Understanding Treatment of Gout and ULT Options

Treatment of Gout and ULT Options GOALS

By the end of this article, you should be able to:

• Examine the pathophysiology and causes of gout, along with the signs and symptoms of acute attacks.
• Compare and contrast recommendations from various organizations’ guidelines for the pharmacological treatment of gout.
• Determine suitable treatment options for acute gouty arthritis and ongoing urate-lowering therapy.
• Recognize approaches that pharmacists can employ to enhance patient adherence to gout treatment.

History

The prevalence of gout has doubled in the past 20 years in the United States, with evidence suggesting that elevated uric acid levels may contribute to the risk of cardiovascular disease and other comorbidities. However, the management of gout is suboptimal, with many patients not reaching the target serum uric acid goal. Pharmacists can play a key role in improving gout management and reducing associated cardiovascular risk.

Key Points

• The prevalence of gout has doubled in the past 20 years in the United States, with approximately 39% of US adults affected.
• Gout is more common in men than in women, but its occurrence in women increases after menopause.
• Gout is associated with an increased risk of cardiovascular disease, and patients who fail to reach the recommended serum uric acid goal have a higher mortality rate.
• Clinical inertia often occurs due to providers’ lack of familiarity with treatment guidelines for gout, resulting in suboptimal management practices.

Clinical presentation

• Acute gouty arthritis occurs when monosodium urate crystals exceed their solubility limit in a joint (SUA level of >6.8 mg/dL).
• This triggers an immune response, leading to inflammation and the formation of tophi, visible nodules containing the crystals.
• Gout is characterized by podagra (red, swollen first metatarsophalangeal joint) and can also affect larger lower-limb joints, smaller joints, and distal joints.
• In elderly patients, gout may present with atypical symptoms, affecting upper limbs and having a higher chance of tophi.

Risk Factors for Gout

• Comorbidities: Metabolic syndrome, diabetes, increasing BMI, and hypertension
• Diet and Lifestyle: High-purine foods, Western diet, and DASH diet
• Medications: diuretics (duration of therapy and increasing dose), other antihypertensives, low-dose aspirin
• Age-Related Factors: increased adiposity, beer and protein intake, suboptimal kidney function, smoking, hypertension

Diagnosis

Gout is typically diagnosed based on clinical presentation, which includes the rapid development of monoarticular arthritis with associated swelling and redness. While aspiration of joint fluid and identification of urate crystals are required for a confirmatory diagnosis, this is rarely done in practice. For more information, you can refer to the American College of Rheumatology (ACR)–European League Against Rheumatism (EULAR) diagnostic criteria available at this link.

Treatment guidelines

• Initiation of ULT:
  • ACP guidelines: Least aggressive, does not recommend ULT after first attack or in patients with infrequent attacks.
  • ACR guidelines: Recommend ULT in patients with tophi, two or more flares per year, stage 2 or higher CKD, and history of urolithiasis.
  • EULAR guidelines: Recommend consideration of ULT initiation from the first attack, based on the impact of hyperuricemia on CV health.
• Agent Preference for ULT:
  • ACP guidelines: No preference given.
  • ACR guidelines: Recommend xanthine oxidase inhibitors (XOI) as first-line ULT, with equal consideration to allopurinol and febuxostat.
  • EULAR guidelines: Recommend allopurinol due to affordability.
• Treat-to-Target Approach:
  • ACR and EULAR guidelines: Recommend treating to a target SUA level of <6 mg/dL and allow for a more aggressive target of <5 mg/dL in patients with more severe disease.
  • ACP guidelines: Do not recommend a treat-to-target approach or ULT initiation due to insufficient evidence of improved outcomes or adherence.

Acronyms: 

• ULT: Urate-lowering therapy
• ACP: American College of Physicians
• EULAR: European League Against Rheumatism
• ACR: American College of Rheumatology
• CKD: Chronic Kidney Disease
• SUA: Serum Uric Acid
• CV: Cardiovascular

Treatment options

• Treatment options for acute gouty arthritis include NSAIDs, corticosteroids, colchicine, and IL-1 inhibitors. The ACR and EULAR guidelines do not have a treatment preference, but the ACP guidelines recommend corticosteroids as first-line treatment.
• Recent evidence has shown corticosteroids to be equally effective as NSAIDs for pain resolution. Colchicine is less favored due to cost increases and side effects.
• NSAIDs are recommended for patients under 60 without major comorbidities. Combination therapy of first-line treatments is allowed, except for corticosteroids and NSAIDs together due to concerns about GI toxicity.
• These treatment options are also recommended when ULT is initiated to prevent gouty arthritis exacerbations or recurrence.
• Anti-inflammatory prophylaxis with ULT may include NSAIDs, colchicine, and low-dose corticosteroids.
• If tophi are present, prophylaxis should continue for 6 months after reaching the SUA goal; if no tophi are present, prophylaxis should continue for 3 months after reaching the SUA goal.

ULT options

• FDA warned about increased risk of heart-related death with febuxostat compared to allopurinol in 2017.
• Febuxostat use is now recommended for patients who have failed to tolerate allopurinol.
• Allopurinol is generally considered the first-line treatment for gout, with febuxostat reserved for patients who are hypersensitive or intolerant to allopurinol.
• Emerging evidence suggests that allopurinol may protect against renal disease better than febuxostat.
• Lesinurad has been discontinued due to efficacy and safety concerns.

ULT pearls

• Allopurinol and febuxostat should be initiated at a low dosage and titrated every 2 to 5 weeks until the SUA level is <6 mg/dL.
• Allopurinol dosage ranges from 100 mg to 800 mg/day, with higher doses sometimes needed for tophaceous gout.
• Febuxostat dosage is typically 80 mg/day.
• Lesinurad should be used in combination with allopurinol 300 mg daily or febuxostat 80 mg daily.
• Verinurad, another medication in this class, is currently in development, and similar renal dosing is expected.
• Fenofibrate can lower uric acid levels as much as 20% to 30% when used in combination with XOI therapy.
• Losartan can reduce uric acid levels, particularly in patients with concomitant diabetes and/or hypertension who qualify for ACE inhibitor therapy or angiotensin receptor blocker therapy.

Gout and diet

Summary

Patients often seek natural therapies for rheumatologic disorders, including cherry extract, vitamin C, celery seed, and turmeric. However, there is inadequate evidence for the safety and effectiveness of cherry extract, while vitamin C has data supporting its effectiveness for preventing acute flares. Celery seed has been used for acute pain treatment during a flare, but there is no recommended dosage, and turmeric also lacks efficacy data.

Key Points

• Cherry extract should not be recommended due to inadequate evidence of safety and effectiveness
• Vitamin C has data supporting its effectiveness for preventing acute flares at dosages of 500 mg/day or more
• Celery seed has been used for acute pain treatment during a flare, but no recommended dosage or data supporting its effectiveness
• Turmeric lacks efficacy data, but a dosage of 1,000 mg/day has been found to be effective for other arthritic disorders

 FAQ

Q: What is hyperuricemia and how is it related to gout?

A: Hyperuricemia is a condition characterized by an elevated level of uric acid in the blood. When the body produces an excessive amount of uric acid or is unable to expel enough of it through the kidneys, hyperuricemia may occur. High levels of uric acid can lead to the formation of uric acid crystals in the body. These crystals can accumulate in the joints causing an acute gout attack; thus, hyperuricemia is associated with the development of gout.

Q: What are the symptoms of an acute gout flare?

A: An acute gout flare, also known as a gouty arthritis attack, often occurs suddenly. It is typically characterized by severe pain, swelling, redness, and warmth in the affected joint, often the big toe. Gout symptoms can be severe and they usually peak within 24 to 48 hours.

Q: What contributes to the development of chronic gout?

A: Chronic gout occurs when a patient experiences repeated gout flares over a long period of time. This can be caused by prolonged hyperuricemia as the uric acid crystals deposit in the joints leading to permanent joint damage. Other factors include inadequate treatment of hyperuricemia and lifestyle factors like diet and alcohol consumption.

Q: Which factors can cause hyperuricemia?

A: Some causes of hyperuricemia include genetics, kidney disease, certain medications, obesity, excessive alcohol consumption, and diets high in purines, a substance that breaks down into uric acid.

Q: How is hyperuricemia diagnosed?

A: Hyperuricemia is typically diagnosed through a blood test to measure the serum uric acid level. However, high levels of uric acid alone are not enough for a diagnosis of gout. Other factors and clinical practice guidelines and consensus statements are considered. A joint fluid test to look for uric acid crystals may also be required.

Q: What is the prevalence of hyperuricemia and gout?

A: Gout is a common condition, and hyperuricemia is even more prevalent. The prevalence of hyperuricemia varies by region and demographics, but it has been increasing globally, likely due to changes in diet, lifestyle, and an increase in conditions associated with hyperuricemia, like metabolic syndrome and kidney disease.

Q: What treatment options are available for hyperuricemia and acute gout attack?

A: Acute gout attacks are usually treated with anti-inflammatory medications to alleviate pain and swelling. For the management of hyperuricemia, treatments aim at reducing serum uric acid levels. This can be achieved with lifestyle modifications and medications that reduce uric acid production or increase its excretion. A review of clinical practice guidelines may be helpful.

Q: How are patients with asymptomatic hyperuricemia managed?

A: Asymptomatic hyperuricemia refers to high levels of uric acid without symptoms of gout. Presently, rheumatology guidelines for the management of such cases prefer lifestyle modifications over medical treatment, unless there are other risk factors present.

Q: What is chronic tophaceous gout?

A: Chronic tophaceous gout is a severe and advanced stage of gout. It occurs when large deposits of uric acid crystals (tophi) accumulate in the joints and can cause deformity and damage to the joints. This stage usually occurs after many years of untreated or inadequately treated hyperuricemia and gout.

Q: What drugs are available for the treatment of hyperuricemia?

A: Several drugs are available to manage hyperuricemia. These include uric acid lowering drugs (like allopurinol and febuxostat), and uricosuric drugs which increase uric acid excretion (like probenecid). It is important that treatment decisions are individualized considering the patient’s overall health, associated diseases, and the risk of ongoing gout flares.

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