Hi, everyone. Thanks to Dr. [INAUDIBLE] for that. And obviously our thoughts are with the 200 people across the street who are very, very excited right now having just opened their match letters. 

But with that, I'll kind of move into introducing our next speaker. So we're very excited to have Dr. Adam Carlson from the division of Rheumatology here to speak with us today. I think most of us know him quite well. 

But in the ways of a brief background, Dr. Carlson started his medical career here at UVA as a medical student, and then went onto residency and fellowship training at UCSF. After his fellowship, we were able to recruit him back to Charlottesville around 2014. 

Since returning, Dr. Carlson has really come to be seen as a role model for clinical excellence and a leader in training education, both in the divisional and the department levels. From med students to residents and fellows, he's impacted hundreds of trainees through activities, including the Foundations of Clinical Medicine course, the rheumatology clinical electives, the Internal Medicine MSK Fellowship, and the Internal Medicine Rheumatology Ultrasound Fellowship program, as well as through his time attending on our general medicine awards. 

For all these efforts, he's been recognized with the UVA's Internal Medicine Excellence in Teaching Award, the UVA Internal Medicine Excellence in Clinical Care Award, and the ACP Virginia Chapter Teacher of the Year Award over just the past few years. 

He taught many of us in internal medicine during morning report. Then when asked what you want in order for the workup, a room panel is not an appropriate answer. Then a couple of years later, the lab rolled out the NA Panel. So we sure showed him. 

So with that background, we're certainly grateful to have Dr. Carlson here today to provide us an update on a condition that affects so many of our patients, yet remains often difficult to manage-- osteoarthritis. So without further ado, I'll pass it along to Dr. Carlson. 

Let's see, can everybody hear me? Because I'm not going to use this mic. Raise your hand if you can hear me. OK, good. All right, so-- OK, got it up there. 

Well, so my job today is to kind of make osteoarthritis a little bit more exciting. I was talking with the chiefs here earlier. And Anthony asked me to do this talk. And he said, will you come do [INAUDIBLE]? I said absolutely, I'd love to. I was like, how about osteoarthritis? He says, how about vasculitis? And I was like, how about osteoarthritis? And he was like, well, there's not really anything new in osteoarthritis. So what I'm trying to do is just give you some updates. But this talk is probably better titled Osteoarthritis for the Internist with Updates. 

So I certainly am going to talk a lot about some novel therapies that are in the pipeline. So I have no disclosures. These are our learning objectives for today. So the first thing I'm going to do is kind of talk about the joints themselves, and the structure, and function of synovial joints, the basic pathogenesis of osteoarthritis, and how that relates to some of the newer therapies that are in development. And then we'll talk about some of the current clinical diagnosis and therapies that are available to us. 

OK, so at the outset, there are different types of joints in the body, of course. So those joints, broadly speaking, are at some level defined and categorized by how much movement they allow. So you have fibrous joints like in your skull where the sutures meet, where you have this dense connective tissue, and they allow for absolutely no movement. 

Then you have cartilaginous joints, which are-- this is like your vertebral body or your pubic symphysis where you have joints that are connected by cartilaginous structure, so like the fiber cartilaginous ring in the vertebral disc. 

And then finally, the synovial joints, which are kind of what we typically think of as joints. So synovial joints are definitely the-- [INAUDIBLE]. Some interesting structures from the pivot joint at this C1-C2, to plain joints, to-- actually one of the more interesting joint structures is actually to the base of the thumb, to CMC, where you have kind of a saddle joint. 

So even though the synovial joints have a different structure sort of at the macroscopic level, at the microscopic level, they all have this basic design. And so we really need to be-- when it comes to osteoarthritis, historically we have thought of it primarily as a problem of the cartilage-- and just the cartilage. 

So for the folks at home, I'm going to try to use the pointer here. So we've always thought about it as primarily an issue of the yellow structure here, which is the cartilage. But really, it's everything that's there. 

And the primary players in the joint are the synovium, the cartilage, and the subchondral. So just real quick, the synovium, in a sense, that's really where the pathology lies in things like rheumatoid arthritis. But its primary job, it's comprised of a thin membrane of synovia sites. It's about two to three cell layers thick. There's a subintima that contains all of the blood vessels, and lymphatics, and some nerve endings, and those sorts of things. But its primary job is to produce synovial fluid. And the synovial fluid's primary roles-- one, actually three-- lubricate the joint. 

In a sense, it also works in sort of managing the compressive loads of joints. But then it also is how the avascular cartilage gets its nutrition. So that the primary constituents of the synovial fluid include things like hyaluronic acid and some other lubricating proteins that are important in joint function. 

So this is a structure-- this is a micrograph of cartilage. And the cartilage itself-- because when we talk about osteoarthritis, we can't help but talk about the cartilage. And really, the primary player in osteoarthritis, even though it involves the entire joint and all the structures that I just talked about, the chondrocyte is really at the center. So with the cartilage, you have the extracellular matrix, which is a collection of type 2 collagen and a whole bunch of different types of proteoglycans, predominantly something called aggrecan. And into that-- the extracellular matrix is about 97% of the cartilage. And the remaining amount of it is chondrocytes. So About, 2% of the articular cartilage are chondrocytes. 

We talked about the extracellular matrix. So the reason that I'm going into this is that these are the new structures-- these are the new therapies that are coming. They help maintain these structures, as we'll see here in a second. 

So the roles of these different structures within that extracellular matrix vary depending on what we're talking about-- so either elasticity and resistance to compressive forces versus tensile or shear forces, which is predominately what the collagen does. 

It's not a uniform tissue, the cartilage. So at various levels you will get different shapes anf essentially a mesh of the type two collagen. And at each level, you'll get varying degrees of different types of proteoglycan and so forth. So this is just a representation of what people have heard about, glucosamine and chondroitin. The thought was that if you supplement with sort of these precursors to these important articular structures, that they would have a benefit in maintaining the articular structure. So we'll talk about those in a bit. 

But there is a very small amount of hyaluronan in the cartilage itself. And it mostly is there to act as a bridging structure. So there are some important proteases that we're about to talk about that will essentially cleave these structures that the aggrecan-- that works in degrading the cartilage matrix. And these are going to be targets for new therapeutics that are coming in the next couple of years. 

So we're going-- so to kind of understand about why these new therapies are important and how they're supposed to work, we're going to talk a little bit about the mechanisms of disease. So what we know about osteoarthritis is that mechanical stress plays a really important role in the process in initiating and propagating osteoarthritis. 

So mechanical forces really stress the chondrocyte and the structure, the extracellular matrix, such that early on, what you get is just sort of this nice, smooth surface becomes kind of roughened, initially. You start releasing some of the extracellular matrix components into the synovial fluid. But that disruption can be sensed by the chondrocytes through endograms, essentially. And then you get stressed out chondrocytes, essentially. 

There are other things that happen where that tissue interface is really important. So where the cartilage and the synovia meet-- so if you disrupt that surface, the normal function of lubricating proteins within the synovial fluid and on the surface of the cartilage are disrupted as well, and so it's kind of-- you're going to see with oh, wait, it's always this feed-forward sort of mechanism. And that's one of the things that can happen with early OA. 

So but at first what happens is that when there's early damage-- so this would be an example of sort of moderate levels of damage-- you start to see these fissures-- oh, you guys can't see that. Here you go. 

So you get these fissures within the superficial portions of the cartilage. And what happens is these chondrocytes then proliferate, and they just start churning out extracellular matrix. The problem is that that extracellular matrix, it's not really good-- it's not high quality stuff. And so what ends up happening is that it's susceptible to further damage. And what ends up happening is that there's actually a subtle inflammatory response that ensues. And what you end up getting is you end up getting this imbalance within the chondrocyte where you're getting excess production of degradative proteolytic enzymes and decreased production of new matrix. 

And one of the big mysteries for a long time has been, why does this happen? What's going on? What's driving the process? And so over the years, what we have learned is that it's actually really complicated. And there's a lot of actually-- like inflammatory markers really play an important, prominent role. We've always thought osteoarthritis as something that is solely a mechanical process where you get degradation of cartilage and so forth. But that's actually not the case. 

So I'm going to go through this just really quickly because I know it's a busy slide. So but in a sense, we begin with mechanical forces. This is sort of a summary slide that gives us a sense about what are these processes, these inflammatory mediators that play a role in osteoarthritis. 

So you have these mechanical forces. OK, there we go. And what they do is, like I said, the chondrocytes can sense that. And then as a result, they begin to produce these inflammatory cytokines-- IL1, nitric oxide species that act in kind of a paracrine and also an autocrine fashion. And what they end up making is they make these-- they start producing more degrading proteolytic enzymes like aggrecanase. And they stop making MMP inhibitors and the like. 

And so what that then leads to is you get further destruction of the cartilage surface, which then gets released into the synovial fluid, which thereby signal, which irritates the synovia sites, essentially. And you just get this feed forward mechanism. 

And so, like I said, osteoarthritis is a condition of the entire joint. It's not only the chondrocytes. The synovia sites play an important role. And as we know, you develop-- this is supposed to be [INAUDIBLE], this is supposed to be an osteocyte-- we know that the subchondral bone is also involved. And there are signals, predominately TGF beta, that promote the formation of these oxy flights. 

I want to come back and talk about what happens with the chondrocytes. What ends up happening is that all these inflammatory signals cause, essentially, the chondrocytes over time and as a population, they fatigue. And essentially, they undergo apoptoses and, so forth and they stop functioning. 

And so what we are learning is that all these inflammatory mediators are really what's driving that imbalance in terms of the turnover of the extracellular matrix. And so what does that look like? So this is from an experimental model of osteoarthritis. And so you can see it early on, in year one, the macroscopic and microscopic appearance of the cartilage. 

And so you can see as time goes on-- so this is an induced form of osteoarthritis. You can see that initially you get these superficial fissures, you get thinning of the cartilage. And eventually it makes its way down to bone. And we know that once the cartilage thins down to the bone, the bone ulcerates and you get this granulation tissue, and then you get this heightened pain response. That's usually because, remember, our cartilage is avascular and it also has no nerve supply. 

So cartilage is not painful. It's when you get down to bone and some of those other media, or you're stressing out the joint capsule, the synovium, that the joint becomes painful. 

All right, so finally we get to the updates. So there are a host of small molecules, most of which are given intra-articulately, that are in phase two, phase three clinical trials, that disrupt all of these proteolytic enzymes. So Matrix Metalloproteinoses, they essentially take out your type ii collagen. You have ADAMTS-4 and ADAMTS-5 inhibitors that are coming to market soon that-- so those particular enzymes degrade, the aggrecan and proteoglycan within the joint. And we have other enzymes like Cathepsin K. And so this is one class of medicines where we now have what we call DMOAD so disease modifying osteoarthritis drugs. 

We've had, for a long time in rheumatoid arthritis, these agents. And we've never really had anything in osteoarthritis where we can either regenerate the structure of the joint or prevent it from degrading. So it's a pretty exciting time for us at this stage. 

I should talk about some of the other newer agents for osteoarthritis. So we talk about the DMOADs and maintaining the structure of the joint. But then we also have pain. So clearly, there's a heightened pain response within the joint for our patients have chronic osteoarthritis and pain associated with it. So there are novel therapies based on nerve-derived growth factor, which are in the works as well to help with pain isolated to or associated solely with osteoarthritis. So those are the things to look forward. 

All right, so we're going to switch gears and this is sort of the part for just sort of an update, mostly for the residents and general internists, hopefully, but for everybody to some extent. So we're talking about the diagnosis of osteoarthritis. 

And really, in those joints that we can wrap our hands around, that we can feel-- so the hand, the knee-- we can diagnose osteoarthritis clinically. You don't need x-rays. So that's a really important concept. And I often am in clinic, and people are like, let's get x-rays. I'm like, why? They have OA. People are like well, we want to prove that it's OA. It's like, why? We know it's OA. 

So you can absolutely diagnose OA clinically. So that said, we often define osteoarthritis by radiographic features. So it's important to note what those radiographic features are. So there are four cardinal features of osteoarthritis, at least when we assess them by plane fill. So those include joint space narrowing, subchondral sclerosis, subchondral cysts, and then bone spurs of our osteophyte formation. 

So the ACR has some classification criteria for both the clinical and essentially radiographic-- I didn't include-- the second column here is clinical and x-ray together. But there are also just radiographic scales that we're going to talk about. 

And this is, again, for the knee. It's the classic symptoms of osteoarthritis pain that we differentiate from inflammatory pain. So it's pain that is worse with activity, better with rest. There is some stiffness. But it's stiffness that's short-lived. It's usually gone after about 30 minutes of activity. 

And we know that-- and ages is, as you'll see, is an important risk factor. One reason for that is just normal healthy cartilage thins quite a bit as we age. And cartilage that's thin is just more prone to more rapid progression of osteoarthritis because there's just not a reservoir matrix, essentially. 

OK, so questions are, what do you order and so forth? So you always want to get standing films. This is a standing AP view. As it turns out, there is actually a better view to get that will pick up really early osteoarthritis. And this is the standing, semi-flex view of the Rosenberg Projection. 

And essentially, what it's doing-- if I go back-- what it's doing is it's highlighting the portion of the femoral condyles that are going to be more prone to the earliest, most symptomatic OA. And so it actually is quite a bit more sensitive at picking up, at least radiographically by plain film, osteoarthritis. So this is what that view would look like. 

Other views that you would get are the lateral and the skyline, or merchant, view. So just remember that the knee has three compartments. You have the medial compartment, you have the lateral compartment, and then you have the patella femoral compartment behind the kneecap. And a lot of morbidity arises-- there are individuals who only have disease there. So if someone has really profound crepitations on exam and you get just standing films without getting these other views, you may miss some stuff. 

So that's the set of films that I would recommend for knee osteoarthritis. And then we talk about Kellgren Lawrence scores to grade osteoarthritis. And it's essentially a combination of-- the questions we ask is their joint space narrowing and are there osteophytes? 

So this is grade one, two, three, and four. So at a, you have some possible osteophytes, no narrowing. You get definite osteophytes and possible narrowing at grade two. And then at grade three, which is really the cutoff when we say, OK, this person's got OA without a doubt, they have joint space narrowing and osteophytes. And then at the later stages, you have actually some architectural changes of the joint that are more profound. In this case, it would be a pretty significant varus change. 

So again, like I said, we can wrap our hands around the knee. We can wrap our hands around the hands, the finger joints. So these are areas of osteoarthritis rice that we can diagnose clinically. That said, so this is how the ACR classification criteria perform. Really, they focus on the thumb, particularly the base of the thumb, the first CMC, which is one of the most common places that we get arthritis at, or osteoarthritis. And then the PIP and the DIP of the index and long finger. 

So and again, you may be asking, well why do they include the MCPs? Because that's not a place where we typically see-- shouldn't see any swelling, ideally. The reality is these are really old criteria. And they were developed to differentiate OA from RA. So they probably perform better if we compare-- the validation group was normal controls. But that's why you may be asking, well, why do they have the MCPs? 

OK, so for the hands we like the PA-- not the oblique, but a Norgaard view, primarily because this view is helpful for us as rheumatologists, and radiologists, and internists to look for areas of errosive disease associated with, say, rheumatoid arthritis. 

So an oblique is really not helpful for us. I typically tell people only get an oblique if you're worried about a fracture. Really, if you're getting x-rays, a joint for arthritis of any sort is a PA and a Norgaard. The other thing is don't x-ray a finger if someone has finger pain. X-ray the whole-- if you're worried about arthritis, x-ray the whole hand. You get the wrist for free. And it's really important for us clinically, as it turns out. Because we can see a lot of stuff that might help a patient just if we had a little bit more of a view. 

OK, so this is what OA-- so I'm going to show you some images of what OA looks like in the joint. So this is hand OA. Do you can see, hopefully, the joint space narrowing, some osteophytes. And you look at the distribution of involvement. It spares the big knuckles, right, the MCPs? And it involves the middle row of knuckles and the further row of knuckles, the DIPs. 

And then look at the base of the thumb. So those are the areas where we're really-- where there is a copism for osteoarthritis. And people often ask, why are my-- why do I have these nodules on the ends of my fingers, and so forth? Well, what's happening is that you can kind of see in profile, you're getting these massive osteophyte that sort of curl over the middle phalanx here. So but right here, these are massive osteophytes. And so those are actually the Heberden's nodes at the ends of the fingers and the Bouchard's nodes. 

There are some clinical variants of osteoarthritis. This one is called errosive osteoarthritis. And it tends to be more symptomatic. And it tends to result in more disability because of really dramatic architectural changes in the hands. I mean, these are people who-- they can't close their fingers. So they can't hold them a mug, they have to hold with both hands, and those sorts of things. 

The kind of buzz word that we use is "gull wing." So it looks like a seagull, right? So here-- because you get these erosions through the end plate. All right, so for the hip, we can't examine the hip very well, right? We can't feel it. We can't wrap our hands around it. So you need x-rays. That's the long and short of it. 

Right, so the views that you want are an AP and then a frog leg. The fried egg is just where you have your have your hip slightly flexed and basically externally rotated and abducted. And the reason for that-- I actually, the frog leg is a very helpful view. Because it really opens up. 

You can see the joint space all the way throughout the joint. And it's also just helpful if you're looking for other things like ADN. It really shows you, in sharp relief, the cortical margin of the subchondral bone. So it's one that's important to get. 

So this is what sort of classic hip OA looks like. You have joint space narrowing here. So you have this superior-- this is classic sort of weight-bearing joint OA. The femoral head moves up superiorly, as opposed to migrating axially. And what you are seeing here is it looks like an ice cream cone, right? So that's called a rim osteocyte or a femoral osteocyte. These would be kind of how osteoarthritis looks in the hip. And this is clearly really severe disease. You can see in this hip, all of the characteristic features of OA-- the subchondrals. And dramatic, right? You have those big geos, these subchondral cysts, the subchondral sclerosis, the joint space narrowing, and the big osteocyte which is up at the top of the acetabulum here. 

OK, so now we kind of know how we would diagnose clinically and radiographically osteoarthritis. So I'll tell you a little bit about the epidemiology. So yes, this is an old study. But it's a good one. And it shows, as we would expect, that with time-- not with time, but at each individual age, the incidence of OA goes up. 

The reason that there is a little tail at the end is just that the people who are most susceptible are starting to die out at a higher rate. And so you get this sort of unexpected downturn in the graph, which we expect to just keep going up. 

So the lifetime risk of symptomatic OA for everybody, it's pretty high, so 40% in everybody. It's higher in women. So women aren't spared from OA. You know, they, of course, get all of their articular problems with RA because they're the folks who get autoimmune conditions. But they're also the folks who get really symptomatic OA as well. 

So it's more common in both the knee, and the hip, and the hand for women to have OA. Particularly in this case, we're just looking at the knee. So black women and men have more symptomatic OA than white women. 

And then obesity plays an important role, particularly the weight-bearing joints. So this is for the hip and the knee in general. A good rule of thumb is that for these sort of intermediate levels of your BMI, you increase the risk by a one and a half or two-fold up developing symptomatic OA. So what does that mean? Well, that means that if you have someone who's been obese most of their life, they're going to have an 80% chance of developing symptomatic knee OA at some point over their lifetime. 

Prior injury-- that can include-- we know this-- prior surgery, prior meniscectomies, those sorts of things also increase your risk of developing symptomatic OA. 

So one question that people often have, or one thing that we've had to explain or are working on explaining is why is it that radiographic OA is so much more common than symptomatic OA? Essentially-- and these are from population studies and this is the prevalence of radiographic OA. Again, you can see it's more prevalent in women. 

But definitely, as you'll see, that it's pretty equally prevalent between the knee and the hands. The hip is less often involved. What you'll see, though, in terms of the symptomatic involvement is depending on the area, it's anywhere from two-- it's a lot less. So let me rephrase it. Radiographic OA is anywhere from two to four times more common than symptomatic OA. So many, many, many more people have radiographic OA than have symptomatic OA. 

And like I said one, of the evolving therapies that we're working on is focused on pain. It's focused on osteoarthritis pain. Because clearly there's something-- and it's not just about the structure-- there's something else that's going on. There's something about the neurobiology of the joint. And so those studies are coming to, again, mostly focused on the use of nerve-direct growth after. 

So a quick case-- and we're going to go through. So in the final third of our time together, we're going to talk about kind of existing therapies, and how we implement them, and how we should think about using them. I think one of the things you'll see is that all of the current therapies that we have for OA are awful. They're awful. 

Actually, I was talking with Dr. Kimball this morning. And we were talking about osteoarthritis and rheumatoid arthritis. And I told him, you know, if you asked me now, knowing what I know, I would take RA over OA any day. 

And the reason is because now with RA , we have all these great therapies. Like if I have a young person who comes in with newly-diagnosed rheumatoid arthritis, I can get them into remission. And I can get a good third of those people basically cured off of therapy. They don't need any more DMARDs later on down the road. But even if they need DMARDs, I can keep it under control. Whereas with OA, if I had a bad knee, it's just going to progress. We don't have anything. And this is going to be borne out here. 

OK, but here's our case. We have a 54-year-old gentleman. He's a nurse here at UVA. He has hand OA. He works in the infusion center. So he's always opening vials, starting IV, doing those sorts of things. And it's just really become more of a problem for him. 

He has GERD. It's well-controlled with a PPI. And for symptom relief, he's been using ibuprofen at a 400 milligram dose three times a day. So the question is-- he's just not doing well. So the question is, is which of the following regimens up here is going to provide-- I was going to do an audience response, but I didn't think we'd have the time. So, just in your head, respond. So Tylenol Arthritis three times a day, Celebrex 100 milligrams twice a day, Naproxen, 250, Diclofenac, 75, and then Glucosamine, 500 milligrams twice a day. Just see what you would think. 

All right, so we have some data on this. So a lot of the data that I'm going to present now are there have been so many studies over the years. So these are all going to be meta analysis, which is adequate here. 

And in 2017, we had a really good meta analysis of the use of NSAIDs in hip and knee OA. So I need to do a little bit of explaining here so that you will kind of understand what the clinical relevance of these numbers are. 

So if you look at the dark line, that's no effect. The dotted line indicates what would be considered a clinically relevant effect. So for pain studies, what does that mean? That means that on the 10-point pain scale, you improve by 1. So that means that if you take one of these therapies that's right on the line, on the dotted line, that means that you'd go from, say your pain is a 7, you would go down to a 6. 

So that's what this effect size means. And in general, the effect size in these systematic reviews and meta analysis, an effect size of minus 0.3 or 0.37, in that ballpark, represents a one-point improvement on your pain scale. That's all it is. 

So first off, what about Tylenol? So Tylenol, at least when you look at larger poll data, it actually-- there is an effect, but it's not really clinically relevant when you look at knee and hip OA. So this is chronic OA, though. Just keep that in mind. So we're not talking about you have a headache, you take Tylenol. So this is for people with chronic pain associated with osteoarthritis. 

So Tylenol doesn't work. So the NSAIDs that work, perhaps the one that works the best, at least we have data on-- it's relatively few studies-- is Diclofenac. So Diclofenac, at least in the data that we have, 75 milligrams twice a day-- so that would be what I would say is the most effective sort of correct answers. 

Now, is that a big difference between ibuprofen and Naproxen or Celebrex? Not really. The point, though, is that the dose does matter here. So when you see-- just as a point of explanation-- when you see Celebrex 200, that's a 24-hour dose. 

So you could get there either by taking 200 once a day or 100 twice a day. So you have to take-- in order to get what would be considered clinically meaningful relief with an NSAID for chronic osteoarthritis, we have to take what would be considered anti-inflammatory doses of ibuprofen, so 800 milligrams three times a day-- Naproxen, 500 milligrams twice a day, and then the Diclofenac at-- 

So that's kind of how the NSAIDs perform. And then of course, there's the question about Celebrex. And I'm going to talk a little bit extra about Celebrex. So I think it's a good-- if you want to know my honest opinion, I think it's a good drug. And I use it a fair amount. I mean, I use all of the NSAIDs. But Celebrex, I would say, of the doses we typically use, is just as good as those other drugs in terms of its clinical efficacy. 

So one big question has been, of course, are the selective NSAIDs more dangerous than the non-selective NSAIDs? And so Pfizer sponsored a study-- it's a non-inferiority trial. This is sort of in the aftermath of Vioxx, of course. And what they wanted to know is-- so they get a non-inferiority trial-- is Celebrex any worse than-- or is it just as good as, when it comes to adverse outcomes, as ibuprofen and Naproxen. And we kind of think about Naproxen as being kind of OK in cardiovascular disease, most of the studies that we have. 

So what they found, essentially, is that Celebrex did quite well. So there were no increased cardiovascular adverse events. As we would expect, it's actually fewer significant mucosal or GI side effects. Certainly, there's still an issue. You know, they're not perfect. Celebrex-- if you still are high risk for GI bleeds, you still need to be on prophylaxis when you're on Celebrex. We know that. 

But one of the other things-- it's World Kidney Day, I guess. Celebrex actually was associated with fewer adverse renal outcomes compared to ibuprofen. No difference with Naproxen. So just something to keep in mind when you're thinking about what drugs you're going to be using and why. 

OK, so now the question is what about Glucosamine and Chondroitin, how did they do? Well, just to, again, reframe things, this is a 10-point scale, basically. This is a visual analog scale for pain. So clinically meaningful is at least a one-point improvement on that scale. 

So if you look at this particular meta analysis, there's really no difference or really no meaningful clinical effect. The other interesting thing is that this particular study went into a little bit more detail. And this sort of highlights why we need to know where funding is coming from and those sorts of things. If you look at the trials that were sponsored by industry, well, it wasn't clinically meaningful, but there's an effect. But if you look at the non-industry funded trials, there's no effect whatsoever. 

And so people are often coming to me asking me, well, what should I do? What should I do? Well, this is again only on pain. It doesn't have anything to do with function. There is no effect on function. So there's really no-- in large populations-- no clinical benefit to being on Glucosamine or Chondroitin for hip and knee OA. These are all hip and knee OS. 

The other kind of interesting thing that was a little odd is that when you look at different salts for the Glucosamine-- which makes absolutely no sense if this is the primary-- it could make sense, but it gave people some pause. If Glucosamine is the active metabolite or ingredient of the drug, there shouldn't be a difference here. 

All right, the one exception-- we have one run randomized clinical controlled trial. So that was hip and knee OA. In hand OA, there is one study, so there's not a lot of data. But it's Chondroitin. Just Chondroitin has some effect, at least in that one study, And so it actually-- in the current guidelines for the European Rheumatology Group, they give it a low recommendation for hand OA. 

OK, so we're going to talk about intra-articular and behavioral interventions here in the last few minutes. So we have a 62-year-old woman, symptomatic knee OA, who is coming in with worsening knee pain. She has medial pain with intermittent swelling when she's active. She has some occasional instability. Read it up here. And her symptoms were previously well controlled with anti-inflammatories. And she was getting some periodic triamcinolone injections. 

She was getting, initially, with the steroid injections, about two months of relief before really significant symptoms would return. And now with the most recent injections. She only got two weeks of relief. Then really bad pain came back. 

On her exam, she has a varus change at the knee and joint line tenderness. There's no laxity. She ends up getting an MRI. And there's actually a small medial meniscal tear and diffuse cartilage loss along the medial femoral condyle. So there's a lot of cartilage, then loss. 

So what would you do next? What's the next best step in management? 

OK, so there's lots of good data that-- don't mess with the meniscus. It's OK. So minuscule tears, like I said, we know that trauma is a risk factor for OA later on down the road. So we know that if you've had a previous meniscectomy, you're going to have OA down the road. When they actually did studies and looked at people with knee pain or they compared people with OA and no OA subclinical meniscal tears, as assessed by MRI, are common and do not correlate with pain. So this is sort of like discs in the back, right? It's the same sort of story. 

And then finally, we talk about-- so degenerative tears, they're just a feature of OA. So we have lots and lots of data now that we should not be doing arthroscopic partial meniscectomies in our patients. 

So to be clear, I'm not talking about people who come in, have a sports injury, have a locked knee because they have a massive meniscus tear. That's not what I'm talking about here. So these are people who just have knee pain without obstructive symptoms who are coming in and are found to have these tears. 

So they've looked at it in multiple populations. So they've looked at it in patients with OA and without OA. These two down here are the ones that are most relevant for the top. So there's no benefit to going in and cleaning out the meniscus and making it nice and smooth for people who have osteoarthritis in these tears. 

So we have really strong data, including sham-- you know, these are these are done with sham surgeries. So they actually went into the OR, did something, and the patient didn't know. They weren't aware of it. They looked at it long-term. So it was very controversial among the orthopedic community. 

OK, so this is just to give you a sense about some of the kinetics for steroid injections. So this is from a study. There's a long acting kenalog that's approved now. It's got these micro spheres. And it basically just resides in the joint longer and releases the medicine slower. So these are the kinetic studies from them. And so these are how people did with respect to pain after their injection. 

And so you kind of see what the kinetics are like. So the WOMAC scale is an outcome-- it's a 24-point item or 24-item survey that we use as an instrument to assess OA outcomes. So an improvement of one on the WOMAC pain scale is essentially like two points on your 10-point pain scale. 

So the regular triamcinolone is black and the long-acting is green. And then this is saline. So you get an immediate improvement with both of-- at least in this study, which I think had 140 randomized patients total. So you get a significant improvement. And then there's this decrement. And then at three months, you're back to where you started. 

And so that's typical. And we often don't inject people but every three months anyway. And the concern had been that the steroids are toxic at some level to the chondrocytes, and that repeated injections would cause problems or a shorter interval would cause problems. 

So this is from the Cochrane Library here. And this looked at the effect of intra-articular steroids for pain. So the take-home here is that-- I don't know if you could appreciate, but the effect sizes are small. So we're having people get short-term relief. And it's not that significant when you look at large populations. 

So in this particular forest plot, this is weeks post-injection and whether or not they get clinically significant pain relief. So over here, 10 would be a one-point improvement on the pain scale. So 20 is two-point improvement. So you can see that most of the benefit of steroid injections is in the first one to three weeks. And then there's nothing, at least based on the data that we have available to us. So they're not great therapies. 

Then add to the mix the study that was done by McClendon in 2017, where every three months for two years, they brought patients in. And they were randomized to either receive intra-articular steroids or just saline. And there was really no difference. 

So the question that they were interested in is if we treat people, if we manage osteoarthritis in this way, do we see meaningful, functional improvement over two years in these patients? And the answer was no. 

The concerning thing was that there was no significant difference in pain or function between these two groups. But what they did notice is they all got MRIs. And what we saw is the group getting the repeated steroid injections actually had thinner cartilage. And we know that thinner cartilage predicts OA. So there's that concern. 

In about three minutes, I'm just going to quickly go through some of these other things. Hyaluronic acid-- its effects take longer. The take-home is that its effects take longer. But they persist longer compared to steroids. And they're pricey. And it may not be worth it. So again, the effect size, you get one-point improvement on your pain scale. And the peak is at eight weeks. The peak of the effect is at eight weeks with hyaluronic acid. 

So the correct answer to the original question is referral for physical therapy. And the reason is because with physical therapy, you get a lot of bang for your buck. So your physical therapist will prescribe a cane. We know that that has a significant-- that, by itself, if you have unilateral knee OA, has a significant impact on joint loading in the progression of OA and an effect size anywhere from one to two points on your pain scale. 

They also do strength training. Strength training has perhaps the largest effect that we can find on long-term outcomes with respect to function and-- so pain and function. That's a big one. You're better able to function. 

So this is a meta analysis. The first group here is strength training alone. The second group is strength training and range of motion. This is strength training, range of motion, and then physical manipulations. 

And so if you look at the forest plot down here, the effect sizes are pretty good. And like I said, when you combine all the things that physical therapists can do, it's truly-- it's really dramatic. And then you add into that, if you can lose some weight it's even more pronounced. So physical therapy, getting people moving, is really important. 

One thing that I didn't mention that I think is important that we should relay to our patients, thinking back to the structure of your articular cartilage-- remember it's an avascular structure. It relies on the synovial fluid for nutrition, and removal of waste, and for trophic growth factors, and the like. 

So the only way to get these things to the chondrocyte is to load the joint. So you can think of the articular cartilage like a sponge under water. So you load the joint, you squeeze the sponge into the synovial fluid. And you get rid of all the-- you dilute the waste. And then you unload the joint. And all of the stuff runs back into the cartilage. So you get your nutrients, and you get your growth factors, and all the rest. So you've got to move. So people who don't move, you're injuring your joints. 

So we know there is strong data to support the importance of daily walking and daily movement and the health of your joints. Things like running-- if you run less than 50 miles a week, you don't have any increased risk of OA. In fact, it's probably protective. 

So I'll leave it with that. We're playing tonight. It's-- I keep saying ACAC. My wife keeps making fun of me. But it's ACC tournament time. We're playing tonight. So go Hoos. And congrats. All my students are texting me. So we have some people who are going to great places from our med school class. 

So if you see our students, congratulate them. It's pretty exciting. Thanks, everybody. 

[APPLAUSE]