Understanding the Role of Uric Acid in Gout

In contrast, injection with the amorphous, non-crystallized solution of sodium urate produced very little inflammatory response, one totally absent in the majority of participants. This was consistent with earlier reports from the 1920s, which had failed to produce an inflammatory reaction using a similar preparation.²

“The detailed sequence of events that occurs in the pathogenesis of acute gouty arthritis is yet to be demonstrated experimentally,” the authors noted. “We would propose that in order for acute gouty arthritis to develop, the following conditions must be met: 1) Needle-like crystals of sodium urate must be present. 2) An inflammatory reaction against sodium urate crystals must be elicited.”²

These two papers and other closely related work at the time helped change the paradigm of gout treatment relatively quickly.^1,2 Clinical evidence followed rapidly, which supported allopurinol’s use in gout as a urate-lowering therapy.⁸ The drug was approved for use in the U.S. in 1966, after which it soon became widely prescribed. And in the ACR’s most recent 2020 gout guideline, it is still a cornerstone of preventive gout treatment.⁹

Present Day

In the intervening years, we have learned quite a bit about specifically how urate crystals help initiate and sustain gouty inflammation through stimulating cellular inflammatory responses and how they also can contribute to long-term inflammation and chronic gouty synovitis. We’ve also learned about some of the local factors hypothesized to play a role in the crystallization of monosodium urate from the blood.¹⁰ But many questions remain.

Ted R. Mikuls, MD, MSPH, the Stokes-Shackleford Professor of Rheumatology and vice chair for research at the University of Nebraska Medical Center, Omaha, was one of the authors of the “2020 American College of Rheumatology Guideline for the Management of Gout.”⁹

Dr. Mikuls

“Questions that were raised in these articles [from 1962] are still being addressed in our gout guideline, which is kind of amazing,” he notes. “To his credit, Garrod was already saying uric acid was a risk factor for gout flares 100 years before these articles were published in the early 1960s. Despite this, the precise links between hyperuricemia and gout flare are still not completely known, but perhaps history tells us not knowing something 60 years later isn’t so bad.”

Seegmiller et al. noted that, at the time, no consistent relationship had been found between the amounts of uric acid in the blood or urine and acute attacks or remissions; this was one of arguments made by some against a role for serum urate in acute gouty arthritis.