Chapters Transcript Osteoarthritis: a Human-Centered Approach Course: NYU Langone Seminar in Advanced Rheumatology (2025) Um, so I'm really, really happy to be here. I'm just very pleased to be invited and to be able to talk about osteoarthritis, which is my favorite thing, unlike many rheumatologists I know, but I'm gonna convince you and Tahina is gonna help me after this. Um, oh. There we go. Um, so, standard kind of things, I will talk about some treatments that are in development. Why? Because we are at the bottom of the pyramid in OA. We have very little, right? We don't even have, we don't even go up the pyramid, we're sort of down here. So, so we're gonna talk about how we might move up the pyramid a little bit. Um, I'll just talk about a little bit, mostly, uh, for the fellows and to remind folks that don't think about it on a regular basis, uh, we'll focus on some management controversies and some new studies. So first, and this is really for any fellows, trainees, um, junior folks in the audience, please don't call it wear and tear. It's not wear and tear, OK? Osteoarthritis is a complex disorder. It involves movable joints, we know that, but it's really characterized by this sort of micro and macro injury, a balance between Degradation and repair, um, that repairs process is very maladaptive and ends up resulting in this derangement that results in the disease. So, it is much more complex than wear and tear, and I'll show you some of the differences between this and aging, which is another one that comes up a lot. There are a variety of mediators. These are gonna look very familiar, right? So Doctor Richland just went over a lot of these. These are involved in a way as well, but we just have this imbalance between the kind of inflammatory catabolic things and the anabolic things and um a mismatch of repair and degradation. What it is not is just aging or just degenerative joint disease, the just being there on purpose, because I hear this from patients, I hear this from trainees, I hear this from my primary care colleagues. It's not just anything, right? This really impacts people's lives. It really impacts their ability to function. And while there are many similarities to aging, and there is certainly a tie with aging as a risk factor, they are not the same process. So aging really the cartilage is intact, it's just thin, it has fewer glycosamuno glycans, it's kind of, you know, got some loss of chondrocyte density. Those chondrocytes are not particularly active. There's really not inflammation, bone mass is going down, it's just kind of, you know, quiescent. Osteoarthritis is an active process, so the cartilage is fibrillating, there's focal complete gag loss, not this diffuse thinning and loss of gags. There's active crosslinking, there are chondrocyte clusters, they're actually more cells clustering together, those cells are activated. There is synovial inflammation, there's cytokine formation like I showed on the last slide, and the bone is actually thickening. So it's a very different process than aging alone, although the both, both of them can certainly happen together, and that's how we result in this sort of all joint tissues being involved in the process of osteoarthritis, which then leads to joint failure and eventual replacement in some joints that can be replaced. Osteoarthritis is also very heterogeneous. We think about this a lot with our other conditions, we, you know, talked about psoriatic arthritis and whether there's dactylitis or enthesitis. Well, osteoarthritis is not all the same beast either, so certainly there is an aging driven phenotype that I mentioned already. There's kind of a metabolic phenotype, right, obesity and metabolic syndrome and fatty liver and all kinds of other things that go along with that. There may be a very inflammatory phenotype with this that's driven primarily by synovitis. The cartilage itself, as I mentioned, there's traumatic, right? So post-traumatic away gets a lot of attention these days. Sometimes the bone is the primary driver. The etiology for that can be completely different. The risk factors vary. There are biomarker and imaging features that are specific to different phenotypes. It may progress, it may not. So the, the heterogeneity here has really not been appreciated on a clinical trials to date, and that's probably part of why we don't have anything beyond the bottom tier of our pyramid. Um, but we'll come back to that in a little bit. Now one of my favorite topics. It's really multiple joint away, and so I'm gonna focus a little bit on this, um, just to kind of give you this sense that this is a thing, right? And clinically it's obvious. We know that our patients come in with more than one joint. However, our studies are of index knees, so we may enroll. 300, 500 patients with osteoarthritis, all of those people have symptomatic kneeOA, right, in one knee, and we MRI that thing, we X-ray it, we, you know, do all these tests to it. We've completely ignored the rest of the human, if we even included them in our study at all. But in clinic, we know that most of our patients say, well, my hand hurts, so I get this thumb and my hip kind of and it's something going on in my back and all of that's probably their osteoarthritis, but why don't we think about it? Well, probably cause it's hard. Um, so, you know, we have to figure out what that means. If you were taught generalized osteoarthritis, please wipe that term from your mind as well. We'll take that right with wear and tear. There is no generalized osteoarthritis, it doesn't mean a thing. There are 35 at least different definitions of whatever more than one joint in OA is defined as in the literature. This is a systematic review we did a couple years ago that sort of tried to distill those into about 10 that are pretty similar, so you'll see hand, hand and knee, hand and hip, 3 sites, 5 sites, all over the place, right? What, what is, so none of those is generalized away, but they're all multiple joint away. And so like any other condition, if we're gonna talk about Connective tissue disease, we're gonna say they have an ANA, a Smith, they have arthritis. We need to do that with OA as well, right? They have osteoarthritis of blah blah blah. It's characterized by this, and it's limiting them in these ways. And so, you know, if we think about it that way, recognizing that this is common. Any of those definitions, and you don't have to remember what they are cause it doesn't really matter. You'll see that they're poor general health and poorer physical function if they have multiple joints involved with osteoarthritis. This is not rocket science. It makes sense, but We just don't think about it, and we certainly don't account for it in trials. So if we just ask people, you know, do you feel pretty good or do you feel pretty bad, they feel bad if they have lots of joints involved with osteoarthritis, and just some examples to compare across, you can see the magnitude of the difference. They really feel quite bad, and it doesn't matter specifically how we define that. Why don't we think about this more? We do biomarkers, right? There's lots of studies of biomarkers and osteoarthritis, they don't work, but Why don't we realize that those biomarkers are really reflecting the whole body. So if we go in and take out a serum sample, a plasma sample, any other kind of urine. And we test a biomarker in that that is not reflective of the cartilage breakdown of the right knee, OK, that is reflective of all of the tissues and all of the osteoarthritic joints in the whole person, plus their obesity, plus their age, plus their comorbid conditions, and that's probably why our biomarkers aren't that great, but it also compliments complicates other biomarkers if you're doing them in a different inflammatory disease, and that person also has osteoarthritis, right? Most of our patients have osteoarthritis. Even if they have RA or gout or psoriatic arthritis. And so these are by their nature systemic, but we just really don't assess that. They can be used to assess burden. There are a few that are useful to look at burden of OA. So overall, how much of this human is involved with osteoarthritis, and some of those are listed here, but kind of brings home the thought that really this is kind of a whole person disorder. We've looked at some different outcomes. I'm just giving you a little sampling here, and this is one of our fellows that did this, but we looked at falls, right? So falls again, osteoarthritis might be associated with that. It's a little bit all over the place in the literature, but if you look at multiple joints, those people that have more than bilateral knees. Even if they have 3 or 4 knees and hips, are much more likely to fall, even if we account for their age and their narcotic use and their lung problems and all the other things that we might think about. So another just kind of hard outcome, yes, if you have multiple joint away, you are not doing as well, you are not as healthy, and we have a bunch of examples of this. Another one that's been a little more in the limelight of late is obesity, right? So we all think about anti-obesity um treatments and things. What better case for multiple joint OA than obesity? This is just a random picture from the internet from Michigan, that's like perfect, right? The body is big, all the joints are involved. It might even be non-weight bearing joints, so we know that hand um joints with osteoarthritis are also more common in individuals with obesity and overweight. Our guidelines do acknowledge this, we should lose weight. Oh, that's helpful. How do we lose weight, right? We know we can, um, and it's really only for the knee and the hip, right? So it's focused for the weight bearing joints, and there is really no guidance on how to do this, how to direct patients to do this, and there's literally nothing about multiple joint involvement in osteoarthritis in the setting of obesity. Now, if we go to our obesity friends guidelines on obesity management. We can actually get some insights here. So, although it's not listed here, it is in the text that osteoarthritis is an obesity related comorbidity. Yes, I added it here, but it isn't the paper. I promise I didn't make it up. Um, so, so this is one of the things, right? Type 2 diabetes, hypertension, hyperlipidemia, uh, you know, sleep apnea, osteoarthritis. They have these things, they have an obesity related condition. Why does that matter? Well, we've done all these things, right? We know that obesity is a chronic disease, we talked about them, about lifestyle management, you know, more physical activity, but It also lowers our threshold for obesity therapy, right? So if we have an obesity related comorbidity such as osteoarthritis, our threshold for treating that obesity goes down from 30 to 27. How many patients you saw in clinic in the last week had a BMI over 27? All of them, OK. So this really impacts a lot of our patients, but we don't think about it this way, right? So if we're thinking about multiple joint osteoarthritis in a patient with obesity and our threshold is only 27, we need to be treating a lot of people, right? Um, this is old, but I, it's, it's nicely sort of reviewed, and I'll, I'll show you a newer slide, a newer image in a minute, but comparing just various, you know, anti-obesity treatments, so that includes bariatric surgery and, you know, lifestyle management, sort of the effectiveness of each of those in a review about osteoarthritis, just to show it, it's been thought about but not well. Moving to OC last year, and this is now in a New England Journal, the step 9 trial, um, and again I have consulted with these folks, so I have to tell you that, um, showed a dramatic difference if we treat individuals for their obesity, in this case with semaglutide, but again, it, you know, we could probably choose a different agent. The Womack pain in this case, but also some other important osteoarthritis measures, dramatically improves. We didn't treat their OA, we didn't replace their knee, we just reduced their obesity, OK. So we agree on a lot of core management things, again, not for multi-join away, but just in general knee and hip in this case, there are some guidance for hands. The green dots mean everybody's happy with that. So we've got ACR, UR, the orthopedic Society, or C, which is osteoarthritis focused, you know, we all say yes, weight loss, self-management, physical exercise. Again, bottom of the pyramid stuff, right? We're, we're perfectly happy with that. Give them some NSAIDs, probably can't take NSAIDs, but hey, you know, if you can, you're lucky. All the other dots are sort of things that were either don't have evidence, are not widely agreed on, or not studied well enough, have risks and benefits, etc. etc. that really are not agreed upon. So there's a lot of stuff you could use, but it might not be um relevant in every guideline. Coming back just briefly to the lifestyle management, and then we'll go into the controversies. I mentioned earlier the challenges of this. I'd like to give a couple of examples just in case there's somebody somewhere that this could help. Um, I give a walking prescription. Like a written walking prescription in Epic that prints out for patients or goes to their MyChart or whatever they want to do, and I can edit this, right? So it talks about their BMI, it's, you know, I change it. This is an end point, right? 30 minutes a day, 5 days a week would be awesome, but usually we're talking about, you know, 5 minutes, 2 days a week, or get up off the couch periodically or something, but some kind of thing to indicate that this is part of your medical treatment, this is being recommended by your doctor, this is an official thing. I'm not just telling you to go out and walk around and lose weight. We also, um, at UNC are the home of the Osteoarthritis Action Alliance, which is an international consortium of groups that are interested in OA. Again, all of those um organizations that develop guidelines are part of OAA. Um, and it puts out a lot of public health messaging. This OA care tools is particularly helpful, um, if you're looking for good educational materials, good guidance to give to patients, it has like videos of how to be active and apps and different things, all freely available at the OA Care tools um site listed down there. It has things like healthy behaviors, little infographics. There's a walk with ease portal where people can actually um hook up to to that program, which is a CDC approved program to try to improve physical activity. So a good place to go to get patients kind of things that might be helpful to them in a short amount of time in a visit. OK. So controversy. So I'm gonna skip over the rest of the things that we all agree on, and we're just gonna move to the things that people always ask me about, right? So, inarticular hyaluronic acid. Depends who you are and where you're from, yes? I think that if we take all of the literature together, all of the differing opinions in the universe, it's probably a reasonable second or third line option for individuals who do not have good other options. It's gonna have modest benefit, right? This is not an out of the park gonna fix your problem kind of thing. But it's also probably safe and probably a reasonable choice, not first line. Platelet rich plasma and mesenchymal stem cells. I have to take a deep breath, you see. Um, I'm gonna show you the PRP trial in a second. So really the main problem here is that these are not standardized by their nature, not standardized treatments, right? So we're taking something out of a patient, we're messing with it, we're putting it back into them, that process, the concentrations, the reagents, the timeline, everything about it is not standardized. So it's really hard to say on a General basis that things are or are not effective. That's leading then to the low quality trials and the lack of long term safety or efficacy data. It is a problem that when we do those trials, we don't follow the patients, right? So, it would be really nice to know, even from a number of lesser quality trials, what actually happened to those people 35, 10 years. We don't have any of that. And so, this is generally something I don't recommend to my patients. It is not recommended by guidelines, although we talk about it a lot. MSCs are even worse off than PRP as far as standardization and clinical trial quality. I will briefly mention nutraceuticals, so this is like glucosamine, chondroitin, etc. Same kind of problem. There are lots of studies, depends who you are and where you live. If a patient comes to me and says, I am really interested in this, I generally, and if they're, you know, as in an obvious contraindication, say, you know, 3 months, 6 months, sure, give it a try. You know, I've reviewed your medications. I don't see any contraindication. This isn't gonna give you a problem, but please, if it doesn't work in 3 months, let's save the money and move on, OK? Cause that seems to build the patient relationship a lot better than saying, no, that doesn't work, right? So sometimes I'll, I'll give a little on the things that I, that I find to be safe, and then I'm gonna talk about the last two in detail. OK, so the restore trial Jamma 2021. 1st thing I hear is groans from orthopedists when I put the slide up. Why is that? Well, it wasn't the right concentration. It wasn't the current protocol. We don't do it that way anymore, etc. etc. etc. Well, it's the only decent clinical trial we have at size, at standardization that we can actually trust, and it shows no effect. I'm sorry, it's just what it is. Um, I can't help the results. But in, in this case, they looked at platelet rich plasma in 144 people, and 144 people got placebo. They got 3 intraarticular injections. It's not enough, OK. Um, leukocyte poor, they should use leukocyte rich, you know, you, you name it on this slide, I've gotten the argument. But the data stand, OK, so it's multi-center, they had a decent primary outcome of change in knee pain scores, and you can see the numbers, the platelet rich plasma had a 2 point decline in knee pain, and the placebo had a 1.8 point decline. Um, the cartilage volume did not really change, there's no significant difference. OK, that's what it is. So, you know, again, depends who you are, where you are. There are orthopedic clinics all over this country, you know, across the street from my office doing this every day, cash out of pocket, but if you need to have a patient that's receptive and you can talk data with them, you know, evidence-based medicine would say not so much. Now I'm gonna get into some, some really interesting ones. So genicular artery embolization. Everybody heard of this? Getting some nods. Um, so these, these next two are sort of out of our hands, which is really interesting, and I'll come back to, to my editorial comments on that in a minute. But this is basically, um, interventional radiology. Going in and embolizing branches of the genicular artery. OK, so they see this blush, where the little yellow arrows are that sort of fuzz, and they say, OK, that's synovial inflammation, we're gonna go in there and block off those arteries with a variety of different things. Another lovely um standardization problem, and then we get this post picture and it's lovely, right? There's no blush of which little vessels are very clean, and obviously that we've reduced the amount of inflammation in this joint, OK. Um, it's angiography, right? So they're in the angiography suite, it's, you know, a procedure, couple hours, they're injecting some kind of particulate or microsphere into these vessels that varies again quite a bit. And if we look at the interventional radiology literature, um, they do systematic reviews. It looks fantastic, right? So 0 here is no change in pain and everything else is like a 40 point change in pain. I think of a boxer, yeah, so there's 0. This is our sample size, right? So this is 10 studies of 280 patients, great. Each study is like 10 people, OK? And they looked at different time frames. They do at least have some longer term file follow up. The adverse events include skin ulceration and site hematoma, just like you might expect from any interventional radiology procedure, which is not ideal. They were all unblinded, no control groups, there's no like sham procedure going on in any of these. But there is one Thank you, uh, Rotterdam, for doing a sham controlled clinical trial of symptomatic NOA and only 58 people, but still that's pretty good in the numbers I just showed you, pretty standard population there for osteoarthritis trials, and we see that the Kose pain, so Kose pain, we want to increase. 100 is perfect for coose pain, so the plus numbers are good. So they're getting getting about 20 points better on their coose pain, but really no between group difference, and the AEs were pretty mild. Most of the time they were embolizing some of the medial. Genicular arteries, you can see the numbers here, but there it's kind of all over the place. So again, hard to standardize if we're gonna, you know, inject different things, we're gonna inject them in different places, sort of depending on what the radiologist feels like at the time. Again, this sort of blush and then no blush situation um going on here. This is just the numbers I kind of told you already, not between group difference. The only one that was interesting is this coose sports, so that implies sort of a higher level of function did have a a almost significant um response to to maybe people did better with that. The other one that is um kind of up and coming this radio frequency ablation or RFA. This can be done in an office setting with this is showing fluoroscopy, you can do it with ultrasound, um, variety of different practitioners are doing these, and the idea here is to address the nerve. Nerves rather than the vessels. So we're going to suppress those uh local fibers. This can be done in a variety of ways. Electrical, non-ablative cooled is FDA approved, or again, different guidance mechanisms, um, other things you can inject. It's again, good luck standardizing that, but you can see where the, the kind of needles are going, and the AEs in general have been a pretty mild. Same idea if we look at the literature of the folks that are doing this, who are mostly orthopedic non-operative orthopedists and PMR kind of doctors, we see a clear benefit, right, for pain and for function. I don't have an arrow on that one, but it's only 7 studies they have various follow-ups again, the procedures are all over the place, although the adverse events here seem much less than are noted in the GAE. I found one pretty OK randomized control trial. There are no sham ones that I can find yet, although hopefully that will be coming. So this one's gonna compare the cooled RFA, which is the FDA approved one, with intra-articular steroids. It's not quite the same thing. Obviously you're getting stuck with lots of needles in one and one needle in another, OK. Most of these studies only look at RFA outcomes in people who respond to a diagnostic nerve block, so they're actually getting two procedures. They're getting stuck with lidocaine to see if we numb the nerves, if they have a response in their pain, and then they're getting whatever the final RFA procedure is. This was in 150 people, symptomatic NOA again, pretty standard population. They gave him the the RFA or 40 mg of Depo-Medrol, and you can see the, the outcome of CRFA is the cooled um baseline. Pain is pretty much the same, and then at 13, and 6 months. Well, what's your response to intrarashicular steroids at 6 months? Right, so, OK, it, you know, it works better than that, but again, you went through this big procedure, you had all these needles stuck in, you had ultrasounds and fluoroscopy and then so, so we so we still need some more studies on this, but it, again, we'll mention that that is approved. I have to put in this quick thing about surgical options, because if you send people to ortho and they recommend arthroscopic debridement, you say no thank you. OK. There have been numerous sham control trials in the New England Journal that tell you that arthroscopic debridement for symptomatic kneeOA does not work, and you do not need to do it. It is still one of the most common procedures performed in this country, OK, and Actually internationally, unfortunately. Additionally, partial meniscectomy is rarely indicated. So if you're sending them to orthopedists, know what you're sending them for pre-counsel, talk about it, OK. If you're sending them for pre-counseling for joint arthroplasty, that's probably OK, right? If they're kind of at that place, this is a very common procedure. Most people do really well with that. 10 to 20% need revision, that same amount have sort of lack of satisfaction, right? They just don't feel like it was what they thought it would be. Plagued by the variety of inequities that I'm sure you're all aware of, but that's my two cents on surgical. And my two cents in general, with all things my two cents, um, is that these controversial treatments are not, we're not doing these, right? These are not rheumatologists, these are physical medicine and rehab, these are non-operative orthopedists, sports med, family practice people, pain specialists, right? Anesthesia, pain will do these interventional radiologists will do these. And most of them are approved as devices, and you probably know that the approval process for device is very different than the approval process for a medication. HA is also a device, so it does not have to go through the rigor of clinical trials and all the surveillance and things that a medication would have to go through. Obviously, vitamin supplements are not even regulated. Most of these are going to be paid for out of pocket by your patient because they're desperate, and because they don't know the data, OK. So if we are gonna do the research, and I can tell you that a lot of the good OA research is being done by rheumatologists, Doctor Nyoji in the audience and myself being some of them, we probably aren't seeing the patients as much, right? So I'm sure that you guys like us are being geared more towards the inflammatory arthritis, things that need biologics, things that need our expertise, and away from seeing osteoarthritis patients. So we really need To be that voice of reason, um, which is becoming more and more of a challenge these days, to try to let our patients know what the evidence is and what we can tell them about it, and if they choose, they choose, but at least we can try to provide that education. OK. So then we're gonna talk about a couple of things. So this is a list of all the failed things for OA for um 2024. There's a slide like this every couple of years, right? So, um, usually David Hunter and somebody in his group does a nice review of all the things that we tried and and didn't work, um, so that's awesome. There's a couple things that you might be interested in, however, hand away, right? Handaway, we had nothing for handaway. The methods trial recently came out, um, 97 people with radiographic handaway, they had to have MRI synovitis, but interestingly, no one was actually excluded for lacking MRI synovitis. They all had it anyway. 70% women, they were randomly assigned to an actual dose of methotrexate, 20 mg a week instead of the homeopathic dose that we usually use in a way. Um, and the effect size was about 0.5, so it's, you know, NSAID level, um, you can see the 10 point improvement of VAS pain and Acan campaign. It's not gangbusters, but at least it's something, um, and we often struggle with people, especially with erosive OA, that's not this group, but if you think about those patients, um, sort of a promising effect and really very safe in this group. Erosive hand away, uh, we've tried everything, right? It kind of looks like RA, so we figure, gosh, maybe we can try all those things. We try all those things, they don't work. Um, but there was an interesting study on denosumab, um, so if you think about, gosh, I have a lot of patients that erosive OA and osteoporosis, you know, what do I do with those folks? It was in phase 2A, um, but it's happening, they're still, uh, pursuing that. So perhaps there'll be an opportunity to treat patients with something that benefits to issues, reduces the number of erosions they develop in that very debilitating disease. Um, there are some other, um, sort of things in earlier phases, uh, big shocker that prednisolone works for that, which for everything. Um, and then we looked at methotrexate for knee, right? So symptomatic knee 155 people placebo or 25 mg, again, a nice decent dose. Little bit of a signal at 6 months, but not very much, um, lost at 12 months, um, so, you know, not the worst thing we've ever seen. There were no new safety signals, but it again did not have a massive uh benefit in NOA, um, and has been looked at in multiple studies, so, you know, it's probably not gonna, not gonna change. I'm only gonna mention NGF to say. That you can't have it, um, so that whole process was discontinued because of a variety of of outcomes that I think, you know, might touch on in a minute, but your dog can. So, but in vetimab um is approved for cat cats and dogs both have an NGF that's given subcu and does not seem to have a safety signal, works great. But maybe, just maybe we'll have a new neurotrophin coming. Um, so this is Levi04, this was presented at the ACR meeting. I have not seen the publication as yet, but this is um trying to target the neurotrophins without giving us the bad side effects, and you can see the dose response curve there for Womack pain on the far left, physical function in the middle, and PGA on the right, all look pretty good compared to placebo, which is the top line, um, and the mean, uh, primary endpoint was met, so. Optimism perhaps we'll see. We always have optimism and then we find out later in a month. So, so away is not just aging, is not wear and tear. It's also not generalized away just. But it is a clinical diagnosis with a variety of important subtypes. We still have the bottom of the pyramid, education, exercise, and weight loss do actually help, um, but maybe there are some new treatments and really some new paradigms for understanding the disease for addressing the disease in a way that might actually benefit our patients, um, that can move the pyramid up a little bit. And thank you very much. Published March 20, 2025 Created by
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