Robert Terkeltaub M.D., the rheumatology section chief of the VA Medical Center in San Diego and the corresponding author of the first-ever treatment guidelines for gout by the American College of Rheumatology, recently spoke with Rheumatology Network about updates in gout treatment.
The therapies for hyperuricemia have changed since the guidelines were issued in 2012.1 Can you summarize what the first-line therapies should be at this time?
We would say that allopurinol should be the first choice therapy, given the uncertainty to febuxostat relative to allopurinol with respect to cardiovascular signals. Second-line therapy would be substituting febuxostat. Third-line is adding uricosuric therapy to allopurinol or febuxostat. However, with available uricosurics, this has not been well studied other than for lesinurad. Though lesinurad was approved by the FDA a few years ago, it was taken off the market in the United States in February of 2019, so we’re back to where we started.
The fourth line is recombinant uricase therapy with pegloticase. There is ongoing work on optimizing that recombinant uricase strategy by potentially adding on immune suppression, specifically with methotrexate, mycophenolate, or azathioprine, something that’s in multiple clinical trials right now.
Advances have been slower in terms of treating acute gout flares. You have the same options that we had in 2012. There is renewed interest into the potential of Interleukin-1 antagonism for treatment and prophylaxis of acute gout flares. This is partly due to the CANTOS trial2 results, whereby canakinumab, given every three months, was associated with less new incident gout, or new gout flares in those with existing gout. This field is under active investigation, including with anakinra in phase II trial work, and orally available NLRP3 inhibition in development.
What about therapeutic targets? Have they changed?
Beyond novel means of directly or indirectly targeting the NLRP3 inflammasome with orally bioavailable molecules, there are multiple other targets. Arhalofenate (a partial PPARgamma agonist and also a uricosuric that works to suppress gouty inflammation in part by stimulating AMP Kinase activity and preserving mitochondrial function), successfully completed phase II trial work with decreased gout flare frequency reported. However, advancement into clinical trials has not yet happened for many other compounds acting on newer and older targets for gouty inflammation.
Next page: New treatments?