Results of a recent study in Arthritis & Rheumatology fail to clarify whether urate-lowering therapies may potentially reduce mortality risk in patients with gout.1 The study also underscores the fact that many physicians are not following the ACR guideline to help their patients achieve target serum urate levels. Partly because of this, it remains unclear whether patients meeting their serum urate goal may have a lowered mortality risk.
Background
Urate-lowering therapies, such as allopurinol, reduce gout flares by reducing serum urate levels. Ted Mikuls, MD, MSPH, is a professor of rheumatology at the University of Nebraska Medical Center in Omaha, Neb., and one author of the recent study. “There have been intriguing reports suggesting that urate lowering therapy in gout may provide benefits well beyond the joints, such as potentially protecting patients against comorbid conditions that are common in this population,” he notes.
In multiple studies, hyperuricemia has been associated with increased vascular inflammation and decreased endothelial function, both potential markers for cardiovascular risk. Conversely, improved endothelial function and reduced blood pressure have been associated with urate-lowering therapies, such as allopurinol. At least two earlier studies demonstrated that patients with hyperuricemia and gout treated with allopurinol showed a modestly reduced risk of mortality compared with untreated patients.2,3
Dr. Mikuls explains the mechanisms underpinning this potential effect are not well understood. “Hypotheses center around the direct effects that urate may have on vascular health and a potential antioxidant role for medicines, such as allopurinol. Reactive oxygen species, implicated in cardiovascular and other inflammatory disease states, are produced in the process of uric acid synthesis—a process that is directly targeted by agents such as allopurinol and febuxostat.”
Under the current ACR guideline, gout patients should ideally be started on a low dose of allopurinol (equal to or less than 100 mg daily), with slow titration upward to achieve a serum urate level less than 6 mg/dL.
The New Study
In their recent study, Dr. Mikuls and colleagues wanted to assess whether a relationship exists between mortality and the dose of allopurinol, the most commonly used urate-lowering therapy. Under the current ACR guideline, gout patients should ideally be started on a low dose of allopurinol (equal to or less than 100 mg daily), with slow titration upward to achieve a serum urate level less than 6 mg/dL (and less than 5 mg/dL in patients with tophaceous gout). The guideline also recommends regular serum urate monitoring during initial drug titration, as well as less frequent measurement once the serum urate target is met.4
Not all patients are optimally treated via dose-escalation therapy, and many instead receive static fixed-dose treatments with allopurinol or other drugs. This gave the researchers a chance to investigate whether patients treated with dose escalation may have improved mortality outcomes.