Subclinical Inflammation in Intercritical Gout

Hi, my name is Ted Michaels. I'm the Stoke Shackleford Professor of Rheumatology at the University of Nebraska Medical Center in Omaha, Nebraska. And I'm here today, I've been asked to talk to you about systemic inflammation in gout with a particular focus on subclinical inflammation, particularly in the setting of intercritical or asymptomatic disease.

Inflammation is obvious in gout flares. We see it every day. We see it routinely in rheumatology clinics and in our consult wards. We see gout flares characterized by the cardinal signs of inflammation, joint swelling, erythema, exquisite joint tenderness to the point where patients are often non-ambulatory with their gout flares. We see consults on wards where patients often present with low-grade fever and are not surprisingly misdiagnosed as having infection or septic arthritis.

In gout flares, we see synovial fluid aspirates done diagnostically that are highly inflammatory with leukocyte total leukocyte counts that are overwhelmingly neutrophil predominant and that sometimes exceed thresholds used to discriminate septic etiologies.

Over the last few decades, we've learned a lot about what drives inflammation in gout flares. We know now that monosodium urate crystals bind to leukocytes, bind inflammatory cells, and that leads to the assembly and activation of the NLRP3 inflammasome, which in turn activates caspase-1, and caspase-1 cleaves pro-IL-1 beta and turns that on, forms the active form of IL-1 beta, with downstream effects that lead to the release of other pro-inflammatory cytokines and the accumulation of white blood cells, leukocytes, etc.

We also know that there's cell priming that happens, that these cells are primed for responses to monosodium urate crystals with TLR agonists that include things like long-chain free fatty acids and particularly palmitic acid, and perhaps even hyperuricemia. Although those studies showing that serum urate may act as a cell primer have been done with superphysiologic concentrations of urate. So the relevance of that remains a bit unclear.

So we know the burden of systemic inflammation posed by an acute gout flare may have consequences that go beyond the joint. There's an interesting study published in JAMA in 2022 by a group in the UK using the Clinical Practice Research Database showing that gout flares were temporally — at least temporally — related to the risk of cardiovascular events, suggesting that that systemic inflammation may be a driver of these poor outcomes in our patients with gout.

But what do we know about systemic inflammation that might persist between flares during asymptomatic or intercritical periods? We understand based on advanced imaging studies that even at the time of presentation, gout is a chronic disease. It's not an acute disease. It's a chronic disease. And with this chronicity in mind, is it possible that systemic inflammation that's so evident during acute flares might also be present and persist between flares during these asymptomatic periods?

Our group and others have looked at this question, and in a study that we published last year, we used biosamples actually from the STOP-Gout study. The STOP-Gout study was a large study examining treat-to-target urate-lowering therapy. But we looked at baseline samples and we were able to obtain age- and sex-matched controls, and we took those biosamples and asked the simple question: are there differences in inflammation in those biosamples, those serum biosamples, that are evident?

We looked at 20 different pro-inflammatory cytokines and chemokines based on a literature review. And indeed, we showed at baseline that these patients, largely asymptomatic at the time of study enrollment, had several clusters of pro-inflammatory cytokines that were increased among gout patients. And those clusters included cytokines such as lactoferrin, myeloperoxidase — which we know is a mediator of neutrophil-mediated inflammation — IL-8, IL-18, IL-1 and its receptor antagonist, calprotectin, and then adipokines such as FGF-21, adiponectin, and leptin. And these differences that we saw that were so evident in gout were independent of other factors, not only age and sex, but independent of comorbid conditions and BMI.

So what are the determinants of subclinical inflammation? Not surprisingly, there's been lots of speculation around the possible role of hyperuricemia acting as a risk for this. We know that hyperuricemia is a necessary risk factor in gout development. But might it have a role in perpetuating subclinical inflammation in gout? And if true, then it would follow that effective urate-lowering therapy — lowering uric acid — could also play a role as an anti-inflammatory strategy in these patients.

In the STOP-Gout study, which was a 72-week non-inferiority RCT that used a treat-to-target urate-lowering therapy approach and compared the two most common ULTs, allopurinol and febuxostat, we actually saw an overall reduction of about 20% in CRP.
levels over the first 48 weeks of the study and that did not differ by agent, so it was true for both urate lowering therapies. So to look at this more, we actually went back to the study I mentioned earlier and looked at 20 different cytokines and the trajectory of those cytokine concentrations over time using the 10 most over-represented inflammatory markers in the STOP-Gout patients. We indeed generated a multibiomarker measure of inflammation and we showed that that overall measure of inflammation decreased markedly over the course of treat-to-target urate lowering therapy and nearly approached that seen in non-inflammatory controls by 48 weeks. And that is at a time where almost all of these patients were off anti-inflammatory prophylaxis.

So others have looked at this using unbiased approaches like proteomics and shown similar results, showing the shift in a pro-inflammatory proteome to a non-inflammatory proteome over the course of highly effective urate lowering therapy. Interestingly, people have also done metabolomic profiling of patients receiving treat-to-target urate lowering therapy and have shown that there's also a diminishment over time in free fatty acids that might act as an inflammatory primer I mentioned earlier. We see that urate lowering therapy acts as an inhibitor of lipolysis and actually inhibits the concentrations of these free fatty acids like palmitic acid that might prime these cells for response to MSU. Now whether this plays a role in subclinical inflammation and whether urate lowering therapy impacts that remains to be seen to some degree.

Now this has some implications. People have looked at urate lowering therapy and specifically treat-to-target urate lowering therapy, and at least this has led to improvements in surrogate measures of some important outcomes, such as measures of endothelial dysfunction, which actually improve over the course of urate lowering therapy. There's a recently published retrospective observational study by the group in the UK that I mentioned showing that effective treat-to-target urate lowering therapy actually does lead to reductions — or is associated with, I should say, reductions — in cardiovascular events over time.

So just to sum up, there's strong and growing evidence of subclinical inflammation being apparent even during intercritical periods of gout, again reinforcing this concept that gout is indeed a chronic condition, not an acute self-limited condition. Assuming that hyperuricemia is shown to be the culprit in this — which I think the jury is still out on — that suggests that we should make even greater efforts to ensure that more patients receive highly effective urate lowering therapy in gout. And if uric acid really in turn is acting more as an epiphenomenon, then we need more research to identify the mechanisms driving subclinical inflammation so we can generate strategies and test strategies to improve outcomes in our patients with gout.

I want to thank you for spending a few minutes with me in our discussion of subclinical inflammation, subclinical systemic inflammation occurring in gout. And like you, I look forward to learning more as research evolves in this really important area.