'Progress Towards Identifying a Psoriatic Arthritis Diagnostic Test' Transcript

0:23 EPISODE INTRODUCTION by moderator Jeff: Hi, my name is Jeff Brown and I’m here today with rheumatologist and clinician scientist Dr. Vinod Chandran with the Gladman Krembil Psoriatic Arthritis Program, Schroeder Arthritis Institute, University Health Network and the Departments of Medicine, Laboratory Medicine and Pathobiology, and the Institute of Medical Science at the University of Toronto for the latest update on the research to find a psoriatic arthritis diagnostic test. So welcome Dr. Chandran. Thank you for being here. As someone who has psoriatic arthritis, this is definitely a topic of interest for me since it took a few years for me to be diagnosed and I've heard diagnostic delays for PsA are common with an estimated 15.5 % of people with psoriasis being undiagnosed with PsA. Why is it so difficult to diagnose psoriatic arthritis?

1:15 Dr. Chandran: Thank you, Jeff. Yes, that's an important question. Psoriatic arthritis is what we say a heterogeneous or a disease with varying manifestations. So, a patient with psoriasis, and sometimes even before the onset of psoriasis, could develop pain. And this pain is usually in and around joints, but also can affect the back, the hands, the joints in the lower extremities, so the feet, knees for example. It could affect the chest wall. So the pain can affect wherever there are joints and wherever there is an attachment of ligament or tendons. So tendons are structures that attach muscles to the bones and ligaments are structures that attach bones together. So these are sites where there is pressure, biomechanical stress, and those sites could get inflamed. Now, unless you're aware of these manifestations or have a family member, or you might not recognize as this being arthritis, an inflammation. If you have significant psoriasis, you might think that the psoriasis itself is causing these manifestations. And so, one of the reasons for the lack of early diagnosis is that the person experiencing these symptoms may not think it will be significant. “Oh, I'm just getting old”. And as you know, many patients with psoriasis are also obese and they'll think, “oh well, it's my body weight that is causing these issues. And so I need to lose weight or exercise”, which is good, but may delay the diagnosis. But if it becomes increasingly problematic, then you'll be talking to your healthcare provider.

2:50 Jeff: What factors impact the delay in the diagnosis process?

2:54 Dr. Chandran: Unfortunately, the knowledge about psoriasis and all its comorbidities is not there. It's getting better over the last couple of decades, but still not there. It's not on top of mind for a busy primary care provider. And so you say, “well, I got psoriasis, okay, and I have some joint pain”. Once again, there might not be careful evaluations to see is this just regular or non-specific pain or is it inflammatory? And then because if there is a suspicion, then you would probably be sent to a rheumatologist for assessment or the primary care might be sending to a dermatologist. Now increasingly dermatologists recognize it. Previously, they were not, and therefore there was a larger proportion of undiagnosed patients with psoriatic arthritis in their clinics. Now, it is better, and since all the drugs have differential effect on skin versus joints, many dermatologists are also trying to get that joint assessed even if there are no symptoms or if there are some minor symptoms. And so as you can see, at each stage of the journey towards the diagnosis, there could be delays because it's not a straight path – “oh yeah, I have joint pain. I need to see a rheumatologist”. There is the nonspecific symptoms and the various care pathways that are required to get to a rheumatologist might delay the diagnosis. And by the time you see a rheumatologist, there might already be joint damage. There is some research from Ireland saying that even a six month delay is a problem, right? And so six months is not a long time if you think about it. So these are issues that we are all, the system level we need to tackle. And that's where patient organizations getting it to the community that “Hey, if it's psoriasis and if you have joint pain, don't assume it's just age or “arthritis”. It could be psoriatic arthritis. So that's from a patient organization and family members. And then from dermatologists and primary care and even rheumatologists is like, hey, when somebody has joint pains with psoriasis, think of psoriatic arthritis. Get the appropriate assessment done is another important aspect. So we need to work on both ends to diagnose early and improve outcomes.

4:56 Jeff: I can relate to a lot of those symptoms and not putting it together. I thought I was just injuring myself from bad running shoes. So recognizing some of the issues you just discussed, in 2019, the National Psoriasis Foundation made a commitment to invest research funding towards identifying a psoriatic arthritis diagnostic test. NPF identified a need to test for, predict, and reliably diagnose PsA to impact the outcomes of the disease progression. Dr. Chandran, you were one of six initial grants awarded in the first year of the PsA Diagnostic Test Grant Project, which NPF was able to fund thanks to donors. What drew you to this research request?

5:36 Dr. Chandran: So my research has been focused in psoriatic arthritis for many years now. After my training in rheumatology in India, I moved to Canada to further study psoriatic arthritis for a dedicated clinical fellowship. So that began in late 2004. And as I got really excited with the disease and the possibilities, you might recall that that's around the time when all the new treatments were coming. There's clear recognition that this disease is under recognized. I went ahead to do my PhD in psoriatic arthritis and psoriasis, looking mostly at genetic markers. And so I was already primed for this, right? After I finished my PhD, I joined as faculty here at the University of Toronto and continued work and shifted from more of a genetic research because my interest wasn't trying to distinguish psoriatic arthritis from psoriasis. And to me, it was evident that the genes are not going to be the solution. We needed what we call functional norms, so things that can change over time, proteins, metabolites, microRNAs and mRNAs. And so I started focusing more on those markers, recognizing that it's going to be difficult to find a diagnostic test. I initially spent more time in identifying protein markers because in many diagnostic laboratories, proteins are the things that we test, the acute phase reactants that we test, and I thought we could try to find some markers that would help. But quickly realized that you probably needed something more. The omics field was maturing very well at that point, and so I was quite interested in multi-omic data sets, mainly to understand the disease -- what are the pathways that are different between psoriatic arthritis and psoriasis? But when the NPF came up with this proposal, I which is to diagnostic test, which is one step more than just understanding pathways, I thought it was a great opportunity to apply some of the learnings that I had through my PhD and early career as an early investigator to see if we can actually work towards developing a diagnostic test with a lot of skepticism inside me, given that the disease is quite heterogeneous, but said, well, if we don't do it, nobody else is going to do it. And NPF is a great supporter so let's try to find something.

7:55 Jeff: Can you please explain what you mean by multi-omic?

7:59 Dr. Chandran: Omics is meant to indicate method where you look at the entire spectrum of variation of a particular molecule in a given system. So, when we look at genes, we look at genetic variations across the whole genome. That's genomics. If we look at the DNA , the gene produces RNA, and we are particularly interested in the mRNA. And so if you look at in a tissue, in the skin, in an animal model, if you look at all the mRNA variations in that particular system, we call that (it's part of the genomics) we’re talking about RNA omics. Similarly, if you look at all proteins in a system, it's proteomics. If you look at all metabolites, small molecules in systems, it is metabolomics. So these are the various different layers of omics that you can investigate. And until recently, and even now, researchers are focusing on one omics or the other. But these omics are related to each other biologically. So a multi-omic approach is saying, okay, let's not just look at the genomics or the transcriptomics or the proteomics or the metabolites. Let's look at all of them, look at the relationship between these different layers and identify mainly pathways and biomarkers that tells us a story and integrates all the information from these different layers which happen, in a system, right? The genomic information, you look at DNA, that's generally stable, so that doesn't really change much with time. So you're born with it and there is very little change over time. You can have heritable variations in the DNA, the epigenome, that changes over time. We can look at that. There is a lot more variation probably in the mRNA and more in the proteins with also post-translational modification and a lot in the metabolites. So when you go down this list, you can see some things are stable, some things are very variable across patients, across time, across treatments, et cetera.

9:57 Jeff: And how does that relate to psoriatic arthritis?

10:00 Dr. Chandran: In a disease that is dynamic like psoriatic arthritis, we can take this multi-omic approach, look at different time points to understand what is happening in the human biology, pathophysiology, and how that impacts the patient, how the patient feels, and outcomes that are happening like joint damage or cardiovascular disease. So we have taken this approach. The challenge, of course, is that we have quite a lot of data per patient. So we have, say, one patient can give you gigabytes of data if you look at all the multiple. And then you have, at one time point, then you have multiple time points, you have a lot more data. So it's a data problem. Less number of patients, lots of data. So how do we really find things of significance in this massive data? And that's where we work with bioinformaticians and data scientists as well as biostatisticians to kind of pick out the signals from all the noise that is there in what happens in everybody's everyday life. So a multi-omic approach is supposed to look at it in a holistic way and then narrow down to what is likely going to help you understand the disease better and hopefully find biomarkers.

11:08 Jeff: That's really helpful, thank you. So how did your efforts differ from the other five grant recipients? And how do you think these projects move the bar towards a greater understanding of psoriatic arthritis?

11:20 Dr. Chandran: I am not fully aware of all the work that others have done. They're all doing great work, very different approaches. My focus from a clinical perspective, was to identify patients with psoriasis who already have psoriatic arthritis. So not in the future, but now. Other groups looked at OK, you have psoriasis now, but what is the risk of getting psoriatic arthritis in the future? Could you predict that now before you actually have it and therefore have an intervention that might prevent that from happening. Which is important because prevention like everybody says, prevention is better than cure, right? So that's one approach. And then because identifying arthritis as well as other manifestations is based on physical examination and some of the imaging tools which are cumbersome and hard to look at the whole patient. Some of the methods I understand looked at imaging where you could scan the whole body to figure out where there is active inflammation. So very different approaches, complementary. And most of them used one omic or other technology where we went in a manner where we thought it’ll be better to evaluate all the different technologies to see what works. And that's why we took a multi-omic approach. But, end of the day, the test would have to be based on one type of assay. So as I said, we’re really think looking at gene expression as what is providing us with the most consistent results. So we did all the other assays and multi-omics, but at end of the day, we're coming to one technology looking at gene expression. So that's one type of assay, right? So our approach in that way started very broad and then narrowed it down. And we didn't test a lot of patients because these are tests that are expensive and we are trying to molecularly characterize smaller number of patients. But now once we have come to a state where we say, OK this test works in our population and some of the data that we can see in the public domain, now we have to actually test it prospectively. Patients being referred from dermatology, from primary care, from rheumatology to say in these different referral populations, as well as other centers, how our test is working. And that's a lot of work and obviously we spend a lot of time, but these next steps are again really very important to figure out if this test is actually going to work. We think it's going to be cost effective based on our modeling. Is it actually true? And is it actually making a difference, is there a clinical utility?

13:46 Jeff: Dr. Chandran, what results from your initial efforts in that first year stood out to influence your research moving forward, which NPF has continued to support?

13:55 Dr. Chandran: So the grant project was for a five year grant and the initial couple of years there was problems because of the pandemic happened around the same time. The first year or so was to see if the approach works. So initially, the NPF supported, I think, six groups, and then the next few years was for two research groups. And so we worked initially with this multi-omic approach to see if we could find a signal and if it's working or not. So the exciting part, the early part of the research was that, yes, we found that about 200 markers across different omic approaches. When you combined it could strongly separate psoriatic arthritis from psoriasis. So that was very encouraging. So that's what we had proposed to the NPF for the second phase. And the NPF liked that approach and funded the next phase where we then narrowed it down to what I mentioned earlier into the mRNA test. But the initial excitement was the results that if you had 200 or so markers we could reliably distinguish psoriatic arthritis from psoriasis.

14:58 Jeff: That's really interesting. So it sounds like you identified some key biomarkers that could indicate the potential development of psoriatic arthritis in someone with psoriasis. How important is messenger RNA or mRNA and microRNA to identify a PsA signature?

15:16 Dr. Chandran: So biomarkers such as mRNA and microRNA have been identified for other diseases and so we were encouraged. Particularly microRNAs have become increasingly popular. They're quite stable and can be relatively easily tested. But in our earlier analysis, we found that the mRNA signature was better than the microRNA. We had some challenges in doing the assays reliably when we asked external vendors to run the samples for us, reliable ones. When we asked external vendors to run these samples, the results that we got were not very encouraging. There was a lot of variability, so especially with the microRNAs. So we therefore decided to stick to mRNAs. MRNAs are not commonly used as a diagnostic test, but it is increasingly becoming common. So I think we could also use this technology to look at arthritis, psoriatic arthritis. We investigated different technologies to evaluate mRNAs. We found mRNA sequencing to be the most reliable. And when talking to major laboratories in Canada, they all recommended that we use mRNA sequencing for our tests because most laboratories, if not now or within the next few years, would have a sequencing machine. Other technologies would have to be implemented in the lab and may not be available. And therefore, for the wide dissemination of such a test, we would get into challenges. So based on the performance of these assays in our lab, plus the recommendation of various clinical laboratories, we decided to focus on mRNAs as a diagnostic test. And obviously, we need to do further testing in a prospective cohort. But I think that's a way to go forward so that the test once available can be disseminated to most laboratories worldwide.

17:08 Jeff: Thank you for that. I know personally as a patient who experienced a delayed diagnosis, I would have appreciated the opportunity to have been diagnosed earlier in my own disease. What will earlier identification of PsA mean for long-term outcomes and risk of developing the disease?

17:24 Dr. Chandran: So in most patients, psoriatic arthritis develops after the onset of psoriasis. In about 10%, maybe 15% it develops earlier. We don't really have a test for that. And so if you develop joint pain, you need to be evaluated. Our focus has been in patients with psoriasis who develop joint pain in the future. The question is, once you have a diagnosis of psoriasis, are you more or less likely to get psoriatic arthritis in the future? Is there a test for that at the moment? No, but that's what a lot of investigations, investigators are working on. And there is research now recently published where they say that there are some changes, cells in the skin that migrate to the joints and there are some cells in the joints that prevent the arthritis and if those cells are not there then you’re more likely to get arthritis, right? So this has been shown in animal models and as well as some human studies. So there is really a skin joint axis and the challenge is to identify those patients who are at risk of this axis to get activated and get arthritis. Our focus was at the next stage where there is something going on in the joints and is that psoriatic arthritis or other forms of joint pain, osteoarthritis most commonly. For the listeners, osteoarthritis is the most common form of arthritis. It's not considered to be very inflammatory. So there's mild inflammation, but not severely inflamed. It's a slow progressive arthritis, which is common in the population. What we are trying to do is to distinguish psoriatic arthritis from other forms of arthritis and osteoarthritis is the most common. The challenge is that the joints that affect osteoarthritis and the joints affected by psoriatic arthritis are very similar and biomechanical stress plays a major role. So a big challenge is trying to differentiate, is it OA (osteoarthritis) or is it psoriatic arthritis? And our diagnostic tests hopefully will help in making that distinction. We have also other projects where we are trying to distinguish psoriatic arthritis from osteoarthritis. The important thing is that when symptoms are present, we need to make the diagnosis as soon as possible, ideally within six months. If not, the joints are more likely to be persistently inflamed, and that leads to significant joint damage. So if you do x-rays or other imaging, you can find more loss of bone and cartilage. And also, that delay might make the drugs that are useful for treating this condition less effective. And ultimately, physical activity, function gets significantly impacted, so your quality of life and physical function becomes impaired. And so idea of a diagnostic test is that you have these symptoms and psoriasis, you need a tool to try to distinguish it from other forms of arthritis. And if it is psoriatic arthritis, start treatment to get it under control as soon as possible.