Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

PSA management has advanced significantly over the past 2.5 decades, yet outcomes remain suboptimal for a substantial proportion of patients. A key contributor to the gap is obesity, which is not only a comorbidity but is an active metabolically driven inflammatory modifier that directly influences PSA disease activity, treatment response, and long-term outcomes. Of note, obesity occurs in up to 40% of PSA patients, partly driven by genetic factors. Despite this, obesity remains under-recognized as a contributor to PSA disease activity and outcomes and is inconsistently integrated into clinical reasoning and treatment decision making. Let's begin with the foundation. Before we can make better treatment decisions, we need to reconsider how we interpret disease activity in patients with PSA and obesity. That starts with understanding the biological impact of obesity in this context. In this slide, we see the obesity inflammation axis in PSA. Starting within the center, adipose tissue, which is a metabolically active inflammatory organ. We see that there is an increase from this tissue of the cytokine TNF alpha, which drives synovial inflammation and attenuates TNF inhibitor response. Also from this tissue is produced interleukin 6, an important inflammatory cytokine which elevates CRP, inflates composite disease activity scores. Leptin emerges from adipose tissue, which is pro-inflammatory and promotes TH 17 polarization and IL-17. Another adipose tissue derived important molecule is resistin, which promotes insulin resistance and amplifies inflammation. And interestingly we see decreased adiponectin, which has normally anti-inflammatory activity in obesity, and there has been loss of protection from this particular hormone. The idea that adipose tissue is not passive but actively fueling inflammation has direct implications for how we interpret the scores we rely on in daily practice. Let's see how our audience is currently thinking about this. Here's a poll question before reviewing a patient's metabolic profile. What is your primary interpretation of persistent symptoms in a PSA patient on a biologic? Inadequate inflammatory control. Consider escalation of current immunomodulatory therapy. B. Mixed picture inflammation and non-inflammatory drivers. C. Likely obesity-driven mechanical load and adipocine activity. Or D. Uncertain. You need more information. Interesting. It looks like we have a variety of responses, so we're going to dive more into this as we go along here. Here we see 4 possible quadrants of interpretation or misinterpretation of inflammatory disease activity based on obesity. In the upper left we see a patient with high BMI but low inflammation. This is a patient who has very little in the way of objective markers of inflammation, such as highly elevated CRP or swollen joints, but does have a high BMI and so we know that obesity may be contributing significantly to their disease activity. The symptoms though are attributed to uncontrolled PSA, and a biologic escalation may be considered, and the metabolic driver of inflammation is missed altogether. In the lower left we see a patient with low BMI and low inflammation, so composite scores are more likely to reflect the true disease activity, which is low, and also obesity is not contributing to driving the inflammatory response. And so we're correctly interpreting the patient as having a state of controlled disease. In the upper right, uh, we see a patient who has both high BMI and high inflammation, a mixed signal, and therefore, we aren't certain what's causing what. In this case, the patient has active synovitis as reflected in swollen joint count. Maybe they have a very high CRP. But we also should keep in mind that the presence of obesity is providing additional inflammatory drive. And so we need to be very careful and detailed about how we're interpreting. distributions from both obesity as well as ongoing active inflammatory activity. And in this patient, it may be justifiable not only to think about switching background immunomodulatory medicine, but also treatment of their obesity. And in the lower right, we see a patient who has a low BMI but high inflammation signals. Uh, this is a patient with active synovitis, swollen joints, maybe a high CRP, active emphysitis, uh, and, uh, so the The fact that the patient has a normal BMI is reassuring us that our interpretation of their disease activity is mostly coming from, say, joint or enthesal inflammation and therefore focusing on adjustment of immunomodulatory. Medication with our standard PSA approved drugs would be our focus and not necessarily needing to treat obesity. Dr. Merola, in your clinical practice, how does a patient's BMI and metabolic profile change the way you interpret their disease activity score? Can you walk us through how you approach this in a consultation? You know, I think for the, for the high BMI patient, um, it can sometimes be tricky on, on a few fronts. Uh, I would say, you know, it can sometimes be a little bit tough to unpack what's inflammatory versus non-inflammatory, uh, you know, with regard to symptom burden, uh, particularly in weight-bearing joints, but it may be the case in, you know, in other areas as well. Um, I think it can be challenging on the physical exam. Uh, sometimes to get a really good handle on the dactylytic digit, for example, from body habitus, which can sometimes lead to some challenges comparing side to side, and we really have to lean into their, uh, you know, uh, the tenderness assessment, for example, it can be a little bit tough maybe to appreciate as much, um, swollen, uh, joint or, or dactylytic digit in that context. So I think there's some clinical features, uh, to think about, um. I also think, you know, increasingly, we're leaning into imaging uh to help us decide whether something is inflammatory, non-inflammatory, or, or where, where it sort of fits in the spectrum. Um, I think, you know, in that case, uh, MRI in particular can, at least in my opinion, be a little bit more objective looking for uh relevant synovitis, um. I will say ultrasound, I think, um, and I have, I use very limited ultrasound imaging in my personal practice, but I know from being part of, you know, this area of the field that in particular uh in. Certain, again, you know, weight bearing uh structures and theses, especially Achilles, etc. we can see sometimes changes that uh recapitulate an inflammatory state, but really may have something to do with weight and stress across that in thesis or across that joint, uh, and sometimes that can be challenging as well as trying to understand what is inflammatory versus non-inflammatory in that, in that context, so. It's not to, uh, you know, uh, uh, undermine our, uh, confidence, if you will, uh, when we discuss this with patients, but I think it's a realistic view of how it's not black and white, uh, and how it can, uh, you know, the, the, um, uh, weaving in the conversation about high BMI in our interpretation of disease activity is relevant. I also hope what it does over time. Is help us as a community think more about objective ways to assess the inflammatory burden from some non-inflammatory contributing elements and, you know, whether that's with.