Chapters Transcript Keynote Lecture: Weighing the Evidence: The Role of Obesity and Diet in Psoriatic Arthritis Course: Eleventh Annual NYU Langone Advanced Seminar in Psoriasis and Psoriatic Arthritis OK, so, um, I'll be talking about obesity in, in psoriatic arthritis, and this is to continue a little bit the, the conversation that we started yesterday at the Pac-Man meeting. Where we talked about our future projects, but this talk is more of a background, why, why I think we need to start thinking about obesity and consider obesity treatment in our strategies for patients with psoriasis and psoriatic arthritis. These are my disclosures, and I'll be mentioning um quite a lot this recent paper that I wrote with Rebecca Haberman, who led this effort and other colleagues that are listed here, where we describe the obesity, inflammation axis in psoriatic arthritis and some of the proposed mechanisms that support or the, the potential causal relationship between obesity and psoriatic arthritis. So the background for this is um We know that there are many patients with PSA that are not meeting treatment targets. Only about a third of the patients in clinical trials in the real world, it's pretty much the same. They don't meet treatment targets, and The question is why is this, and there are many reasons, but I'll focus today on obesity, I think, are, we have lots of modes of action. We know how to treat inflammation um well, um, but the problem is that we don't address obesity and inflammation that is associated with obesity, the metabolic inflammation. We don't consider this at all in our treatment strategies, and I'll show you evidence that I believe support these causal relationships. So if we fail to address an important component of this, then this potentially could explain why so many patients are failing to achieve targets. So the question is, does obesity have a causal role in psoriatic arthritis, and if so, could anti-obesity treatment be a sort of a DMAR in, in um the management of psoriatic arthritis? I don't have all the answers, and many of the things that I'll mention are mostly hypothesis, and that's why I think we need to study this a lot more in, in PSA. But just going for a little bit to the basics and what is obesity, I think it's important to understand that obesity is not a lifestyle choice, OK, because I see many guidelines that the treatment of or consideration of obesity is considered in the lifestyle changes paragraph of guidelines, and we now know more about the pathophysiology of obesity, which is in fact a disease, it's a relapsing and progressive disease, and the essence of this is it's accumulation of fat in. Abnormal areas, so in, in visceral organs, uh, and this abnormal accumulation and distribution of fat leads to disease, so it leads to uh many of the conditions and metabolic abnormalities that we know. Um, obesity is defined usually by BMI, um, and BMI of more than 30 is, is, uh, the common and acceptable definition of obesity, but this is just part of the story. We know that it's also important when the adipose tissue. Accumulates and mostly the central obesity is the problem and one of the metrics that has been suggested is waist to height, height ratio, which if it's more than 0.5, that's considered abnormal adiposity. So what are, uh, what links obesity and um PSA? Um, I think there are many steps along the way, the continuum from a pre-clinical disease to psoriasis to psoriatic arthritis to established PSA where obesity could play a role, um, and this is important because if we want to intervene, it's important to think about when do we want to intervene, what population we want to consider. And I'll be um showing you first some evidence to support the role of obesity as a risk factor, possi possibly causal role in the development of psoriasis and psoriatic arthritis. So thinking about maybe prevention of psoriasis or prevention of progression from psoriasis to PSA, uh, this is where anti-obesity could potentially play a role. Um, so first going to epidemiology, um, there is a strong link between obesity and, and psoriasis, psoriatic arthritis. On the left hand side you can see data from Canada, where, um. Even though rheumatoid arthritis, another form of inflammatory arthritis, is associated with obesity here, this could be a secondary effect of patients just gaining weight after the diagnosis. In PSA, you see that the risk of being obese is almost threefold higher compared to the general population, and this is much higher than in RA and in psoriasis alone. And on the right hand side you can see that the majority of patients that we see in clinic have either obesity or overweight. So this is from Corevita US data. Over 80% of the patients are overweight or obese. So it affects most of the patients that we see in our clinic. Um, and I, I mentioned causality, and one of the ways of assessing causality is by doing a Mendelian randomization study. So here, this is like an experiment of nature. You take, uh, you evaluate genes that are associated with a certain trait like obesity. And you see whether in patients with PSA and psoriasis, these genes are more frequent than in the general population, and there's been quite a lot of studies, and this is There are a meta-analysis that summarized all of these studies, so looking at different traits, including BMI and adult and childhood body size and visceral adiposity, all of them are showing and supporting this potentially causal relationship between both psoriasis and psoriatic arthritis and obesity. Another proof for this is to show that from an epidemiological perspective, showing that the risk factors come before the disease itself. And um again, there has been now quite a few studies, longitudinal population-based studies that Showed and this is from the UK showing that there is a dose response association between BMI and the risk of developing psoriatic arthritis in patients with psoriasis, and you can see here the odds ratios are increasing as the BMI category increases in psoriasis patients. What about weight loss? So there is not a lot of data about weight loss and whether weight loss could prevent progression, because just because there has not been very effective treatments until very recently, but bariatric surgeries are, even though they are invasive, they are very effective treatments, and there's been studies, this one is from Denmark, that looked at bariatric surgery and specifically gastric bypass. Which is the more effective form of bariatric surgery that showed that patients, that people that underwent bariatric bypass had lower chances of developing both psoriasis and psoriatic arthritis. Interestingly, with the gastric banding, there was no difference, and One hypothesis is that this uh surgery is less effective, the effect is uh relatively short term, and it's also not associated with some of the metabolic abnormalities that um are associated with the, with a more effective treatment. Um, so this is, uh, just a little bit about, um, uh, obesity as being a risk factor for psoriasis and PSA. Let's talk about people with psoriatic arthritis, established psoriatic arthritis. What is the evidence that obesity uh could be a factor that is important and for us as rheumatologists consider in our treatment management. So, again, there has been quite a lot of data now to support the fact that obesity is associated with poor outcomes in PSA. This is from the Toronto cohort showing those response association between BMI and the chances of achieving a minimal disease activity state. People that have obesity have 50% lower chances of achieving this treatment target. We also know that the biologics tend to be less effective in the context of obesity. There, there's been a lot of studies in TNF inhibitors in particular, and this one is a meta-analysis that shows that patients who are obese have 50% lower chances of achieving and or have 60% higher chances of failing. Um, and very interestingly, this was seen in both the fixed dose, like adalimumab, and as well as in the weight-based doses like infliximab. So there, it may not be just dose dependent effect or the pharmacokinetics of the drugs. There is less information on other biologics, but, um, specifically for IL-17 inhibitors and in the context of psoriasis, there's been trials that looked at weight as a factor and show that um higher weight in people that um are that have higher weight, higher dose of secuinumab, sorry, is associated with a more effective response of psoriasis, and there was another study with similar results for exekizumab, so. Those are the adjustments for some of the biologics is, is recommended in this context. There is very little data on newer biologics or targeted synthetic therapy in the context of obesity, but some signals with the JAK inhibitors and alpha 23 inhibitors, but less consistent compared to the TNF inhibitors. So I'll talk a little bit about some of the proposed mechanisms. And, and one of the leading hypothesis of why obesity is associated with uh PSA and how it could affect uh the disease is through the, um, adipose tissue dysfunction. So we know now that the adipose tissue serves, we know that it serves as an organ to store energy, but also beyond that. Um, there are lots of, uh, cells and other functions that are happening and that they change in the context of obesity, so. Obesity is essentially when there is more energy and it needs to be stored, and it's stored within these adipose cells, and in the context of obesity, these cells undergo hypertrophy, so they become bigger, and this can lead to some changes within these tissue, so abnormal blood flow, hypoxia, and this could trigger inflammation within this tissue. Um, that attracts immune cells that we know from psoriasis like TH1, TH17, macrophages, and these all leads to this tissue becoming, becoming inflamed and producing TNF, IL 6, I1, as well as adipokines that are mediators that could speak to the immune system. Um, so overall, this can happen at the The systemic level, so this could lead to um a chronic low grade inflammation, as we know that uh in the context of obesity, but there is also fatty tissue in the joints, and so, for example, in the knee, there is Hoffa fat ps, and they're there to help cushion the um biomechanical stress, but if this tissue change their phenotype. This could also potentially happen or affect the joint or the synovium in a Perne way. Uh, this is hypothesis and it's mostly been studied in OA, not studied in PSA, but, um. Again, it's something that could potentially happen as well in the context of psoriatic arthritis. Another mechanism is through um biomechanical stress. We know that biomechanical stress is important in, in psoriatic arthritis, the Kobner phenomenon, um, and this could lead to um enthesitis, um, um. By having increased biomechanical stress, especially on the lower limbs and lower limb hysis such as the Achilles tendon, um, this could potentially trigger chronic low grade inflammation. Um, we do know from ultrasound studies that people that are obese have more enthyseal changes, for example, so, uh, this is an alternative mechanism or complementary mechanism. Another proposed mechanism is through amplifying pain. Um, this is again not specific to psoriatic arthritis, but in the context of obesity and chronic low grade inflammation, there are some changes in the way the peripheral nervous system, as well as the central nervous system interpret uh pain, and um I won't get into the mechanism. I would encourage you to read the review paper, and this, this one. Um, and again, this study was studied a lot in the context of OA and showing that patients that are obese have higher levels of pain, and there are some changes there in, uh, some of the, um, um, central nervous systems and, and functions there that would be more responsive to pain signal and therefore, um, amplify pain sensation in these patients. And finally, uh, comorbidities, I think it's important to acknowledge that as well. We know that obesity accelerates many comorbidities, and many of these comorbidities have been associated with low response to treatment. So for example, uh depression. And sleep apnea can be associated with fatigue. General physical dysfunction can be associated with diabetes and heart disease, and osteoarthritis is another common condition that often exists in many patients with PSA and could potentially make this treatment less effective. Oh, I forgot this one, this is important here. Uh, so the gut microbiome, um, so gut microbiome, uh, as, um, Jose and others have shown, plays a role in, in psoriatic arthritis development, so. Theoretically, um, Obesity is often associated with abnormal diet. And this could influence the gut microbiome and making this environment less diverse, leading to barrier dysfunction, leading to some other changes like changes in production of short chain fatty acids and bile acids that could interact directly with the immune system. Uh, gut dysbiosis have also been shown to be associated with obesity, so this is kind of an indirect way, uh, where, where, uh, diet and obesity could be affecting patients with psoriatic arthritis. So speaking about that, I, I know this is something that uh patients keep asking us um what they should be eating or shouldn't be eating to make their arthritis better, and there are lots of advice online, um, but um the data there is, um, I should say. Quite sparse or I mean the quality is also not that great. Uh, there is more in psoriasis and psoriasis is um. There has been a meta-analysis that looked at um diet studies and particularly diet-induced weight loss, and they show that there is a significant but modest effect of um of dietary induced weight loss in psoriasis. So uh if you compare it to placebo, this is significant with almost 50% higher chances of achieving. PASI 75, but the absolute reduction of PASI is relatively small, 2.6 points. It's not a lot compared to the um biologics, but still, I think it's uh it's important because of other um effects of healthier diet, um, and the fact that it's safe and uh it could serve as an adjunct therapy. In psoriatic arthritis, there is even less, and I, you don't need to read that. I summarize here 4 studies. I think that the best and the, the one that was the largest with the best methodology was published quite a long time ago now in by Dimino from Italy. And this study looked at patients who were starting TNF inhibitors and um they randomized them to low caloric diet versus control, and they showed that patients that were able to lose weight had better chances of achieving a minimal disease activity state. There were a few other studies, usually single arm, um, uncontrolled, unblinded, uh, studies. Some of them were using um. Powder-based strategies with very, very low caloric, um, um, dietary changes, um, and showing mostly um a favorable response. But the, the problem is that, um, diets are, um, especially if the diet is very strict, it's very hard to maintain for a long period of time, and patients often gain weight, so, We, um, uh, were thinking, could we maybe try to change the metabolic milie by um um promoting Mediterranean diet, which is a form of healthy diet been associated with multiple metabolic effects, also some modest weight reduction. Could we improve outcome in psoriatic arthritis in those people that are You know, keep complaining of pain and stiffness, and we, we don't see a lot of inflammation, so not, we're not talking about the people that have 20 swollen joints, but those that have kind of lower grade symptoms, could this be served as a as an adjunct therapy? So, uh, this is the design of the DPSA study, um, that I had the pleasure of, uh, doing with uh Alexis and, um, uh, other, uh, colleagues, um, and this is a, a study that asked the question of could we. Random if we randomize patients that are experiencing residual disease activity in psoriatic arthritis, uh, we randomize them to a Mediterranean diet, and we're here the, the goal was to improve their dietary patterns rather than losing a lot of weight. Compared to low caloric diet, the goal there is to lose weight versus controls, and the control arm just received general advice, uh, printed the materials about what they should be changing compared to the other two groups that were meeting with the dietitian and received very personalized advice. Uh, could we improve DASA score? So these were patients with DPSA score of more than. Uh, 10, they were overweight and they were on stable treatment, and we followed them for 6 months, uh, with interim visits, uh, both in person and, uh, it's uh 6 months. Um, there were some, uh, we spent a lot of time thinking about it, uh, because diet studies I learned are very hard, and I probably won't be doing it again. Um, it's, it took us, uh, it took a lot of thinking, and, and also I learned that in order to be successful in diet, it needs to be personalized, so patients need to meet with the dietitian, and each one of us has their own schedules and preferences and allergies, and so, um, every patient met with the, with the dietitian, and the dietitian followed key principles for each of these interventional arms. We also want to encourage patients to adhere with these diets, so um we um. For the Mediterranean diet, patients received shipments of olive oils and nuts, and there were also some um um more electronic ways of encouraging them and sending them text messages and uh providing advice on a weekly basis and then monthly. So it, it, it was, um, we did our best to implement these uh interventions. Um, so I wanted to share with you the results. These were presented at the ACR last month. What we found is that all of the patients lost weight, so it irrespective of the arm, and this is the first message is that I guess just being in a trial is is encouraging people to Change their um diet or their habits. I think one is just a constant reminder and people get to think about what they eat and report about it, so that probably promotes change. Um, on the left hand side you can see here that um the Mediterranean arm. Lost weight, but the least amount of weight. I think this was again by design because they did receive the olive oils and nuts that are rich in in energy and calories, but all of the groups lost weight, modest amount, but significant compared to the baseline, as well as reduced their waist circumference. Looking at the PSA outcome, so that our primary endpoint was DASA score, and um on the left hand side you can see again that there was a significant reduction in DASA score across all arms, but uh no difference between the. The different interventional arms and with the MDA um it's 12 weeks there may be a borderline difference between the dash low caloric diet compared to control, but the 24 weeks they were all the same. So again, the, the bottom line here is that um. No matter what arm, people improved and both in terms of weight reduction as well as in PSA outcomes. Um, and when we went back and looked at how much weight loss affected these changes, and you can see that there is a significant correlation between the weight that people were losing and the extent of improvement, and this was seen for DASA score for tender joint count for pain, and you can see there on the bottom, the four plots are showing you. On top here, patients that were lost at least 5% of their body weight were those that had the greatest improvement, and it doesn't really matter what arm they were randomized to. So, um, The take-home message from this is that Both personalized diets, but also general recommendation. I think especially in the context of a study, uh, leads to um an improvement in um cardio metabolic outcomes, uh, this in particular, this particular case, uh, weight loss and concurrent reduction improvement in in disease activity measure. And many patients are asking about specific diets, so I think the take home from this is that it's mostly about the weight and maybe not, at least at the group level. We don't see any significant differences between these types of diets. So no matter what diet you use to lose weight, that the weight, the amount of weight loss is, is important. Um, and it seems like weight is, weight reduction is driving most of the effect here. So, um, so diet is great, but it's so hard, uh, it's hard to implement, uh, especially as a, as an, um, isolated intervention and especially in people with morbid obesity. Um, in our study, in the DPPSA study, we limit the BMI to 40 because our dietitians were telling us that diet alone is really not very effective, um, in a BMI of more than 40. So, Fortunately, we have now um effective treatments that could address obesity, um, diabetes, and many other potential conditions. And, so we can study this more effectively. And it's also been suggested that um GLP-1 medications might have a direct anti-inflammatory effect. Um, this is, uh, again from that review paper that I mentioned. Uh, there were a few studies that show that, um, there are GLP-1 receptors on uh in various NKT cells that we know are important cells in the context of psoriasis and, and also psoriatic arthritis. Um, so, Um, these medications, when they bind to the GLP-1 receptors, they can trigger intracellular, um, um. Uh, pathways that um eventually lead to a decrease of inflammation, uh, reduced production of a pro-inflammatory cytokines such as IL-17 and more. Um, this is being actively investigated, so this is very preliminary data, but there is again some suggestion that the effect might also be direct, not just through the weight reduction. And, um, We also know now that Weight reduction is an important intervention that can help people with osteoarthritis. Uh, this is from, um, a, a publication from about a year ago, um, semaglutide in GLP-1 receptor agonist in patients with a knee OA who were obese. This was a big study. It showed that in parallel with the reduction in weight, there was an improvement in pain in these patients, um, but you can see that this is, um, it, it takes quite a lot of time. This study lasted 68 weeks, more than a year, um, so it's not an immediate effect like we typically expect with the biologic. It's a long, it's a long term effect. So in parallel with the weight reduction, we, we can see that improvement, and this is a recent, uh. Uh, from a recent announcement, um, this is a triple agonist, so I won't be trying to say the name ratutriid or something like that. That's a, a new triple, um, GIP, GOP, and glucagon agonist, um, that has been studied for NOA again, the same population showing, um, significant reduction in weight and in parallel improvement in, um. In pain in these patients. So, in patients with OA, um, certainly this is, we, we don't have a lot of options of treatment, and this is important, and I did mention many of the patients that we see in clinic in, in with PSA have osteoarthritis. So, another reason why we should be considering this. What do we know about GLP-1 in psoriatic disease? We don't know a lot. There's been a few small case series that were published, and most of them looked into relatively older agents like lyralutide, that were less effective, and the majority of them looked at the skin disease, and they showed some mixed effects. Some studies showed an improvement in the skin disease, in psoriasis, and some of the patient reported outcomes. Others didn't show much of a difference. So we decided to look into GLP1 receptor agonist um in our cohorts. Um, so this is a combined effort of the um team from NYU, um, and, and the, the Toronto cohort. We performed the retrospective cohort analysis, uh, within our two cohorts. Uh, we were looking for, for patients who are starting treatment with semaglotide or trazepatide. And that we had information on in their disease activity at least a year before they started these treatments and, and, and, and then after. So these are the uh results again pub presented the. At the ACR last month we identified 48 patients um and with a mean age of about 50, most of them were females, um, and most of the, the prescribed drugs were semaglutide, minority was tzepatide in Canada terzepatide. It was just recently approved for weight loss, so the majority of the patients in Canada are still being prescribed semaglutide for weight reduction. And the BMI was almost 35. Um, you can see the profile of comorbidities here. Um, I mentioned, um, many of these patients have multiple comorbidities that have been associated with, um, poor response to treatment, sleep apnea, depression, osteoarthritis. These are common in these patients. And these medications lead to significant reduction in weight. So on average, people lost more than 6, almost 6.5 kg. 14 pounds and we're looking at a percentage of weight loss from baseline. Almost 80% lost weight and more than half of the patients lost a substantial amount of weight, which is at least 5% of their body weight. Just as a comparison in the diet study. This was around 3%, so this is typically diet studies are looking at 3 to 4% reduction. So these are substantial reduction. This is substantial reduction in weight. Looking at PSA outcomes, so, um, I, I wanted to mention first that many of these patients did not have a very active disease at the time of prescribing these drugs, so it's harder to show a change if a patient doesn't have a lot of pain or active disease. But we still saw a signal for an improvement in disease activity measures, and you can see a significant reduction in CRP in swollen joints and in pain, and numerical reduction in the DASA score. And when looking at how much weight reduction influence the improvement, um, similar to what I've shown you in the diet study, you can see that those that were able to lose weight, a significant amount of weight showed the greatest reduction in DAPSA score, um, and we're also showing more improvement in the, in cardio cardio metabolic outcomes like lipids and blood pressure. So to summarize this, I hope I convinced you that obesity is important in PSA. It's not, it's more than just the comorbidities. I think there is a lot of epidemiological evidence, genetic. There are also some basic research that supports causal relationship between psoriasis, psoriatic arthritis, and obesity. Uh, it does affect patients with established disease. Um, so I think we need to start thinking about how we can incorporate anti-obesity treatments in our treatment strategies more actively than, uh, we have done so far now that we have more effective treatments. I think diet is is still important. It's um it, it, it can lead to improvement in um. In disease activity measures, it can serve as an adjunct therapy. It's important for overall health and cardiovascular cardio metabolic outcomes, but overall, especially in patients with morbid obesity, it probably is not enough as the only treatment. And therefore, uh, thinking about GLP-1 medications. I, uh, I think becomes very relevant for us as rheumatologists, but we still have significant gaps that, um, we hope to study, um, in, um, in a new, uh, cohort that we hope to put together, um, uh, within, uh, Pac-Man in collaboration with, uh, um, Rebecca Haberman and Jose. Uh, where we hope to study the mechanism, we, we hope to understand what is driving this, um, close link between obesity, psoriatic arthritis. Who should we prioritize? Should we think about difficult to treat disease? Should we think about early disease? Uh, we also want to study the real world effectiveness. We know that, um, many patients start treatment and stop because of side effects, so this is, uh, an issue in many patients. Sarcopenia is, is another problem that may happen in, in some patients. So in, in concurrent with losing, um, adipose tissue, they can lose muscle mass. So how much this is an issue in, in our patient population. Um, so overall, the, the idea is to try and, um, bring. And, and, and generate real world data that could help us inform recommendations about obesity and the management of obesity in the context of psoriatic arthritis. So, um, I wanted to thank, uh, this, this is my team in Toronto, um, and I want to thank, um, the NYU team for this close collaboration and Alexis for, uh, her collaboration, uh, as well as Daphne and Vinod in Toronto for, um, being, um, great collaborators for many years, uh, and our founders, and thank you for your attention. Published December 19, 2025 Created by
CME Knowledge Hub