FROM ANNALS OF THE RHEUMATIC DISEASES

In the treatment of gout, dose escalation of allopurinol to achieve target serum urate levels at or below 6 mg/dL appears safe and effective, even among patients with chronic kidney disease, according to a new open-label, extension study. The results build on a 12-month study that had shown safety and efficacy of the strategy.

The new results compared adverse events and serum urate levels between patients who stayed at increased allopurinol doses after achieving target serum urate levels, and control patients who were switched to a strategy of treating to target.

A total of 52% of the patients in the study had chronic kidney disease, making the study population representative of gout patients. “Slow allopurinol dose escalation is effective and generally well tolerated, even in people with kidney impairment,” Lisa Stamp, MBChB, PhD, said in an interview. Dr. Stamp is professor of medicine at University of Otago in Christchurch, New Zealand, and the lead author on the paper reporting the open-label, extension study ( Ann Rheum Dis. 2017 Aug 22. doi: 10.1136/annrheumdis-2017-211873 ).

Dr. Stamp did emphasize the need to monitor liver and kidney function, as well as for rashes.

Allopurinol is approved at doses as high as 800 mg/day in the United States, and 900 mg/day in Europe, but most physicians rarely exceed 300 mg/day for fear of side effects. Existing guidelines and recommendations offer different opinions. The European League Against Rheumatism (EULAR) recommends switching to another urate-lowering therapy if the maximum dose adjusted to creatinine clearance (CrCl) isn’t effective, while the American College of Rheumatology recommends gradual dose escalation (DE) beyond CrCl-based doses, even in patients with chronic kidney disease.

The earlier study included 183 patients who had failed to achieve serum urate target levels at CrCl dose, which is intended to avoid allopurinol hypersensitivity syndrome and other potential adverse events. The short-term study results favored the DE approach. At 1 year, there was no difference in adverse events between the 93 control subjects and the 90 DE subjects. The DE group experienced an average serum urate reduction of 1.5 mg/dL, compared with 0.35 mg/dL in the control group (P less than .001). Overall, 32% of controls and 69% of the dose escalation group had achieved serum urate of 6.0 mg/dL or less.

In the extension study, subjects in the control group were switched to a strategy of dose escalation (control/DE), while the patients in the original treatment group remained at their existing allopurinol doses (DE/DE). Those who switched had a mean reduction in serum urate of 1.1 mg/dL, compared with an increase of 0.1 mg/dL in the DE/DE group (P less than .001).

From baseline to month 24, the control/DE group experienced a change in serum urate from 7.13 mg/dL to 5.7 mg/dL, while the DE/DE group experienced a change from 7.18 mg/dL to 5.4 mg/dL.

Both groups had a significant reduction in gout flares, but there was no difference in flare reduction between the two groups at 24 months.

Of those with a tophus at baseline, 6 (16%) of 37 of the control/DE group and 4 (13%) of 31 of the DE/DE group had complete resolution of all tophi between months 12 and 24. Measurable tophi completely resolved between baseline and 24 months in the same percentage of patients (29%) in each group. Tophus size decline significantly overall in both groups together, and there was no difference between the randomized groups.

In the control/DE group, there were 38 serious adverse events in 14 patients, compared with 33 serious adverse events in 22 patients in the DE/DE group. None of the serious adverse events were believed to be related to allopurinol. There were four deaths in the control/DE group and three in the DE/DE group between months 12 and 24, but none of the deaths were believed to be related to allopurinol.

“It is common that people don’t respond to allopurinol at doses based on kidney function and then the dose is not increased. This should give prescribers more confidence to increase the dose,” Dr. Stamp said.

The Health Research Council of New Zealand funded the study. Dr. Stamp has received grants from Ardea Biosciences. One coauthor reported receiving grants and personal fees from AstraZeneca and Ardea Biosciences; personal fees from Takeda, Teijin, and Menarini; grants from Fonterra; and personal fees from Pfizer, Crealta, and Cymabay.

rhnews@frontlinemedcom.com

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