Gradual dose escalation of allopurinol achieved target serum urate levels without causing excess adverse effects in patients with gout who tolerated but responded inadequately to creatinine clearance–based dosing, including in patients with chronic kidney disease, investigators reported in Annals of the Rheumatic Diseases.

The study is the first randomized, controlled trial to examine treat-to-target allopurinol dose escalation in gout. “We believe this approach can be undertaken in all patients who tolerate allopurinol,” lead investigator Lisa Stamp, MD, said in an interview. However, it is important to monitor kidney and liver function.”

Managing serum urate levels is the cornerstone of treating gout, and international guidelines recommend targets of less than 6 mg/dL, or less than 5 mg/dL in the presence of tophi. Allopurinol is the most commonly used urate-lowering therapy worldwide, but concerns about adverse effects have inspired debates about dosing strategies for years, noted Dr. Stamp of the University of Otago, Christchurch, New Zealand. For example, the American College of Rheumatology recommends gradual, treat-to-target dose escalation of allopurinol regardless of renal status, the European League Against Rheumatism (EULAR) suggests creatinine clearance–based dosing in renally impaired patients, and the American College of Physicians (ACP) advocates for corticosteroids, nonsteroidal anti-inflammatory drugs, and colchicine over urate-lowering therapy.

To help settle these debates, Dr. Stamp and her associates recruited 183 patients with gout whose serum urate levels averaged 7.15 mg/dL (standard deviation, 1.6 mg/dL) despite at least 1 month of at least a creatinine clearance–based allopurinol dose (average, 269 mg/day). For the next 12 months, patients either continued this dose or increased it monthly until serum urate fell below 6 mg/dL (Ann Rheum Dis. 2017 March 17. doi: 10.1136/annrheumdis-2016-210872).

At month 12, 69% of dose-escalation patients and 32% of controls reached this target (P less than .001; odds ratio, 4.3; 95% confidence interval, 2.4-7.9). Serum urate levels dropped by a mean of 1.5 mg/dL with dose escalation and by 0.34 mg/dL in controls (P less than .001). Thus, dose escalation cut serum urate levels by an additional 1.2 mg/dL (95% CI, 0.67-1.5 mg/dL; P less than .001). The average final daily allopurinol dose was 413 mg (range, 0-900 mg) with dose escalation and 288 mg (0-600 mg) for controls.

Gradually ramping up the dose of allopurinol did not significantly increase the risk of rash or other adverse events, compared with continuing at the lower dose, although the study was not powered to detect the rare allopurinol hypersensitivity syndrome, Dr. Stamp said. The only serious treatment-related adverse event was increased international normalized ratio (INR) in a dose-escalation patient who received warfarin after elective mitral valve replacement. There were five deaths in each study arm, none of which were considered treatment related.

Notably, renal function measures did not differ between arms. “There has been long-standing concern about whether it is safe to escalate allopurinol doses in persons with chronic kidney disease,” said Kenneth Saag, MD, of the University of Alabama at Birmingham, who was not involved in the trial. “This study contributes to the limited literature supporting the practice of treating to serum urate targets, even in patients with underlying kidney disease.”

Fully 52% of trial participants had chronic kidney disease, and 44% had tophi. “Thus, our population is representative of people with gout, represents real-life clinical practice, and the results are generalizable to other gout populations,” the investigators wrote.

The findings support the ACR recommendation to gradually titrate urate-lowering therapy while performing close laboratory monitoring, said Tuhina Neogi, MD, of Boston University, who was not involved in the study. This approach is “efficacious and relatively safe for patients who have already tolerated lower doses of allopurinol, but have not yet achieved their serum urate target,” she said. “This is akin to finding the right regimen and titrating doses of medications for patients with diabetes or hypertension in a patient-centered manner.”

Dr. Saag agreed. “Rheumatologists and other physicians who commonly treat gout should treat to target in all their patients,” he said. “In patients with chronic kidney disease, providers should more slowly escalate the allopurinol dose, as slowly as by 50 mg every month.”

Patients in both groups developed mild increases in liver function tests, and a few in the dose escalation group developed more pronounced rises in gamma glutamyl transferase (GGT), as previously reported in the LASSO trial (Semin Arthritis Rheum. 2015 Oct;45[2]:174-83). Allopurinol has been linked to liver enzyme abnormalities, and the GGT finding is of unclear significance, but laboratory monitoring is important, Dr. Neogi said. If primary care providers who treat gout cannot routinely measure serum urate and other relevant laboratory measures, they should consider referring patients to a rheumatologist, she added.

Gradual dose escalation meant that patients did not reach the serum urate target until month 7, Dr. Neogi added. “Since the trial was 12 months long, the time over which serum urate was less than 6 mg/dL was not long enough to demonstrate the benefits on flares and tophi,” she said. The open-label extension phase of the trial should shed more insight on these important questions, she added.

For now, providers should know that “patients with gout are not well served if their serum urate levels remain elevated, as that means they are at ongoing risk for flares and tophi,” Dr. Neogi said. “This trial provides evidence and further support for the feasibility, efficacy, and relative safety of escalating allopurinol beyond creatinine-clearance dosing to achieve this important and critical goal for gout management.”

The Health Research Council of New Zealand funded the study. Dr. Stamp and two coinvestigators disclosed grant support from the Health Research Council of New Zealand. Dr. Stamp also disclosed grants from Ardea Biosciences and the Health Research Council of New Zealand outside the submitted work, and her coinvestigators disclosed grants and personal fees from AstraZeneca, Ardea Biosciences, Takeda, and several other pharmaceutical companies. Dr. Neogi had no disclosures. Dr. Saag has received meal compensation from Eli Lilly.

First treat-to-target gout trial supports allopurinol dose escalation