Hello and welcome to my presentation today. My name is Prakash Jayabalan. I'm the director of clinical musculoskeletal research at the Shirley Ryan Ability Lab. I'm an attending physician scientist and also an assistant professor at the Northwestern University Feinberg School of Medicine. And today I'll be presenting my work funded by the Foundation for PM&R, which was awarded the Scott F. Nadler Paso Musculoskeletal Research Grant Award in 2019. I don't have any formal disclosures other than this work is funded by the Foundation for PM&R, who I'm very grateful to for the grant award. The presentation I'll be giving today is the development of a cartilage stress test for early knee osteoarthritis. So the outline for the talk today, I'll be talking briefly about the biology of knee osteoarthritis and then using biology to essentially develop our diagnostic and treatment modalities for our patients. I'll also be talking about biology and exercise briefly, and then stressing the system, which is really the focus of the project for which I was funded from the Foundation. And then I'll be talking about some future avenues of research that we're undertaking using some of the preliminary data we've developed from this research grant. So a common clinical scenario we face as musculoskeletal physiatrists is the patient here on the left. So a 58-year-old former soccer player presents with 78-month history of medial-sided knee pain. And our typical evaluation paradigm is to examine them and perform radiographs. And then we'll typically diagnose them with knee osteoarthritis. And then our treatment plan is as such. So essentially we'll prescribe them medications to treat their pain. We'll talk about weight loss, exercise, physical therapy, and prescribe those as physiatrists. We'll also talk about injectable treatments. Most commonly, currently, nationally, we use steroid injections or visco supplementation. And then that leads all the way to arthroplasty, which involves the use of inert metals and plastics to replace the joints. And our goal really as non-operative physicians is trying to optimize the left side of the screen. So we delay or prevent the need for total knee arthroplasty. And that's really my goal as a musculoskeletal physiatrist treating patients in knee osteoarthritis. But when I think about this case from a research perspective, there are a number of issues. The first thing is, can we have diagnosed this earlier? How do we decide what is the best treatment for our patients? What level of physical activity should we recommend for our patient? And what sort of rehabilitation should we prescribe that optimizes a patient's disease to them? So we're not talking about a one size fits all approach, but rather one where we're actually able to individualize our exercise prescription to the patient. And that's really the focus of much of the research that I undertake. The other thing that is also important to remember is that in knee osteoarthritis, there's a number of different factors that are at play. So it's not just necessarily a biological disease or a biomechanical disease, but it's a complex interplay between the two that's very, very important to think about. So for example, in osteoarthritis, we know that there's abnormal loading on the joint, and there's also abnormal biological processes in the joints. And what happens is that we know that these abnormal biomechanics can potentiate some of the degradative and inflammatory processes within the joint, leading to the abnormal biology and vice versa. And our goal as sort of non-operative physiatrists is to try and limit this vicious cycle. So we'll tell patients to lose weight, we'll tell them to modify the activity so we're able to optimize their activity to this particular disease, and try and find measures which load the joint slightly differently to limit some of that biological processes. But we'll also prescribe medications with limit some of the biological processes in the joint, such as anti-inflammatories, which target the inflammatory mediators here, such as R1 beta, TNF alpha, and others. And some medications that are being developed that actually target some of the cartilage degradative enzymes such as MMPs in the knee joints. And so it's very important to think about this complex interplay between biomechanics and biology when we're thinking about managing patients with osteoarthritis. The other thing that's important to think about is that when we talk about the joint, the joint is really an organ. And there's many different aspects to the joint. So we know that there is not just the cartilage, but there's also the subchondral bone, which is important for giving cartilage its structure, as well as the synovium, which surrounds the knee joint. And this produces some nutrients which bathe the cartilage from the synovial fluid. And the synovial fluid itself, as I said, contains nutrients which are important to the health of cartilage. And in the articular cartilage itself, it's a shock absorber and it allows frictionless motion. But one of the challenges that we have as non-surgical practitioners of osteoarthritis is that cartilage is avascular, alymphatic or aneural. So when it's initially damaged, we really have no way of knowing that it's damaged because of this a neural issue. But it also has very limited healing potential, which limits some of our treatment options for our patients. So what happens in osteoarthritis? So in osteoarthritis, we in a typical joint such as this, we have normal cartilage, you have a synovium surrounding the joints, and then you have subchondral bone. But in the osteoarthritic state, we know that there's thickening or inflammation of the synovium, there's osteophyte formation. And there's also degradation, of course, of the cartilage and some injury to the subchondral bone. And over time, as the patient bears weight on their joint, there's, there's thinning or damage to the cartilage further. But there's also the release of inflammatory mediators, cartilage degradative enzymes, and also breakdown products of the cartilage that we are able to measure within the synovial fluid or bloodstream of our patients. And so the balance within the joints gets tipped more towards catabolic processes as opposed to anabolic processes. So this really leads to the development of biomarkers for osteoarthritis. And the challenge that we have as non operative practitioners is that often the patients are presenting to us quite later on in their disease. And that's because radiographs are probably the most common type of modality used for osteoarthritis. But the challenge is that radiographs have a very poor sensitivity to early disease, and they do not correlate to symptom severity. MRI is expensive. And many of the MRI scanning protocols, which are very, very developed for cartilage imaging, are not available to the vast majority of the population. And similarly, arthroscopy, this idea of sort of washing out the joints that is was pertained that was talked about in orthopedics has really gone out of favor because there's very limited evidence for it. And as physiatrists, obviously, we're very focused on function. And it's very limited correlation of some of these modalities to function. So really, this leads to the work that I'm trying to do, which is trying to decide or trying to figure out if we can be fortune tellers for osteoarthritis, can we tell someone how their osteoarthritis is going to develop and in turn, and in turn, try and prognosticate how they're going to respond to a specific treatment that we're going to develop for that patient. And this would really lead to earlier intervention on the bottom of the screen here rather than later on, which is often what we're trying to do with osteoarthritis. So just before I get into the nuts and bolts of the project that we undertook, it's important to think about the structure of cartilage. So cartilage consists of a chondrocyte surrounded by an extracellular matrix. And that extracellular matrix consists of collagen, which gives cartilage its tensile strength, and proteoglycans such as agrican, which gives cartilage its compressive strength. Now, we know in osteoarthritis, there's damage to the extracellular matrix is also, which is potentiated for some of these cartilage degradative enzymes called MMPs. And some of these fragments of some of those proteins from the extracellular matrix as well as MMPs can be measured in the bloodstream. And that's really the premise of much of the work which I do. Studies have shown that actually some of the measurements of these markers actually predates clinical development of osteoarthritis. So even pre-radiographic osteoarthritis, you can actually see some of these molecular changes in the bloodstream of some of these patients who go on to develop full-blown osteoarthritis. So that really leads to the concept of using this biological approach in evaluating an individual's response to loading or exercise. So my lab is essentially focused on the development of a stimulus response framework for osteoarthritis. This is analogous to a cardiac stress test. So for example, in a cardiac stress test, we give someone a musculoskeletal task or physiologic task, this is running or walking on a treadmill. And we look at the physiologic response to that. So we look at EKGs in these individuals. And looking at the EKGs, we're then able to stratify risk for the development of coronary artery disease in these patients. So similar to that, we've developed a stimulus response framework for osteoarthritis. This is where you essentially provide someone a biomechanical stimulus. So this is typically walking on a treadmill where you're loading the joint. And many studies have shown that you can measure some of these biomarkers of cartilage stress while someone's on a treadmill. So we place an IV in our patients, and we draw blood from that IV. And studies have shown that if you, that immediate response to the biomechanical stress does have some diagnostic or prognostic value. The unique capacity of this methodology is that we are able to look in real time at the stress response of the cartilage, it allows dynamic real time assessment. And by looking at this early on in the disease process, we're able to outline individuals with compromised cartilage, which is very important. So a study out of Stanford in 2012 actually showed that if we get someone to walk on a treadmill for 30 minutes, and we measure the serum biomarker response by measuring a biomarker, which I'll mention called COMP, that response to that 30 minutes of loading actually predicted cartilage thickness five years down the line on an MRI. Some of our preliminary studies have shown, we did a study basically comparing continuous walking on a treadmill to interval walking on a treadmill. And what we were interested in seeing was how does the biological response vary? And does it have any relationship to the joint contact forces in these individuals? And interestingly, the red bar here is continuous walking on a treadmill, and the blue is interval walking. And we found that at 30 minutes, there was approximately a 20% increase in the knee joint contact forces in individuals with OA when they walk continuously on a treadmill, as opposed to walking with interval regimen. And there was a walking time effect. So the longer they walk, the more there was a significant difference between the two types of walking regimens. So this essentially is the premise of that study, when we looked more closely at these biological markers that on the top here, the individuals walk continuously on a treadmill for 45 minutes. And on the bottom, they walked at an interval walking regimen, they do the same amount of walking, where they walk for 15 minutes, take a rest break for one hour, 15 minutes rest break for one hour, rest break, and then walk for 15 minutes, a total of 45 minutes as well. And we measured some of those biomechanical parameters I mentioned, we also measured their blood based markers. And the marker that we looked at is something called comp. So comp is part of the extracellular matrix actually ties together collagen type two fibrils. So every time you take a step on your cartilage or in your joints, it actually transduces that mechanical signal from the extracellular matrix to the chondrocyte to maintain its health. And when cartilage breaks down, and such as an OA, we're able to measure comp in the bloodstream at higher levels. So for the premises of the study, increased comp is analogous to increased cartilage stress. So what we found was while walking on a on a treadmill continuously, there was actually a significant increase in serum comp compared to when the same individuals walk to the interval walking regimen. And this also matched an increase in pain as well as an increase in joint contact forces. So it's important to remember that maybe a continuous walking program, not only not a continuous walking regimen, which he had some effects or some worsening effects on the biomechanics of the joints in terms of some of the joint contact forces, it also led to an increase in pain. And it also led to an increase in the serum marker of cartilage stress. So that was probably the first study that we did in this in this realm. The next phase, which we're really focusing on now is trying to use some of this pilot data that we've generated to stressing the system. And this really talks about the way that we manage osteoarthritis. So the current evaluation of our individuals who present to our clinic is that they'll present with symptoms of OA, we'll then examine them and we'll form imaging studies of these individuals, typically x rays in the clinic. And then we'll prescribe a program of treatment on the basis of that. But one of the biggest challenges that we have is that this really provides us no information on the metabolic state of the joints. And most importantly, how that joint is going to respond to loading, which is very important to our patients, particularly if we're going to prescribe exercise to them as part of that rehabilitation regimen. So the real focus of the work that I'm doing now is to try and see if we can develop a test in early knee osteoarthritis that can provide information on the biological state of the joint, and in turn how that joint will respond to load. And this was really the premise of the Nadler Award that that I've been performing. So this is really the premise of the stress test. So on the left here, we have an individual just walking a healthy individual with normal knees who's just walking on a flat treadmill. And on the middle here, we basically are able to tilt the treadmill to 10 degrees. And that, as I'll show in a second, has some biomechanical effects on the knee joint specifically. And then on the right here is an individual with knee osteoarthritis, and they undergo the same sort of testing protocol. So what we found was, based on kinematics, was that the lower knee joint, so that's the, that's the left knee in our study, was actually if we got individuals to walk, the lower knee joints in this case actually had the highest amount of varus angulation, or knee adduction, compared to any of the other joints in the frontal plane that we saw. So taking that back, explaining that further, the angular change of the particular joint was the highest in the lower knee joint out of all of the joints of the lower extremity. The beauty of this type of methodology being that we can differentially load each joint and then look at how that biomechanics correlates with some of the biochemical changes that we see. So this suggested that the knee joint that is lower is taking the highest stress. So we would anticipate that potentially some of these biological changes that we see are most likely coming from the lower knee joint. Next up, we actually did some much more formal kinematic analysis. And what we found, again, was that during the gait cycle, when it's tilted, the lower knee joint in particular has a highest change during heel strike in knee adduction compared to the higher knee joint. So that was important to show that there was a difference in the biomechanics of the knee joint. Then we wanted to look at some of these serum markers. And what we found was the orange bar here is when the individuals walk on the treadmill with the tilted treadmill, and the blue is when they are walking flat. And on the left here is the normal healthy control. So these are individuals in their 20s on average. And on the right here are individuals in their 60s with known clinical and radiographic osteoarthritis. And what we found was that individuals with osteoarthritis had a significantly larger biochemical or biomarker response in terms of serum comp compared to normal healthy controls. The other part that's also important to remember is that the tilting paradigm actually caused, whether you are a healthy control or an OA subject, there was a significant increase in serum comp with tilting compared to flat walking. So the orange bar essentially showing is about a 42% increase in serum comp with tilting compared to OA subjects, and about a 21% increase in serum comp with tilting compared to walking on the treadmill. So the response was higher in individuals with osteoarthritis. And this paradigm shows a significant increase in serum comp compared to normal healthy controls. Let's look at another marker that's associated with osteoarthritis. So this is MMP-13, which is essentially a breakdown enzyme of the extracellular matrix of cartilage. And what we found again was that in response to this tilting paradigm, there was a significant increase in MMP-13 in the OA subjects compared to the healthy controls. Well, the normal subjects when tilted compared to flat. So again, there was a significant difference between normal subjects and OA subjects in terms of their response to this tilting paradigm. The other interesting thing to think about is also mechanistically, there was a correlation to the change in comp, which is that marker of cartilage stress, to the MMP-13, which is that marker or that enzyme, which breaks down the extracellular matrix of cartilage. And so that may suggest a mechanistic pathway that may also be important and is another opportunity in using this sort of tilted paradigm in individuals with osteoarthritis. Next, we wanted to look at how individuals with certain risk factors for osteoarthritis respond. So we compared individuals with OA who are above the age of 60 and below the age of 60. And we know higher age, female sex, and also higher BMI are associated with the development of osteoarthritis as well as progression. And what we found was that older individuals above the age of 60 actually had a significantly higher response to the tilting paradigm compared to younger individuals less than 60. When we looked at differences in sexes, again, we found that female subjects, who again are at a higher risk for development and progression of OA, these individuals actually had a higher serum biomarker response in terms of comp compared to the male subjects. And similarly with BMI, we also found that individuals with higher BMI above 30, and these are individuals with OA, they had a higher biomarker response compared to individuals who had a BMI less than or equal to 30. Finally, we wanted to see, I've already shown some data suggesting that this paradigm was able to differentiate people with OA to those without. We wanted to see whether it was actually able to differentiate different types of radiographic grade of knee osteoarthritis. And really interestingly, individuals who had lower grade osteoarthritis, so this is KL grade one to three, so this is sort of mild to moderate OA, compared to individuals with KL4, the ones with mild to moderate OA actually had a higher response to the tilting paradigm compared to those with very severe OA. This makes sense because individuals with severe OA have less cartilage, and so they're likely to have less of a biomarker response because of that, because many of these individuals have negligible amounts of cartilage in their joint. And so that's important to think about that this also did show we were able to differentiate severity of OA using this paradigm in our subjects. So putting this all together, this cartilage stress test was able to differentiate individuals with knee OA and normal controls and we were able to show age, sex, and BMI differences in responses. And this is important because these are risk factors for the development and progression of OA. So clinically, this could be important because we may be able to look at differential response based on some of these risk factors in our individuals. And also there was differences in response based on the severity of an individual's cartilage disease, at least based from radiographs. So the next step that we're undertaking is actually looking at graded cartilage stress, so looking at how zero degrees versus five degrees versus 10 degrees, whether there's a differential or dose response using that sort of approach. We also wanna look further at some of these relationships between individual biomarkers to outline potential mechanistic pathways for knee osteoarthritis. That really led, this study has really led into some of the therapeutic stuff that we're now utilizing this methodology for. And another grant that I did receive from the Foundation for PM&R was the Justice Layman Award. And this really was to look at the developments or the use of lower body positive pressure treadmill walking in individuals with knee osteoarthritis. And commonly, this is, the term is the anti-gravity treadmill. This treadmill is often used in individuals post ACL repair to allow a graded loading to their joint over time. And the anti-gravity treadmill works by changing the air pressure that's actually placed on the low extremities. And as clinicians, we're able to control the amount of weight that's placed on the low extremities. And our goal was really to see how does some of these biological, how does this sort of loading using an anti-gravity treadmill change some of the biomarkers of cartilage stress? And importantly, is this treadmill effective at reducing load to reduce pain? Now, of course, this is an expensive treadmill. So in terms of a clinical relevance, this really speaks to offloading strategies that we might use in rehabilitation, such as pool walking or other type approaches. And that was really the premise of trying to perform this study is to see whether this sort of offloading strategy, how it impacts the biology as well as the pain of individual joints. So what we did was to look at how does joint offloading affect cartilage stress and pain in individuals with knee osteoarthritis. So we had each individual would come in and they would do 100% loading versus 50% loading. And we randomized which regimen they performed first. So the hypothesis was that compared to fully loaded walking or 100% body weight walking, 50% body weight or offloaded walking would be associated with a significant decrease in a serum biomarker of cartilage stress, as well as a significant decrease in pain. And the biomarker that we looked at was SerumCom. So on the left here is an individual who's 100% fully loaded walking, 100% body weight walking, and on the right is 50% body weight walking. And just to point out, as you can see on the left, these aren't videos, but you can appreciate, is on the left here, when they walk at 100% body weight, there's a very narrow base of support, whereas on the right here, there's a more wide base of support, which is more in keeping with healthy, normal joints. And so first of all, just looking at that, you can tell that that sort of offloading may actually have some gait parameter effects, which may be important. So what we did was that individuals essentially rest for 30 minutes when they come to the lab, so that we offload their joints for 30 minutes. And they walk for 45 minutes at 100% or 50%. And then we draw blood from them while they're on the treadmill at 15 minute intervals. And then they take a rest break for an hour at the end of that. So what we found here is firstly, and this is based, this study is currently ongoing, is that when we looked at pain using the Numeric Pain Rating Scale, we found that the blue line here is the 100% walking and the 50% is the red. We found that when they do the 100% at 45 minutes, or even as early as 15 minutes, there's a significant increase in individual pain compared to the 50% loading paradigm, where there's actually a overall reduction in the pain in these individuals. And this is knee joint pain, I should clarify. Next, we looked at serum comp, which is that marker of cartilage stress. And what we found was with 100% fully loaded walking, which is the blue here, there was also a significant increase in serum comp that plateaued at 45 minutes, which we did not see with the 50% walking paradigm, which was important to think about in terms of the stress that's being placed on the joint in these individuals. Finally, we also looked at a marker of, an anabolic marker or a marker that's anti-degradative. So, TMP1 is actually inhibitor of some of those cartilage degradative enzymes I mentioned before. And what we found is when individuals walk at 100%, there's an overall reduction in TMP1 during the rest period. Whereas we started to see with individuals who walk, when the individuals walk at 50%, there's an overall increase in TMP1 compared to 100%. And so, this may suggest some sort of potential beneficial effects of this paradigm, the 50% body weight walking paradigm in using anti-gravity treadmill in these individuals with OA. But this needs to be certainly teased out further in these individuals. So, looking at this overall, the anti-gravity treadmill did decrease pain, it decreased markers of cartilage stress. And the other important thing when we're thinking about in using it as a prescription for individuals with OA, it did allow them, these individuals did meet, there was no significant difference, I should clarify, in terms of the degree of how active the individuals were during this. So, how active were they in terms of their mobility during this, or how high their heart rates reached during these exercise regimens. So, there was no significant difference. And so, they got the same workouts where they did 100% or 50%, which was interesting. I think, as I said, the clinical relevance of this is not necessarily that the treadmill itself could be something that's a benefit, but it may be that the treadmill is beneficial, but also other offloading strategies, such as pool therapy and other things, or getting individuals to walk in a pool, where you're using the buoyancy to offload the joint, could actually be a benefit in individuals with knee osteoarthritis. And that's something to potentially look at in the future. So, what's the future? Well, putting this all together, and certainly our research is still ongoing in this area, is that my hope is that when we have an individual with knee osteoarthritis, we won't just use a one-size-fits-all approach. Rather, we'll, of course, take a history, we'll examine them. We may perform very specific imaging studies to look at their cartilage health, but we'll also look at biological markers, either in their synovial fluid or in their bloodstream, to give us an indicator of their disease state. And we'll also look at psychosocial factors, because those have a big impact on individual patient outcome going forward, and that's something else to also think about in addressing. Importantly, as physiatrists, I think I'm preaching to the converted here when I say, we treat every patient as an individual. So it's important to think about that when we're thinking about knee OA management. And rather than using a one-size-fits-all approach, we should really think about trying to individualize our treatments based on the biology and health of our patients going forward so that we're able to give them the optimal quality of life in the context of their disease process. I'd really like to thank many of my collaborators and students and residents that have worked with me. I wouldn't seriously be here without their help, particularly many of my mentors, such as Dr. Tom Schnitzer, Dr. Levi Hargrove, and Dr. Rick Lieber. I'd also like to thank my outside collaborators, and most importantly, for the purposes of this study, the Foundation for PMNR. All three major studies that I presented today were funded by the Foundation, and I constantly feel lucky that the Foundation has supported me throughout my career to date. And I know for sure that I wouldn't be here without them. Certainly, some of our projects have been limited recently because of COVID, but the support of the Foundation during that and allowing me to continue my research has been phenomenal. And I'd like to thank them personally for giving me that opportunity. And finally, I'm just very lucky to have a great team of researchers, such as undergraduates, residents, students, research assistants. Four of my research assistants, all four of them have gone on to medical school or residency in PMNR. So I'm extremely proud of them and what they're achieving. And I just want to thank you for your time today. And please feel free to reach out to me if you have any questions. My email is pjabalin at sralab.org. And I'd be happy to take any questions that you may have through email. Thank you.

Dr. Prakash Jayabalan

clinical musculoskeletal research

cartilage stress test

early knee osteoarthritis

diagnostic and treatment modality

abnormal biomechanics

abnormal biological processes