our fellows lecture and we're honored tonight to have Jeff Abrams who's an assistant professor for the department of orthopedic surgery at Stanford, also a team physician for the varsity athletics team. Jeff's going to talk about inflammation and tendinopathy and implications for treatment. This will be recorded for the AOSSM learning management system and will be posted the following week. So please ask everybody to go on mute and if you have any questions, please add it to the chat and welcome to have Jeff Abrams tonight. Go ahead, Jeff. Thanks. Audio still okay? Okay. All right. So the first kind of third portion, maybe half the talk is going to be a little basic sciency, but it's really setting the stage to try and get us all on the same page of terms of the kind of the pathobiology and pathoanatomy tendinopathy. I'll briefly set, and that'll set the stage for a brief review of kind of traditional treatments, which we all know can be frustrating and spend more time at the end of the talk, really kind of utilizing the inflammation based pathways we've talked about in this talk to think about some novel treatments, some of which are being tried and some of which we are in the early stages of kind of getting up and running just in the lab here at Stanford. So hopefully we'll teach you something new. So we all know that tendinopathy is a big problem. You know, I'd say a huge portion of our non-operative patients come in for tendon related disorders all over the body. You guys have seen them yourself. These are circa $2,010 amounts, so they're probably double or triple the amount now, but $30 billion in annual treatment. That's just the USA for our international visitors. And then about 30%, which is still a number that we quote a lot in tendinopathy, about 30% of all MSK offices, it's not just orthopedic surgeons, it's also the primary care physicians, non-operative sports medicine specialists, et cetera, are related to tendinopathy. Takes a long time to treat them, even if you happen to get a cortisone injection or PRP treatment or things like that. The effect is not immediate, often requires a lot of therapy, work, time away, rest, et cetera. And so this is something that requires a little patience on the patient's part. And then despite all this, about a third of them actually never get back to their same level of physical activities. A little bit lower than that, obviously, or better response rate in kind of the higher level athletes. But if you look at the overall population who this happens to, the return to same level of activity is pretty bad. Where does this happen? So we see that the shoulder really kind of takes over. And of course, when we look at this, this is from a database, a large database that there's a lot of other things in the shoulder that can happen and cause discomfort. But the shoulder, if you look at tendinopathy in general, gets a large share of the attention. Hip, mostly hamstring and abductors account for a large portion of it too, with a little bit of psoas and a little intolerature. And then of course, we have a lot of studies on lateral epicondylitis, which makes up a majority of the elbow. Achilles and then patella is relatively low incidence, just because it happens to younger, typically healthier patients, and we'll see as we get older, tendinopathy happens more. So what about as we get older or younger? So the only really outlier on this graph, this is an incidence as reflected by age, is really a patellar tendinopathy. That's obviously in our jumpers. We don't see too many middle-aged people doing jumping-type sports, so it tends to fall off and get back in the line as we get older. But all the other stuff, including Achilles, we have plenty of our 30-, 40-, 50-year-old patients doing higher-level activities, week-in-order-type stuff. And so we see even Achilles popping up just a little bit sooner than the others. And then the shoulder, elbow, and hip, we see it in the older populations. And you'll see this throughout the literature. And then once we get into our 50s, 50-pluses, then our incidence goes through the roof. Who gets it? We won't spend too much time, but repetitive jobs, manufacturing, things like that, office workers with lateral epicondylitis, even some risk tendinopathies also. And then for our younger, healthier patients, obviously the patella with jumping sports, Achilles in our runners, and then upper-extremity sports, volleyball, swimming, tennis, really at risk for the shoulder, elbow. So risk factors. I start with hypercholesterolemia just because it's something that not everyone thinks about. The incidence of tendinopathy with hypercholesterolemia, the association is there. And we haven't, in a non-familiar hypercholesterolemia situation, kind of worked out the exact path of anatomy and what's going on, but the xanthomas that some of these people get and the subsequent tendon disorders are a good clue for sure. Some people actually talk about patients who come in with tendinopathy, however young and healthy they may be. Some people talk about screening them for cholesterol disorders or just simple hypercholesterolemia. I don't do that in my younger people, but certainly recalcitrant cases, things like that, I'm thinking about that issue in some of my older patients. Fluoroquinolones, we know. I really don't use much of that. I think as orthopedics surgeons we don't, but certainly many, many case reports and case series of tendon ruptures associated with fluoroquinolone use, not just tendinopathy. Hypertension is associated in the literature. Even large database studies show that hypertension has been a risk factor for tendinopathy. And of course we all know significant metabolic diseases, diabetes being the least of which in this category here. So kidney disease and inflammatory arthropathies, of which we see them all the time for the tendinopathies, and we're going to talk about how some of the inflammatory arthropathies and the treatments for them has led us kind of to a new way to think about current treatments for tendinopathy. We talk about obesity, alcohol use, smoking, etc. for kind of overall health. Obviously, the more medical morbidities you have, the more risk for systemic disease and tendon related disorders as well as other things you can have. I'll be honest, the literature is really mixed. Some studies say obesity, alcohol use, and smoking are not associated. Some do. So it's a bit of a mixed bag when you come to those topics. So what about other risk factors? So again, another mixed bag in terms of duration of training and kind of volume, intensity, etc. The patellar tendon and the Achilles, I'll just kind of highlight because if you're going to say that there is training volume and intensity associated with tendinopathy, the best literature is going to be from the patella and Achilles. Other issues come up with biomechanics. So you can have decreased ankle dorsiflexion and decreased flexibility associated with patellar tendinopathy. That's a little bit older. There was a newer article that came out in BGSM just recently looking at basically 20 different biomechanical factors and trying to pair it with patellar tendinopathy. They didn't find any association with some of the previous studies did before that. Achilles, decreased plantar flexion, strength and some deep disturbances have been shown to be risk factors. And these are some of the things with our tendinopathy and certainly our collegiate and professional athletes that we look for and we ask our physical therapists and sports performance people to help out with. So we'll get into a little bit to the basic science. I know it's more of a clinical series of talks, but we just need to understand a little bit of basic science on how to approach tendinopathy because it's not really a wear and tear disease. As we may have been taught, there is a significant inflammatory component, hence the title of the talk. I just need to go through a few of the anatomy slides first. So tendon, just like nerve and other fascicular related structures in the body, has a really organized, well-defined framework. It has this triple helix that allows this helical properties and everything kind of folds neatly together with this type 1 collagen. We look at the weight of the entire tendon, about 85% or a great majority of the dry weight is collagen. And of that collagen, almost exclusively is type 1 collagen. Anywhere from 98, some people say kind of 90, 95, but it's a great proportion of the collagen is type 1. It's a great proportion of the collagen is type 1. And we're going to see that in disease tendons that can change. The tenocytes are the cellular components there. So the tenocytes are the cells that are pumping out all the good stuff into the extracellular matrix actually makes up the organized structure. And they're really sparse in tendons. We're going to talk about later how that is important in terms of thinking about where to get cells potentially for tendon regeneration. So what's the issue in tendons? I think no one would probably argue with you that if you're going to sit on the couch and eat food and never be physically active, the tendinopathy is probably not going to be a problem for you. So this repetitive load is what really starts the process. The question is, and we're going to see is, well, how does that lead to tendinopathy and why does that happen? And we're going to see it's not just a physical, mechanical property of tearing of the fascicles or the fibrils. And there's really two ways to go that determines whether you can have healthy tendon and keep it or go on to the picture on the right and have your tendinopathy type of picture. So there is a little bit of turnover that happens in the tendon. It's not a great amount, but there is some. And if there's a small kind of below threshold level of damage, then you can have an adequate turnover and adequate healing response and you're going to be doing, you'll do okay. If you reach some type of arbitrary threshold load, repetitive type activity compiled with your overall kind of metabolic status, you're going to be above that threshold in your body. And that turnover is not going to be able to keep up with it. And we think that that's really the early portion that's really the silent disease. The progressive structural damage, when we see kind of, you know, we'll see the changes on the Achilles MRI or patella tendon MRI, that partial, you know, proximal tearing on the patella, that's when they're symptomatic. And that process has probably been going on for many months, if not years. And they just became symptomatic from it, but obviously the molecular and biological changes have been going on for a while. So type one collagen, I mentioned is predominant kind of extracellular components in tendon. And this thing, as you guys probably remember from medical school and residency, this thing lines up perfectly in nice H and E sections of tendon. And the reason it lines up perfectly is meant it's designed to take that load and share it across all the entire structure. And so if we have kind of, as I mentioned before, if we have this low kind of short-term loading profile, this turnover in this collagen synthesis that the tenosites are pumping out and the remodeling efforts that the tendon is going through that can keep up. But if not, and you go above that arbitrary threshold, then that remodeling is not going to be able to keep up and you're going to accumulate damage over time. So this remodeling, unfortunately, doesn't happen a lot in tendon. It's a very low rate. And this was an interesting study done a couple of years ago, looking at the carbon-14 dating within Achilles tendon, I believe, Achilles tendon. And the reason we think about carbon-14 dating for fossils and things like that, but apparently can also do it in human tissues. And after I saw this article a while ago, I realized there's a whole field, and not only this is a small portion of orthopedics, obviously, but others in other fields rely on this a lot. But what happened in the 1950s is that they started setting up nuclear bombs and testing. And so the rate of carbon-14 in the atmosphere started going up. And what they found by analyzing carbon-14 and a bunch of fancy math that I don't understand is basically, if you look from birth until the time that these patients were biopsied, these patients were adults by the time they were biopsied and went back and look at their birth year, the rate of the collagen tendon turnover in the Achilles is only about 40%. So about 60% of that carbon-14 was gone by the time it got to adulthood, versus if you think of muscle, where the turnover basically is every few months. So you can just see the kind of metabolic rate in tendon is much, much lower than that for muscle, primarily because of the blood supply and also how it's organized. And that is why we have such clinical challenges with tendon disease. So on the right are slides from samples from my lab that are basically just showing normal tendon up top, a nice type I collagen arranged. You can see the dark staining is the tenosites themselves and the collagen is the light pink. And then versus down below where you have this wavy disorganized appearance, the cells are a little more elongated and fattened, we call kind of just dysmorphic basically. And then on the right side, you see some blood vessels coming in, and this is just a much more disorganized pattern. What happens with this disorganization is in this healing, in this apparent healing response is when we have tendinopathy, you get this increase in type III collagen. Well, type III collagen is great on the initial portion of the disease because it's actually, you can think of it as a scaffold that the type I collagen gets laid down upon and provides a framework for the type I collagen. The problem is when it sticks around for longer than it should, it's not only it's disorganized enough or less biomechanically strong, so it's a problem within tendinopathy. When people started first publishing on tendinopathy, this whole process of disorganization was really classified as non-inflammatory. I was in medical school. I remember learning the term angiofibroblastic hyperplasia, and sometimes that comes up on the OEDs and things like that back in the day. But we're going to see, and I'm hopefully going to prove to you that it is an inflammatory disease. So inflammation is certainly gaining in popularity, and we're thinking about tendinopathy as an inflammatory condition, but there are many other hypotheses as to why it happens. Mechanical overload is pretty much agreed upon that that's the inciting event that happens, but what happens after that is the question. You can have a lot of different things. There's hypoxia. There's genetics that come into it. There's neuronal proliferation that we talk about for patients with a lot of pain in tendinopathy. But if we'll see and hopefully make the argument here that inflammation is really the spinal common pathway of a lot of these different hypotheses, and so if we can get a handle on inflammation and get a way to treat it, maybe we can overcome not only inflammation but also everything that's leading to it. So this is some work from Neil Miller. He's out of Glasgow, and he's been really one of the thought leaders in this field. You'll see a couple pictures from his presentations later on in the talk, and he's clearly shown as an AGSM article from now 10 years ago that inflammation is clearly present in early tendinopathy. Their group basically took partially torn supraspinatus and intact subscaps and looked at and compared them, and this is just mast cell and macrophage staining between the two groups, and there's clearly inflammatory infiltrate in terms of macrophage and mast cell infiltration in the tendinopathy supraspinatus group versus the intact subscapularis group. Just some other data from our lab here now a few years ago basically showing the same thing. This is CD68 macrophage and CD45 staining just showing, again, in control and rotator cuff pathology, there's just clearly cellular infiltrates that are present in rotator cuff tendinopathy and rotator cuff disease. The reason that back in the day we called this kind of wear and tear, we thought of tendinopathy as this wear and tear disease and kind of angiofibroblastic hyperplasia is that we just didn't have the techniques and these modern techniques to see it with PCR immunofluorescence, and so those initial H&E slides we got back in the mid-1900s basically, they didn't see an increase in white blood cell presence in tendinopathy, so I said, okay, it's not inflammatory. Well, we know now that's not the case and would submit to you that anyone who tries to argue otherwise probably isn't up to date on the literature with that. So we're going to look at this picture, come back to this picture quite a few times here as we go through each of these different compartments, and we're going to break this picture down into three different three different areas. The first that we're going to talk about is a stromal compartment, and that's basically where you have the tenosites hanging out, pumping out their collagen and all the other portions of the extracellular matrix. There is some resident immune cells in there, but not a ton. We're going to talk about this immune sensing compartment with the mass cells, and then we're going to go back up to the infiltrating compartment, excuse me, with where all the immune cells, macrophages, et cetera, come in once there has been recognized damage, and once these players below have gotten going, that's when the infiltrating compartment starts to say, hey, we need some help here and recruit the extra cells. So we'll start with the stromal compartment. As I said, these are where the tenosites hang out in a normal tendon. They're hanging out, doing their thing, pumping out the collagen and other extracellular matrix. But with overload, we actually see itself without any significant yet inflammatory component, altered extracellular matrix expression, and then later on, or concomitant with that, but not caused by the inflammation, we can see the chemokine and cytokine production going on here once this whole process has started. I'm going to talk about this not as isolated compartments. We'll see they're all going to kind of go together. I can't tell you where it starts because nobody knows yet, for sure, but this is a good kind of a good framework to think about it. So we have these issues beginning in the stromal compartment that eventually leads to tendinopathy, right? So the heart of the issue is the tenosites, because that's what's changing the extracellular matrix. That's what's causing the disorganization. So the end result of this whole process is them getting changed. I'm going to show you here that they actually themselves, once they sense problems, have a role in starting that entire process. And so how do we activate those tenosites? So as we'll see again later on in the talk, we're getting a lot of information and taking a lot of our data from the inflammatory arthropathy and spondyloarthropathy research. And so this is just another example of that. So we talked about stromal cell activation. So in this particular case, the tenosites are the stromal cell in our model here. The image on the right shows a rheumatoid joint. We'll just call it a knee, for example. But the same is being applied here to the tendon. And so what happens when you have a stromal cell, they found this study had the stromal cells that altered extracellular matrix production and chemokine and cytokine synthesis just from the initial damage that they caused. So the inflammatory process hadn't even started yet, and we started to see changes in the cells themselves reacting to the outside stimulus. And one way that they saw this and were able to identify these cells is these two different markers, GP38 and CD248. Obviously, the numbers and the names don't matter. But the reason I bring this up to you is this is potentially in the future some way to identify this primary problem in which cells are becoming simulated and leading to this initial insult once mechanical load is seen. So this is an abstract presented over in Europe a couple of years ago from a group at Oxford, basically just being able to identify this stromal activation, in this case, tenosite activation with the presence of those two surface markers. So they even found that when they added interleukin one beta, again, something we're going to talk about at the end, this increased GP38 expression, but not CD248. So this just really speaks to the complexity of this entire process where we have one interleukin causing a problem, but another, sorry, causing increased expression in one cell surface marker, but not in another of stromal activation. But going back to the main point is we have to understand these things because these are potential therapeutic targets, and we can maybe block this process to just help this progression in its path before it really gets started. So I'll move on to the second compartment. That's the immune sensing compartment. So basically you have your mast cells, and you do have some macrophages here, but mostly mast cells, if we think about it, trying to stratify these different compartments, basically hanging out here. Mast cells are damage sensors. So if they see something going on and they see inflammation and altered extracellular matrix from the tenocytes and from resident macrophages in the stromal compartment, they're going to start to pump out their chemokines and cytokines, and that's going to continue to feed forward and cause additional problems. As I said, there are macrophages present. They can be M1 or M2s. I'll talk about that when we get to the infiltrating compartment above. But the reason that mast cells are also important is that normally, they regulate the collagen synthesis and immune expression, and that slow kind of turnover with matrix metalloproteases, for instance, MMPs. And so they have a function there in its normal homeostatic state that's important, but the problem is once they get activated, that's when the whole process gets ramped up. I'm going to talk about this concept here just briefly in a few slides called DAMPs and alarmins. So DAMPs, and it's related to what these macrophages and mast cells are seeing and why potentially they get activated. And this is, again, another therapeutic area where we can potentially intervene. So DAMPs and alarmins. So DAMPs, I'll start with. I'm not going to talk about alarmins too much later. I'll just mention it briefly here. But DAMPs, I want you to think about it. It's a normal structure that's been cleaved in half, all right? So think about a typical type 1 collagen that's getting damaged in tendinopathy. If you have some mechanical insult to it, say, you know, running, overuse, whatever it's going to be, that collagen gets damaged. And from the simplest form, think about it, it just gets cut in half. Well, now you've got these two different pieces of collagen with exposed ends in the middle where it got cut. That's normally not seen in the body. And the immune system, we'll talk about it in a sec, the innate immune system basically says, wait a minute, I don't recognize this. And that's why these DAMPs, or damage-associated molecular pathogens, are a really important concept because it's going to start up the immune process here. So going back to medical school, which for some will be a while and others not so much, but we really have two portions of the immune system, right? Innate immunity and adaptive immunity. So innate immunity is this shotgun, nonspecific, immediate immune response. And adaptive immunity is that whole slower, weeks to months, antigen-specific immune response with your antibodies, et cetera. And I'm not going to spend more time on that other than I want you to recognize the difference between innate and adaptive immunity. So what does innate immunity do? What's its main function? Well, it's to quickly take care of any local pathogens and, unfortunately, DAMPs in this particular situation. But the way it was built is to take care of pathogens quickly and then recruit that adaptive immune system in and activate that adaptive immune system. And we'll see here, though, unfortunately, with DAMPs, that with damage-associated molecular pathogens, it unfortunately gets activated beyond what it should be. It has other roles here, which is out of this. I just put them in gray here. But activation of complemental complement cascade is one of the things that one of my colleagues here at Stanford looked at a while ago and was published in a Nature paper. So it's an important component. There's other things to this. I'm just going to focus on more of the basics. So think about, again, innate immunity as this just brief, big, shotgun approach, taking care of quickly the problem in a nonspecific type of way. And adaptive immunity is more like your sharpshooter with the antibodies later on. Well, how does innate immunity work, and what is the heart of it, right? So you don't just get this, you know, it doesn't just happen, right? There's this whole process that it has to go through. And the key receptor in this are these pattern recognition receptors, okay? So this is what the DAMPs are binding to to start the whole inflammatory cascade. So these pattern recognition receptors have a whole, have literally hundreds of different subtypes, sometimes probably thousands. But the most important ones here in this are these toll-like receptors, and they're just one class of the receptors. Here is that they're known to activate primarily NF-kappa-beta, which is the major transcription factor. So, right, if you have NF-kappa-beta being activated, goes to the nucleus, activates all your fancy chemokines, cytokines, and then the calf's out of the bag, and the horse is out of the barn, and things are running, and you're not going to be able, you're going to have more difficulty stopping it. So it was built to respond to DAMPs or pathogens, right? If you've got bacteria, viruses, fungi, yeast, whatever, that's what this was built for. But unfortunately, it can also respond to your DAMPs. And so it does respond to these, you know, conserved patterns in nature from the microbes, which is what we want it to work for. But the problem and the whole issue is that once you have this cleaved portion of collagen with these two ends that are no longer recognized, now those things can bind to the toll-like receptors and begin the whole process. So this is just kind of a brief schematic for the inflammatory cycle, right? And you can see, you can think about it, I didn't put the arrows in right, but this whole thing just goes around and around and around. So you start in the upper left there with some mechanical insult leading to DAMPs. It binds to your pattern recognition receptors here. All your NF-kappa B gets activated and you get your cytokines and chemokines. You get all this whole increase in inflammatory cytokines within the stroma or wherever you're activating, could be a joint and arthritis. And then it goes back to the cells themselves and damages them more, which gives you more DAMPs, et cetera. So this whole process just feeds forward on itself and we've got to find a way to stop it. All right, so the last compartment of it is going to be the infiltrating compartment. And right, this is kind of the final coup de gras, right? You have a little isolated stromal compartment, an immune sensing compartment kind of doing its own thing. Maybe things aren't going so well in that compartment, but at least it's contained, right? You've got, you have a contained process and you're not bringing in systemic issues. Well, now, unfortunately, the body says, hey, what the heck is going on here? And you get blood vessel dilation. There's not a ton of them in tendon tissue, but of course everything needs vasculature and oxygen. And so you get dilation in your blood vessels and you get this huge influx of mast cells, T cells, macrophages, et cetera, all coming in. And this is kind of just the coup de gras for the final process that's going to really feed forward on the entire inflammatory cascade. We talked about M1, M2s. I'm not going to go into great detail other than to say that if you are somehow below that threshold and maybe you don't have a threshold of chronic inflammation and chronic tendon damage, maybe you'll get, for whatever reason, a little bit shift more towards the M2 phenotype, macrophage II phenotype, which is more of a healing macrophages. And they can go in, pump out their anti-inflammatory cytokines and kind of take care of the problem. But if you're above that arbitrary threshold, you're going to get a preponderance of these M1 macrophages, and they're just going to contribute to this entire process of local inflammation. And that's just going to keep going. You're going to get more blood vessel dilation, more macrophage, T cell, mast cell infiltration, and the whole thing just blows up in your face. And that's what we see in these end-stage tendinopathy type of pictures when we're looking at them molecularly. Cytokines are not that exciting, but I just want to bring up a couple of them because they're related. And we'll focus on a few of them in terms of therapeutic treatments at the end of the talk. This is another slide from Neal Miller in one of the Nature publications. Again, I use it because I could never have done this myself. And so I love his work. And it's just a great figure, kind of thinking about tendinopathy from a novel treatment modality standpoint. And we're going to start talking about IL-1 superfamily, and that's here. And we can just see the common theme will be some type of receptor ligand-mediated interaction that goes on to have some type of small molecule. And then you have your MAP kinases or NF-kappa B. The end result, and I don't care about the details in this talk, but the end result, right, is this entire box right here. Inflammation, collagen remodeling, cell proliferation, and neoangiogenesis, right? Those are the hallmarks of inflammation. And we think that this is one of the, that the inflammation leads to that, and therefore we're targeting inflammation here. And this describes it a little bit better than I ever could. So the IL-1 superfamily, we're going to see that includes IL-33, and we'll talk about it in a minute, is clearly pro-inflammatory. IL-1 beta, if we have tenosites in addition, you throw IL-1 beta in it, they go crazy off the wall, doing exactly the opposite of what we'd want normal tenosites to do. So clearly, in the long term, not a good thing. Of course, you need inflammation just like bone healing and fractures. You need early inflammation to kind of start the process along. But if you have overexpression or increased duration of IL-1 presence, IL-1 beta in particular, it's going to cause a big problem. So this is definitely a source of therapeutic treatment that has been tried, and we'll talk about that in a minute. IL-33 is more of a novel one. There is a drug out that can do this that we'll see at the end. It is pro-inflammatory, and the reason it's so important is because it's been published that we think it's one of the main cytokines that's responsible for that switch to collagen-3. Remember, collagen-3 is upregulated in tendinopathy, and that's the bad stuff if it sticks around, because it's less organized and therefore more biomechanically weaker, and we don't want it around in the long term. So this may be one thing to target. IL-6, we talk a lot about IL-6 just in general in terms of inflammation, and some of these we even see in terms of trying to figure out inflammation and, for instance, looking at infected arthroplasties and things like that. There's a lot of literature looking at the presence of IL-6 and being able to detect a kind of infection related to the presence of inflammation, and it's clearly, if we look at biopsies in tendinopathic tissue, IL-6 is off the charts. It can lead to increased total collagen production, so I throw it in here to say that it's not totally bad, maybe even in the long term, because you can get some beneficial effects out of it. So it may be a little bit better than IL-1 beta, but again, in the long term, probably not that great. Interestingly, I did hear of a clinical trial the other day looking at a few other ways to target this, but again, there are monoclonal antibodies for it, but nothing really in the great pipeline at the moment. TNF-alpha, we all heard about it in general, again, in the chronic stages, very bad for tendons, interestingly, and we talked about those toll-like receptors, it upregulates the toll-like receptor to mRNA, and expression on macrophages, so even worse is that not only does it pump out the chemokines and cytokines, it increases expression of the chemokines and cytokines, but it actually affects the heart of the macrophage and upregulates that toll-like receptor, so the whole process gets even worse. IL-17, we'll talk about, there's a drug to target that, important that, again, it's one of these other less-known interleukins that can affect type 3 collagen matrix and production. What about resolution? Well, there are actually some things, again, therapeutic targets that have been shown to help with tendinopathy, CD206 is really a macrophage, M2 macrophage marker, and so that's the presence of this particular cell surface receptor is there, there's just a higher preponderance of M2, which is good. There's also ALOX-15 and other cell surface markers, and there was an interesting study done a few years ago that I talk about a lot, but I'm not sure it has that much importance, just looking at pain-free and painful postoperative treatment, and showed that those patients with less pain after surgery basically had an increase in ALOX-15 and CD206, and you can actually express these two things with aspirin, so it's, again, one of these novel kind of therapeutic treatments that we can think about. Maybe from a systemic standpoint, it's not working because everyone takes aspirin, but there are maybe other injectable or topical uses that may be possible. Okay, so sorry about the basic science, just wanted to kind of have a framework to talk about treatment, and so now we'll do that. I'm going to start briefly with the stuff we probably all know about. I'm going to give you really the bastardization and the summary of the literature on a few of the things, such as cortisone injections, PRP, exercise training, so there's a huge amount of detail, and probably each one of these treatment slides could have an entire hour or two talk on it alone. I'm just going to give you the highlights and the summary and kind of my looking at this for a number of years, my interpretation of the literature. So exercise-based, does it work? Yes, of course. The literature is really clear on this. We all talk about eccentric training, and certainly that's one of the things I myself give my patients, tell them to go to therapy and give them the exercise eccentric program. There's probably, if you look at the literature as a whole, much better evidence for it for achilles and patella than there is for the upper extremity, but still, you know, if we have your lateral epicondylitis, yep, go do your wrist exercises, go work on your eccentric strength training, and of course, I've seen success with that in my patients, and I'm sure my partners have too. Two other things that are more recent literature you may have not heard about is isometric training. A paper came out a number of years, maybe a few years ago now, looking at isometric training, right, so just isometric contractions, going up and, you know, trying to extend your knee against a wall or something that's immovable, right, so an isometric contraction. And there's some evidence that actually showed that it helped in patellar tendinopathy, and it's made its way down to the strength and conditioning coaches, the athletic trainers, physical therapists, and so these are techniques that they're actually using now for the past couple years, and we're using them on our college and pro athletes in the rehab setting for tendinopathy. Heavy slow resistance training is something you may hear about also. It's starting to gain a little bit of steam in the rehab world. Just like it says, instead of eccentric, it's really just heavy, slow, concentric exercises, and those have been shown to help in the lower extremity also. Again, this is all in the context of still doing the eccentric program, but they're looking for ways, we're always looking for ways to augment it, and some of these techniques certainly have helped in our study in the literature. So corticosteroid injections, right, it seems reasonable, right, I just talked for 20 minutes on how tendinopathy is an inflammatory condition, and so I've had many people come up to me after a talk similar to this that I've done before, okay, well, what about cortisone injections and how should I be giving it? It actually, it's falling a little bit out of favor in tendinopathy, and certainly in our higher level athletes, we're really not doing it much at all. I still, I'll be honest, I still do it for people like me, office workers, things like that who maybe need just a quick boost or have something important coming up, a single shot's probably not gonna do long-term damage, but now the literature's pretty clear that the cellular repercussions of this are not very good, so decreased collagen synthesis in organization, decreased fibroblast proliferation, so if we look at it, if we look at the cortisone itself and the effect on the fibrocyte or tenocyte, it's pretty bad, it's toxic. The clinical summary I'll have for you, again, a bastardization, a little bit of literature because we can talk about the elbow, we can talk about the knee, the Achilles, we can talk about all the different joints, but in general, it does give you a quick pop, a quick relief, but the long-term clinical results are probably not very good after four to six weeks, and there's certainly no long-term benefit for the tendon itself, and it can argue in the long-term based on the basic science, it's probably detrimental, and we're seeing that now in the rotator cuff literature, right, we have a number of studies coming out that's showing preoperative cortisone injection into the subacromial space leads to higher revision rates after rotator cuff repairing, so our basic science is really kind of matching what we're seeing in the long-term. PRP, again, I put this in seven lines here, we could spend six hours talking about PRP and tendinopathy, I'm going to summarize it again just to say that there's good evidence and level one evidence for lateral epicondylitis and patellar tendinopathy, there's less evidence, but still decent evidence for Achilles tendinopathy, however, in the rotator cuff, it's really weak, I, for a non-operative treatment of rotator cuff tendinopathy, I really do not use PRP occasionally, I get some patients coming in and saying, look, doc, I just, I'm at my wits end, I don't want to, you know, any other treatment, I want this PRP, I read about it, it's magic in the news, I got all the money in the world to just give it to me, and I say, sure, we can try it, but I'll say it may not help you. Obviously, different formulations for Weibullet's, for PRP, Weibullet cell rich versus poor, I'm going to again make a general global, a global comment just saying Weibullet cell is probably a little bit better for your tendon-related disorders, although if you act, if you inject Weibullet cell rich PRP into a tendon, you're going to have a lot longer recovery than a Weibullet cell poor from a clinical standpoint, so those are things to keep in mind if you're doing it, for instance, in season and inactive. Other treatments, oral anti-inflammatories, sure, probably helps in the short term, but not long-term function, and there's no real good evidence that it has, that systemic NSAIDs have an effect on long-term kind of pathobiology. Shockwave therapy can work, there is some evidence for it, it's not great, there's different types of shockwave therapy, so don't go out there and just say, oh yeah, shockwave is awesome after you hear this talk. There's kind of low energy versus high energy. Low energy ones are the ones you may see in your athletic training rooms or physical therapy clinics, obviously they deliver just a lower biological effect to the tendon, and the efficacy is probably less because of that. The higher energy ones are bigger machines and actually can be painful delivering the treatment, if you ever talk to someone who has it, they actually say it can hurt quite a bit, and this is really taken from the urology literature, and so we stole it in the tendon world, we stole it from the urologist as they were breaking up kidney stones, so we figured at some point somebody tried it and found that it worked, and actually over the years it's been studied and does have some effect, so if they want to try it, sometimes it is covered by insurance and I'll send out for it, but again, you have to lay your crepe and have a caveat that it may not, of course. We'll hear about high volume injection, this is mostly just a couple of case reports in the literature regarding high volume injections of saline, usually with corticosteroid in it, sometimes not, but basically you're injecting kind of the peritendinous tissue back of the Achilles and a few case reports show that it has helped. Other things, George Morell down in Australia was a proponent, actually had a couple of level one studies looking at nitroglycerin, topical nitroglycerin, this is the same thing people put on for heart attacks and things like that, and actually showed some good evidence and some level one studies that worked for Achilles and lateral epicondylitis. Mechanisms we think are anywhere from vasodilation to intrinsic kind of nitrous oxide presence and leading to healing, but I've used this in my athletes, even at the professional level, and other than headache, which is possible, there's very little other downside to it, so it's another treatment to consider. Sclerotherapy is in the United States, we don't use it much, it had a run in Europe a while ago and I know some people in Europe still do it, basically you're sclerosing the small vessels and because the nerves run with it, it's probably not, I'm fairly certain it's not changing the actual pathoanatomy of the tendinopathy, it's just making it less painful, but some people still use it, but not so much in the United States. And then modalities that are seen in the clinic, we talk about antiphoresis and phonophoresis, just ways to get typically a steroid type of drug through the skin and into the tendon, just because the tendon's subdermal there. Therapeutic ultrasound, hyperthermia, friction massage, all have their role, but from an MD standpoint, these are kind of modalities that can be used in the clinic. And then low-level laser therapy, so I remember when I first heard this a few years ago, I said, there's no way that works, and I don't prescribe this certainly, but it is out there in the literature, you know, you have a number of other different kind of alternative practitioners talking about laser therapy for a whole host of different conditions, and there is some evidence that it maybe has an effect, but certainly I don't use it, and most of the literature out there on it is in kind of laser therapy-targeted journals. Autologous tenosyte injections, so this has been done, there's numerous case series and case reports, there's a numerous case series on it. We can't do it in the U.S. because you have to, just like an ACI type of procedure, you have to harvest the genocides and then examine the culture. So, we can't do it, but other countries can. It has been shown to have different good outcomes and actually may affect the actual pathobiology and tendon healing processes. But again, really small sample sizes and very few studies, but it is one option that is out there. I put this in, not because I'm a believer, because when I had a talk on this a number of years ago, I didn't include this and I got about 6 million questions on it, so I'm just going to put one slide on it. Tenex is a company. I have no affiliation with them whatsoever, but it's percutaneous ultrasound tenotomy, basically. Their sale is that you put in and you basically ablate the bad tissue. They have sponsored a couple trials looking at it, particularly in the elbow and other tendons. The elbow was their probably best one that found it comparable to PRP. But again, it's no large trials, and if you ask me about it, I'll say, eh, I don't know, is the answer. Surgical incision, obviously, is kind of the last stage. This is a picture from Rob LaProd's arthroscopy and technique article from a number of years ago. It's just showing a really tendinopathic patellar tendon there. And of course, in general, we try not to operate on these, but sometimes we're out of options and we go in and we do it. Pretty good support for elbow and patella, less for Achilles, and then going in and performing pure debridement of a tendon in a shoulder as not very good evidence. We look at the randomized control trials, going in and just doing a brisectomy, plus or minus a decompression, probably is not going to help you too much from a tendon pain standpoint. Okay, the last 10 minutes here are the translational therapies. And so we're going to come back a little bit to those cytokines, and we're going to talk about specific drugs which target those cytokines and receptors. So the first one we mentioned back in the middle of the talk was IL-1 and IL-1 beta, in terms of the cytokines. So there's a number of drugs that actually target this. These are all coming from the inflammatory arthropathies, and they're FDA-approved for use in inflammatory arthropathy, particularly rheumatoid arthritis. So anitinra is one. It's an IL-1 receptor antagonist, and it's been shown to definitely help the pathobiology and the structure of tendon in animal models. We don't have great data in human models. There has been some small studies looking at injection of the medication, not systemically, but injection directly into the tendon, but the results are a little mixed. Other ones, Rylonacept is another one. It's just a soluble IL-1 receptor. So instead of allowing IL-1 to bind to the receptor, it goes into the cytoplasm and into the stroma and just binds it up so that there's less IL-1 around. Other ways to get to it are having a monoclonal antibody to it, obviously, so you can bind the receptor and block it up with the antibody. And so therefore, no matter how much IL-1 beta or IL-1 you have, it's not going to matter because the receptor is blocked. And then we talked about IL-33. That was one of the important ones in the IL-1 superfamily that's important for the collagen switch, the type 3 collagen switch. And so there's a phase one trial by a company developing an IL-33 monoclonal antibody. That is certainly obviously in phase one and not approved. Other one, IL-6, we talked about the kind of general inflammation. IL-6 is a really nonspecific inflammatory cytokine. So again, there's Actemra, which is approved for use in the inflammatory arthropodies and spondyloarthropodies. Another potential target, no great literature on the tendon world regarding these particular drugs. Interestingly, one of them is being studied for treatment of kind of that cytokine storm in COVID-19 here. It's just another little fun fact about some of these drugs. So other ones we've heard of infliximab and tenorsep. These are the big TNF off inhibitors that have really changed the face and treatment of rheumatoid arthritis. They've been transformational in that disease. There's reports, again, similar to the IL-1 receptor antagonists and Akinra, injection into Achilles for really end-stage spondyloarthropathy-associated tendinopathy with decent results. No good studies looking at kind of run-of-the-mill tendinopathy, and certainly it's not to the point where I'd give this to anyone in my clinic yet. Cosentyx is another drug that you've probably seen advertisements for. I think it was approved in the past number of years. It's approved for psoriasis and spondyloarthropathies as an IL-17A monoclonal antibody. But again, just another way to blunt that inflammatory response. And Novartis, which owns Cosentyx, owns the rights to Cosentyx, is obviously looking to expand their indications. And so they're in phase one, two for use of this drug with tendinopathy. Well, other ways to do it that are not associated with the kind of cell surface receptors but are deeper inside the cell are the small molecule inhibitors. And again, there's a lot of these. I mentioned just a couple of them here. One pathway that gets targeted is the Wnt and beta-catenin pathway. And the reason I mention it is because the company in San Diego is in phase one and maybe by now early phase two looking at it for tendinopathy as well as psoriatic plaques. So it's a topical Wnt inhibitor. And the reason that they've gone down this road is that some of the basic sciences really show that Wnt and beta-catenin are overexpressed in animal models of tendinopathy. And the reason that we think that's important is because the data suggests that it blocks Mohawk, tenomodulin, and scleraxis. And the reason those are important and those are all important molecules in anywhere from tenosite expression and maturation of kind of tendon progenitor cells all the way through expression of type one collagen. So Wnt and beta-catenin get in in that way, it's going to lead to kind of a decreased rate of turnover and inability of your tendon to handle that low-level damage that hopefully it can overcome. The other ones are these JAK inhibitors. So Xeljanz is one you've seen on the TV probably for, again, spondyloarthropocys and rheumatoid arthritis. Again, it's just looking at different ways to block that central response. And for one instance, that translation of NF-kappa beta-nucleus so that it doesn't pump out those cytokines. And so you just see your JAK kinases here hanging out. And when they get, when you get your ligand binding, those are the things that activated. So again, just another product on the market that we may be able to use. The last one is, last couple of slides are just cellular. So this is an important paper in my world, looking at a tendon stem progenitor cell. I'm not going to use the word stem cell anymore, and I won't get into why, but I'm going to call it a tendon progenitor cell. So Marianne Young, she's an NIH investigator back in Bethesda and had a lab there for a long time, basically found where these cells hang out in tendons and isolated them and was the first to do so back in 2007. And it's unique because obviously, you know, progenitor cells have been isolated for other tissues, but she was the first one to do it in tendon. The downside, as we'll see, is they're not very prevalent in tendon. They're pretty sparse compared to other sources. And this has led to just an exponential area of research, obviously within orthopedics in general and tendinopathy in particular, about how to manipulate these. So again, as I said, they're not very common in tendon. So we think about taking them from another source, such as bone marrow, fat, or ammion. And some studies have looked at basically viral transfection of different transcription factors and proteins to try and get the cells there to create a milieu that favors more healthy tenosyte growth. And so again, just an area of future potential. We're a little bit limited in what we can do in person here in the USA, so a lot of this work is getting done clinically in other countries. I'll mention lastly is microRNAs. It's an area of research of mine. So microRNAs basically have been shown to be kind of central regulators of cells and inflammatory cascades. And what they are is that they're these little short strands of RNA and base pairs that can bind to an entire mRNA molecule. And it has to bind complementary. And so this is a big regulatory response. Once it binds, it basically just blasts the mRNA to pieces and completely gets rid of it. And so you can see this has a whole host of implications, not only in orthopedics, but we really, this began in the cancer literature, looking for systemic cancer treatments and ways to regulate it. And we've taken this into the orthopedic realm, not only in tendinopathy, but a lot of my colleagues are looking at for osteoarthritis and things. But you can imagine there is so much that can happen with microRNA. It can regulate stem cells. It can regulate IL-1. It can regulate TNF-alpha. It can regulate NF-dapper beta. And so really the hard part is figuring out kind of where it fits in the whole cascade of problems that comes along within tendinopathy. So we went through a lot actually. We're looking for really this unifying theory and looking to find out why this inflammation starts, how the collagen switch happens, and then maybe how we can regulate these progenitor cells. MicroRNA could be it, could not be it. There could be other things that come around and you can see how complex this whole problem is. And that's the reason it's such a struggle, right? They've been working on tendinopathy for 20 years and working on inflammation and osteoarthritis for even longer. And we have yet to come up with kind of a good drug to treat these. And these are the reasons why, is because there's so many factors involved. So again, I just want to impress upon you that tendinopathy is inflammatory. If it's not the only reason that tendinopathy occurs, I think it's going to be known as kind of a final common pathway. We have the treatments that we've talked about, but they're not very good to be honest with you. So we're still looking for others. And one way to look for others is to really focus on the inflammatory pathobiology of it in terms of looking towards novel regulators and how to harness that inflammation cascade. Steve, you're muted. Steve, you're muted. Sorry, Jeff. I muted everybody else except for me. Jeff, thank you for an amazing basic science presentation. And obviously tying this in with the clinical side of it. So I've unmuted some of our faculty to allow for some discussion. I know we're kind of up against the eight o'clock hour. A couple of questions from the fellows, from Meg Flynn. Thanks, Dr. Abrams. What are your thoughts on BFR, blood flow restriction, as it's been shown to help decrease the inflammatory cascade you've outlined? Yeah, so good question. And the answer is it hasn't been shown to help so much on the inflammatory cascade. However, what has been shown to be is more a release of anabolic factors. And so for tendinopathy, it can work. I'd say the majority of the literature on BFR is looking more at muscle rebuilding after injury or surgical procedures. And a lot of it is focused on ACL rehab. And what the basic science shows on BFR is that it's more anabolic in nature and not as much anti-inflammatory. But you're right, there are a couple of anti-inflammatory factors. But I'd say the major effect from BFR is from an anabolic standpoint. And then your next question, maybe, well, do we use it? Yes, absolutely. So on a higher level athletes, they're getting BFR all the time. Does it work in basic science evidence? Yes. Does it work clinically? We don't know, but the downside is pretty low. So we use it all the time. Next question is from Sandeep Manaba. I'm going to try to summarize a little bit. But basically, is the classification of tendinitis of the rotator cuff different to some of the ones you described? And do the principles of management apply? Yeah. So Sandeep, an answer that we haven't yet reached the stage for these novel medicines that I talked about for their regular clinical use in the orthopedic realm. So other than the established ones I talked about, I use nitroglycerin, as I mentioned. That's kind of one of the lesser known ones. I don't use any of the spondyloarthropathy medications in regular clinical practice. I leave that up to the rheumatologist, mainly from a medical legal standpoint, is that we don't have the evidence to say that it's safe to inject, basically. So if something happens, I'm really out there on a limb. But certainly, you will hopefully see evidence coming out soon that some of these things may work in the future. But it's probably going to be a couple of years. They're obviously off-label indications at best. I do not currently use them in current clinical practice. I'd like to ask just a few of the, I know we're, like I said, we're a little bit after eight, but just a couple of the faculty that are on board. Jim, as far as, you know, things that you're using for tendinopathies, I know in the past from working with you what some of the things that you use, but can you, in about 30 to 45 seconds, can you describe what you use in certain circumstances? So, tendinopathy, Achilles, is three injections one week apart of a low white cell. I use ACP. We just published our study. 30 of 31 got better that way. For the rotator cuff, I am an anti-steroid. I haven't used it for a long time. I try to stay away. I totally agree with that. I've been using regular low platelet PRP, and it's been worked just as well as steroids. The only problem is it takes longer, but it's better long-term. For acute tendinopathies in my athletes and my professional guys, I bump up the white cells. So, I use an angel system, and I'll use seven percent hematocrit, and at four cc, seven percent hematocrit, which bumps up my white cells, and only one injection, and I've had a lot of luck with those. In fact, that's probably the best thing I've done was change, and I agree with you. You need more white cells in tendinopathy, so that's kind of a quick overview. Hello, Joel. So, can you hear me? Good job, Jeff. I was lucky to be able to travel with you two years ago on the Traveling Fellowship, and here's some of the stuff. I think I got a lot smarter. So, in those patients with hypercholesterolemia, what are you doing for those patients? Is it something that you identify as a risk factor? Is it treatable? And likewise, have you seen any anecdotal evidence that patients on hypercholesterolemia or cholesterol lowering meds have less tendinopathy? Yeah, the first question is, it's clearly a risk factor, but I'm not sure if it's a risk factor or not. It's clearly a risk factor. At what level, you know, LDL or total cholesterol, we don't know. For recalcitrant cases, I don't do their cholesterol testing myself. I'll say, look, cholesterol is a risk factor. If they haven't been checked or don't know, I'll have them check with their primary care physician. I don't take the onus in the orthopedic clinic of following up on the cholesterol levels. The second question was, does it make a difference? Was that the second question? Cholesterol lowering medications. Oh, yeah. Yeah, I don't know because it's such a mixed bag and people, I don't know the answer to that. You know, if I had to think about it, if I had to think about it, I mean, clearly the lower cholesterol levels associated, sorry, higher cholesterol levels associated with increased sensitivity to tendinopathy, so I would think that'd be a reasonable conclusion. Winston, what do you use in certain circumstances? You know, I'm using it around the hip a lot. I've seen a lot of tendinopathy with the gluteal tendons and the hamstring, proximal hamstring tendons. I do defer a lot to my physiology colleagues. He uses a lot of prolotherapy and PRP, sort of an area around the tendon, which I've seen some efficacy with. And the gluteal tendons, you know, if they fail, sometimes they'll be associated with partial tears and I will move to surgery with those. But, you know, PRP, I mean, I actually do use cortisone periodically, primarily because I think it's anti-inflammatory. It can be helpful to be an augment for therapy and help patients get back sort of into the game as far as being able to do eccentrics and things like that in the therapy realm. But I tend to defer to my physiatrist because tendinopathy, as Jeff is explaining, is kind of the bane of our existence. I'd rather have a tear than tendinopathy, frankly. But I do my best to kind of keep them feeling better. So maybe just really, you know, great talk, Jeff. Just a comment and maybe a question for you. It seems like this is a continuum where it's inflammation driven first and maybe there's a critical period by which anti-inflammatory type, you know, attack works. And then later on, you know, we need to try to stimulate some sort of healing response. So should we be looking at this more in depth as far as what's actually, you know, not just the clinical picture, but, you know, structurally on imaging studies, ultrasound, MRI, and come up with some sort of plan where we are in the, you know, in the thick of things, you know, getting really down to the cellular level and then back to the patient. I don't know how to attack it from here. Yeah, great, great suggestion. And there are a number of studies looking at the MRI and ultrasound correlation with biopsy, either a small case series, because you've got to, you know, those are patients typically heading to surgery, of course, but which isn't super common, but yeah, that it would be great to look at that. You know, the issue is we don't know, you know, what that inflammatory threshold is going to be. So where, where does it, you know, those types of patients obviously would be at the end stage of disease. And I mentioned by the time they develop symptoms, we think that that process has been going on for years or decades or really a long time. So, you know, the cat's a little bit out of the bag by that point. And so we would need, you know, to be, if we were to think about it, you know, from a, in a perfect world, we'd be screening and intervening earlier, whether that be with, you know, pharmacology or with load management or whatever it's going to take to kind of bring them back down so that the time above the threshold is lower or they don't reach that threshold in general. Hey, Mark, any final comments or anything you want to add? I didn't realize Jeff was that smart when we hired him. So, you know, no, I mean, I, you know, it's funny. I remember, you know, George Murrell got a lot of press about his nitro stuff when his initial prospective trial, and then he did a much larger trial. It didn't seem to bear up results. I mean, are you finding much efficacy on using that, using the nitro patches? Yeah, it's a mixed bag. Definitely a mixed bag. Some I've had runs the gamut from patients swear by it and they loved it all the way down to a couple of patients got a headache from it and thought it was the worst thing ever. And so they pulled it off within, you know, 24, 48 hours. You know, and obviously they know they're, you know, when I give it to them, they know they're getting it, the active ingredient. So I think there is a placebo effect for it also. It's definitely not first line treatment for it. You know, we all have our patients who just keep coming back and, you know, maybe we don't want to operate on them or, you know, operating is not a good idea. And we're trying to get them through the season. And so I think it is whether how well it works or not, I think there is some effect and some basic science evidence for it. And so it's worth a try. Mark Bradley always told me that you should surround yourself with smarter people. So you obviously, obviously done that at Stanford. Yeah, well, you know, I set the bar low, so they, you know, but I got, luckily I got really smart folks around me. I learned from Winston Latul and Seth. Yeah, there you go. Jeff, thanks very much for a great presentation. I think tomorrow night we are moving on to shoulder instability with Dean Taylor. I think he's going to be moderating tomorrow and we look forward to seeing everybody then. Thanks, Steve. Thanks, Jeff. Good to see you, Jeff. Thanks, guys. Good seeing you, brother. Thanks, guys. See you.

tendinopathy

inflammatory nature

traditional treatments

prevalence

cytokines

IL-1 beta

IL-33

IL-6

exercise-based treatments

innovative treatments