Chapters Transcript Video Knee Osteoarthritis: Using Biology to Optimize Exercise Prakash Jayabalan, MD, PhD, from the Shirley Ryan AbilityLab presents at the Johns Hopkins Department of PM&R’s Grand Rounds on May 17, 2022. Welcome uh to the PM R uh department at John Hopkins Grand Browns. Uh Today is uh May 17th 2022. It gives me great pleasure to uh introduce and welcome uh Doctor Prakash Chaya Bala. Hopefully, I've been practicing a little bit on this although I can chop my name with my accent. Um So Prakash uh I know Prakash for, for many, many years and uh he's a great colleague. Um and I'd like to give a little of a formal introduction. So, Doctor Prakash Chalan is a physician scientist and director of the Nancy knows strength and endurance lab at the Ryan Ability Lab and an assistant professor at Northwestern University Feinberg School of Medicine in Chicago. Uh He received his medical degree from King's College in London and a phd from the University of Missouri in Pato Biology. He's a board certified PM N R and sports medicine doctor. He completed residency training at the University of Pittsburgh and then a fellowship in Sports Medicine at Northwestern University. Since finishing his fellowship, he has received multiple grants, publications and research awards for his laboratory work including the best paper award from the A P, the Scott F Nadler and Justin Justice uh Justice Lehman Awards from the Foundation of PR Community Engagement Award from the Alliance for research in uh Chicago Land Communities Young Investigator Award from the A MS S M and recent grants from the restore center of the N I H and Pepper Center. His lab's work focuses on using biological markers to develop novel individualized rehabilitation and exercise strategies for individuals with knee osteoarthritis. He's a, a proud graduate of the R MST P program and his current er er in the P program in the A P. Um and I just wanna point out his accomplishments uh were recently recognized that he was chosen as a 40 under 40 in Chicago area as a scientist and he will be receiving the early career commission award at the uh coming association or coming fiats meeting in in next week. So, Prakash, thank you so much for joining us here today. It's a, a great uh honor and privilege to have you speaking to all of us. Thank you very much, Doctor Sick and thank you for the kind introduction and the invitation today. I'm very honored to be here. Uh I just wish it, I wish it was in person but maybe one day. But um, but today's talk is on knee osteoarthritis using biology to optimize exercise. And as Doctor Elick mentioned, my laboratory really uses biological markers to individualize strategies for individuals with knee osteoarthritis. And that's the optimal goal of what we're trying to do. I don't have any disclosures, uh, pertaining to this presentation. Um, these are the objectives that were sent out, sent out to you. But, um, what I want to really focus on is the outline of what I'm gonna be talking about today, which is, uh, the biology of knee osteoarthritis using, uh, biomarkers potentially for diagnosis and treatments. Uh, looking at the relationship between biology and exercise, stressing the system and then targeting the right patient for the right treatment at the right time. So what I want to start with is a case. Um And this is a case that anyone that's uh that's a psychiatrist is probably seated in residency or as a attending physician. So this is a 67 year old former runner who presents with a 7 to 8 month history of medials sided knee pain. And our classic evaluation of these patients is to examine them and perform radiographs and we diagnosed them with osteoarthritis of their knee. Now, my challenge as a, as a or my interest, uh I should say as a clinician scientist often is that this approach really doesn't take into account the complexity of osteoarthritis care. And I from a research standpoint, really have asked these questions so far in my career. Could we have diagnosed this condition earlier? How do we decide the best treatment for this patient? And what level of physical activity should we recommend to optimize a cartilage disease. And as a psychiatrist, what sort of rehabilitation regimen should we prescribe? That? Optimizes her disease and preserves her joints. So, our current treatment paradigm is we will treat patients with medications such as Acetominophen Nsaids. We will advocate for weight loss, exercise and rehabilitation. We'll talk about certain uh injectable treatments and there's really only two that our insurance covers right now, which are stone injections, which for that very acute pain and viscosupplementation, which is essentially the only biological agent that is, uh, which is uh approved insurance wise for injectable treatment, at least in my state. And this leads all the way to total joint replacements where you use inert metals and plastics and replace the joint. Now, my goal as a non operative practitioner is really to optimize the left side of the screen to optimize or delay the need for total joint replacement. So having said all of that and how we currently treat patients with osteoarthritis. If I was to ask a patient, I'll ask a sorry, a resident or a trainee or even sometimes some of my colleagues, what would you, how would you describe osteoarthritis? The most common answer I get is that osteoarthritis is wear and tear within the joint. And if there's one thing that you take away from this uh presentation is to say that osteoarthritis is much more complex than that osteoarthritis is really a joint disease where you have abnormal biomechanics, which interplay with abnormal biology within the joint. So when we think about the abnormal biomechanics studies have shown that an individual with osteoarthritis compared to a nor an individual without osteoarthritis puts increased stresses on the joint, which leads to this degradated cascade and inflam an increase in inflammatory mediators. But there's also an abnormal biological cascade which feeds into that as you'll see on the bottom side of the screen. Now, why that's important is because our current modern day treatments try to target both of these factors. Um We talk about things such as bracing and other things to manage some of those biomechanical processes within the joint. But we also target our medications towards limiting those inflammatory degradated processes through nsaids, for example. And there are a number of medications that are being targeted towards M MP S which are those cartilage degradated enzymes within the joint and those are not currently available on the market. But some other things that also have both a biological effect and a biomechanical effect is that we advocate for our patients to lose weight and we also advocate for them to uh increase their activities such as walking exercise. And studies have shown that both of those treatments have both a biological effect but also a biomechanical effect. The other part in that's an issue with modern day osteoarthritis management is that often our treatments are really targeted just to the cartilage. But the other part that I want you to remember is that the joint is an organ. It's essentially an encapsulated structure with multiple different cells that have an individual uh that have different um functions. So, for example, in addition to the cartilage, you have the synovium that's bilayer that produces hyaluronic acid, which is this film that sits on the surface of the cartilage. But also provides, it also is releases constituents of the synovial fluid which baths the cartilage which provides or maintains its health. We also know there's the subchondral bone which is a supportive structure that has this cross talk with the articular cartilage above. So we know that if someone has diseased subchondral bone, that in turn leads to the propensity to develop osteoarthritis as well. In turn, that the cartilage becomes damaged. And then the other part is the Synovia fluid. As I said that that bathes the cartilage and studies have shown that individuals with osteoarthritis tend to have more acidic uh synovia fluid compared to individuals without osteoarthritis. And then finally, of course, the articular cartilage, which is the main component that is damage in osteoarthritis. And the challenge for us in such as myself who try and manage individuals with osteoarthritis is that when a patient presents to our clinic, it's often quite late down the line. And that's because carl is avascular, a lymphatic and aural. So it has very poor reparative potential because it's a vascular and a lymphatic and it's aural. So if someone has cartilage thinning someone at early stages of osteoarthritis, they often don't know that they're developing osteoarthritis unless the bone underneath is damaged as well. Um, because bone actually has a nerve supply, not the cartilage. So we know as well that in that healthy joints, there's an optimal balance between cata bolic and anabolic processes. Now, what happens in osteoarthritis is that there's damage to the articular cartilage and many other parts of the joint such that as the patient bears weight of the time that damage is potentiated. So you have the, you have the creation of osteophytes. You have synovial thickening or uh inflammation. And you also have subchondral cyst formation. And we also know that the release of some of these cartilage degradated enzymes called matrix metallo protein proteases such as M MP S, um other inflammatory medias which potentiate their joint damage. As I mentioned earlier, this eventually leads to fur further cartilage thinning, which leads to bone on bone motion, which leads to pain, which is what our patients present with. And that balance within the joint gets tipped more towards cata bolic processes as opposed to anabolic processes. So, we've talked about some of the path of physiology of osteoarthritis and some of the issues that we face as non operative practitioners trying to manage the disease and the bottom line is it's not just wear and tear. There. Is this abnormal interplay between abnormal biology and abnormal biomechanics. So, next, what we're going to talk about is biomarkers for diagnosis and treatment, which is really the focus of much of the research that I do. So, the first part in trying to evaluate someone with osteoarthritis is that is our issues with imaging or the way that we evaluate patients. So classically, when each of us has seen a patient in clinic, we will perform radiographs to diagnose their osteoarthritis. The challenge is is that radiographs have very poor sensitivity to early disease. Similarly, by the time someone actually presents two with osteoarthritis on a radiograph uh to our clinic, they have less interventional options avail available to them. And the other challenge is that radiographs often do not correlate to symptom severity in our patients. We've all seen the patients with bone and bone osteoarthritis or grade four osteoarthritis who actually are very functional. So it doesn't necessarily correlate to function at all. MRI S. There are many novel scanning protocols that have been developed to look at osteoarthritis. But these scanning protocols are expensive and they do not provide information often on the pain generator within the joint and many individuals within our country will have access to these novel scanning protocols. And that's a big issue. And finally, the other thing that particularly orthopedic practices will talk about is this idea of arthroscopy for knee osteoarthritis. Now, this is invasive and expensive and studies have shown it's really not beneficial. But we've all seen that patient who says that the orthopedic surgeon has gone in and washed away their arthritis, which I've definitely seen, um, patients describe, but that's not the case often. And the other thing, uh from a practical standpoint is that uh arthroscopy really only allows you to look at the surface layer of the cartilage. We don't know the entire biological health of that cartilage as well. And overall, all three of these imaging modalities really have limited correlation to symptoms and function. So my work really focuses on trying to be fortune tellers for individuals with osteoarthritis. Can we tell someone that they're developing osteoarthritis even before they know it? Can we intervene earlier? And also can we prognosticate how patients are going to do with specific treatments? And in turn, can we intervene on the bottom part of the screen here as opposed to the top part of the screen when someone's eventually going to need total joint replacement? Now, I know it's it's your lunchtime. So I apologize if this gets a little bit scientific at this point. But what I want to talk about is just the structure of cartilage because it's important for some of the things that we describe describing later. Now, we know that cartilage consists of a chondrocyte surrounded by an extracellular matrix here on the right. And that extracellular matrix has three major components. Firstly, it consists of water and that's what uh that's contained within glycosaminoglycans. These give cartilages, compressive strength and then there's also collagen type two fibros these gives cartilages, tensile strength. Now, we know in osteoarthritis, in particular, there's damage to the extracellular matrix such as the patient bears weight at the time. Those cartilage constituents are, are released. There are M MP S as we talked about potentiating that damage. These are the enzymes that break down uh some of that cartilage and we can measure some of these breakdown products in the bloodstream urine or synovial fluid of our patients. And many studies have shown that and studies have shown then when you look at these biomarkers that we can measure in some of these biological fluids in relation to osteoarthritis. We think about the right side of the screen where someone's got total needs a total joint replacement and the left side of the screen where we're sort of talking about early osteoarthritis. Some of the increase in these increases in these biological markers actually show up earlier than even radiographic findings of osteoarthritis, imaging findings of osteoarthritis. And that's important to remember that they potentially we can see some of these in the bloodstream of our patients who could be developing osteoarthritis. So we've talked about now the basis of using some of those biomarkers in modern day, uh osteoarthritis and how they potentially could be beneficial over modern day imaging modalities. But the next thing I want to talk about is really the focus of my research which is looking at this relationship between biological markers and exercise. So the first thing to say is that, uh, it is really one of the biggest things that we advocate for in individuals with osteoarthritis, which is weight loss. And the biggest thing with weight loss is that is to remember is that when we're trying to counsel a patient, it's not osteoarthritis is not just wear and tear and increased loads, uh, causing osteoarthritis. We know that for every pound of weight that someone loses, they lose £4 of weight from their knee joints. And that's an important metrics for sure. But weight loss also to an extent is anti inflammatory as well. And osteoarthritis has been described particularly in the literature of late that it's a chronic inflammatory state. Now, we know that this is because in individuals who are obese, they have a higher propensity to develop hand osteoarthritis. Now, the hand is a non weight bearing joint. So it's thought that this propensity to develop hand osteoarthritis is because of the increase in systemic inflammation that you see in individuals who are overweight or morbidly obese. Similarly, studies have also shown that white adipose tissue, which is that belly fat that we see in, in many individuals with osteoarthritis, that actually also has the propensity to release adipokines such as adipo nein and leptin. And these essentially are pro inflammatory markers that we can measure in individuals and are higher in individuals with high amounts of body fat. And there's also release of some of these other inflammatory meters such as T N F alpha ale one beta and aisle six. And these are associated with other inflammatory conditions such as rheumatoid arthritis and also insulin resistance. So, weight loss again, is not just a biomechanical treatment, but it's also a biological treatment. It decreases some of that inflammatory load. There are also studies looking at individuals who undergo bariatric surgery and there's a completely different inflammation profile, particularly with the dios after bariatric surgery surgery in relation to osteoarthritis as well. So now when we look at exercise, which is really the title of our talk today, my work really is focused on this is that our current exercise regimens that we prescribe of our to our patients is greater than or equal to 30 minutes of moderate intensity activity five times per week. And that's the American College of Sports Medicine Guidelines and the A H A guidelines for cardiac health. Now, we don't know if this level of activity is actually detrimental to individuals, joint disease, particularly if they have osteoarthritis. So we did a study trying to look at whether objectively measured physical activity was associated with progression of osteoarthritis um uh on a radiograph. So, uh we use the osteoarthritis initiative which I believe Johns Hopkins is one of the sites for this initiative. So this is a nationally available cohort from four centers where essentially they've been following individuals with early osteoarthritis and following to see if there are pro prognostic factors for the development of progression of their osteoarthritis down the line. And they're now eight years down the line. And a sub cohort of these individuals actually had accelerometer data baseline. So they actually had objectively measured physical activity. So we know how physically, physically active they were on incorporation into the study. And so what we wanted to look at was at four years down the line that whether their physical activity at baseline was related to radiographic progression of their osteoarthritis. So for example, what we wanted to look at was an individual with mild osteoarthritis on a radiograph at baseline. What factors were associated with progression of knee osteoarthritis? Four years down the line? So how, what factors are associated from that radiograph going from mild to moderate o a four years down the line? And as you would expect the factors that we find that our biggest risk, risk factors for the development of osteoarthritis such as being older age, female sex and higher BMI were all associated with radiographic progression of osteoarthritis. And also having higher baseline pain factors that were not associated with osteoarthritis was physical activity either on at the low end of the spectrum or at the high end of the spectrum. A history of prior knee surgery or prior knee injury prior to inclusion in the study was also not associated with radiographic progression of osteoarthritis. So the first thing to say from this data is that physical activity, it was not associated with radiographic progression of osteoarthritis. So this is good because we can counsel our patients that physical activity can actually be is is not detrimental to their joint disease overall. On the basis of this. Now, obviously, this is limited by the fact that we were just looking at radiographs uh as the outcome, we don't have MRI findings or symptomatic findings in these patients. The other thing to also say is that we talk about Ortho biologics often for osteoarthritis. And that's definitely a big push in the PM and R field. But I also want to sort of challenge, challenge you all to think about uh also a normal normal physiatry treatment for osteoarthritis having a biological effect as well. So for example, Hunter, a group out of Wake Forest actually did this idea trial where they did a diet and exercise intervention over 18 months in individuals with osteoarth art arthritis. And what they found was that this intervention actually decreased joint contact forces and also decreased systemic inflammation, which had a relationship to improved symptoms such as in our patients such as function and improved pain. Similarly, a physi a progressive aquatic resistance program over 16 weeks out of a group out of Finland actually improved the biochemical content of articular cartilage which had relationships to improved symptoms and gauge speed in this cohort of patients with osteoarthritis. And finally, another study which is similar to one we did, which actually looked at 12 months of physical activity monitoring found that individuals in the highest turtle of physical activity actually had regional regional improvements in their extracellular matrix constituents of their cartilage, which had relationships again to improved global function. And these patients also had improved cardiovascular fitness. So overall exercise is beneficial to cartilage and our physical therapy also potentially has some biological effects on people's cartilage as well based on these preliminary studies. So when I started taking all of what we've just talked about and some of my, my that first study that I mentioned, I sort of came up with what I saw as like the potential, uh probably a naive attempt to say that this is what I see the future of osteoarthritis care. And, and now I've realized that it's much more complicated than that. But my hope was that when we see individuals with osteoarthritis, we'll examine them, we perform imaging studies, but we will also take a biological sample from them from that biological sample. We will create a unique biomarker profile for that patient and we'll review their biology and relationship to their function. We'll prescribe an individualized exercise regimen for that patient. Um That's individualized to them based on type intensity and duration. And then we'll measure some of these biological markers going forward to look at the pathology progression and the response to treatment as well. But the first thing to say is that can these biomarkers correlate to functional abilities and then can we actually use them to actually assess whether how an exercise is impacting an individual? So this really leads to what my lab has developed, which coined the phrase this idea of a cartilage stress test. So when we think about a cartilage stress test, it's analogous to a cardiac stress test. So we in a cardiac stress test, we get people to walk on a treadmill, we look at EKG changes and we stratify the risk for the development of coronary artery disease based on those EKG changes. So similar to that, we've, we're developing a cartilage stress test where we get someone to walk on a treadmill, we load their joints and we, while they're walking through an I V, we take blood from them and measure the blood for biomarkers of cartilage stress. And studies have shown not just in my lab but in other labs as well that this sort of approach has potential diagnostic and prognostic value. The unique capacity of this is that we can measure this cartilage stress response in real time. So we're taking blood from them while they're walking. It allows potentially dynamic assessment. And it also potentially could look at, we could allow us to look at individuals with compromised cartilage earlier on in the disease process. There was a group out of Stanford who actually showed that this type of approach when they got people to walk on for 30 minutes on a treadmill, they measured a serum biomarker response. And this is a bio marker of cartilage stress that I explained that initial acute biomarker response was able to predict cartilage thickness five years down the line on an MRI. So the first study that we did in this round was essentially looking at continuous walking on a treadmill versus interval walking on a treadmill. So the reason that we looked at this is that often when we tell patients to go exercise, we'll say go and work 30 to 45 minutes and exercise a physical and, and that will be your physical activity for the day. Now, like I said, we don't know if that physical activity may be too much for someone's particular joints. So what we did was we got individuals with osteoarthritis to walk on a treadmill continuously for 45 minutes. And every 50 minutes we took blood from them, we measured certain biomechanical parameters and we asked them their pain score and then we got the patients to come back on a separate day about a week later. And they walked the same walking exercise regimen incorporated with two rest breaks for one hour. So they would do the same duration of walking in a session. So 15 minutes, 15 minutes, 15 minutes, that's 45 minutes. And each 15 minute block was, was separated by a one hour rest break. And we did the same outcome metrics in this, uh study as well. So what we found firstly was that when they walked continuously on a treadmill. So the blue bar here is when they walk with the interval walking regimen. And the, the red is when they walked continuously, there was a significant increase in knee joint contact force when they walked continuously on the treadmill as opposed to uh when they um walked in an interval walking approach, and there was a walking time effect. So these differences were stronger, the longer they walked on the treadmill. The other thing that we also measured was a serum bio marker of cartilage stress. And the marker that we chose was uh comp or cartilage oligo meric matrix protein. Now, this uh marker is an extracellular matrix of cartilage and it holds together collagen type two fibros. And the important thing to remember is that when you, when this marker, in fact, is mechanosensory, every time we walk, it helps transduce that mechanical signal from the extracellular matrix to the chondroid. And we know that that's important because cartilage is mechanosensory. If you don't put stress on your cartilage, it actually will uh is unhealthy to it and can die out. So you do need some level of stress. And this marker is very important and protein is very important in transduce that mechanical signal. But when we see high amounts of it in the bloodstream of our patients, it usually means that there's increased cartilage stress or cartilage degradation in the bloodstream. So, in the study, I'm going to present right now, I just want to remember increased comp for the purpose of this is analogous to increase cartilage stress. So essentially what we found. And again, the red line here is when they walk continuously. And the blue is when they walked through the interval walking approach, we found that there was a significant increase in serum comp when they walked continuously on the treadmill as opposed to the interval walking regimen. So that suggests that this sort of interval walking approach, they got the same cardiovascular benefit. I didn't show the pain scores, but there was decreased joint pain, but it also maybe could be protective to their joints as well as there's not that increase in abnormal learning for a long duration uh compared to when they walk continuously at 45 minutes. So we did that study and then what we wanted to look at was then to apply it to a particular leisure time activity in our patients. And we were approached by one of my collaborators who's the European Ryder Cup team physician. So he's the head of sort of research trying to show the health benefits of golf in a multitude of individuals with different diseases. And what he approached me about was trying to show whether uh whether could be a beneficial physical activity for individuals with knee osteoarthritis. The interesting thing to say is that uh golf in the UK, for example, is on prescription. So if you lived in the UK on the, in the NHS. And I'm from the UK. Originally, if you, if you lived in the UK, you could actually get health club membership for golf rounds of golf on the NHS because they see it as such an important health intervention for individuals that probably will never happen in the United States. But it's something nice to dream about in the future. But his goal was really to show that golf could easily help people attain these physical activity guidelines that are set nationally and it could be beneficial to patients in a number of different ways. So as we talked about aerobic exercise is strongly advocated for people with osteoarthritis. And what I see in my patients and is borne out in the literature is that many people with osteoarthritis don't want to exercise because they're worried about worsening their disease, provoking their symptoms. And there's a lack of knowledge overall regarding exercise and its benefits. So maybe golf could be the solution over 17 million people in the United States above the age of 50 play golf. And the average round of golf, you walk 10,000 steps or seven kilometers, which is quite a significant amount. And as we talked about golf in, in Europe is really can be on prescription and what we're thinking about. Well, let's take a step back and think about golf being a prescribable sport for individuals with osteoarthritis. Now, the challenge is is that golf is played differently in the UK as it is in the US. So in US, 45% of rounds of golf are played with the golf cart and, and that was in the eighties and then in the early two thousands, a study also that was close to 70% of rounds were played with a golf cart. And this is actually data from the golfing folks. Not from me that if you played golf, you're actually more likely to be overweight and obese. And it's thought to be related to the pervasive use of the golf cart golf court as opposed to Europe where the golf court is, golf, golf cart is nowhere near as pervasive. So knowing that what we wanted to look at was whether comparing individuals when they walk, uh walk around as opposed when they use a golf cart, maybe this is analogous to higher dose walking versus lower dose walking. And so could this be beneficial to our patients with osteoarthritis? So essentially what we did was very similar to what we described before is that players played two rounds, they walk the course and every ninth hole we took blood from them, we asked them their rating of perceived desertion, we measured their heart rate and we asked them their pain score and we did the same with the golf club. We randomized which round they did first. This was obviously a very challenging study because I was out on the golf course during the summer, taking blood from individuals and watching them on the golf course. I'm obviously being sarcastic when I say that. So the first thing to say is that when we looked at the physical activity of these players, as you would expect, when they walked the course, there was a significant increase in their step count. There was higher ratings of perceived exertion and the maximum heart rate that they achieved during the round was significantly, was generally higher, not significantly higher overall. Though, if you see the golf cart, they, they'd still attained about 7000 steps and a significant proportion of the round was, was a high level. It was a moderate intensity physical activity and we'll talk about that in a second. Then when we looked at significantly inflammation and pain, there was a significant increase in pain when they walk the course as opposed to when they use the golf cart. And similarly, when we looked at T N F alpha, which is a degradated protein or Degra sorry inflammatory mediator, we actually found that there was a significant increase in this, in this inflammatory mediator only when they use when they walk the course. But we did not see this when they uh use the golf cart and aisle one R A which is actually an anti degradated marker. So it actually blocks aisle one beta actually studies. This study actually showed that when they used the golf cart, there was actually a significant increase in this anti degradated marker as opposed when they walk the course, which was interesting. Then when we looked at that serum bio marker of cartage stress throughout the round, there was a significant increase when they walk the course as opposed to when they used the golf cart, which was only at the final time point, was there a significant increase? So the cartilage stress was throughout when they used, uh, at at least based on this, this study as opposed to when they use the golf cart, where we only saw this increase in this biomarker of cartilage stress. At the end, we looked at the duration of the round. There actually was not a significant difference between the two types around and you can imagine that it's still still individuals who are out on the course for four, close to four hours, irrespective of whichever round they did first. Um But there was a significant increase in the amount of moderate intensity exercise that they did when they walked the course. As opposed to when they used the golf carts, we still about 30% of the round was in that moderate intensity or vigorous intensity exercise. Um Type. The other important thing is that we often say that exercise is beneficial to patients and we measured B endorphin, which is a hormone associated with feelings of well-being. And when they walked the course, there was a significant increase in B 10 dolphin as opposed to when they use the cough cart, the most important thing to these players, however, was whether their scores were better. And when they walked the course, their core, the scores were significant. Well, when I don't say it was significant, but they were better as suppose to when they used the golf cart. And that's what our, our participants were most worried about in this study. So we've talked about now where we've gone with some of these studies, looking at some of these biomarkers in response to cartilage stress and how we've applied it to a specific sport and how that sport could impact someone's joint disease. Next. Next, I want to talk about some of the work we're doing right now, which is looking at stressing the system. So if you go back to our patient at the beginning, we talked about that patient presenting to our clinic with symptoms of osteoarthritis, we examine them, we perform radiographs, but the, and we diagnose them with osteoarthritis. But the major challenge is that this sort of treatment approach really provides us no information on the metabolic state of the joint, how that joint is going to respond to load and potentially early diagnosis of the disease even before we get to this point. So what we've been working on is developing a stress test or a test that can in early knee osteoarthritis that can provide us information on the biological state of someone's joint. And in turn how that joint is going to respond to loading. So our laboratory has actually developed a treadmill. So this treadmill is in the middle here. So on the left here, you can see this is just an individual walking on a treadmill as you would normally. But in the middle to the middle. And on the right here, we have a tilted treadmill. So this is a treadmill as opposed to an anterior posterior incline, it actually provides a media lateral tilt. And so this provides unique individualized stress to the joints of a particular side, particularly the knee joint as some of our biomechanical studies have shown. So this potentially allows us to do when we just get individuals to walk on a treadmill, we're not able to look individually at a particular joint, but this type of approach will be very distressed on these joint, could allow us to look at a biomarker response of a particular joint. Um at least um hypothetically. So, so what we found was that when we did this sort of approach that the knee that was lower in the uh so, so the knee that was lower in the knee, frontal plane, uh which is the left knee, uh which is the um the left knee joint in this particular study actually had a higher knee abduction moment. And this is a biomechanical parameter that's associated with radiographic progression of osteoarthritis. And it's well documented in the literature. So, we were able to increase the biomechanics or increase the biomechanical parameter that is adverse in individuals with, uh, with osteoarthritis while they're walking on the treadmill. And this is both healthy and individuals with osteoarthritis. So we can uniquely provide a stress to a knee joint as opposed to some of the other joints while someone is walking. So then when we measured some of these biological markers of cartilage stress. So the, the orange bar here is when they're walking with a tilt and the blue is when they're walking with the flat. And what we found was that when, when individuals walk with this tilt, there's a significant increase in that bio marker of cartilage stress comp um whether they walk with uh normal, whether they have healthy knees or if they have osteoarthritis. The other thing that we were able to also see was that there was a differential response dependent on the type of, of whether they had a way or not. So individuals with osteoarthritis had a significant increase in this biological marker as opposed to individuals who had normal healthy needs. And then when we looked at a biomarker associated with cartilage degradation. So M MP 13, which is that cartilage degradated bed time. Similarly, we found that there was this, we were able to differentiate individuals with normal healthy knees as opposed to those with osteoarthritis based on their response to tilt walking. We didn't see that when they just walked flat on the treadmill. And this level of increase in this bio marker of cartilage stress was significantly higher than what we've seen in other studies which have tried to incorporate this sort of cartilage stress or stimulus response framework that I was describing earlier. And it was, and that was a very exciting finding for us based on our biomarker responses. The other thing that was also interesting was that we also were able to see differences based on age sex and B M I. And as I mentioned, being older, age being female sex and having I B M I are all associated with radiographic progression of osteoarthritis or the development of osteoarthritis. And we found some of those risk factor differences in individuals based on their disease. And then finally, in the bottom right here at the red bar being when they walk through tilt and the blue being when they walk flat, we found actually that individuals with kale four grade osteoarthritis, which is the highest level of osteoarthritis as opposed to kale three grade, which is slightly more modern osteoarthritis. Individuals with more moderate osteoarthritis had a more a higher biomarker response. And we think that's because individuals who are great for osteoarthritis have less cartilage in their knee joints leading to less release of some of that pump into the bloodstream. So overall, this study actually showed that we were able to differentiate individuals with early with knee osteoarthritis compared to normal controls. And we're now what we're planning to do and we were able, we were able to see age, sex and BMI differences, as I said, and also differences in severity of cartilage disease and now what we have done and we're testing those biomarkers now is now applying it to individuals with early osteoarthritis or at risk of early osteoarthritis in particular individuals who have AC L injuries. So we're testing those in this tilt walking paradigm. And my hope is to present that very soon and have that publish that very soon, that data. But so far, our preliminary studies are pretty encouraging in what we're finding. So that's some of the work that we're doing right now. Now, we want to think about treatment. So we've talked about sort of apply, sort about assessing someone's osteoarthritis and the development of osteoarthritis. Now, we want to see if we can use that biomarkers, those biomarkers in trying to evaluate a treatment response in individuals with osteoarthritis. So, one thing that we've done is actually to, uh, test the use of an anti gravity treadmill or a lower body positive pressure treadmill, um, in individuals with osteoarthritis, and this treadmill is commonly used in individuals with AC L re uh, reconstructions as part of their rehabilitation process, but it's not as commonly used in individuals with full blown osteoarthritis. So this treadmill, essentially, individuals are, are placed into a, um, a vacuum and you can vary the, the strength of that positive pressure in that vacuum and that can raise individuals legs up. And based on the manufacturers uh uh recommendations, you can actually vary the amount of body weight that someone placed on their low extremity while they're walking. And this is a commercially available treadmill that I'm sure is available at Johns Hopkins as well. So what we wanted to look at was can this treadmill effectively reduce load to reduce pain? And how does it change some of those biological markers of osteoarthritis in response to walking? So, what we looked at was how does this, uh, joint offloading impact cartilage stress? So, what we wanted to do is compare 100% body weighted walking versus 50% body weighted walking. Um, in individuals with osteoarthritis, this are medical student, Sarah who worked with me on this specific study. So, what we looked at was, uh, individuals, so individuals would come in, they'd walk at 100% body weight and then they'd come in and walk 50% body weight in this treadmill. And we'd randomize which one they did first and we'd measure these biomarkers of cartilage stress and also measure their pain response to this. Now, what you're so these are the two walking regimen approaches. So as you can see here, they'd come into the, to the lab, they'd rest for 30 minutes, then we'd walk for them for 45 minutes on the treadmill and then they'd have a rest break for an hour at the end. So the first thing is to say is that we looked at the cardiovascular benefit of each type of approach. And what we found was that there was no significant difference in rating of perceived exertion and no significant difference in the amount of moderate vigorous intensity exercise that they did, whether they did 50% body weight versus 100% body weight that all we looked at was joint pain or knee, joint pain. And what we found was that when they walk, the blue line here is when they walked at 100% body weight. And the red line is when they walked at 50% body weight. And what we found was when they walked at 100% body weight, there was a significant increase in joint pain compared to when they walked at 50% body weight weight, there was a negligible increase in their joint pain. Then when we looked at that serum bio marker of cartilage stress, what we found was that when they walked at 100% body weight, there was a significant increase in that biological marker of cartage stress that we call comp. And that was compared to 50% body weight where again, there was no significant change in that biomarker concentration at 45 minutes of walking. We also measured a biomarker that is anti degradated. This is a biomarker called tip one, which is actually, which actually inhibits uh M MP. So those cartilage degradated enzymes. And interestingly, we had a trend though, it's not significant an increase towards, uh, an increase in this tip. One bio marker of car, uh, an anti degradated marker, uh, when they walked at 50% body weight as opposed to 100% body weight. And then when we looked at some biomechanical parameters of osteoarthritis, what I'm going to, to look at here is that on the left ear is when an individual walks at 100% body weight. And on the right here is when someone walks at 50% body weight. And what you see is that on, on the left here, they actually walk with a narrow, very narrow base of support compared, which is what we see more in pathological gate features of osteoarthritis as opposed to 50% body weight where they walk with a wider base of support, which is what we want to see. The other thing that we also saw was certain reduction in some biomechanical parameters associated with osteoarthritis. So at 50% body weight, there was a reduction in cadence increase in step length and a wider base of support. All good things that we want to see if we're thinking about a biomechanical intervention. So this biome biomechanical improvement also matched some of those bio and pain related features that we saw. So this treadmill, decreased pain, decreased the marker of cartilage stress and allowed our individuals with osteoarthritis to easily obtain exercise targets. And my thought on this is that this treadmill is obviously a very expensive treadmill that many individuals in the country will have access to. But it's very analogous to sort of off loading, walking through pool therapy. For example, where that buoyancy of the water actually takes some of the stress of the joints. But pool therapy has never been really studied as a walking exercise intervention. So I'm pleased to say we just got, we just got grant funding to actually do a clinical trial, a randomized clinical trial of this anti gravity treadmill versus pool walking versus standard of care walking. Um to see the benefits of this 8 to 12 week approach in individuals with osteoarthritis and see if we're able to improve both some of the biomechanical parameters, but also some of the cardiovascular parameters of these patients with, with uh joint disease. So finally, I just want to talk about the future and what we're going through. So some of the application of some of the things that we've looked at is now to look at other diseases where individuals are at risk for the development of osteoarthritis. And we've got a grant to actually look at individuals with cerebral palsy, a common thing that we treat as psychiatrists, but individuals with cereal, cerebral palsy have a high development of joint disease. And so what we wanted to look at was whether the serum concentrations of some of these markers varied between individuals with osteoarthritis as opposed to individuals, individuals with cerebral palsy, as opposed to individuals without cerebral palsy. And so, what we looked at was the relationship between function C P grade or the presence of C P versus not and joint pain. And what we found was as you'd expect that on um is that as individuals G M F CS criteria went up, their function went down and their muscle strength, et cetera went down as well. So, and they had a worsening joint pain as a whole. What we also looked at was then these correlations of some of these joint uh of these markers. And as you can expect with individuals with um more profound G F CS criteria, they actually had less mobility. And so they, there was a negative correlation between uh with joint pain and some of these serum biomarkers. And as I mentioned earlier, these serum biomarkers are actually mechanosensory. So if someone's not placing weight on their joints, these actually go down in their bloodstream. So we overall found that there was a negative correlation in cerebral palsy between the level of joint pain, particularly at the hip and the serum biomarker of cartilage stress and some of these inflammatory mediators. And we're doing some um metabolin maring of this uh of this cohort as well uh in this study. And we, we, we will present that soon. Similarly, we then want to apply it to a disease where individuals don't put weight on their joints as they talked about, cartilages are kind of sensitive. So in individuals with osteoarthritis, we know that there's a normal loading which leads to thin tissue, eroded articular surface, which we see in a way. But in individuals who under load their joints, such as individuals with spinal cord injury, we actually see this idea of this cartilage atrophy. And studies have shown that if you take this an individual potential cartilage atrophy because they're not placing weight on their joints and then reload their joints, they actually can grow back some of their cartilage. So, what we wanted to look at was was this um this issue in individuals with spinal cord injuries. So we did MRI with them at baseline and then we did MRI in individuals at six months and these are um individuals who weren't able to place weight on their joint and we took soa fluid from them serum uh biomarkers and also did MRI s and so what we found was that as you see here and this was preliminary analysis at six weeks, we were actually able to show that this is an individual who was paraplegic. He didn't put any weight on his joints. There was a significant increase in uh in, in a a few of these individuals in terms of their uh cartilage, uh thinning that we see at six weeks as opposed to what we see at beside. So these individuals are not placing weight on their joints, but their cartilage is thinning just from the fact that they're not placing weight on their joints. And so we're gonna look at this a little further in our studies. So we have some biomarker and snowy fluids that we need to test on these individuals going forward. And then very finally, I just want to talk to that idea of targeting interventions to the right patient at the right time. So just to talk about some of the things that we're doing right now, as I talked about many of our treatments involve injections. And we know that we're doing some work to actually look at how the environment of someone's synovia fluid impacts the outcome of the injection. So we're looking at whether that milieu of biomarkers in the synovia fluid has a relationship to the outcome of a steroid injection or hyaluronic acid injection. Similarly, we're also looking at whether the ultrasound assessment, whether you can use ultrasound to actually actually evaluate someone's osteoarthritis and how closely that correlates with someone's joint disease. But the other part that I see in my clinic is that psychosocial factors also have a big impact on, on the on our treatments and access to care, socioeconomic status, demographics and patient expectations all play a role in the outcome. If you purely look at biology, we aren't going to optimize the outcome of our patients. So what we did was actually to look at and this is really an epidural injections. But it's recently published was actually to look at individuals who underwent epidural injections for uh lumbar ridiculed. And what we wanted to look at was factors associated with pain reduction at two weeks down the line. And we looked at a whole remit of demographic factors. And what we found was that there were two major factors associated with the outcome of the injection. We found that socioeconomic status uh based on median household income as well as physical activity. So the higher level of physical activity, the better they did and the socioeconomic status. So the, the less baseline pain they had, I I correct myself and the higher socioeconomic status, they had the less response they had to an injection. And that will make sense here. And that what you see here is an individual based on their toile, their percentile of median household income, which were used as a surrogate of socioeconomic status. We actually found that individuals at the lowest lower end of uh uh a median household income had a higher response to an injection as opposed to the 95th percentile where they had lower baseline pain and less response to injection. We hypothesize that this might be due to lack of pain, uh access to pain management at baseline in these individuals as well as insurance status as well, has a big role to play as well in this. And this is just showing that a, a little differently similarly, when we looked at, look at baseline pain in individuals with osteoarthritis, we, we certainly found certain demographic factors were associated with and this is well documented the literature. But certain things like marital status, disability status and employment status are all associated with higher baseline in pain. And then finally, when we looked at expectations of a procedure, when we looked at individuals both who underwent knee injections or underwent spine injections, we looked at their pain at baseline and pain at four weeks. And we wanted to look at whether their expectations of a procedure, how that related to their outcome. As you would expect, the injections did help. There was improvement in joint pain and an improvement in disability following these steroid injections. But these did have a, a mild relationship to their expectations of a procedure. If a patient felt that the procedure was going to help them, they tended to have a better response and less disability post injection as opposed to preinjection. So finally, just to say, you know, we've gone through a lot today, but my hope for the future of osteoarthritis care is that we won't just examine or perform radiographs in our patients, but we'll have novel imaging modalities. We'll look at some of these biomarkers and assessing biology of someone's joint disease. And we'll look at some of these psychosocial factors in our patients as well. And it really speaks to what we do as psychiatrists is that we try and treat patients in an individual. My hope is that we'll do that for osteo arthritis care in the future. I want to thank many of my collaborators and mentors for my K awards and during my residency and, and uh and my phd in graduate school training. Um This is my team. I have a fantastic team of uh research assistants over the last few years as well as residents who've worked with me. And I want to thank Doctor Sick. Uh I found this picture. He looks, he looks very much younger here. But no, but um doctor sick is someone I met uh 10 years ago when I first started out as a clinician scientist. It's crazy to think that I've been in this field for that long when I started residency and I know you have some fantastic clinician scientists at Johns Hopkins. Um But I think doctors has been a tremendous role model to me, particularly as an immigrant uh to the country as well as also uh someone who has uh really mentored me from afar in much of what I do. And I with that, I'll take any questions. Thank you so much, Rakesh. Thank you so much for wonderful talk. And uh also thank you so much for that uh acknowledgement, appreciation of mentoring and so on. Uh It's been uh great to, to, to be able to connect with you on and, and, and meant from the fire. And so on uh I just wanna say one thing and then I let take to ask questions. Thank you also for addressing these psychosocial aspects of uh and one effort that we have been doing in the department is uh to highlight something related to diversity, equity inclusion in the, in the context of talks. And I think you've done that a little bit just by the science that you are addressing some of these socioeconomic disparities and, and other aspects. So I appreciate for that. Um You know, yeah, was a fantastic uh talk. I really enjoyed it. I'm so glad that somebody is actually doing biological approach to osteo. Like I said, I think, I don't think it's actually just wear and tear. Now, I have a, just a quick question. I have to go for the clinic. Uh First uh uh just two quick questions. First is uh so um it seems like the comp protein is really the key molecule that trans this mechanical pressure to all the inflammatory cytokines. So why don't you just uh kind of develop a comp, I don't know, blockers or whatever so that they can actually exercise without, you know, causing or inflammatory markers. And second quick question is, uh we see uh uh like a lot more incidents of osteoarth and aging. I think biology of aging, I'm sure it play uh come into play. What do you think about the mechanisms of aging and inflammation and oor mechanic mechanically Yeah, thanks. Thanks so much. And uh, that's a great question. So, the first thing I think with comp, I, I might, I might have underplayed it. There isn't this? Um It doesn't really lead to the inflammatory cascade as well as that. Um, a lot of the Sy, the Synovium releases a lot of the inflammatory mediators into the joints. So we don't really have a good, uh, so it's not blocking comp would lead to that. I think comp is a increasing comp as a result of cartilage injury or cartilage stress. So I think blocking comp probably would not lead to a decrease in inflammation. There's sort of two separate pathways. So um that's the first thing to say. The second question is a really sorry. Yeah. And then are there any drug targets around there then what's that? Are there any drug targets around the? Um there are, so the bigger one is that a lot of, a lot of pharmaceutical companies are developing anti M MP or uh an uh um blockers essentially. So those are the cartilage degradated enzymes that are released by microphage so that there are companies trying to develop those. And similarly, there are ale one receptor antibodies that are also being developed. So, so those have also been uh developed to try and limit that inflammatory cascade. So I think the focus of the field particularly from a pharmaceutical standpoint is blocking the degradated enzymes as well as the inflammatory cascade. Um, the challenge is inflammation could sometimes also be a good thing. So it's not necessarily always a bad thing. The second question I think is a really good point and I think you speak to phenotyping individuals of osteoarthritis. So there is this naturally aging type of osteoarthritis. There's a mechanical overload type of osteoarthritis and there's the pro inflammatory type of osteoarthritis. And that's where the field is moving. And my goal in developing this cartilage stress test is actually to try and phenotype individuals based on their response that that would be probably a long time r one application. But that's really where I see the, the utility of that is trying to phenotype individuals based on acute biomarker response to it because each one of those has a very different treatment. So someone who has a post ac L injury that's leading to osteoarthritis as opposed to a person who's just getting older and developing osteoarthritis, those are two very different patients. And so that's the way the field is moving is exactly as you said it. Thank you so much. That's really fascinating as you know, I do a agent research, collaborate. Yeah. Oh, that would be great. That would be great. I'll be on it. That would be awesome. Thank you so much. Thank you. Yeah, I gotta go. No problem. Thank you. Bye bye bye and, and um I think so we are at the top of the hour and uh, so I don't know if anybody has any last minute question. Otherwise I would encourage folks to reach out to you Prakash uh offline. Um So, so with these, I, I really, I mean, we, we are running out of time, but uh thank you so much for uh for joining us today. Really fascinating work and very interesting. And I will ask you some questions next week when I see you there. Thank you. OK. no problem. Thank you so much and it's great to see you. I hope to see you next week. Um Thank you for the comments as well. I I I I see those as well, so I appreciate, I appreciate it um so much and then look forward to seeing you all at A P next week. Hopefully. Great. Awesome. Ok, thank thanks. Thanks. Bye bye bye. Created by
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