Years after serving in the Vietnam War, Virginia Byers Kraus’s father had his hip replaced—three different times. Each time, she said, outcomes were worse. Joint replacement is often the result of osteoarthritis, a degenerative joint disease commonly known as “wear and tear” arthritis. There are no disease-modifying drugs for osteoarthritis and early diagnosis is difficult. But even though the CDC estimates that nearly one in four people in the United States has osteoarthritis, Kraus rejects that idea that the disease—and resulting pain and surgical treatment—is inevitable. Her group at Duke is developing a proteomic panel of biomarkers that will be able to identify people with active disease before the evidence is visible on an MRI or X-ray.
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Years after serving in the Vietnam War, Virginia Byers Kraus’s father had his hip replaced—three different times. Each time, she said, outcomes were worse. Joint replacement is often the result of osteoarthritis, a degenerative joint disease commonly known as “wear and tear” arthritis. There are no disease-modifying drugs for osteoarthritis and early diagnosis is difficult. But even though the CDC estimates that nearly one in four people in the United States has osteoarthritis, Kraus rejects that idea that the disease—and resulting pain and surgical treatment—is inevitable. Her group at Duke is developing a proteomic panel of biomarkers that will be able to identify people with active disease before the evidence is visible on an MRI or X-ray.
Scope of Things Links:
Clinical Research News
Scope Summit Europe
Speaker 1: Hello and thanks for joining us for this month's edition of the Scope of Things, a no-nonsense look at the realities and enigmas of clinical research based on those closest to the action who aim for great and, if need be, are willing to shake things up. I'm Deborah Borffitz, senior Science Writer for Clinical Research News. In today's episode, i'll be speaking with Dr Virginia Byers-Krauss, professor in the Department of Medicine, pathology and Orthopedic Surgery at Duke University School of Medicine, who is part of a devoted team of researchers who have come up with a panel of blood proteins that can reliably predict if knee osteoarthritis is or is not progressing. Welcome to the show, dr Krauss, and put on your seatbelt, because I have a lot of questions about this exciting development for the millions of suffering patients out there And, more importantly, clinical trials needing a way to identify people with worsening disease for enrollment purposes.
Speaker 2: Thank you, deb. So much for the invitation. Be assured I am firmly strapped in.
Speaker 1: Okay, good to hear Okay, off we go. Well. before we delve into particulars about this new blood test, i'd like to chat a bit about knee osteoarthritis itself, as well as the burgeoning field of proteomics. Let's start with the prevalence of this disease and current clinical realities for people affected by it, including how it is diagnosed and treated.
Speaker 2: Sure Well, the CDC estimates that one in four people, or almost 60 million adults in the US have some form of arthritis, and that's projected to increase to about 78 million in the year 2040. The reason for that is, it's estimated that osteoarthritis is increasing with age and with being overweight and obese, and of course, that is a major epidemic in the United States, and so vast majority is due to osteoarthritis. And although there are 100 different types of arthritis, osteoarthritis is the most common, currently affecting about 33 million people in the US alone. The other thing that is important to recognize is the fact that, even though older adults are affected, it's also possible for younger adults who have had joint injuries, such as ACL tears, to also get osteoarthritis at a young age, and there are a staggering 100,000 to 200,000 of these types of ACL ruptures every year in the United States alone, in the average age of people affected as 16.
Speaker 1: Whoa, that seems almost impossible.
Speaker 2: It is an incredible burden, and especially at such a young age. And currently, you ask how do we normally diagnose it? Well, we don't have very sensitive tools for diagnosing it. Usually we diagnose it with an X-ray, sometimes with an MRI. We rely upon people's symptoms And all of these types of diagnoses are really late. So we know that the disease is happening at a stage before the X-ray changes, But we're really not able to evaluate or diagnose until we have definitive evidence from imaging right.
Speaker 1: And the treatment of it is there standard treatment.
Speaker 2: So currently we basically rely upon what we call analgesic treatment, which is treating the symptoms with Tylenol or with non-steroidals like motrin or leave, and we also try to do our very best to modify risk factors such as being overweight or being inactive.
Speaker 2: We also look carefully at bone health, because we know that people who have osteoporosis or high bone turnover also have worsening osteoarthritis. So the bone and the cartilage seem to keep company, and so we look at all of those types of factors, but currently there are no FDA approved drugs to treat the disease, and when we call the disease treatment when it's effective, we call those disease modifying drugs. There are currently no disease modifying drugs that are FDA approved, but the good news is that there are many companies now trying to develop such treatments, and we think that part of the problem has been that they haven't been able to diagnose the disease early enough, because we haven't had since and enough tests. We also think that you know, haven't really been able to identify the people who are actively in the stages of active disease, because you know, if you're relying upon late, late stage changes in the X-ray or the MRI, you're not picking up the early active disease that might actually be the most amenable to disease modifying treatments.
Speaker 1: As with any disease right or any injury. Let's talk a little bit about the proteomics part of this. As I understand it, proteins were first known to provide early signatures of disease more than like 100 years ago, but we have been hearing an explosion of news about proteomics only over the past decade or so, presumably due to advances in protein sequencing technology. So can you please talk a bit about how far we've come and if the proteins being detected are generally coming from either urine or blood, and if it matters which it is?
Speaker 2: You are exactly right, deb. There has been, since the explosion of the molecular age, you know, a wealth of knowledge around proteins, genes, et cetera, and really about biology in general. But before we really launch into a deep dive into proteomics, i just wanted to draw your attention to an analogy with the disease of malaria.
Speaker 2: And this will speak to the importance and the power of biomarkers. Okay, as you know or can infer, the word malaria means bad air. It was the most common illness on the American frontier in the year 1800. It was responsible for one in 20 admissions to London hospitals. The cause was unknown. People thought it was caused by bad air rising from swamps. They were sure it was definitely not contagious And it was just part of life, like hard work, and many refused to regard it as a disease.
Speaker 2: Well, in 1897, a Dr Ross was actually dissecting the stomach of a mosquito and found the malaria parasite that he had gotten these mosquitoes that had bitten a patient with malaria four days before And he made. He concluded, amazingly, that that was what had caused the disease. And suddenly, when he was able to see them under the microscope and have a so called biomarker of the disease, suddenly it became a disease. It was no longer just a part of life And 37 years later quinine was developed and available for treatment. So we're sort of in that same you know arena right now for osteoarthritis.
Speaker 2: We really need biomarkers to tell us what is the disease, because a lot of people think that it's just a normal cause of, you know, normal accompaniment of aging.
Speaker 2: It's a wear and tear disease, just part of life, inevitable, and even though you know 85% of the population over 75 years of age suffers from this, you know they suffer, thinking there's nothing that can be done about it. But we feel strongly that the advent of a biomarker that really depicts what the disease is can really have a substantive impact on the development of drugs, just like finding the you know the malaria parasite under the microscope was what suddenly turned malaria from a bad ear, you know entity to a disease. So we're really excited about biomarkers and proteomics. That you alluded to is one of the many ways. That is a very powerful way of looking at multiple proteins all at one time, with a thing called mass spectrometry that allows you to look at, you know, thousands of different proteins from less than a drop of blood. And then the challenge really is to try to figure out from that gigantic haystack pull out the needles you know that are really definitive and depicting the disease state or activity that you are interested in And it doesn't have to be blood.
Speaker 1: Can it also be urine? It doesn't matter.
Speaker 2: Anything. So it could be even joint fluid, but that's not typically typically a fluid that people like to, you know, give away. Yeah, It can be urine, it can be any and it can be, you know, saliva. There are a whole host of different sources, but blood of typically is one that is very reliable and is easy to get in the clinic Urine as well. There are some clinical tests that are in the urine that are available, but certainly currently there are no clinically available blood or urine tests for osteoarthritis, Just research use only tests, okay.
Speaker 1: Nothing's actually made it into everyday use, got it Okay? So talk about what the Duke team has come up with, this blood-based test for knee osteoarthritis. You know first, what exactly is it detecting and where are you at in its development.
Speaker 2: Thank you. That's it topic near and dear to my heart as you.
Speaker 1: Yes, I do know Yes.
Speaker 2: So we really recognize that clinical trials have a great deal of difficulty enrolling people who are in active state of disease. So if all of the people you're trying to treat aren't really in an active state, you cannot tell if your drug made them any better because they're sort of static. So you really need, when you're enrolling people, to try to pick out the people who are most at risk at that time of active progressing disease, and those are also the people most in need of the treatment at that particular time. So about over a decade ago, we decided that we would try to find specific tests that were protein-based, that would be predictive of osteoarthritis progression, and so we started out with joint fluid in fact. So we had some 159 brave souls who gave us joint fluid, who had neosteoarthritis, and we have delved into those very, very deeply. So we picked out a subset of those who had neosteoarthritis progression over three years And then another subset of those with neosteoarthritis that didn't progress. So we compared the joint fluid of the two and we found a host of proteins that seemed to be indicative of the people who were the progressors. But knowing as we do that people don't like to give joint fluid, we decided that.
Speaker 2: Let's look now in their blood.
Speaker 2: So we had their companion blood and tried to figure out which of the proteins that we saw in their joint fluid were reflected in the amounts in the bloodstream, and so, as you might imagine, not all of them make it into the bloodstream and are useful, but a subset of those were.
Speaker 2: So we had over 100 of those that were measurable in the blood and that gave useful information in the blood, and then, subsequent to that, we took that group or list of high contenders and then we looked at them in a group of 600 people who had a beautiful control that didn't progress, and another group that had pain progression and another group that had x-ray progression and the fourth group that had x-ray and pain progression.
Speaker 2: And we looked to see across those four different groups which of these particular blood markers that we had identified as promising were actually predictive of progression in this cohort, and what we found was that as few as 11 blood proteins could predict the risk of knee x-ray worsening over the subsequent two to four years, and only 10 were needed to predict pain worsening. And there's one protein that is of great interest, called Cargillage Acidic Protein 1, or Crack 1, that predicted both x-ray and pain progression, and since then there have been a number of studies now that have also corroborated that particular protein as being really informative, and there was an earlier study in 2021 from the Netherlands that found that that particular protein predicted the risk of knee or hip replacement 10 years subsequently. So we feel really great about this Great bio markers.
Speaker 1: As you should. This is all very promising sounding. What does this all mean? potentially for treating patients in the clinic as well as studying new therapies in a clinical trial setting? Like what's going to happen when? what can we really expect?
Speaker 2: Well, in the first instance, we think it's going to be of most use for clinical trials, particularly the disease modifying trials that I mentioned, and to determine if a drug is effective by stopping disease progression. But it's also possible that it might be able to be used in the absence of the x-ray or MRI changes in people who have symptoms of their joints, to tell them are you at risk for a trajectory of progression or is this just a nuisance symptom? And the reason I say that there's the promise of that is because we've also taken that list of over 100 proteins and we looked in a cohort of women from the London area 200 women and we found that, low and behold, as few as eight of those bio-markers, including crack, one that we mentioned before, strongly predicted the risk of x-ray development, of x-ray changes eight years later. Wow, that's early. So we think that we may actually be able to inform that pre-x-ray period, you know, when people are having symptoms, not really knowing whether they're something to worry about or not.
Speaker 1: Yeah, that's amazing. Okay, now, last we spoke you mentioned that the volume of osteoarthritis clinical trials has historically ebbed and flowed, based on sort of this excitement disappointment cycle, tied in part to sponsors not having enough of the progressors enrolled to enable study success. Are these trials ebbing or flowing right now, and how do you imagine future clinical studies benefiting from your test and other similar types of biomarker panels so that we might see less of these constant fluctuations?
Speaker 2: Well, i'm really happy to report that the trials are definitely currently flowing. Yay, yes. At the international osteoarthritis meeting that we had of the society called Orsi in March of this year, 12 scientists representing the endeavors of 13 companies presented on promising disease modifying drug development programs for osteoarthritis And it was really exciting, the value of their work. Now I mean some of the better treatment approaches that we've ever seen before. And everyone has taken stock of the fact that if the drug development is used accompanied by a biomarker to help select the patients and help select the drugs as they go along in the development process, their chance of success in the long run is increased markedly. It goes from an 8% chance of success overall up to a 26% chance overall, and this actually is a huge number when it comes to the cost of the endeavor of making a drug.
Speaker 1: This is well recognized at this point, or is this breaking?
Speaker 2: At this point. I think the companies have taken stock of this and everyone is incorporating biomarkers into their programs to try to get corroborating evidence that they're seeing something, not just changing a symptom, but they're really changing the disease process.
Speaker 1: So there's going to be great uptake of your test. How soon?
Speaker 2: Well, we've gotten a few inquiries already and at least one trial is going to incorporate them, and I think that it's just the beginning. I mean, i think that part of what's exciting for us is showing that this paradigm works, and you know I call these the second wave. You know we have already some traditional research use only tests, particularly a urine test, but it does not function as well as this test, and it's possible that this second wave is going to be followed by a third wave at some point, you know, once we get more knowledge, a deeper understanding of the causes of osteoarthritis And I certainly wouldn't be sad if we get something even bigger and better, because ultimately, we really want to make a dent in this terrible disease that now even the FDA recognizes officially since 2018 as a serious condition a serious disease.
Speaker 1: That's interesting in the fact that you're an MD. I believe treating, doing surgery on the knees of actual patients has to change your perspective on all this and give you a passion that perhaps investigators not in the same position would not have. True.
Speaker 2: That's absolutely true, and my father had a single hip replaced three times and with each successive one, you know, it worked less and less well. And having been through that and seeing someone who was very active, who actually got this as an injury in Vietnam, that you know to ultimately believe that maybe as a young man there might have been something different that could be done someday for all the other young men who are in similar situations. I would be absolutely delighted if in my career, i could contribute to that type of success.
Speaker 1: Well, that actually brings me to my next question, which was about osteoarthritis. You know can affect, obviously, any joint in the body you just mentioned, you know, the knees in addition to the, i mean the hips in addition to the knee, and also small joints in the hands. Does this proteomic panel have, then, potential utility in all these other areas?
Speaker 2: Some of these protein components, particularly many of them are. They reflect inflammation and show definitively that this condition, that when it's active, has a low grade inflammatory component. Many of these components are common to different joints across the body. But I like to think that it's also an opportunity, because there are some proteins that are very different. I say not all cartilages created equal. There are some tremendous differences across different cartilages in different parts of the body. It makes sense now in retrospect that you know you have different joints doing different jobs, so they are somewhat different. But until recently people thought the while it's all the same, cartilage is cartilage but it's not. We think that there will be some that are common that might give us sort of an overall burden of disease, so the level could reflect overall osteoarthritis. But some might actually be specific for the hip, some might be actually very specific for the ankle, for instance, so we might be able to go after hand specific biomarkers and so that's sort of maybe part of that wave three that I mentioned.
Speaker 1: That you'll definitely be a part of. You're not abandoning this, this line of research, anytime soon, i'm sure By no means. Okay, well, certainly many patients stand to gain from your long time of labor of love, dr Krauss, and I am sure a clinical trial sponsors working on next generation drug treatments will be welcoming of anything that can help them better select patients for studies to break the current log jam and getting useful therapies to market. Thank you for being a guest on the show today and doing your part to lead medicine to a better tomorrow.
Speaker 2: It is my pleasure. Thank you so much for the invitation.
Speaker 1: You are so welcome and, as always, a big thank you to everyone out there for listening in. If you're not subscribed to this podcast yet, please consider going to Apple podcasts and doing so right now so you don't miss your monthly dose of news and perspectives. You'll be hard pressed to find anywhere else And if you're up for it, i'd be so very grateful if you believe a rating and review on Apple podcast. To one final note, if you like today's conversation, it is only a glimpse of what you can expect from presenters and panelists we have on tap for CHI's summit for clinical ops executives Europe, aka scope Europe. Please plan to join us October 17th and 18th in Barcelona, spain, and be sure to use discount code SOT 10 for a 10% discount off any current rate. For more information, visit scope summit Europe dot com. Bye for now.