Pharmacologic Urate-Lowering Therapy

Introduction

While the treatment goals for acute gout are to relieve pain and terminate the attack as quickly as possible, the goal of therapy in subjects with multiple recurrent gout flares, with or without clinically detected tophi, is to prevent disease progression by reducing the body urate burden. The two-pronged approach to gout treatment has caused confusion in the minds of both patients and clinicians since drugs like colchicine may be used for both treating the acute symptoms of gout and prophylaxis against future attacks. However, the only evidence-based, long-term approach for preventing flares and lessening the destructive potential of gout is to lower serum urate well below the solubility threshold (i.e., well below 6.8 mg/dL) and reduce the total body urate burden. Figure 8-1 delineates these two separate approaches to the optimal management of gout. While the drugs used to control acute and chronic pain from gout have no benefit in reducing serum urate levels, the appropriate use of the urate-lowering therapy (ULTs) will, over time, reduce or eliminate the risk of future gout flares.

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Indications and Goals of ULT

Treatment strategies will vary between patients depending on many factors, including the serum urate level, the presence of comorbid diseases and other medical conditions, and the use of other medications. Few patients with gout are started on ULTs following their initial attack, but all patients should be instructed on the benefits of weight reduction and other diet and lifestyle modifications at this stage. The indications for initiating ULT are listed in Table 8-1. Patients experiencing two or more acute gouty attacks per year are considered candidates for urate lowering. In 60% of all gout patients, this means therapy could be initiated after the second attack. Clearly, any patient presenting with advanced gout or demonstrating tophi on physical examination should be started on ULT. Because of the potential for gout and hyperuricemia to worsen the disease progression of any form of chronic kidney disease (CKD), subjects with gout and renal disease or a prior history of renal stones should receive ULT. Finally, uric acid overproducers who are generally characterized by early onset and rapidly progressive diseases should be treated as early as possible.

The goals of ULT are outlined in Table 8-2. The widely accepted therapeutic target of reducing serum urate to <6.0 mg/dL (at a minimum) has many demonstrated advantages (Table 8-3). The clinical goals and the patient-centered goals can all be achieved with adherence to a lifelong course of ULT at a level sufficient to achieve the therapeutic target.

In essence, the appropriate strategy for ULT is termed “treat to target,” (T2T) and replaces the old, failed strategy of “treat to avoid symptoms.” The objective of ULT is also to maintain gout patients at the serum urate target of <6.0 mg/dL lifelong, and this requires checking the serum urate level regularly (e.g., every 6 months once the target has been achieved). Several lines of evidence favor the T2T approach over the treat-to-avoid-symptoms strategy. A UK-based, nurse-led study randomized patients with uncontrolled gout (≥1 gout flare in the previous 12 months) to either nurse-led T2T care or to a general practitioner (GP)-led “usual care.” The trial nurses were trained to conduct gout care according to the current guidelines, notably to treat to the serum urate target of <6 mg/dL; the study rheumatologists were available to provide guidance to the nurses on a per-need basis. The nurse-led care group demonstrated numerically lower flares compared to the usual care group. Similar results were reported in a US-based trial where a pharmacist-led T2T intervention (primarily administered by automated telephone technology, and much less intensive than the aforementioned nurse-led intervention) demonstrated a 6-16% lower rate of gout flares compared to usual care. However, neither of these results reached statistical significance. By contrast, a 2022 analysis of data from two randomized trials, one of which was the UK nurse-led study, established that a significantly lower proportion of “responders” (i.e., patients who maintained an average SU level <6 mg/dL at 6, 9 and 12 months after baseline) experienced a gout flare 12-24 months after baseline compared to non-responders (ie, patients whose average SU level was ≥6 mg/dL) (27% vs 64%; P <0.0001). Available evidence thus favors the application of the T2T strategy in gout management.

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Urate-Lowering Drugs

Weight loss and certain dietary restrictions are important in most patients with gout but are insufficient to achieve adequate urate lowering in the majority of gout patients, although helpful in reducing risk of flares and improving overall health. The urate-lowering agents in Table 8-4 are usually necessary to reach the target of a serum urate of <6.0 mg/dL. The first-line agents (uricostatic) account for >97% of all therapeutic lowering currently prescribed in the United States. Both allopurinol and febuxostat effectively block urate production by inhibiting the terminal purine catabolism enzyme in humans, xanthine oxidase (Figure 8-2).

The uricostatic agents have several advantages over uricosuric agents. Both allopurinol and febuxostat are effective in gout patients whose hyperuricemia is caused by either uric acid overproduction or underexcretion. Uricosurics should not be used in overproducers of uric acid or in those with a history of urolithiasis. The uricostatics can be administered as once-daily medications, which increases compliance. Probenecid requires 2 to 3 doses per day for optimal function.

The uricostatic agents function well in the face of renal insufficiency, whereas uricosurics may require a glomerular filtration rate (GFR) of at least 50 mL/min for optimum efficacy and should not be used with GFR <30 mL/min. In fact, febuxostat appears to function better than any other option in subjects with renal impairment. Finally, the uricolytic (pegloticase) class of ULT is generally reserved for patients failing conventional therapy or those with a large urate burden (multiple tophi) where conventional therapy may take many years to control gouty symptoms.

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Allopurinol

Allopurinol is the most widely used ULT and has been available for over 50 years. It is considered the preferred first-line ULT by the current (2020) ACR guidelines for gout management. Allopurinol is approved by the FDA in doses of 100 to 800 mg/day, but in most primary care practices, a dose of 300 mg/day is seldom exceeded. Yet, in clinical trials of allopurinol at a dose of 300 mg/day, only ~40% of patients with gout will achieve the targeted serum urate of <6.0 mg/dL (Figure 8-3). The reasons why most primary care prescribers do not push the dose of allopurinol beyond 300 mg/day are complex and poorly understood, but are based mostly on the paucity of data on efficacy and safety of allopurinol in doses >300 mg/day. Allopurinol, when given above 300 mg daily, can be divided into 2 doses per day if nausea occurs with single dosing.

Because elevated serum urate is linked with CKD progression and adverse cardiovascular (CV) outcomes, two trials were conducted to test the efficacy of allopurinol in patients with CKD and CV disease. The CKD-FIX trial randomized patients with stage 3 or 4 CKD and no history of gout to daily allopurinol 100 mg, allopurinol 300 mg, or placebo. Allopurinol failed to demonstrate efficacy in slowing CKD progression, as the change in estimated GFR did not differ between the study groups. The ALL-HEART trial compared allopurinol (titrated up to 600 mg daily) to usual care (no placebo was used) in older (≥60 years) patients with coronary artery disease and no history gout. Like in the CKD-FIX trial, allopurinol failed to demonstrate efficacy in ALL-HEART, with the rate of primary endpoint (a composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death) event rate not differing statistically between the allopurinol and the usual care group.

Rash will develop in ~2% (and in some populations up to 4%) of patients started on allopurinol. Most rashes are benign and dose related, but allopurinol is one of the more common drug causes of severe cutaneous reactions in the form of Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), or rashes as a component of DRESS syndrome (drug rash [or drug reaction] with eosinophilia and systemic symptoms, which is more commonly known as allopurinol hypersensitivity syndrome [AHS]).

Rash is seen in ~20% of subjects on allopurinol when ampicillin or amoxicillin is coadministered. Other important drug-drug interactions for allopurinol are listed in Table 8-5. Other common reasons for drug discontinuance are dyspepsia, nausea, diarrhea and headache or other nonspecific CNS effects that are typically dose dependent. A rise in liver transaminase enzymes is seen in ~4% of patients. In total, 6% to 10% of patients started on allopurinol are found to be intolerant of the drug.

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How Allopurinol Should be Dosed for Prevention of Severe Allopurinol Hypersensitivity Reaction

The most feared complications of allopurinol treatment are Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and the major, potentially fatal severe Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) or allopurinol hypersensitivity syndrome (AHS). SJS and TEN (Figures 8-4A and 8-4B), are potentially devastating complications of allopurinol, with mortality up to 20% to 25%. HLA-B*5801 is one of several risk factors that markedly increases the risk of severe cutaneous reaction to allopurinol. HLA-B*5801 is most common is Southeast and East Asians and those of African ancestry (Figure 8-5). The hazard ratio for severe allopurinol hypersensitivity reaction in HLA-B*5801-positive Koreans with CKD stage 3 is >100:1 and in HLA-B*5801-positive Han Chinese and Thai is ~80:1. The predictive value of HLA-B*5801 is decreased in White and Hispanic patients. Pre-screening of subpopulations at high risk for severe allopurinol hypersensitivity reaction, via rapid and relatively inexpensive single polymerase chain reaction-based testing for HLA-B*5801, is an appropriate measure to consider, given evolving knowledge.

The AHS drug reaction occurs in ~1/1000 patients in the United States (but in some study populations up to 4/1000 patients) started on allopurinol. The adjusted OR for hospitalization for AHS in the United States for White, Black and Asian patients are 1.0, 2.8 and 8.1, respectively. The clinical description of AHS is presented in Table 8-6. The risk factors associated with AHS are summarized in Table 8-7. Some studies suggest that this severe reaction is a dose-related phenomenon and this assumption had led to widely-used but non–evidence-based guidelines for adjusting the final maintenance dose of allopurinol based on creatinine clearance (CrCl). Other studies show no association between the maintenance dose of allopurinol and the likelihood of developing AHS. The results of renally-adjusted dosing on achieving the target serum urate of <6.0 mg/dL is shown in Figure 8-6. Because there is no evidence that severe allopurinol hypersensitivity is diminished by renally adjusting the maintenance dose of allopurinol, such advice is markedly flawed, with only a minority of patients achieving the target level of urate lowering.

In contrast, adjusting the starting dose of allopurinol for renal function, and steadily titrating allopurinol upwards is a core aspect of using the drug safely.

Most AHS develops in the first 60 days of therapy, with the highest risk in the first 30 days (Figure 8-7). One case-controlled retrospective analysis suggests that starting the dose of allopurinol higher than 1.5 mg per mL/min GFR is associated with markedly increased risk of AHS (Figure 8-8). Recognizing the impact of the data but limitations of the retrospective design, the authors of this handbook boil this down to simpler advice—that the starting dose of allopurinol should be no more than 100 mg daily (in accordance with both ACR and EULAR guidelines) and that in those with a GFR ≤30, the starting dose of allopurinol should be no more than 50 mg per day. The authors recommend that every 2 to 4 weeks after starting allopurinol, the maintenance dose should be titrated upwards by 100 mg (per day), but only by 50 mg (per day) in those with a GFR ≤30. Long-term safety data for allopurinol >300 mg daily are sparse. However, there is evidence that titrating allopurinol above prior renal dosing adjusted recommendations and >300 mg daily, if necessary to achieve the serum urate target, is effective but should be accompanied by patient education and monitoring (including serum urate and liver function tests). The patient should be instructed, in clear terms, to first stop allopurinol immediately if pruritus and/or skin rash develops and second, to contact the prescribing clinician in the event such symptoms occur.

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Febuxostat

Febuxostat is a nonpurine analogue uricostatic agent. It is structurally different from allopurinol (Figure 1-2 and Figure 8-2) and cross-reactive toxicity is rare. It is taken orally in doses of 40 mg initially, with escalation to 80 mg after 2 to 3 weeks if the target serum urate of <6.0 mg/dL is not achieved on the lower dose. Unlike allopurinol, there is no recommended need for maximum dose reduction in mild-to-moderate renal impairment (stage 2 and stage 3 CKD). The efficacy of febuxostat (Uloric) compared with allopurinol in subjects with stage 2 and 3 CKD renal impairment is demonstrated in Figure 8-9.

The CONFIRMS trial was a phase 3 study comparing the safety and efficacy of febuxostat with allopurinol. Forty milligrams of febuxostat was similar to 300 mg of allopurinol in efficacy, while 80 mg febuxostat outperformed allopurinol in those with normal renal function. In renally impaired subjects, febuxostat 40 or 80 mg was more efficacious than allopurinol 200-300 mg daily in the treatment group as a whole. All doses of febuxostat and allopurinol had similar safety profiles with serum transaminase elevation, with nausea and headache being the most common adverse events. Superiority of febuxostat 80 mg daily to allopurinol 300 mg daily was reported in post hoc analyses in subpopulations of women and the elderly with gout. The STOP Gout trial, published in 2022, was another noninferiority study comparing the efficacy of febuxostat and allopurinol; in this trial, the two agents were used according to the current ACR and EULAR guidelines for gout management, i.e., as part of a T2T strategy to achieve a serum urate level of <6 mg/dL. A total of 940 patients with gout and hyperuricemia (of which 33% also had chronic kidney disease [CKD]) were randomized (1:1) to receive allopurinol starting at 100 mg with a maximum titration to 800 mg (n = 468) or febuxostat 40 mg with a maximum titration to 120 mg (n = 472). The trial was split into three phases: titration (weeks 0 to 24), maintenance (weeks 25 to 48) and observation (weeks 49 to 72); most dose adjustment occurred during the titration phase to meet the serum urate target, but adjustments were allowed up to week 33. The primary endpoint was the proportion of patients with one or more gout flares during the observation phase. Allopurinol was shown to be noninferior to febuxostat for gout flare control, with 36.5% and 43.5% of patients in the allopurinol and febuxostat groups experiencing at least one gout flare (P_{noninferiority} <0.001). Allopurinol was also noninferior to febuxostat in the CKD subgroup, in which 31.9% of allopurinol-treated and 45.3% of febuxostat-treated participants experienced at least one flare during the observation phase of the trial.

The efficacy of febuxostat for the prevention of major adverse cardiovascular events (MACE) – the risk of which is increased in patients with gout – was assessed in the active-controlled CARES trial. A total of 6190 patients with gout and history of major CV disease were randomized (1:1) to receive a once-daily dose of up to 80 mg of febuxostat (n = 3098) or up to 600 mg of allopurinol (n = 3092). Febuxostat was noninferior to allopurinol, with 10.8% and 10.4% of patients in the febuxostat and allopurinol groups experiencing the primary endpoint (a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization)(P_{noninferiority} = 0.002). The cumulative rate of primary endpoint events is shown in Figure 8-10.

Interestingly, the CARES trial observed increased all-cause mortality (hazard ratio [HR], 1.22) and CV mortality (HR, 1.34) with febuxostat compared to allopurinol. This observation made it difficult to draw definitive conclusions from the CARES trial, particularly considering a high dropout rate (56.6%), a higher prevalence of NSAID use (associated with CV events) in the febuxostat group compared to the allopurinol group (13.1% vs 10.5%, respectively), the lack of a placebo group (leaving the possibility that both febuxostat and allopurinol are cardioprotective, though not to the same degree) and questions about whether the trial was powered to detect a difference in the secondary endpoints. Nevertheless, the FDA issued a safety alert for febuxostat and mandated the addition of a black box warning about higher rates of CV death compared to allopurinol in the prescribing information. A 2021 study of the CARES data concluded that most deaths occurred after discontinuation of the study drugs, suggesting that discontinuation of febuxostat, rather than continued treatment and the resulting rebound hyperuricemia, are the true cause of increased mortality.

Following the publication of the CARES trial, the EMA recommended that another trial be conducted to test the CV safety of febuxostat compared to allopurinol. This trial, FAST, randomized (1:1) a total of 6128 patients with gout and at least 1 CV risk factor (of which 33.4% had documented CV disease) to either allopurinol (n = 3065) or febuxostat (n = 3063).³⁵ In the on-treatment analysis, the primary endpoint (a composite of hospitalization for non-fatal MI or biomarker-positive acute coronary syndrome, non-fatal stroke, or cardiovascular death) occurred at comparable rates in the febuxostat (5.6%) and allopurinol (7.9%) groups (P_{noninferiority} = 0.002). Figure 8-11 shows the cumulative incidence of the primary endpoint in the on-treatment analysis. Crucially, febuxostat was not inferior to allopurinol with respect to either CV death (2.0% vs 2.7%; P_{noninferiority} = 0.018) or all-cause death (3.5% vs 5.7%; P_{noninferiority} <0.0001). Febuxostat also demonstrated noninferiority to allopurinol with regard to the primary endpoint, CV death, and all-cause death in the intention-to-treat analysis. These findings suggest that febuxostat is not associated with increased CV or all-cause mortality, in contrast to the CARES results; however, it is worth pointing out that the study populations were different, notably in the proportion of patients with established CV disease (all patients in CARES, about a third in FAST).

The open-label FREED trial tested the efficacy of febuxostat in the prevention of cerebral, cardiovascular, and renal disease. This trial randomized (1:1) a total of 1070 elderly Japanese patients with hyperuricemia and at risk of cerebral, cardiovascular, or renal disease, to either a febuxostat (n = 537) or non-febuxostat (n = 533) regimen; ~27% of patients in the latter group received allopurinol. The primary endpoint – a composite of cerebral, cardiovascular and renal events and all-cause mortality – occurred at a significantly lower rate in the febuxostat group (23.3%) than in the non-febuxostat group (28.7%; P = 0.017).

In patients with one or more tophi detected on physical exam, the ACR Gout Treatment Guidelines suggest a serum urate target of <5.0 mg/dL. In certain patients with advanced disease and multiple tophaceous deposits, lowering the serum urate level to <4.0 mg/day is the preferred strategy by the authors to help optimize therapy outcome. The achievement of the serum urate target level of <4.0 mg/dL promoted decrease in size of the index tophus of a “velocity” of ~2 mm per month in one analysis, where index tophus size was an average of 27 mm in largest diameter (Figure 8-12) and this implies that average-sized tophi can be made to resolve in a year or two with highly effective ULT.

The ability of different doses of febuxostat and allopurinol to achieve specific serum urate targets is compared in Figure 8-13. Febuxostat has the potential to induce a hypersensitivity reaction, but febuxostat use is appropriate in those with a history of prior mild hypersensitivity reaction to allopurinol. It is not yet known whether those with past severe hypersensitivity reaction to allopurinol are at altered risk for hypersensitivity to febuxostat. Hence, caution is advised when giving febuxostat to those with past severe hypersensitivity reaction to allopurinol. Coadministration of febuxostat with the purine analogues azathioprine and 6-mercaptopurine is not advised, as is the case with allopurinol. Febuxostat use is well justified for ULT in severe renal impairment (stage 4 or worse CKD), but we do not yet know whether adverse events are more frequent in this clinical setting. CV events were more common in both allopurinol and febuxostat groups than in the placebo group in past clinical trials. CV risk was statistically similar in the two treatment groups but was numerically higher in the 80-mg febuxostat group.

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Probenecid

Probenecid is a uricosuric agent available in the United States since the 1950s. Probenecid is a weak organic acid that functions by inhibiting multiple organic acid transporters in the proximal tubules of the kidney including several that effect uric acid handling (URAT1, OAT1, OAT3 and GLUT9). Probenecid is usually started in gout patients with adequate renal function (GFR >50 mL/min) at 250 mg twice daily. The dose can gradually be increased to 1000 mg twice daily. If serum urate is still not at target at this dose, consider a change to a three times per day schedule or adding a xanthine oxidase inhibitor.

Patients must ensure adequate hydration (at least 6 glasses of water daily); probenecid should not be used in patients with a previous history of urolithiasis or in those with known overproduction of uric acid. An adequate 24-hour urine collection for uric acid should be performed before starting probenecid and probenecid should not be used if there is 1,000 mg or more of daily urinary excretion of uric acid (and generally avoided if there is 700 mg or more urinary uric acid excretion per 24 hours, or a urine level of greater than 40 mg/dL uric acid with an acid urine pH). Collectively, these measures will limit the risk of urolithiasis, which has an incidence of ~9% with probenecid. In this context, use of extended-release potassium citrate at a dosage of 60 mEq/day raises urinary pH by ~0.7 units which enhances uric acid solubility in urine. The nonselectivity of probenecid’s transport inhibition results in several important drug-drug interactions that should be avoided or closely monitored (Table 8-8). Rash and GI intolerance are the most common adverse reactions and are the cause of discontinuance in 20% of patients started on probenecid and nonspecific CNS symptoms also may occur.

Other Uricosurics

Other commonly used medications such as losartan, fenofibrate and the dietary supplement vitamin C (ascorbate) have some uricosuric properties as well. When combined with allopurinol or febuxostat, these agents can increase the effectiveness of ULT. Fenofibrate in daily doses >200 mg/day is helpful in patients with gout who have coexisting dyslipidemia, but care must be taken when using this agent in subjects with stage 3 or worse CKD. The angiotensin receptor blocker, losartan, has beneficial uricosuric properties when given to patients with gout and hypertension. This is especially helpful if losartan is used to replace hydrochlorothiazide, a drug that promotes renal urate reabsorption and thereby causes hyperuricemia. The uricosuric benefits of losartan may be transient, maximal at 50 mg daily and do not usually lower the serum urate by more than 10%. Neither fenofibrate nor losartan is FDA approved for urate lowering. Ascorbate (vitamin C) uricosuric effects are discussed in Management of Acute Gouty Arthritis.

Benzbromarone is a potent and effective uricosuric available only on a restricted basis and only outside the United States. Benzbromarone retains urate-lowering efficacy in those with a creatinine clearance as low as 25 mL/minute. However, the drug is limited by substantial safety concerns.

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Pegloticase

Uricase or uric acid oxidase is the final purine catabolic enzyme in all mammals except for simians (monkeys and apes, including humans). In a multistep process, the heterocyclic purine-ring structure of uric acid is opened by uricase to form an oxidative intermediate, which is then converted over a few hours to form a very soluble product, allantoin (Figure 8-14). The use of this enzyme to dissolve uric acid is called uricolytic therapy. Rasburicase is a recombinant Aspergillus flavus uricase that is used clinically in an FDA-approved manner specifically to prevent tumor lysis syndrome induced by chemotherapy. Neutralizing antibodies develop rapidly in most people receiving rasburicase. This, along with its short half-life of 18 hours, limits the use of this IV agent in the treatment of chronic hyperuricemia and gout; the use of rasburicase therapy for gout is not FDA approved and is not recommended.

The covalent attachment of polyethylene glycol (PEG) to the uricase protein has been shown to prolong circulating half-life and reduce immunogenicity (Figure 8-15). The PEGylation decreases immunogenicity of the uricase and increases active enzyme half-life well over that of non-PEGylated uricase. Pegloticase, a PEGylated recombinant porcine-baboon uricase, is FDA-approved for the treatment of adult patients with chronic gout refractory to conventional therapy. Pegloticase can suppress serum urate levels to very low values and maintain this suppression with every-2-week IV infusions, as first shown in clinical trials (Figure 8-16).

Patients in phase 3 trials of pegloticase had chronic (>15 years) and severe (>70% with tophi) gout and were either intolerant of allopurinol or had not achieved the urate-lowering target of <6.0 mg/dL with maximum medically appropriate doses of allopurinol. The urate-lowering capacity of pegloticase in all study subjects is demonstrated in the top panel of Figure 8-16. The bottom panel of Figure 8-16 demonstrates results for the “responder” group when the treated subjects are classified as “persistent responder” or “nonresponders.” Subjects who sustained effective urate lowering over the 6-month trial period did not develop high titers of anti-pegloticase antibodies and generally had fewer infusion-related adverse events. Among patients who sustained a serum uric acid (SUA) <6.0 mg/dL, fewer than one in 100 infusions were accompanied by signs or symptoms of infusion reaction (IR). This compared with 0.4% in the placebo group and >5% in those who lost response and had a preinfusion SUA rise to >6.0 mg/dL (these subjects are “nonresponders”) (Figure 8-16). Monitoring for loss of urate-lowering efficacy (serum urate >6.0 mg/dL prior to infusion) helps signal those patients in whom therapy should be discontinued before infusion-related reactions occur. As such, it is critical to avoid masking loss of urate-lowering effect of pegloticase by stopping use of any oral urate-lowering agents during the course of pegloticase therapy.

As a proof of concept study with the primary rationale of improving efficacy by reducing the development of anti-pegloticase antibodies, the RECIPE trial tested the safety and efficacy of a combinatorial regimen of pegloticase and the immunomodulator mycophenolate mofetil (MMF). Patients due to start a 24-week 8 mg biweekly pegloticase regimen (n = 32) were randomized (3:1) to receive a 14-week course of 1000 mg MMF twice daily or a placebo, starting 2 weeks before the commencement of pegloticase treatment. The primary endpoint (serum urate ≤6 mg/dL at 12 weeks) was achieved by more patients (86%) in the MMF group than in the placebo group (40%; P = 0.01). Overall safety was similar in the two groups, with more infusion reactions observed in the placebo group. Data from the MIRROR and RECIPE trials collectively suggest that pegloticase efficacy may be improved by concomitant immunosuppression.

Using a similar rationale, the safety and efficacy of co-administering pegloticase together with the immunomodulatory drug methotrexate (MTX) was next tested in the MIRROR trial. Patients with uncontrolled gout were randomized (2:1) to receive pegloticase 8 mg biweekly with oral MTX 15 mg weekly (n = 100) or pegloticase 8 mg biweekly with an oral placebo (n = 52). The primary endpoint (serum urate <6 mg/dL for ≥80% of visits during trial weeks 20–24) was achieved by a significantly greater proportion of patients in the pegloticase + MTX group (71.0%) compared to patients who received pegloticase and placebo (38.5%; P <0.0001). Another analysis of the MIRROR trial showed that pegloticase treatment also reduced blood pressure in patients with or without CKD.

A microsimulation model revealed that a broader adoption of pegloticase treatment in patients with gout and CKD would greatly reduce the health and economic burden of these commonly co-morbid conditions; if all patients with uncontrolled gout and CKD started pegloticase, by the year 2035 approximately 301,000 uncontrolled gout cases would be avoided, 208,000 quality-adjusted life years gained and 53,000 complications (diabetes, hypertension, stroke) prevented.

Gout flares were the most common adverse event in the phase 3 trials of pegloticase monotherapy, occurring in 80% of both placebo and treated patients; however, it is important to understand gout flares are an expected outcome when initiating ULT. Infusion-related reactions were the second most common adverse event, occurring in 26% of treated and 5% of placebo subjects (Figure 8-17). Serious IRs occurred in 5% of treated patients, requiring either discontinuation of the infusion or slowing the rate of the infusion. Most often, these serious IRs were in the form of a musculoskeletal constellation of chest pain/discomfort, back/flank pain and muscle spasms. There were five subjects in the trial who were classified as having anaphylaxis according to the new National Institutes of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network definition. This included an infusion-emergent rash with either a drop in blood pressure or symptoms of dyspnea. All episodes were judged as mild or moderate IRs by the treating physician and all responded to either antihistamines or glucocorticoids without need for hospitalization (Table 8-9).

The MIRROR trial demonstrated that co-administration of MTX with pegloticase improved the safety profile of pegloticase, lowering the IR rate (4.2% vs 30.6% with pegloticase alone; P <0.001) Anti-drug antibodies developed at a numerically lower proportion of patients in the MTX co-treatment group (11.6%) compared to the placebo co-treatment group (20.4%). An analysis of the pooled data from pegloticase trials revealed that the incidence of cardiovascular and thromboembolic adverse events was similar in pegloticase-treated patients (35.4/1000 person-years) and the general population with gout (20.99-44.7/1000 person-years).

Please see Difficult Gout and Hyperuricemia for additional discussion.

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Urate-Lowering Agents in Development

Several novel ULT agents are currently in various stages of development, including the xanthine oxidase inhibitors (XOI) tigulixostat and topiroxostat, the URAT1 inhibitors verinurad, dotinurad, ruzinurad and AR882, and the uricase pegadricase (as part of the combination regimen SEL-212).

Tigulixostat has established serum urate lowering properties, and is currently in phase 3 trials with an estimated completion at the end of 2024. Topiroxostat, another selective XOI, has also been shown to also inhibit ABCG2 in vitro. Topiroxostat has been approved and used in Japan since 2013.

Verinurad is a selective urate reabsorption inhibitor (SURI) in development for lowering SU levels in patients with chronic kidney disease and heart failure with preserved ejection fraction. It has been found to be 3 times more potent than benzbromarone and 100 times more potent than probenecid. Several trials have demonstrated that verinurad in combination with allopurinol or febuxostat exhibits superior serum urate-lowering effects compared to monotherapy. Dotinurad is a novel SURI that inhibits URAT1 in the apical surface of renal proximal tubular cells. Developed as a safer alternative to benzbromarone, after the completion of phase 3 studies in 2020 it received approval in Japan for the treatment of gout and hyperuricemia. Ruzinurad is another highly selective URAT1 inhibitor that has been shown to lower serum urate levels in patients with hyperuricemia. A phase 3 trial on ruzinurad is currently ongoing. Finally, AR882, another novel and selective URAT1 inhibitor, demonstrated efficacy in two phase 2B proof-of-concept randomized double-blind trials. One trial (AR882-202) focused on SUA lowering, with 82% and 73% of patients treated with AR882 showing an sUA level <6 mg/dL and <5 mg/dL, respectively (from a mean baseline of 8.6 mg/dL. The other phase 2B trial demonstrated greater tophus resolution efficacy of AR882 compared to allopurinol, with 29% of patients in the AR882 75 mg group showing complete resolution of 1 or more tophi, compared to 8% in the allopurinol group.

SEL-212 is a combination therapy that includes pegylated uricase pegadricase co-administered with rapamycin-containing nanoparticle ImmTOR, added for its ability to reduce the formation of anti-drug antibodies.

Two phase 3 trials of SEL-212 in refractory gout patients (DISSOLVE I and II) have recently been completed, but the results have not yet been published in a journal; however, data presented at the 2023 ACR meeting showed significantly improved sUA-lowering efficacy of SEL-212 compared to the placebo, with a favorable safety profile.

Finally, SGLT2 inhibitors, agents widely used for glycemic control and cardioprotection in patients with type 2 diabetes (T2D), have also been shown to lower serum urate. A meta-analysis of 43 randomized controlled trials demonstrated lower serum urate levels with SGLT2 inhibitors compared to the placebo both in patients with T2D (between group difference in serum urate: -0.53 mg/dL) and patients without T2D (-1.54 md/dL).

Urate-Lowering Strategy

In patients requiring ULT (Table 8.1), the following approach should be followed:

Initiate anti-inflammatory prophylaxis with low-dose daily colchicine or low-dose NSAID 1 to 2 weeks prior to starting the urate-lowering agent.

Initiate a uricostatic agent at an initial low dose (100 mg/day for allopurinol or 40 mg/day for febuxostat). Escalate the dose every 2 to 4 weeks while closely monitoring for toxicity until the serum urate is <6.0 mg/dL (at a minimum) or the maximum approved dose is reached or toxicity is present.

If a reduction of serum urate to the target value is achieved, maintain the anti-inflammatory prophylaxis for 3 to 6 months after the last gouty flare (and longer when tophi persist on physical exam). Maintain the urate-lowering agent at this dose indefinitely and check serum urate levels every 6 to 12 months thereafter.

If toxicity occurs with one of the uricostatic drugs, try the other agent in a similar manner. There is no evidence of cross-reactive toxicity between allopurinol and febuxostat.

If the target serum urate is not achieved with a uricostatic drug, a uricosuric agent (probenecid) can be added.

Pegloticase can be tried, especially in patients with large tophaceous deposits (discussed further in Importance of Patient Education and Comprehensive Disease-Management Plan for Gout).

Once started, ULT should not be discontinued or adjusted during gout flares. This will generally make the flare worse.

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Take-Away Messages

• The goal of therapy in subjects with multiple recurrent gout flares or tophaceous gout is to prevent disease progression by reducing the body urate burden.
• Any patient presenting with advanced gout, or simply demonstrating tophi on physical exam, should clearly be started on ULT.
• Both allopurinol and febuxostat are effective in gout patients whose hyperuricemia is caused by either uric acid overproduction or underexcretion.
• Uricosurics should not be used as monotherapy in overproducers of uric acid or in those with a history of urolithiasis.
• The uricostatics can be administered as once-daily medications, which increases compliance. Probenecid requires 2 to 3 doses per day for optimal function.
• The uricostatic agents function well in the face of renal insufficiency, whereas probenecid requires a GFR of at least 50 mL/min to be most effective. In fact, febuxostat appears to function better than many other options in subjects with mild-to-moderate renal insufficiency.
• Rash will develop in at least 2% of patients started on allopurinol. Most rashes are benign and dose related, but allopurinol is one of the more common drug causes of severe cutaneous reactions in the form of SJS or TEN and rashes as a component of the DRESS syndrome, which is more commonly known as AHS.
• HLA-B*5801, which is common in patients of Southeast Asian ancestry, is a marked risk factor for severe allopurinol cutaneous reaction particularly in Koreans with CKD and persons of Han Chinese and Thai descent.
• In essence, the appropriate strategy for ULT is termed “treat to target,” with the evidence-based target of a serum urate of <6.0 mg/dL, at a minimum. This requires checking the serum urate level regularly (eg, every 6 months once the target has been achieved).
• In patients with one or more tophi detected on physical exam, the authors prefer a serum urate target of <5.0 mg/dL and in certain patients with advanced disease and multiple tophaceous deposits, lowering the serum urate level to <4.0 mg/day is the preferred strategy by the authors to help optimize therapy outcome.
• In certain patients with advanced disease and multiple tophaceous deposits, lowering the serum urate level to well below 6.0 mg/dL, such as in the range of 4.0 mg/dL, appears to help optimize therapy by accelerating resolution of tophi.
• The recombinant PEGylated uricase, pegloticase, is FDA-approved as an approach for potent and rapid reduction of serum urate and achieves rapid debulking of tophi (within 6-12 months) in drug responders (which were between 40% to 50% of subjects in phase 3 clinical trials, using 8 mg IV every 14 days).
• Urate-lowering therapy, once initiated, should keep the serum urate less than 6.0 mg/dL (at a minimum) for the remainder of the patient’s life, even after tophi and gouty arthritis attacks are no longer present.