Sage Journals: Discover world-class research

Abstract

Gout is a common and painful inflammatory arthritis caused by monosodium urate crystal deposition into joints in the setting of hyperuricemia. Recent reports indicate an increase in prevalence and incidence of gout worldwide. While genetics, dietary habits, and lifestyle play a significant role in the development of gout, risk factors also include diabetes, hypertension, obesity, chronic kidney disease, and metabolic disease among others. As such, accompanying comorbidities must also be considered when choosing therapeutic agents for urate-lowering therapy (ULT) and gout flares. This article will focus on reviewing gout pathophysiology and discussion of currently available pharmacological and nonpharmacological options for chronic gout management, gout flare therapy, and prophylactic measures. Despite an increase in prevalence, optimal gout management remains elusive and challenging with only a third to half of patients receiving definitive treatment and fewer than half of patients remaining adherent to treatment. Current strategies for optimal chronic gout management include the “treat to target” method, which focuses on targeting serum urate level of 5–6 mg/dL or lower. Additional approaches for chronic gout management include starting ULTs with 3–6 months of prophylaxis to reduce the risk of precipitating gout flares during initiation. Both improvement of the recognition and diagnosis of gout and more widespread provider adherence to international rheumatology society recommendations for gout management remain barriers to optimal gout management worldwide. This article will also serve as a review of current urate-lowering pharmacological options including xanthine oxidase inhibitors, uricosurics, and uricase therapy as well as burgeoning new medications on the horizon including novel potent xanthine oxidase inhibitors (including tigulixostat), sodium-glucose transporter-2 inhibitors, and selective URAT1 inhibitors. Additionally, this article will review pharmacological approaches to treating gout flares (including nonsteroidal anti-inflammatory drugs, glucocorticoids, and colchicine) and discuss the role of patient comorbidities in selection of optimal therapy. The present review will also discuss the role and limitations of novel interleukin-1 (IL-1) antagonists (including anakinra and canakinumab) in the treatment of gout flares. Lastly, this article will also discuss nonpharmacological intervention for gout management and discuss novel therapies for chronic gout management, gout flare, and prophylaxis on the horizon.

Keywords

crystalline arthritis gout

Introduction

Gout is a common, painful, and often debilitating inflammatory arthritis with increasing global prevalence and incidence. Recent reports estimate a prevalence of 1.0%–6.8% of the population worldwide and 5% of U.S. adults.¹ Additional studies suggest the incidence of gout has increased by 63.4% over the last 20 years.² Gout tends to affect males and older patients more frequently. Risk factors associated with gout include obesity, diabetes, chronic kidney disease (CKD), hypercholesterolemia, and hypertension.³ Patients with gout suffer from intermittent and disabling flares, which can drastically affect quality of life and functional capabilities. Patients with gout also have frequent interactions with the healthcare system in the form of emergency room visits, hospitalizations, and prolonged hospital stays, which contribute to overall costs to both patients and the healthcare system at large.⁴ Optimal management of gout and early treatment are crucial given its high prevalence, morbidity associated with disease progression, and cost.

Gout is characterized by the precipitation of monosodium urate (MSU) crystals and deposition in joints and surrounding periarticular spaces in the setting of hyperuricemia. Urate, the final product of purine metabolism, is associated with a high purine diet (including meat and seafood), sugar intake, and alcohol use.^5,6 Urate excretion is primarily mediated by the kidney and the gastrointestinal tract. Defined as serum urate level of 6.8 mg/dL or higher, hyperuricemia is required for the development of almost all cases of gout.⁷ However, elevated serum urate levels alone do not necessarily lead to gout.⁸ Gout flares occur when MSU crystals accumulate in joints and periarticular tissues and trigger an acute inflammatory response.⁸ This inflammatory response leads to NLRP3 inflammasome activation, which subsequently releases pro-inflammatory cytokines, such as IL-1β, leading to a gout flare.⁹ Gout flares typically involve the acute onset of painful warmness and swelling in a peripheral joint classically involving the first metatarsophalangeal joint, ankle, or mid-foot.¹⁰ Gout flares commonly are self-limiting with average durations of 7–10 days followed by asymptomatic “inter-critical periods.”⁸ Suboptimal treatment of gout and persistence of hyperuricemia may progress to more severe and frequent flares and polyarticular involvement and shorter inter-critical periods.¹¹ Early and aggressive treatment may help to prevent disease progression. The present review will discuss pharmacological options for the treatment of gout, including urate-lowering therapies (ULTs) and anti-inflammatory therapies for the treatment of gout flares.

Urate lowering therapies

There is currently a debate regarding the strategy for treating gout, especially after the publication of the American College of Physicians (ACP) recommendations against a “treat-to-target approach” with the initiation of ULT in most patients or those with fewer than two flares per year.¹² Both rheumatology experts and major international guidelines or recommendations support a treat-to-target strategy with ULT to decrease or eliminate the deposition of urate crystals.^13–15 There is growing evidence supporting that in patients with a sustained reduction of uricemia to a target level of 6 mg/dL or less, we can decrease the number of flares, reduce the number and size of tophi, lower mortality, and improve quality of life.^16,17 EULAR/ACR guidelines also support a more aggressive serum urate level target of 5 mg/dL or lower for patients with tophaceous gout.¹⁵ Despite clinical evidence of tophi, some patients may not recall previous flares due to a variety of reasons, including dementia, vascular disease, or polyneuropathy. These patients with silent tophaceous gout often have high morbidity and present clinically with reduced hand function, difficulty with ambulation, or even foot ulcers. Therefore, patients with silent tophaceous gout benefit from the “treat to target” strategy and more tightly controlled serum urate levels. ULT is considered the primary treatment for gout, as it is responsible for the elimination of the pathogenic element.

The objective of ULT is to achieve serum urate levels below the solubility threshold (6.8 mg/dL) to eliminate crystals. It is known that lower urate levels result in faster disappearance of crystal deposits. The European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR) guidelines recommend maintaining urate levels below 6 or 5 mg/dL continuously, depending on patient characteristics or disease severity.^13,15 Figure 1 offers an approach to implementation of this “treat-to-target” method. There are also uncertainties regarding which patients should initiate ULT. It is clear that it must be started in patients with recurrent gout flares (two or more per year), presence of erosions or tophi, or history of nephrolithiasis. Also, ULT initiation should be considered after the first flare in patients with comorbidities (including CKD, cardiovascular disease, and hypertension), very high uricemia levels (above 8 or 9 mg/dL), or early onset of the disease. Nowadays, it is also clear that asymptomatic hyperuricemia should not be treated.^13,15 There are limited data on when to discontinue ULT once the goal of crystal deposit elimination has been achieved. What is clear is that then the therapeutic target can be adjusted to levels close to the solubility threshold of urate in plasma (~7 mg/dL) instead of treat-to-target objectives.¹⁸ It is also important to highlight that several studies have shown that ULT initiation during a flare does not increase its intensity or duration.¹⁹ Therefore, the classic recommendation of starting ULT after the flare is resolved must be invalidated. The timeline for ULT initiation depends on the individual characteristics of each case.

Figure 1.

Approach to urate-lowering therapy in gout management.

Currently, there are three available mechanisms of action to reduce serum uric acid levels: xanthine oxidase inhibitors, uricosurics, and uricases.

Xanthine oxidase inhibitors

Allopurinol and its main metabolite, oxypurinol, decrease uric acid levels in plasma by inhibiting xanthine oxidase (XO). Allopurinol is the treatment of choice for most patients.^13,15 A “start-low, go-slow” strategy is recommended with xanthine oxidase inhibitors (XOI). Initiating treatment with low doses of the drug can prevent attacks at the start of treatment (thus improving adherence) and can decrease the risk of allopurinol hypersensitivity syndrome. It is recommended to start with a dose of 1.5 mg per unit of estimated glomerular filtration rate (GFR) (mg/mL/min).²⁰ From there, the dose should be progressively increased until the therapeutic target of serum urate level 6 mg/dL or lower is achieved. Allopurinol dosage may be increased to maximum dose of 800 mg/day per FDA guidelines.¹³ However, most patients typically will not require doses of more than 400 mg/day.²¹ Special care should be taken with individuals with renal insufficiency and carriers of the HLA-B*5801 allele (especially in patients of Southeast Asian descent (e.g., Han Chinese, Korean, Thai)). For patients with moderate-to-severe CKD, allopurinol should be initiated at a dose of ⩽100 mg to avoid precipitation of allopurinol hypersensitivity syndrome.²² However, allopurinol dosage should still be increased to reach target serum urate levels and can be done safely in CKD, even with patients with creatinine clearance of <30 mL/min.^22,23 Notably, patients with CKD may require doses of allopurinol ⩾300 mg/day to achieve target serum urate level.²²

Febuxostat is a potent XOI inhibitor approved at doses ranging from 40 to 120 mg/day, depending on the country. It is metabolized in the liver, so renal elimination is not the primary pathway. This allows for simplified dosing in patients with mild-to-moderate kidney failure. It is recommended to use febuxostat in cases where treatment with allopurinol is insufficient or not tolerated. The publication of the “Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout (CARES)” study alerted about a possible increase in cardiovascular risk in patients with gout taking febuxostat compared to those taking allopurinol.²⁴ The following publication of “Long-Term Cardiovascular Safety of Febuxostat Compared with Allopurinol in Patients with gout (FAST)” study, as well as certain limitations of the CARES study, have shown that the use of febuxostat does not imply a higher risk of cardiovascular events.²⁵ It is clearly demonstrated that febuxostat 80 mg/day is superior to allopurinol 300 mg/day in reducing uricemia. However, there are no differences when comparing febuxostat and allopurinol when following the titration of dose strategy.²⁶

Uricosurics

Although the main cause of hyperuricemia is the renal hypoexcretion of uric acid, uricosurics are second-line drugs. Uricosurics promote the urate excretion and can be used as monotherapy or in combination with a XOI.²⁷ Uricosurics should be carefully used in patients with a history of urolithiasis and a high fluid intake is recommended (~2 L/day). A recent network meta-analysis shows that dotinurad, verinurad, and benzbromarone are the most effective urate-lowering treatments.²⁸ Dotinurad has just been approved in Japan and verinurad is currently not marketed. Benzbromarone is a potent uricosuric that, as monotherapy, has an efficacy equal or superior to low doses of febuxostat and probenecid.²⁹ Patients treated with benzbromarone have a higher risk of urolithiasis and can rarely cause hepatotoxicity, so liver function should be monitored during initiation.^29–31 Probenecid is the only uricosuric available in the Unites States after lesinurad was discontinued for commercial and safety reasons.

Uricase therapy

Pegloticase is a uricase approved by the US Food and Drug Administration for refractory gout. It metabolizes urate to soluble allantoin, a water-soluble molecule readily cleared by the kidney, leading to undetectable urate concentrations in responders. Both in clinical trial and in real-world evidence, it was not uncommon that patients suffered infusion reactions due to the development of antidrug antibodies.^32,33 In order to avoid this, different strategies have been developed including the use of mycophenolate mofetil, methotrexate, or rapamycin.^34,35

Additional therapeutic considerations

There are available treatments without current indication for gout that can reduce serum urate. Some of these therapeutic agents are indicated for comorbidities associated with gout and may be of special interest in clinical practice. For example, angiotensin II receptor blockers (losartan) or hypolipidemic agents (fenofibrate) may be used in cardiac patients with gout and may reduce serum urate levels.^36,37 Additionally, sodium-glucose transporter-2 inhibitors (such as empagliflozin) may also help to reduce serum urate levels in diabetic patients with gout,³⁶ besides having an independent effect in preventing inflammation leading to flares.

Future possible therapies

Several ULTs are currently under investigation. ALN-XDH, an RNA interference-based XOI, is in early phase clinical trials (phase I and II). Tigulixostat, another XOI, has advanced to phase III trials.³⁸ Additional novel uricosuric agents are being studied, including the selective URAT1 inhibitors—lingdolinurad (ABP-671) or ruzinurad (SHR 4640).³⁹

Flare and prophylaxis therapies

While chronic management of gout focuses on optimizing serum urate levels via ULT therapy, management of gout flares aims to reduce inflammation acutely. Per 2020 ACR/EULAR guidelines, nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and glucocorticoids (oral, intraarticular, or intramuscular (IM)) alone or in combination were strongly recommended for gout flare management.¹³ Given the effectiveness of each medication class, each patient’s comorbidities should be thoughtfully considered when selecting the optimal anti-inflammatory agent for gout flares (Figure 2). Additionally, the 2016 EULAR guidelines highlight the importance of early flare treatment.¹⁵ On a related note, initiation of ULT can also precipitate a gout flare. As such, the 2020 ACR/EULAR guidelines also outlined the importance of concurrent anti-inflammatory prophylaxis administration for at least 3–6 months while starting ULTs.¹³

Figure 2.

Approach to treatment of gout flares.

Nonsteroidal anti-inflammatory drugs

NSAIDs are one of the first-line options for the treatment of gout flares. Both cyclooxygenase (COX) enzyme inhibitors, such as indomethacin and naproxen, and selective cyclooxygenase (COX-2) enzyme inhibitors, such as celecoxib, lead to decreased prostaglandin production and are effective in the treatment of gout flares.⁴⁰ A trial comparing indomethacin and etoricoxib in gout flares showed no difference in the achievement of pain relief.⁴¹ An additional study revealed that higher doses of celecoxib (800 mg/400 mg) are more effective than lower doses of celecoxib (50 mg twice daily) for treatment of pain in acute gout flares. This same study also showed celecoxib and indomethacin showed minimal difference in success of pain control.⁴² Usual doses of NSAIDs for gout flare include naproxen 500 mg twice daily, indomethacin 50 mg three times daily, or etoricoxib 120 mg daily with the goal of administering higher doses for shorter periods of time to achieve resolution of flare.⁸ Regardless of a specific drug, high-dose NSAIDs are highly effective for gout flares.

While NSAIDs successfully reduce inflammation, there are adverse effects to consider, especially in the context of each patient’s comorbidity profile. NSAIDs can have renal, gastrointestinal, and cardiovascular side effects.⁴³ NSAIDs can worsen hypertension and facilitate salt and water retention, which can result in heart failure exacerbations. NSAIDs can also increase the risk of acute kidney injury in all patients, but particularly in patients with CKD. As such, NSAIDs are largely contraindicated in the advanced CKD patient population with GFR <60.^22,44 Additionally, caution should be utilized in patients with a history of major gastrointestinal (GI) bleed, prior or active peptic ulcer disease.⁴⁵ NSAIDS can also interfere with anticoagulation therapy and increase the risk of bleeding. Thus, patients already on anticoagulation therapy should be monitored closely for signs of bleeding or be considered for alternative medication for flare management. Finally, NSAIDs, along with colchicine, are considered first-line agents for prophylaxis medications for initiation of ULT for at least 3–6 months.⁸ Prolonged use of NSAIDs should lead to closer monitoring for these adverse events, mainly in those of advanced age, medical comorbidities, or polypharmacy.

Glucocorticoids

When compared with NSAIDs, glucocorticoids are just as effective in the management of gout flares.⁴³ Typical dosing of prednisone is 30–35 mg daily for the duration of the flare – often 5–7 days.⁸ Method of glucocorticoid administration is selected based on the patient. Oral glucocorticoids are the most common route of administration, but other methods include intravenous (IV), IM, or intraarticular. IV glucocorticoids are considered for hospitalized patients with a functional IV line and who are unable to take oral glucocorticoids. IM glucocorticoids may be considered for patients in the outpatient setting who are unable to take oral glucocorticoids or for local patient or provider preference. Depot methylprednisolone (typically 40 mg) or triamcinolone (40 or 60 mg) are commonly used in the United States. Although uncommon, there is a risk of gout flare symptom recrudescence after 5–7 days and a second dose can be used. Similarly to NSAIDs, the objective of glucocorticoid use in gout flares is to limit the duration and avoid unnecessary prolonged treatment intervals.

Adverse effects of glucocorticoids include hyperglycemia, osteoporosis, hypertension, and peptic ulcer disease among others. Thus, glucocorticoids may be avoided or minimized in patients with diabetes mellitus. Additionally, glucocorticoids may be contraindicated for patients with recent surgery or concern for active, ongoing infection. Although undesirable as a prolonged treatment option, low-dose glucocorticoid therapy (approximately five daily milligrams of prednisone or an equivalent) may be considered for ULT prophylaxis for patients who are unable to take colchicine or NSAIDs due to lack of toleration, contraindications, or ineffectiveness.⁸

Colchicine

Colchicine disrupts microtubule polymerization and prevents neutrophil activation and migration.⁴⁶ As with NSAIDs and glucocorticoids, colchicine is among the first-line agents for gout flare treatment per the 2020 ACR/EULAR gout management guidelines. The data for timing and administration of colchicine were derived from the AGREE trial, which compared administration of low-dose colchicine (initial dose of 1.2 mg followed by 0.6 mg dose after 1 h once for a total of 1.8 mg), high-dose colchicine (1.2 mg followed by 0.6 mg dose every 6 h for a total of 4.6 mg), and placebo. This trial demonstrated similar efficacy for pain control and improved side effect profile of low-dose colchicine compared to high dose colchicine.⁴⁷ After the first day of administration, once or twice daily colchicine should be continued until the resolution of the flare, typically for 5–7 days. The 2016 EULAR guidelines also highlight the importance of early initiation of treatment for gout flare and recommend utilizing the “pill-in-pocket” approach, so that patients can recognize symptom onset and initiate treatment early.¹⁵

Adverse effects of colchicine predominantly include diarrhea, GI upset, abdominal cramping, vomiting, and neuropathy. Colchicine should be avoided in patients with simultaneous hepatic and renal dysfunction. For patients with renal dysfunction or advanced CKD, further dose reduction may be necessary to avoid adverse effects.^8,48 Colchicine interacts with several medications including statins, clarithromycin, antifungals, antiretrovirals, and nondihydropyridine calcium channel blockers. If a patient is on a cytochrome P450 3A4 (CYP3A4) or P-glycoprotein inhibitor, colchicine may need to be further dose-reduced to avoid side effects.⁸ Along with NSAIDs, colchicine is also considered first-line therapy for prophylaxis of gout flares while starting ULT. Colchicine prophylactic dosing is lower than treatment dosing and is typically 0.6 mg once or twice daily for at least 3–6 months.

IL-1 inhibitors

The activation of NLRP3 inflammasome and subsequent release of pro-inflammatory cytokines, such as IL-1β, has made IL-1β inhibitors an intriguing target for the management of gout flares. Therapeutic agents including anakinra, canakinumab, and rilonacept, involving different mechanisms of achieving IL-1 antagonism have become progressively integrated into the landscape of gout management. Anakinra, a recombinant IL-1 receptor antagonist, did not demonstrate superiority to triamcinolone, but was effective in controlling pain associated with gout flares and a viable option when mainstay treatment was not appropriate.⁴⁹ Another study in 2019 revealed that anakinra was noninferior when compared to the mainstay treatment of NSAIDs, colchicine, and/or glucocorticoids.⁵⁰ A small study from 2019 highlighted the role of anakinra as an efficacious method for gout flare treatment of hospitalized patients, particularly those with comorbidities preventing use of first-line therapies.⁵¹ Anakinra seems to be equally effective in a wide variety of gout flare scenarios (age, number of joints involved, and different comorbidities).⁵² Another study from 2012 revealed that canakinumab, a targeted IL-1 β monoclonal antibody, adequately controlled pain during acute gout flare and reduced future flares.⁵³ A scoping review from 2023 with more than 500 patients treated with anakinra showed that it had been used safely in patients with active infection, transplantation or dialysis.⁵⁴ Another recent systematic review from 2023 demonstrated that rilonacept, a modified soluble decoy IL-1 receptor, and canakinumab achieved better pain control and demonstrated the reduction of gout flare frequency compared to other active comparators (including triamcinolone and colchicine).⁵⁵

The 2020 ACR/EULAR gout management guidelines favored the use of IL-1 inhibitors in lieu of no treatment when first-line methods (glucocorticoids, NSAIDs, and colchicine) were ineffective or not well-tolerated from a patient or comorbidity standpoint.¹³ Compared with NSAIDs, colchicine, and glucocorticoids, IL-1 inhibitors have a relatively favorable side effect profile with minimal metabolic, renal, or gastrointestinal side effects, which are particularly notable in the management of patients with gout and concomitant CKD, diabetes, and/or history of bleeding.⁴⁶ Adverse events of IL-1 inhibitors include the potential for development of infection. Canakinumab was shown to be associated with lower neutrophil and platelet counts and higher risk of infections.⁵³ Although used for gout flare, IL-1 inhibitors are not currently approved for prophylactic use in the United States, and there is very little efficacy or safety data.⁸ A 2014 systematic review revealed canakinumab is superior to colchicine for prophylaxis in the initiation of urate lower therapy.⁵⁶ Important limitations of widespread adoption of IL-1 blockade for gout flares and flare prophylaxis include high cost and limited access.

Nonpharmacologic approaches

Nonpharmacologic approaches to gout management focus on lifestyle modification of factors associated with gout. Patients with gout have an increased cardiovascular risk due to the disease itself and its association with metabolic syndrome. For this reason, it is particularly relevant to recommend healthy lifestyle interventions for patients with gout, and not because of the classical association between an indulgent lifestyle and gout. Genetics play an important role in the development of gout, but a healthy lifestyle may be protective.^57,58 Per the 2020 ACR/EULAR gout management recommendations, dietary limitation of alcohol, high-fructose corn syrup, and purine-rich foods in conjunction with weight reduction for obese or overweight patients with gout is highly recommended for chronic management of gout.¹³ There are several foods associated with a higher risk of hyperuricemia. Meat, fish, and seafood have high purine content, which can be a risk factor for hyperuricemia and potential triggers of gout flares.⁵⁹ Additionally, food and beverages with high-fructose corn syrup can increase gout risk. Increased alcohol intake is also associated with hyperuricemia, particularly beer. Several diets, including low-fat, Mediterranean, low-carbohydrate and the Dietary Approaches to Stop Hypertension (DASH), have demonstrated reduced urate plasma levels. In general, they are effective, but the results usually do not exceed 1 mg/dL, which is often insufficient as monotherapy for patients with gout. Additionally, weight loss has been shown to be effective in reducing uric acid levels in overweight and obese patients, especially with weight loss of >7 kg.⁶⁰ Topical ice and rest may augment pharmacological methods during gout flares.⁶¹ Notably, Vitamin C and tart cherry were previously thought to be helpful in reducing flares but have been found to not be effective.¹³ It is important to note that incorporating dietary and lifestyle modifications may only modestly reduce serum urate levels and can be challenging and overwhelming for patients. This may result in poor adherence to effective pharmacological ULT and minimally adopted lifestyle changes. Careful measures should be taken to avoid placing undue blame on patients. Lifestyle modifications should be encouraged in conjunction with ULT.

Conclusion

Gout is a common and painful inflammatory arthritis with increasing prominence. However, despite increased prevalence and incidence of gout worldwide, inadequate management of gout continues to persist with only a third to half of patients receiving definitive treatment in the form of ULTs and fewer than half of patients adequately compliant with treatment.⁶² A summarized version of the pharmacological approaches to gout treatment can be found in Figures 1 and 2. Initiation of ULTs with 3–6 months of prophylaxis serves to reduce serum urate levels while preventing gout flares during initiation of therapy. Employment of the “treat-to-target” approach to gout management serves to reduce the serum urate level to at least 6 mg/dL and empowers providers to increase ULT with guidance, leading to improvement of hyperuricemia and reduction of gout flares. Failure of adoption of “treat-to-target” methods in favor of “treatment to avoid symptoms” methods result in the persistence of inadequate treatment of gout. In addition to ULT, careful selection of pharmacologic agent for gout flare treatment and early initiation of prophylaxis also serves to reduce the burden of gout symptoms and restore patient quality of life (Table 1). In addition, multidisciplinary management of gout with “augmented” clinic, involving nurses, clinical pharmacists, primary care doctors, or rheumatologists are progressively being implemented and improving outcomes compared with routine care.¹⁷ Nurse-led gout treatment approaches have demonstrated robust ULT adherence, urate level reduction, and improved outcomes for many patients, including those with multiple comorbidities.⁶³ With aggressive management, disease progression can be halted and patient quality of life and functionality restored. Finally, gout management and flare prevention are acquiring new relevance as these painful episodes seems to be associated with an increased incidence of adverse cardiovascular outcomes⁶⁴ and pleiotropic agents for prevention of cardiovascular disease, metabolic management in diabetes, and progression of CKD are promising for inclusion in the gout armamentarium.³⁶

Table 1.

Review of pharmacologic options for urate-lowering therapies and gout flares/prophylaxis.

Medication	Mechanism of action	Side effects	Contraindications/Considerations for special populations	Role in gout treatment
Urate lowering therapies
XOI
Allopurinol	Reduces uric acid level by xanthine oxidase inhibition	Severe cutaneous reaction	Special care should be taken for patients with renal insufficiency or HLA-B*5801 carriers (Han Chinese, Korean, Thai descent); contraindicated for patients with prior hypersensitivity reaction	First line
Febuxostat	Reduces uric acid level by xanthine oxidase inhibition	Severe cutaneous reaction		Recommended second line after allopurinol failure or intolerance
Uricosurics
Probenecid	Inhibits organic anion transporters to promote urate excretion via urine		Avoid use in patients with GFR <30; careful use in patients with history of urolithiasis; potential for multiple drug–drug interactions	Second line after XOI failure, may be used as monotherapy or in combination with XOI
Benzbromarone	URAT1 inhibitor; promotes urinary excretion of urate	Higher risk of urolithiasis, rarely can cause hepatotoxicity	Avoid use in patients with liver disease	Second line after XOI failure
Uricases
Pegloticase	Metabolizes urate to soluble allantoin for renal excretion	Patients can develop infusion reactions (including anaphylaxis) due to the formation of anti-drug antibodies	Contraindicated for patients with G6PD deficiency; contraindicated for patients with history of serious hypersensitivity reaction or anaphylaxis to prior use of pegloticase; may precipitate heart failure exacerbations	Avoid use as first line therapy. May be reasonable therapy for patients who have failed XOI and uricosuric therapies who have not reached targeted serum urate level, and continue to have frequent flares OR who have persistent tophi
Gout flare/prophylaxis
NSAIDs
IndomethacinNaproxen	COX inhibitors	Acute kidney injury, peptic ulcer disease, GI bleed	Avoid in patients with history of major bleed, avoid in patients with renal insufficiency (GFR < 60), may precipitate heart failure exacerbation	First-line therapy
Celecoxib	Selective COX-2 inhibitor	Acute kidney injury, peptic ulcer disease, GI bleed	Avoid in patients with history of major bleed, avoid in patients with renal insufficiency (GFR < 60), may precipitate heart failure exacerbation	First-line therapy
Glucocorticoids	Activate glucocorticoid receptor to reduce inflammation	Hyperglycemia, osteoporosis, peptic ulcer disease, hypertension	Cautious use in patients with diabetes (particularly uncontrolled), cautious use in patients with concern for infection or recent surgery	First-line therapy
Colchicine	Disrupts microtubule polymerization, prevents neutrophil activation and migration	Diarrhea, abdominal cramping, gastrointestinal upset	Avoid use in patients with hepatic and renal dysfunction; dose reduce in patients with CKD or renal dysfunction to avoid adverse effects; high potential for drug–drug interactions (particularly with P450 3A4/CYP 3A4 or P-glycoprotein medications)	First-line therapy
IL-1 blockade
Anakinra	Recombinant IL-1 receptor antagonist	May increase infection risk	IL-1 inhibitors have a relatively favorable side effect profile with minimal renal, metabolic, or gastrointestinal side effect profile	IL-1 inhibitors may be used in lieu of no treatment when first-line therapies (glucocorticoids, NSAIDs, or colchicine) are ineffective or not well-tolerated from a patient or comorbidity standpoint. They are not currently approved for prophylactic use in the United States.
Canakinumab	Targeted IL-1 β monoclonal antibody	May increase infection risk, may lower neutrophil and platelet counts	Barriers to widespread adoption of IL-1 inhibitors include high cost and limited access
Rilonacept	Modified soluble decoy IL-1 receptor	May increase infection risk

CKD, chronic kidney disease; NSAID, nonsteroidal anti-inflammatory drugs; XOI, xanthine oxidase inhibitor.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Kate L. McCarty

Angelo L. Gaffo

Cesar Diaz-Torne

References

Yokose

McCormick

, et al. Trends in prevalence of gout among US Asian adults, 2011–2018. JAMA Netw Open 2023; 6: e239501.

Mok

Sin

, et al. Global, regional, and national prevalence of gout from 1990 to 2019: age-period-cohort analysis with future burden prediction. JMIR Public Health Surveill 2023; 9: e45943.

Singh

Reddy

Kundukulam

. Risk factors for gout and prevention: a systematic review of the literature. Curr Opin Rheumatol 2011; 23: 192–202.

Rai

Burns

De Vera

, et al. The economic burden of gout: a systematic review. Semin Arthritis Rheum 2015; 45: 75–80.

Choi

Liu

Curhan

. Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2005; 52: 283–289.

Choi

Ford

Gao

, et al. Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2008; 59: 109–116.

Martillo

Nazzal

Crittenden

. The crystallization of monosodium urate. Curr Rheumatol Rep 2014; 16: 400.

Dalbeth

Choi

Joosten

LAB

, et al. Gout. Nat Rev Dis Primers 2019; 5: 69.

Martinon

. Inflammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol 2017; 13: 639–647.

10.

Vargas-Santos

Taylor

Neogi

. Gout classification criteria: update and implications. Curr Rheumatol Rep 2016; 18: 46.

11.

Gutman

. The past four decades of progress in the knowledge of gout, with an assessment of the present status. Arthritis Rheum 1973; 16: 431–445.

12.

Qaseem

Harris

Forciea

, et al. Management of acute and recurrent gout: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2017; 166: 58–68.

13.

FitzGerald

Dalbeth

Mikuls

, et al. 2020 American College of Rheumatology Guideline for the management of gout. Arthritis Care Res (Hoboken) 2020; 72: 744–760.

14.

Dalbeth

Bardin

Doherty

, et al. Discordant American College of Physicians and international rheumatology guidelines for gout management: consensus statement of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN). Nat Rev Rheumatol 2017; 13: 561–568.

15.

Richette

Doherty

Pascual

, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis 2017; 76: 29–42.

16.

Pérez Ruiz

Richette

Stack

, et al. Failure to reach uric acid target of <0.36 mmol/L in hyperuricaemia of gout is associated with elevated total and cardiovascular mortality. RMD Open 2019; 5: e001015.

17.

Doherty

Jenkins

Richardson

, et al. Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial. Lancet 2018; 392: 1403–1412.

18.

Perez-Ruiz

Herrero-Beites

Carmona

. A two-stage approach to the treatment of hyperuricemia in gout: the “dirty dish” hypothesis. Arthritis Rheum 2011; 63: 4002–4006.

19.

Tai

Gow

Stewart

, et al. An updated systematic review and meta-analysis of randomised controlled trials on the effects of urate-lowering therapy initiation during a gout flare. Semin Arthritis Rheum 2024; 65: 152367.

20.

Stamp

Taylor

Jones

, et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum 2012; 64: 2529–2536.

21.

Stamp

Chapman

Barclay

, et al. A randomised controlled trial of the efficacy and safety of allopurinol dose escalation to achieve target serum urate in people with gout. Ann Rheum Dis 2017; 76: 1522–1528.

22.

Kannuthurai

Gaffo

. Management of patients with gout and kidney disease: a review of available therapies and common missteps. Kidney360 2023; 4: e1332–e1340.

23.

Stamp

Chapman

Barclay

, et al. The effect of kidney function on the urate lowering effect and safety of increasing allopurinol above doses based on creatinine clearance: a post hoc analysis of a randomized controlled trial. Arthritis Res Ther 2017; 19: 283.

24.

White

Saag

Becker

, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med 2018; 378: 1200–1210.

25.

Mackenzie

Ford

Nuki

, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet 2020; 396: 1745–1757.

26.

O’Dell

Brophy

Pillinger

, et al. Comparative effectiveness of allopurinol and febuxostat in gout management. NEJM Evid 2022; 1: 20220203.

27.

Perez-Ruiz

Dalbeth

. Combination urate-lowering therapy in the treatment of gout: what is the evidence? Semin Arthritis Rheum 2019; 48: 658–668.

28.

Chen

Yang

, et al. Comparative efficacy and safety of uricosuric agents in the treatment of gout or hyperuricemia: a systematic review and network meta-analysis. Clin Rheumatol 2023; 42: 215–224.

29.

Chen

. Comparison of the efficacy and safety of benzbromarone and febuxostat in gout and hyperuricemia: a systematic review and meta-analysis. Clin Rheumatol 2024; 43: 1745–1754.

30.

Lee

Song

. Comparative efficacy and safety of dotinurad, febuxostat, and benzbromarone in hyperuricemic patients with or without gout: a network meta-analysis of randomized controlled trials. Int J Clin Pharmacol Ther 2022; 60: 159–166.

31.

Kang

Shin

Park

, et al. Risk of urolithiasis associated with allopurinol versus benzbromarone among patients with gout: a population-based cohort study. Rheumatology (Oxford) 2024; 63: 2433–2441.

32.

Sundy

Baraf

Yood

, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. Jama 2011; 306: 711–720.

33.

Holladay

Mudano

Xie

, et al. Real-world effectiveness of pegloticase associated with use of concomitant immunomodulatory therapy. Arthritis Care Res (Hoboken) 2024; 76: 1361–1370.

34.

Baraf

HSB

Khanna

Kivitz

, et al. The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout. Rheumatology (Oxford) 2024; 63: 1058–1067.

35.

Botson

Saag

Peterson

, et al. A randomized, placebo-controlled study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase: primary efficacy and safety findings. Arthritis Rheumatol 2023; 75: 293–304.

36.

Yokose

McCormick

Abhishek

, et al. The clinical benefits of sodium-glucose cotransporter type 2 inhibitors in people with gout. Nat Rev Rheumatol 2024; 20: 216–231. 20240312.

37.

Lai

Hwang

Kuo

, et al. Risk of gout flare after medication: prescription symmetry sequence analysis. Clin Rheumatol 2024; 43: 1183–1188.

38.

Terkeltaub

Lee

Min

, et al. Serum urate-lowering efficacy and safety of tigulixostat in gout patients with hyperuricemia: a randomized, double-blind, placebo-controlled, dose-finding trial. Arthritis Rheumatol 2023; 75: 1275–1284.

39.

Gurwith

Smith

Bird

, et al. A double-blind, placebo-controlled ascending dose phase 2a study of ABP-671, a novel, potent and selective URAT1 inhibitor, in patients with gout or hyperuricemia. In: ACR convergence. Philadelphia, PA: Arthritis Rheumatology, 2022.

40.

van Durme

Wechalekar

Landewe

, et al. Non-steroidal anti-inflammatory drugs for acute gout. Cochrane Database Syst Rev 2021; 12(12): Cd010120.

41.

Sutaria

Katbamna

Underwood

. Effectiveness of interventions for the treatment of acute and prevention of recurrent gout—a systematic review. Rheumatology (Oxford) 2006; 45: 1422–1431.

42.

Schumacher

Berger

Li-Yu

, et al. Efficacy and tolerability of celecoxib in the treatment of acute gouty arthritis: a randomized controlled trial. J Rheumatol 2012; 39: 1859–1866.

43.

Janssens

Janssen

van de Lisdonk

, et al. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet 2008; 371: 1854–1860.

44.

Pisaniello

Fisher

Farquhar

, et al. Efficacy and safety of gout flare prophylaxis and therapy use in people with chronic kidney disease: a Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN)-initiated literature review. Arthritis Res Ther 2021; 23: 130.

45.

Hoskison

Wortmann

. Management of gout in older adults: barriers to optimal control. Drugs Aging 2007; 24: 21–36.

46.

Pillinger

Mandell

. Therapeutic approaches in the treatment of gout. Semin Arthritis Rheum 2020; 50: S24–S30.

47.

Terkeltaub

Furst

Bennett

, et al. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010; 62: 1060–1068.

48.

Bausson

Keller

Von Hunolstein

, et al. Safety and efficacy of colchicine in crystal-induced arthritis flare in 54 patients with severe chronic kidney disease. RMD Open 2024; 10: e003872.

49.

Saag

Khanna

Keenan

, et al. A randomized, phase II study evaluating the efficacy and safety of anakinra in the treatment of gout flares. Arthritis Rheumatol 2021; 73: 1533–1542.

50.

Janssen

Oude Voshaar

MAH

Vonkeman

, et al. Anakinra for the treatment of acute gout flares: a randomized, double-blind, placebo-controlled, active-comparator, non-inferiority trial. Rheumatology (Oxford) 2019 20190102.

51.

Desmarais

Chu

. Utility of anakinra in acute crystalline diseases: a retrospective study comparing a University Hospital with a Veterans Affairs Medical Center. J Rheumatol 2019; 46: 748–750.

52.

Ahmed

HMA

Sun

Gaffo

. Factors affecting response to anakinra in crystalline arthritis flares. J Clin Rheumatol 2022; 28: 196–200.

53.

Schlesinger

. Canakinumab in gout. Expert Opin Biol Ther 2012; 12: 1265–1275.

54.

Jeria-Navarro

Gomez-Gomez

Park

, et al. Effectiveness and safety of anakinra in gouty arthritis: A case series and review of the literature. Front Med (Lausanne) 2022; 9: 1089993.

55.

Schlesinger

Pillinger

Simon

, et al. Interleukin-1β inhibitors for the management of acute gout flares: a systematic literature review. Arthritis Res Ther 2023; 25: 128.

56.

Seth

Kydd

Falzon

, et al. Preventing attacks of acute gout when introducing urate-lowering therapy: a systematic literature review. J Rheumatol Suppl 2014; 92: 42–47.

57.

Lin

McCormick

Yokose

, et al. Interactions between genetic risk and diet influencing risk of incident female gout: discovery and replication analysis of four prospective cohorts. Arthritis Rheumatol 2023; 75: 1028–1038.

58.

Zhang

Yang

Dove

, et al. Healthy lifestyle counteracts the risk effect of genetic factors on incident gout: a large population-based longitudinal study. BMC Med 2022; 20: 138.

59.

Abhishek

Valdes

Jenkins

, et al. Triggers of acute attacks of gout, does age of gout onset matter? A primary care based cross-sectional study. PLoS One 2017; 12: e0186096.

60.

Nielsen

Bartels

Henriksen

, et al. Weight loss for overweight and obese individuals with gout: a systematic review of longitudinal studies. Ann Rheum Dis 2017; 76: 1870–1882.

61.

Abhishek

Doherty

. Education and non-pharmacological approaches for gout. Rheumatology (Oxford) 2018; 57: i51–i58.

62.

Dehlin

Jacobsson

Roddy

. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol 2020; 16: 380–390.

63.

Rasmussen

Larsen

Christensen

, et al. Optimising gout treatment: insights from a nurse-led cohort study. RMD Open 2024; 10: e004179.

64.

Cipolletta

Tata

Nakafero

, et al. Association between gout flare and subsequent cardiovascular events among patients with gout. Jama 2022; 328: 440–450.

Gout therapy updated

Abstract

Keywords

Introduction

Urate lowering therapies

Xanthine oxidase inhibitors

Uricosurics

Uricase therapy

Additional therapeutic considerations

Future possible therapies

Flare and prophylaxis therapies

Nonsteroidal anti-inflammatory drugs

Glucocorticoids

Colchicine

IL-1 inhibitors

Nonpharmacologic approaches

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References