Hiperürisemi ve gut tedavileri için yeni kılavuz

Hiperürisemi ve gut tedavileri için yeni kılavuz (İng)

New Guidelines for the Treatment of Hyperuricemia, Gout 

News Author: Janis C. Kelly
CME Author: Laurie Barclay, MD

Gout results from an excess body burden of uric acid, with hyperuricemia variably defined as a serum urate level exceeding either 6.8 or 7.0 mg/dL. Tissue deposition of monosodium urate monohydrate crystals in supersaturated extracellular fluids of the joints and in certain other sites results in acute gouty arthritis, chronic arthritis, and renal disease.

The goal of the 2012 American College of Rheumatology (ACR) guidelines was to develop systematic nonpharmacologic and pharmacologic recommendations for effective treatments in gout with an acceptable risk/benefit ratio. Four specific areas of gout management covered by the guidelines were urate-lowering therapy (ULT), chronic gouty arthritis with tophaceous disease, analgesic and anti-inflammatory management of acute gouty arthritis, and pharmacologic anti-inflammatory prophylaxis of attacks of gouty arthritis.

Study Synopsis and Perspective

New gout guidelines from the ACR are meant to improve gout management by providing clinicians with clear, readily implemented guidance on ULT (including diet and lifestyle changes), chronic tophaceous gouty arthropathy (CTGA), analgesic and anti-inflammatory management of acute gouty arthritis, and drug prophylaxis of acute attacks.

The guidelines, reported in 2 parts in the October issue of Arthritis Care & Research, include guidance on the new drugs febuxostat and pegloticase, which have been recently approved for gout management and are not yet addressed in the European League Against Rheumatism or British Society for Rheumatology gout guidelines.

Senior author Robert Terkeltaub, MD, told Medscape Medical News,”This is the first time in the 78-year history of ACR that there have been guidelines for the management of gout. This indicates how seriously people in rheumatology take this and how common the problem has become, with more than 8 million cases in the US, affecting 3.9% of adults. What we have here is a disease that is very well understood but ridiculously poorly managed.” Dr. Terkeltaub is chief of rheumatology at the Veterans Affairs Medical Center in San Diego, California, and professor of medicine and associate division director at the University of California in San Diego.

Old Disease, New Management

Part 1 of the guidelines focuses on hyperuricemia and CTGA. The top recommendation is for more intensive education of patients on diet, lifestyle choices, treatment objectives, and management of concomitant diseases; this includes recommendations on specific dietary items to encourage, limit, and avoid.

“We provide a comorbidity check-list for the clinician that I expect will be very useful in day-to-day practice,” Dr. Terkeltaub said. “We have also provided a cohesive set of diet and lifestyle recommendations. This has been a problem because of the fact and fiction mixed in to diet and lifestyle approaches to gout. The guideline is an advance because it provides a more actionable set of recommendations for physicians to talk about with their patients.”

Table. Comorbidity Checklist for Patients With Gout

Dr. Terkeltaub added, “Many patients feel that diet and moderation alone should be sufficient to manage their gout. Diet is important, but what is really important is getting the serum urate to a target appropriate for that patient. At a bare minimum it should be less than 6 mg/dL. In clinical practice, the serum uric acid level is no longer part of the routine metabolic panel, but it is inexpensive and should be monitored regularly in gout patients.”

Dr. Terkeltaub noted that dietary or alcohol excess can increase uric acid and trigger acute gout attacks in susceptible individuals, but he said that dietary restrictions alone may not reduce serum urate levels enough to prevent joint damage in gout patients.

“The average-age gout patient in our clinical trials has a serum uric acid level between 9.5 and 10 mg/dL. Even ideal diet and alcohol intake will likely lower that by only 10% to 15%, which will not bring the typical gout patient to a serum uric acid of 6 mg/dL. Often people need urate-lowering drugs to get them to the target level and keep them there. People feel that if they have fewer gout attacks, they are better, but the disease will progress unless serum uric acid is reduced to a level where deposits of urate crystals in the joint tissues will disappear,” Dr. Terkeltaub said.

Start Low, Go Slow With Allopurinol

The ACR guidelines recommend treating patients with a xanthine oxidase inhibitor (XOI), such as allopurinol, as the first-line pharmacologic ULT approach. The recommended goal is to reduce serum urate to less than 6 mg/dL, and the initial allopurinol dosage should be no greater than 100 mg/day, the guidelines say. This should be followed by gradual increase of the maintenance dose, which can safely exceed 300 mg even in patients with CKD.

“Clinicians often start allopurinol at doses that are too high but maintain allopurinol at doses that are too low,” Dr. Terkeltaub said. “We give specific guidance on start low, go slow dose escalation.”

To avoid allopurinol toxicity, the guidelines recommend considering HLA-B*5801 prescreening of patients at particularly high risk for severe adverse reaction to allopurinol (eg, Koreans with stage 3 or worse kidney disease and all patients of Han Chinese and Thai descent).

For CTGA, the guidelines recommend combination therapy with 1 XOI (allopurinol or febuxostat) and 1 uricosuric agent when target urate levels are not achieved. They advise using probenecid as an alternative first-line urate-lowering drug in the setting of contraindication or intolerance to at least 1 XOI (except in patients with creatinine clearance below 50 mL/minute). They also recommend pegloticase in patients with severe gout disease who do not respond to standard, appropriately dosed ULT.

“We provide guidance for dose-escalation of urate-lowering therapy for specific case scenarios of mild, moderate, and severe disease, including for patients with destructive joint disease that is chronic to their gout. These provide ways to assess the patient in an office setting on clinical findings alone, with serum uric acid. Pictorial representation of most severe patients should help identify who needs more intensive uric acid–lowering therapy,” Dr. Terkeltaub said.

Acute Gout Requires Prompt Treatment

Part 2 of the guidelines covers therapy and prophylactic anti-inflammatory treatment for acute gouty arthritis. These guidelines recommend initiating pharmacologic therapy within 24 hours of onset of acute gouty arthritis attack while continuing urate-lower therapy without interruption.

Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or oral colchicine are the recommended first-line treatment for acute gout, and combinations of these medications can be used for severe or unresponsive cases.

To prevent the acute gout flares that may accompany the early stages of ULT, the guidelines recommend oral colchicine or low-dose NSAIDs as long as there is no medical contraindication or lack of tolerance.

Dr. Terkeltaub advised caution with colchicine dosing. “One of the major problems in quality of care is that people were getting drowned in colchicine for acute gout. We assessed the evidence and decided to go with the [US Food and Drug Administration]-approved regimen of low-dose colchicine for early acute gout flare. That is a major recommendation. When people get drowned in high doses of colchicine for a long time for acute gout, the rate of adverse events is quite high.”

The recommendations were prepared during a 2-year project by an ACR task force panel that included 7 rheumatologists, 2 primary care physicians, a nephrologist, and a patient representative. The draft guidelines then went through 3 rounds of peer review, Dr. Terkeltaub said.

“I’d like to see better education of physicians and other primary caregivers, including nurse practitioners and physician assistants, and then better education of gout patients. If we only accomplish that, we’ll have accomplished a lot. There has been a systematic failure of both quality of care and patient education in gout,” Dr. Terkeltaub said.

Doug Campos-Outcalt, MD, scientific analyst for the American Academy of Family Physicians, reviewed the new guidelines for Medscape Medical News. Dr. Campos-Outcalt is chair of the Department of Family Medicine at the University of Arizona College of Medicine in Phoenix.

Dr. Campos-Outcalt said, “This is a reasonable, limited number of guidelines that are implementable. You don’t like to see guidelines that have 50 recommendations. The ACR guidelines also present, from a family physician perspective, no major changes in standard of care.” However, Dr. Campos-Outcalt suggested that a broader effort to disseminate the guidelines to primary care physicians will be needed because few of them regularly read the journal in which the guidelines appear.

Dr. Campos-Outcalt told Medscape Medical News that the guidelines seem reasonable but that before being influenced by them, he would like to take a closer look at the level of evidence each recommendation is based on. “We don’t like to see recommendations based on low-level evidence,” he said. Only about 20% of the ACR recommendations were based on top-quality “level A” evidence (supported by more than 1 randomized clinical trial or meta-analysis). About half of the recommendations were based on level C evidence (consensus opinion of experts, case studies, or standard of care).

Dr. Terkeltaub has received consultant fees from Takeda, Savient, Ardea, BioCryst, URL, Ajanta, Anadys Celgene, Isis and Prescription Solutions, and Novartis; has received grant support from the Veterans Affairs San Diego Healthcare System and the National Institutes of Health; and has served as a paid investment consultant for Leerink Swann, Medacorp, and Guidepoint. Dr. Campos-Outcalp has disclosed no relevant financial relationships.

Arthritis Care Res. 2012;64:1431-1446, 1447-1461. Part 1 abstract Part 2 abstract

Study Highlights

• New guidelines from the ACR offer updated recommendations on the management of hyperuricemia.
• Patient education regarding diet, lifestyle, treatment objectives, and management of comorbid conditions is a core therapeutic measure for gout and for hyperuricemia.
• The first-line pharmacological ULT in gout is XOI therapy with either allopurinol or febuxostat.
• Target serum urate level should be lower than 6 mg/dL, and often lower than 5 mg/dL, to maintain improvements in gout signs and symptoms.
• The starting dosage of allopurinol should not exceed 100 mg/day (or less in moderate to severe CKD). This should be gradually titrated upward.
• Even in patients with CKD, the maintenance dose of allopurinol can exceed 300 mg daily.
• Before starting allopurinol, rapid polymerase chain reaction–based HLA-B*5801 screening should be considered for subpopulations with elevated HLA-B*5801 allele frequency and with high risk for severe allopurinol hypersensitivity in HLA-B*5801-positive patients.
• These high-risk groups include Koreans with stage 3 or worse CKD and all persons of Han Chinese and Thai descent.
• When appropriate dosing of an XOI does not achieve the serum urate target, combination oral ULT with 1 XOI agent and 1 uricosuric agent is recommended.
• For patients with severe gout disease burden and lack of response to or intolerance of appropriately dosed oral ULT, pegloticase may be used.
• Updated recommendations for the management of acute gouty arthritis were also presented.
• Pharmacotherapy should be started within 24 hours of onset of an acute gouty arthritis attack.
• During an acute attack of gout, established pharmacologic ULT should be continued without interruption.
• Appropriate first-line therapy for acute gout includes NSAIDs, corticosteroids, or oral colchicine.
• For severe or refractory attacks, certain combinations of these drugs may be used.
• All patients with gout who are starting to receive ULT should receive pharmacologic anti-inflammatory prophylaxis.
• This should be continued if there is any clinical evidence of continuing gout disease activity and/or the serum urate target has not yet been reached.
• Except for patients with a lack of tolerance or medical contraindications, oral colchicine is an appropriate first-line choice for prophylaxis of gout attack and may be used with appropriate dose adjustment in patients with CKD or drug interactions.
• Except for patients with a lack of tolerance or medical contraindications, low-dose NSAIDs are appropriate for first-line prophylaxis of gout attack.

Clinical Implications

• According to the 2012 ACR guidelines, core therapy for management of gout and for hyperuricemia includes patient education about diet, lifestyle, treatment objectives, and management of comorbid conditions. First-line pharmacological ULT in gout is XOI therapy with either allopurinol or febuxostat to achieve a target serum urate level of less than 6 mg/dL, and often less than 5 mg/dL.

For an acute gouty arthritis attack, pharmacotherapy with NSAIDs, corticosteroids, or oral colchicine should be started within 24 hours of onset, and ULT should be continued without interruption. All patients with gout starting ULT should receive pharmacologic anti-inflammatory prophylaxis with oral colchicine or low-dose NSAIDs.