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Table 1.  Clinically relevant data for febuxostat and pegloticase.

Despite these downsides, the target patient for this drug is often miserably symptomatic and often has no other options. Monitoring for a rising serum urate level as a sign of antibody development and impending infusion reaction will allow for safer administration [Wright et al. 2009]. A recent report described a group of patients who were safely maintained on pegloticase alone for a median follow up of 2.5 years [Hamburger et al. 2010]. The frequency of infusion reactions was low in this group, even in subjects with up to 6-month breaks between infusions. Nevertheless, this drug has significant potential toxicity and should only be administered at experienced infusion centers capable of dealing with serious reactions, including anaphylaxis.

Drugs in Development

IL-1 Inhibitors

Elegant studies in the mouse demonstrated 25 years ago that IL-1 is an important mediator of the early inflammatory response to monosodium urate crystals in vivo [Di Giovine et al. 1987; Malawista et al. 2011]. More recently, IL-1 receptor (IL-1R)-deficient mice and mice treated with an IL-1 inhibitor (Rilonacept) had significantly reduced inflammation in response to intra-articular injection of urate crystals [Martin et al. 2009; Torres et al. 2009]. We now know that the innate immune system responds to a variety of pathogens and endogenous molecules, the latter including urate crystals, through recognition of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Recognition of these patterns occurs through germline-encoded, or innate, pattern recognition receptors (PRRs). NLPR3, one of several intracellular macromolecular platforms termed inflammasomes, is activated through this pathway and plays a key role in the IL-1 response in gout [Martinon et al. 2006].

The current paradigm (Figure 2) suggests that monosodium urate crystals bind innate immune system receptors, including Toll-like receptors (TLRs) 2 and 4, on the cell surface of monocytes, leading to enhanced transcription of pro-IL-1β and phagocytosis of the crystals [Chen et al. 2006; Scott et al. 2006]. The phagocytosed crystals then stimulate the assembly of the NLPR3 inflammasome by an as yet undefined pathway, and thus subsequent activation of caspase-1 [Martinon et al. 2006; Kingsbury et al. 2011]. Activated caspase-1 then cleaves pro-IL-1β to active IL-1β. Secreted IL-1β then binds to IL-1R on local endothelial cells and macrophages, signaling them to produce further pro-inflammatory cytokines and chemokines, including TNF-α, IL-6, and neutrophil chemoattractants [Liu-Bryan et al. 2005; Di Giovine et al. 2006; Chen et al. 2006]. These amplify the response, attracting other inflammatory cells, including neutrophils, into the area.

Figure 2.

Initiation of the inflammatory response to monosodium urate crystals (MSU) by the innate immune system. MSU are recognized as danger-associated molecular patterns (DAMPs) by innate immune receptors, including Toll-like receptors (TLRs), on monocytes. A dual signaling process begins. One pathway, involving the adapter protein used by TLRs, MyD88 (myeloid differentiation primary response gene 88), leads to translocation of activated NFκ-β (nuclear factor κ-β) to the nucleus where it activates transcription of pro-IL-1β. Simultaneously, phagocytosis of MSU and processing by the phagosome and lysosome results in assembly and activation of the NLRP3 inflammasome in a cathepsin-B and K+ flux dependent fashion. As a result, procaspase-1 is cleaved to active caspase-1, which in turn cleaves the nascent pro-IL-1β to its active form, which is secreted into the cellular milieu. (IL-18 is released in a similar fashion.) Binding of IL-1β to its receptors on local macrophages and synoviocytes activates a signaling pathway that includes MyD88 and IRAK-4 (ILR1-receptor associated kinase), resulting in NFκ-β activation and translocation to the nucleus. There, NFκ-β mediates transcription of multiple inflammatory cytokines and chemokines, thus greatly amplifying the original danger signal. Other cells are recruited to the area, including neutrophils, and a full blown attack of gout ensues. ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase recruitment domain.

Proof of concept has been established in clinical trials of several IL-1 inhibitors, both for treatment and prophylaxis of gout flares. These agents include anakinra, an IL-1R antagonist, rilonacept, an IL-1 decoy receptor, or Trap, and canakinumab, an anti-IL-1b monoclonal antibody. Note that anakinra and rilonacept inhibit both IL-1α and IL-1β function. In the earliest published study, anakinra, FDA-approved for the treatment of rheumatoid arthritis (Kineret©, Amgen, Thousand Oaks, CA, USA; Swedish Orphan Biovitrum, Stockholm, Sweden), was very effective at 100 mg subcutaneously daily for 3 days in 9 of 10 patients with acute gout at day 3 [So et al. 2007].

Rilonacept. Rilonacept (Araclyst©, Regeneron Pharmaceuticals, Tarrytown, NY, USA) was approved by the FDA in 2008 for children with the autoinflammatory cryopyrin-associated periodic syndromes (CAPSs). In a pilot 14-week, nonrandomized study, 10 patients with treatment failure chronic gout received rilonacept 320 mg subcutaneously, followed by 160 mg subcutaneously per week for 5 weeks [Terkeltaub et al. 2009]. Median pain scores decreased significantly after 2 weeks, and that effect was maintained at 8 weeks. Five of the 10 patients had more than 75% improvement. In a phase II RCT, hyperuricemic patients with at least two gout attacks per year were started on allopurinol. For flare prophylaxis, patients were randomly assigned to either rilonacept 160 mg subcutaneously per week or placebo [Schumacher et al. 2012]. During the 16-week trial, 39/42 patients receiving placebo had flares versus 9/41 patients receiving rilonacept ( p = 0.0036). Adverse events were similar and not serious in both groups. A RCT of the safety and efficacy of rilonacept for acute gout flare compared with indomethacin and both rilonacept and indomethacin has been completed, but the results have not yet been reported. Other studies are active (see http://clinicaltrials.gov/ct2/results?term=rilonacept).

Canakinumab. Canakinumab (Ilaris©, Novartis Pharma AG, Basel, Switzerland) is a fully human monoclonal anti-IL-1β antibody with a 28-day half-life that was approved by the FDA and EMEA in 2009 for CAPS. In an 8-week, multicenter RCT, 147 patients with acute gout, refractory or with contraindications to NSAIDs and colchicine, received one subcutaneous injection of canakinumab at various doses, while 57 similar patients received a single intramuscular injection of 40 mg triamcinolone acetonide (TCA) [So et al. 2010; Schlesinger et al. 2011a]. The canakinumab 150 mg dose was significantly more effective than TCA at reducing pain and did so more rapidly. In the canakinumab group, only 3.7% of patients experienced another flare over the trial period, whereas 45.4% of patients given TCA had another flare ( p = 0.006). A recently published study examined canakinumab as flare prophylaxis in 437 patients starting allopurinol [Schlesinger et al. 2011b]. The 16-week RCT randomized patients to single doses of canakinumab ranging from 25 to 300 mg, or 4 weekly shots (50 mg, 50 mg, 25mg, 25 mg), or colchicine at 0.5 mg a day. At doses over 50 mg, the mean number of flares per patient and the risk of experiencing at least one flare were both significantly reduced (~60–70%) in the canakinumab versus the colchicine group. Presented with these and other as yet unpublished data (see http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM259596.pdf), a FDA advisory board recommended against the proposed approval of canakinumab for acute gout in patients who cannot tolerate NSAIDs or colchicine. The board cited too many safety concerns, including infection, cardiovascular and renal risk, and inadequate pharmacokinetic data in older patients. Several trials are planned or underway for canakinumab in gout (see http://clinicaltrials.gov/ct2/results?term=canakinumab).

Despite this setback, it seems probable that canakinumab or another IL-1 inhibitor will ultimately be approved for the treatment of acute gout and/or prophylaxis for gout flares in those starting ULT. There is a definite need in this area as there are many gout patients who have failed or cannot take colchicine or NSAIDs, and whose only option remains corticosteroids, a problematic approach.

Better Uricosurics

Most patients with gout have inefficient renal excretion of uric acid as the mechanism of hyperuricemia [Wyngaarden and Kelley, 1976; Simkin, 2003]. The readily available uricosuric, probenecid, and the variably available sulfinpyrazone and benzbromarone, are now known to inhibit uric acid reabsorption by URAT1, the major transporter of uric acid from the renal proximal tubule [Enomoto et al. 2002; Endou and Anzai, 2008]. However, they also inhibit transporters on the basolateral aspect of the renal epithelial cell, including OAT4 and GLUT9, affecting reabsortion into the circulation [Burns and Wortmann, 2011]. A newly developed uricosuric now in clinical trials, lesinurad (RDEA594; Ardea Biosciences, San Diego, CA, USA), has specificity for URAT1, and does not significantly affect other transporter [Anzai et al. 2008; Dalbeth and Merriman, 2009]. The chief advantage of this is a lack of the drug interactions seen with other uricosurics. In addition to being developed as a standalone uricosuric, the investigators are emphasizing the use of diuretics such as lesinurad in combination with a xanthine oxidase inhibitor to more effectively lower serum urate in gout, an approach previously reported to be effective [Perez-Ruiz et al. 2002; Goldfarb and Smythe, 2007]. Several lesinurad combination clinical trials are underway (see http://clinicaltrials.gov/ct2/results?term=RDEA594).

Recently presented data on Ardea’s related compound, RDEA3170, demonstrated this newer agent’s high potency due to direct binding and functional inhibition of URAT1. All known URAT1 inhibitors probably bind in the same general area within the molecule, but each inhibitor binds a specific, yet overlapping set of residues, and this accounts for major differences in inhibition of URAT1, at least in vitro. For example, RDEA3170 is equipotent to benzbromarone, but 200 times more potent than sulfinpyrazone and 500 times more potent than probenecid in in vitro assays [Tan et al. 2011]. RDEA3170 has not been used in any clinical trials yet, but the fine tuning of the specificity and potency of URAT-1 inhibition at a molecular level now seems within reach. These potent uricosurics would be contraindicated in patients with urate nephrolithiasis, and if they deliver the dramatic drops in serum urate promised, alone or in combination, prophylaxis for the inevitable gout flares will be essential.

Along similar lines, arhalofenate is a novel oral agent in development as an insulin-sensitizer for type II diabetes. Serendipitously, in vitro studies found arhalofenate to be a uricosuric that inhibits URAT-1. In analysis of two of their phase II diabetes trials in which serum urate levels were obtained, in patients with a baseline serum urate ≥6.0 mg/dl (mean 6.8–7.1 mg/dl), arhalofenate at doses of 200 mg ( n = 29), 400 mg ( n = 37), and 600 mg ( n = 35) resulted in 48%, 78%, and 83% of patients achieving a serum urate target of <6.0 mg/dl versus 25% in the placebo group ( n = 61) [Gopal et al. 2011]. The drug was well tolerated and no cases of nephrolithiasis were reported. Arhalofenate may prove to be a dual-purpose drug with benefit for patients with the common comorbidities of gout and type 2 diabetes.

Novel Targets

Other attractive targets for drug development in acute gout include any step along the early IL-1β pathway. Two small molecule drugs that inhibit the active site of caspase-1, VMX-740 (pralnacasan) and VMX-765, were studied some time ago in several inflammatory conditions. Pralnacasan had unacceptable toxicity, and results of a phase II trial of VMX-740 in plaque psoriasis, completed in 2005, were never published [Cornelis et al. 2007; Mitroulis et al. 2010]. Interleukin-1 receptor-associated kinase 4 (IRAK-4) is a signaling molecule located downstream of the IL-1R. Recently presented data on a highly specific IRAK-4 small molecule kinase inhibitor demonstrated its ability to block human IL-1 responses in vitro and was effective in a gout-like murine peritonitis model [Bree et al. 2011]. The promise of a small molecule, presumably a less expensive and more convenient approach to inhibition of IL-1B pathway, would be an attractive alternative to biologics. An even more novel approach could evolve from recent evidence that activated CD4+ T cells expressing CD40 ligand (CD154) regulate the inflammasome [Guard et al. 2009]. In vitro, a CD40 ligand construct, the adiponectin fusion protein (ADIPOQ–CD40L), engages CD40 on activated macrophages and shuts off the NLRP3 inflammasome and caspase-1. This may be a mechanism by which the adaptive immune system dampens the intense innate inflammatory response to urate crystals and other ‘danger’ signals.

Compliance With Treatment

Except in situations such as chronic renal failure or organ transplantation where consultation with a rheumatologist is recommended, the available treatment for gout is so straightforward that management should be effective and outcomes excellent. Unfortunately, even in typical patients accurately diagnosed, good outcomes may be elusive. Improper prescribing or poor compliance is the usual cause of urate-lowering therapy failure. Compliance is often a problem when treating chronic asymptomatic conditions. Associated alcoholism may contribute. Perhaps more importantly, patients may have to initially take up to three different medications on different schedules for gout, and that’s confusing. Presumably, patients who understood why they were taking medications would likely be more compliant. The senior author has developed an analogy that helps some patients with compliance [Wortmann, 1998]. Whatever the technique, establishing an alliance with the patient to achieve compliance is critical. The perfect choices of therapeutics without compliance still results in treatment failure.

Other Factors

Factors independent of medication and compliance may determine whether recurrent attacks, chronic gouty arthritis, nephrolithiasis, or nephropathy develops. Nowadays, strict dietary purine restriction is rarely recommended, as it lowers mean serum urate levels by only about 1 mg/dl. In fact, weight loss in an obese individual will have a greater urate lowering effect than a purine-free diet [Dessein et al. 2000]. The ingestion of products containing fructose sweeteners, such as soft drinks, promotes hyperuricemia [Rho et al. 2011]. A diet with moderately decreased calories and carbohydrates, and increased protein, dairy products, and unsaturated fats can be beneficial for the patient with gout [Dessein et al. 2000; Choi, 2010]. Consumption of alcoholic beverages or rich foods can trigger gout attacks in some patients, and the individual patient should avoid indiscretions known to precipitate attacks. Diet is more important in the management of other medical problems coexistent with gout, including obesity and hyperlipidemia, the latter affecting 75% of gout patients [Choi, 2010].

Alcohol consumption is an important factor in gout. Acute excesses may exacerbate hyperuricemia by causing hyperlactacidemia. Chronic alcohol ingestion can stimulate increased purine production. The more one drinks, the higher the risk [Choi et al. 2004]. Beer contains a large purine load and regular ingestion may contribute to hyperuricemia and gout. Drinking beer is more likely to lead to the development of gout than drinking liquor, whereas moderate wine consumption does not increase risk [Choi et al. 2004]. Finally, compliance with medication is worse among patients who consume alcohol.

About one third of gouty subjects have hypertension, and that condition should be treated aggressively. Many hypertensive gouty patients require a thiazide diuretic, which will raise serum urate levels, requiring adjustment of concomitant urate-lowering therapy. Losartan is an alternate anti-hypertensive medication and fenofibrate is a lipid-lowering agent that have mild uricosuric activity, and may be useful adjuncts in this population [Wurzner et al. 2001; Yamamoto et al. 2001].

Future Directions

Gout is an ancient malady whose incidence continues to rise despite being one of the best understood diseases in all of medicine in terms of pathogenesis and treatment [Roddy et al. 2007]. An epidemic of obesity and the metabolic syndrome has, in part, driven this increase. Our understanding of the biochemistry of hyperuricemia and the immunology of acute gout has increased greatly over the last few years. Febuxostat and pegloticase are now available and other new therapeutics are in the pipeline. Years of dedicated gout research are now paying off. An effort to improve lifestyle choices as a society and better management of the disease by clinicians should have a positive impact on gout incidence and outcome in our lifetimes.

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Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ther Adv Chronic Dis. 2012;3(6):271-286. © 2012  Sage Publications, Inc.