Intensive urate target hard to achieve with oral ULT, fails to improve erosion in gout
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A more intensive serum urate target is difficult to achieve with oral urate-lowering therapy, compared with a standard target of 0.3 mmol/L, and fails to improve bone erosion scores in patients with erosive gout, according to a study.
“In laboratory studies, [monosodium urate (MSU)] crystals have a profound inhibitory effect on function and viability of bone-forming osteoblasts and osteocytes,” Nicola Dalbeth, MD, FRACP, professor of medicine at the University of Auckland, in New Zealand, and colleagues wrote in Arthritis & Rheumatology. “Collectively, these findings indicate that dissolution of MSU crystals may be an important strategy to prevent or heal bone erosion in gout.
“There is a clinical need to identify more feasible strategies for intensive urate-lowering therapy using oral medications, and to determine whether these strategies allow for structural improvement in people with gout,” they added.
To determine whether intensive serum-urate lowering resulted in improved bone erosion scores in erosive gout, Dalbeth and colleagues conducted a 2-year, double-blind, randomized controlled trial.. The study included 104 participants with erosive gout receiving oral urate-lowering therapy (ULT), with serum urate equal to or greater than 0.3mmol/L. Participants were randomized to either an intensive target — defined as a serum urate below 0.2mmol/L — or the standard target — below 0.3mmol/L, as recommended in rheumatology society guidelines. Researchers used maximum approved doses of allopurinol, probenecid, febuxostat and benzbromarone to titrate oral ULT to target.
The primary endpoint was change from baseline in total computer tomography bone erosion score. Key secondary endpoints included mean serum urate concentration, percentage of participants with allocated serum urate target achieved, change from baseline in plain radiographic damage score and frequency of adverse events.
According to the researchers, serum urate levels were significantly lower in the intensive-target group, compared with those held to the standard target (P = .002). However, only 62% of participants in the intensive target group achieved target serum urate levels at year 2, compared with 83% of those within the standard group (P < .05). The intensive target group also used more combination therapy (P = .0004) and required higher doses of allopurinol, with a mean dose of 746 mg per day versus 496 mg per day in the standard group (P < .001). Both groups achieved small increases in bone erosion scores over 2 years, with no between-group difference (P = .20).
Outcome domains, including gout flares, tophus, pain, patient global assessment, health-related quality of life and activity limitation, improved in both groups, with no observed between-group differences. Both groups also demonstrated similar rates of adverse events and serious adverse events.
“Intensive serum urate lowering to a target <0.20mmol/L is difficult to achieve with oral urate-lowering therapy, leads to high medication burden and does not improve bone erosion scores in people with erosive gout,” Dalbeth and colleagues wrote. “When using oral urate-lowering therapy, a serum urate target <0.30mmol/L is sufficient to achieve clinical benefit in this patient group.”
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Charles Pritchard, MD, FACP, FACR, RhMSUS
The goal of this study was to see if intensive lowering of serum urate in patients with baseline high serum urate and erosive disease would limit erosive damage, and perhaps allow for erosion healing. This was seen in a small longitudinal pegloticase study referenced in the article.
The New Zealand researchers performed a double-blind, controlled trial that included 104 patients with longstanding active gout and randomized them into two groups — a standard-target group where serum urate was lowered to less than 0.3 mmol/L (5mg/dL), and an intensive-target group lowering to less than 0.2 mmole/L (3.6mg/dL) — and followed them for 2 years. The primary endpoint was total CT erosion score of the feet, measured at baseline and years 1 and 2. Secondary endpoints included mean serum urate concentration, percent of patients achieving the serum urate target, change in plain radiograph score and many others.
The patients were given a standardized protocol of medications, including allopurinol that was increased to a maximum of 900 mg daily, probenecid maximum 1 g, febuxostat maximum 120 mg and benzbromarone (not approved in the United States) to reach the intended serum urate targets.
At the 2-year study visit, the mean dose of allopurinol was 746 mg per day in the intensive group and 497 mg per day in the standard group. Only 62% of the intensive group and 83% of the standard group achieved the serum urate targets.
At 2 years, there was no difference in the CT erosions scores. In fact, both groups had minor worsening. There was also no significant difference in the secondary endpoints, either including gout flares or side effects. I would have liked to see a comparison of the erosion scores in the subgroup that achieved the intensive serum urate level, compared to the subgroup that reached the goal in the standard group.
So, what is important for us?
First, higher doses of allopurinol were not associated with increasing side effects. Achieving very low serum urate is hard and requires more drugs and higher cost. Erosions persisted, and perhaps worsened, despite lower serum urates, but note that IV medication pegloticase causes much lower serum urate levels that may be associated with some healing, but these levels may be impossible to achieve with oral medications.
An implication is that once gouty damage has happened, the processes driving the damage may persist. Prevention of gouty erosions with early aggressive treatment may be an important strategy.
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The results of the study performed by Dalbeth and colleagues on whether intensive lowering of serum uric acid levels will reduce bone erosion is very informative. It helps gain insight into the fact that despite high doses of urate lowering treatment such as xanthine inhibitors, it is still difficult to achieve serum uric acid levels below 5.4 mg/dL (0.3mmol/L).
The goal for patients in the intensive treatment group was 3.6 mg/dL (0.2mmol/L), which did not reduce bone erosion. This information is helpful because the medications used to lower urate levels have potential side effects that can be dose dependent. When treating patients, benefit vs. risk is a key consideration. This study shows that more is not better.
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