– Management of difficult-to-treat gout calls for a familiar therapeutic goal: lowering the serum urate level to less than 6 mg/dL. Underused treatment approaches, such as escalating the dose of allopurinol or adding probenecid, can help almost all patients reach this target, said Brian F. Mandell, MD, PhD, professor of rheumatic and immunologic disease at the Cleveland Clinic.

Dr. Brian F. Mandell, professor of rheumatic and immunologic disease at Cleveland Clinic Jake Remaly/MDedge News

Dr. Brian F. Mandell

“The major reason for treatment resistance has nothing to do with the drugs not working,” Dr. Mandell said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “And it does not even have to do ... with patient compliance. It is actually due to us and lack of appropriate monitoring and dosing of the medicines. We do not push the dose up.”

The urate saturation point in physiologic fluids with protein is about 6.8 mg/dL. Physicians and investigators have used 6 mg/dL as a target serum urate level in patients with gout for decades. “The bottom line is lowering the serum urate for 12 months reduces gout flares. There is absolutely no reason to question the physicochemical effect of lowering serum urate and dissolving the deposits and ultimately reducing attacks,” Dr. Mandell said. Urate lowering therapy takes time to reduce flare frequency and tophi, however. “It does not happen in 6 months in everyone,” he said.

Addressing intolerance and undertreatment

Clinicians may encounter various challenges when managing patients with gout. In cases of resistant gout, the target serum urate level may not be reached easily. At first, gout attacks and tophi may persist after levels decrease to less than 6 mg/dL. Complicated gout may occur when comorbidities limit treatment options or when tophi cause dramatic mechanical dysfunction.

“There is one way to manage all of these [scenarios], and that is to lower the serum urate,” Dr. Mandell said. “That is the management approach for chronic gout.”

Because this approach does not produce quick results, patients with limited life expectancy may not be appropriate candidates, although they still may benefit from prophylaxis against gout attacks, treatment of attacks, and surgery, he said.

Intolerance to a xanthine oxidase inhibitor is one potential treatment obstacle. If allopurinol causes gastrointestinal adverse effects or hypersensitivity reactions, switching to febuxostat (Uloric) may overcome this problem. Desensitizing patients with a mild allergy to allopurinol is another possible tactic. In addition, treating patients with a uricosuric such as probenecid as monotherapy or in combination with a xanthine oxidase inhibitor may help, Dr. Mandell said.

Increasing the dose of the xanthine oxidase inhibitor beyond the maximal dose listed by the Food and Drug Administration – 800 mg for allopurinol or 80 mg for febuxostat – is an option, Dr. Mandell said. In Europe, the maximal dose for allopurinol is 900 mg, and physicians have clinical experience pushing the dose of allopurinol to greater than 1,000 mg in rare instances, he noted. “There is not a dose-limiting toxicity to allopurinol,” he said. There is a bioavailability issue, however, and splitting the dose at doses greater than 300 mg probably is warranted, he added.

If these approaches fail to lower the serum urate level to below 6 mg/dL, rigid dietary changes may be a next step. Adjusting other medications also may be an option. For example, physicians might weigh using losartan as a blood pressure medicine instead of a thiazide.

Finally, physicians can debulk urate deposits with pegloticase. “Dramatically lower the body load of serum urate, and then come back and use your traditional drugs,” he said. After treatment with enzyme replacement therapy, patients almost invariably require lower doses of allopurinol or febuxostat, he said.

Also, in severe cases when the time necessary for traditional urate-lowering therapy to work may not make it the most appropriate route, aggressive therapy with pegloticase may be warranted, Dr. Mandell said.

The FAST trial

The ongoing Febuxostat versus Allopurinol Streamlined Trial (FAST) has provided data about undertreatment with allopurinol and the effects of increasing the dose. The prospective, randomized, open-label study is comparing the cardiovascular safety of allopurinol and febuxostat in patients with symptomatic hyperuricemia. It enrolled patients who were on allopurinol in normal clinical practice. To enter, patients had to have a serum urate level below 6 mg/dL. If patients’ levels were not below 6 mg/dL, investigators increased the dose of allopurinol to try to reach that target (Semin Arthritis Rheum. 2014 Aug;44[1]:25-30).

“Basically, this part of the study is a dose-escalation trial for efficacy,” Dr. Mandell said. “Of 400 patients taking allopurinol, 36% still had a urate above 6 [mg/dL]. ... If you uptitrated the dose, 97% of people were able to get to 6. Uptitration works. You just actually need to do it.” The results indicate that a 100-mg increase in allopurinol dose decreases serum urate by about 1 mg/dL.

Allopurinol hypersensitivity and chronic kidney disease

Patients with chronic kidney disease may have increased risk of allopurinol hypersensitivity. For a while, researchers postulated that oxypurinol, the active component of allopurinol, built up and caused toxicity in some patients with chronic kidney disease. As a result, researchers suggested adjusting the dose for patients with chronic kidney disease.

One problem with this approach is that only about 20% of patients with chronic kidney disease would reach the treatment target with the suggested doses, Dr. Mandell said. “You are exposing them to some potential risk with a very low chance of actually getting any efficacy at all,” he said.

Furthermore, allopurinol hypersensitivity behaves like an allergic reaction, not a toxicity reaction. Small studies suggest that starting allopurinol at a low dose and slowly increasing the dose may be safe in patients with chronic kidney disease. Allopurinol is not nephrotoxic, and some data indicate that it may be nephroprotective, he said.

Dr. Mandell reported that in recent years he was a clinical investigator and consultant for Horizon and a consultant for Takeda and Ardea/AstraZeneca/Ironwood.

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