subcutaneously as a single 150 mg dose that may be repeated 12 weeks later if symptoms recur. Flare management Schlesinger et al. [7] conducted a trial, albeit single blind, on 200 patients who had acute gouty arthritis who could not take NSAIDs and/or colchicine. Patients were randomized to receive either subcutaneous canakinumab (doses ranging from 10 to 150 mg) or an i.m. 40 mg dose of triamcinolone acetonide (standard dose 40–100 mg [8]) and were followed up for 8 weeks. The results found that the 150 mg dose of canakinumab provided a significantly greater and faster reduction in the signs and symptoms of inflammation (tenderness and swelling) and pain compared with triamcinolone acetonide. Following the results from these previous two trials, two further trials were conducted using 150 mg of canakinumab compared with 40 mg of triamcinolone acetonide, using a larger pool of patients with difficult-to-treat gout. The two trials (B-RELIEVED and B-RELIEVED II) were double-blinded, phase III trials reported together in one paper [9]. The patients included in the B-RELIEVED trials had had an acute gout flare-up for <5 days and had a pain intensity of >50 on a 100-point visual analogue scale. The patients also had a contraindication, intolerance or not adequate response to NSAIDs and/or colchicine. A total of 225 patients received canakinumab 150 mg and 229 received triamcinolone acetonide 40 mg. The results showed that a single dose of canakinumab of 150 mg reduced the risk of new flares, provided fast and sustained pain relief and reduced the signs and symptoms of inflammation. Over the 24-week period of the trials the risk of subsequently gouty arthritic attacks was reduced by 56% with canakinumab compared with triamcinolone acetonide (P = 0.0001). While these findings are promising, the 40 mg dosage of triamcinolone acetonide is considered to be low by specialists and therefore may be a suboptimal comparator [10]. Furthermore, the significant findings for the reduction of pain have been considered to be of ‘borderline clinical significance’. Considering a 150 mg dose of canakinumab costs £9926.31 more than 40 mg of triamcinolone acetonide, the National Institute for Health and Care Excellence (NICE) advise that all treatments should be optimized before canakinumab is considered [10]. Flare prophylaxis Schlesinger et al. [11] conducted a double-blind trial with 432 patients with gouty arthritis who were initiating allopurinol treatment and divided them into groups to receive one of three treatments: (i) a single dose of canakinumab, with dosing ranging from 25 to 300 mg subcutaneously, (ii) 4 × 4 weekly doses of canakinumab or (iii) daily 0.5 mg of colchicine for 16 weeks. The results showed that patients treated with canakinumab experienced a 62–72% reduction in the mean number of flares for doses >50 mg compared with colchicine (P < 0.0083), and the number of patients experiencing more than one flare was significantly lower for all canakinumab doses compared with colchicine. Furthermore, there was a 64–72% reduction in the risk of experiencing more than one flare in patients taking >50 mg of canakinumab compared with colchicine. There was no difference in the number of adverse effects suffered by patients between any of the three groups. Adverse events Despite the positives, canakinumab is associated with an increased risk of infection. In the 24-week period of the B-RELIEVED trials, the infection rate was 20.4% in patients treated with canakinumab compared with 12.2% in those taking triamcinolone acetonide. In the development of canakinumab, hypersensitivity reactions have been reported, mainly ranging from mild to moderate [12], and this is reflected in the literature. During the B-RELIEVED trials, two participants receiving canakinumab injections reported mild or moderate reactions at the injection site. Furthermore, canakinumab should not be commenced in patients with active or latent tuberculosis or neutropenia, and patients should be monitored for the symptoms of both tuberculosis and the development of neutropenia [12]. Currently, canakinumab is approved for use in Europe for patients who have contraindication to NSAIDs, colchicine and steroids [3]. Anakinra Anakinra is an IL-1 receptor antagonist originally approved for use in treating RA. A small pilot study investigating its use for gout, conducted by So et al. [13], involved 10 patients who had failed standard therapies (NSAIDs, colchicine or steroids) or were otherwise contraindicated. The patients received 100 mg anakinra subcutaneously daily for 3 days. The results found all 10 patients responding rapidly to the drug, with the main response seen in the first 24 h; all patients had responded within 48 h. When the patients were examined clinically on day 3, 9/10 patients showed complete resolution of signs of arthritis. Despite these findings, there have been no further trials using anakinra for gout treatment [3], although there are a series of case reports highlighting its potential [14]. Small studies in which patients were given 100 mg subcutaneously for 3 days [15–19] showed a significant improvement in gout symptoms after treatment, usually within 24 h, as well as good tolerability. Reports using anakinra in hospitalized patients and critically ill patients [14, 17, 20] found that either the majority or all of their patients had a significant response to anakinra. So et al. reported no treatment-related side effects or relapses, similar to two case reports totalling 29 patients. One retrospective analysis of anakinra use in 10 patients notes that relapses occurred in 90% of patients within 3–45 days [15]. Furthermore, the largest retrospective analysis of anakinra used in 40 patients reported that 13 of their patients relapsed after a median time of 15 days [16]. Other side effects of anakinra include drug-site reactions and infection. Of the 40 patients analysed, seven infections were reported, with six of these infections occurring in patients with long-term continuation of anakinra (predominantly staphylococcal infections) [16]. Anakinra is not currently recommended for the treatment of gout, but formal clinical trials comparing it with conventional anti-inflammatories are proposed by EULAR [3]. There are concerns about the pharmacokinetics of anakinra, such as a short half-life [21]. A recent study suggested an additional anti-inflammatory mechanism of anakinra [22], although concerns remain about drug-site reactions with its use [23]. Rilonacept Rilonacept acts as a soluble decoy receptor for IL-1α and IL-1β [24]. A trial investigating its use recruited 225 patients compared across three groups: a rilonacept (320 mg) plus indometacin group (50 g, three times a day for 3 days), a rilonacept plus oral placebo group and a placebo s.c. injection plus indometacin group [25]. Patient-reported pain was recorded over 3 days. All groups improved over the 3 days, but there was no difference found between the indometacin only and the indometacin and rilonacept group. The rilonacept-only group was inferior to both the other groups. The theory behind its ineffectiveness concerned the time-scale by which rilonacept was administered (<48 h of symptoms onset). In comparison with both anakinra and canakinumab, rilonacept is the largest (∼250 kDa), and has the longest half-life, of all of the IL-1 inhibitors. Therefore the size of rilonacept may have limited its rate of distribution to target tissues during an acute attack. The long half-life of rilonacept means that its future may reside in preventing gout flares, as opposed to its use in acute flares, where it has been recently rejected by the US Food and Drug Administration (FDA) due to safety concerns [23]. Research looking at rilonacept has focused now on its role in flare prevention, as opposed to a treatment for the flare itself, where it has demonstrated significant reductions in gouty flares both with allopurinol [25] and against placebo [26]. The PRESURGE trial [25] compared three groups of patients (n = 82–84), all treated with allopurinol, with either 80 mg or 160 mg of rilonacept or placebo over 16 weeks. Allopurinol was titrated every 2 weeks in each group, as needed, to a maximum daily dose of 800 mg. They found that both rilonacept groups had significantly fewer gout glares, significantly longer median time to the first gout flare and significantly less pain compared with the placebo. When compared against placebo in patients currently taking or initiating ULT in the RESURGE trial [26], those treated with 160 mg of rilonacept were found to have significantly fewer gout flares per patient and flare days relative to placebo over the course of 16 weeks. Adverse reactions for rilonacept are generally classed as mild-to-moderate, with the most commonly reported being headaches, dizziness and injection site reactions [25–27]. Despite these effects, rilonacept has been considered to demonstrate an acceptable safety and tolerability profile [25], and its future use may be reserved for lower gout flares to cover those patients initiating ULTs, rather than to treat an acute flare alone. ULT Allopurinol is the current mainstay of treatment for hyperuricaemia, and two RCTs have confirmed its superior urate-lowering efficacy compared with placebo in the last 10 years [28, 29]. Furthermore, studies have reported the cost-effective protocol of dose-escalating allopurinol [30, 31]. Other ULTs include febuxostat, uricosuric agents and pegloticase. Febuxostat Febuxostat, currently second-line for the treatment of hyperuricaemia, is a non-purine analogue inhibitor of xanthine oxidase. It is currently approved at daily doses of 80–120 mg in Europe [3]; it is metabolized via the liver and its pharmacokinetics are not especially dependent on renal clearance, allowing it to be used in patients with moderate kidney failure [24]. Febuxostat has been the subject of four large trials and has been shown to have superior urate-lowering efficacy at 80 or 120 mg doses when compared directly with a standard fixed daily dose of allopurinol (300 mg, usual dose 300–600 mg [32]) (P < 0.001) [28, 33–35], although, two trials [33, 35] failed to include those with a serum creatinine >133 μmol/l, a patient group who would comprise a significant number of the patients receiving the drug. Febuxostat 40 mg/day was also shown to be non-inferior to allopurinol 200 or 300 mg/day. A large number of case reports have demonstrated the urate-lowering capabilities of febuxostat in either tophaneous or refractory gout resistant to other ULTs [14, 36–38]. The urate-lowering effect of febuxostat is unaltered in patients with renal impairment, and trials looking at patients with both gout and renal impairment (defined either as an estimated creatinine clearance of 60–89 ml/min [34] or a serum creatinine level of between 1.5 and 2.0 mg/dl [28]) have found febuxostat to be effective in lowering MSU levels. There are, however, no studies comparing the efficacy of febuxostat with allopurinol using a dose-escalation approach [3]. The antihyperuricaemic activity of febuxostat is largely dose dependent. Febuxostat 80 mg/day was found to be significantly more effective than 40 mg/day, and 120 mg/day was found to demonstrate greater urate-lowering efficacy than 80 mg/day, which simultaneously evaluated these doses. Febuxostat has been shown to be effective in reducing serum UA levels below 300 μmol/l and maintaining this level over long-term treatment [39, 40]. Furthermore, this sustained reduction in UA level was associated with reduced gout flares and preservation of renal function [41, 42]. A Cochrane review, however, found that patients taking febuxostat compared with allopurinol experienced more gout flare-ups during early treatment [43]. EULAR recommends that patients treated with allopurinol should be switched to febuxostat if there is failure to achieve the pre-determined serum UA target with allopurinol alone [3], or if there is a history of allergy to allopurinol. These findings were echoed in a recent review for the use of febuxostat in the UK [44]. Additionally, febuxostat has been reported to be a cost-effective second-line agent to allopurinol [45]. As febuxostat may become more common in the population, especially among those with renal failure, clinicians should be aware of its potential side effects. The most commonly reported adverse events with febuxostat are abnormal liver function tests, so it is recommended that these are performed prior to initiation. Rarely, allergy and hypersensitivity reactions occur in patients receiving febuxostat, so patients are closely monitored, especially during the early stages of treatment, as the majority of reactions occur within 1 month of starting febuxostat [46–48]. In the long-term clinical extension studies of febuxostat, there was an increase in investigator-reported cardiovascular events with febuxostat compared with allopurinol [49]. Although this observation was not significant, the European Union Risk Management Plan for febuxostat indicated that a study to evaluate the cardiovascular safety of the drug was to be conducted. The trials, FAST [49] and CARES [50], are ongoing prospective studies designed to evaluate the cardiovascular safety profile of both drugs. Uricosuric agents Uricosuric agents promote the renal excretion of UA. Compared with the 2006 EULAR recommendations, the 2016 recommendations highlight using the so-called uricosuric agents, either as an alternative to febuxostat or in combination with a xanthine oxidase inhibitor. Included in the recommendations were the more potent benzbromarone and the less potent probenecid. Both work by inhibiting organic anion transporters in the kidney. In an add-on trial with patients who were without proper control on allopurinol, daily benzbromarone 200 mg was shown to be more effective than daily probenecid 2 g with 92% of patients reaching an UA target of 0.30 mmol/L [51]. Another trial [52] used 100 mg benzbromarone vs 300 mg allopurinol (stage 1), or 200 mg benzbromarone vs 600 mg allopurinol (stage 2) if the target UA was not reached. In stage 1, 52% of patients in the benzbromarone group reached the target UA compared with 26% in the allopurinol group. In stage 2, however, 78% of each group reached the target. This led the authors to suggest that benzbromarone is more potent than allopurinol, but as they are titrated allopurinol becomes equally effective. These findings were also found in another trial comparing allopurinol vs benzbromarone at various dosages [53]. In the lower dosage group (100 mg benzbromarone vs 300 mg allopurinol), 100% of benzbromarone patients reached their UA target (6 mg/dl), whereas only 53% of patient on allopurinol reached theirs, although with up-titration 100% of the allopurinol group reached the UA target. Case reports on benzbromarone claim that, when used with other ULT, the combination therapy is able to lower MSU levels below the target of 6 mg/dl [36, 54]. However in one of these reports, with a patient receiving long-term benzbromarone who is started on allopurinol and febuxostat, the MSU levels were actually increasing, and reached a peak of 28.2 mg/dl, until the allopurinol treatment was initiated [36]. Probenecid is a less potent uricosuric agent. A trial involving probenecid 1000 mg as an add-on therapy to allopurinol 300 mg led to 65% of patients reaching their UA target of 0.30 mmol/l [51]. A case series looking at probenecid monotherapy (n = 30) compared with probenecid and allopurinol combination therapy (n = 27) found that 33 and 37% of patients reached their UA targets, respectively [55]. The recommendation for the usage of uricosuric agents comes from uncontrolled trials suggesting that combination therapies with uricosuric agents and allopurinol are more effective than allopurinol alone [55–58]. In terms of side effects, benzbromarone is associated with abnormal liver function tests, and probenecid is associated with impaired renal function [24]. Recently, the FDA approved a uricosuric agent called lesinurad, a selective UA resorption inhibitor. Clinical trials have demonstrated that, when used in combination with allopurinol, lesinurad reduces mean UA concentrations [6]. The results of two replicate RCTs, CLEAR-1 [59] and CLEAR-2 [60], have recently been published. Following a run-in period with allopurinol, participants were randomized into three groups, all with allopurinol plus either: lesinurad 200 mg, lesinurad 400 mg or placebo. In the CLEAR-2 study at 6 months, 66.5% of patients in the lesinurad 400 mg had reached the UA level of <6.0 mg/dl, compared with 55.4% in the lesinurad 200 mg and 23.3% in the allopurinol-alone group. The onset of UA reduction in the lesinurad groups was much higher than in the allopurinol-alone group, and significant differences were present from month 1. The study concluded that lesinurad was generally well tolerated, with adverse events occurring more often in the 400 mg group compared with the 200 mg and allopurinol-alone groups. The CLEAR-1 study published similar results, with the percentages who reached the UA target at 59.2, 54.2 and 27.9% for the 400, 200 mg and allopurinol-alone groups, respectively. Similar to other uricosuric agents, lesinurad is associated with the development of kidney stones [6]. Pegloticase Since the 2006 EULAR recommendations, the ULT pegloticase has emerged as a treatment for refractory gout. Pegloticase is a PEG-conjugated uricase that aims to convert urate to allantoin, a more soluble and easily excreted end product [61]. The drug is produced by a genetically modified strain of Escherichia coli [3]. Assessment of pegloticase has involved two replicate, 6-month trials in patients with severe gout [62, 63]. Patients either received 12 biweekly intravenous infusions of pegloticase 8 mg (biweekly treatment group), pegloticase alternating with placebo (monthly treatment group) or placebo. The primary end point was a plasma UA level of < 6.0 mg/dl, which was reached by 47% of the patients in the biweekly group, 20% in the monthly group and 0% of patients treated with placebo. Further trials have demonstrated that pegloticase has a statistically significant improvement on quality of life [64] and can reduce tophus burden in patients with refractory tophaceous gout [65]. Similar results were found in case reports using pegloticase for treatment in patients with tophaceous polyarticular gout [66–68], with two claiming reversal or resolution of gouty tophi, although one patient developed a severe reaction during treatment despite an initial improvement [66]. The main problem with pegloticase is that its efficacy can be limited by the development of antibodies, which may in turn lead to allergic reactions [69]. In a trial following 169 patients receiving pegloticase, 89% of patients generated measurable anti-pegloticase antibody, though only 41% developed a high enough titre to have the capacity to affect drug levels. Those who developed the high titre antibody were typically non-responders, whereas responders had a low titre of the antibody [69]. NICE published guidance in 2013 for the use of pegloticase [70]. NICE do not currently recommend pegloticase for people with severe gout with tophi (despite acknowledging that it had worked well), due to its high cost, and concluded that it does not provide enough benefit to justify its cost. NICE were also concerned at the risk of anaphylaxis with pegloticase treatment. EULAR’s updated guidance recommends the use of pegloticase for patients with ‘clinically severe’ gout that cannot be properly treated with a conventional ULT or a combination therapy. It comments that there was ‘no firm agreement’ for the duration of treatment with pegloticase, but there was a consensus to switch to an oral ULT once all tophi had disappeared [3]. Rasburicase Rasburicase, a recombinant uricase, is an agent that was originally approved for tumour lysis syndrome. Trials looking at this agent in the treatment of gout have found that it significantly reduces UA levels and acts faster than first-line allopurinol [71]. An exploratory study conducted by Richette et al. [72] evaluated the short-term safety of raburicase in two patient groups, both of whom had topaceous gout not treatable with allopurinol and who suffered with renal failure. The first group (n = 5) received an infusion each month for 6 months, whereas the second group (n = 5) received an infusion each day for 5 days. All patients were pre-medicated with 60 mg of methylprednisolone. The authors found that UA levels decreased significantly in the first group following their six infusions. The second group experienced a marked decrease in UA levels during treatment, but following completion of treatment, UA levels rose again to pre-treatment levels in all patients. When measured at 1 and 2 months following treatment, UA levels were not significantly lower than baseline. Eight of the 10 patients experienced an adverse event, the most common being an acute gout flare, despite prophylactic colchicine treatment. Furthermore, two of the patients in the second group experienced an allergic reaction (rash and bronchospasm) following their sixth infusion, prompting discontinuation of treatment. The long-term efficacy of rasburicase has been shown in a series of case reports in the literature [73–77]. Two out of the five patients reported acute gout flares following the infusions of rasburicase [74, 75], although all showed either an important reduction in tophi or complete disappearance of tophi. One of these reports [76], which used monthly infusions of rasburicase to accelerate the resolution of disabling tophi in a patient already using a combination of allopurinol, benzbromarone and colchicine, found that initiation of rasburicase reduced UA levels to undetectable levels for a period of time, although, rasburicase was discontinued following its fifth infusion because of flushing and urticarial development. Despite the significant, fast reduction in UA levels with rasburicase and evidence of tophi regression in responding patients, chronic treatment with it is not without risk, and more studies to assess its long-term safety are needed if it is to be considered as a treatment option. Discussion Overall, the management of gout has changed radically since the last EULAR guidelines, and there are a number of treatments now available for both acute flares and for lowering urate levels. While the number of drugs for the treatment of gout are increasing, with more in the pipeline [6], it would possibly be more useful for future research to validate the medications that we currently have at our disposal, such as anakinra [3] rather than pursuing new ventures. Considering the number of newer treatments available, clinicians, rheumatologists or otherwise, should be aware of the side-effects of these newer medications, and should be encouraged to report any such findings, beneficial or otherwise, of these newer medications. Such findings could help shape the already congested number of trials for gout treatments to help us identify which agents are worth pursuing. The EULAR 2016 guidelines, however, provide clinicians with easy-to-follow guidelines for both the acute treatment of gout and for ULTs. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. 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Published: Sep 14, 2017

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