Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout

INTRODUCTION — Management for the prevention of recurrent gout flares and damage to joints and other tissues from urate crystal deposition includes drug therapy, lifestyle modifications, and other strategies for risk reduction. Gout is monosodium urate (MSU) crystal deposition disease; the symptoms and signs of gout do not occur in the absence of urate saturation of extracellular fluids, which is reflected by hyperuricemia (serum urate levels >6.8 mg/dL [405 micromol/L]), urate crystal deposition, and inflammatory responses to crystal deposition. Long-term maintenance of subsaturating urate levels results in cessation of gout flares, resolution of tophi, and improvement in patient physical function and health-related quality of life.

The use of urate-lowering drugs for the prevention of recurrent gout flares and disease progression and the treatment of tophi will be reviewed here, as will antiinflammatory prophylaxis of gout flares during initiation of urate-lowering therapy. The prevention of recurrent gout flares and disease progression by use of nonpharmacologic lifestyle modifications for urate lowering and risk reduction involving drug choices for management of comorbid diseases (eg, hypertension), the clinical manifestations and diagnosis of gout, the treatment of gout flares, and issues related to asymptomatic hyperuricemia are discussed separately. (See "Nonpharmacologic strategies for the prevention and treatment of gout" and "Clinical manifestations and diagnosis of gout" and "Treatment of gout flares" and "Asymptomatic hyperuricemia".)

MANAGEMENT PRINCIPLES AND INITIAL POSTDIAGNOSTIC ASSESSMENT — In most patients with gout, the disease can be successfully managed by achieving and maintaining a subsaturating target serum urate level with a combination of lifestyle modification/risk reduction strategies (in all patients) and pharmacologic therapy (in most patients). In a few patients with complications due to tophaceous disease, surgical intervention may be an adjunct to medical management.

The prevention of recurrent gout flares, tophi, and progressive structural joint damage generally requires the long-term use of drugs that reduce the serum urate concentration either by enhancing renal excretion of uric acid (uricosuric agents) or by decreasing urate synthesis (xanthine oxidase inhibitors [XOIs]), a combination of both, or by uricolytic medications, such as uricases. The choice of specific drug therapy depends upon several factors. (See 'Choosing the urate-lowering drug' below.)

In the absence of evidence that serum urate reduction to levels that remain above the limit of solubility carries with it clinical benefits equivalent to those achievable at subsaturating levels, the importance of regarding gout as a "threshold" disease is underscored, as is the specific therapeutic requirement for lowering and maintaining urate levels in the subsaturating range.

Upon resolution of a gout flare, the patient is said to have entered an intercritical (between flares) period (see "Clinical manifestations and diagnosis of gout", section on 'Intercritical gout and recurrent gout flares'). In newly diagnosed patients, the following preventive issues should be addressed during this period:

●Risk reduction – Identification of reversible causes of hyperuricemia to facilitate lifestyle modification and other changes that may be helpful in risk reduction, such as dietary changes, weight loss, reduction in alcohol intake, and substitutions for medications that can promote hyperuricemia and the risk of gout and may reduce the efficacy of urate-lowering drug therapy [1-3]. (See "Nonpharmacologic strategies for the prevention and treatment of gout".)

●Comorbid disorders – Management of comorbid diseases common in patients with gout, such as hypertension; obesity; diabetes; hyperlipidemia; atherosclerosis; unbalanced diets rich in animal-based purines, sugar-sweetened drinks, and low in dairy protein; and high ethanol use [4]. These issues and strategies to address them, such as changes in diet and careful attention to the impact of medications used for the management of hypertension on hyperuricemia and gout, are reviewed in detail separately. (See "Nonpharmacologic strategies for the prevention and treatment of gout".)

●Drug therapy for urate lowering – The need for pharmacologic urate-lowering therapy should be determined. (See 'Indications' below.)

●Antiinflammatory gout flare prophylaxis – Prophylactic nonsteroidal antiinflammatory drug (NSAID) or colchicine therapy may be required, primarily to reduce the risk of gout flares during initiation of urate-lowering therapy. (See 'Prophylaxis during initiation of urate-lowering therapy' below.)

While prolonged use of colchicine and NSAIDs may prevent recurrent gout flares (see 'Prophylaxis during initiation of urate-lowering therapy' below), they do not prevent the development of silent bony erosions and tophaceous deposits, which may ultimately result in impaired joint function and skeletal deformity. Similarly, the excessive use of glucocorticoids in the absence of adequate, subsaturating urate-lowering therapy has been associated with the development of extensive tophaceous deposits, as well as the characteristic adverse effects of extended glucocorticoid use. (See "Major adverse effects of systemic glucocorticoids".)

●Patient education – Patients should receive education regarding the nature of the disease, the therapeutic interventions, the importance of adherence to drug regimens, the treatment target for serum urate lowering to be therapeutically effective, and the duration of therapy needed to effectively prevent flares and other disease-related injury.

During the intercritical period, classification of the patient with regard to the mechanism(s) underlying hyperuricemia and gout (including hyperuricemia due to either increased purine biosynthesis and/or urate overproduction (table 1) or decreased uric acid clearance (table 2)) may also be helpful in disease management. (See "Asymptomatic hyperuricemia", section on 'Evaluation'.)

APPROACH TO DRUG THERAPY — Timely introduction, monitoring, and adjustment of urate-lowering therapy to achieve and maintain subsaturating urate levels are important factors in successful accomplishment of suppression and reversal of the signs and symptoms of gout.

Indications — The main indications for pharmacologic urate-lowering therapy in patients with a diagnosis of gout are:

●Frequent or disabling gout flares – Precise definitions of frequent or disabling flares are not strictly established. Two flares or more annually is often described as an indication for urate-lowering treatment [5]. However, a lower threshold for treatment may be chosen after discussion with the patient if even infrequent flares are especially prolonged, interfere with vocational or avocational activities, and/or continue to recur over several years.

●Tophi and structural joint damage – Clinical or radiographic signs of severe gout, including structural joint damage (eg, gouty bone erosion), polyarticular disease, and tophaceous deposits in soft tissues or subchondral bone.

Urate-lowering therapies such as allopurinol, probenecid, or febuxostat can help reduce tophaceous deposits that may be present [6,7]; in addition, pegloticase, a polyethylene-glycolated, modified mammalian recombinant uricase (urate oxidase), which converts urate to the more soluble purine end product allantoin, may be effective as a treatment for refractory tophaceous gout due to the more intensive reduction of serum urate with this agent. (See 'Uricase' below.)

●High risk of severe gout – Treatment decisions should be individualized in patients at a high risk of severe gout who do not have recurrent or severe attacks or tophi. Risk factors to consider include:

•High baseline serum urate levels

•Early onset of symptoms

•Genetically determined disease

•Intolerance of medications used to manage acute gout

•Ultrasound evidence of monosodium urate (MSU) deposits or inflammation [8]

These issues are discussed in greater detail in other topics. (See "Clinical manifestations and diagnosis of gout", section on 'Epidemiology and risk factors'.)

In patients with these risk factors, we discuss the balance of individual risks and benefits of initiating urate-lowering therapy. This approach is consistent with European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) guidelines [9].

The role of urate-lowering pharmacotherapy in patients with uric acid nephrolithiasis or recurrent calcium oxalate nephrolithiasis is discussed in detail separately. (See "Kidney stones in adults: Uric acid nephrolithiasis", section on 'Treatment' and "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'High urine uric acid'.)

Serum urate goals and targeted therapy

●Target urate level – In practice, the most widely recommended goal range of urate-lowering therapy is serum urate <6 mg/dL (<357 micromol/L) [10], which is substantially below the urate solubility limit (serum urate of 6.8 mg/dL [405 micromol/L]) [11,12]. Although this specific goal was selected empirically, it has proven useful from an operational point of view [13,14]. A goal serum urate of <5 mg/dL (<297 micromol/L) should be used in patients with tophi, as lower serum urate levels appear to speed resolution of tophi. The maintenance of subsaturating levels impedes the nucleation of new crystals in tissues and dissolves those already formed. Most expert groups have supported this treat-to-target approach. (See 'Recommendations of major groups' below.)

●Monitoring to maintain target – A key to successful long-term gout management is monitoring of serum urate levels to assure maintenance of concentrations in the goal range and to permit urate-lowering drug dose adjustment as needed. One approach is to determine serum urate concentration after at least two to four weeks on a given dose before considering a dose adjustment; testing should be repeated again three months after the goal has been achieved to confirm that the target level has been maintained. Once goal values are confirmed, measurement every six months for the next year and then annually is usually acceptable unless drugs or lifestyle factors potentially altering urate levels have been introduced in the interim.

●Efficacy of targeted approach – Evidence that strongly supports the "treat-to-target" approach includes a randomized trial involving 517 patients from general practices in the United Kingdom, which compared laboratory, clinical, and quality-of-life outcomes for nurse-led care that involved a protocol of individualized education, regular serum urate monitoring, and urate-lowering therapy titration according to the serum urate target with usual care by the patients' general practitioners [6]. At two years, the patients receiving nurse-led care were more likely to reach target urate levels of less than approximately 6 mg/dL (360 micromol/L; 95 versus 30 percent; risk ratio [RR] 3.18, 95% CI 2.42-4.18) and had a reduced number of flares during the second year of the trial (eg, frequency of ≥2 flares/year of 8 versus 24 percent; RR 0.33, 95% CI 0.19-0.57). Patients in the nurse-led group also had a greater reduction in tophi and improved quality-of-life measures.

The efficacy of lowering of serum urate to less than 6 mg/dL (<357 micromol/L) was also illustrated by a retrospective study of Japanese patients with newly diagnosed gout [13]. Among patients with average serum urate levels in this range over three years of observation/treatment, 71 of 81 patients (86 percent) had no flare recurrences in the second and third years, a substantially lower proportion than in patients with higher average urate levels. Another retrospective review found that the optimal range of subsaturating serum urate concentrations to avoid gout flares that occur in treated patients in the early months of urate-lowering therapy was 4.6 to 6.6 mg/dL (273 to 392 micromol/L) [15]. Lowering serum urate slowly (no more than 0.6 mg/dL [36 micromol/L] per month during the first six months) was associated with the lowest rate of early gout flares.

●Safety of low urate levels – For patients receiving urate-lowering therapy, no lower limit for serum urate concentration has been established or is widely accepted. Population-based "lower limits" of normal for urate levels in adults reported by clinical laboratories are commonly in the range of approximately 3 mg/dL (180 micromol/L). Adverse neurologic or cardiovascular consequences of very low urate levels have been postulated based upon epidemiologic associations, but mechanistic and clinical evidence of such relationships have not been established [16]. Experience with pegloticase (pegylated recombinant modified mammalian uricase) (see 'Uricase' below) has not identified adverse consequences in patients maintaining profound reductions of urate, often to unmeasurable levels, over many months to several years.

Similarly, patients with hereditary xanthinuria, who have very low urate levels as a consequence of absent or nearly absent xanthine oxidase activity, along with patients with renal hypouricemia type 1 (lack of expression of uric acid transporter 1 [URAT1]) and type 2 (lack of expression of glucose transporter 9 [Glut9]), are reported to have normal longevity and no increase in the incidence of neurologic or cardiovascular disease. There is considerable variation in individual responses to the available oral urate-lowering agents or combinations of agents [17]; values less than 2 to 3 mg/dL (120 to 180 micromol/L) are rarely encountered.

Initiation and duration of urate-lowering pharmacotherapy

●Timing for the initiation of urate-lowering drug therapy – We generally wait until at least two weeks after a gout flare subsides to initiate urate-lowering medication. However, in selected patients, a reasonable alternative is to initiate urate-lowering therapy during a flare. This latter approach is most useful, in our view, in a cognitively intact patient with documented gout in whom a baseline serum urate has been recorded during a flare-free period, particularly in patients with very difficult-to-manage, almost perpetual flares. In such patients, with rapidly recurring flares, successful initiation of urate-lowering therapy during flare may be effective and tolerated in conjunction with prednisone or other antiinflammatory cotreatment followed by very slow tapering (over weeks to months) of the dose of the glucocorticoid or other agent (see 'Prophylaxis during initiation of urate-lowering therapy' below). Some experts have suggested that urate-lowering medication can more broadly be started together with antiinflammatory therapy during a gout flare [18].

In either case, once medications are started, urate-lowering therapy should not be interrupted in patients who experience a subsequent acute flare.

The rationale supporting the well-established practice of delaying the start of urate-lowering therapy until after a flare has resolved is based upon the following:

•Urate lowering in gout is a long-term treatment for which there is no evidence that initiation during a gout flare promotes better outcomes or long-term adherence

•Serum urate levels are in a normal range in 25 to 40 percent of patients with gout flares, and immediate addition of urate-lowering medication precludes obtaining an accurate baseline (pretreatment) serum urate level, unless this has been established earlier in the patient's course

•Introduction of urate-lowering therapy in the course of intensive antiinflammatory flare treatment has the potential to cloud the interpretation of which agent may be implicated in an adverse event accompanying antiinflammatory flare treatment, a problem of some significance given the rather narrow range of available urate-lowering agents of substantial efficacy

•There is no evidence that initiation of urate-lowering treatment during flare hastens accomplishment of goal-range serum urate levels (<6 mg/dL [<357 micromol/L]), for which periodic titration of the selected agent to effect is recommended

The practice of delaying the start of urate-lowering drug therapy until after flare resolution has been based upon observations that acute urate-lowering can precipitate a gout flare and a concern that initiation of urate-lowering therapy during a gout flare may worsen or prolong the inflammatory arthritis. However, the absolute risks of these complications of early urate-lowering therapy have not been established [19,20].

One rationale for initiating urate-lowering drugs during an ongoing flare is that this presents an educational opportunity to support the patient in an overall gout pharmacotherapeutic plan that would, in any event, initially involve urate-lowering and antiinflammatory flare prophylaxis cotherapy. This approach is supported by a small trial in which 51 patients with gout flares were randomly allocated to receive either allopurinol or placebo, along with a 10-day course of antiinflammatory gout flare medication (indomethacin 50 mg every eight hours and colchicine 0.6 mg twice daily) [21]. The investigators found no differences between the groups in mean pain scores, the frequency of additional gout flares, or in levels of acute phase reactants. Subsequently, another small trial has shown similar findings [22].

The initiation of urate-lowering therapy together with flare treatment is compulsory, per the European Union label, when canakinumab, an interleukin (IL) 1beta inhibitor, is prescribed to treat a gout flare.

●Prophylaxis during initial therapy – During the initial period of urate-lowering therapy, patients should also receive prophylactic treatment to decrease or prevent recurrent episodes of gout flare. Typically, colchicine, or alternatively, a nonsteroidal antiinflammatory drug (NSAID; or less often, a glucocorticoid) are administered for this purpose. (See 'Prophylaxis during initiation of urate-lowering therapy' below.)

●Duration of therapy – Once the decision is made to begin therapy to lower serum urate, the treatment is usually indefinite and should be continuous if needed to maintain lifelong subsaturating urate levels and to remain clinically effective. The rationale and importance of ongoing therapy should be emphasized in initial patient education and subsequently over the course of therapy in an effort to reduce nonadherence to treatment and to optimize patient outcomes.

Selected patients may benefit from the withdrawal of urate-lowering medication but then should be carefully observed to determine the safety of this approach, including:

•Patients who adhere to lifestyle changes and risk reduction only after urate lowering is initiated, to assess the potential efficacy of nonpharmacologic management.

•The rare patient in whom the diagnosis of gout is unconfirmed by the demonstration of urate crystals, and oral urate-lowering therapy achieves unusually low serum urate levels (for example, <3 mg/dL [<180 micromol/L]) with minimal daily doses of an oral urate-lowering agent. This is done to determine whether the diagnosis of gout was correct or if so, whether any urate-lowering medication would be needed.

The majority of patients who achieve control of gout with long-term urate-lowering therapy will have recurrent symptoms and/or tophi if treatment is stopped [23-26]. In addition, lower serum urate concentrations during treatment correlate with a longer delay before flares resume or tophi reappear. In one study, for example, patients with average serum urate concentrations less than 5.05 mg/dL (<300 micromol/L) during continuous treatment for at least five years had the longest time to recurrence (mean of three to four years) after the cessation of urate-lowering therapy, probably due to a greater reduction in the total body urate pool [27]. Another study found reduced benefit from intermittent allopurinol (two months per year) compared with continuous therapy [28]; gout flares occurred with similar frequency in both groups during the first year, but after one year, the continuous allopurinol treatment group experienced fewer flares.

Nonadherence to recommended treatment is an important issue in patients with gout [29-31]. Treatment is prolonged (perhaps lifelong), and the patient is asymptomatic for the vast majority of the time. The extent of patient nonadherence was illustrated in a study that tracked use of allopurinol over two years in a managed care setting [30]. Less than 20 percent of patients who initiated treatment complied well with therapy (defined as using the drug on 80 percent or more of the days during the study). As noted, nurse-led follow-up has been associated with high levels of adherence [6]. (See 'Serum urate goals and targeted therapy' above.)

PROPHYLAXIS DURING INITIATION OF URATE-LOWERING THERAPY — In patients who are beginning urate-lowering therapy, we recommend low doses of oral colchicine to decrease or prevent recurrent episodes of gout flare. In patients unable to use colchicine, we suggest a nonsteroidal antiinflammatory drug (NSAID). (See 'Colchicine prophylaxis' below and 'NSAID prophylaxis' below.)

In patients who experience frequent flares during initiation of urate-lowering therapy and cannot tolerate low-dose colchicine or NSAIDs, low-dose glucocorticoids can be used (eg, prednisone 5 to 7.5 mg daily) during the initiation phase in our experience; however, there are no clinical trial data to demonstrate the efficacy or safety of this approach.

Resolution of the urate crystal burden may require many months to several years to attain, even after subsaturating urate levels are achieved. During this period of crystal dissolution, a risk for gout flare remains and is the primary basis for gout flare prophylaxis with antiinflammatory agents.

Moreover, an acute fall in serum urate concentration often precipitates a gout flare [28,32], although gradual titration of urate-lowering medication appears less likely to do so. As an example, in a randomized trial comparing nurse- versus physician-led initiation of urate-lowering therapy, slow up-titration from low doses of allopurinol needed to reach serum urate goal of <6 mg/dL was not associated with increased numbers of flares during year 1 of treatment, despite virtually no use of antiinflammatory drug flare prophylaxis [6].

In addition, the increase in uric acid excretion early in the course of treatment with uricosuric agents can promote urinary stone or gravel formation, but the risk of precipitating urinary stone formation and a gout flare can be minimized by starting with low doses of urate-lowering therapy and by hydration (two or more liters of fluid daily). Alkalinization of the urine is unnecessary in most patients. (See "Kidney stones in adults: Uric acid nephrolithiasis".)

A tenable explanation for the mechanism by which the acute fall in serum urate concentration may precipitate a gout flare is that urate lowering disrupts the physical state and/or surface chemical composition of preformed crystal deposits and thus makes the component crystals interactive with local cells competent in initiating interleukin (IL) 1-mediated acute inflammatory responses emanating from activation of toll-like receptors and the formation of NALP3 inflammasomes [33,34].

Identification of IL-1 as a major cytokine in the initiation of gout flares [34] has prompted interest in potential roles for IL-1 inhibitory agents (eg, anakinra, canakinumab, or rilonacept) both in treatment of ongoing flares [35-37] and as prophylaxis to prevent gout flares in patients with or without a previous diagnosis of gout [38], and during the initiation of urate-lowering therapy [39-41]. The role of these biologic agents in routine clinical practice remains to be defined. (See "Pathophysiology of gout", section on 'Inflammation'.)

Colchicine prophylaxis — Oral colchicine can reduce the frequency of recurrent gout flares early in the course of urate lowering with uricosuric agents or xanthine oxidase inhibitors (XOIs) [42-45]. A typical colchicine regimen at the initiation of urate-lowering therapy is 0.5 to 0.6 mg orally once or twice daily for patients with normal renal function [19]. Available colchicine formulations may include tablets in doses of 0.5, 0.6, or 1 mg. Many patients, particularly older individuals, develop loose or diarrheal stools that preclude use of the recommended colchicine dose. Satisfactory prophylaxis in such patients is often attained with the lower colchicine doses of 0.5 to 0.6 mg once daily or even every other day.

The dose of colchicine should also be reduced to 0.5 to 0.6 mg per day in patients with stage 3 chronic kidney disease (CKD; creatinine clearance [CrCl] 30 to 60 mL/minute) and to half of a 0.5 or 0.6 mg tablet daily (if tablets can be split) or one 0.5 or 0.6 mg tablet every two to three days in patients with stage 4 CKD. Colchicine should not be used in patients with stage 5 CKD undergoing dialysis for end-stage kidney disease. (See "Definition and staging of chronic kidney disease in adults".)

In patients without tophi, colchicine is generally continued for at least three months and up to six months after the initiation of urate-lowering therapy. Colchicine has a narrow therapeutic index and does not prevent monosodium urate (MSU) crystal accumulation. It is thus infrequently used for long-term prophylaxis, compared with the usual long-term use of uricosuric drugs and XOIs. (See 'Duration of prophylactic therapy' below.)

Drug interactions of colchicine with other agents that may impact dosing are described in detail separately, and further information is provided in the drug interactions program included in UpToDate.

Colchicine-induced neuromyopathy is a potential complication of chronic therapy, particularly in patients with a reduced CrCl. It should be suspected in patients who complain of paresthesias, numbness, and/or weakness. Most cases occur in patients treated with daily low-dose colchicine for months to years. Patients taking 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) that interact with cytochrome enzyme CYP3A4 may be at increased risk for colchicine-induced myopathy [46]. (See "Drug-induced myopathies", section on 'Colchicine'.)

Organ transplant recipients who develop gout and are treated with colchicine while receiving cyclosporine are at increased risk for colchicine myopathy [47]. Such patients should be treated, if at all, with low doses of colchicine and for as brief a period of time as possible. (See "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)

The efficacy of prophylactic colchicine in patients beginning urate-lowering therapy was demonstrated in a randomized trial in which 43 patients were assigned to treatment with colchicine or placebo prior to initiation of urate-lowering therapy [44]. The patients were then followed for at least three months beyond the time their serum urate levels were reduced to a level of less than 6.5 mg/dL (<387 micromol/L). At six months, there were significantly fewer gout flares in those who received colchicine (mean number of flares 0.1 versus 1.8 with placebo).

The cost of prophylactic use of colchicine tablets is not a problem in many countries; however, it may be for many patients in the United States. In the United States, one manufacturer's brand is approved for use, and the cost of the US Food and Drug Administration (FDA)-approved product was reportedly USD $4.30 per tablet in 2009 [48] and approximately twice that amount in 2020. A capsule form of colchicine (0.6 mg) was subsequently made available as an alternative preparation. Both manufacturers reportedly offer programs to defray the cost for eligible patients [49]. Resources for patients who need assistance paying for colchicine or other medications are reviewed separately. (See "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)", section on 'Help paying for your medicine'.)

NSAID prophylaxis — Low-dose nonsteroidal antiinflammatory drugs (NSAIDs; eg, naproxen 250 mg twice daily) appear to be effective for prophylaxis in many of the patients who do not tolerate low-dose colchicine, although the data are very limited [50,51]. Other NSAIDs prescribed at a low dose may also be effective. Gastrointestinal toxicity is a potential complication of all NSAIDs, often prompting coadministration with a proton pump inhibitor once daily. NSAIDs should not be used in patients with moderate or more severe renal impairment or significant heart failure. (See "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs: Adverse cardiovascular effects", section on 'NSAIDs and heart failure'.)

Duration of prophylactic therapy — Because of potential toxicity, the continued use of colchicine or NSAIDs is not recommended after persistent normouricemia has been achieved with urate-lowering drugs. The recommended duration of prophylactic colchicine or NSAIDs during the initiation of urate-lowering therapy varies with the clinical setting:

●Manufacturer's suggestions in some drug labels for prophylaxis when initiating urate-lowering therapy suggest concurrent therapy for flare prophylaxis for up to six months. However, we have found that in some patients without evident tophi, prophylaxis medication can often be safely discontinued three to six months after normal serum urate values have been attained.

The 2020 American College of Rheumatology (ACR) guidelines support the use of colchicine prophylaxis for at least three to six months, and note that the duration of therapy should be extended in the setting of frequent ongoing flares [5].

●The optimal duration of prophylactic therapy for patients with tophi is uncertain. Our practice for such patients is to continue colchicine for at least 6 months; treatment for greater than 12 months is uncommonly needed [52].

CHOOSING THE URATE-LOWERING DRUG — Several uricosuric drugs and xanthine oxidase inhibitors (XOIs) are highly efficacious urate-lowering medications; these agents can establish normouricemia, ultimately decrease or abolish gout flares, and prevent or resolve tophi (see 'Uricosuric drugs' below and 'Xanthine oxidase inhibitors' below). A number of factors can be determinants of which agent is chosen as the initial agent. The most important of these are:

●Limitations on choice or dose of an agent due to comorbidities, which are frequent in gout patients

●The range of agents approved and thus available to the clinician to prescribe

●The dose range recommended for each approved agent in the particular clinical circumstance

For example, probenecid is the only potent uricosuric drug available in the United States as urate-lowering monotherapy, but it is neither as efficacious as benzbromarone, which is available in several other countries but not in the United States, nor as likely to achieve goal-range serum urate levels in patients with moderate or severe chronic kidney disease (CKD) [53]. Similarly, febuxostat is approved for treatment of gout in the United States in doses of 40 or 80 mg; by contrast, European approval of febuxostat is for doses of 80 or 120 mg. The 120 mg dose has shown superior urate-lowering efficacy compared with lower doses.

We take the following approach to the selection of urate-lowering therapy, given the considerations noted above:

●Role of allopurinol as usual first-line therapy – For most patients in whom a urate-lowering medication is indicated, we suggest the XOI allopurinol as first-line urate-lowering therapy. We initiate therapy with allopurinol at a low dose, typically 100 mg daily in a patient with a weight-adjusted creatinine clearance (CrCl) >60 mL/minute, with dose titration by 100 mg every two to four weeks to reach and maintain the urate-lowering goal range <6 mg/dL (<357 micromol/L) or, in the case of patients with tophaceous gout, <5 mg/dL (<297 micromol/L). (See 'Allopurinol' below.)

Our preference for allopurinol is based upon conflicting data regarding concerns with febuxostat regarding cardiovascular adverse effects (in patients with elevated cardiovascular risk), the ease of use of allopurinol compared with probenecid, and the reduced effectiveness of probenecid in patients with decreased renal function. Allopurinol, when dosed using a treat to serum urate target approach, has similar clinical efficacy to febuxostat [54]. Uricosuric agents should be avoided in patients with urolithiasis and risk of uric acid nephropathy and may be less effective in patients who are overproducers of urate. (See 'Allopurinol' below and 'Uricosuric drugs' below.)

•HLA-B*5801 testing – We suggest screening patients who are Chinese, Thai, Korean, or another ethnicity with similarly increased frequency of the human leukocyte antigen (HLA) B*5801 genetic variant for this allele and do not administer allopurinol in patients who test positive. Patients who are HLA-B*5801 positive are generally candidates for febuxostat, as described below.

In patients who are HLA-B*5801-positive, allopurinol should be avoided because of the substantially increased risk of severe cutaneous adverse reactions (SCARs) in this group; Han Chinese and Thai patients and patients with kidney disease who are of Korean descent are the major high-risk populations who have been documented to have this association.

Additionally, evidence of a higher prevalence of the risk allele among African American populations than among non-Hispanic White populations suggests that a similar precaution could be considered in these patients [55], as well as in patients with a family history of SCARs to allopurinol. In patients in whom testing is indicated but unavailable, we use allopurinol according to standard dosing guidelines with appropriate precautions based upon the patient's renal function, potential risk of adverse reactions, and other comorbidities; and counsel patients regarding the importance of immediate drug discontinuation should a rash or other signs of a possible adverse reaction occur. (See 'Allopurinol' below.)

•Dosing for reduced renal function – In patients with stage 3 or greater chronic kidney disease (CKD; chronic renal insufficiency), the starting dose of allopurinol and the rate of dose adjustment should be modified. The allopurinol dose should be titrated (by a similar amount but no more than 50 mg) every four weeks to achieve and maintain the same target serum urate goal as in patients with normal renal function. (See 'Allopurinol' below and 'Management of gout in advanced chronic kidney disease' below.)

•Stop therapy for rash or signs of hypersensitivity – Patients on allopurinol should be instructed to stop their medication immediately and seek medical advice if they develop a rash or other evidence of hypersensitivity to the drug.

●Role of febuxostat as alternative to allopurinol for patients without high cardiovascular risk – For most patients unable to take or intolerant of allopurinol who are not a high cardiovascular risk or with a history of a previous cardiovascular adverse event (eg, myocardial infarction), we suggest febuxostat rather than a uricosuric agent. Febuxostat, an XOI with different structural and metabolic properties than allopurinol, is easier to use than most uricosurics.

Febuxostat provides efficacious urate lowering in patients with estimated CrCl as low as 15 mL/minute; the US Food and Drug Administration (FDA) advises that febuxostat dosing should not exceed 40 mg daily in patients with a CrCl <30 mL/minute but notes that patients with mild to moderate renal impairment (30 to 89 mL/minute) do not require febuxostat dose adjustment. (See 'Urate-lowering therapy in chronic kidney disease' below and 'Dosing, drug interactions, and efficacy' below.)

●Alternative to allopurinol for patients with high cardiovascular risk – For patients unable to take or intolerant of allopurinol who are at a high risk of an adverse cardiovascular event or have a history of a previous cardiovascular adverse event (eg, myocardial infarction), we prefer an initial trial of a uricosuric agent rather than febuxostat, given regulatory restrictions and some uncertainty regarding safety based upon the available clinical trial data. (See 'Febuxostat' below.)

Pegloticase, where available, is a reasonable alternative for these patients (see 'Pegloticase' below). Febuxostat is also an alternative for these patients when no other safe and effective option is available. Treatment of patients with high cardiovascular risk should be exercised with particular caution and regular clinical monitoring. The therapeutic options, regulatory guidance, and uncertainty regarding the evidence should be reviewed with the patient in such cases.

●Inadequate response to allopurinol or febuxostat at optimal dosing

•Patients without elevated cardiovascular risk – We switch to the alternative XOI (ie, allopurinol or febuxostat) in such patients and optimize dosing if not already achieved; for patients in whom the therapeutic goal is not achieved, we add a uricosuric agent (such as probenecid). (See 'Uricosuric drugs' below and 'Combination therapy' below and 'Agents and dosing' below.)

In the infrequent patient in whom the available oral urate-lowering monotherapies fail to achieve the serum urate goal at the highest dose medically indicated, combination therapy using both an XOI and a uricosuric agent may be of benefit. (See 'Uricosuric drugs' below and 'Combination therapy' below.)

•Patients at high risk of cardiovascular disease – In patients at high risk of cardiovascular disease who do not achieve the target serum urate range with maximal allopurinol doses (but tolerate the drug), we prefer an alternative to febuxostat, for example, allopurinol in combination with a uricosuric agent (such as probenecid or benzbromarone [where available]), consistent with the American College of Rheumatology (ACR) 2020 guidelines. (See 'Uricosuric drugs' below and 'Combination therapy' below and 'Agents and dosing' below.)

●Unable to take an XOI or receiving azathioprine or 6-MP – In most patients who are unable to take a xanthine oxidase inhibitor (XOI; ie, allopurinol and febuxostat) or in whom such use would convey a substantial potential risk (eg, patients receiving azathioprine or 6-mercaptopurine [6-MP]), we suggest a uricosuric agent. In patients with gout who are willing to adhere to multiple daily dosing and who do not have limitations to uricosuric treatment (such as moderate or more severe renal impairment or urate overproduction), probenecid monotherapy provides a mechanistic alternative to treatment with an XOI. (See 'Uricosuric drugs' below and 'Febuxostat' below.)

There is no evidence that tailoring urate-lowering therapy to the results of 24-hour urine testing for uric acid excretion improves outcomes. Nevertheless, such an approach is suggested if uricosuric monotherapy is being considered [56]. Patients with gout who excrete less than 800 mg (4.76 mmol) of uric acid per day on a standard diet are potential candidates for uricosuric monotherapy unless otherwise contraindicated.

●Other options in patients with hypertension or hyperlipidemia – For patients with gout and hypertension or hyperlipidemia, an additional option is combining an XOI with one of the following mildly uricosuric agents (see 'Other drugs' below and "Nonpharmacologic strategies for the prevention and treatment of gout"):

•Losartan – In patients with hypertension.

•Atorvastatin – The only statin with a urate-lowering effect (if indicated for hypercholesterolemia or as secondary prevention of cardiovascular events).

●Role of pegloticase in refractory gout or with severe tophaceous disease – For patients with advanced gout refractory to conventional treatment or with tophaceous disease significantly affecting physical function or health-related quality of life, use of pegloticase (see 'Pegloticase' below) is a therapeutic consideration.

URATE-LOWERING MEDICATIONS

Xanthine oxidase inhibitors — Allopurinol and febuxostat are the only commonly available xanthine oxidase inhibitors (XOIs); topiroxostat, which is also an XOI, is available in Japan. Oxypurinol, an active metabolite of allopurinol, was formerly available on a "compassionate use" basis for patients intolerant of allopurinol, but some patients treated with this agent have experienced adverse reactions similar to those when previously receiving allopurinol [57].

Indications — XOIs are likely to be effective in virtually all circumstances warranting urate-lowering therapy for gout, in contrast to probenecid, although safety considerations limit XOI use in some patients. (See 'Choosing the urate-lowering drug' above and 'Allopurinol' below and 'Febuxostat' below and 'Uricosuric drugs' below.)

Allopurinol — Allopurinol is our preferred urate-lowing agent for most patients. In clinical trials, it has comparable efficacy to other agents, including febuxostat and benzbromarone, and is generally well tolerated [58].

Dosing

●Usual dosing – We usually initiate allopurinol treatment at 100 mg daily in patients with weight-adjusted creatinine clearances (CrCl) >60 mL/minute and titrate the dose every two to four weeks to the minimum dose required to achieve and maintain the goal range of serum urate. An initial dose of 100 mg or less of allopurinol is associated with reduced risks for developing severe cutaneous adverse reactions (SCARs) and gout flares that are otherwise common during initiation of urate-lowering therapy. (See 'Adverse effects' below.)

Serum urate levels begin to fall within two days of allopurinol administration and reach stable levels in one to two weeks. Thus, when titrating allopurinol dose, the urate-lowering effect of the current dose can be assessed after two or three weeks of treatment. Allopurinol may not induce goal serum urate levels early in the course of therapy of patients with extensive tophaceous deposits. However, true refractoriness to the drug is rare and most often reflects a failure of patient adherence or of clinician-patient communication [11,59].

A majority of gout patients require doses of allopurinol exceeding 300 mg/day in order to maintain serum urate <6 mg/dL (<357 micromol/L) (see 'Serum urate goals and targeted therapy' above), although the most commonly used total daily dose of allopurinol is 300 mg, despite approval in the United States and Europe of daily doses up to 800 and 900 mg, respectively. There is considerable variation among patients in the daily dose required to achieve control of the serum urate concentration, ranging from 100 to 800 mg or even more. Some studies suggest that baseline serum urate concentrations may have increased among gout patients compared with values encountered several decades ago when allopurinol was in clinical development [28,60].

We prefer to prescribe allopurinol in a single daily dose, regardless of the total dose required, and this approach may enhance medication adherence. In an occasional patient with gastrointestinal distress when starting or increasing the dose of the medication, we administer the drug in a divided dose (two or three times daily), but this is usually only necessary temporarily.

●Dose adjustment in renal disease – In patients with reduced renal function (stage 3 or more severe CKD), we initiate allopurinol at a dose not exceeding 1.5 mg per mL/minute of estimated glomerular filtration rate (eGFR). As an example, for an eGFR of 30 mL/minute, the initial daily dose of allopurinol should not exceed 50 mg daily. In a study of older adults (aged ≥66 years) with an eGFR <60 mL/minute/1.73 m², patients who started allopurinol at a dose >100 mg/day were twice as likely to require hospitalization for SCARs in the next 180 days (0.40 versus 0.18 percent, weighted risk ratio [RR] 2.25, 95% CI 1.50-3.37) [61].

The allopurinol dose should then be titrated (by a similar amount but no more than 50 mg) every four weeks to achieve and maintain the same target serum urate goal as in patients with normal renal function (see 'Urate-lowering therapy in chronic kidney disease' below). In patients with acute kidney injury (AKI; acute renal failure), it may not be advisable to initiate allopurinol, as the serum creatinine during the acute episode will not initially reflect the severity of the reduced renal function.

Titration of allopurinol to urate-lowering goal range is likely to be safe in the great majority of patients with impaired renal function. The half-life of oxypurinol, the major active allopurinol metabolite, is prolonged in renal functional impairment. This fact and the belief that metabolites of oxypurinol may play a role in severe allopurinol toxic reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS) and SCARs (including Stevens-Johnson syndrome and toxic epidermal necrolysis [TEN]), led to the publication of recommendations for reducing allopurinol doses for patients with renal functional impairment. However, a subsequent analysis of 54 patients with allopurinol hypersensitivity syndrome (AHS) and 157 patients receiving allopurinol for gout without evidence of hypersensitivity confirmed that allopurinol hypersensitivity reactions are more likely to occur in patients with renal insufficiency in whom the initial dose of allopurinol exceeds 1.5 mg per mL/minute of CrCl, particularly in those with renal functional impairment also receiving a thiazide diuretic [62]. (See 'Management of gout in advanced chronic kidney disease' below.)

Adverse effects — Side effects and adverse reactions, sometimes severe, are infrequently encountered with use of allopurinol [11]. As with all urate-lowering therapies, allopurinol administration can precipitate gout flares early in therapy, especially if antiinflammatory flare prophylaxis has been omitted (see 'Prophylaxis during initiation of urate-lowering therapy' above). Among an array of largely mild adverse reactions occurring in approximately 3 to 5 percent of patients treated with allopurinol are rash, leukopenia or thrombocytopenia, and diarrhea. Severe reactions, such as DRESS and SCARs, may occur but are very rare, with higher incidence, but still occurring infrequently, in individuals with the human leukocyte antigen (HLA) B*58:01 allele (discussed below), chronic renal impairment, and thiazide/loop diuretic use. Additional adverse reactions to allopurinol include vasculitis, drug fever, and interstitial nephritis.

Urolithiasis or crystalluria composed of xanthine or oxypurinol crystals are also rare and are more likely to occur in patients with significant urate overproduction, resulting either from an inherited defect in an enzyme of purine nucleotide synthesis or cytolytic cancer chemotherapy.

●Rash, hypersensitivity, and severe cutaneous reactions – Severe cutaneous reactions (eg, TEN, Stevens-Johnson syndrome, epidermolysis) are commonly associated with allopurinol [63]. Even a mild rash may be a harbinger of allopurinol hypersensitivity. Patients initiating allopurinol therapy should discontinue treatment and contact the caregiver promptly upon development of a rash. We would stop allopurinol if a patient develops any of these features soon after starting the drug:

•Generalized rash

•Dark, blistering skin patches

•Fever

•Flu-like symptoms (eg, myalgias, arthralgias, loss of appetite, fatigue)

•Angioedema

•Photophobia

•Mucositis

•Peripheral eosinophilia

Many types of allopurinol rashes have been described, but most rashes are mild and remit with dose reduction or drug discontinuation. Most cases of allopurinol-associated SCAR will appear within the first three months of exposure, so a rash appearing after long-term treatment with allopurinol is less likely to represent SCAR.

●HLA-B*5801 – Allopurinol should be avoided in individuals who are HLA-B*5801-positive; this has been best shown in several populations, including Chinese, Thai, and Korean patients [64,65]; and the risk allele is more than five times more common among African Americans than among White and Hispanic Americans, consistent with the threefold greater risk of SCARs among African Americans compared with White Americans [55,66]. Accordingly, we suggest testing for this HLA allele in Chinese, Thai, and Korean patients, as well as in African American patients and other ethnicities with similarly increased frequency of the risk allele. Screening has been advised by several expert groups for high-risk patients (eg, Chinese and Thai populations, Korean patients with renal impairment, and African Americans) because of its effectiveness in reducing SCARs, as well as analyses suggesting cost effectiveness in these groups [5,55,65]. However, the benefit of widespread application of testing in other populations is less clear [55], and negative testing does not preclude the development of this adverse effect, particularly in patients of European descent [18,64]. (See 'Choosing the urate-lowering drug' above.)

As examples of the data regarding HLA-B*5801 and risk of SCARs, in one report from Taiwan, each of 51 patients with severe cutaneous reactions to allopurinol was found to carry the HLA-B*5801 allele [67]. Subsequent studies have confirmed this association, including: a study in Thailand, which described the association of this haplotype with severe cutaneous reactions to allopurinol in each of 27 patients [68]; a study of 38 Han Chinese patients with cutaneous adverse reactions to allopurinol, all of whom had the HLA-B*5801 allele [69]; and others, summarized in a 2013 systematic review [64]. An analysis using the US Food and Drug Administration (FDA) adverse event databases also confirmed these findings [70]. Based upon the pooled published data, this study estimated markedly elevated risks of allopurinol-associated SCARs in HLA-B*5801 carriers, compared with healthy controls and with allopurinol-tolerant controls (odds ratios [ORs] 73, 95% CI 32-164 and 165, 95% CI 23-1174, respectively), although the ORs were very imprecise.

●DRESS syndrome – Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome consists of an erythematous rash, fever, hepatitis, eosinophilia, and acute renal failure. DRESS syndrome is an unusual but potentially life-threatening reaction to several medications, most commonly allopurinol, when it is referred to as AHS. AHS has a mortality rate approaching 25 percent [71,72]. Although the incidence of AHS is unlikely to exceed 0.1 percent of allopurinol-treated patients, this dramatic side effect has, in our opinion, influenced allopurinol prescribing patterns toward use of lower and often inadequate doses of this agent. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Desensitization protocols have been developed for the reintroduction of allopurinol to patients with mild past cutaneous hypersensitivity reactions (generally maculopapular exanthems). However, desensitization should be limited to patients with mild reactions limited to the skin and without evidence of other organ involvement. There are several published protocols, each involving oral solutions of gradually increasing concentration, given over multiple days to weeks [73-75]. However, desensitization protocols are cumbersome, and recurrence of hypersensitivity reactions has been reported [76]. Whenever feasible, consultation with an allergy specialist is helpful.

Drug interactions — There are several important drug interactions with allopurinol:

●Azathioprine and 6-MP – Allopurinol can potentiate the immunosuppressive and cytolytic effects of 6-mercaptopurine (6-MP) and azathioprine, which are metabolized in part by xanthine oxidase; thus allopurinol should generally be avoided in patients treated with these agents [29,77]. In patients with severe gout who nonetheless require allopurinol, we have reduced the azathioprine dose (by at least 50 percent) and carefully monitored the white blood cell count. Azathioprine eventually has to be discontinued in many such patients. A possible alternative in some disorders is switching from azathioprine to mycophenolate, which does not interact with allopurinol. (See "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)

●Alkylating agents – Bone marrow suppression has been noted in patients receiving alkylating agents, such as cyclophosphamide [78].

●Ampicillin – An increase in the likelihood of an ampicillin-induced rash has also been reported; although patients should be monitored for its occurrence, in our experience, it is very rare [79].

Mechanism of action — Allopurinol inhibition of urate production is in large part due to inhibition of xanthine oxidase (xanthine dehydrogenase) by both the native drug and the active metabolite oxypurinol. Allopurinol and oxypurinol are pyrazolopyrimidine analogs of the purine bases hypoxanthine and xanthine, respectively [80,81].

Allopurinol has multiple effects on human purine and pyrimidine metabolism:

●It is a competitive inhibitor of xanthine oxidase and, along with oxypurinol, produces pseudo-irreversible inactivation of the enzyme. As a result, urate production falls, but hypoxanthine and xanthine accumulate in body fluids, producing a state of pharmacologic xanthinuria.

●It substantially reduces total urinary purine (uric acid plus hypoxanthine plus xanthine) excretion in most patients. This effect is due to inhibition of the pathway of purine synthesis de novo by drug-derived and endogenous nucleotide products of enhanced purine base reutilization. This effect requires activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) and potentiates the fall in serum urate levels.

●Through nucleotide derivatives of oxypurinol, it induces a state of oroticaciduria and orotidinuria, due to inhibition of the enzyme orotidylate decarboxylase in the pathway of pyrimidine nucleotide synthesis [82].

Febuxostat

Dosing, drug interactions, and efficacy

●Dosing – Febuxostat received approval from the FDA for treatment of hyperuricemia in gout patients at daily doses of 40 and 80 mg [83]. The American manufacturers recommended that the starting dose is 40 mg once daily. Titration to a daily dose of 80 mg is suggested for patients whose serum urate level does not fall to <6 mg/dL (<357 micromol/L) after two weeks of treatment on the lower (40 mg daily) dose. In Europe, higher doses have also received regulatory approval (up to 120 mg/day) [84].

Very gradual increases in the febuxostat dose when starting therapy can help reduce flare frequency during this period. In a study in Japan, the gradual titration of the febuxostat dose upon initiation of therapy (10 mg daily for four weeks, then 20 mg daily for four weeks, then 40 mg daily), without colchicine prophylaxis, resulted in a comparable number of gout flares in the first three months of therapy to patients started on febuxostat in a fixed dose (40 mg daily) together with prophylactic colchicine (0.5 mg daily; 21 and 19 percent of patients) [85]. The combination of gradual titration of febuxostat with colchicine prophylaxis was not examined in this study.

Febuxostat, initiated at 40 mg daily, is also an alternative XOI for use in patients with reduced renal function; it is metabolized in a different manner than allopurinol. (See 'Urate-lowering therapy in chronic kidney disease' below.)

●Major drug interactions and mechanism of action – Decreased metabolism of azathioprine, mercaptopurine, and theophylline is an expected result of administration of an XOI, and a need for continued use of any of these three drugs is considered by the manufacturer to be a contraindication to the use of febuxostat [86]. As noted above, we and others have used reduced doses of azathioprine or mercaptopurine with the XOI allopurinol while carefully monitoring for bone marrow toxicity (ie, development of cytopenias). It is uncertain whether such a strategy can safely be pursued with febuxostat, but severe hematologic adverse events have also been reported with this agent [87,88].

Febuxostat is an XOI. It is a thiazolecarboxylic acid derivative that, unlike allopurinol, is not a purine-base analog. It inhibits xanthine oxidase by occupying a channel in the xanthine oxidase dimer and impairing access of purine-base substrates to the active site of xanthine oxidase catalysis. The difference in the mechanism of inhibition may underlie the greater specificity of febuxostat for inhibition of xanthine oxidase compared with allopurinol.

●Cost – The cost of treatment with brand name febuxostat is substantially higher than with either generic allopurinol or its brand name equivalents, although generic febuxostat is available at a lower cost in some countries, including the United States and those in the European Union. (See 'Choosing the urate-lowering drug' above.)

●Efficacy – Febuxostat produces a dose-dependent decrease in serum urate levels [89]. A daily dose of 40 mg produces a reduction that is roughly equivalent to that seen in patients who are treated with allopurinol at a dose of 300 mg per day [28,58,90]. A major limitation of most of the evidence comparing febuxostat with allopurinol is the use of a fixed allopurinol dose without titration to achieve optimal benefit. (See 'Allopurinol' above.)

•A 52-week randomized trial assigned 760 patients with gout and serum urate ≥8 mg/dL (≥476 micromol/L) to febuxostat at daily doses of 80 or 120 mg or to allopurinol at 300 mg daily (fixed dose) [28]. A sustained reduction of serum urate to a target level <6 mg/dL (<357 micromol/L) was more common in the 80 and 120 mg febuxostat groups than the allopurinol 300 mg group (53 and 62 versus 21 percent, respectively). Reductions in gout flare incidence and in tophus areas over time were similar in the three groups. The incidence of adverse events did not differ across the groups, but withdrawal from the study due to gout flares and abnormal liver function studies was more common in both febuxostat groups than in the allopurinol group.

•In a six-month trial, febuxostat (80, 120, or 240 mg daily) was compared with allopurinol (300 mg) and placebo [91]. The efficacy of febuxostat in reducing serum urate at both doses was superior to the fixed dose of allopurinol and placebo, both in subjects with normal renal function and in a small subgroup of subjects with mild to moderate chronic renal impairment whose allopurinol dose was 100 mg daily. However, allopurinol dosing was not escalated to achieve target serum urate levels. No dose reduction in febuxostat appeared necessary in subjects with these levels of renal function.

•The use of febuxostat in patients with mild or moderate renal functional impairment (defined, respectively, as estimated CrCl of 60 to 89 mL/minute and 30 to 59 mL/minute) was assessed as part of a six-month trial that randomly assigned 2268 subjects with gout and baseline serum urate ≥8 mg/dL (≥476 micromol/L) to receive febuxostat 40 or 80 mg daily or allopurinol (300 mg daily in subjects with normal or mildly impaired renal function or 200 mg daily if baseline renal function was moderately impaired) [90]. Approximately 65 percent of subjects had either mild or moderate renal impairment. In this subset of patients, a single final urate level <6 mg/dL (<357 micromol/L) was achieved with febuxostat 40 and 80 mg daily in 50 and 72 percent of patients, and allopurinol (in the initially assigned doses) in 42 percent of patients. Safety was comparable across all treatment groups.

•In patients with early gout (one or two gout flares), febuxostat can reduce the frequency of subsequent gout flares and the degree of synovitis in the affected joint [92]. In a randomized 24-month trial involving 314 patients, febuxostat (40 mg daily, increased to 80 mg daily in patients with serum urate remaining greater than or equal to 6 mg/dL) was more likely than placebo to decrease the incidence of gout flares (29 versus 41 percent) and the synovitis score on imaging compared with baseline (rheumatoid arthritis magnetic resonance imaging scoring [RAMRIS], -0.43 versus -0.07). After two years, the active treatment group included a greater proportion of patients with serum urate <6 mg/dL (63 versus 6 percent). Joint erosions were minimal in both groups.

•In one randomized trial involving 940 patients with hyperuricemia and gout, in which allopurinol (up to 800 mg daily) and febuxostat (up to 120 mg daily) were compared after a period of dose titration to target serum urate levels, similar numbers of patients reached target serum urate levels and exhibited similar degrees of risk of serious adverse effects, including cardiovascular events [54]. Although the trial was designed to determine whether allopurinol was noninferior to febuxostat, fewer allopurinol-treated patients had one or more gout flares in the observation phase of the trial, following drug titration and after discontinuation of antiinflammatory flare prophylaxis (36.5 versus 43.5 percent). Approximately one-third of patients had stage 3 CKD (eGFR <60 and ≥30 mL/minute/1.73 m²) with comparable results with both drugs with patients with greater kidney function.

Adverse effects — Several types of adverse effects have been associated with use of febuxostat, some of which, including cardiovascular and hepatic abnormalities, may be more common with use of febuxostat than with allopurinol [86,93-96]. A greater incidence of liver function test abnormalities, nausea, arthralgia, and rash has been noted in febuxostat-treated patients than in placebo controls, but not in allopurinol-treated subjects, during clinical trials. Periodic monitoring of liver function, principally hepatic transaminase enzyme levels, is suggested by the manufacturer of febuxostat [86]. Postmarketing studies have shown that hypersensitivity reactions can also occur in people taking febuxostat, and those with a prior drug reaction on allopurinol appear to be at higher risk for hypersensitivity to febuxostat [97].

As with any urate-lowering treatment, the risk of gout flares is increased when febuxostat is initiated, and patients should receive prophylaxis for flares. (See 'Prophylaxis during initiation of urate-lowering therapy' above.)

During clinical trials, patients treated with febuxostat had a higher incidence of thromboembolic cardiovascular events than comparators who received allopurinol (0.74 [95% CI 0.36-1.37] versus 0.60 [95% CI 0.16-1.53] events per 100 patient-years, respectively) [86]. However, such an imbalance was not confirmed in a subsequent randomized trial [90]. The additional possibility of a febuxostat safety signal regarding heart failure has been raised in Europe, in Canada, and by the World Health Organization (WHO), but remains uncertain [93,94].

As reported in a 2017 FDA drug safety communication [95], a greater frequency of adverse cardiovascular events with febuxostat than allopurinol was described in a preliminary review of a large postmarketing trial comparing the cardiovascular safety of febuxostat and allopurinol therapy in gout patients at high risk for cardiovascular events [98,99]. Subsequent to this communication, the full trial report has been published [96]; this safety trial was requested of the manufacturer by the FDA at the time of febuxostat approval. The subsequent randomized active comparator-controlled trial was conducted in 6190 patients with a diagnosis of gout and a prior history of major cardiovascular disease; the median follow-up was for 32 months. Major prior cardiovascular diseases defined for inclusion of patients in the trial included myocardial infarction, hospitalization for unstable angina, stroke, hospitalized transient ischemic attack, peripheral vascular disease, and diabetes mellitus with evidence for micro- or macrovascular disease. The primary endpoint of the trial was the time to occurrence of any of a combination of events including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina with urgent revascularization.

When the individual cardiovascular outcomes were evaluated separately, febuxostat showed an increased risk of cardiovascular mortality and all-cause mortality, compared with allopurinol (hazard ratios [HRs] 1.34, 95% CI 1.03-1.73 and 1.22, 95% CI 1.10-1.47, respectively); however, febuxostat was not associated with an increased risk of the combination of events composing the primary endpoint [95,96]. The absolute risks of cardiovascular mortality, all-cause mortality, and the primary endpoints comparing febuxostat and allopurinol were 4.3 versus 3.2, 7.8 versus 6.4, and 10.8 versus 10.4 percent, respectively. The trial was not placebo controlled, and 45 percent of patients discontinued follow-up; thus, it remains unclear whether allopurinol had beneficial effects on mortality in this high-risk population or whether febuxostat had deleterious effects.

In 2019, the FDA added a boxed warning for increased risk of death with febuxostat [100]. The FDA has advised that febuxostat should be reserved for use only in patients who have failed or do not tolerate allopurinol. Patients should be counseled about the cardiovascular risk with febuxostat and advised to seek medical attention immediately if they experience symptoms of a cardiovascular event.

Subsequently, another large post-marketing safety trial has failed to confirm greater cardiovascular risk with febuxostat than allopurinol. In the open-label Febuxostat versus Allopurinol Streamlined Trial (FAST), involving 6128 patients with gout in the European Union, who were ≥ age 60 and being treated with allopurinol, patients were randomly assigned to switch to febuxostat or continue allopurinol, with dose adjustment to maintain target serum urate levels [101]. One-third of patients had a history of a previous cardiovascular event; the others had at least one cardiovascular risk factor but no prior event. After a median follow-up of approximately four years, there were no significant differences between the groups in overall mortality; cardiovascular mortality; or in a composite outcome of cardiovascular events, which included hospitalization for nonfatal myocardial infarction or biomarker-positive acute coronary syndrome, nonfatal stroke, and cardiovascular death. At the time of the report's publication, neither the European Medicines Agency (EMA) nor the FDA had taken a new position regarding its warnings, continuing to recommend not prescribing febuxostat in patients with a history of cardiovascular events unless there is no other therapeutic option available.

Uricosuric drugs

Indications — Patients with relative renal underexcretion of uric acid (ie, low or normal values for urinary uric acid excretion in the presence of hyperuricemia) are potentially candidates for uricosuric drug therapy (see "Urate balance"). Decreased efficiency of renal uric acid excretion is responsible for at least 85 to 90 percent of patients with primary or secondary hyperuricemia (table 2). Uricosuric drug monotherapy should be avoided in those with a history of nephrolithiasis to avoid renal stone recurrence.

Uricosuric treatment has been used rather uncommonly in the United States and other countries since the introduction of the XOI allopurinol in 1966, although a substantial proportion of gout patients with indications for urate lowering could be candidates for a uricosuric agent. Reasons for this discrepancy include the smaller range of gout patients for whom uricosuric agents are appropriate in comparison with XOIs; the multiple drug interactions with probenecid and sulfinpyrazone; and the requirement for multiple daily dosing of probenecid, the only potent uricosuric agent available for monotherapy in the United States [18]. The use of uricosuric therapy is less uncommon in countries where benzbromarone is available, as this uricosuric agent is highly effective and can be administered in a single daily dose [10,102]. (See 'Agents and dosing' below.)

One potential benefit of probenecid has been suggested by a large observational study of older adults that described a modestly lower risk of adverse cardiovascular events in patients receiving probenecid compared with those taking allopurinol (incidence ratio 2.36 versus 2.83 per 100 patient-years) [103]. However, the study had a number of limitations with respect to potential confounding by indication (ie, due to nonrandomization) and misclassification of outcomes (due to reliance upon billing and procedure codes used in the Medicare database). There were also insufficient data to directly evaluate the cardiovascular risk factors and other comorbidities in the populations in each cohort, and other potentially relevant clinical and laboratory data were incomplete or lacking.

Several trials have suggested that uricosurics, particularly benzbromarone, can be effective in patients who are underexcretors and in some patients with genetically induced overproduction of serum urate [60,104-106].

Probenecid and sulfinpyrazone are effective for most patients but are likely to be ineffective in those with moderate to severe CKD [18]. Benzbromarone, where available, may be more effective for patients with mild to moderate renal insufficiency (CrCl 30 to 59 mL per minute), including some patients who have not responded to or tolerated allopurinol [107-109]. Dotinurad is a potent uric acid transporter 1 (URAT1) inhibitor that became available for use in Japan in early 2020 [110,111].

Combination therapy — In the infrequent patient in whom the available oral urate-lowering monotherapies fail to achieve the serum urate goal at the highest dose medically indicated, combination therapy using both an XOI and a uricosuric agent may be of benefit. (See 'Choosing the urate-lowering drug' above and 'Uricosuric drugs' above.)

Support for such a dual-mechanism approach to urate lowering was suggested at the time allopurinol was approved in the United States in 1966 and was included in the 2012 American College of Rheumatology (ACR) guidelines for the management of the hyperuricemia of gout [18]. In the experience of the authors, however, this approach has rarely been necessary because we have had success in titrating doses of allopurinol or febuxostat to effect (ie, doses necessary to reach subsaturating urate levels) in the great majority of patients.

It is clear, however, that in the broader practice setting, there is continued reluctance to titrate allopurinol to doses higher than 300 mg per day [112-114], despite substantial evidence that only a minority of current gout patients achieve goal serum urate levels on this dose [28,90,91]. Although we strongly prefer and have had success in treating to goal with one or another agent as monotherapy, we acknowledge the potential for uricosuric therapy added to maximum doses of XOIs to improve the overall outcome of urate-lowering efforts in gout. Limited evidence of the efficacy and safety of combined XOI and uricosuric therapy has been published [7,115-117], but we await the results of randomized trials directly comparing the urate-lowering efficacy and safety of XOI dose titration with combined XOI and uricosuric therapy in a substantial number of patients.

Agents and dosing — The uricosuric drugs are weak organic acids that promote renal clearance of uric acid by inhibiting proximal tubule urate-anion exchangers that mediate urate reabsorption [118,119]. Probenecid, although infrequently used, is the only agent of this class specifically approved by the FDA for the purpose of promoting renal uric acid clearance that is currently available in the United States, where sulfinpyrazone is no longer marketed. Uricosuric agents in use elsewhere, in addition to probenecid, include benzbromarone [10,102] and sulfinpyrazone.

●Probenecid – Probenecid is started at a dose of 250 mg twice daily; increments in dose are titrated according to the serum urate concentration. The dose is typically raised every several weeks to a usual maintenance dose of 500 to 1000 mg two or three times daily, aiming for the usual target for urate lowering in gout of a serum urate <6 mg/dL (<357 micromol/L). The maximal effective dose is 3 g/day.

●Benzbromarone – Benzbromarone, where available, is increased from a starting dose of 50 mg/day to a maximum of 200 mg/day in 50 mg/day increments to achieve the desired level of serum urate. The dose of 100 mg/day is commonly used [10,120].

●Sulfinpyrazone – Sulfinpyrazone, where available, is started at a dose of 50 mg twice daily, with increments over several weeks to 100 to 200 mg three or four times daily as needed. The maximum effective dose of sulfinpyrazone is 800 mg/day.

Lesinurad, another uricosuric agent, has been withdrawn from the worldwide market for commercial reasons.

Side effects and interactions — The major side effects of uricosuric drugs are precipitation of a gout flare (see 'Prophylaxis during initiation of urate-lowering therapy' above), rash (probenecid), gastrointestinal intolerance, and uric acid urolithiasis. A scheme for monitoring the course of uricosuric therapy to reduce the risk of excessive uric acid crystal deposition and stones or obstructive uropathy emphasizes adequate fluid intake and serial measurements of urinary uric acid and pH as well as the serum urate concentration [108]. Probenecid also increases urinary calcium excretion in patients with gout, reinforcing the contraindication for its use in patients with prior nephrolithiasis [121].

Interference with the transport of other organic anions across cell membranes by uricosuric drugs is the basis of numerous drug interactions. As an example, urinary excretion of penicillin and ampicillin are decreased by probenecid, resulting in prolongation of the half-lives of these antibiotics.

The uricosuric effect of probenecid may be reduced by relatively large doses of salicylates [122]. However, low-dose daily aspirin, as used to prevent cardiovascular disease, may not have such an effect. In a crossover trial of 11 patients, the addition of low-dose aspirin (325 mg/day) to an ongoing regimen of probenecid did not change the serum urate concentration or daily uric acid excretion [123].

The availability and use of benzbromarone have been restricted in some countries because of concerns regarding several reports of patients with severe hepatotoxicity [10,120].

Other drugs

●Losartan – The angiotensin II receptor antagonist losartan is unique among this drug class in having a modest uricosuric effect that appears to plateau at a dose of 50 mg/day [124]. Losartan may be an option for patients who need an antihypertensive agent and in whom the use of probenecid is not feasible due, for example, to allergy or intolerance. (See "Diuretic-induced hyperuricemia and gout", section on 'Benefits of angiotensin inhibition and losartan'.)

●Atorvastatin – Atorvastatin, approved for the treatment of hyperlipidemia and for secondary prevention of cardiovascular events, exerts a mild uricosuric effect that could be of some clinical utility if indicated. This effect is not shared by other statins [125].

●Fenofibrate – Fenofibrate, a fibric acid derivative used for the treatment of hyperlipidemia, also has uricosuric activity. In a short-term, unblinded study of 10 patients with gout who were already being treated with allopurinol, the addition of fenofibrate (200 mg/day) resulted in a 19 percent reduction in serum urate and a mean increase in uric acid renal clearance of 36 percent [126]. However, the ACR 2020 guidelines for management of gout caution against switching from other cholesterol-lowering agents to fenofibrate despite its urate-lowering effects [127], as the risks, including side effects of the medication, were felt to outweigh potential benefits [5]. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Fibrates'.)

Uricase — Recombinant forms of uricase, including pegloticase, are potent agents that can rapidly reduce serum urate levels. Uricase (urate oxidase) is the enzyme that catalyzes conversion of urate to a more soluble purine degradation product, allantoin. Uricase is present in most mammals but is absent in humans and some primate species due to mutational inactivation of the uricase gene. Urate-lowering therapy for gout with uricase is aimed at supplying the absent enzyme activity safely and for a sufficient period of time to promote depletion of body urate pools, thus resulting in clinical benefits such as gout flare reduction and tophus resolution. Pursuit of these aims has resulted in the development of recombinant uricases, modified by covalent linkage to polyethylene glycol, in order to prolong enzyme activity and potentially reduce immunogenicity. (See 'Pegloticase' below and 'Rasburicase' below.)

Pegloticase

●Indications and mechanism – Pegloticase is a porcine-like uricase [128] linked to methoxy polyethylene glycol that is an alternative therapy for patients with severe gout in whom treatment with other urate-lowering agents has failed to be effective. We use this biologic agent as an option for patients whose gout is advanced and actively symptomatic or when use of other urate-lowering therapies is either contraindicated or ineffective in achieving and maintaining subsaturating serum urate levels. An important criterion in support of the candidacy of such patients for pegloticase treatment is the need for rapid improvement in clinical outcomes, such as flare and tophus reduction, restoration of function, and quality of life, outcomes that take several years to achieve with oral agents and only months in some pegloticase-treated patients. The maintenance of lower serum urate goal ranges (eg, <2 to 5 mg/dL [119 to 297 micromol/L]), which may be achieved with pegloticase, is associated with more rapid reduction or reversal of gout signs and symptoms than other urate-reducing therapies.

Although approved for use, pegloticase has been withdrawn by the manufacturer in the European Union.

Use of pegloticase, with appropriate prophylaxis for gout flares and for infusion reactions, can be expected to be effective in approximately 40 percent of the patients with gout who had not responded to other available treatments (which was required for inclusion in the randomized trials with this agent), and in those patients with contraindications to other urate-lowering therapies [129,130].

●Dosing and administration – Pegloticase is administered intravenously every two weeks as 8 mg of the agent diluted into 250 mL of 0.9 percent (or 0.45 percent) sodium chloride (NaCl) infused over at least two hours. Serum urate should be monitored prior to each infusion to confirm sustained urate-lowering efficacy (serum urate <6 mg/dL [<357 micromol/L]) [131]. Pegloticase should also be coadministered with weekly oral methotrexate 15 mg along with folic acid or folinic acid supplementation, as addition of methotrexate leads to a higher proportion of pegloticase responses and fewer infusion reactions [131]. When methotrexate is used, it should be started at least four weeks prior to initiating pegloticase and continued for the duration of pegloticase treatment. If methotrexate is not tolerated or is contraindicated, other immunosuppressive therapies such as azathioprine, mycophenolate mofetil [132], and leflunomide could be considered as alternatives. Pegloticase alone may be used in patients for whom immunosuppression is contraindicated or not clinically appropriate. All pegloticase-treated patients should also be receiving gout flare prophylaxis for at least the first six months of treatment (see 'Prophylaxis during initiation of urate-lowering therapy' above). Additional information regarding dosing and monitoring considerations for methotrexate and folic acid supplementation can be found elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration' and "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Folic acid supplementation'.)

Premedication for infusion reactions to pegloticase includes an oral antihistamine the evening before and the morning of each infusion, and oral acetaminophen and intravenous hydrocortisone (200 mg) during a period of hydration preceding infusion. Should an adverse reaction occur during infusion, the infusion should be stopped and restarted at a lower rate or discontinued at the discretion of the treating clinician. After infusion, observation of the patient for up to one hour is recommended. Pegloticase should be administered in a health care setting and by health care providers prepared to manage anaphylaxis and infusion reactions [133].

Pegloticase treatment should be discontinued, as recommended by the manufacturer and regulatory bodies, if there is loss of urate-lowering effectiveness as indicated (during monitoring of each pre-infusion serum urate concentration) by serum urate values >6 mg/dL (>357 micromol/L) on one occasion, particularly if accompanied by an infusion reaction, or on two successive occasions. These situations were reported to be associated with an increased risk of infusion reactions due to the development of antidrug antibodies. Other urate-lowering therapies should not be given to patients receiving pegloticase because they may mask recognition of the increasing serum urate levels associated with an increased risk for infusion-related reactions and loss of effectiveness resulting from the effects of high titer pegloticase antibodies [130,134].

Use should also be discontinued, regardless of the level of serum urate, following a moderate to severe infusion reaction with features suggestive of hypersensitivity (eg, stridor, oral/lingual/pharyngeal edema, wheezing, or hemodynamic instability).

Pegloticase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

●Efficacy and adverse effects – In the six-month randomized clinical trials of pegloticase, involving a total of 225 patients with treatment-resistant gout and serum urate levels ≥8 mg/dL (≥475 micromol/L), efficacy (defined as lowering of plasma urate to less than 6 mg/dL [357 micromol/L] for 80 percent of the time during months 3 and 6 of the trial) was observed much more often in patients receiving pegloticase (8 mg infusion every two weeks and 8 mg every four weeks) compared with placebo (42 and 35 versus 0 percent) [130]. Complete resolution of at least one tophus by the final visit was more frequent in those receiving pegloticase every two weeks than placebo (40 versus 7 percent). There was a similar but statistically nonsignificant trend for those receiving pegloticase every four weeks (21 versus 7 percent).

Both efficacy and safety of pegloticase are influenced by the development of antidrug antibodies, which, at high titers, are associated with both a rise in serum urate levels and the appearance of infusion reactions [135,136]. In a pooled analysis of the randomized trials and open-label extension studies, infusion reactions were reported in 45 percent of the patients [135]; in most instances, this was associated with an absence or loss of the urate-lowering response that had been observed. Serious infusion reactions occurred in 7 percent of the patients. Loss of urate-lowering efficacy among patients with infusion reactions preceded the first infusion reaction in 91 percent of patients (20 of 22) receiving pegloticase every two weeks.

Gout flares and infusion reactions were the most common causes for patient withdrawal from the trials, despite prophylaxis for both; withdrawals due to adverse events were more frequent in the two- and four-week pegloticase-only groups than in the placebo group (18 and 19 versus 2 percent, respectively). As with the initiation of other urate-lowering therapies, gout flares were more frequent in those receiving pegloticase than placebo during the first three months of the trials, although they were less frequent with pegloticase during the last three months of the trials.

Patients in the trials commonly had multiple comorbidities, including hypertension, obesity, dyslipidemia, diabetes, and atherosclerotic vascular disease; and patients with unstable angina, uncontrolled hypertension (>150/95 mmHg) or cardiac arrhythmia, uncompensated heart failure, renal dialysis, or solid organ transplant were excluded from the trials. However, although cardiovascular events were more frequent in patients on pegloticase, no direct relationship could be ascertained, and a reduction in blood pressure has been reported [137].

No new safety signals were observed in an open-label extension of the two randomized trials during up to 2.5 years of pegloticase treatment [130,138,139]. As most of the responders maintained serum urate responses during the extension studies, reductions in flare rates and tophus resolution among patients maintaining urate-lowering efficacy continued during the open-label extension, compared with treated patients in whom the agent had lost its efficacy.

The rationale for coadministration of pegloticase with methotrexate was based on data supporting that patients on methotrexate are less likely to develop antibodies and more likely to tolerate the drug [131,140]. In a 52-week trial including 152 patients with uncontrolled gout, patients who were randomly assigned to receive pegloticase plus methotrexate were more likely to have a urate-lowering response to pegloticase (pegloticase response rate in the group randomized to receive methotrexate was 71 compared with 39 percent with placebo) [131]. Participants randomized to methotrexate were also less likely to have an infusion reaction compared with those treated with pegloticase alone (4 versus 31 percent, respectively) [131]. In both groups, the majority of infusion reactions occurred at the first or second infusion and during the time of infusion. Infusion reactions consisted of urticaria (10.6 percent), dyspnea (7 percent), chest discomfort (9.5 percent), chest pain (9.5 percent), erythema (9.5 percent), and pruritus (9.5 percent). Coadministration of methotrexate did not appear to decrease the risk of anaphylaxis as the rates were similar in both arms (0 versus 1 percent for the pegloticase-only versus pegloticase-plus-methotrexate arms, respectively). Limited data also suggest that other immunosuppressive therapies including azathioprine, mycophenolate mofetil [132], and leflunomide also appear to reduce the development of anti-pegloticase antibodies [141].

Rasburicase — The role of brief courses of nonpegylated recombinant uricase (rasburicase) for the prevention of acute uric acid nephropathy due to tumor lysis syndrome in patients with high-risk lymphoma and leukemia is discussed elsewhere. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Rasburicase'.)

Experience with this agent for the treatment of gout is limited [142], and rasburicase has not been approved by the FDA for use in gout. It has a very short (less than 24-hour) half-life, and it is thought that this unmodified foreign protein is likely to be more immunogenic than pegylated uricases over the longer term of treatment needed for achieving the aims of gout management (see 'Pegloticase' above). However, repeated infusions of modified or unmodified uricase can reduce the size of tophi in patients with tophaceous disease, including those with solid organ transplants [143-145].

MANAGEMENT OF GOUT IN ADVANCED CHRONIC KIDNEY DISEASE — Treatment to prevent gout flares and to reduce the size of tophi is challenging in patients with advanced chronic kidney disease (CKD). The choice of agents and drug dosing for the prophylaxis of gout flares and for urate-lowering therapy are influenced by significant impairment of renal function, and nonsteroidal antiinflammatory drugs (NSAIDs) should be avoided; treatment of hyperphosphatemia caused by kidney disease can also affect serum urate levels. (See 'Prophylactic therapy' below and 'Urate-lowering therapy in chronic kidney disease' below.)

Prophylactic therapy — Particular caution should be taken in patients with CKD treated prophylactically with colchicine. The clearance of colchicine is reduced in patients with CKD, increasing the risk of neuromyopathy [146]. If given for prophylaxis, the recommended colchicine dose is 0.6 mg once daily at a creatinine clearance (CrCl) of 35 to 49 mL/minute and 0.6 mg every two to three days at a CrCl of 10 to 34 mL/minute. Colchicine is not dialyzable and is contraindicated at a CrCl below 10 mL/minute.

A discussion of colchicine-associated toxicities and drug interactions may be found elsewhere. (See "Treatment of gout flares", section on 'Colchicine'.)

Low doses of glucocorticoids may reduce the frequency of gout flares, but a prophylactic benefit for glucocorticoids is not supported by adequate evidence. Adverse effects of chronic glucocorticoid use should be anticipated with long-term therapy. If used for prophylaxis, the glucocorticoid dose should be the minimum necessary to prevent recurrent flares. (See "Major adverse effects of systemic glucocorticoids".)

Urate-lowering therapy in chronic kidney disease — The half-lives of allopurinol and its active metabolite, oxypurinol, are prolonged in renal failure [71]; we thus reduce the starting dose of allopurinol in patients with CKD, depending upon the severity of the reduction in the estimated glomerular filtration rate (eGFR) [18,62]. The initial daily dose of allopurinol should not exceed 1.5 mg per mL/minute of eGFR. As an example, for an eGFR of 50 mL/minute, the initial daily dose of allopurinol should not exceed 75 mg daily, and for such a patient, half of a 100 mg pill daily could be used as a starting dose. (See "Definition and staging of chronic kidney disease in adults" and "Assessment of kidney function", section on 'Glomerular filtration rate for drug dosing'.)

The desired serum urate concentration is often not achieved if treatment is limited to the dose used to initiate therapy [147]. In such patients, cautious up-titration of the dose of allopurinol is warranted (in 100 mg increments every two to five weeks in patients with eGFR ≥60 mL/minute and in 50 mg increments in patients with CKD stage 3 or with more severe disease); this approach to dose adjustment, with careful observation for adverse effects, has been successful without increased toxicity [18,148-151]. We advise continued and careful dose titration and monitoring of serum urate and eGFR in this clinical setting. (See 'Allopurinol' above.)

Both allopurinol and febuxostat have been shown to effectively reduce serum urate levels and to reduce the frequency of gout flares in patients with stage 3 CKD with comparable safety and efficacy with each other and with patients with greater renal function [54]. (See 'Dosing, drug interactions, and efficacy' above.)

Febuxostat has also been effective in safely reducing the serum urate in patients with moderate to severe renal impairment (eGFR 15 to 50 mL/minute/1.73 m²), as shown in a randomized 12-month trial involving 96 such patients who were treated with febuxostat 30 mg twice daily, febuxostat 40 mg once daily (increased after one month to 80 mg once daily if serum urate was ≥6 mg/dL after 14 days of therapy), or placebo [152]. The mean serum urate decreased from baseline to month 12 in both groups receiving febuxostat (difference from placebo -4.8 mg/dL, 95% CI -5.7 to -3.9 mg/dL, and -4.0 mg/dL, 95% CI -4.9 to -3.1 mg/dL). There was no notable imbalance in renal adverse events or renal function between the febuxostat and placebo treatment groups.

Uricosuric drugs, such as probenecid, may be less effective in patients with moderately impaired kidney function and are relatively ineffective, except for benzbromarone, when the eGFR is more substantially reduced. Uricosurics should not be used in patients with severe CKD (stages 4 to 5).

A modest lowering of serum urate is a potentially beneficial side effect of treatment of hyperphosphatemic CKD patients with phosphate-binding agents (eg, calcium-containing antacids or sevelamer). However, it is uncertain if serum urate lowering with these drugs results in fewer gout flares or reduction in the size of tophi, and phosphate-lowering therapy should not be used in patients with normal serum phosphate because hypophosphatemia may ensue. The management of hyperphosphatemia in CKD is described in detail separately. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

Organ transplant recipients — Patients with gout and impaired renal function due to organ transplantation have additional issues including interactions between urate-lowering therapy with xanthine oxidase inhibitors (XOIs; allopurinol, febuxostat) and immunosuppressive agents, particularly azathioprine and mercaptopurine. Treatment of gout in patients following renal transplantation is discussed separately. (See "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)

SURGERY — The role of surgery in the management of gout is generally limited to the complications of tophaceous disease, which include infection, compression due to the mass effect of a tophus, joint deformity, and intractable pain [153]. Although pharmacologic urate-lowering therapy can slowly reduce the size of tophi, and pegloticase can reduce the size of tophi more rapidly [154], some patients desire surgical excision for cosmetic reasons. Similarly, deformities due to joint damage may require arthroplasty. Such surgery may be safely performed in the absence of skin attenuation, ulceration, or soft tissue infection.

Whenever possible, institution of urate-lowering therapy should precede surgery in order to increase the likelihood of prompt postoperative healing. Exceptions to this approach are nerve compression and active infection, due to the greater urgency. Local surgery is not a substitute for effective systemic control of serum urate levels.

Tophaceous deposits may compress peripheral nerves, the cauda equina, or the spinal cord [155-157]. In these instances, prompt surgical decompression is essential to prevent permanent neurologic impairment.

Tophi may erode through the skin, producing chronic ulcers. With the loss of skin integrity, infection of the adjacent soft tissues, joint space, and bone is more likely.

In one report of 45 patients with tophaceous gout who required surgery, the most frequent indications were infection (51 percent) and mechanical problems caused by foot, elbow, and hand tophi (27 percent) [158]. Delayed wound healing was seen in 24 patients, 16 of whom had infected or ulcerated tophi prior to surgery.

Less often, surgical excision of a soft tissue mass leads to the initial diagnosis of tophaceous gout. In addition, permeative or erosive bone lesions have been mistaken for osteomyelitis and have led to excisions or amputations prior to establishing a diagnosis of gout. In some cases, it may be impossible to distinguish soft tissue or bone involvement due to gout from that due to infection using noninvasive studies; in this setting, needle aspiration or a surgeon's assistance in obtaining an excisional or needle biopsy may be invaluable. Biopsies should be examined for crystals fresh, frozen, or fixed in alcohol, as formalin dissolves monosodium urate (MSU) crystals. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)

PROGNOSIS — The capacity for effective urate-lowering treatment of gout has led to a dramatic reduction in chronic gouty arthritis and tophaceous gout, particularly among gout patients who receive long-term urate-lowering therapy [159]. A prevalence of these unsatisfactory outcomes of less than 5 percent has been reported in some series. However, a number of factors appear to contribute in patients with gout to suboptimal clinical outcomes, including both recurrent gout flares and progression to tophaceous disease and chronic gouty arthritis [29,79,160]. When progression does occur, it is most often in the context of nonadherence or nonpersistence of urate-lowering therapy, those in whom the management scheme has not been adequately communicated or properly prescribed, and those in whom the diagnosis of gout was incorrect. (See 'Management principles and initial postdiagnostic assessment' above.)

Other patients liable to show progression of gout include those intolerant or treated with inadequate doses of urate-lowering agents, those receiving medications (usually for comorbidities) that interfere with urate-lowering agents, and organ transplant recipients.

Further impediments to successful management include inadequate monitoring of serum urate levels to guide dose titration of urate-lowering agents, failure to titrate urate-lowering agents to doses necessary to achieve and maintain subsaturating serum urate concentrations, few management guidelines directed to primary care practitioners who manage the majority of gout patients, and limited urate-lowering treatment alternatives [160].

These considerations differ from those associated with the manifestations of acute hyperuricemia (primarily acute renal failure) seen in the tumor-lysis syndrome or with other causes of massive tissue breakdown. (See "Uric acid kidney diseases", section on 'Acute uric acid nephropathy'.)

As examples:

●Residual prevalences of chronic polyarticular and tophaceous gout approaching 50 percent have been reported in some series of men with gout whose major risk factors were excessive alcohol consumption, diuretic use, and, most importantly, suboptimal management or poor patient adherence [161,162].

●The triad of diuretic-induced hyperuricemia, renal insufficiency, and nodal osteoarthritis plus overrepresentation of women represents a distinctly different presentation from the classically described group of middle-aged men with tophaceous gout who have a higher incidence of hypertension, obesity, and ethanol abuse. Patients in the former group are typically older adults and prone to develop polyarticular and tophaceous gout in osteoarthritic joints:

•In one report, 8 of 60 patients with gout were older women (mean age 82 years), all of whom were receiving diuretic therapy; most had tophi in osteoarthritic interphalangeal joints [163].

•In a second series, 17 percent of 149 patients with osteoarthritis had gout, often with low-grade inflammation, in osteoarthritic finger joints [164]. These patients were older (mean age 71 years) and were evenly distributed in sex. Over 70 percent were receiving diuretics, 60 percent had impaired renal function, and the mean serum urate concentration was 11 mg/dL (654 micromol/L).

●Organ transplant recipients treated with calcineurin inhibitors (and often diuretics as well) are at increased risk for the accelerated development of chronic tophaceous gout [165,166]. Both renal and cardiac transplant recipients, particularly those with compromised renal function, have developed severe and often difficult-to-manage complications of the hyperuricemic effects of cyclosporine (and less commonly of tacrolimus), which result from impaired renal urate excretion [165]. (See "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)

●Other patients at increased risk for chronic tophaceous gout are those who have chronic kidney disease (CKD) that has been felt to preclude full-dose urate-lowering drug therapy, those who are allergic to or intolerant of urate-lowering agents, and those receiving doses of urate-lowering agents that are inadequate to achieve goal serum urate levels in a subsaturating range (usually defined as <6 mg/dL [<357 micromol/L] in most gout patients or <5 mg/dL [<297 micromol/L] in patients with tophaceous gout) [10,18].

RECOMMENDATIONS OF MAJOR GROUPS — Several professional organizations have published guidelines or recommendations for the management of gout, including the European Alliance of Associations for Rheumatology (EULAR) [9,10]; the American College of Rheumatology (ACR) [5,18,50], which issued new guidelines in 2020; the Japanese Society of Gout and Nucleic Acid Metabolism [167]; and the American College of Physicians (ACP) [168]. Our recommendations are generally consistent with the approaches recommended by the first three of these groups (EULAR, ACR, and the Japanese society) but disagree strongly with the ACP guidelines, which in contrast with the other groups, reject recommending the treat-to-target approach of monitoring or even measuring serum urate levels and basing dosing and drug choice on such data. Instead, ACP guidelines suggest monitoring the adequacy of urate-lowering drug dosing based upon the frequency and severity of gout flares (treat-to-avoid-symptoms approach). The ACP guidelines further do not address urate-lowering drug titration with monitoring of therapy and make rather limited mention of either allopurinol initiation dose or a dose titration schedule. The treat-to-target approach has also been supported by an international expert task force [169]. (See 'Approach to drug therapy' above and 'Serum urate goals and targeted therapy' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gout and other crystal disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Gout (The Basics)")

●Beyond the Basics topics (see "Patient education: Gout (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Therapeutic rationale – Long-term success in achieving and maintaining subsaturating serum urate levels is attended by clinical benefits that include cessation of gout flares, resolution of tophi, and improvement in patient physical function and health-related quality of life. (See 'Management principles and initial postdiagnostic assessment' above.)

●Strategy for reaching clinical remission – Once the subsaturating serum urate target is achieved and maintained, complete clinical remission may require many months to several years to achieve, due to the slow reduction in body urate crystal burden that has accumulated in most patients over years of hyperuricemia preceding the onset of gout. Even after sustained remission is achieved, maintenance of medical management is required. (See 'Management principles and initial postdiagnostic assessment' above.)

●Indications for urate-lowering in patients with gout – Indications for urate-lowering therapy in patients with a history of gout include frequent or disabling gout flares, clinical or radiographic signs of chronic gouty arthritis, tophaceous deposits in soft tissues or subchondral bone, and in selected patients, high future risk of severe gout flares or substantial risks from flare treatment. (See 'Indications' above.)

●Choice of urate-lowering therapy – For most patients who plan to initiate urate-lowering therapy, we suggest allopurinol as first-line urate-lowering therapy rather than febuxostat (Grade 2C).

•Our preference for allopurinol is based upon concerns with febuxostat regarding cardiovascular adverse effects (in patients with elevated cardiovascular risk). However, febuxostat is a reasonable alternative for patients unable to take or intolerant of allopurinol at doses needed to reach therapeutic serum urate target levels that are within the range approved by local regulatory authorities. (See 'Choosing the urate-lowering drug' above and 'Allopurinol' above and 'Febuxostat' above.)  

•Uricosuric agents are much less frequently used but are appropriate in patients receiving azathioprine or 6-mercaptopurine (6-MP) and in patients unable to take either of the xanthine oxidase inhibitors (XOIs). Probenecid may be difficult to administer and has reduced effectiveness in patients with decreased renal function. (See 'Uricosuric drugs' above and 'Adverse effects' above and 'Adverse effects' above.)

●HLA B*5801 testing – We test patients who are Chinese, Thai, Korean, African American/African descent, or another ethnicity with similarly increased frequency of the human leukocyte antigen (HLA) B*5801 genetic variant for this allele and do not administer allopurinol in patients who test positive. Such patients are at increased risk of a severe cutaneous adverse reaction (SCAR) to this drug. (See 'Adverse effects' above and 'Drug interactions' above.)

●Contraindications to uricosurics – Uricosuric agents should be avoided in patients with urolithiasis and risk of uric acid nephropathy. (See 'Allopurinol' above and 'Febuxostat' above and 'Uricosuric drugs' above.)

●Allopurinol dosing and titration – We initiate therapy with allopurinol at a low dose, typically 100 mg daily in a patient with a weight-adjusted creatinine clearance (CrCl) >60 mL/minute, with dose titration by 100 mg every two to four weeks to reach and maintain the urate-lowering goal range <6 mg/dL (<357 micromol/L) or, in the case of patients with tophaceous gout, <5 mg/dL (<297 micromol/L). (See 'Allopurinol' above.)

•In patients with reduced renal function (stage 3 or more severe chronic kidney disease [CKD]), we initiate allopurinol at a dose not exceeding 1.5 mg per mL/minute of estimated glomerular filtration rate (eGFR). The allopurinol dose should be titrated (by a similar amount but no more than 50 mg) every four weeks to achieve and maintain the same target serum urate goal as in patients with normal renal function. (See 'Allopurinol' above and 'Management of gout in advanced chronic kidney disease' above.)

•For patients not achieving serum urate target on allopurinol, switching to febuxostat or initiating combination therapy with allopurinol and a uricosuric drug, such as probenecid or benzbromarone (where available), are additional alternatives. (See 'Choosing the urate-lowering drug' above.)

●Refractory to oral therapy – In patients with treatment-refractory gout who have advanced, tophaceous, and actively symptomatic disease, pegloticase (administered intravenously every two weeks) is a treatment option. Pegloticase should be coadministered with weekly methotrexate along with folic acid or folinic acid supplementation. If methotrexate is not tolerated or is contraindicated, other immunosuppressive therapies such as azathioprine, mycophenolate mofetil, and leflunomide could be considered as alternatives. Pegloticase alone may be used in patients for whom immunosuppression is contraindicated or not clinically appropriate. Patients most likely to benefit from pegloticase treatment include those with frequent flares, large and numerous tophi, potentially reversible functional limitations, and poor quality of life. In such patients, pegloticase provides more rapid improvement compared with oral agents. (See 'Choosing the urate-lowering drug' above and 'Pegloticase' above.)

●Therapeutic target and rate of urate lowering – In patients receiving urate-lowering therapy, we suggest titration of the urate-lowering medication to achieve a serum urate in the subsaturating range <6 mg/dL (<357 micromol/L) (Grade 2C). We lower the serum urate slowly (no more than 1 to 2 mg/dL/month) in an effort to minimize the occurrence of gout flares, which occur more frequently in the early months of urate-lowering treatment and which consequently may impair adherence to treatment. A goal serum urate <5 mg/dL (<297 micromol/L) may hasten resolution of tophi. (See 'Serum urate goals and targeted therapy' above.)

●Dose adjustment and monitoring – Serum urate levels should be monitored to assure maintenance of concentrations in the goal range and to permit urate-lowering drug dose adjustment as needed. One approach is to determine serum urate concentration in two to four weeks of a dose adjustment, with confirmation three months later. Once goal values are confirmed, measurement every six months for the next year and then annually is usually adequate, unless drugs or lifestyle factors potentially altering urate levels have been introduced in the interim. (See 'Serum urate goals and targeted therapy' above.)

●Prophylactic therapy for flare prevention during initial period of urate-lowering – For patients initiating urate-lowering drug therapy, we suggest colchicine for prophylactic therapy to prevent flares during treatment initiation rather than no prophylactic therapy or a nonsteroidal antiinflammatory drug (NSAID) (Grade 2C). We use low-dose colchicine (0.6 mg once or twice daily for patients with normal renal and hepatic function). An NSAID is a reasonable alternative for patients who cannot tolerate colchicine; however, there is less available evidence to support its use. Prophylactic therapy should be continued for three to six months after initiating urate-lowering therapy. A longer duration of colchicine prophylactic therapy may be needed for patients with ongoing gout flares and/or tophi. (See 'Prophylaxis during initiation of urate-lowering therapy' above.)

●Indications for surgery – Surgery for gout is appropriate for patients with complications of tophaceous disease, including infection, nerve compression, joint deformity, and intractable pain. Some patients also desire surgery for cosmetic reasons. (See 'Surgery' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Michael A Becker, MD, who contributed to an earlier version of this topic review.