STEP Talks from RNL26 Part #2 Save

You're listening to a podcast session from RoomNow live recorded on 02/07/2026. These STEP lectures are made available to the rheumatology community by our sponsor Pfizer. I hope you enjoy the lectures. But first, a message from our sponsor.

This podcast is sponsored by Pfizer. At Pfizer, we believe collaboration is essential for advancing the treatment of chronic immunoinflammatory diseases. Through research and education, we remain dedicated to supporting the health care community to improve the lives of those impacted by rheumatic diseases. To find out more about our commitment, visit pfizer.com.

Welcome back everyone. We had a great morning here, RheumNow Live twenty twenty six. We got a whole lot more learning to do. So let's get everybody back in their seats if we can please. A couple of announcements to start us off.

As you're seeing tonight, we have a performance by Colin Boyd. Don't miss that. It's gonna be great and it's after the evening reception. Hopefully everyone knows that you get what's sure to be a collector's item very soon, the RheumNow Live twenty twenty six t shirt. So go by the booth out in the Exhibit Hall and double XL XL, large or medium, get your shirt.

These will be worth something. You'll be selling them on eBay in a couple of years and, you know, make it very worthwhile. And most importantly, please write down your comments and let us know. What worked good, what didn't work well, what things that you wanna see changed at all. We want this meeting to be even better next year than it is this year.

This is gonna be a great meeting, but we wanna make it better. The way to do that is with your comments. So with that, we're gonna start off. We had a great pod one. This is pod two, and it's advancing practice.

Very pleased to have two great speakers. First, have Doctor. Usma Haak from Hopkins, who's gonna talk to us about obesity and inflammation, weight management, rheumatology. We tried not to have this too close to lunch, so no one felt particularly guilty. But it's a super important topic and extra pleased to have an expert here to talk to us about that.

Doctor. Heck.

Thank you so much. Thank you so much for your kind introduction and for the invitation. And it is certainly a pleasure for me to be here in Dallas today and to speak to you about a topic that is really, you know, very much a buzz of the moment, weight loss. And how this may impact our diseases is indeed something that we as rheumatologists should be thinking about. So I think it's a very timely and opportune topic to be discussing this.

I have no disclosures except the fact that this is home, and I'm certainly very happy to be in 65 degree temperature rather than minus four degrees back home. So here are some of my objectives. I'm going to just quickly walk you through those. What I want to do is give you a sense of this obesity inflammation axis, and how it impacts patients with rheumatic diseases. I want to discuss the gathering data on use of anti obesity medications, specifically the GLP receptor agonist in rheumatic diseases.

And to really mention or discuss the role of rheumatologists in this evolving landscape. Let's first start by defining obesity. WHO defines it as a state of abnormal or excess body fat accumulation which presents a risk to health. Obesity is a chronic, relapsing, multifactorial disease. And using BMI as a measurement, we define overweight individuals as having a BMI of twenty five to twenty nine point nine, and obese individuals as having a BMI of greater than thirty.

Obesity is a global health challenge. In 2022, sixteen percent of the adults worldwide were obese, and this worldwide adult obesity has more than doubled since 1990. But the twenty seventeen-twenty eighteen enhanced data, forty two percent of U. S. Adults are obese.

Sobering statistics, certainly. Now let's look at this graph, which tells you about the trend of obesity in The United States over a ten year period from 02/2008 to twenty seventeen-twenty eighteen. And as you can clearly see, this rising trend, so that in 2007, thirty two percent of The U. S. Adults were obese, but in 2017, forty two percent are.

It is estimated that by the year 2030, fifty percent of The U. S. Adults will be obese. Now, this has been catapulted by consumption of nutrient poor, energy high dense foods, and by decreased physical activity due to the nature of our work, access to transportation, etcetera. We are becoming more and more sedentary.

Actually, if you're living up in the Northeast and you look at the number of steps you have taken in a day, most of us as active clinicians will not have taken more than 2,000 to 3,000 steps a day. So certainly this is something which is concerning. And again, think about remote jobs and the rise of remote jobs and our younger generation sitting in front of computers most of the day, indeed this is alarming. As clinicians, we recognize that there is a tremendous impact of obesity on our patients. We recognize the comorbidities associated with obesity.

And here is a recent report by the Milken Institute that estimates that the total direct and indirect cost of obesity in The United States is about $1,400,000,000,000 annually. So obesity is common, and obesity is expensive. Now with that background, let's walk to the adipose tissue. So the primary purpose of the adipose tissue is to perform energy storage in the form of lipids. However, we have known from the mid-1950s that the adipose tissue is a very active endocrine organ secreting cytokines, adipokines, and chemokines that are important in regulation of diverse and very important functions such as metabolic homeostasis, etcetera.

In our body, this adipose tissue is organized as subcutaneous adipose tissue, predominantly present in buttocks, thighs, upper arms, and that's where women carry most of their adipose tissue, versus the visceral adipose tissue, which is actually present inside the abdominal cavity. And it is well known that the visceral adipose tissue is highly metabolic, and is associated with increased risk of type two diabetes and metabolic syndrome. Now, let's see what obesity does to the adipose tissue. So here on the left, sorry. Here on the left is the lean adipose tissue.

These adipocytes right here release anti inflammatory cytokines and chemokines such as adiponectin, which is very important in regulation of metabolic homeostasis, IL-ten, IL-four anti inflammatory cytokines. Now what happens with obesity is that as these adipocytes become full of fat, there's hypertrophy, there's hypoxia, there's cell death and necrosis, there's infiltration of immune cells like cytotoxic T cells and macrophages. And this entire organ now becomes a highly pro inflammatory organ, secreting cytokines and chemokines, such as the cytokines such as TNF alpha and IL-six. Of course, we are all familiar with them. But also chemokines and adipokines like leptin, which is associated with insulin resistance, also is associated with the IL-twenty three, IL-seventeen pathway.

So I would say that if you look at this, it would be easy for us to understand, it would be easy for us to understand how obesity can transform the adipose tissue into a highly inflammatory organ, and this is what constitutes the adipose inflammation axis. Now, how would this inflammation axis impact rheumatic diseases? We have known for quite some time now that overweight or obese individuals have a higher risk of developing rheumatoid arthritis. In fact, this risk is the same as that attributable to smoking. We also recognize that obese patients with psoriasis have a one point seven times greater risk of developing psoriatic arthritis.

Moreover, I think I will not have to convince you about this slide, because as astute clinicians, you all know that when you see that patient with rheumatoid arthritis or psoriatic arthritis who's obese, they often have higher disease activity, and they have poorer response to DMARR biologics. In fact, these obese patients have a twenty to twenty five percent lower chance of reaching remission in inflammatory arthritis despite the availability of our current DMARDs and biologics. So I guess this behooves us to ask this question of whether obesity is modifiable risk in our patients with rheumatic diseases. Our colleagues, several of our colleagues make a case for that. So here is a review that was published six months ago in which the authors make a very strong case of how obesity, directly and indirectly, makes an impact on management of our diseases and makes it more challenging for us to manage rheumatic diseases.

For example, obesity amplifies pain, fatigue, mood disorder, poor mobility, symptoms that our patients already struggle with. Moreover, obesity is associated with many comorbidities, as we know, and also increases the risk of infection, increases the risk of metabolic associated liver disease, thus making it difficult for us to manage these patients and making it challenging for us to use some of the medications that we use to treat these diseases. Now, from that, should we extrapolate that as good rheumatologists we should care about obesity management? And I would say that that is probably true because if you want to have optimum outcomes in our patients, then this it is important for us to pay attention to this very important variable. While management of obesity is an entire field, and of course, there are many layers to it, it's multimodal, I would say that as rheumatologists, it's important for us to recognize that lifestyle and behavior intervention, including diet and exercise, forms the very core of this pyramid.

American College of Rheumatology, of course, recommends a Mediterranean diet, a low calorie diet, and a moderate degree of exercise for about one hundred and fifty minutes weekly for our patients. But today, for the interest of time, and also because in the interest of what is really exciting out there, I will be focusing on the anti obesity medications, specifically GLP-one receptor agonists that have now been approved for management of obesity. So let's talk about these medications. They have certainly transformed the field of obesity medicine. Glucagon like peptide one receptor agonist.

What do they do? They mimic the action of GLP-one. And what is GLP-one? GLP-one is a hormone that is secreted by the intestinal mucosa, as well as by the pancreas and some neurons, usually in response to a meal, and the GLP-one receptor is present widely, and this is important in regulating several diverse functions, but mostly appetite, insulin metabolism, glucagon secretion, etcetera, as well as homeostasis of metabolism. So what are the glucagon like peptides, I'm sorry, what are the glucagon like peptide one receptor agonist medications doing?

They are causing insulin secretion. They stimulate insulin secretion, inhibit glucagon secretion, slow gastric emptying, and promote weight loss. We've all seen this. Our patients who have lost twenty, thirty, forty, fifty, sixty, may I say up to 80 pounds of weight, these were our patients who were struggling with weight loss, who had tried many other interventions in the past and had failed. And right in front of our eyes, we are seeing this, especially as clinicians, and really applauding how our patients are feeling better with the use of these medications.

Of course, I'm talking about obese patients. So FDA has now approved these medications for type two diabetes, which it was initially approved for, as well as for obesity, cardiovascular disease, chronic kidney disease, and most recently, sleep apnea. And I feel that this list will likely continue to grow. So if you think about these incredible medications, I want to now review with you some of the retrospective data as well as clinical trial data that is emerging in terms of using these medications in our realm. So let's first look at inflammatory arthritis.

I'm going to walk directly to this study. This is known as the Together Psoriatic Arthritis Study. We should all be familiar with this. This is a phase 3B randomized multicenter open label study. We got some initial results recently.

So this is thirty six week data that was reported as a news release just two weeks ago. So fresh, it's hot off the press. And so let me walk you through this study. What they did in this study is that they enrolled patients, two seventy one patients who had active psoriatic arthritis who had a BMI of greater than twenty seven. Again, if you go back and think about the BMI ranges that we have talked about, and they had one other weight related comorbidity, and they randomized these patients to either ixekizumab plus tirzepatide arm versus ixekizumab arm alone.

And in both these groups, these patients were counseled regarding diet and physical activity. The primary co endpoint was the ACR 50 response in psoriatic arthritis and greater than 10% weight reduction. The secondary endpoint was ACR fifty response only. Let's look at the results. So at week thirty six, the combination arm met the primary and all the key secondary endpoints for superiority against the monotherapy.

So this primary endpoint of, remember what we are talking about is ACR twenty response for psoriatic arthritis plus more than 10% weight loss achieved by 31% in the treatment arm, point 8% in the placebo arm, and you would say, well, this is not that impressive. We know that tirzepatide is just incredible in terms of weight loss, and so we are not so impressed by this difference. But look at the secondary outcome, which was only the ACR fifty response uncoupled with weight loss in the two groups. And you can see that even here, the combination group that is far superior than the execizumab alone group. So again, this is so interesting in that it is suggesting that there may be a disease modifying effect of the GLP receptor agonist that goes beyond weight management.

All right. Let me now, as I said, I have a few studies that I want to walk you through. So this is a study of rheumatoid arthritis patients. Let me walk you through that. So here, this is unlike the first study that is a randomized controlled trial, this is a single center retrospective observational study.

So of course, the results have to be, you know, evaluated carefully. But what this, the authors did was they looked at patients who have rheumatoid arthritis with a BMI greater than twenty seven who were prescribed a GLP receptor agonist between 2018 and 2024. And the treatment group consisted of 173 RA patients who took the GLP receptor agonist, and the control group were the forty two patients who did not. Now, again, this is retrospective data, so we really do not know why the GLP, they were not able to really identify exactly why the GLP was prescribed in this group, but it was most likely because of type two diabetes. The outcome measures, I'm sorry, the outcome measures here included RA disease activity, cardiovascular risk markers, and patient reported outcomes.

Let's look at what they found. So they found that the GLP treated RA patients experienced significantly greater reductions in RA disease activity, in the pain score. Of course, they lost more weight, and they had significant improvement in total cholesterol and hemoglobin A1C. They also noted that nearly one third of the patients who were prescribed GLP-one actually discontinued it because of the side effects. So this suggests this study, while retrospective, still suggests that perhaps use of the GLP receptor agonist in patients with rheumatoid arthritis may improve RA disease activity and cardiovascular profile.

Here is another small retrospective study, and I'm not going to focus too much on this except to let you know that in this study, again retrospective study, they noted that addition of a GLP receptor agonist to RA patients receiving baseline DMARDs resulted in a reduction in frequency of RA flares. So that was about inflammatory arthritis. Now let's walk to osteoarthritis. I was hoping that Doctor. Neil G.

Will mention this study, and that might make my job a little easier, but I guess she did not, so let's walk through this. Again, as rheumatologists, I think we should all be familiar with this data. So this study was published in New England Journal of Medicine in October 2024. This is a sixty eight week double blind randomized controlled trial of 61 sites, 11 countries. And what they did was they took four zero seven obese patients who had moderate knee osteoarthritis with moderate pain, and I think this is great in terms of setting up how you should look at this data in terms of what Doctor.

Nioji has just taught us, and then they randomly assigned them to receive either semaglutide or placebo, plus again exercise and guidance and counseling regarding a reduced caloric diet. Their primary endpoints were, of course, a change in weight, and number two, a pain scale as measured by WOMAC. Let's look at the sixty eight week trial results here. So, we're not surprised, but weight loss was achieved in thirteen percent of people in the treatment arm versus three percent of the people in the placebo arm. The pain score was remarkably improved, forty one percent in the treatment arm versus twenty seven percent in the placebo arm.

The people who were treated with semaglutides also reported greater improvement in their SF 36 physical function scores. Now, again, important to note that about seven percent of the treatment group were needed to discontinue their medications due to side effects, mostly being GI side effects. And while this trial, I think you will, in your mind you will say, sorry, that this is certainly impressive, but maybe not surprising because, semaglutides are associated with 13% weight loss. The patients are going to feel better. They have less weight, less biomechanical loading of their joints, and so they have less pain.

And I agree with you on that. So at this point, there is another trial that is, clinical trial that is being conducted known as STOP Knee OA trial, where they are actually evaluating structural data with use of GLP-one agonists. Evaluating their MRIs and what happens to MRI over time as patients lose weight. So tune in for that study. I can tell you that after this publication, again, we have our colleagues really advocating for FDA approval of use of GLP receptor agonists for hip and knee osteoarthritis in overweight patients.

And so as rheumatologists, please tune in and we'll see what the next steps are with osteoarthritis and use of GLP receptor agonists. Now let me walk you to our next most common disease, that's lupus. And see what is the data regarding these medications in lupus. So this study, again, is a multi center, retrospective observational study using U. S.

Electronic health records of patients who are greater than 18 years of age who have lupus and have type two diabetes. They evaluated these patients over these years, and they found that patients with lupus plus type two diabetes, there were nine zero one patients, nine ten, sorry, who were started on a GLP receptor agonist versus one thousand patients who were started on another oral hypoglycemic agliptin in this case. Their primary outcome were MACE events and progression of kidney disease. Think about your lupus patients in your clinics. What do we worry about?

We worry about their cardiovascular health. We worry about lupus nephritis, which is so common in lupus. And we worry about the fact that thirty percent of your patients with lupus nephritis will go on to develop end stage renal disease despite the best treatment options that are available at this time. So, if you put it in this context, let's see what this trial shows us. Again, as I said, it is a retrospective trial.

So, we have to evaluate the results carefully. But here, in the primary analysis, lupus patients who were diabetic and were on a GLP-one had a marked reduction in all of these primary outcomes. MACE outcomes decreased by almost thirty three percent, thromboembolic outcomes decreased by fifty percent, kidney disease progression decreased by thirty percent, all cause mortality decreased by almost seventy five percent. So certainly, even though this is retrospective data, again, these results are quite novel and unique. Now, when they looked at a subgroup of patients, so this was lupus plus type two diabetes.

Here was a subgroup analysis of lupus patients with lupus nephritis and diabetes. They again looked at this analysis, and they again found that the MACE events were lower with GLP-one receptor agonist, and kidney disease progression was lower with GLP receptor agonist. Again, not entirely surprising because we know that patients with chronic kidney disease do much better if they are put on GLP-one receptors, and that it is cardio protective as well. However, I think it is, as I said, you know, for our lupus patients, if we can add something to their therapy that can give them a better chance at fighting these chronic comorbidities, it will certainly be a welcome change for us all. Now, this is again, just quickly I wanted to mention this study as well.

It's again kind of impressive data that was presented as an ACR abstract. Again, it is retrospective. What they did was they went back and they looked at all patients who had lupus nephritis, and were ever prescribed GLP-one receptor agonist versus never prescribed a GLP-one receptor agonist. And what they found is that at five years, the risk of progression to end stage renal disease was cut down by half in patients who were prescribed GLP-one receptor agonist with lupus nephritis. Again, as I said, this is retrospective study, and it just indicates that there may be a benefit of nephroprotection in these patients.

All right, so I think I've gone through a lot of the data with you. Now what I want to do is just kind of you know, bring us, all of us back to reality. The reality is that of course there's good emerging clinical trials that suggest that these medications may be beneficial in our patients. But there are significant challenges, right? Not everybody can get a GLP-one.

Not everybody who needs a GLP-one gets a GLP-one. There are issues of access and cost, and these are expensive medications. Of course, we are thinking about long term safety of these medications. There are side effects. So again, not everyone can tolerate a GLP-one agonist.

And some of these side effects can be quite significant, including pancreatitis, small bowel obstruction, aspiration during procedures, etcetera. So again, we have to, if we step into this field, we step into this field with caution. And I think there are some very interesting future questions, right? I think I've hopefully convinced you that there is a uncoupling between weight loss and the anti inflammatory properties of GLP-1s. There's likely an uncoupling.

So the question is, are these medications good for our patients patients who are not obese? Other questions like, will we be needing fewer DMARDs in our patients who have inflammatory arthritis whose BMI comes down from twenty eight down to twenty six? And is there a minimum weight loss that is associated with the anti inflammatory properties of these medications? All very interesting future questions, which I think will be answered in the near future. And I will say that despite all the excitement about these medications, I think we as physicians, it's very important for us to play the role of the safe gatekeeper here.

You know, it's very important that the distribution of these medications is regulated. It's prescribed by healthcare providers who are qualified to prescribe it. That there is, it is associated with patient education and equity of distribution. Because that is what is needed and is critical to ensure safe and equitable treatment of our patients with these diseases. Clinical applications.

I would say that when you go back to the clinic, I'm a clinician, and so anytime I'm giving a talk, I'm always thinking about how do I take this information and take it back to my clinic. I would say for every patient, please glance at their BMI. If their BMI is more than twenty five, or actually twenty seven, I would say you should predict a more severe disease activity, poorer response to DMARDs, and presence of comorbidities that would make it difficult for you to manage that patient. And again, in your mind, you're thinking, all right, there is this gathering data regarding the possible disease modifying effects of GLP-one, is this something that would be appropriate for this patient of mine? And really, we are ready or not, our patients will be.

So we as rheumatologists have to be ready to speak to our patients, to talk to our patients about this, and to become their good partners in this co management. So I'm supposed to give three, last three lessons learned. I would say that I hope that I've convinced you that there is an obesity metabolic dysfunction inflammation axis, which negatively impacts patients with rheumatic diseases. That there's emerging data that these medications can be beneficial in our patients to treat our diseases and to treat the comorbidities that often accompany our patients, often accompany these diseases. And finally, to say that as rheumatologists, we really should be on the forefront of this interdisciplinary collaboration with our patients, with the primary care physicians, with obesity medicine experts, so that we can ensure an integrated approach to anti obesity medication, especially regarding the potential side effects, and really long term use of our medications as immunosuppressive DMARDs in combination with the GLP receptor agonist.

I'm going to end by a quote by an astute discerning clinician, Sir William Osler, who observed that the good physician treats the disease, the great physician treats the patient who has the disease. I think Doctor. Osler at that time was alluding to holistic care of our patients. And I think as good clinicians and rheumatologists, we try to live by this every day. With that, I think I'm done.

This is where I work. I want to thank you for your All

right, well thank you very much Doctor. Hack. We have a bunch of chat and a bunch of questions that we'll get to after our next speaker. Changing things up a little bit, a super important topic, and that has to deal with the perioperative management of patients with rheumatic diseases. Super pleased to have an expert on this to tell us the answers what to the important questions that we all have, doctor Susan Gooden from the Hospital for Special Surgery.

Welcome.

Well, thanks for having me, and I'm delighted to be here in warm Dallas to talk to you about this. No relevant disclosures. This is not, oh it is advancing, it wasn't there. So the context of this talk is that our patients with inflammatory arthritis have continued to undergo hip and knee replacement surgery despite the effects of our DMARDs and biologics. They have great results, they have the same sort of 30 improvement in pain and function that patients with osteoarthritis have, but they do have more adverse effects.

We see that if, this is a private insurance database study, that looked at patients at several points after surgery, and hip replacement patients with inflammatory arthritis clearly had an increased risk of transfusion. They had an increased, these are knee replacements, sorry, increased risk of infection, and a significant increased risk of readmission for all causes. Hip replacement patients had similar adverse events, but additionally are more prone to things like dislocation, other mechanical problems. So the outcomes in terms of pain and function are great, but there are a lot of complications that our patients are prone to. Unsurprisingly, the complications tend to relate to the specific disease features.

So if we look at our patients with ankylosing spondylitis, for instance, respiratory complications are significantly increased, almost a two fold increase in risk for respiratory complications and pneumonia. And that makes sense. When you think about it, when our AS patients have limited chest wall expansion, what do they get when they have thoracic ankylosis, cost of vertebral junction involvement, or anterior chest wall involvement, something as simple as costochondritis. Once they can't expand their chest wall more than two and a half centimeters, they become obligate diaphragm breathers. And that has obvious considerations in terms of common perioperative issues like ileus or atelectasis.

So clearly if you have a very severely affected AS patient, mobilization, bowel preparations become critical. It also has implications in terms of scaling nerve blocks. A scaling block, which is commonly used for upper extremity shoulder surgery, that sort of thing, paralyzes ipsilateral diaphragm. It's usually reversible, but if you're a diaphragmatic breather, that can be pretty difficult in the post op period. Lupus patients are very different, as is not surprising.

This was an interesting, again, a database study using the Taiwan Insurance Research Database, and they had lots of patients with lupus who underwent all kinds of different surgical procedures. And what they found, if they looked at patients who'd never been hospitalized for lupus related problems, they had risks for all of these outcomes that were no different than the risks of patients without lupus, the rest of the population. But if they looked at their lupus patients who'd been hospitalized hospitalized either within two years or within six months, there was an almost dose related increase in risk for complications like renal failure, stroke, death, that were clearly related to either lupus severity or lupus activity. You can't tell from these data, there's no patient level data, but if you've been hospitalized for a lupus related cause, your risk of a perioperative complication is very high. Psoriatic arthritis is different yet again.

This is data that we presented at UR and actually submitted yesterday for publication, but of the sixty patients that we enrolled, what we found when we systematically collected perioperative and post op data, all patients met Caspar criteria. Psoriatic disease activity was moderately active with ADAPs of almost 16. Very few patients had active skin disease, so that might have changed things a bit. Nonetheless, ten percent of the patients had a severe adverse reaction, things like sepsis fractures, prosthetic joint infections, acute kidney injury, CHF or stroke. But the adverse events weren't this linked to the PSA features.

So if you look, you can see of the patients with and without severe adverse events, it really was associated not with dapsa, there was no difference in those cases, you can see, but with obesity and comorbidities. So for the psoriatic arthritis patients, again, it's more obesity comorbidities that drive the adverse events. For our patients with RA, and again most of the published data is on RA, the real risk is infection. And one of the problems we have with our inflammatory arthritis patients is it's very hard to distinguish a prosthetic joint infection from a disease flare. For the RA patients, the PJI risk persists for the life of the implant, whereas for patients with osteoarthritis, non immune diseases, the risk becomes negligible after the first two years.

PJI risk is consistently fifty to eighty percent higher in the patients with RA. And this difficulty in differentiating between septic arthritis and then RA flare is important because a delay in diagnosis will impact the outcome. The longer duration of symptoms before appropriate treatment, which usually includes a surgical debridement, the worse the outcome is. And of course, our patients are taking immunosuppressants. We know that seventy five to eighty five percent of our patients are on immunosuppressants at the time they undergo arthroplasty.

So what are the risks in RA patients for a prosthetic joint infection? And we'll go over all of these, but the catalog is really active RA, staph aureus colonization, allogeneic transfusion, interarticular injections, overall disability and disease severity is a big one, and in fact is probably the surrogate for why the presence of a prosthetic joint is a risk factor for septic arthritis, and then of course medications are kind of low hanging fruit. The other key point to bear in mind when you're assessing a patient at the time of surgery is that these risk factors are additive. Unsurprisingly, BMI greater than forty, there's almost a fourfold risk of prosthetic joint infection. Staph aureus colonization, twofold increase, but if you look and you combine a BMI over forty with smoking, that risk goes up from a four fold to a seven fold increase.

Similarly, staph aureus colonization plus smoking. We increase the risk from a relative risk of two point three to a relative risk of, that one goes up to three point five almost. So all of those are additive, and you start adding in all of the other factors, including comorbidities, and you can see you've got to think through each individual. Now this was a patient who typified a lot of the problems that we have treating these patients. He's a 49 year old man, CCP positive RA.

He'd undergone bilateral knee replacements, and he was on a high dose of infliximab on a monthly basis. And he came in with acute knee pain and swelling. He'd had a routine follow-up a month earlier and was doing well, pretty well, and then he suddenly developed a fever of 102, malaise, and then worsening right knee and left elbow pain. Knee aspiration revealed a lot of fluid with a Y count of 30,000, and antibiotics were instituted. His past medical history includes significant comorbidities, obesity, diabetes, and coronary artery disease.

He had a presumptive diagnosis of prosthetic joint infection, and underwent an IND and liner exchange. And if you look here, you can see there's some loosening around the tibial plate, you don't see that on this side, clearly something's going on, could just be wear, no recent x rays. But if you look at the tissue, there are really very few polys. Polys are one of the diagnostic features of septic arthritis, this was an acute illness. But the histopathology really looks like a chronic inflammatory infiltrate.

You see the fibrin, you see a lot of lymphocytes, but really no polys. So the treatment was appropriate, but I'm not quite sure what he really had. And to really belabor this point, if you look at what the difference is between medication use and disease activity, this is one of those wonderful Scandinavian registries where they can link arthroplasty registries and biologics registries, and using that method they identified almost four thousand RA patients undergoing hip and knee replacement. The PGI risk overall in that group was increased. But if you look, the hazard ratio increase was related to disease activity, high DAS, and glucocorticoid exposure.

Biologics didn't really, whoops, biologics didn't really have much of an effect. You can see that that's not really a statistically significant difference. So although we talk about medication management, it may not be everything we think it is. Oops, there we go. So let's talk about some of those other factors and why it gets a little confusing.

Disease activity, as we've now mentioned a few times, clearly increases the risk of infection. So these are RA patients who underwent hip or knee replacement, and we actually, when we looked at the Synovium, what we found that was only thirty percent of them had low disease activity at the time of surgery. Fifty percent had moderate disease activity, and almost twenty percent went to surgery with high disease activity. But to make things a little more confusing, this is the tissue taken from a patient in remission. That doesn't look like a very quiet joint.

I mean, are sheets of lymphocytes. And if you look at those patients in remission, about half had moderate to marked lymphocytic infiltrates, and almost two thirds had high levels of synovial gene expression. So we say disease activity is a risk factor, but we really don't know who has an active joint at the time of surgery. Staph aureus colonization is another known risk factor for prosthetic joint infection, and biologics use turns out to be a significant risk factor for staph colonization. If you look at RA patients who were just screened in the outpatient setting, thirty seven percent of the RA on biologics grew staph from their nose, their Nares culture.

Twenty four percent of RA on traditional DMARDs, and twenty percent of the OA patients. And if you look at what increased that risk, only whoops, I keep doing that, don't I? Only biologics were a risk for staph colonization. Not BMI, not diabetes, not glucocorticoids, not antibiotics, and not hospitalization within three months. So biologics clearly drive susceptibility to staph colonization.

Transfusion we know is another risk factor for bad outcomes, plus it increases length of stays, and we always have economic considerations these days. Anemia is the most common RA comorbidity, and transfusion definitely increases length of stay. Overall though, allogeneic transfusion both increases surgical site infection, both superficial infections almost twofold, and deep infections with an adjusted odds ratio of one point six. So clearly, anemia, because what we can see is that of the patients with anemia, a significant proportion have either a component of iron deficiency or pure iron deficiency, so it's something we should be aware of and we may be able to correct easily prior to surgery. Now inarticular steroid injections are something we all use a lot of.

I know I do. And we used to think of it as a way to kind of tie the patient over before they went for knee replacement. But what you can see is that clearly the risk of infection at three months, this is for an intra articular injection within three months of hip or knee replacement, and the increase in three to six month infection is really significant. If beyond six months there's no difference, but injections within three months of surgery are clearly a bad idea. Again, comorbidities are additive.

This is a Charleston comorbidity index, and patients with RA go in with one comorbidity. As you can see, a comorbidity score of five, you have a two and a half times odds of infection compared to patients with a score of zero. So the more comorbidities you have, the more your risk is. So what about medications? These were a series of really well designed pharmacoepidemiologic studies that used Medicare billing data to look at a precise interval between the last infusion of infliximab and the date of surgery.

And by using infusions rather than patient report, you could get a really accurate dose interval. And if you look at serious infections within thirty days or PJI within a year, there's really no difference if the patient stopped the last infusion was four weeks or sixteen weeks before their surgery. I know this is supposed to be a talk about medication, but there's a few confounding factors. And again, if you look at glucocorticoid use, that clearly drives a lot of the complications. So same studies, you can see that even five milligrams of prednisone can significantly increase the risk of hospitalized infection or readmission.

We updated an older systematic review. The earlier study looked at either yes TNFs, no TNFs, and it didn't really account for who had been prescribed, just whether they were taking them at the time of surgery. And in the older study, we concluded that TNFs did drive, there's almost a the odds ratio was in the two point four range. If you then update it to patients who all of whom were prescribed TNFs, but some stopped and some continued. This also includes those two pharmacoepi studies I mentioned, which in fact drive about eighty percent of the data.

But if you look at this, there's really no significant difference in the patients who stopped or those who continued the TNF inhibitors. So here we come to our guidelines. This is about medication management, and I think I've pointed out a few of the difficulties we have with our data set. And the biggest data set here, and when you look at a guideline, the guideline's only as good as the data. We did a good literature review, but there's no randomized controlled trial data.

So what we advised was that all JAK inhibitors should be withheld, that was independent of the procoagulant effect. For patients with mild lupus, we recommended withholding all immune suppressants. And for inflammatory arthritis patients, we recommended withholding all biologics. We recommended continuing all conventional DMARDs, all medications in patients with severe lupus, with the thought that a flare of someone with severe lupus would be very prone to organ damage, and you probably wouldn't want to risk a flare in those patients. These guidelines though are significantly weakened by the lack of RCT data.

These are all based on mostly retrospective or case control data. There's a lot of confounding by indication and publication bias for both DMARD and biologic use. And again, all recommendations in the guideline are conditional. We recommend not giving super physiologic doses of steroids. Modern surgery isn't as traumatic as it was.

Patients rarely need transfusions, the surgery's well under two hours, and it's usually under a local anesthetic. So unless there's some other reason, they probably don't need stress dose steroids. And then you can safely restart the medications at the two week mark when the wound's well healed, assuming there are no other complications. So our conclusions from this, clearly patients with rheumatic diseases, more patients with AS and lupus, in fact, are utilizing and benefiting significantly from hip and knee replacement. Most are on medications or biologics at the time of surgery, and medication management in the context of multimorbidity is really the most accessible modifiable risk factor.

The ACR guideline recommendations are significantly weakened by the lack of RCT data, and that leads us to the need for shared decision making. Adverse events are more frequent in our patients, and they typically relate to specific known disease features, and they're different for each disease. AS, it's a pulmonary risk factor that's going to be most significant. Lupus, it's lupus severity. For psoriatic arthritis, again, it seems to be driven by obesity and comorbidities.

And for patients with RA, although they're prone to problems like dislocation, really infection and the difficulty in making that diagnosis is what drives the risk. So I think we're ready for questions. If

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