The use of colchicine prophylaxis during the process of up-titrating allopurinol slowly to reach target serum urate levels for patients with gout proved necessary to reduce the risk of flares in a randomized, double-blind, placebo-controlled noninferiority trial conducted by researchers in New Zealand.
Use of colchicine led to fewer flares during the first 6 months after initiating treatment with allopurinol, but when colchicine and placebo were stopped at 6 months, the number of flares rose, and there was no overall difference in the average number of flares between the placebo and colchicine groups over 12 months.
“Gout flares are common when starting urate-lowering therapy, although may be less frequent using the newer allopurinol ‘start-low, go-slow’ dose escalation strategy,” Lisa Stamp, MBChB, PhD, of the University of Otago, Christchurch, New Zealand, and colleagues write in Annals of the Rheumatic Diseases. “This study was undertaken to determine whether colchicine prophylaxis is required with the more gradual dose escalation of allopurinol to achieve target serum urate.”
The study was published online in the BMJ.
The researchers randomly assigned 200 participants to receive colchicine 0.5 mg daily or placebo. At the same time, allopurinol 50 mg daily was initially given to those with an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2, and 100 mg daily was given to those with eGFR greater than or equal to 60 mL/min/1.73 m2; doses were increased monthly by 50 mg daily for those with eGFR less than 60 and by 100 mg daily for those with eGFR greater than or equal to 60 until the target urate level of less than 0.36 mmol/L (about < 6 mg/dL) was achieved. In total, 93% of patients were male, and 69% were White. Patients were enrolled from February 2019 through December 2021. The final study visit was in January 2023. Researchers tracked the mean number of patient-reported gout flares per month with a prespecified noninferiority margin of 0.12 gout flares/month. After the first 6 months, colchicine and placebo were stopped, and researchers continued to track outcomes up to month 12.
From baseline to 6 months, there were more gout flares per month in the placebo group (0.61) than in the colchicine group (0.35). From 6 to 12 months, there were more gout flares among patients who previously received colchicine, compared with those who received placebo. While 22.8% of patients in the colchicine group experienced flares at month 6, the following month – after stopping the drug – 41.2% experienced flares. For comparison, 30.8% of the placebo group experienced flares at month 6, and in month 7, 23.5% experienced flares. The spike in flares in the colchicine group began to decline after month 9.
Among the colchicine and placebo groups, reductions in serum urate at 6 and 12 months were similar, and mean serum urate levels declined below 0.36 mmol/L at 4 months and thereafter. Both groups reached a mean allopurinol dose of 280 mg/d at 6 months.
It is not clear what caused this rise in flares in the colchicine group, Stamp noted in an email to this news organization. Overall, there was no difference in the average number of gout flares between either group over the entire 12-month study period.
The study findings make a case for continuing colchicine prophylaxis considerably beyond the point at which the target urate serum level is reached, said Robert Terkeltaub, MD, professor emeritus of medicine in the division of rheumatology, allergy, and immunology at the University of California, San Diego. He was not involved with the research.
“The flare burden with this really conservative allopurinol dosing regimen is really stunning,” he said in an interview. Despite this “start low and go slow” strategy, flares remained a problem, he noted. “It argues that you need at least a year to get out of the woods and have a lower flare burden, even if colchicine prophylaxis is used for the first 6 months.”
The current standard of care in rheumatology for gout treatment includes flare prophylaxis when starting urate-lowering therapy. In daily practice, “this can (and often does) mean continuing flare prophylaxis for longer than the recommended minimum duration from [established] gout treatment guidelines for an individual patient,” explained Elizabeth R. Graef, DO, assistant professor of medicine at Boston University and a rheumatologist at Boston Medical Center.
There are many different factors to consider when determining a patient’s flare risk beyond serum urate levels and date of last flare, she noted. Flare severity, concurrent diuretic use, dose changes, tophus count, and additional health conditions such as diabetes can all contribute to individual patient outcomes.
“Gout is an erosive arthritis, and every time someone flares, there’s a risk of permanent erosive damage, so I tend to be more aggressive with prophylaxis,” she said.
The study was funded by the Health Research Council of New Zealand. Dr. Graef disclosed no relevant financial relationships. Dr. Terkeltaub consults for LG Chem, Fortress/Urica, Selecta Biosciences, Horizon Therapeutics, Atom Biosciences, Acquist Therapeutics, Generate Biomedicines, AstraZeneca, and Synlogic. Dr. Terkeltaub serves as the nonsalaried president of the Gout, Hyperuricemia, and Crystal-Associated Disease Network, which annually receives unrestricted arms-length grant support from pharma donors.
A version of this article first appeared on Medscape.com.