Obesity & Inflammation: Understanding the Impact on Rheumatic Disease

Hello everyone. Welcome to Tuesday Night Rheumatology. I'm Jack Cush with RheumNow. 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. Lehi. Hi, I'm Leeder from University of Toronto. Excellent. Juliana. Hi everyone. Juliana Simonetti from University of Utah, Salt Lake City. And Naveed. Yeah. Hello everyone. Naveed Sattar. I'm not a rheumatologist but metabolic medicine from the University of Glasgow, Scotland. Excellent.

We may be joined midshow by Dr. 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 together — the PsA trial and the STEP 9 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.

This month 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. And it's guided by a survey that we did overnight. We sent out a survey yesterday. We had almost 200 responses from 32 countries, 62% from the United States. And you can see that it's pretty similar to last week's discussion where the majority obviously are rheumatologists, 82%. But 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, you know, 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? You know, other than the obvious biomechanical loading, stress, degenerative OA — where does it ignite the immune system or autoimmune features? Juliana, do you want to tackle that?

Sure. Yeah, so I think it's a really interesting way of thinking of obesity beyond just the mechanical load — thinking of it as this excess mass that puts pressure on the joints leading to more joint damage and inflammation. Thinking of obesity as this immunomodulator organ really, that releases adipokines — adipokines being hormones — thinking of leptin as a pro-inflammatory hormone. So when we have excess nutrition, we have an increase in the fat cell, and that does release leptin, and leptin is pro-inflammatory and leads to the secretion of IL-6, 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 pro-inflammatory, low-grade, localized inflammation — and then stimulating systemic inflammation as well, and contributing to what we see with many of the autoimmune dysregulation that we see with psoriatic arthritis, rheumatoid arthritis, and some others, even osteoarthritis, when we see more joint inflammation and more inflammatory processes.

Naveed, 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 Iain McInnes and colleagues in Glasgow, and also having done bits of work with Leeder and various colleagues around the world and various rheumatology guidelines — it's complex. But obesity doesn't just perhaps directly impact the immune system; when people put on weight, which is not really usually about willpower — I think we have to overcome stigma. Obesity is about the environment mostly, and
you know and it sucks susceptible people in and um but my sense of it is that also people also eat too much salt and salt can affect the immune system you know perhaps you get salt in lymph nodes uh maybe alters the microbiome in the gut that might then also affect the immune system through the cytokines as has been mentioned um you know um the adipose tissue looks like the macrophage um it could also potentially potentiate pressure within the skin that somehow might interact with you know pre-existing immune factors I don't know uh excess fat in the liver will affect some other aspects of the you know obesity uh immune function and there might be you know 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 the clinical evidence is crystal clear that people living with obesity do get more psoriasis and psoriatic arthritis. It's crystal clear that they get you know that obesity also affects many other manifestations of those individuals you know diabetes risk fatty liver disease hypertension cardiovascular risk and it's crystal clear that people fail faster on biologics you know with with these and so that then becomes a storm you know and and quality of life in obesity matters not just to their disease but it matters 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 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 wave. We've now the diabetes obesity link is even stronger. It's substantially strong and we're now getting to the point that actually we now realize the first pillar in diabetes should be substantial weight loss. I don't think it's the first pillar in rheumatic conditions but it's an important pillar that is now starting to be recognized. That's that's for the reasons I've mentioned.

Well, interestingly, I think I wrote about this yesterday or that our guidelines from GRAPPA and from EULAR don't 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. Um, and that obviously that's going to be changing I would assume with all the uh tremendous amount of data that's been coming in.

Lehi, what's the conversation here? Uh, you know, we've always told our patients, you know, exercise more, eat less, lose weight, you know, and it just seems to be a sort of a no-brainer, but that's number one a hard conversation to have. Not often well received by patients, very often not well done by doctors, but it seems to be a no-brainer in that, you know, less weight, you know, less pain kind of thing. Um, is it best left like that or how do you have the what's the conversation you have with patients?

Yeah, I think it's going back to how obesity is perceived by patients and by rheumatologists and I think in many times it's still perceived as a comorbidity and as a comorbidity I can speak as a rheumatologist we sometimes would just uh put it in the notes and say we had the conversation but we leave it to the family physician or you know to a specialist to manage. And um one of the I think with the great advances now with therapy is the understanding that we now have good tools um 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 um and have a more active role in management of obesity. It's not an easy discussion because unlike um obesity specialists um patients that see us are not expecting this conversation and it's not an easy conversation to have discussing weight for many people because of the stigma. Um and and the other I guess gap is the fact that we were not trained in this and we we have a lot to learn and a lot to um I guess understand how we actually manage this, how we um include it in our um very limited time that we have with patients learning how to start prescribing these drugs is is not an easy thing.

And so um one of the challenges again is understanding how obesity what are the mechanisms that link obesity with some of the rheumatic diseases. I'm I'm sure that people with lupus that live with obesity their outcomes are not great as well. So it may not be should not be ignored as well. But uh there seem to be a stronger epidemiological role for uh obesity in certain rheumatic conditions. You mentioned psoriasis, psoriatic arthritis, osteoarthritis and probably gout which makes a lot of sense. Um so I think but by um more education, more understanding, more research eventually hopefully will uh convince rheumatologists that uh we should start to take ownership and be responsible and that would lead to
changing guidelines managing obesity. And I must add, Jack, that you know 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 times of famine and war we're more likely to survive, and now we live in this obesogenic environment where we have access to food 24/7.

But as we try to lose weight, we have an increase in hunger hormones and we have a decrease in the satiety hormones. We have decreasing leptin, increasing ghrelin. And metabolically our metabolism goes down because our body likes to be in a steady state, making it really hard to lose weight.

And I think with obesity one thing I always talk about is how much stigma — with any other condition like diabetes, hypertension, heart disease, we apply the basics of behavior modification, which is you know dietary changes, increasing physical activity, behavioral 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 and when we're thinking of this overlapping inflammatory system — 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.

So yeah, and Jack — can I — sorry, Jack, you're on mute. Can I sort of add on the great comments from my colleagues, which I fully agree with? And I think this ownership aspect is happening in other specialties. With diabetes, you know, till 10 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, we're able to manage the disease better with disease-modifying drugs. But that also means that because they've got other issues, you know, like 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 heart failure specialists — now particularly in HFpEF I 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, who are starting to think about it because of the big blood pressure reductions. And then there are several — you know, sleep apnea is another condition — 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've ever met in my life, because you treat — so there's no reason why they can't learn to do this. [laughter]

You know, being modest — this can happen. The one issue is I think people start thinking, well, it's not my area. Well, actually no, it's all of our areas. Every specialty 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 you know, Juliana can't see all these patients herself — as much enthusiasm as she has, she doesn't have all the time in the world to treat 10 million patients. Certain realities. So we're all going to have to do this.

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

Yeah, let's answer that question. Marilyn Solski asks 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, is a major restriction. Insurance restrictions which are being tightened as time goes on. And the cost hasn't come down a lot, but there are some things out there that can help your patients. 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. Um, someone came up with a program that was on TV about now, uh, Medicare patients can get these drugs for $50 a month. Um, does any of you want to address the the horizon on cost? That's maybe a little cheerful, optimistic. I think Juliana should cover. Yeah, sure. I'll 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 um with very limited resources. So currently all the with the new oral agents that we do have here in the US that became available um — Orforglipron, which became available at the end of last year, and oral semaglutide that became available this year — the pricing has come down. Um we can start by $150. Um that still can be a lot of money for for many of the patients that we do see in clinical care. Um and then now the bridge program for those patients who are on Medicare who don't qualify, don't meet other criteria for the medication. Um they can pay $50 and get the medication. And as of July 1st, we have had quite an increase in the number of patients being able to um get treatment because of 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. Um so one key factor I think coming from rheumatologists or thinking of our patient population is also looking at other um weight-related 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 um as Naveed talked about it um or they might cover for fatty liver disease with fibrosis. So we do screen for those other conditions and trying to see what is it that we can get, and it will be really interesting as we see potential — um as we have potential approval of some additional medications for the 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 we're much better in a more positive place and as more drugs enter the market, I do think the 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 um and that is that um the data shows that uh most doctors — where obesity is a big issue — less than 30% 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 and you'll intermittently see signs of inflammation by looking inside the joint, but we know it's an important component, and anti-inflammatory therapy hasn't always worked in OA. But does that — can that inflammation be driven by obesity? And uh most of you got that right. 73% said yes.

Um a corollary question was um 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. So um 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 in the setting of obesity that activates the immune system? Anybody want to tackle this issue?

Yeah I can, I'm happy to to talk about this and I 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. And in particular we mentioned the biomechanical stress — so biomechanical stress can induce inflammation. We know that in spondyloarthritis in general, in psoriatic arthritis, Koebner phenomenon is activation of inflammation as a result of trauma. Um and um there's a lot of evidence to to show that biomechanical stress in animal models can trigger inflammation — um very nice experiments have shown that. So um in psoriatic arthritis it may be that um obesity is inducing inflammation at the entheses, especially the lower extremities, supporting that — when doing ultrasound of entheses in people who are living with obesity you see more inflammation at the enthesis. So especially in the lower extremities, in the Achilles tendon, in the plantar fascia. So this is um sort of a support to that that that potential role of biomechanical stress in in psoriatic arthritis. And it brings up the question of okay, is this — if if people lose weight, is this going to help mostly the inflammation in the lower extremities or is it going to be a more systemic effect? I think the answer is we still don't know and we we do need to understand how much of this beneficial effect is mediated through biomechanical stress and how much is mediated
through more systemic anti-inflammatory effect — 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 — you know, how the story is going to end and how you're going to 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 adipokines more so than biomechanical stress — 95%. Same answer last week when we asked the question.

And then we tie it again to psoriatic arthritis. To what extent does obesity drive the bus in driving activity? You know, 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, you know, 20 to 25% in some studies, it's up to 50% in other studies. I [clears throat] think most of you were right — 67% and 15%. But who wants to tackle this issue? I think adipokines — we're going to clarify in the next slide — you know, 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?

Well, Jack, I can probably take the second one. I mean, I don't know to what extent it's an adipokine, 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 think, look at things like lipids and blood pressure and volume: obesity affects so many things. You know, as you're living with obesity you have more volume in your system, there's more hemodynamic stress that stresses your kidneys and your pumps and pipes and filters, but at the same time your blood is thicker and you get more thrombotic events with VTE and PE with obesity. At the same time your triglycerides are higher, at the same time your CRP is higher, your hemoglobin A1c is higher. So it affects so many pathways.

And in terms of the attribution, I think it's probably not 67%. You know, if I was to say which two diseases are most strongly linked to obesity in terms of causality, it's probably sleep apnea and type 2 diabetes. And that's what the epidemiology says. And that's why, I guess, where the companies went first — they went for type 2 diabetes and sleep apnea trials because they realized the epidemiology was so strong that that's where you're likely to have the most benefit. And in fact we see that — you know, 50% improvement in sleep apnea, substantial remission in diabetes possible, substantial, you know, with weight loss, and it's almost a straight line.

So I think somewhere between 15% et cetera 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 to 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 15 to 20% — but I'd love to hear what Lee thinks, you know, because Lee, 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 a medication they've lost a lot of weight and the disease has gone away. I'm not saying that applies to every patient, and also I've seen the contra. So Lee, I'll pass it to you.

Yeah, thank you. Sorry — go ahead, Lee.

I absolutely agree with you. I think especially in psoriatic arthritis, which is such a heterogeneous disease, there are patients who are lean, and 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. So in these people we might not expect that weight loss will improve their disease activity. And in fact in the TOGETHER PsA, as you know, Navid — because you were part of it — more than 80% of the patients lost 10% of their body weight, but the ACR50 was maybe 40% or so. So it might not be the main driver in all patients. In some it might be 100% 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. 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 pre-clinical RA. You don't have RA, but you're going to get it — and what factors. It really is 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 Dr. Lee Kaplan. Dr. Kaplan, introduce yourself to the audience if you will. Yes. My apologies for being late. It's late at night here where I am. 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 Nave brought up just — I want to clarify things for the rheumatology audience — that the 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 Dr. Kaplan, you might have something else to add, but at least based on these studies we saw that 50% of the patients that went on tirzepatide completely improved their sleep apnea, and the majority of them did improve on the number of apneic events that they did have on the medication versus not. And in general, even before we had those medications, when patients were being treated with gastric bypass, with bariatric surgery, we saw that by the time they lost on average 50 pounds or so they did have improvement of their sleep apnea.

Okay. Yeah. I would add that there is evidence that you can improve sleep apnea — not to the same degree — 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 Dr. Sinetti has just talked about, you are getting both benefits. You're getting an improvement in any underlying diabetes or pre-diabetes 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 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 pathological 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.

Yeah, so I'll add one more point to what Lee said. 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 ways that we don't fully understand. And 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, as Lee said, that we understand, but there's so much we don't yet fully understand. We need more data and trials going forward. And 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, 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, not granulomatous, nothing else. And then visceral fat — 70% got it right that it's an endocrine organ that should be
considered. Um, but I don't — sorry. Yeah, let me see that acute inflammation thing. So I think you're right, it is low grade, but — and I, you know, I think all of us have seen — and Lee and Juliana probably in particular — you know, when people are at very, you know, very morbid levels of obesity you can get CRP levels at 20 and 30, you know, substantially elevated CRP levels.

Um, 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 prespecified — but nominally in the SELECT trial and in SURPASS-CVOT there was evidence of reductions in death from infections, which — and if you look at the epidemiology, obesity is linked to more infections. So there's both chronic and there's probably the potentiation of acute infection, or the buffering capacity against acute infection is somewhat diminished with obesity, which again is relevant to many of the patients that you treat because, you know, they're often given drugs that can interfere or lead to more infection risk. So, you know, this — 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 — or does fat breakdown — is that viewed as a toxin? Is that taken up as a damage-associated molecular pattern affecting NLRP3, inducing IL-1, or is it downstream NF-κB 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 going to say anything, I would — the easiest answer there is all those things, because the inflammation that is associated with decreased resistance to viruses — and what Navid 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-inflammatory, or, you know, sort of like immunosuppression — it's two sides of the exact same coin. And 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. And 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 — and I know with some of the patients with psoriatic — psoriatic arthritis disease — they have a higher amount of visceral fat for their BMI, and that does seem to be an additional link with the percentage of visceral fat and the amount of inflammatory disease that we do see in a particular patient. And I think that also reflects, like, you know, 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 — and measuring waist circumference and looking at bioimpedance, or, you know, where the fat is accumulated and how we are going to be treating those patients.

So I think the fact that we're thinking of this as being a more pro-inflammatory kind of adiposity, and how we might intervene on that — I think it's an important factor as well.

You know, 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 going to get into. And, you know, making them aware can change the conversation.

Yeah, Jack, I was only going to — sorry. Sorry, Lee. You go ahead. No, it wasn't me. I think it was Juliana. A small piece just on fat. There is fat in the joint as well, right? So, you mentioned before osteoarthritis — there's been a lot of research on the infrapatellar fat pad, showing that in imaging and in biopsies this fat tissue can become pro-inflammatory, and when it is pro-inflammatory there is more leptin, for example, which can communicate with the immune system, and more inflammation in that infrapatellar 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. And similarly, there are small fat beds in every joint. So we don't know enough because it's very hard to get a hold of this fatty tissue but it is potentially affecting the joint locally not just as a systemic — we talked about systemic effect — but can 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 one of the weight loss drugs that happens to be with tirzepatide and execabtagene etc. So it almost linked it toward 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 mechanisms a bit more.

Um yeah, I mean the visceral fat — I'm still not less certain if it is visceral fat or is it ectopic fat, you know. I always get a bit confused. In diabetes we know that actually the dominant fat level — well it's probably liver and pancreas rather than visceral — that kind of contributes to diabetes risk. But I mean who knows, but certainly central adiposity gain is certainly more toxic to metabolic, and it may well be to 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 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 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 now 30 years, I almost feel like I know less than I did 30 years ago. Not because I'm becoming senile, although that may be true in part, but because we now recognize 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 the scientific ones, as much as I've been a basic scientist my whole career.

And one of the things — we talked 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 our center up there with psoriatic arthritis. And I realized that this isn't just a weird little thing — that's one of the 200 complications of obesity. This was a serious problem. We were seeing a few cases of axial 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 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 obviously caused by the obesity.

So let's get ahead. No, I was just going to say that 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 patients — you know, this NHS data — and it looks as if the average BMI 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: 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 27, 30 years ago, and I think in Scotland certainly the average BMI for psoriatic arthritis runs about 32. So it's gone up substantially. And I suspect that might be an exaggeration compared to some other parts of the world, but I'm pretty sure that's what Lehi is seeing in her clinics, as more and more of their patients are living with obesity in the same way that more and more patients with heart failure are living with
obesity and multiple other conditions as well. Yeah. Uh Philip, me last week uh quoted US numbers on overweight obesity — the population is 72% but in the psoriatic arthritis population it's 82%. So it is certainly higher.

Let's get into the biology, uh, and if you can explain this for us. I'm going to show you how much we don't know this answer. Which adipokine is primarily pro-inflammatory? The right answer is leptin. Um, most rheumatologists got that wrong. Which is anti-inflammatory? The right answer is adiponectin. Only a minority got that right. Um, I'll let you look at this for a second. So, and really I think this is indicative of um 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 um how does this happen? Maybe Dr. Kaplan, maybe you could say — in the resting state before we're having — before we have 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, I — pro-inflammatory and anti-inflammatory are very broad uh strokes or brush strokes to be using because each of these peptides or proteins — signaling proteins — has multiple functions. The general concept of adiponectin being anti-inflammatory and leptin being pro-inflammatory is correct, but that doesn't mean that in every tissue and in every way it's a classically pro-inflammatory hormone. Uh, leptin has numerous effects, particularly on bone, beyond the effects that it has on reproduction, beyond the effects that it has on uh fat and fat mass. So these general concepts as listed here are exactly correct as best we understand them. But 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 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 these less 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 in other tissues, or have an 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 — tirzepatide — which has GLP-1 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-1 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 going to improve inflammation. There's no evidence that giving adiponectin is going to 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 or anti-inflammatory.

Okay. Anybody want to add that? Yeah, go ahead. Actually, um, just to add to Dr. Kaplan's comment about the complexity — especially with adiponectin. There are um a few studies, one from our center looking at psoriatic arthritis, but there are several others in rheumatoid arthritis, that show that 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 adiponectin actually has different effects when it comes to different tissues, and while it might have an anti-inflammatory or immunomodulatory effect systemically, in the joints it might have a different role. So there is a lot that we don't know and we still need to understand in terms of what these um peptides are doing when it comes to — specifically when we're talking about the joint.

Juliana, 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, like when we have an increase in nutrition, we have
increase in the fat tissue. We have an increase in leptin secretion or adiponectins that then are signals to other — you know, 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 hyperinflammatory 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 an audience that might not be dealing with this all the time. And Dr. Kaplan, please add on to just the basics to have a basic understanding on how adiposity or excess adiposity leads to this excess leptin in general, knowing that there is a lot more complex than what, like you said.

Yeah. I mean, I think to simplify — and I agree with that, we need to have basic concepts — and as you probably have already discussed before I got on this webinar, obesity is a pro-inflammatory condition. We know it; 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 adiponectin — 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 a good therapy for obesity. In fact, multiple studies have demonstrated that it's not.

And then you look at the drugs that are the most effective — the GLP-1 receptor agonists. If you get rid of GLP-1 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 is 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 want to 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 you have all said, and Lee, you said it as well, is that you know this is very complex and we just don't know, to be honest with you. And we went right back to the beginning — we rhymed off about half a dozen other mechanisms that may link obesity to immune dysfunction beyond the adipokines. So I don't think — I just don't think we fully know.

But then if you look at — you know, if the rheumatology colleagues are listening — there's abundant evidence obesity is relevant to 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.

And 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 80-odd percent living with overweight and obesity — many of your patients that you're treating, 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 the obesity not just to improve disease activity but a 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 I think if nothing else, whatever the mechanisms are — and it is very complex and we just
don't fully understand them the clinical reality is clear and I think just like diabetists, just like hypertension doctors, heart failure doctors, you know, obesity is now starting to become really relevant.

We're not hearing you. I 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. The question seven about the role of gut dysbiosis in this 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 30-second or so final comment before we close. Let's begin with Lehi.

Well, okay. Lehi, sorry. [laughter] We have similar names. Yes.

So yeah, I would say that I do think understanding the mechanisms is important because clearly obesity may be a comorbidity in some rheumatic conditions. We 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. And I think even understanding that 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. So I would end here and I think it's exciting times, but then doing more research in this area is really needed.

Okay. 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 know 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 to the clinical aspect, we know that treating obesity is key for improvement of many of these conditions. And we've got to treat obesity and we've got to approach it with the underlying physiology, and we know that many of the medications that we now have do address that and lead to improvement not only in the conditions but also in patients' quality of life. And I do think approaching the patients — I know that when we are in the obesity medicine clinic it's easier because they have already made the decision to come and to take care of their weight, but when they are in the rheumatology 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 additional recommendations for them to lose weight and how we have so many more tools now. So I think the approach is really, really important as we're caring for patients with obesity and rheumatological conditions.

Okay, final comments, Dr. Kaplan.

Sure. 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 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. And we're seeing that in more and more diseases the more we look at it. And so from a rheumatologist's 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 — I'm sorry, I dropped that — but I'm not going to repeat what my colleagues said. I think Lehi said it nicely as well. I think it's now at the point where rheumatologists do need to engage with the evidence and learn how to even start to have that conversation with their patients in a way that doesn't stigmatize, 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 have a patient with a BMI of 36 and you don't even mention obesity — which often happens in many clinical scenarios — then we're doing our patients a massive disservice, now with 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 next few years and they are going to get cheaper and more affordable.
So I think we're at a really good crossroads. I would say the key thing is rheumatologists are very, very bright people who 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 oncologic ones. Juliana will be here, Grace Wright, I believe Katherine Bakewell, and another person. Please be sure to tune in. I want to thank Dr. Satar, Kaplid, Simonetti, and Eer for their great perspective and great guidance tonight. Everyone be well.