Q&A: Treatments for Gout

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Robert Terkeltaub, M.D.

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?

Have any new treatments been approved since the guidelines were written?

In the United States, beyond the lesinurad approval and then dropout from marketing, there is nothing new yet, other than a liquid formulation of colchicine to improve titrated dosing. Canakinumab was approved in Europe for gout. A good read is the article by Dan Solomon and colleagues, who showed significant reductions in rates of gout attacks with canakinumab without any changes to baseline serum uric acid levels. This same canakinumab program has had a broader reach, with observed reductions in cardiovascular events, a slower rate to needing total hip replacement for osteoarthritis, and decreased incidence of new lung cancer-there’s just a tremendous amount of new information from the CANTOS study.

Since 2012, has focus of current research into gout changed?

Yes, I think people are really looking at comorbidities differently and trying to understand whether managing gout and hyperuricemia in particular can have a positive impact on the outcome of comorbidities, including the progression to chronic kidney disease and the incidence of cardiovascular events. To date, research has not been conclusive due to lack of randomized clinical trials.

Do you find, in retrospect, that the guidelines should have been written differently in any way?

I think the 2012 ACR guidelines were sound given the information present at the time. The guidance on treat to target urate-lowering in different case scenarios, treatment of acute gout flares, and on preventative measures using HLA B*5801 testing in high risk groups to limit severe allopurinol hypersensitivity syndrome, have held up very well in the time frame where added evidence has emerged. The largest issue is discordance between primary care and rheumatology in perceptions and treatment approaches to gout. If we had been required by ACR to use a different methodology, we could have also taken more into account patient preferences and the influence primary care has on that.

The most recent studies including the trial from Nottingham by Doherty in The Lancet and a trial by Nicola Dalbeth show that if you go long enough with urate-lowering treat to target, you can decrease flares and also improve MRI scores for synovitis. And that is important information that has come out in the last few years.

REFERENCES

1.  Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology Guidelines for Management of Gout Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia. Arthritis Care Res (Hoboken) 2012;64(10):1431-46. doi: 10.1002/acr.21772.

2. Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2018;391:319-328. doi: 10.1016/S0140-6736(17)32814-3.

3. McWherter C, Choi YJ, Serrano RL, et al. Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMP-activated protein kinase (AMPK) signaling. Arthritis Res Ther 2018;20(1):204. doi: 10.1186/s13075-018-1699-4.

4.  Solomon DH, Glynn RJ, MacFadyen JG, et al. Relationship of Interleukin-1β Blockade With Incident Gout and Serum Uric Acid Levels: Exploratory Analysis of a Randomized Controlled Trial.  Ann Intern Med 2018 Oct 16;169(8):535-542. doi: 10.7326/M18-1167.

5. Dhorepatil A, Ball S, Ghosh RK, Kondapaneni M, Lavie CJ. Canakinumab: Promises and Future in Cardiometabolic Diseases and Malignancy. Am J Med 2019;132:312-324. doi: 10.1016/j.amjmed.2018.10.013.

6.  Doherty M, Jenkins W, Richardson H, et al. Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial. Lancet 2018 Oct 20;392(10156):1403-1412. doi: 10.1016/S0140-6736(18)32158-5.

7. Dalbeth N, Saag KG, Palmer WE, Choi HK, Hunt B, MacDonald PA, Thienel U, Gunawardhana L. Effects of Febuxostat in Early Gout: A Randomized, Double-Blind, Placebo-Controlled Study. Arthritis Rheumatol. 2017 Dec;69(12):2386-2395. doi:10.1002/art.40233.