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Let's move into the heart of today's discussion. How do we translate this understanding into better, more individualized treatment decisions? This is where the clinical stakes are highest. Default escalation of biologic therapy in patients whose disease activity is partly driven by unaddressed obesity may expose patients to unnecessary risk, cost, and complexity while missing the opportunity to address a modifiable driver of inflammation. Let's explore how we can do better. As we see in this slide, up to 40% of PSA patients have obesity, defined as a BMI greater than or equal to 30. Approximately double the rate seen in rheumatoid arthritis. There is 2.5 to 3 times higher likelihood of inadequate biologic response in patients with obesity versus normal BMI. And approximately 1 in 3 PSA patients have evidence of metabolic syndrome. So we see that obesity is both the most prevalent, but also unfortunately one of the most under-addressed comorbidity in PSA. Now let's turn to a case example. Let's meet our patient, David, who is 47 years old, diagnosed with PSA for 6 years, and has a BMI of 41 kg per meter squared. He is currently on a TNF inhibitor at standard dosing and presents with a DapSA score of 32, which is in the high disease activity range. He has no enthesitis or axial involvement. His rheumatologist is considering switching to an IL-17 inhibitor. He was recently started on a GLP-1 receptor agonist by his endocrinologist who has been seeing him for type 2 diabetes. Now let's look at polling question number 3. What is your most likely next step for David? Switch to an IL-17 inhibitor due to inadequate TNF inhibitor response? B, optimize current TNF inhibitor by considering dose adjustment. C. Address obesity and metabolic factors before changing agents. Explore co-management with use of a GLP-1 receptor agonist along with current biologic before switching, or E refer to a multidisciplinary team before making a treatment decision. Thank you for your responses. And now, uh, turning to Doctor Gottlieb, looking at David's profile, including high disease activity, significant obesity, and GLP-1 receptor agonist use, how do you approach the treatment decision here and what is the evidence base that informs your thinking? To me, it's clear that he is not responding to the current dose of TNF inhibitor. He has just started the GLP-1 receptor agonist, so we do not expect quick response to that. It takes a while to get up to therapeutic dosing and also to see the effects, and this patient is in pain and is uncomfortable. So if it were my patient, the first thing I would do would be to switch to an IL-17 blocker. That doesn't mean that the adipose tissue is not playing a role, but this patient is uncomfortable and. Time is bone, as they say, and so you don't want him to go for a few months longer, which it can take to get a GLP-1 receptor agonist in the optimal dosing. Um, I, I think it's an excellent idea to use the GLP-1 receptor agonist as an adjunct treatment because, uh, the adipose tissue is contributing to the inflammation and the patient has diabetes. And all of the other good things that GLP-1 agonist receptors, receptor agonists do in the, on the cardiovascular front. So my, I, I would, I would, I would switch them. I would definitely be aggressive assuming side effects don't limit it in, in updosing the GLP-1 receptor agonists. Um, that's what I would do, assuming, of course, that all treatments are available. OK, if, if I live in a, in, in a situation where they can get only TNF inhibitors, that's a, you know, that's it, then I would adjust the dose or switch, try to switch to a different TNF inhibitor. But if all drugs are available and there's no issue of access or cost, I would switch to an IL-17 blocker. Could you also uh talk us through some of the evidence base in this particular topic area? Well, there's not a whole lot of comparator studies, OK, to say that one approach is better than another. So, uh, this is still interpretation of limited data. You're going to hear later from Doctor Morola, who I believe wrote the protocol for this, that using exechizumab in combination. With a GLP-1 receptor and ago and a GLP-1 receptor agonist would, is better. In terms of uh joint and and arthritis outcomes than using ixekizumab alone and ixekizumab is pretty effective all by itself. So we have evidence of combination of, of uh GLP-1 receptor agonists and a highly effective IL-17 blocker is better than IL-17 blocker alone. But we do not have comparative studies whether increasing TNF and, and, and uh blockers when they're not working and, and optimizing the GLP-1 receptor um agonist, though it, it might, might be equally good to switching to an IL-17 blocker with the, with the GLP-1 receptor uh agonist, but I, I, I think basically we're basing this on Doctor Morola's seminal study. Let's take a look at a study that addresses the point that successful weight loss increases the chance of achieving a desirable target of minimal disease activity in psoriatic arthritis. Here's a study that was conducted in Naples, Italy. Uh, the lead author is a nutritionist named Domino. And what was done here was that there was a group of patients that were Uh, treated with a weight loss, uh, diet, uh, pretty strict low caloric diet, and then another, uh, uh, group that was a control group that did not have a particular dietary restriction. And what was shown is that if there was at least a 10% weight loss, there was a significantly increased chance of achieving minimal disease activity criteria. MDA is a composite measure that includes 7 items such as achieving a tender joint count of less than or equal to 1, a swollen joint count of less than or equal to 1, and so on. And if you achieve 5 of these 7 item thresholds, then you're in a state of MDA. And here we see that the more weight loss that occurred, there was a higher odds ratio, in this case, 6.67 of achieving MDA. If there was a 5 to 10% weight loss, slightly less achievement of MDA, and then if there was no Weight improvement, then they were less likely to achieve MDA. So as we can see, working against obesity, it raises our possibility of achieving a desirable treatment outcome. In this slide, I would like to review for you the data from the important Together PSA trial, which was recently published and provides findings supporting a dual obesity and PSA treatment. Together, PSA is a phase 3B randomized 52 week trial. Patients with very active psoriatic arthritis, many of whom had been on previous immunomodulatory treatments for the disease, were randomized to receive either ixekizumab, an IL-17A inhibitor, alone, or a combination of ixekizumab and terzepetide, which is a GLP-1 and GIP receptor agonist. There were 271 patients with, as mentioned, very active PSA and overweight with at least one weight-related comorbidity or obesity. And at baseline, uh, this patient group had a very high BMI. The primary endpoint was the simultaneous achievement of ACR 50 and at least a 10% weight reduction.