VBCR - October 2012, Volume 1, No 5 - Gout

By Neil Canavan

For the first time in its 78-year history, the American College of Rheumatology (ACR) has issued guidelines for the management of gout in October, which were published in 2 parts (Khanna D, et al. Arthritis Care Res. 2012;64:1431-1461).

The first part, titled “Systematic Nonpharmacologic and Pharma­cologic Therapeutic Approaches to Hyperuricemia,” addresses several key considerations for treating pa­tients with gout, including:

  • The need for lowering serum uric acid levels to <6 mg/dL
  • The appropriate dosing for first- and second-line treatment options, including guidance on the recently US Food and Drug Administration (FDA)-approved drugs febuxostat (Uloric) and pegloticase (Krystexxa)
  • Dietary recommendations
  • Recommendation that patients who are at high risk for severe allopurinol (Zyloprim) sensitivity undergo genetic testing for the HLA-B*5801 allele.

“Acute gout attacks can be debilitating and [can] adversely affect patients’ quality of life,” said one of the lead authors of the guidelines, John D. Fitzgerald, MD, PhD, Act­-ing Rheumatology Division Chief at the University of California, Los Angeles, in a September 28, 2012, press release on the guidelines ( print=true). “In order to improve pa­tient care, the ACR funded this collaborative effort among US re­searchers to produce guidelines, outlining pharmacological therapies and nondrug treatments to manage gout,” Dr Fitzgerald said.

Answering the Need
Gout is the most common inflammatory arthritis representing a metabolic disorder that is characterized by inadequate elimination of uric acid from the blood; uric acid is a breakdown product of purines, which are essential components for making DNA and RNA. Elevated serum levels of uric acid (ie, hyperuricemia) lead to eventual precipitation and to deposition of urate crystals in the joints of the extremities, thereby causing severe inflammation and, often, debilitating pain.

Gout affects an estimated 8.3 million adults in the United States, and its prevalence has been increasing in the past 20 years. Factors driving this increase include more incidences of comorbidities that promote hyperuricemia (eg, hypertension and type 2 diabetes), the use of diuretics for cardiovascular disease, and dietary trends.

Although the number of patients with gout is rising, the authors of the new ACR guidelines state that, “Despite advanced understanding of the molecular bases of hyperuricemia and gouty inflammation and the extensive practice experience of many providers, substantial quality of care gaps exist in gout management.”

The new guidelines were requested by the ACR and reflect the conclusions of recent clinical research in gout mechanisms and management, including recommendations regarding new pharmacologic agents for gout.

To formulate the ACR recommendations, Dr Fitzgerald and colleagues reviewed medical literature published from the 1950s to the present. A task force panel of experts in the field, including 7 rheumatologists, 2 primary care physicians, 1 nephrologist, and 1 patient representative, then ranked and voted on the key findings.

The recommendations reflect the role of a genetic component in gout in relation to testing for the HLA-B*5801 allele before the initiation of therapy with the xanthine oxidase inhibitor allopurinol, acknowledging the potential role of personalized medicine in gout.

Core Recommendations
1. Patient education on diet, life­style, and the management of comorbidities is a recommended core thera­peutic measure in patients with gout
Clinicians are urged to look for comorbid conditions that may be causing hyperuricemia (ie, renal disease); a checklist of these conditions
is provided in the guidance. Accord­ingly, agents used to treat such comorbidities should be considered for their urate-elevating potential (ie, thiazides and loop diuretics). Those medicines deemed nonessential to the management of comorbid conditions should be reduced or eliminated.

Regarding diet, the task force pan­el has provided a table of items grouped into the 3 recommendation categories of “avoid,” “limit,” and “en­courage.” Examples include avoiding organ meats that have a high purine content, high fructose corn syrup, and, during a gout attack, any consumption of alcohol; limiting intake of most meats, sugar, salt, and alcohol; and encouraging a low-fat diet with vegetables.

2. Serum urate level should be lowered sufficiently to durably improve the signs and symptoms of gout, with the target of <6 mg/dL at minimum, and often <5 mg/dL
The panel recommends a serum uric acid target of <6 mg/dL in all patients with gout, and a target of <5 mg/dL in patients who remain unable to achieve a durable reduction in gout episodes or symptoms, including tophi that are palpable or visible by physical examination.

During the titration period after treatment initiation, the panel recommends monitoring serum uric acid every 2 to 5 weeks. After target levels are achieved, serum uric acid levels should be assessed every 6 months.

3. Xanthine oxidase inhibitor (XOI) therapy with allopurinol or with febuxostat is recommended as the first-line pharmacologic urate-lowering therapy (ULT) approach    
In cases where XOIs are contraindicated as a result of concurrent medications or conditions or because of XOI intolerance, probenecid (Benemid) is recommended as an alternative first-line ULT. Regarding timing, ULT may be initiated during an acute gout attack, as long as effective anti-inflammatory management has been instituted as well.

4. The starting dosage of allopurinol should be ≤100 mg daily and up to 80 mg daily in patients with moderate-to-severe chronic kidney disease (CKD), followed by gradual upward titration of the maintenance dose, which can exceed 300 mg daily, even in patients with CKD
These recommendations are consistent with the previous guidelines from the FDA and the European League Against Rheumatism. The panel’s rationale for starting with this lower dose is to mitigate the potential for a severe allopurinol hypersensitivity reaction.

Prescribing allopurinol in a dose of <300 mg daily is deemed valid by the task force panel in consideration of data showing that roughly 50% of all patients with gout fail to achieve target serum uric acid levels below that threshold. As the task force panel states, “Maintenance dosage of allo­purinol can be raised above 300 mg per day, even in those with renal impairment, provided there is adequate patient education and regular monitoring for drug hypersensitivity and other adverse events.” The maximum FDA-approved dose of allo­purinol is 800 mg/day.

The maximum dose for febuxostat is 80 mg/day; however, the task force panel has found data to support a maximum dosing level of 120 mg/day. This dose level is approved in many countries outside of the United States in the setting of active disease refractory to appropriately dosed oral ULT.

5. Before the initiation of allopurinol, HLA-B*5801 screening should be considered in subpopulations where the allele is frequently elevated and where allele-positive subjects are at high risk for severe allopurinol sensitivity reactions (eg, Koreans with ≥stage 3 CKD and all patients of Han Chinese and Thai descent)
The panel recommends that HLA-B*5801 screening be performed with the rapid, widely available polymerase chain reaction–based ap­proach. For inconclusive results, HLA-B*5801 sequencing is advised. If a patient tests HLA-B*5801–positive, alternatives to allopurinol should be prescribed.

The panel did not recommend universal HLA-B*5801 screening, citing data that indicate a prevalence of <2% of the allele for individuals outside of the highlighted risk groups.

6. Combination oral ULT with 1 XOI agent and 1 uricosuric agent is appropriate when the serum urate target has not been met by appropriate dosing of an XOI
The panel recommends the uricosuric agents probenecid, fenofibrate (TriCor; off-label use), or losartan (Cozaar; off-label use) as adjunctive therapy in a comprehensive ULT program in the refractory disease setting. Nine refractory disease case scenarios are described within the guidance.

7. Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or in­tolerance of, appropriately dosed oral ULT options
Supporting this recommendation, the task force panel cited data from 2 large clinical trials where 8-mg pegloticase every 2 weeks was effective in reducing serum uric acid to appropriate levels in 42% of patients. Of note, pegloticase as a first-line ULT was not recommended for any patient with gout.

Safety and Quality of Care
Commenting on the effort overall, Dr Fitzgerald stated in the press release, “The ACR gout guidelines are designed to emphasize safety, quality of therapy, and to reflect best practice based upon medical evidence available at this time. Our goal is that these guidelines, along with educating gout patients in effective treatment, will improve adherence, quality of care, and management of this painful and potentially chronically debilitating condition.”

Part 2 of the guidelines, titled “Therapy and Antiinflammatory Pro­phylaxis of Acute Gouty Arthritis,” will be discussed in the December issue of this publication.

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