Systemic Burden of Gout Part 1 Save

Hi. I'm Bob Tripletob, UC San Diego, and it's my pleasure to talk to you about three things that it pays to know about gout pathobiology. The first topic of discussion is that IL-one beta is not the only target cytokine in acute gout flare, except we haven't really gotten to the stage where we're targeting other cytokines, in the clinic yet. That second point is that the tophi are complex structures that take on a urate crystal autonomous life of their own. And the third, thing that pays to know is that we have a new target in tophis biology, osteopontin, secreted phosphoprotein one, SPP one, which is central in TOFIS pathobiology from a recent manuscript.

So the first topic is why it's important to understand the pathobiology of the gout flare. We know in the clinic that we're we're looking at a unique phenotype of excruciating incapacitated pain, most characteristically, in the inflammatory setting of acute gouty arthritis flare. And we have the usual therapeutic suspects, anti inflammatory colchicine, corticosteroids, also anti inflammatory, and then the anti inflammatory analgesic NSAIDs. And in the clinic, the best response that we get for acute gout flare is about fifty percent pain improve improvement in about fifty percent of patients at forty eight to seventy two hours. That's the repeated theme in all the clinical trials that are run.

Anakinra does no better than corticosteroids in the ANEGO clinical trial that was published, and canakinumab does significantly better than, steroids, triamcinolone acetonide intramuscularly, but not by that much, but significantly enough that it's FDA approved to treat acute gout flare, but not yet used that often. There are some other considerations involved. And then opioids are not very effective at adding to that baseline pain relief. So we need to break through the ceiling on how quickly and well we can relieve pain in acute gout flare. And so the paper that I'll discuss is from Nature Communications a few years back by Yun et al.

It's not a paper that's really penetrated a lot in the rheumatologist's mindset, but it's penetrated a lot in my own mindset as somebody interested in gout. So CXCL5, which is a cytokine very much like IL-eight, that's a neutrophil chemotactic cytokine, was shown to drive acute pain in a preclinical model of gout, and CXCL5 is primarily induced by pro inflammatory stimuli and bacterial toxin, cellular stress. And the primary inducers go beyond IL-one to include TNF and IL-17A, and they work with some synergy TNF and IL-17A. And the study findings here were preclinical and clinical. In their mouse model, CXCL five activated the promiscuous receptor CXCR two on the pain sensing sensory neurons to drive gout pain and the inflammatory response, and the neuronal CXCR two receptor contributed to that CXCL five induced neutrophil chemotaxis.

So the neurons actually were a contributor to the inflammatory response, and that was by triggering a CGRP and substance P mediated response. We know that CGRP is very much implicated in migraine. CXCL five, this this chemokine, was increased in the ankle joints in a model of acute gout, and CXCR two was expressed preclinically in the joint innervating sensory neurons, and CXCL five activated those neurons to trigger an ion channel activation, the TRPA one ion channel, another target potentially for gout flare pain, and that all resulted in hyperexcitability pain and more inflammation. And then in a knockout model, CXCR two deletion ameliorated joint pain, neutrophil infiltration, and the gait impairment in the mice. So in humans, CXCR two is expressed in dorsal root ganglion neurons, and both serum CXCL five and IL one beta were elevated in patients with acute gout flares.

So a really nice study that argues for perhaps a better avenue to more rapid pain response in gout flares, and that's the pain response is the primary endpoint we're looking for and the primary endpoint in clinical trials. So the second thing that it really pays to know about is that synovial and subcutaneous tophi are not just some rubberized rocks of monosodium urate crystals. In fact, the literature for a few years now, including work by Nicola Dalbeth using dual energy CT, shown that only up to one third of the tophus area is comprised of the urate crystal deposits. And these urate crystal deposits are multifocal, and they're embedded in a sea of fibrosis with also areas of chronic synovitis and of granulomatous inflammation with a corona rich in B and T cells that surrounds the urate crystal core and then a fibrovascular zone. And the cell content revealed by a paper by Hua and colleagues recently, the cell content shows way more macrophages, monocytes, and T and B cells than neutrophils, and also more fibroblasts and mast cells way more than neutrophils in these tophi.

And in the clinic, what we see is that really the monosodium urate crystal deposits in the tophi dissolve and disappear actually on urate lowering therapies much faster than the chronic inflammatory tissue reaction will subside. So the way the TOFAS is structured really can take on a life of its own independent of the urate crystals that are deposited in these TOFI. And so the really linked thing that it pays to know is from a paper that appeared recently by Hua, et al, in the Annals of Rheumatic Disease showing that secreted phosphoprotein one, SPP1, formerly known really as osteopontin, osteopontin, is central entophus pathobiology. And osteopontin's a funny molecule. It has cytokine like activities, and it has chemokine like granulocyte and monocyte recruiting functions that are, you know, basically induced by other cytokines, and SPP1 will also induce other cytokines.

But it's also an extracellular matrix protein that plays the conductor of the orchestra in many different physiologic and pathologic processes, including bone remodeling, regulation of chronic inflammation and tissue repair and how tissue is remodeled, tumor progression and metastasis of tumor tumors and how tumors hide from the immune system. So, you know, in retrospect, really, like looking at the at the findings of Hawaii et al, it it would be predicted that some molecule like this would be organizing and orchestrating the biology of the ptofus. And osteopontin, you know, is also relevant in terms of the erosions that we see in people with topaceous gout that are next to the tophi, very much like PANAS and rheumatoid arthritis, because osteopontin SBP1 is crucial to regulate the attachment of osteoclasts to the bone surface. And it's a biomarker and a player, a major one, in fibrosis as well. So what Hua and L found was they did the first transcriptomic profile of Synovium of TOFI in patients with tophaceous gout.

But here they used a very powerful single cell RNA seq technique to look at clusters of the cells that were there, and their results were really groundbreaking because they linked the processes of chronic inflammation, fibrosis, matrix remodeling, and bone erosion. And they offered up SPP1 as a biomarker predictive factor and a novel potential target for drugs that target SPP1 for decreasing the harmful effects specific to TOFI in chronic severe gout. And these are effects that we see in the clinic, and the effects also include the chronic systemic inflammation that we see in patients with dofaceous gout. And so they also identified a unique subset of macrophages with SPP1 positivity as well as a matrix degrading metalloproteinase MMP-nine and a molecule called YKL-forty. And these macrophages that had these triple positivity markers were unique subset specific to TOFI with osteoclast differentiation and active involvement in extracellular matrix remodeling.

So this was a really important interacting cell type, and these macrophages really were like a transitional cell between macrophages and fibroblasts. And these co the coexpression of fibroblast markers in these SPP one positive macrophages in the corona zone that surrounds the crystalline core of the tophis points to a really novel cell type as well that can be targeted. So we have not only SPP1 as a target, but a specific cell type as a target to reduce the joint damage and systemic inflammation linked to ptophaceous gout. So these were my favorite talking points about what it pays to know about the pathobiology of gout and ptophis biology and pain in gout, And I hope you enjoy the presentation, and I hope you all have a good day. Thank you.

Hi, everyone. I'm Nicola Delbeth. I'm a rheumatologist from Auckland, New Zealand. I treat a lot of people with gout and I've also studied gout for many years. And I'm going to talk today about outcomes in people with tophaceous gout.

So first of all, what is the TOFIS? So the TOFIS clinically appears as a nodule, underneath the skin, often at very characteristic, areas, particularly over the joints that are often affected by gout, also, over the electron bursa, ears, finger pads and also over tendons, particularly the Achilles tendon. What's going on underneath is this is essentially an organised chronic granuloma like structure. It contains lots of monosodium urate crystals or MSU crystals, and these are surrounded by, inflammatory cells and also, connective tissue. So generally having tophaceous gout means that the person has a large amount of MSU crystal deposition.

So why are tophi important? Well, the first thing is that they're important for, the patient themselves and in qualitative work, what we've heard from patients is that Tofi have an impact on function. They can be painful, not always, but they can be. They restrict joint movement. They can cause deformity.

They often cause a lot of problems with people actually being able to access good footwear because they have rubbing and irritation on their, feet. They also have a psychological impact. So often people are quite embarrassed about the appearances of the Tofi, and they may cause actually poor low self esteem as well. When we first started studying Tophi, we did a number of studies, actually measuring function, including hand function. And what we found was that, the number of Tophi on the hands, for example, was actually one of the strongest predictors of hand function in people with gout when we actually measured grips objectively.

So TOFI do contribute to disability, and they are very strongly associated with poor health related quality of life in people with gout. They're also important because we know that, they're an important risk factor for, gout flares and in a study looking at, predicting which people with gout would experience a flare during hospital admission, the presence of TOFIS was actually a very important predictor. Again, probably, representing, the large volume of MSU crystal deposition and the risk factors associated with that. Another reason that TOFI are really important is because it's hard to get into gout remission. So remission is now the goal of treatment when we're treating people with gout and a study from Mexico, demonstrated that in those people who had multiple TOEFI, actually, virtually no people, developed or were able to achieve remission, even with a treat to target urate lowering therapy over five years.

So it's really important, to recognise this and realise that it is going to be much harder for people with, tophaceous disease to actually achieve disease remission. TOFI are also important because they're a strong, driver of structural damage and gout. So in studies of people with early gout, or recent onset of gout, we found that those people who developed, TOFI over follow-up were those people who also developed erosive disease. And on, studies, particularly with MRI and dual energy CT studies, we can very closely map the TOFIS to bone erosion, and structural damage in people with gout. And I think it's also really important to recognise that although urate lowering therapy, can lead to ptofus regression, it's very difficult to reverse that structural damage with oral urate lowering therapy, even once the TOFI are effectively treated.

Often bone erosion and structural damage, really doesn't reverse once it's established. So again, I think another really important, reason why we should be trying to avoid, development of TOFI. And finally, TOFI are important because they actually are important predictors of mortality in people with gout. And this is now being shown in a number of different, studies. This was initially shown by Fernando Perez Ruiz, who showed that in his large gout, cohort, that, the presence of TOFI, were an independent risk factor for mortality in people with gout.

And we've also observed this in, people with a short duration of gout, with a hazard ratio of almost three for mortality and this is a risk factor for both cardiovascular and non cardiovascular related mortality. So I think if we're thinking about, assessment of TOFI in clinical practice, we do need to be actually examining for this. People may not be aware that they have TOFI because they may be relatively asymptomatic, but looking for TOFI, particularly in these characteristic areas in the ear, extensive surfaces of the elbows, also the first MTP joint. Also look at the, tendons, particularly the Achilles tendon, because this is a site where we often see Tofi. And then if we do confirm ToFi, I would always recommend urate lowering therapy in this situation and generally we do want a lower serum urate target of below, five milligrams per deciliter or zero point three millimoles per litre, we may need to use higher doses of urate lowering therapy or combination urate lowering therapy, careful cardiovascular risk assessment and management, thinking about footwear, assessment and management, thinking about hand therapy for those people who have ToFi and surgical referral if there's infection or very large ToFi that are impacting on function.

But we really do need to be optimising medical therapy in this setting as well. I think the other thing that's really important when we're thinking about tophaceous gout is that tophaceous gout is generally preventable and once tofacious gout, is established, it actually takes a long time to get rid of those MSU crystals and joint damage may be irreversible. So I think this really does suggest that we need to be thinking about earlier use of urate lowering therapy, using treat to target urate lowering therapy to avoid development of TOFI and ultimately prevent these poor outcomes that we see in people with tophaceous gout. Thanks.

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

We see it every day. We see it routinely in rheumatology clinics and in our console 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 nonambulatory 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, 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 NLRP three inflammasome, which in turn activates caspase one and caspase one cleaves pro IL-one beta and turns that on forms the active form of IL-one beta with downstream effects that lead to the release of other pro inflammatory cytokines and the accumulation of white blood cells, leukocytes, etcetera. 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 super physiologic 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 inner critical 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 a study that we published last year, we use bio samples actually from the STOP GOUT study. 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 bio samples and asked the simple question, are there differences in inflammation in those bio samples, those serum bio samples 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 cytokines that were increased among gout patients. And those clusters included cytokines such as lactotransferrin, myeloperoxidase, which we know is a neutrophil mediator of inflammation, interleukin eight, interleukin 18 IL-one and its receptor antagonist calprotectin, and then adipokines such as FGF21, 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 seventy two week noninfor inferiority RCT that used treat to target urate lowering therapy approach and compared the two most common ULTs, allopurinol and febucestat, we actually saw an overall reduction about 20% in CRP levels over the first forty eight 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 the study I mentioned earlier and looked at 20 different cytokines and the trajectory of those cytokine concentrations over time.

Using the 10 most overrepresented inflammatory markers in the stopgout patients, we indeed generated a multi biomarker 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 scene in non inflammatory controls by forty eight 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 showed 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 and whether you're lowering therapy, impacts that, remains to be seen to some degree. Now this has some implications. People have looked at your rate lowering therapy and specifically treat to target your rate lowering therapy. And at least this has left led to improvements in surrogate measures of some important outcomes such as measures of endothelial dysfunction actually improve over the course of urate lowering therapy.

There's a recently retrospective observational study published 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 inner critical periods of gout. Again, reinforcing this concept that gout is indeed a chronic condition, not an acute self limited condition, a chronic condition. So assuming that hyperuricemia is shown to be the culprit in this, which I think is the jury is still out, 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.

Hi, everyone. My name is Michael Pillinger, and I'm a rheumatologist at NYU Grossman School of Medicine. I'm here today to share some thoughts with you about gout and cardiovascular disease. How big an issue is this? Well, studies indicate that patients with gout compared to similarly aged populations experience cardiovascular disease and major CV events at a rate of somewhere between 1.5 the general population.

This rate is comparable to that of patients with rheumatoid arthritis, which is increasingly recognized as being associated with CV risk. So when a patient with gout walks into your office, at the very least, you want to be aware of the potential for cardiovascular disease. But why do gout patients have this increased cardiovascular risk? Well, like most things in gout, it's complicated. First of all, gout patients have much higher prevalence of both hypertension and kidney disease than the general population.

And this may be a chicken and egg situation, since studies that I don't have time to discuss here suggest that hypertension and kidney disease may both be made worse by gout. But even after adjusting for these comorbidities, patients with gout continue to have increased cardiovascular disease rates. Another explanation may be the direct effects of hyperuricemia. In vitro studies show that exposure to higher levels of soluble urate causes endothelial cell dysfunction and smooth muscle hypertrophy. More recent work by Leo Justen's group indicates that urate is a driver of so called trained innate immunity.

That is, soluble urate can cause white cells to reset their activation levels, potentially driving an inflammatory state that could promote vascular disease. In any event, population data mostly suggest that patients with asymptomatic hyperuricemia have increased CV risk, but not as much as patients with actual gout. So what happens with gout? Well, in gout, we can add on to hyperuricemia the fact that gout patients have baseline levels of inflammation that are increased even above those of pure hyperuricemia with elevated CRP and many other cytokines and even between acute flares. Part of the reason for this may be that many gout patients have persistent urate deposition in their joints and possibly these crystals can cause a low level but Also, although controversial, dual energy CT studies are suggesting that patients with gout may actually have urate crystal deposition within arterial walls, possibly driving local inflammation.

From a functional point of view, my group has demonstrated that the arteries of gout patients are physiologically impaired and don't dilate in response to flow, a recognized marker of future MI risk. We've also directly sampled vascular endothelial cells from the brachial vein and found that these are activated and quite different from normal endothelial cells. Finally, we looked at markers of neutrophil activation and found that neutrophils in intercritical gout patients are semi activated. That is, they might be primed for a rapid response should an event transpire. All of these add up to a sort of powder keg of cardiac events waiting to happen.

Then add to this the highly inflammatory nature of the actual gout flare, which in some cases could be the match that lights the fuse. In fact, Abhishek's group has reported that after a gout flare, the risk of major cardiac events is essentially doubled for up to one hundred and twenty days and we have shown that one hundred and twenty days is the actual window during which inflammation is elevated post flare. Well, if gout can raise cardiovascular risk, can treating gout lower it? This is an area of ongoing investigation, but the data do point to a CV benefit. As you know, there are two aspects to treating gout.

The first involves addressing the inflammation and the second addressing the urate level. When it comes to inflammation, we need to talk mainly about colchicine since NSAIDs and steroids raise cardiovascular risk but by different mechanisms. We and others have shown in retrospective studies that patients with gout who are on colchicine experience fewer cardiovascular events than those not on colchicine. We've also shown that gout patients without cardiovascular disease are less likely to develop it if they are on colchicine and that patients with cardiovascular disease are less likely to get MIs when they are taking their colchicine than when they aren't. And when it comes to gout flares, two groups have reported that patients starting urate lowering therapy and experiencing gout flares as a result had fewer MIs if they were taking colchicine than if they were either taking nothing or NSAIDs.

And finally, what about the impact of urate lowering, not in the immediate period but over the long haul? As recently presented in a RoomNow Tuesday Night Journal Club, Sipaleta, et al. Recently reported a large emulated trial in which, compared to no urate lowering, patients who got urate lowering had significantly fewer cardiac events than those who did not get urate lowering. So what are the take home messages? Well, first of all, be aware, be very aware that your patients with gout have increased cardiovascular risk.

It's not trivial. Make sure you or another physician is appropriately managing their comorbidities. And when it comes to gout therapy, be aware that reducing cardiovascular risk may well be at least an important side benefit of guideline compliant treatment. Remember, gout is more than the joint. Thank you.