An update on the pathology and clinical management of gouty arthritis

Anakinra is a recombinant, nonglycosylated form of the human IL-1 receptor antagonist approved for use in patients with moderate to severely active rheumatoid arthritis who have failed first-line therapies. Studies in patients with gout are restricted to small case series in ten or fewer patients [18, 19]. In one case series, patients with a history of recurrent gouty arthritis or tophaceous gout received open-label anakinra at a dose of 100 mg/day administered as a subcutaneous injection for 3 days [19]. All patients responded rapidly to treatment, with a mean decrease in pain rating of 79% by day 3 after the initial injection. Another case series of ten patients also reported favorable short-term responses to anakinra; however, recurrent flares after discontinuation of treatment were common, occurring in nine of ten treated patients [18].

A small proof-of-concept study has investigated the efficacy and safety of rilonacept, a soluble receptor–Fc fusion protein trap for and inhibitor of IL-1α and IL-1β, in the treatment of chronic gouty arthritis [20]. In this 14-week study, ten patients with chronic active gouty arthritis underwent a 2-week lead-in period (during which patients received single-blind placebo) and then received rilonacept for 6 weeks followed by a 6-week follow-up period. Rilonacept was administered as a single loading dose of 320 mg during week 2 followed by 160 mg once weekly during weeks 3–7. Compared with the placebo run-in phase, treatment with rilonacept was associated with a significant improvement in patient pain scores, global assessment of “feeling well” and symptom/severity adjusted scores. There was also a significant reduction in levels of high-sensitivity C-reactive protein (CRP) compared with the lead-in phase. One patient discontinued during the second week of active treatment because of severe injection site erythema and induration related to study medication, and three patients developed anti-rilonacept antibodies [20].

Canakinumab (ACZ885) is a fully human monoclonal antibody that neutralizes the activity of human IL-1β, leading to inhibition of IL-1β signaling and suppression of inflammation [21]. It has shown activity in small studies of patients with rheumatoid arthritis and cryopyrin-associated periodic syndrome and is approved in the USA and Switzerland for treatment of Muckle–Wells syndrome and familial cold auto-inflammatory syndrome [21]. In a phase 2 dose-ranging study in patients with difficult-to-treat gouty arthritis, canakinumab (10, 25, 50, 90, and 150 mg as single intramuscular doses) was associated with a dose-related decline in pain rating at 72 h after administration [22]. At the highest dose, canakinumab resulted in a significantly greater mean reduction in pain compared with intramuscular injection of triamcinolone acetonide (40 mg) at 24 h, 48 h, 72 h, 4, 5, and 7 days after dosing. All doses evaluated resulted in a numerically greater reduction in pain at 72 h (as assessed using a visual analog scale) compared with triamcinolone acetonide; however, evaluation of pain levels at 48 h postinjection indicates that a canakinumab dose of 23 mg (95% confidence interval [CI], 3–96 mg) has equivalent efficacy to triamcinolone acetonide (40 mg). Furthermore, the incidence of flare at 8 weeks posttreatment was 3.7% in patients receiving canakinumab (150 mg) and 45% in those who received triamcinolone acetonide. Canakinumab treatment (at doses 20–150 mg) was also associated with normalization of CRP and serum amyloid A protein (SAA) levels by day 7 after treatment; however, these inflammatory markers were largely unaffected by triamcinolone acetonide. There were four serious AEs in patients receiving canakinumab (appendicitis, n = 2; bronchitis, n = 1; and carotid artery stenosis, n = 1), all considered to be unrelated to study medication. The tolerability profile was otherwise similar in patients receiving canakinumab and triamcinolone acetonide [22]. Subsequent analyses of the data from this study have reported that at a dose of 150 mg, canakinumab shows superiority over triamcinolone acetonide (40 mg) in terms of pain relief, reduction in signs of inflammation (as assessed using a Likert scale and also through inflammatory markers), and health-related quality of life measures [23]. Additional phase 3 studies of canakinumab in patients with gouty arthritis are ongoing [21].

Agents that interfere with IL-1β signaling therefore appear to represent an important therapeutic class in the future treatment of gouty arthritis; however, clinical experience with these agents in patients with rheumatoid arthritis suggests that their use may be associated with an increased risk of infection [24]. At this time, the extent to which this association is related to comorbidities that are unique to patients with rheumatoid arthritis is unknown. Data from additional randomized controlled trials in patients with gouty arthritis will help provide a better understanding regarding the benefit-risk profile of these agents.

Weight reduction is recommended for overweight or obese patients [16], supplemented by an increased intake of selected food types. Patients should be encouraged to include skimmed milk, low-fat yogurt, soy beans, vegetable protein sources, and cherries in their diets, and high-purine foods such as liver, kidney, shellfish, and red meat should be discouraged [16, 25, 26]. Alcohol consumption <21 units/week for men and <14 units per week for women is also strongly advised—beer, stout, and port should be avoided, and patients should be encouraged to maintain 3 days each week in which alcohol is completely avoided [16]. Finally, management strategies should also take into account concomitant medications that could increase serum uric acid levels. Thiazide or loop diuretics, low-dose aspirin, cyclosporine, niacin, pyrazinamide, and ethambutol may each cause increased serum uric acid levels [6].

Patients who experience recurrent acute attacks, arthropathy, tophi, or radiographic changes are candidates for urate-lowering therapy (Table 2) [14]. The therapeutic goal is to promote crystal dissolution and prevent crystal formation by maintaining serum urate concentrations below the saturation point for MSU [14, 16].

Allopurinol and probenecid have for many years represented the cornerstone of treatment for chronic gouty arthritis. Allopurinol, a xanthine oxidase inhibitor that acts by blocking the production of uric acid through a reduction in purine catabolism, is considered to be an appropriate long-term urate-lowering therapy (Table 2) [14]. Typical AEs associated with allopurinol include diarrhea, nausea, and increases in alkaline phosphatase, ALT, and AST levels (Allopurinol (tablet); Watson Laboratories, Inc., Corona, CA). Probenecid is a uricosuric agent that increases excretion of uric acid by blocking tubular reabsorption (Table 2) (Probenecid; Watson Pharmaceuticals Inc., Corona, CA). It is used largely as an alternative to allopurinol, although it is considered less efficacious [14].

Febuxostat is a more recent addition to treatment options for chronic gouty arthritis. It is a nonpurine, xanthine oxidase inhibitor approved for the chronic management of hyperuricemia in patients with gouty arthritis (Table 2) (Uloric® (Febuxostat) tablet for oral use; Takeda Pharmaceuticals America, Inc., Deerfield, IL). Like allopurinol, febuxostat inhibits the synthesis of uric acid by xanthine oxidase. However, animal studies have suggested it provides a more potent and longer-lasting hypouricemic effect compared with allopurinol, an effect attributed to its potent inhibition of both oxidized and reduced forms of xanthine oxidase [27]. The approval of febuxostat was based on the data from three phase 3 clinical trials, Allopurinol- and Placebo-controlled Efficacy study of febuxostat (APEX) [28], Febuxostat versus Allopurinol Controlled Trial (FACT) [29], and CONFIRMS [30].

The phase 3 clinical studies showed febuxostat (80–240 mg/day) to be significantly more effective than allopurinol (200–300 mg/day). In all studies, the proportion of patients with a urate concentration <6 mg/dL at the end of treatment (the primary end point) was significantly higher among patients receiving febuxostat compared with allopurinol [28‐30]. However, it is also noteworthy that these studies did not allow for allopurinol to be dose titrated above 300 mg/day, despite higher doses being recommended for patients with moderately severe tophaceous gout (Allopurinol (tablet); Watson Laboratories, Inc., Corona, CA). In APEX and FACT, prophylaxis against gout flares with naproxen (250 mg twice daily) or colchicine (0.6 mg/day) was administered for the first 8 weeks of treatment, and in both studies the incidence of gout flares was highest during the 4 weeks immediately following withdrawal of prophylaxis [31]. However, in CONFIRMS, prophylaxis for gout flares was administered for the full 6-month treatment period, and unlike the previous two studies, there was no peak in the incidence of flares at weeks 9–12, but instead a steady decline in the incidence of flares throughout the 6-month treatment period [32].

Overall, AEs were similar across all treatment groups in these studies [28‐30]. In APEX, febuxostat at 240 mg/day was associated with high levels of diarrhea and dizziness, and the incidence of hypertension was also higher in the febuxostat 80-mg/day arm [28]. Abnormal findings on liver function tests and rash-related AEs were generally similar across treatment arms, and AEs leading to treatment withdrawal were similar in patients receiving febuxostat and allopurinol [28]. In FACT, the incidence of treatment-related AEs was also similar between treatment arms, with liver function abnormalities, diarrhea, and headache occurring at a similar incidence in each treatment arm. Abnormal liver function tests and rash were the most frequent AEs leading to treatment discontinuation in patients receiving febuxostat [29]. In CONFIRMS, rash, liver function abnormalities, and diarrhea occurred at broadly similar rates in patients receiving febuxostat or allopurinol [30]. Premature treatment withdrawal because of an AE was also similar across treatment arms (6.5–8.5%) [30]. Overall, pooled study data of the most frequently reported AEs for febuxostat and allopurinol showed similar rates of liver function abnormalities (4.6–6.6% vs 4.2%, respectively), nausea (1.1–1.3% vs 0.8%, respectively), arthralgia (0.7–1.1% vs 0.7%, respectively), and rash (0.5–1.6% vs 1.6%, respectively) (Allopurinol (tablet); Watson Laboratories, Inc., Corona, CA).

Most mammals possess the enzyme urate oxidase that catalyzes the conversion of uric acid to 5-hydroxy isourate and hydrogen peroxide, ultimately leading to the formation of allantoin, which is a more soluble and easily excreted purine metabolite [33, 34]. However, as a result of mutations to the urate oxidase gene during evolution, this pathway for urate elimination is not functional in humans. Pegloticase is a genetically engineered pegylated mammalian urate oxidase enzyme indicated for the treatment of chronic gout in adult patients refractory to conventional therapy, such as those who have failed to achieve normal serum urate levels or whose symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum tolerated dose (Table 2) (KRYSTEXXA™ (pegloticase) injection, for intravenous infusion; Savient Pharmaceuticals, Inc., East Brunswick, NJ).

In a randomized phase 2 study of 41 patients with gouty arthritis who had been unsuccessfully treated with, or had contraindication to, urate-lowering therapy, pegloticase at doses of 4 or 8 mg every 2 weeks, or 8 or 12 mg every 4 weeks, was associated with a rapid decrease in plasma urate levels to ≤6 mg/dL [34]. This decrease was seen within 6 h of commencing treatment, and was sustained for the 10-week treatment period in all dose groups, except the 4-mg-every-2-weeks group. Two patients experienced rapid regression of tophi within 12 weeks of starting treatment [35]. The most commonly reported AEs were nephrolithiasis (15%) and arthralgia (12%), followed by anemia, dyspnea, headache, muscle spasms, nausea, and pyrexia, each reported in 10% of patients. Overall, 76% of patients showed anti-pegloticase immunoreactivity during the study, which was associated with a shortened pegloticase half-life and an increase in urate area under the curve. Among patients who were antibody negative, treatment response was 100% [34].

Subsequent phase 3 studies have also confirmed the urate-lowering ability of pegloticase in patients with severe gouty arthritis who are refractory or intolerant to allopurinol and with serum urate ≥8 mg/dL [36]. In two 24-week, randomized, double-blind, placebo-controlled studies, the proportion of patients with plasma urate levels <6 mg/dL for ≥80% of the time during months 3 and 6 (corresponding to the 4-week periods immediately following week 9 and week 21 infusions) was significantly higher in patients receiving pegloticase (8 mg biweekly or every 4 weeks) compared with those receiving placebo (42% and 35% vs 0%, p < 0.001 for both comparisons). Complete response in one or more tophi (defined as 100% reduction in tophus area) was seen in 40% of patients receiving biweekly pegloticase, 21% of those receiving monthly pegloticase, and 7% of those receiving placebo (biweekly vs placebo, p = 0.002; monthly vs placebo p = 0.2). Pegloticase antibodies were present in 134 of 150 treated patients and were significantly associated with an impaired response to therapy and a higher risk of infusion-related reactions. Gout flares (despite prophylaxis with colchicine or NSAIDs throughout the study) and infusion-related reactions (despite pretreatment with fexofenadine, acetaminophen, and hydrocortisone) were the most frequently reported AEs [36].