Obesity & Inflammation: Understanding the Impact on Rheumatic Disease Save

Hello, everyone. Welcome to Tuesday Night Rheumatology. I'm Jack Cush with RoomNow. We're here to discuss the obesity imperative. This is our campaign during the month of September where we're going to discuss how obesity affects your patients, your treatment, disease onset, disease outcomes.

It's a gigantic issue throughout medicine, but especially in rheumatology. I'm joined by a great faculty. We have a fourth that might join us because he's traveling, but I'm going to ask the faculty to introduce themselves. I'm Jack Cush in Dallas, Texas. Lihi?

Hi, I'm Lihi Eder from University of Toronto.

Excellent. Juliana.

Hi, everyone. Juliana Simonetti from University of Utah in Salt Lake City.

Hi, Navid.

Yeah. Hello, everyone. Navid Sattar. I am not a rheumatologist, but metabolic medicine from the University of Glasgow in Scotland.

Excellent. We may be joined mid show by Doctor. Lee Kaplan, who is on the fly traveling. Again, this campaign started on the first of the month. We got a lot of content up.

There'll be a lot of podcasts up. There's a lot of good reading. You may have seen last week's TNR where we did a journal club on two really important trials in obesity and rheumatology, the Together PSA trial, and the STEP nine trial in osteoarthritis. Really good discussions, makes for a good one hour listen or viewing. And this is going to be the same.

We'll put this up as a video you can view, a podcast you can listen to, tell your friends and neighbors about it. Month and the campaign has been sponsored by Lilly. Thanks to them for supporting what we think is an important educational objective. So today, we're going to discuss this topic of inflammation related to obesity that affects our disorders. It's guided by a survey that we did overnight.

We sent out a survey yesterday. We had almost 200 responses from 32 countries, sixty two percent from The United States. You can see that it's pretty similar to last week's discussion where the majority obviously are rheumatologists, eighty two percent. What's unique, last week I think was almost 90% rheumatologists. This week we have more other MDs.

So we have 8% that are advanced practice providers, nurse practitioners, physician associates, and 8% that are probably dermatologists, internists, primary care, maybe some GI. I hope a lot of endocrine are tuning in, but they're the ones who answered our survey. So there's a skew there obviously towards the rheumatologist mindset. So let's get into what we asked them. We did ask them, we know obesity makes disease worse, we know obesity may color treatment responses.

We're mostly aware that obesity causes RA and psoriasis. But the question was, does obesity cause a risk for lupus? The answer is no. But I want our panel to just consider how and when does obesity cause disease? Now other than the obvious biomechanical loading stress degenerative OA, where does it ignite the immune system or autoimmune features?

Julianna, do you want to tackle that?

Sure. Yeah, so this I think it's a really interesting thinking of obesity beyond just the mechanical load that we think of it of the success mass that puts pressure on the joints leading to more joint damage and inflammation. Thinking of obesity as this immunomodulator organ really that releases a dipokines, a dipokines being hormones, thinking of it as leptin as a pro inflammatory inflammatory hormone. So when we have excess nutrition, we have increase in fat cell. And that does release leptin and leptin is a pro inflammatory and leads to the secretion of IL-six, TNF alpha.

And also sometimes when we have hypertrophy of those cells, we have cell apoptosis, and then the release of additional cytokines and attraction of macrophages and T cells leading to this really like pro inflammatory, low grade pro inflammatory localized inflammation. And then, you know, in stimulating systemic inflammation as well in contributing to what we see with many of the autoimmune dysregulation that we see with psoriatic arthritis, rheumatoid arthritis, and some other, even osteoarthritis when we see more joint inflammation and more inflammatory processes.

Naved, it sounds like obesity creates the perfect storm with an ugly outcome. How do you consider this when you're talking to patients?

Oh, wow. You know, not having grown up in the immune field, but obviously having spent many years with people like Ian MacInnis and colleagues in Glasgow, and also having done bits of work with Leahy and various colleagues around the world and various rheumatology guidelines, it's complex but obesity doesn't just perhaps directly impact the immune, but when people put on weight, which is not really usually about willpower, think we have to overcome stigma. Obesity is about the environment mostly and it sucks susceptible people. But my sense of it is that also people also eat too much salt and salt can affect the immune system, perhaps you get salt in lymph nodes, maybe it alters the microbiome in the gut that might then also affect the immune system through the adipokines as we mentioned. The pre atypical site looks like the macrophage.

It could also potentiate pressure within the skin that somehow might interact with pre existing immune factors, I don't know. Excess fat in the liver will affect some other aspects of the immune function and there might be some, I don't know, underneath the skin excess fat that releases local cytokines. So I don't think we really know the exact nature of this, but it could be a multitude of factors, but the clinical evidence is crystal clear that people living with obesity do get more psoriasis and psoriatic arthritis. It's crystal clear that obesity also affects many other manifestations of those individuals, diabetes risk, fatty liver disease, hypertension, cardiovascular risk. And it's crystal clear that people fail faster on biologics with these.

So that then becomes a storm, quality of life in obesity matters not just to their disease but to how people live and their quality of life and how they feel about themselves. So morbidity, how they feel about themselves and the disease process itself. That's my take on it, and therefore these conditions, like many other conditions we're leading to, and I think diabetes is the front way. Diabetes, obesity link is even stronger, it's substantially strong, and we're now getting to the point that actually we now realise the first pillar in diabetes should be substantial weight loss. I don't think it's the first pillar in your conditions, but it's an important pillar that is now starting to be recognized.

That's that's for the reasons I've mentioned, Jack.

Well, interestingly, I think I wrote about this yesterday or that our guidelines from GRAPA and from UR, they say we should address obesity, but they don't make it a pillar. They don't make it an upfront first thing you must do. That's going to be changing, I would assume, with all the tremendous amount of data that's been coming in. Lihi, what's the conversation here? We've always told our patients, exercise more, eat less, lose weight, and it just seems to be a sort of a no brainer, but that's number one, a hard conversation to have.

Two, not often well received by patients, very often not well done by doctors. But it seems to be a no brainer in that less weight, less pain kind of thing. Is it best left like that? What's the conversation you have with patients?

I think it's going back to how obesity is perceived by patients and by rheumatologists. I think it's still many times perceived as a comorbidity. I can speak as a rheumatologist, we sometimes would just put it in the notes and have we had the conversation, but we leave it to the family physician or you know, to a specialist to manage. One of the I think with the great advances now with the with therapy is the understanding or now that we have good tools, and understanding how important obesity is as a causal factor, especially in psoriasis and psoriatic arthritis that rheumatologists should start taking ownership of this and have more active role in management of obesity. It's not an easy, easy discussion because unlike obesity specialist, patients that see us are not expecting this conversation.

It's not an easy conversation to have discussing weight for many people because of the stigma. The other gap is the fact that we were not trained in this and we have a lot to learn and a lot to understand how we actually manage this, how we include it in our very limited time that we have with patients. Learning how to start prescribing these drugs is not an easy thing. One of the challenges again is understanding what are the mechanisms that link obesity with some of the rheumatic diseases. I'm sure that people with lupus that live with obesity, their outcomes are not great as well.

So it should not be ignored as well. But there seem to be more stronger epidemiological role for obesity in certain rheumatic conditions. You may mention psoriasis, psoriatic arthritis, osteoarthritis, and probably gout, which makes a lot of sense. And so I think but by more education, more understanding more research, eventually, hopefully will convince a rheumatologist that we should start to take ownership and be responsible. That would lead to change in guidelines managing obesity.

I must add, Jack, that I always tell my patients as an obesity medicine specialist, if it was easy, I wouldn't have a job. We know how complex obesity is and how challenging it is to lose weight. I think any of us who have tried to lose weight know that you can get to a certain point and then your weight, the tendency is that you might even gain more than what you lost. And the reason for that is that as humans, we have evolved to protect against energy deprivation. So in time ends of famine and war, we're more likely to survive.

And now we live in this obesogenic environment where we have access to food 20 fourseven. But as we try to lose weight, we have increase in hunger hormones and we have decrease in the satiety hormones. We have decreasing leptin, increasing ghrelin Metabolically, our metabolism goes down because our body likes to be in a steady state, making it really hard to lose weight. I think with obesity, one thing I always talk about is how much a stigma any other condition like diabetes, hypertension, heart disease, we apply the basics of like behavior modification, is dietary changes, increasing physical activity, behavior health as a base, but we do address the underlying physiology and with obesity, as with inflammation, as we're thinking of rheumatological conditions, you have to address the underlying physiology. It's really important that we're talking about all the tools that we have, but we have to address the underlying physiology and that's where the medications do play a role when we're treating obesity.

When we're thinking of this overlapping inflammatory systems, both that coming from obesity as this baseline causing this overall systemic overall inflammation and then from psoriatic arthritis, rheumatoid arthritis or some of the other rheumatological conditions.

Yeah, and Jack, can I Oh, sorry? Jack, you're on mute. Can I sort of add on? Great comments from my colleagues, which I fully agree with. And I think this ownership aspect is happening in other specialties.

So diabetes, know, ten years ago obesity might have been mentioned as a little bit down the stream, now it's right up front because it's moved. Heart failure specialists are now starting to think more and more about obesity because their patients are more often living with obesity because guess what, they're able to manage the disease better, disease modifying drugs, but that also means that because they've got other issues, they're able to move less well, as many of your patients are, they're more susceptible to the obesogenic environment and it's also part of the pathophysiology, so they're putting on more weight. And so heart failure specialists are now, particularly in HFpEF, think are having to manage obesity, and they've got used to prescribing their drugs, having to work with primary care. The next band includes people who treat hypertension are starting to think about it because it's big blood pressure reductions. Then there's several, you know, sleep apnea is another condition.

Now respiratory specialists are starting to get involved in as well, you know COPD and asthma. So there's no reason, and rheumatologists are incredibly bright people, I think you're one of the brightest groups I ever met in my life, so there's no reason why they can't learn to do this, so you know, they are, it is being modest, know, that this can be happening. The one issue is I think people start thinking well it's not my area, well actually no, it's all of our areas, you know, Every speciality is going to have to think about obesity because it's affecting so many disease entities. And I think what we need to do is develop good partnerships with our primary care colleagues as well, because Julianna can't see all these patients herself. As much enthusiasm she has, she doesn't have all the time in the world to treat ten million patients in certain modalities, so we're all going to have to do this.

And the good news is, of course, there's more treatments coming forward, and hopefully over time, I saw one of the questions, the prices will come down as well. That's the direction of travel.

Let's answer that question. Marilyn Solski asked a question about, you know, it's great that we are considering this, it's great that we have new drugs, but the cost as was indicated last week in our survey, it's a major restriction, insurance restrictions, are being tightened as time goes on. And the cost has come down a lot, but there are some things out there that can help your patient. I work in a charity clinic, I can get these medicines by applying for compassionate use if you have patients that don't have the funds and whatnot. Someone came up with a program that was on TV about Medicare patients can get these drugs for $50 a month.

Does any of you want to address the horizon on costs that's maybe a little cheerful, optimistic?

I think Julianna should cover that.

Yeah, sure, I'll take that one. So yes, we deal with this on a daily basis in our clinical practice, and I see a variety of patients, those that have insurance, those on Medicare, Medicaid, with very limited resources. So currently, with the new oral agents that we do have here in The US that became available, or Wegovy, which became available in the end of last year, and orfroglopron that became available this year, the pricing has come down. We can start by $150 That still can be a lot of money for many of the patients that we do see in clinical care. And then now the bridge program for those patients who are on Medicare, who don't meet other criteria for the medication, they can pay $50 and get the medication I had.

As of July 1, we have had quite an increase in the number of patients being able to get treatment because of this program. But it's still the truth is it's still unaffordable for many of our patients. And I still have to be very creative in how I can prescribe the drug. So one key factor I think coming from rheumatologists or thinking of our patient population is also looking at other conditions that those medications are approved for because sometimes the insurance doesn't cover for the treatment of obesity, but they might cover for sleep apnea, as Navin talked about it, or they might cover for fatty liver disease with fibrosis. So we do screen for these other conditions and trying to see what is it that we can get.

And it will be really interesting as we see potential, right? As we have potential approval of some additional medications for treatment of psoriatic arthritis, I think from a rheumatology perspective, you might be able to get covered for those drugs too. So I do think we're much better in a more positive place. As more drugs enter the market, I do think that the pricing is going to continue to come down, it has come down significantly over the last year.

I want to make one more point, that is that the data shows that most doctors where obesity is a big issue, less than thirty percent actually discuss it during their medical visits, and that needs to be something that should change. I asked this question, is inflammation of the knee augmented by obesity? We know osteoarthritis in general has inflammation as a minor component, it's not the major driver and you'll intermittently see signs of inflammation by looking inside the joint. But we know it's an important component, but anti inflammatory therapy hasn't always worked in the away, but does that, can that inflammation be driven by obesity? And most of you got that right, seventy three percent said yes.

A corollary question was biomechanical stress accelerates which kind of arthritis? We know weight and biomechanical stress accelerates osteoarthritis, but is also an accelerant to the onset and worsening of psoriatic disease as well. But here is an important component in that, is it the obesity and the activation of the immune system or is it the biomechanical stress that in the setting of obesity that activates the immune system? Anybody want to tackle this issue? Lihee?

I'm happy to talk about this. I would say that we still don't understand entirely how obesity is causing arthritis, whether it's osteoarthritis, whether it's psoriatic arthritis, I think there are several mechanisms that might act simultaneously and on different joints. In particular, we mentioned the biomechanical stress. So biomechanical stress can induce inflammation. We know that in spondyloarthritis in general, in psoriatic arthritis, Kevner phenomenon is activation of inflammation as a result of trauma.

And there's a lot of evidence to show that biomechanical stress in animal model can trigger inflammation in. Very nice experiments have shown that. So in psoriatic arthritis, it may be that obesity is inducing inflammation on the enthesis, especially the lower extremities, supporting that when doing ultrasound of entities in people who are living with obesity, you see more inflammation at the entities. Especially in the lower extremities in the Achilles tendon in the plantar fascia. So this is sort of a support to that, that potential role of biomechanical stress in psoriatic arthritis and brings up the question of, okay, this if people lose weight, is this going to help mostly the inflammation in the lower extremities, or it's going to be a more systemic effect?

I think the answer is, we still don't know. And we do need to understand how much of this is beneficial effect is mediated through biomechanical stress and how much is mediated through more systemic anti inflammatory effect.

You're muted. Thank you, we can hear

you.

It's really accentuated when we understand it with knee OA, but hand OA. Obesity still is a risk factor for hand OA where biomechanical stress isn't the driving factor. So there's more to it than what seems obvious, right? And that's why I think you'll hear from our panel that there's a lot we know and a lot of information is evolving. But I think the story still needs to, how the story is going to end and how you're gonna tie up these different factoids will be interesting.

But if you look at the literature on this, it's really quite impressive. So we asked our audience also what mechanism links obesity to increased activity in psoriatic arthritis and overwhelmingly, they chose the deeper kinds more so than biomechanical stress 95%. Same answer last week when we asked the question. And then when we try to tie it again to psoriatic arthritis, to what extent does obesity drive the bus in driving activity? This is a hard question.

It's actually a hard question if you look at it from a research standpoint. But in my research and I'd ask my panel to correct me, it's twenty to twenty five percent in some studies, it's up to fifty percent in other studies. I think most of you were right, 6715%. But who wants to tackle this issue? I think adipokines we're gonna clarify in the next slide.

The role of adipokines, where they come from, how they contribute and whatnot. But, again, obesity driving disease activity aside from just the biomechanical effect, is it just the adipokines or is it more than that?

Jack, I can probably take the second one. Mean, I will I'm not I don't know what what extent it's adipokines. You know? It's probably relevant, but it could be as I said, it could be a whole host of other things, you know, excess salt, microbiome, you know, I don't know, multiple aspects. I mean, one of the things people forget, and even as metabolic work, you know, that I'm involved in and guidelines, even if you look at things like lipids and blood pressure and volume, obesity affects so many things, know.

As you're living with obesity, you have more volume in your system. There's a more hemodynamic stress that stresses your kidneys and your pumps and pipes and filters. But at the same time, your blood is thicker, you get more thrombotic events with VTE and PE with obesity. At the same time, your triglycerides are heavier. At the same time, your CRP is higher, your hemoglobin A1 is higher.

So it affects so many pathways. And in terms of the attribution, I think it's probably not 67%. If I was to say which two diseases are most strongly linked to obesity in terms of causality, probably sleep apnea and type two diabetes. And that's what the epidemiology says. And that's why I guess where the companies went first.

They went for type two diabetes and sleep apnea trials, because they realised the epidemiology was so strong that that's where you likely have the most benefit. And in fact, we see that, you know, fifty percent improvement in sleep apnea, substantial remission in diabetes possible with weight loss, and it's almost a straight line. So I think about somewhere between fifteen percent, etcetera, is probably correct on average, But it also might differ within individual patients. It may be that somebody has a kind of low immune load and needs additional factors lead to the clinical manifestation of the disease. So for one individual, the obesity might be more relevant to their manifestation of clinical disease.

For others, it may be less. So that's my sense of it. On average, about fifteen percent, twenty percent, but I'd love to hear what Lihee thinks, because Lihee, you've been thinking about this. And the reason I say that it might be different attributions, I've seen patients and heard of patients where they're supposed to come to our clinic when they've started the medication, they've lost a lot of weight and the disease has gone away. I'm not seeing that in every patient.

Also I've seen the contrary. Leahy, I'll pass it to you.

Yeah, thank you, Noveda.

Go ahead, Leahy.

I absolutely agree with you. Think especially in psoriatic arthritis, which is such a heterogeneous disease, there are patients who are lean and there in these patients, it might be the genetic, the HLA B27 that is contributing to the disease, and maybe they have obesity secondary because of their bad joints. In these people, we might not expect that weight loss will improve their disease activity. In fact, in the together PSA, as you know, Navid, because you were part of it, more than eighty percent of the patients lost 10% of their body weight, but the ACR fifty was maybe forty percent or so. So it might not be the main driver in all patients.

In some, it might be one hundred percent. And in others, it may not be. So I think one of the critical things is to understand in which patients obesity is a major driver in these patients, we need to focus our attention and as rheumatologists do our best to encourage weight loss in these patients.

You know, I think when we talk about this, this is very reminiscent of discussions on preclinical RA. You don't have RA, but you're gonna get it and what factors. That's a perfect storm too. The more factors you get, the more likely you are to cross over from psoriasis to psoriatic arthritis, from just arthralgia to having swollen joints. Same thing here, you can be predisposed and obesity becomes a big factor immunologically that gets you into these other disease states.

We're joined by Doctor. Lee Kaplan. Doctor. Kaplan, introduce yourself to the audience if will.

Yes, my apologies for being late. It's late at night here where I am. And my name is Lee Kaplan. I'm a professor emeritus of medicine from Harvard Medical School. And my focus is on obesity and liver disease.

So Naved brought up just a I want to clarify things for the rheumatology audience that incretin class is FDA approved for sleep apnea. Exactly how does that work? Do they lose enough weight that they have less pharyngeal fat, or is it a centrally acting mechanism? Anybody want to tackle that? Juliana?

Sure, I think it's a combination of the two, right? You do have the decrease in weight with the medication, but also overall you do have, we talked about decreasing inflammation and metabolic improvement of metabolic conditions that do overall improve sleep apnea. And Doctor. Kaplan, you might have something else to add, at least based on these studies, saw that fifty percent of the patients that do that went on tirzepatide completely improved, there is sleep apnea, and the majority of them did improve on the number of ethnic events that they did have on the medication versus not. And in general, even before we have those medications, when patients being treated with gastric bypass with bariatric surgery, we saw by the time they lost on average of 50 pounds or so that they did have improvement of their sleep apnea.

Okay.

Yeah. I would add, I think though, that there is evidence that you can improve sleep apnea, not to the same degree, by by treating underlying diabetes. So that would argue that there's some component that's a metabolic component. So with weight loss alone, you get a dramatic improvement. But when you're treating with a drug like tirzepatide, which, of course, doctor Saminetti has just talked about, you are getting both benefits.

You're getting an improvement in in any underlying diabetes or prediabetes, which may be contributing, and you're getting obviously the weight loss. Historically, we always thought that the problem of sleep apnea was a physical problem with too much fat, you know, around the neck and the airways, and we now know that it's much more complicated than that. And the more we look at obesity complications, the more we realize that there are components of those complications that are indeed physical, and there are frequently many more components that we hadn't realized before that are physiological. It's not the fat getting in the way of anything. It's the fat and the physiological implications of that fat, the pathophysiology of that fat, which lead to all these complications.

Yeah, it reminds me a little bit of the data on knee osteoarthritis where it is I think the infrapatellar or prepatellar fat pad that does contribute almost in a paracrine kind of way to the pathogenesis of the OA. You could almost say the same thing about what's going on with the fat mass in sleep apnea.

So I'll add one more point to what Lee said. But even the process of putting on weight or getting to a higher weight means you're eating more calories and more salt, which is then affecting various cellular functions in the ways that we don't fully understand. And you know, as I said, salt can get into lymph nodes, excess calories affect cells in ways that, and then different cells may be more adversely affected in certain susceptible individuals. So there's so much about the mechanism, you know, as Lee said, we understand, but there's so much we don't yet fully understand. Need more data and trials going forward.

This is in this area, in psoriatic arthritis, I think we've just started to scratch the surface of what the mechanisms may be. We know the evidence is there, we know that the benefits are there, or starting to be there, but as to the exact mechanism and the attribution again may be somewhat different in different patients as well.

Okay, let me go on to the next question. Obesity causes what kind of inflammation? Everyone said chronic low grade, not acute, non granulomatous, nothing else. And then visceral fat, 70% got it right that it's an endocrine organ that should be considered. I don't Sorry,

yeah, let me see that acute inflammation thing. So I think you're right, it's low grade, And think all of us seen, and Lee and Juliana probably in particular, when people have very morbid levels of obesity, you can get CRP levels at twenty and thirty, substantially elevated CRP levels. And the other thing I would say, what we've also started to discover in the trials, and you can't say it's definitive because they were not kind of pre specified, but nominally in the SELECT trial and in SURPASS CBT, there was evidence of reductions in death from infections. And if you look at the epidemiology, obesity is linked to more infections from all age. So there's both chronic and there's probably the potentiation of acute infection or the buffing capacity against acute infection is somewhat diminished with obesity, which again is relevant to many of the patients that you treat because they're often given drugs that can interfere or lead to more infection risk.

It's not just unidimensional is what I'm trying to say here.

Does anybody want to tackle the issue of how we get to chronic low grade versus acute. Do the adipokines does fat breakdown, is that viewed as a toxin? Is that taken up as a damage associated molecular pattern affecting NLRP3 inducing IL-one IL-eighteen? Or is it downstream NF kappa B and whatnot that gives you that chronic low grade? Or is it all those things being played out at the same time?

If I were gonna say anything, would the easiest answer there is all those things because the inflammation that is associated with decreased resistance to viruses and what and what Naved was talking about largely is infections with viruses. We saw this with COVID, and we also see it with influenza where people with obesity have a lower resistance to influenza. So, you know, defining something as being inflammation and defining something as being anti inflammation or an you know, sort of like immunosuppression, it's two sides of the exact same coin. And so so here we're talking about inflammation or the inflammatory process making you more susceptible to certain diseases, and then of course they can cause certain diseases. And so as far as which components, if we're talking about cardiac disease, obviously we know what the cardiac inflammatory risks are.

We'd already talked about HSCRP, but there are others. But when you talk about other forms of inflammation, the kinds that are suppressed by corticosteroids, the kinds that are suppressed by anti inflammatory drugs, those are all different wings of the inflammatory process. It appears that obesity activates many of them. I don't know enough to say which ones, but I can say that many different aspects of inflammation are activated by obesity. And some of them are local in various tissues and some of them are systemic.

Juliana?

Yeah, no, I was just going to add the question about the visceral fat too, thinking of the visceral fat. I know with some of the patients with psoriatic disease have higher amounts of visceral fat for their BMI. That does seem to be an additional link with the amount of percentage of visceral fat and the amount of inflammatory disease that we do see in a particular patient. I think that also reflects moving towards the newer guidelines where we're moving away from really having this particular BMI number that we're treating to thinking more of the adiposity where the fat is at and measuring, looking at waist circumference and looking at bio impedance or fat, where the fat is accumulated and how we are going to be treating those patients. So I think the fact they're thinking of this raw fat and being a more pro inflammatory kind of a paucity and how we might intervene on that, I think it's an important factor as well.

I don't think enough rheumatologists think of obesity as a chronic or acute low grade condition. And I don't think that they consider that fat could be their second largest organ beyond their skin. And it's metabolically active and the more they have of it, the more trouble they're gonna get into. Up, make nowhere can change the conversation.

Jack, I was only gonna say Sorry, Lihi, you go ahead.

No, it wasn't me. I think it was Julian.

A small piece just on fat. There is fat in the in the joint as well, right? So you mentioned before osteoarthritis, there has been a lot of research on the pre patellar fat pad and showing that in imaging and in biopsies, this fat tissue can become pro inflammatory. When it is pro inflammatory, there is more leptin, for example, which can communicate with the immune system and more inflammation in that patellar fat pad is associated with more inflammatory osteoarthritis, even though we don't think of OA as an inflammatory condition. When you have this fatty tissue sitting next to the joint itself, it can affect the joint itself.

Similarly, there are small fat pads in every joint. We don't know enough because it's very hard to get ahold of these these fatty tissue, but it is potentially affecting the joint locally, not just as a systemic we talked about systemic effect, but it cannot potentially affect this in a paracrine effect.

Yeah. And can I just bounce off that, Lee, because we're doing a small trial at the moment where we're trying to you know, before and after, you know, one of the weight loss drugs that happens to be with tirzepatide and exekinumab, etc? So it almost linked it toward we're trying to measure both synovial biopsy skin and adipose at the same time. It's hard work, you know, you need very motivated patients before and after. But those are the kind of studies we need to try and help us understand the mechanisms a bit more.

Yeah. I mean, the the visceral fat, I still I'm not less certain if it is it visceral fat or is it ectopic fat? You know? I don't know. I always get a bit confused.

In diabetes, we know that actually the it's you know, the dominant fat level was probably liver and pancreas rather than this so that kind of contributes to diabetes risk. But I mean, who knows? But, yeah, certainly central yeah. Central adiposity gain is certainly more toxic to metabolic, and it may well be too inflammatory. You

know? But we have to be I think we have to be careful about making generalizations. The more we learn, the more we learn about the heterogeneity of obesity in every respect, where where people, when they develop obesity, put the fat at different stages of life where fat is stored, where ectopic fat goes. It doesn't always go into different to the same place in different people. The response to every therapy is very broad in terms of the differentiation.

And when you think about these things, I mean, I know from my own experience, I've been in this field for, you know, now thirty years, I almost feel like I know less than I did thirty years ago, not because I'm becoming senile, although that may be true in part, but the but because because we've now recognized just how complicated obesity is. And so I always start with the clinical observations because I think they teach us the most, even more than than the scientific ones as much as I've been a basic scientist my whole career. And one of the things, we're talking about psoriatic arthritis, and I may have missed part of this discussion, but when I went up to Dartmouth to help them set up their program a couple years ago, one of the things I saw was that there was really an epidemic of psoriatic arthritis. And in the early phases of my career, even in obesity, we didn't see much psoriatic arthritis. We saw psoriasis, of course, because dermatologists did.

But we had dozens of patients on the waiting list to get into to our center up there with psoriatic arthritis. And I realized that this isn't just a weird little thing that's one of the two hundred complications of obesity. This was a serious problem. We were seeing a few cases of eczematous arthritis. And, of course, we know that rheumatoid arthritis and osteoarthritis are not merely physical issues of weight bearing joints, but they occur in all joints.

And so I think that just looking at that one thing, whatever the mechanism, this is a real clinical phenomenon that has to be addressed, and we learn mechanisms so that we can address it more targeted in a more targeted way and a more direct way. But even if we don't understand the mechanisms exactly, they are there, and they are they are obviously caused by the obesity.

So once ahead, RheumNow. I was just gonna say that's these are the very fair points that Lee mentioned. And, we've got some data from Scotland where we have historical follow-up data from cohorts of patient you know, this NHS data. And it looks as if the average BMI in in Scotland for people with psoriatic arthritis has risen faster than the general population. And I suspect that's two things.

One is obviously you're treating the disease better, so stopping unintentional weight loss. And two, obviously, I think obesity is part of the pathophysiology, but there's another factor is that if you have groups of patients who are able to be less active, they're more susceptible to the rising obesogenic environment. So the average BMI, I think, used to be something like twenty seven, thirty years ago. And I think in Scotland, certainly the average BMI for psoriatic arthritis has run about 30 two. So it's gone up substantially.

I suspect that might be an exaggeration to some other parts of the world, but I'm pretty sure that's what Leahy is seeing in her clinics as more and more of our patients are living with obesity in the same way that more and more of patients with heart failure are living with obesity and multiple other conditions as well.

Yeah, Philip Meese last week quoted US numbers on overweight and obesity in the population of seventy two percent, but in the psoriatic arthritis population it's eighty two percent. So it is certainly higher. Get into the

biology

and if you can explain this for us. I'm gonna show you how much we don't know this answer. Which adipokine is primarily pro inflammatory? The right answer is leptin. Most rheumatologists got that wrong.

Which is anti inflammatory? The right answer is adiponectin, only minority got that right. I'll let you look at this for a second. And really, I think this is indicative of, some degree of confusion about this. So I want you to answer the question, how should rheumatologists consider this?

Here's a summary slide of pro inflammatory and anti inflammatory. Let's begin with, how does this happen? Maybe Doctor. Kaplan, maybe you can say in the resting state before a lot of obesity, we're sort of set up to be anti inflammatory, are we not? And then inflammation arises with obesity, with a shift in the cytokine profile.

Do you want to take a first stab at that?

Well, you know, once again, pro inflammatory and anti inflammatory are very broad strokes or brush strokes to be using because the each of these peptides or proteins, signaling proteins, has multiple functions. The the general concept of adiponectin being anti inflammatory and and leptin being pro inflammatory is correct, but that doesn't mean that in every tissue and in every way, it's it's a classically pro inflammatory hormone. Leptin has numerous effects, particularly on bone beyond the effects and on reproduction beyond the effects that it has on fat and fat mass. So these general concepts as listed here are exactly correct as best we understand them, there are so many things that we don't understand. For example, leptin deficiency we know is associated with obesity, but most obesity has leptin excess, and it's been interpreted as having leptin insensitivity or leptin resistance.

But it's not leptin resistance like insulin resistance because insulin resistance can be overcome with more with more insulin. Leptin resistance cannot be overcome with more leptin as best as we know. So what we're talking about is let's think about LES as inflammatory peptides or proteins, think of them as regulatory proteins where they can turn on certain aspects of the inflammatory diathesis and maybe have no effect on others and have no effect on other tissues or have the opposite effect in some tissues. The most recent thing to comment on that emphasizes the complexity of the system is that we have a drug which has, tirzepatide, which has GLP-one receptor agonist activity, and it has GIP receptor agonist activity. And it's a very effective anti obesity medication.

There's another medication in development which has the same GLP-one activity, but it has the opposite GIP activity. It inhibits GIP receptor, activation, or it's an inactivator or an antagonist. That is also a very effective medication to treat obesity. Now how can medications that have two opposite effects both be effective in treating obesity? This emphasizes that this biology is so complex, and until we start to sort it out to a much greater degree than we understand right now, I wouldn't be so concerned about measuring inflammatory or anti inflammatory for individual peptides.

There's no evidence that giving an antibody to leptin is gonna improve inflammation. There's no evidence that giving adiponectin is gonna improve inflammation. These are markers of a diathesis that is pro inflammatory or anti inflammatory. That's different from saying that these are peptides or proteins that are specifically pro inflammatory, anti inflammatory.

Okay. Anybody

want to add to that? Go

Actually, ahead, just to add to Doctor. Kaplan's comment about the complexity, especially with adiponectin, there is a few studies, one from our site, our center looking at psoriatic arthritis, but there are several others in rheumatoid arthritis that show that a higher levels of adiponectin are actually associated with higher disease activity in both PSA and RA and with more joint erosions. So it's possible that the adiponectin actually have different effects when it comes to different tissues. And While it might have an anti inflammatory effect systemically or immune modulatory effect systemically in the joints, it might have a different role. There is a lot that we don't know and we still need to understand in terms of what are these peptides are doing when it comes to the specifically we're talking about the joints of the joints.

Julia?

I was just going to say to simplify because it sounds like we have a bigger audience here too, just thinking of leptin in general. When we have increase in nutrition, we have increase in the fat tissue, we have increase in leptin secretion or adiponectins that then are signals to other, that is not just localized but systemic signals that could be, like you say, pro inflammatory and overall decreasing inflammation. And systemically, we do tend to see this hyper inflammatory state that is associated with many conditions that we see with increasing adiposity. So I just wanted to summarize because I feel like sometimes it just gets a little complicated in particular if there's audience that might not be dealing with this all the time. And Doctor.

Kaplan, please add on to just the basics to have like a basic understanding on how adiposity or excessive adiposity leads to this accessing leptin in general, knowing that there is a lot more complex than what, like you said.

Mean, think to simplify though, is, and I agree with that, we to have basic concepts. And as you probably have already discussed before I got on this webinar, obesity is a pro inflammatory condition. That we know. That's just a clinical observation that is fact. How that manifests itself is what's different in different people.

And we shouldn't assume that if you have what is basically an anti inflammatory, protein like adabonectin, first of all, it's not uniformly so as we just heard, but also that doesn't mean that adiponectin is going to be a good therapy. As we talked about, leptin deficiency we know is associated with obesity, but that doesn't mean that leptin is is a good therapy for obesity. In fact, multiple studies have demonstrated that it's not. So and then you and then you look at the the drugs that are the most effective, the GLP one receptor agonist. If you get rid of GLP-one signaling in the body by a genetic fluke or by inhibiting it, you do not get obesity.

So the simple matter of, well, if something is pro inflammatory in a pro inflammatory disease, we should interrupt it, or something that's anti inflammatory in a pro inflammatory disease, we should give more of it. It doesn't work that way. The body is so complex, I would argue one of the most complex bits of construction. I only say biology, but it's even more than biology. It's the most complex thing on the face of the earth.

And so as a result, when you talk about these complex diseases like metabolism, inflammation, neurobiology, all of those are probably well more complicated than the little bits of information that we have that this molecule does this and that molecule does that. So it is complicated, but the one thing that we should always recognize is that obesity is pro inflammatory and that many of the classic inflammatory diseases, including in the liver, including in the kidneys, including in the pancreas, including everywhere, of course, we're now talking about the joints, are direct effects of obesity.

And, Jack, can I just round this off? Because as as you have all said and Lee, you you said it as well, is that, you know, this is very complex and we just don't know, to be honest with you, you know. We went going right back to the beginning, we, you know, all rhymed off about half a dozen other mechanisms that may link obesity to immune dysfunction beyond the dipakin. So I don't think it's I just don't think we fully know. But then if you then look at, if the RheumAtoll colleagues are listening, there's abundant evidence obesity is relevant, immunity, you know, pro inflammatory, abundant clinical evidence, you get more disease, more disease activity, you get more TNF failure, you get more infections.

You know, what else do you need to prove that it's linked to immunity or immune functionality than those major observations? And then you further add observations that oh now we've got evidence that if you lose the weight, whether it's a low calorie diet or a drug, actually you get improvements in disease activity, you get less infections, you get less failures. So it all adds up. Going right back to the beginning, if more of your patients are now living with obesity, and I didn't know that data that you mentioned Jack, about eighty odd percent living with overweight and obesity, many of your patients that you're treating are because they're living with much more obesity, are having many more of the complications linked to obesity and the disease activity and other aspects are going to be worse. So you have to think about obesity not just to improve disease activity but holistic benefit beyond just even the disease activity to improve their quality of life and their other future risks or other morbidities that may substantially adversely affect their quality of life and their morbidity.

It's a no brainer nowadays, so you know I think if nothing else I think whatever the mechanisms are and it is very complex and we just don't fully understand them, the clinical reality is clear, and think just like diabetologists, just like hypertension doctors, heart failure doctors, you know obesity is now starting to become really relevant.

We're not hearing you, don't think.

We have a few minutes left. I want each of you to make a final comment and I'll even offer up that you can comment on any one of these questions. Question seven about the role of gut dysbiosis in complex mechanism, insulin resistance we haven't talked about, and the M1 pro inflammatory phenotype, or you can end with whatever, but I'll ask each of you to make a thirty second or so final comment before we close. Let's begin with Lihi.

Well,

We have similar names, yes. I would say that I do think understanding the mechanisms is important because clearly obesity may be a comorbidity in some rheumatic conditions. Talked about lupus, but it is a direct driver of diseases like OA and psoriatic arthritis. And in order for rheumatologists to take ownership, as we talked before, we want to understand how they work. I think even understanding that obesity or obesity management could have a disease modifying effect would convince rheumatologists to start thinking about obesity as a way to treat rheumatic conditions rather than a comorbidity.

I would end here and I think it's exciting times, but then doing more research in this area is really needed.

Okay, well, Juliana.

Sure. And I think just to add on that knowing you know, we talked for about an hour and how complex it is and how you have the heterogeneity of obesity, how patients might have different phenotypes, different presentations. So keep that in mind as we're treating patients. But going back for the clinical aspect, we know that treating obesity is key for improvement of many of these conditions. We got to treat obesity.

And we got to approach the underlying physiology. And we know that many of the medications that we now have do address that and lead to improvement in not only on the conditions, but also in their patients quality of life. And I do think approaching the patients, I know that when we are in obesity medicine clinic, it's easier because they already have made the decision to come and to take care of their weight. When they are in the office, that conversation becomes a lot more complicated. But it's important to approach without stigma, without bias and letting patients know why we are offering addition recommendations for them to lose weight and how we have so many more tools now.

I think the approach is really important as we're caring for patients with obesity and rheumatological conditions.

Okay, final comments, Doctor. Kaplan.

Sure. I mean, I think very simply, we have to not only recognize that obesity is associated with and often causative in rheumatological conditions, but we also have to recognize that this is due to this inflammatory diathesis, and it's not merely due to carrying excess weight, putting pressure on weight bearing joints. It's also true that that when we treat obesity, we're not just causing weight loss. We're frequently treating obesity with drugs that have dramatic effects on metabolism and the inflammation that obesity causes, independent of the weight loss. We're seeing that in more and more diseases the more we look at it.

And so from a rheumatologist perspective, we should be thinking about treating obesity with the therapies that have as a side effect that they treat the inflammatory disease associated with obesity, maybe above and beyond the weight loss itself. So we have weight loss and then we have the above and beyond. And the only way you're going to do it is to keep thinking about obesity as a contributor to many of the diseases that a rheumatologist takes care of.

Excellent. And Navi?

Sorry. I dropped out, but I'm not gonna repeat what my colleague said. I think Lehi said it nicely as well. I think it's now at the point where rheumatologists do need to engage with evidence and learn how to even start to have that conversation with their patients in a way that doesn't stigmatise. Because the only way you're going to address this is by actually explaining to the patients why we're talking about it without giving blame.

Because actually if you don't, you know, if you if you have a patient with a BMI thirty six and you don't even mention obesity, which often happens in many clinical scenarios, then we're doing our patients a massive disservice now where we are with the evidence and with the new treatments coming forward. Perhaps we can't use the treatments at the moment, but they are going to come in the few years and they are going to get cheaper and more affordable. So I think we're at a really good crossroads. So I would say the key thing is rheumatologists are very, very bright people, can learn how to talk about obesity with their patients as the starting point to have that conversation, to improve care and the quality of life for the patients that we treat.

Okay, I want to remind our audience next week on Tuesday night rheumatology treatment of obesity, we'll talk about the many treatments, not just the pharmacologic ones. Juliana will be here, Grace Wright, I believe Catherine Bakewell and another person, please be sure to tune in. I want to thank Doctor. Sittar, Kaplan, Simenetti and Eder for their great perspective and great guidance tonight. Everyone be well.