Obesity as a Risk Factor for Rheumatic Diseases Save
Transcription
Hi, I'm Alexis Ogdie and thanks so much for joining Lehi and I today. So Lehi, we have worked together for a really long time on obesity and obesity-related outcomes in psoriatic arthritis. So today we're going to talk a little bit about obesity as a risk factor for rheumatic diseases and this is part of our series the obesity imperative. So, um, let me just kick it off by, uh, having you introduce yourself and then I'll introduce myself as well.
Okay. Hi, Alexis. Um, so I'm Li. I'm a rheumatologist, clinician scientist from the University of Toronto and my main area of interest is psoriatic arthritis. Um, very interested also in cardiometabolic abnormalities in rheumatic diseases.
And I'm Alexis Ogdie. I'm a rheumatologist and epidemiologist at the University of Pennsylvania in Philadelphia.
And so I'm going to lead us off by talking a little bit about the epidemiology of obesity in rheumatic diseases. So Lehi and I happen to be both psoriatic arthritis specialists and we've really studied the impact of obesity in psoriatic arthritis. So we're going to use psoriatic arthritis as an example here as we talk through some of these studies, but then we'll kind of expand along the way.
Um, so it kind of makes sense that obesity is a risk factor for osteoarthritis. We've known this for a long time. And it makes sense also that obesity is a risk factor for gout. What may not be as intuitive is that obesity is also a risk factor for the development of psoriatic arthritis among patients with psoriasis and within the general population. And in fact, obesity is also a risk factor for development of psoriasis.
Now, there's been a lot of risk factors studied. Um, actually the two of us have done a lot of these different studies looking at what is it that portends a higher risk for psoriatic arthritis among patients with psoriasis and of all the risk factors identified, obesity is usually one of the strongest risk factors aside from maybe having psoriasis itself. Um, but in addition to that, it's also been replicated the most times in the most different studies in the most different settings. And in fact, there's at least one study that suggests that with bariatric surgery, if you decrease weight, you also decrease the long-term risk for psoriatic arthritis. So pretty convincing that multiple studies have demonstrated this. And in fact, it's also significant when you adjust for other risk factors like the severity of the psoriasis and risk factors like depression.
So Lehi, why do you think this is — like, what are the mechanisms behind this?
Yeah, I think it's a good question. We generally know that there is a good signal from the observational studies that you mentioned but also of course now with the incretin-based therapies to suggest that weight loss is beneficial for psoriatic arthritis, for osteoarthritis, but we really don't understand yet what the mechanisms are — what connects obesity and psoriatic arthritis or osteoarthritis. And there's been some studies and some animal models and some other studies mostly in osteoarthritis, and there are several potential mechanisms.
So the leading hypothesis is probably through adipose tissue dysfunction. So what happens during obesity is that the adipose tissue becomes inflamed and this can happen at the systemic level, but there is also adipose tissue within the joint. So potentially through a paracrine effect, and this adipose tissue — there is infiltration of macrophages and other inflammatory cells and it starts producing cytokines that we all know of, like IL-6 and TNF, as well as adipokines that interact with the immune system and may intensify inflammation both at the joint level but also systemically.
Okay. Um, so that is one hypothesis. There is another potential mechanism which is through biomechanical stress. Um, we know that biomechanical stress is important in osteoarthritis and also in psoriatic arthritis. Um, through the synovio-entheseal complex model, trauma leads to enthesitis, leads to synovitis. So by reducing biomechanical stress we might be reducing some of this inflammation, probably mostly in the lower extremities.
And then there are other potential mechanisms like through the microbiome — gut dysbiosis — and an unhealthy diet that leads to obesity can change the gut microbiome and that can also intensify inflammation.
Um, and I guess the last potential thought is through just overall well-being and health. Um, people living with obesity have, as we know, a lot of comorbidities. These could be heart failure, sleep apnea, and other conditions that just cause general deconditioning and intensification of pain. And of course convergence with osteoarthritis, which — as we know, many patients with PsA would have both PsA and OA — and then that can contribute to the pain and just general dysfunction of joints.
So these are some of the thoughts. Any other thoughts from your end about
um mechanisms and why would be important to study this? Yeah. So I think um you know the point that you made about maybe it's OA that we're seeing in our psoriatic arthritis patients or maybe they're being diagnosed as psoriatic arthritis because they have OA and OA is already more common in obesity. I think that's a comment I get frequently with with my papers and I think you probably had the same comment is is there misclassification from an epidemiologic standpoint that's what we like to call it and it it is possible we definitely see that and we also know that obesity is associated with not only more hip and knee OA but also more hand OA which is fascinating that may contribute to some of our poor understanding maybe of um the mechanisms also potentially overdiagnosis of psoriatic arthritis in the psoriasis patient. So I guess those are all those you know maybe confounders or misclassification or um that may be the counterpoints to some of that. Uh but I agree with you. I think it it is probably biomechanical and also inflammatory and the why is it important is exactly that. So if we can you know one of the things that we have talked about a lot is you know psoriatic arthritis is really difficult to treat. We can get a good proportion of patients to a lower disease activity, but then not all of them will get to remission. So if we could prevent the disease altogether, wouldn't that be really the win? And so if we could among patients with psoriasis get people to a healthier weight and then if that would reduce the risk for PsA, maybe that's the route we want to go. And I think understanding whether that is a viable approach um would be helpful. I think I don't know what are your thoughts.
Yeah, I think one of the um key questions that we still are not sure of is um if we'll just think about the incretin-based therapies um is there a direct anti-inflammatory effect beyond weight is it all mediated through weight or is there is another effect that we um um we can expect from these medications and um the data is like at least in terms of joints, we we just don't know. It's very hard to get samples from joints, right? But there are some clues from um some um psoriasis studies suggesting that there might be some um direct effect on on immune cells of of GLP-1 and um dual agonist GLP and GIP agonists.
Um you are the senior author on the TOGETHER PsA study. Um, any thoughts there about a potential anti-inflammatory effect in in of of these therapies in PsA? I think it definitely has to be demonstrated yet in the right way, but there's some clues in the TOGETHER PsA trial, including that the CRP and the inflammatory, you know, whether disease activity as measured by both the patient and the swollen tender joint counts and the CRP starts to drop as early as week four when really patients are still on the lowest dose and there hasn't been much of a weight much of weight lost yet. So maybe that is enough that maybe that's a drug effect. So I think that those are the kinds of things that we want to see in future studies.
Yeah, absolutely. I think this would be really important if we are able to show that there is a direct anti-inflammatory effect beyond weight then considering this in people who are not necessarily morbidly obese but in people with lower weight or metabolic abnormalities that would be um a potential therapy beyond the conventional drugs that we currently have. Exactly. And I think the we imperative I really like that title because I think it really is an imperative. We have an opportunity to really make major progress in inflammatory arthritis but also osteoarthritis. Hand osteoarthritis is really awful and deforming and uh limits function for a lot of patients and then gout is also a terrible disease. So if we can decrease prevalence of obesity before patients get the disease and there are now tools to do that. I think it is an imperative to understand how we might better do that.
Absolutely. So we we we both agree this needs some more research and some more work and but these are exciting times and for all of us. Exactly. Well, thanks so much for talking through this topic with me and we'll uh we'll be back with more topics in the near future. Thank you.
Okay. Hi, Alexis. Um, so I'm Li. I'm a rheumatologist, clinician scientist from the University of Toronto and my main area of interest is psoriatic arthritis. Um, very interested also in cardiometabolic abnormalities in rheumatic diseases.
And I'm Alexis Ogdie. I'm a rheumatologist and epidemiologist at the University of Pennsylvania in Philadelphia.
And so I'm going to lead us off by talking a little bit about the epidemiology of obesity in rheumatic diseases. So Lehi and I happen to be both psoriatic arthritis specialists and we've really studied the impact of obesity in psoriatic arthritis. So we're going to use psoriatic arthritis as an example here as we talk through some of these studies, but then we'll kind of expand along the way.
Um, so it kind of makes sense that obesity is a risk factor for osteoarthritis. We've known this for a long time. And it makes sense also that obesity is a risk factor for gout. What may not be as intuitive is that obesity is also a risk factor for the development of psoriatic arthritis among patients with psoriasis and within the general population. And in fact, obesity is also a risk factor for development of psoriasis.
Now, there's been a lot of risk factors studied. Um, actually the two of us have done a lot of these different studies looking at what is it that portends a higher risk for psoriatic arthritis among patients with psoriasis and of all the risk factors identified, obesity is usually one of the strongest risk factors aside from maybe having psoriasis itself. Um, but in addition to that, it's also been replicated the most times in the most different studies in the most different settings. And in fact, there's at least one study that suggests that with bariatric surgery, if you decrease weight, you also decrease the long-term risk for psoriatic arthritis. So pretty convincing that multiple studies have demonstrated this. And in fact, it's also significant when you adjust for other risk factors like the severity of the psoriasis and risk factors like depression.
So Lehi, why do you think this is — like, what are the mechanisms behind this?
Yeah, I think it's a good question. We generally know that there is a good signal from the observational studies that you mentioned but also of course now with the incretin-based therapies to suggest that weight loss is beneficial for psoriatic arthritis, for osteoarthritis, but we really don't understand yet what the mechanisms are — what connects obesity and psoriatic arthritis or osteoarthritis. And there's been some studies and some animal models and some other studies mostly in osteoarthritis, and there are several potential mechanisms.
So the leading hypothesis is probably through adipose tissue dysfunction. So what happens during obesity is that the adipose tissue becomes inflamed and this can happen at the systemic level, but there is also adipose tissue within the joint. So potentially through a paracrine effect, and this adipose tissue — there is infiltration of macrophages and other inflammatory cells and it starts producing cytokines that we all know of, like IL-6 and TNF, as well as adipokines that interact with the immune system and may intensify inflammation both at the joint level but also systemically.
Okay. Um, so that is one hypothesis. There is another potential mechanism which is through biomechanical stress. Um, we know that biomechanical stress is important in osteoarthritis and also in psoriatic arthritis. Um, through the synovio-entheseal complex model, trauma leads to enthesitis, leads to synovitis. So by reducing biomechanical stress we might be reducing some of this inflammation, probably mostly in the lower extremities.
And then there are other potential mechanisms like through the microbiome — gut dysbiosis — and an unhealthy diet that leads to obesity can change the gut microbiome and that can also intensify inflammation.
Um, and I guess the last potential thought is through just overall well-being and health. Um, people living with obesity have, as we know, a lot of comorbidities. These could be heart failure, sleep apnea, and other conditions that just cause general deconditioning and intensification of pain. And of course convergence with osteoarthritis, which — as we know, many patients with PsA would have both PsA and OA — and then that can contribute to the pain and just general dysfunction of joints.
So these are some of the thoughts. Any other thoughts from your end about
um mechanisms and why would be important to study this? Yeah. So I think um you know the point that you made about maybe it's OA that we're seeing in our psoriatic arthritis patients or maybe they're being diagnosed as psoriatic arthritis because they have OA and OA is already more common in obesity. I think that's a comment I get frequently with with my papers and I think you probably had the same comment is is there misclassification from an epidemiologic standpoint that's what we like to call it and it it is possible we definitely see that and we also know that obesity is associated with not only more hip and knee OA but also more hand OA which is fascinating that may contribute to some of our poor understanding maybe of um the mechanisms also potentially overdiagnosis of psoriatic arthritis in the psoriasis patient. So I guess those are all those you know maybe confounders or misclassification or um that may be the counterpoints to some of that. Uh but I agree with you. I think it it is probably biomechanical and also inflammatory and the why is it important is exactly that. So if we can you know one of the things that we have talked about a lot is you know psoriatic arthritis is really difficult to treat. We can get a good proportion of patients to a lower disease activity, but then not all of them will get to remission. So if we could prevent the disease altogether, wouldn't that be really the win? And so if we could among patients with psoriasis get people to a healthier weight and then if that would reduce the risk for PsA, maybe that's the route we want to go. And I think understanding whether that is a viable approach um would be helpful. I think I don't know what are your thoughts.
Yeah, I think one of the um key questions that we still are not sure of is um if we'll just think about the incretin-based therapies um is there a direct anti-inflammatory effect beyond weight is it all mediated through weight or is there is another effect that we um um we can expect from these medications and um the data is like at least in terms of joints, we we just don't know. It's very hard to get samples from joints, right? But there are some clues from um some um psoriasis studies suggesting that there might be some um direct effect on on immune cells of of GLP-1 and um dual agonist GLP and GIP agonists.
Um you are the senior author on the TOGETHER PsA study. Um, any thoughts there about a potential anti-inflammatory effect in in of of these therapies in PsA? I think it definitely has to be demonstrated yet in the right way, but there's some clues in the TOGETHER PsA trial, including that the CRP and the inflammatory, you know, whether disease activity as measured by both the patient and the swollen tender joint counts and the CRP starts to drop as early as week four when really patients are still on the lowest dose and there hasn't been much of a weight much of weight lost yet. So maybe that is enough that maybe that's a drug effect. So I think that those are the kinds of things that we want to see in future studies.
Yeah, absolutely. I think this would be really important if we are able to show that there is a direct anti-inflammatory effect beyond weight then considering this in people who are not necessarily morbidly obese but in people with lower weight or metabolic abnormalities that would be um a potential therapy beyond the conventional drugs that we currently have. Exactly. And I think the we imperative I really like that title because I think it really is an imperative. We have an opportunity to really make major progress in inflammatory arthritis but also osteoarthritis. Hand osteoarthritis is really awful and deforming and uh limits function for a lot of patients and then gout is also a terrible disease. So if we can decrease prevalence of obesity before patients get the disease and there are now tools to do that. I think it is an imperative to understand how we might better do that.
Absolutely. So we we we both agree this needs some more research and some more work and but these are exciting times and for all of us. Exactly. Well, thanks so much for talking through this topic with me and we'll uh we'll be back with more topics in the near future. Thank you.
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