Some common misconceptions about osteoarthritis with Tonia Vincent

hello and welcome to this edition of joint action [Music] this podcast is dedicated to all those out there who have osteoarthritis on the show we unpack the truth and demystify the myths about the disease and its management if you have joint pain and want to know more about how to manage it from the world's best experts you've come to the right place without further ado it is time to welcome your host david hunter hello and welcome to this edition of joint action this week we have the privilege of discussing some common misconceptions in osteoarthritis now

despite the prevalence impact and disability associated with osteoarthritis it is still relatively poorly understood new insights however are forwarding a window into previously held strong beliefs that we now consider as misconceptions many people in the community believe that this disease is simply a consequence of getting older others that the joint has no capacity for a pair some have suggested that we should just use treatments widely used for other inflammatory rheumatic diseases these misconceptions have consequences both in terms of the language that is used with terms like wear and tear osteoarthrosis degenerative joint disease being widely

used but notoriously inaccurate descriptors of this disease in addition these misconceptions have consequences as far as a person's understanding of the disease and treatment implications for example a person who does not appreciate that the joint has capacity for repair and is worried about loading the joints may choose the couch instead of the bike many are subjected to treatments with potential harms used for other inflammatory rheumatic diseases where there is little potential to help their osteoarthritis in today's conversation we try to unpack some of this complicated and controversial area and look at some of the new

insights that hopefully will put some of these myths and misconceptions to bed and we're joined by none other than tonya vincent tonya vincent studied medicine at ucl in the uk qualifying in 1993. she trained as a junior doctor in london later specializing in rheumatology in 1998 she took time out to do a phd at the kennedy institute of rheumatology under professor jeremy sakleta she continued at the kennedy institute as a welcome trust clinician scientist and subsequently as an arthritis research uk senior fellow in 2012 the kennedy institute moved to the university of oxford and she

was appointed professor of musculoskeletal biology she directs the center for osteoarthritis pathogenesis which is funded by versus arthritis her research interests include pathways that drive mechanosensitive responses in cartilage the role of the pericellular matrix in determining these responses and how they modulate osteoarthritis in vivo her work is funded by versus arthritis the medical research council erc and the kennedy trust for rheumatology research she continues to be clinically active running both osteoarthritis clinics and the multidisciplinary marfan syndrome clinic tonya welcome to the show thank you very much david yeah great to have you along and a

good opportunity to chat where we haven't had a chance to see each other for a while but before we get into um the main content of the show any conflicts or disclosures that you feel are important to reveal the only active disclosure i have at the moment is that we have a large consortium which i hope will get onto talking about later called step up her way which is co-funded by a sort of mixed package of academia uh industry and charities so there's a number of different industry partners who are part of that that's fantastic

thank you for sharing that now the first part of the show i usually just try to probe you a little bit to get to know you a little bit better both for myself but also for the audience obviously but if you had to describe yourself in five words what words would you choose yes i think it's fair to say that if my husband would he were here he would probably describe me as irratible and impatient and i suspect that those are probably both true i think that um i'm i'm quite demanding i'm demanding i have

quite high integrity i would like to think so and i think i'm quite a holistic person i like to have the big view of something i'm not just sort of squirreled away looking at something down the microscope i do actually like to step back and see everything in a bigger picture it's a great way to look at the world as well and i'm sure it brings a lot of insights that are very meaningful to the work that you do now when you are at work can you just tell us a little bit more about what

it is that you might be doing on a day-to-day basis yes so i describe myself as an academic rheumatologist and i actually spend much more time doing academia than i do clinical so my day-to-day work is 80 academic and only 20 clinical and in a normal pre-covered day i would be going into the kennedy institute into the lab and i would spend most of my time having meetings i think increasingly meeting with students meeting with prospective students meeting with colleagues to discuss science a fair amount of admin in there as well i share the education

policy standards for our department i look after other institutional things like the histology service and the pre-clinical department as well so quite a mixture of both clinical things once a week and also a lot of admin and a lot of meetings with people and just occasionally i get a chance to sit down and think about science on my own and write a paper and so forth one question i never asked but i'm pretty sure i showed on a regular basis particularly after you've just given me that laundry list is where do you find the time

i don't know it's interesting isn't it one just keeps on adding extra things into the diary and one thinks that one can't possibly fit anything more in but somehow you just you just become more efficient and i think that's what happens as you get older you learn you learn which of the corners you can cut and which are the things you can spend less time on and which are the things that are really important and so you just keep on cramming more and more and more into the diary of course you know there's the home

life bit which one we have we have to include that as well and i think that probably my husband and my daughter get the brunt of this because they probably don't see me quite as much as they might want to but somehow i don't know one just manages to to become more and more efficient in what one does i haven't learned that secret yet but hopefully one day i will but when you're not doing your day job what is it that you enjoy doing well my husband is a musician he's a conductor so we have

a lot of music in the house my daughter's a talented pianist you know junior she's still at school but so she plays so we have a lot of music in the house and he conducts concerts when it's not covered era and so we're often uh out and about um sort of doing performing or seeing music and i suppose that that's all consuming because he's as all consumed by his career as i am i suppose so that that takes up most of our collective time the other thing that we've learned to love in recent years is

that we bought a small apartment in the isle of wight which is this little island off the south coast of britain and that is just a glorious haven and we go there and sit and just look at the sea and it's a very relaxing place to be that's wonderful do you play an instrument as well no i actually i met my husband singing so i used to sing in a choir in london and so i don't sing very much anymore but uh i certainly used to sing as an amateur we'll have to listen to that

one day with a bad bad karaoke or something like that all right now the topic of the day is obviously trying to dig into a number of misconceptions and myths that people potentially have out there about their understanding of osteoarthritis and one of the first ones that i just want to dig into that i know you have a particular interest in is about the concept of aging now is osteoarthritis an inevitable consequence as someone gets older no i don't think it is and i think the epidemiology tells us that and i like to think that

aging is just one of many strong risk factors in the development of osteoarthritis and you know i i firmly believe and and i think this isn't my own discovery this is just taken from the epidemiology literature if you look at great populations of patients with osteoarthritis there is only one feature that's absolutely common to every single patient who has osteoarthritis and that is mechanically loading through the joint if you have a paralyzed joint or if you are in a wheelchair for instance and so forth and you don't have any mechanical load going through your joint

you simply can't get osteoarthritis so i like to think of mechanics as being the only obligatory risk factor for osteoarthritis and all these other things then on top of that just determine your risk and the course of that disease thereafter so clearly aging is a really important one and there are probably multiple reasons why aging is associated with osteoarthritis which would include the fact that as we get older the muscle groups across the joints become weaker and so we don't stabilize the joint as well when we're walking on it we lose the ability to to

activate appropriate reflexes during the normal walk cycle and that also affects the impact of load that goes through the joint and then there's the biology because we know that as we get older our repair responses are reduced we know that the cell response to mechanical injury is also radically different so i think all of those things confer this increased risk as we get older but it's not inevitable i had a milestone birthday relatively recently and i just want to know that i've got some preservation left in my joints and that it's not necessarily going to

happen to me as well now historically i think a lot of particularly rheumatologists have felt inclined to want to treat osteoarthritis the same way as they treat other inflammatory rheumatic diseases like rheumatoid arthritis and lupus and so on you know obviously recent imaging studies have suggested that inflammation is a common part based on synovitis and other characteristics that we might see on mri as part of the osteoarthritic process but is the inflammation in osteoarthritis similar to rheumatoid arthritis and what treatment implications does that have well i think this is a very active and important question

that i don't think we have full clarity on yet in my view is that you know some of the reasons why we've gone down this route and it you can see exactly why it happened osteoarthritis and rheumatoid arthritis are both managed by rheumatologists and the patient comes into the clinic and they complain of the same thing essentially they complain of painful joints they complain of tenderness around the joint margins they complain that it hurts when they use the joint they have a sort of moderate amount of in the case of osteoarthritis of stiffness first thing

in the morning when they get up then in rheumatoid arthritis which where it's very profound and so there are lots of commonalities in terms of how the patients present but i don't think the biology makes us feel that this is the right way to target it because when you look at the preclinical models of osteoarthritis when you look at the in vitro experiments that people have done in the lab looking at which pathways are activating osteoarthritis it's really quite a different disease to rheumatoid arthritis and you and i as rheumatologists both know that that's the

case we actually can distinguish between a rheumatoid patient and an osteoarthritis patient in the clinic and so i think it was to partly because there are such good drugs out there that were developed for rheumatoid arthritis that really work in rheumatoid arthritis that it seemed like you know it was a sensible thing to test you know we may as well look to see whether if we neutralize particular inflammatory molecules in osteoarthritis we might just get the same response that people have seen in rheumatoid arthritis but as you know they've been a number of randomized control

trials now targeting either interleukin-1 which is one of these molecules or tumor necrosis factor one of the other molecules tumor necrosis factor works extremely well in rheumatoid arthritis but all of these studies have failed in osteoarthritis and there really was never any very good evidence that those were the molecules that were driving the process in osteoarthritis and even when you look at the imaging studies you look at the mri scans of patients joints there is evidence that there is inflammation in the synovium the lining layer of the joint but actually it's very modest compared with

what we see in rheumatoid and the biopsies are quite different as well so when you look down a microscope and you look at the cells that are represented in those tissue samples they also look quite different so i'm not convinced that i've never been convinced that those were the best targets to try and osteoarthritis and i suppose you know at one level it doesn't matter i think well it matters a lot to patients obviously but it doesn't matter that you've had a failed trial because that tells you quite a lot about disease and it brings

us closer to the truth but one thing that worries me a lot is that every time one of these very expensive clinical trials fails another pharmaceutical company will say oh oa is not for me thanks very much but this is a really difficult disease i'm going to stick to things that are easy to treat and that's what worries me more than anything else how do we change the philosophy then in industry in terms of i guess giving them better concrete idea of targets because you know i don't think they've necessarily done this mechanistically in as

nuanced a way as they could but moving forward knowing full well that there is a graveyard of different trials that have been conducted out there and a lot of big pharma that's potentially got dismayed about continuing the osteoarthritis space how do we as a group of osteoarthritis researchers as a community change the way we approach this disease with our pharma partners i think that's a really good question and i don't know what the right answer is i think everybody was so keen to jump into diseases like osteoarthritis because the gain if they've got a treatment

that really does work is so huge and so it's worth the gamble but my view has always been that you know ten years ago we really really didn't understand the basic molecular processes going on in osteoarthritis and it would have been far too early to be speculative about what we think is the best treatment for oa and i would never have anticipated clinical trials in their way five ten years ago just it just seemed to be terribly premature and that's why when i started working on osteoarthritis 20 years ago what i wanted to do is

really start from scratch and unravel the molecules the processes the pathways that are driving it the importance of mechanical load for instance and the importance of all the different responses in the joint tissues that occur over that time and i think that only after 20 years are we just beginning to get a bit of a feel for what this osteoarthritis is about and now i'm beginning to have a feel for what i think the best targeting strategies would be but i still don't i don't think i if the industry knocked on my door tomorrow and

said tell us what to put into the patient next i would still be speculative i'd say these are the three areas we're looking at these are the three areas that i think are sort of most exciting going forward but i'm not quite sure what the best target is at the moment so you know come back in another couple of years and i might have the answer now of course that might be just disappointing news for anybody who's got osteoarthritis at the moment but i honestly believe it's better for the community that we get the right

targets at the right time and then test them appropriately in patient groups so that we get positive results out of clinical trials rather than doing lots of trials that are slightly less thought through i think perhaps and end up with negative studies that don't help anyone completely agree with you about your comment with regards previous trials looking at immunomodulatory type agents including disease modifying agents that are treated well used in treatment of rheumatoid arthritis like hydroxychloroquine and methotrexate as well as agents targeting il1 and tnf what do you make of the recent trial that looked

at another agent called canakinumab and admittedly it's it's not a direct osteoarthritis trial that's looking and inferring from a larger heart disease study but what do you make of the results there well i think that they're obviously quite interesting so just for our um listeners this is a another aisle one interleukin-1 targeting clinical study it's a huge study several thousand patients in it but they were enrolled to look at the cardiovascular ischemic heart disease outcomes and the idea was that you take a group of individuals who are sort of late middle age early elderly if

you like in their 60s plus uh with ischemic heart disease and you give them this drug to see whether you could reduce the incidence of further ischemic events and it did work for their ischemic heart disease but because it was such a huge trial they were able to also capture data on patients who had osteoarthritis and one of the things that they observed was that the reported symptoms of people who said that their arthritis had got worse or had got better and so forth over the course of the trial period was significantly lower in those

that were taking this drug so that's tantalizing and if this drug had come before all the randomized controlled trials you would certainly say well look this is definitely worthwhile exploring in a randomized controlled trial properly and of course not panicking but some of the other il1 agents have been used and they failed one of the things that concerns me a lot about this study as you said it wasn't specifically looking at osteoarthritis outcomes in fact it didn't even capture people with a diagnosis of osteoarthritis unless they were reporting symptoms and if you look at the

numbers that they actually had in their placebo group of people who were reporting symptoms it's actually only six percent of the total placebo group now if you think about this group of 65 plus individuals who've got um probably slightly overweight and got other risk factors we would expect the incidence or the prevalence of osteoarthritis in that group to be ten times as high so we're looking at a tiny tiny fraction of those that actually had osteoarthritis in that study who are reporting symptoms so i think we just have to interpret it with enormous caution it

doesn't sway me into thinking that we need another randomized controlled trial stratified according to whether they've got ischemic heart disease in order to test this drug i think that would probably not be what i would choose to spend my money on yeah no i completely agree now i'm not sure whether you coined the term or someone else coined the term but there's this term that's banded around called mechanoinflammation we've spoken about the importance of mechanical loading a moment ago but i'm just wondering if you could just explain a little bit about what that term means

and the inferences of that with regards to mechanisms of disease yeah we we termed a phrase mechanophlegma we get rid of the in in the middle of it just to make it a little bit easier to trip off the tongue yeah we recognize this as being a really important driver of inflammatory processes that go on in the tissues of the joint in response to this mechanical load this abnormal load that i mentioned to you which i think is the common driver of osteoarthritis in all patients and the key thing about it that marks it is

different from the other types of inflammation that people talk about is that it's got nothing to do with immune cells you don't have to have white cells swimming around and getting activated and releasing lots of things that then drive with damage this is intrinsic to the cells of the joint so the cells of the cartilage the cells of the bone the cells of the synovium they all are able to respond in a similar fashion to injurious mechanical insults and they can activate the same signaling pathways inside the cell that would be activated if you put

interleukin-1 or tumor necrosis factor onto the cell but there's no there's no soluble factor there's nothing swimming around that's mediating this that at least that we can find it really is something to do with the cell sensing that mechanical abnormal load in the first place we don't know what that sensing mechanism is we're sort of working on different pathways that might be related to this at the moment and we think it's a really highly conserved pathway because every tissue we've looked at i mean the skin will respond in the same way certainly all your connective

tissues will respond in the same way some of the ligaments bone cartilage etcetera they all they will all respond to injury in the same way but i suspect everything you know the endothelium your blood vessels and so forth all have this innate ability to respond to mechanical injury it's it's how we signal that we want to repair our tissues so that's what we mean by mechanoformation it's inflammation in the tissue but it isn't mediated by a white cell it's not mediated by an inflammatory cytokine or molecule that's floating around you've teased us now a couple

of times and i probably should ask because i'm sure people will be really disappointed if i don't but you've mentioned three pathways that you potentially could be implicated in this process do you want to talk about what they are in layman's terms so the ones that i think are the ones that are most exciting are ones that that are actually agreeing very closely with genetic studies and i think that gives us huge confidence that pathways that are replicated by people's genes just to that pedal a second i'll explain what i mean by that there have

been lots of very big genetic studies which we call genome-wide association studies looking in very large numbers of patients with osteoarthritis and then asking across the whole of the genome you know what are the what are the changes that happen in the patient genome that are different from those that happen in patients who don't have osteoarthritis and by looking at that we can get a map of the sorts of areas and sorts of pathways and molecules that might be implicated in in having a more risk of developing osteoarthritis later in life and those studies have

been really insightful because whilst we've focused on inflammation and and whether it's by cytokines or whether it's by this tissue inflammation that i've mentioned and that seems to be where most of the molecular field has been traveling in the past 10 15 years actually when you look at genetics you don't see any inflammatory molecules you don't see anything that we really recognize as being mediators of inflammation what you see instead is you see things on the other side of the coin you see things that would normally mediate repair of the cartilage which are coming up

you see growth factors coming up a lot and there are some really common growth factors that are relevant and important in repair responses throughout the body such as the tgf beta growth factors and then there's things called fibroblast growth factors as well and so forth and they come up in these genome studies and that aligns really well with lots of the work that we've done over the years where we've shown that there are growth factors that are sitting in the carthage just waiting to be released in response to injury and it's like this alarm system

it's so perfectly primed that these molecules that you don't need any energy to release them you just need the mechanical compression of the tissue and they just fall out of it and then they activate pathways which we think are driving repair responses and those same growth factors are the ones that we're finding in these genetic studies so that's a really exciting area and i'm sure you'll want to come on to this but one of the clinical trials david that was published in recent years was the spree fermin clinical study and that is also a truncated

form of one of these growth factors an fgf of fibroblast growth factor so these things align really well to suggest that actually if you have low levels of these growth factors you're predisposed to osteoarthritis if you're a human if you injure your cartilage there's a mechanism by which these growth factors are released instantly to help stimulate a repair response we've just shown recently that in osteoarthritis you lose that ability to release these growth factors and i don't need to go into the details but it's because you lose the sodium that's trapped in the matrix and

that loses the ability to be able to release these in response to injury and then we've got the evidence from this clinical trial that shows that if you give additional growth factor you can to some extent replenish and renew that ability to be able to respond to injury so i would say we're all on the other side of the equation at the moment so that's certainly one really major pathway and there are a number of growth factors and we're we're looking at several of them at the moment another area which impacts i'm only going to

give you two not three um another area that impacts on the inflammatory signaling this mechanoflamation is also a pathway that speaks very strongly to genetics which is involving a pathway called retinoic acid and the retinoic acid genetic hit is a very strong very common variant a genetic variant in patients who have hand osteoarthritis and there's some really fascinating biology of how retinoic acid is good at suppressing that mechanoformation and that's another thing that we're working on at the moment now you've already started digging into an area that i was going to get to but i

think in in order to address the question directly can cartilage repair i think there's really compelling evidence from the literature that carthage is able to repair itself and we see that through observational studies people have looked with an arthroscope telescoping to the knee joint and they've seen individuals after say sporting injuries who have little focal defects in their cartilage and if you follow those individuals up over a number of years um about 30 of them will just close they'll just spontaneously repair 30 will probably stay the same and about 30 probably go on to get

more damage in the joint and develop osteoarthritis so that's been around for some time as an observation it's also been observed that if you take biopsies of the articular cartilage and people do this for cell-based repair work you tend to take the biopsy from an area of the joint that's not usually under mechanical load because it's thought to be less important and those regions of the cartilage which have been damaged in that way they also spontaneously repair and so you know there's a lot to do with mechanics here which i'll come back to in a

moment and then the most compelling evidence i think in human patients with osteoarthritis is the work of joint distraction and these are a number of studies now uh not just performed by colleagues in utrecht but all over the world people have replicated these where they put an external fixator so one of these metal frames across the joint and they pull the joint apart very slightly by that half a centimeter and the individual wears this frame for six weeks and then at the end of the six week period the frame is removed and they're slowly rehabilitated

and the studies are really quite remarkable they've got cohorts of 20 patients and so forth that they've been following now for up to five years and they not only see really very marked improvement in pain and also in function and this seems to be sustained long after you remove the joint distractor but also when you look by mri it really appears that there is articular cartilage that has regrown back in that most effective part of the joint such that there is a statistically significant increase in thickness of the cartilage and the reduction in the area

that was actually eroded all the way down to the underlying bone so we're talking about people with very severe disease can actually fill that gap with something that resembles articular cartilage and is sustainable for several years so you know to me that those studies are the best examples of how we know that there is regenerative capacity of the articular cartilage even in somebody who's got established severe osteoarthritis but the key thing this comes back time and time again i sound like a broken record it's all down to mechanics isn't it because i say to my

patients you know you we you and i both know that that the skin repairs extremely well but if you've got a blister on your foot because you're wearing a shoe that is new and doesn't fit very well you know perfectly well that that skin will not heal if you carry on wearing the shoe you just take it off and after a few days the skin heals up and you can put the shoe back on and i think exactly the same analogy applies for the articular cartilage how would we expect big cartilage to repair itself if

we carry on mechanically loading it day in day out while we're trying to get treatments that are going to replenish that matrix so i i really do think that probably the way forward is to try and combine some of these mechanical off-loading devices with the drugs in order to get really good quality articular cartilage back in the joint which we can then train people to use their joints better to strengthen their joints to lose weight and do all of those things so that it doesn't come back a second time or at least if it does

it's it's warded off for another five to ten years so how do we unload the joint so to speak without putting a metal frame on our legs for three months how do we simulate that well i don't know whether you can but i mean it's worth trying isn't it there are all sorts of braces and things that people have described some of which have some success in clinical studies but i think often not not tremendous success and nor are the studies particularly well designed i think one of the big problems with something that you can

take off is that you know nobody likes having a completely immobile limb it's just not convenient you can't get in and out of a bath you know it's uncomfortable at night and so forth and so the question is it does that matter does it matter if you're only offloading it for a few hours during the day and you're not wearing it the rest of the time or do you need to have that complete mechanical off-loading period do you have to enforce it by putting an external frame across the joint i don't know it's obviously it's

not acceptable to lots of people to have this operation and obviously comes with side effects and so forth although they're pretty well tolerated and the side effects are fairly modest but then is it any any any less barbaric or yeah it's considerably less barbaric than doing a joint replacement on someone so if it's that or doing a joint replacement i think i know what i would have i guess dig into some of the cartilage repair therapies a little bit further and speak specifically about spree ferment for a moment which is the fibroblast growth factor trial

that you mentioned a moment ago they've convincingly demonstrated that you can improve cartilage sickness after repeat administration of this agent over you know a number of years but unfortunately there wasn't concomitant improvement in symptoms how do you best explain that discordance yeah i i think this is really interesting it is of course it's a fantastically important question and we work quite a lot on pain in pre-clinical models and everything that we've found thus far suggests that it is that cartilage damage that is actually triggering that pain response and so you really need to probably anticipate

building that cartilage back up to something that was you know pre-pain era before you can hope to get reversal of pain and so i think one of the issues with this performance study is that although it showed increased thickening of cartilage that increased thickening was predominantly in the non-weight-bearing part of the joint and that's what they found initially on the non-affected side of the joint and i've yet to see data analyzed in huge detail about how much reversal of that cartilage damage there is in this preference study because i think that's really important to know

whether or not you would have anticipated a reversal of pain because i think you have to build that cartilage up where it's most damaged you have to take the cartilage that's worn down right to the underlying bone and you have to layer layer new cartilage back on top of it and if you are to really realize therapeutic response so i personally think that they're very tantalizing those studies i think they're very positive but i know everybody lacks a certain amount of enthusiasm for them because they say oh well there's no pain signal therefore they're meaningless

but i think if you for instance if you combine that with mechanical off-loading and you could really build the cartilage upper in the most effective part of the joint then i think i would anticipate and this is entirely speculation on my part based on on our pre-clinical work that i would anticipate that you could actually reverse pain if you build up enough of that cartilage so don't know is the simple answer i think building up cartilage is absolutely the right way to go in the joint distraction paper patients where they have built up the cartilage

they also see reduction in pain and it's sustained for a long time i i clearly except that there's no placebo group in a lot of those studies but i think it is possible so i guess taking that forward historically we've gone after one molecular pathway at a time and we haven't necessarily looked at combinations of therapies in in order to address symptoms structure inflammation cartilage whatever it might be how best do we move forward so that we do get more positive trials do we combine different therapies do we look at combining different mechanistic underpinnings what

do we do yeah well that that's a perfectly good idea i mean combination treatment if you gave something like anti-nerve growth factor which we know has got really good effectiveness in clinical trials with something that built up the matrix would you a you know restore your patient to good health yes almost certainly b would you stop them getting some of the side effects that they can get if you just give them excellent analgesia on its own that's possible as well so you might be able to reduce it but see would you bankrupt every healthcare system

in the world yes you probably would because these are both really expensive drugs and osteoarthritis is a really prevalent disease so i slightly prefer the combining mechanical off loading with a you know stretch modified drug at one level because it could be transient you know you could just treat patients for intensively for six weeks or three months and then you could stop the treatment and put them back on the street as it were and see how they got on with that and that might be well that would certainly be a more cost-effective way of managing

this the industry might not buy into it but there are plenty of patients with osteoarthritis out there so i think they would still get their revenue so yeah you could you could combine everything but it would be incredibly expensive i think i understand where you're coming from on the lumping or splitting argument which we'll come to in a moment but let's say theoretically we were able to identify uh specific subgroups of people for example who'd had an injury that may be prognostically at greater risk of more rapid deterioration of their joint are there any factors

that would allow us to predict who those people might be and what would we do about that yeah that's a really important question there are a number of groups who have and are working on this including those in in lund and also my colleague fiona what who works on that at the kennedy institute and we we started off a few years ago again being informed by some of the studies we've done in the pre-clinical models we looked at a number of molecules that we knew were regulated very early on in in osteoarthritis after joint injury

and then we looked we've been looking to see whether they predict outcome and i think uh the jury's still out because we haven't completed that study yet we're only two years into a five-year follow-up some of the patients have completed the five years but we don't have all the data yet so that will be coming out probably in the next year or so but the two-year interim data didn't show a tremendous signal i mean there is there is a suggestion that a couple of the inflammatory markers like interleukin 6 seem to add something to that

prediction model so and but that that might just be a marker i mean it is just a biomarker it just tells you that people who have high levels of aisle six at the time of injury might be just slightly more likely to go on to develop osteoarthritis there are other things that are more important and one of the things that fiona has shown recently is that actually having blood in the joint at the time of injury which is not not um having corrected for the severity of the injury so this is independent of the injury

itself but that just by having blood in in the joint might also be a stronger predictor of whether you go on to get osteoarthritis after your joint injury so although we're looking for things that might predict that they don't necessarily tell you that those are targets so you have to be very careful that's where the mouse studies for instance are very useful because the mouse studies at very least are good models of post-traumatic osteoarthritis and of course people have identified targets through those now studies that might be useful but whether or not you can stratify

patients at the time of injury and then select the right treatment for them i don't know the answer to that question yet well we look forward to seeing that when it comes out and kudos to yourself and fiona for pushing that forward now obviously i've heard you in a debate where you took one stance where you were very much i think on the lumping side of that equation historically i think a lot of people have described osteoarthritis as a very heterogeneous disease in terms of the risk factors that predispose towards it and in terms of

its presentation we obviously have a strong interest in phenotyping and potential stratification for trials to inform trials what role if any do our better understanding of phenotypes and endotypes have with regards identifying and targeting people that might be more suitable for particular treatment mechanisms well the only thing i would say about that at the moment is that there just isn't really any evidence that there are different molecular pathways that are driving different endotypes of patients that you would be able to then recognize and put into different types of clinical trials i'm not saying that they

don't exist i'm just saying that there isn't any evidence thus far i mean that from a clinical perspective you know better than than i that you know one of the things that really does lock patients out is their course the disease course so it's very clear that there are some individuals who will just stay very stable for a number of years and their x-ray changes don't change much and their pain may fluctuate a bit it doesn't change much and then you've got some individuals who will rapidly progress for whatever reason and those are the ones

that you kind of want to be able to identify to put into your clinical trials because then you would be able to have a group that you could then assess your drug against with a little bit more ease and more quickly so there's an advantage for being able to identify those individuals and i don't know whether you've made progress in trying to identify them but i'm not aware of any molecular studies that have suggested that there are certain molecules that help you to identify them and that's one of the reasons why we decided to set

up this big consortium called step up away which is exactly that it's taking very very large numbers of patients and that we've currently collected a thousand but we're planning to um well we've got more samples but we're going to look at 2 000 individual samples and these are examples of the joint fluid the synovial fluid in the knee joints this is all in the osteoarthritis for now and we've taken each of those 2000 samples and we're going to analyze them using a very sophisticated new protein platform which is by a company and the company have

have devised this platform which allows us to measure over 5000 proteins from a single 100 micrometers of fluid from the joint i mean it's the most extraordinary uh sophisticated system and then what we'll do is we'll get all that data back and we'll put it all into a machine and then without any preconceived stratification you know we won't we won't ask the machine we won't tell the machine what which of which patients are which which ones have uh oa which ones have severe oa mild away males females age we won't tell the machine anything we

just put all the data into it and then we say find find us clusters in the data find us patients that stick together in groups and the idea of this is to be able to answer exactly the question that you're asking which is if you look at the molecular level not at the clinical level if you look at the molecular level are there distinct signatures within patients that you could say that signature that group of patients has a different molecular driver of their osteoarthritis or different signature of molecules in their joint compared with another cluster

and that then would be testable to say well what is the difference when you look at the patient so is there a phenotype match between these molecules or not and then you could start asking the question will this group of patients respond differently to different treatments compared with the other ones so i think the experiment needs to be done we need to ask that question i have no idea whether we're going to find more than one cluster at the moment we're very much looking forward to seeing that data and really i think it'll provide a

lot of insights that we currently don't have because i think a lot of the time we've already pre-ordained with our pre-existing theories that there are certain phenotypes and mechanisms that predispose to osteoarthritis and more than likely we're probably wrong but on that note what do you think are the most pressing research needs in the field oh do you know i think increasingly i just think we all need to slow down a little bit i mean i know it's it's so tempting to want to get drugs out drugs out to get get them into patients as

quickly as possible but you know we're so close to really understanding this disease for the first time i just don't want to preempt things by jumping in too early and having another failed clinical trial in osteoarthritis i really don't think it's going to take us very long you know one or two years to to get there and i just think that the most pressing need is for everybody just to take a deep breath and sit back and just review what we've got already review what we think is real what we thought 20 years ago whether

we still believe it's true now and just you know perhaps give ourselves a chance to think objectively outside the box about what is really important in this disease we all need to do that i'm not saying i'm not exempt from it myself i think the nature of most people who are engaged in this space is not necessarily one where we regularly pause uh reflect and move on i think it's very much breakneck speed most of the time and i completely agree i think there's a definite time where we should do that and a better time

than a pandemic now are there any patient-friendly resources or links that you might like to share that might shed further light on the topic of what we've been talking about well we we certainly have a website to our oa center which i will i am embarrassed to say i can't remember the address off and so i will send that to you and that can be on your on your site but we have a patient uh friendly site on that so people can uh see what we're up to in our center for oa pathogenesis in oxford

all right so we'll definitely include that in the show notes now moving on from the topic of the day and just digging a little bit more into tanya and just finding out about what makes you tick why do you do what you do what's the primary motivation well i'm embarrassed to say i just i just feel so lucky that i'm doing something that i just find absolutely thrilling i mean it's just it's so varied our work it's like being given a brand new christmas game you know with the batteries in and you know it's it's

just it's putting all those bits of the puzzle together it's having that flexibility to go ah that's an interesting result i wonder if and doing the next experiment and then reading a paper and going oh that's interesting how does that fit with that and putting it all together and it's it's just a thrill a minute i'm so lucky to have found that niche that seems to suit my personality um and to enable me to hopefully i do feel there's a rush on you know we've got to deliver these things within a lifetime haven't we and

this is a hell of a nut to crack osteoarthritis so there's a big challenge there but i think we're making great progress and so that is what keeps me going every day you maintain the enthusiasm and you're doing brilliant work now is there any one piece of advice knowledge or wisdom that you'd like to give for people out there who have osteoarthritis i suppose is to stay hopeful i mean one of the things that i despair of really is people who aren't osteoarthritis physicians saying oh there's no point in referring patients with their way up

to the hospital because there's nothing you can do there's no treatments for it i think there's an enormous amount we do to patients just by sitting them down and saying you know your your disease i'm really interested in your disease and i can tell you lots about you know the the course of disease which you probably didn't realize you didn't realize that actually most people stay stable over time rather than progress and necessarily going to end up with a joint replacement there's there's a lot of myth out there for patients as well and and fear

about their disease which we can actually help a lot with when we speak to them and so what i would say is stay hopeful and stay positive and and don't be afraid to exercise to strengthen the muscles around your joint because that will actually protect them not worsen it that's a wonderfully optimistic and positive way to finish tanya thank you so much for spending time with us and sharing those really important insights and continue doing the great work that you do thanks very much david i enjoyed it thanks for listening to joint action with david

hunter if you like our show and want to know more check out www.jointaction.info if you have any questions you can email us at hello joint action dot info and follow us on twitter at joint action org this podcast was hosted by david hunter edited by vicky duong music produced by jordan hunter the information posted on this podcast is not intended to diagnose treat cure or prevent disease anyone seeking medical advice should consult a health professional you