US Pharm. 2023;48(1):37-42.

ABSTRACT: Gout, an inflammatory condition, is caused by elevated serum uric acid concentrations. Acute gouty arthritis is managed with nonsteroidal anti-inflammatory drugs, colchicine, or corticosteroids. The prevention of gout attacks and treatment of chronic gout require use of a xanthine oxidase inhibitor, a uricosuric agent, or a combination of these agents, along with lifestyle modifications. Allopurinol is a first-line agent for gout prevention in patients requiring urate-lowering therapy who have no contraindications. Pegloticase, a specialty drug, should be reserved for patients in whom other treatment has failed. Specialty pharmacists involved in gout management should educate and counsel patients, provide assistance with any prior authorizations, and find ways to minimize the impact of the treatment cost when the patient has a financial barrier.

Gout is an inflammatory condition resulting from the precipitation of monosodium urate crystals in both articular and nonarticular tissues. The prevalence of gout varies worldwide based on many contributing factors, such as genetics, sex, age, and diet. Based on current estimates, gout affects about 9.2 million adults in the United States.¹ Gout and hyperuricemia are more common in older adults. Dietary factors, including consumption of alcoholic beverages, red meat, seafood, and foods sweetened with high-fructose corn syrup, increase the risk of gout.²

The diagnosis of gout is made based on the presence of clinical symptoms rather than abnormal laboratory results. Some patients with hyperuricemia present with symptoms leading to a gout attack, whereas other hyperuricemic patients are asymptomatic. In those who are asymptomatic, the use of pharmacologic agents is not recommended; rather, lifestyle modifications should be considered.¹

Acute gout presents with symptoms such as swelling around the joints and intense pain.³ A subcutaneous tophus occurs when serum uric acid (UA) concentrations are elevated, causing the crystallization of monosodium urate around an affected joint. The first metatarsophalangeal joint is the site most often affected (in this location, the condition is called podagra); other sites include the ankles, fingers, and elbows.² The presence of tophi can signal chronic gout. The presence of flares and pain makes routine activities challenging and affects the patient’s quality of life.³ Excess UA in the blood, or hyperuricemia, may be present in patients with metabolic syndrome and is considered a risk factor for many comorbidities, including gout, hypertension, nonalcoholic fatty liver disease, chronic kidney disease (CKD), and cardiovascular disease (CVD).⁴ In gout, the treat-to-target goal for serum UA concentrations is <6 mg/dL.¹

Humans lack the enzyme uricase, which converts UA to more soluble allantoin.⁵ UA is produced from purines that originate in three different sources: dietary purines, conversion of tissue nucleic acid into purine nucleotides, and a de novo pathway of purine base synthesis. Various enzymes are involved in purine metabolization, and regulatory-system abnormalities could result in overproduction of UA. Increased phosphoribosyl pyrophosphate synthetase activity and decreased hypoxanthine-guanine phosphoribosyl transferase activity are two abnormalities that can lead to UA overproduction. It is estimated that two-thirds of the UA produced daily is filtered through the proximal tubules, where the UA is reabsorbed through the urate anion transporter called urate transporter 1 (URAT1). In the presence of conditions that cause increased sodium reabsorption, such as dehydration, UA reabsorption is consequently greater.⁵

GOUT TREATMENT

Managing Gout Flares

The management of acute gout requires the use of nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or corticosteroids, all of which the 2020 American College of Rheumatology (ACR) guideline for gout management recommends as first-line treatment for acute attacks.¹

NSAIDs: Short-term use of NSAIDs has been shown to have favorable efficacy and minimal toxicity in patients who are suitable candidates. NSAID selection should be based on the patient’s prior response and concerns regarding adverse effects (AEs). Three NSAIDs—indomethacin, naproxen, and sulindac—are FDA approved for the treatment of gout. Naproxen and other NSAIDs, including celecoxib, have been used to manage gout flares.⁶ Patients may experience typical NSAID-related AEs, including dyspepsia, edema, and headaches, as well as an increased risk of cardiovascular (CV), gastrointestinal (GI), or renal events.^7,8

Colchicine: This alkaloid is FDA approved for treating acute gout flares. The initial (day 1) dosage is 1.2 mg followed by 0.6 mg 1 hour later; on day 2 and for 48 hours after flare resolution, colchicine is given prophylactically at a dosage of 0.6 mg once or twice daily, depending on the severity of the flare.^9,10 With colchicine, the most commonly occurring AEs are GI effects such as nausea, vomiting, and diarrhea, especially at higher dosages.¹⁰

Corticosteroids: Corticosteroids are used either systemically or via intraarticular injection for the treatment of acute gout flares, and their use is common when other therapies are contraindicated. Prednisone used for the treatment of acute gout flares should be initiated at a dosage of 30 mg to 40 mg per day until symptom improvement, which should occur in 2 to 5 days. The corticosteroid should then be tapered gradually over 7 to 10 days, or even up to 21 days in patients who have had multiple recent flares.¹¹

ACR Guidance: The ACR guideline strongly recommends using anti-inflammatory therapies for 3 to 6 months, as stopping these agents early can cause a recurrence of flares.¹ Due to their lower cost, accessibility, and overall tolerability, the ACR guideline recommends NSAIDs, colchicine, and corticosteroids over interleukin-1 (IL-1) inhibitors or adrenocorticotropic hormone for treating gout flares.¹

Nonpharmacologic Options: Consuming a diet low in purine-rich foods, avoiding high-fructose corn syrup, and restricting alcoholic beverages could reduce serum UA in hyperuricemic patients. Additionally, weight loss and exercise should be promoted to reduce serum UA concentrations in candidate patients. Topical ice is recommended as adjuvant therapy during flares to further reduce pain and inflammation.¹

Pharmacologic Treatment of Gout Hyperuricemia

For established or chronic gout, treatment aims to lower urate levels and prevent future episodes. The ACR guideline recommends initiating urate-lowering therapy (ULT) after two or more attacks per year or the presence of one or more tophi with radiographic damage.¹ Xanthine oxidase inhibitors (XOIs), including allopurinol and febuxostat, work by blocking the production of urate, lessening the possibility of hyperuricemia.

Allopurinol: Currently recommended as first-line therapy even in patients with moderate-to-severe CKD, allopurinol should be initiated at a dosage of 100 mg and titrated slowly every 2 to 4 weeks to a maximum dosage of 800 mg per day until the desired serum UA concentration is achieved. While on allopurinol treatment, patients may experience skin rash, nausea, vomiting, headache, fever, and other mild AEs.^12,13 In certain populations, notably persons of Southeast Asian descent and African Americans, it is conditionally recommended to test for the HLA-B*5801 allele prior to initiating allopurinol because of the threefold higher risk of allopurinol hypersensitivity syndrome in these populations.¹ If allopurinol treatment is ineffective, the patient usually is switched to febuxostat.

Febuxostat: This agent is initiated at a dosage of 40 mg once daily and increased to 80 mg after 2 weeks if a serum UA concentration <6 mg/dL is not achieved.¹⁴ Febuxostat carries a black box warning for CV death; for that reason, allopurinol should be the treatment of choice in patients in whom allopurinol is not contraindicated.^6,13 In the 2018 FDA-mandated CARES trial of febuxostat versus allopurinol, which included 6,190 patients, febuxostat was noninferior to allopurinol in terms of composite rates of CV AEs such as CV death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina.¹⁵ Although the primary endpoint had inconclusive results, febuxostat was associated with a higher risk of CVD-related deaths and death from any cause compared with allopurinol. In this and other studies, confounding variables may have been inadequately addressed, which led the ACR to recommend shared decision making when considering febuxostat use in patients with high CVD risk.¹ Patients taking febuxostat may also experience AEs including skin rash, nausea, changes in liver-function tests, and joint pain.¹⁴

Other Recommendations: For flare prophylaxis during ULT, the use of NSAIDs or colchicine is acceptable at lower doses.¹

Maximizing Therapy

Losartan: Losartan is the only angiotensin receptor II blocker (ARB) that the ACR guideline lists as an option for reducing UA concentration.¹ Losartan acts selectively and competitively, leading to its antihypertensive effect.¹⁶ This uricosuric (e.g., promoting UA excretion) agent inhibits URAT1 in the proximal tubules, leading to decreased UA concentrations.¹⁷ Such a reduction in UA has not been shown to be a class effect, and losartan exerts this effect via cis inhibition as opposed to trans stimulation.^18,19 Other ARBs, such as valsartan, candesartan, and olmesartan, have a trans-stimulatory effect rather than a cis-inhibitory effect, resulting in increased UA concentrations.²⁰ The degree to which losartan reduces UA has been challenged and seems to differ among patients. Losartan is metabolized via CYP450 2C9, and genetic polymorphism studies suggest that CYP2C9*2 and CYP2C9*3 alter the pharmacokinetics of losartan and its metabolite.²¹ In addition, URAT1, a member of the organic anion transporter family, is subject to polymorphism, leading to an imbalance in UA concentration. Losartan’s uricosuric action is influenced by the genetic polymorphism of URAT1.^22,23 Gout-management guidelines further support the view that losartan is the only ARB that has UA-lowering effects; they conditionally recommend choosing or switching to losartan as a hypertensive agent, when feasible, as the risks inherent in switching to losartan are low compared with its urate-lowering effects.^1,24

Several studies have demonstrated the uricosuric effect of losartan, which was observed in patients with or without gout and those with thiazide-related hyperuricemia.^18,25 In a population-based case-control trial that examined antihypertensive drugs and the risk of gout formation, losartan was associated with a lower risk of developing gout (relative risk reduction [RRR], 19%), compared with an increased risk with diuretics, beta-blockers, ACE inhibitors, and non-losartan ARBs.²⁶ The use of calcium channel blockers (amlodipine, nifedipine, and diltiazem) was also associated with a lower risk of gout (RRR, 13%).²⁶ The uricosuric effect of losartan was evaluated in a prospective, randomized, double-blind, crossover study in 13 patients.²⁷ In this study, losartan 50 mg once daily significantly (P <.01) reduced serum UA concentrations from 9.05 (± 0.44) mg/dL to 8.25 (± 0.34) mg/dL, although the higher dosage had no additional UA-lowering effects. Although this study demonstrated significant results, it included a small number of patients and had a short observation period.²⁷

Fenofibrate: Fenofibrate, a fibric-acid derivative used as adjunctive therapy to diet for treatment of adults with severe hypertriglyceridemia, reduces UA concentrations by increasing the clearance of hypoxanthine and xanthine, leading to lower urate concentrations.^28-30 Despite its effect on UA concentrations, the ACR guideline conditionally recommends against switching cholesterol-lowering agents to fenofibrate in gout patients, as it is not considered a preferred therapy in hyperlipidemia guidelines.¹

Probenecid: Probenecid, a uricosuric agent, increases urinary excretion of UA and decreases serum urate concentrations.³¹ It is currently FDA approved for hyperuricemia and gout prevention.³² Due to probenecid’s reduced efficacy in renal impairment, XOIs are strongly recommended instead, especially in patients with CKD stage 3 or higher.¹ However, if probenecid is necessary, the ACR guideline conditionally recommends initiating it at a lower dosage and titrating as needed to reduce the risk of flares.

Lesinurad: Lesinurad, an inhibitor of URAT1, is indicated in combination with an XOI for treatment of hyperuricemia associated with gout when target concentrations are not reached with an XOI alone.³³ As monotherapy, lesinurad has a black box warning for acute renal failure.³³ Although this agent was discontinued, it retains FDA approval.

Drug Discontinuation: A strategy to mitigate hyperuricemia and gout is to consider discontinuing drugs that cause elevated UA concentrations. For example, hydrochlorothiazide (HCTZ) has been shown to cause and worsen gout by increasing UA concentrations; therefore, its use is not recommended. The ACR guideline conditionally recommends that HCTZ be switched to an alternative antihypertensive such as losartan, which can manage a patient’s blood pressure and gout simultaneously.¹

SPECIALTY DRUGS

Pegloticase

In cases of severe gout in which typical ULTs have failed or are contraindicated, the biological agent pegloticase may be initiated as an alternative therapy option.¹ Pegloticase, a PEGylated UA-specific enzyme, attains its pharmacologic effect by catalyzing the oxidation of UA to allantoin, thereby reducing serum UA.³⁴ Pegloticase is indicated for treatment of chronic gout in adults who are refractory to conventional therapy. Pegloticase 8 mg is given as an IV infusion over 2 hours once every 2 weeks, and it should be administered by a healthcare provider in a healthcare setting that is equipped to manage anaphylactic reactions. To lower the risk of infusion reactions, patients should be premedicated with agents such as antihistamines and corticosteroids. Methotrexate and folic acid have also been utilized to reduce the occurrence of infusion-related reactions.³⁵

Two replicate, randomized, double-blind, placebo-controlled, international trials assessed the efficacy and tolerability of pegloticase in managing refractory chronic gout, and data from the trials were pooled. Participants, all of whom received 12 biweekly IV infusions, were randomized into three treatment arms: pegloticase 8 mg IV (biweekly group), pegloticase alternating with placebo (monthly group), or placebo only (placebo group). The primary endpoint of plasma UA normalization (<6.0 mg/dL) in months 3 and 6 was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), compared with 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%) and 0 of 43 placebo patients (0%; 95% CI, 0%-8%). There was an initial increase in the incidence of gout flares in pegloticase-treated patients during months 1 to 3, but with continued treatment, the biweekly group had significant reductions during months 4 to 6. The most common AEs were gout flares and infusion-related reactions, both of which were more common in the biweekly and monthly groups. In patients responding to pegloticase therapy, mean plasma UA remained <6.0 mg/dL throughout the 6-month trial period; in nonresponders, mean plasma UA normalized until week 10 and then was above target for the rest of the trial period.³⁶

IL-1 Inhibitors

The ACR guideline conditionally recommends IL-1 blockers for patients experiencing a gout flare, unable to take anything by mouth, or in whom other anti-inflammatory therapies are insufficient because of inefficacy, poor tolerance, or a contraindication.¹

Rilonacept: Rilonacept is an IL-1 blocker indicated for treatment of pericarditis, cryopyrin-associated periodic syndromes, and deficiency of IL-1 receptor antagonist.³⁷ The safety and efficacy of rilonacept in acute gout attack patients were evaluated in a phase III, randomized, double-blind, double-dummy, controlled trial.³⁸ Patients received rilonacept 320 mg subcutaneously plus oral indomethacin or a subcutaneous placebo plus oral indomethacin. Pain reduction (the primary endpoint) was greater with rilonacept plus indomethacin than with indomethacin alone; however, the difference was not statistically significant.³⁸ A few studies that evaluated the use of rilonacept for prevention of gout flares suggested that this agent was effective and well tolerated.^39-41 However, the ACR guideline did not include IL-1 inhibitors for use as prophylaxis during ULT initiation.¹

Canakinumab: This IL-1 beta-blocker is FDA approved for the treatment of a number of periodic fever syndromes and active Still’s disease (including adult-onset Still’s disease  and systemic juvenile idiopathic arthritis).⁴² The European Alliance of Associations for Rheumatology recommends that IL-1 use be considered in patients who have frequent flares and either have failed therapy with first-line agents or have contraindications to these agents.^1,24 The safety and efficacy of canakinumab were examined in two randomized, controlled trials, which found this agent to be superior to triamcinolone acetonide for reducing pain in patients with a gout flare who were unable to take colchicine or NSAIDs because of a contraindication, intolerance, or lack of response.⁴³ Canakinumab is approved in Europe for the treatment of gouty arthritis.⁴⁴ However, it has not been approved for prophylactic treatment of gout despite positive reports of flare prevention during initiation of allopurinol.⁴⁵ A single dose of canakinumab can effectively relieve pain and prolong the onset of new flares, making it an important treatment option in patients in whom first-line agents are not appropriate.⁴⁵

THE PHARMACIST’S ROLE

Pharmacists can play a key role in personalizing the management approach in patients with gout and hyperuricemia. The available therapeutic agents should be tailored to the individual patient’s risk factors and comorbidities while also taking into account the agents’ benefits versus AE profiles. Currently approved agents (e.g., pegloticase) and certain pipeline agents fall under the category of specialty pharmacy management. Specialty pharmacists involved in the management of gout should educate and counsel patients on potential AEs, therapy considerations, and drug-drug interactions. Pharmacists can assist patients in the process and required elements for prior authorizations, when necessary. If patients have a financial barrier to obtaining the selected drug, pharmacists can help find ways to minimize the impact of the treatment cost.

CONCLUSION

Gout is a significant burden on patients and is associated with poorer quality of life, as acute gouty arthritis is extremely painful. Optimal management of acute gout includes NSAIDs, colchicine, and corticosteroids. Prevention of recurrent gout requires ULT involving XOIs, uricosuric agents, or both. Evidence-based guidelines recommend aggressive, target-directed reduction of serum urate as a primary strategy for prevention of recurrent gouty arthritis. Because ULT initiation can provoke an acute gout episode, dose titration and concomitant anti-inflammatory prophylaxis are recommended.

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