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Stanley Cohen, MD: Hello. I'm Dr Stan Cohen. Welcome to Medscape's InDiscussion series on psoriatic arthritis. Today we'll be discussing basic science advances in psoriatic arthritis (PsA). I'm very pleased today to have an old friend and colleague here, Christopher Ritchlin. Dr Ritchlin is a professor at the University of Rochester Medical Center and director of the Clinical Immunology Research Unit. His basic science research efforts are directed toward understanding the mechanisms that underlie pathologic bone resorption and new bone formation in both PsA and RA (RA). Chris, welcome to InDiscussion.
Christopher T. Ritchlin, MD, MPH: It's a pleasure to be here and to be here with you.
Cohen: Tell me a little bit about how did you get interested in PsA? What was the genesis of the results of what you developed — a wonderful lab and contributions to the field. What pulled you in that direction?
Ritchlin: I decided in my second year of my fellowship at NYU that I wanted to learn how to do molecular biology because I thought that was the future. This was back in late 1980s. I went into Bob Winchester's lab and studied the basic mechanisms that underlie RA and was working on developing transcriptional profiles of RA. This is way before modern transcriptomic abilities, and we focused on rheumatoid synovial tissue.
When I moved to Rochester, I decided that RA was a pretty busy field, but no one was looking at PsA. Those were some of the most fascinating patients I saw as a fellow. I called Dafna Gladman, who's across the lake, in Toronto, and she almost jumped out of the phone when she saw a young person was interested in PsA. I started collecting samples from the surgeons, and that's how I got my career started. A grant from the National Psoriasis Foundation got me started off and I never looked back.
Cohen: It's been an interesting evolution through our careers. I'm a little older than you, but in the beginning with Verna Wright and other people, I think about how little we knew about the other types of arthritis out there. It was all lumped together as rheumatoid disease initially. We've obviously come a long way.
Tell me what your lab has been working on over the past several years. What's been your primary interest? Then I'm going to push you to teach me a bit about the risk of developing PsA.
Ritchlin: For many years, we've focused on the mechanisms that underlie, as you've mentioned in the opening, the destruction of bone by osteoclasts and the link between what's happening with the resorption. As we all know, patients with PsA can develop new bone formation both in the axial skeleton and the peripheral joints. We focused on dendritic cell–specific transmembrane protein (DC-STAMP), which is a molecule that's expressed by monocytes and is required for cell-cell fusion to make that multinucleated osteoclast. We found that DC-STAMP expressed in the cell surface of these osteoclast precursors, which are monocytes destined to become osteoclasts, was a marker of these cells and was the first marker that had been identified. We worked for several years with that, using it as a biomarker of severity and response.
More recently, we wanted to find a mouse model that would capture what's happening in human disease. We turned to a humanized mouse model; this is a mouse model that's used in cancer. The mouse has no mouse T cells or B cells, and it's got a number of human growth factors that it overexpresses that allows human tissue or cells to engraft on the mouse.
One of the PhDs in my lab said, "Dr Ritchlin, why don't we see if we inject the blood cells and the sera from patients with PsA and psoriasis and see if these mice develop psoriasis and arthritis?" I was skeptical, but lo and behold, she was right. These mice develop psoriasis; if they have psoriasis, they develop psoriasis and PsA. Most importantly, the phenotype of the mouse mirrors the phenotype of the patient. If the patient has dactylitis, the mouse gets dactylitis. If the patient has psoriatic erosive arthritis, the mouse gets erosive arthritis. We can go back in, Stan, and pull those human cells out of the joint, or out of the skin, or out of the blood, and then study them and figure out what kind of chemokines they're making, what kind of cytokines, what they're expressing on their cell surface, looking at the transcriptome of these cells.
That's what we're doing now. The idea is that we can also look at patients who are nonresponders, for example, to anti–tumor necrosis factor (TNF) agents, and take the cells from them, put them in the mouse, and find out why are they nonresponders — what are their cells making that's different than the ones that are responders. You talk about precision medicine; this is a way for us to maybe do that, and we're pretty excited about this model.
Cohen: What an incredible model. With a nonimmunology background, you've got the opportunity to see what's going on. The fact that these mice develop the phenotype of the cells that are put in them is just incredible. That should be a goldmine to investigate. That'll keep you busy forever.
Ritchlin: Yes, that's true, Stan, at least until Alabama wins their next football game.
Cohen: Hopefully longer than that. That's fascinating and should provide us a lot of insight into pathogenesis of the disease, resistance and so forth. Congratulations, that's wonderful.
In RA, we've been interested in coming up with a definition, which we don't really have, of what is preclinical RA or pre-RA. In PsA, we have a model where we know that frequently, psoriasis is present for many years before someone develops PsA. We'll take the easy part first, the clinical part, the phenotype features. What features in a patient with psoriasis may increase their risk of developing PsA down the road?
Ritchlin: This is an active area of investigation for a number of different groups, many of us working together. Lihi Eder in Toronto, Jose Scher at NYU, Alexis Ogdie-Beatty at Penn. There are several risk factors that seem to increase the likelihood of a patient with psoriasis developing PsA. Where psoriasis is a biomarker of PsA — and about one third of patients with psoriasis will develop arthritis over time — usually the psoriasis precedes the arthritis. Nail pitting, inverse psoriasis, and the severity of psoriasis are factors, as is family history of psoriasis in PsA. When you put them all together in a multi-regression model, they are not all that predictive. Lihi Eder is developing a tool called Prediction of Psoriatic Arthritis Tool (PRESTO), which puts these together and has a reasonable area under the curve, but it's still not great.
What we've been working on is performing ultrasounds in patients with psoriasis with no musculoskeletal symptoms. In a paper that we're going to be submitting shortly and that we presented at an American College of Rheumatology (ACR) meeting, we found that patients that had ultrasound abnormalities on their joints without musculoskeletal symptoms, compared with those who did not have psoriasis, were more likely to develop arthritis. We now have a trial where we are recruiting patients with psoriasis with no joint pain. In that trial, patients that meet an ultrasound threshold, which we previously determined, are randomized to receive either guselkumab, an interleukin (IL)–23 inhibitor, or placebo. Then we have a third observational group composed of patients with psoriasis who are not going to take any systemic medications, with two primary outcomes: the change in the ultrasound score at 6 months vs placebo and the guselkumab (Tremfya) group, and the development of PsA, with the hypothesis that IL-23 blockade will either delay or prevent the onset of PsA. This study has been going for about 6 months, and we're going to go for another couple of years and we'll have some answers, I hope.
Cohen: Before we move on, why did you pick IL-23? I know there was a recent paper — I think it was more of a retrospective analysis — looking at patients progressing that suggested that IL-23 might have some type of benefit in preventing the development of PsA. Is that why you went with IL-23? Why not IL-17 or something else?
Ritchlin: I'm aware of that paper. In fact, the editorial was written by Alexis Ogdie-Beatty and Jose Scher, part of our group. The problem with the approach that was taken is that when you look at administrative databases (and they bring this out beautifully in their editorial), there are a number of biases that are involved in the coding of the patient and the timing of the drug. That makes this kind of approach almost impossible to reliably tell you whether or not treatment of a patient with a drug will prevent the onset of arthritis. There have been four studies on this in the past year. Alexis Ogdie-Beatty did one of them (we were participants in that), and because of how she designed her model, it really geared the outcome because of these different biases. That's why we designed the prospective trial. When it comes to why we selected IL-23 inhibition, IL-23 is the executive that sits in a top office on the 20th floor. It's directing downstream events, and we think is really critical in inducing psoriasis and PsA. We think that by blocking that cytokine, we can inhibit the early phases of arthritis and that may have an impact, or might even prevent the onset of joint disease. That is based on studies that have been performed in vitro and in animal models, but I think most rheumatologists and dermatologists are pretty convinced that IL-23 is very critical in the early stages of the arthritic process.
Cohen: That's intriguing, and I look forward to seeing what the results are.
Are you having ease in recruiting patients — are patients willing to do it? IL-23 is such a wonderful treatment for skin disease. These days, in our clinical research efforts, it's always a struggle to recruit patients. I was just curious about how things are going as far as recruitment.
Ritchlin: In Rochester, we're going gangbusters. In our current medical system, it's good. It's often difficult for patients with psoriasis to get medications like this because of insurance obstacles. In 6 months, we've been able to recruit about 12 patients at my site alone. NYU is doing well, and the other sites are coming along. We're going to add a couple more sites. As you know, we're going to have 350 patients recruited, and that's a lot.
Cohen: That's fascinating. So you did ultrasound on these folks, and you found some who had power Doppler changes or grayscale changes and so forth. One of the discussions we're having in RA is about whether it's already RA, or it's already PsA because they have ultrasound changes. Is that really pre-disease? I think it's very important that we come up with a unifying diagnosis, which we all agree on, because without that, all of the studies are going to have different outcomes and different phenotypes involved.
Lastly, what we all hope for is that we will have therapies that will blunt the effect, or reduce the number of patients who go on to develop active disease. You'll never get it paid for unless you have regulatory approval, and you're only going to get regulatory approval if you have a unified diagnosis. Certainly the ACR and the European Alliance of Associations for Rheumatology (EULAR) are working on trying to come up with the appropriate nomenclature for what pre-disease really is.
Ritchlin: We published a paper in Nature Reviews Rheumatology last year about this, where we basically did a Delphi consensus study and put together nomenclature for psoriatic disease. For us, the patient can't have any joint symptoms. We're very clear about that. If you have joint symptoms, you are not going to be in our study. I think part of the problem is not with Kevin Deane and Mike Holers' work, but with some of the European studies, like the ARIAA study. Those patients, they have stuff going on; they have severe arthralgias. My own bias — and it's totally a bias — is that by then, the horse might be out of the barn. That's why we're trying to get patients who are truly asymptomatic. They do have some imaging things, which are mild, but we couldn't clinically call them PsA because they don't have joint pain. I'm hoping that might give us a leg up, but we'll have to see.
Cohen: It's been very interesting in clinical trials in PsA. We've got a number of phenomenal medications for our patients now, and we're still having clinical trials with new therapies. To this day it still amazes me — and you can speak to it because your interest has been in bone resorption and bone formation — that the US Food and Drug Administration (FDA) still requires radiographic outcome studies in PsA. Generally in the trials, about two thirds of the patients are on background therapy, usually methotrexate. We struggle to find patients who have radiographic damage to be included in the study. Things have changed over the years. We used to see it, not to the degree that we saw in RA. What are your thoughts about that? When you're developing a new therapy for PsA, how necessary do you think it is that a claim of structural protection is pursued?
Ritchlin: Like you, I'm part of the era where when we started biologics with Phil Mease's etanercept trial in 2000. We had had a barn full of patients who had severe erosive disease with PsA, and it was easy to find those patients. Now, it's really challenging because most patients are treated pretty aggressively early on, and you don't see that kind of a phenotype very often. I haven't seen arthritis mutilans in years. Because of that, fewer and fewer sites in the United States can find these patients, and so the companies are going to Eastern Europe and other places where the patients are unable to get biologics. I think it's a real problem. I know we struggle with the trials now. Even to have C-reactive protein (CRP) as a requirement cuts down recruitment by up to two thirds. We may be not testing great medicines because you can't recruit based on these kind of entry criteria. I agree with you — I think that the radiology bar is something that is historical and is causing problems for recruiting into trials now, and probably isn't all that meaningful.
Cohen: I see more and more dermatologists talking about combination therapy. I don't know how they get combination therapy paid for at times. What's your perspective on combinations, whether it be biologic therapy or apremilast and other IL-23, IL-17, and TNF inhibitors? What kind of experience do you have in Rochester? How often do you use combination biologics or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in patients who might have more refractory disease?
Ritchlin: We see a lot of refractory disease. We use apremilast and biologics pretty frequently. Jose and I worked with Janssen to design a trial, and we now have a trial, in which patients with PsA in whom one anti-TNF agent fails are going to be randomized to golimumab, another TNF, with guselkumab vs guselkumab alone. That trial is up and running around the world. It's based on the VEGA trial, which was a similar design done in ulcerative colitis. The results from that study show that there were no increased safety signals in the group that received combination therapy with anti–IL-23 and an anti-TNF agent, and they had better healing and better responses. With those results, we were able to go ahead with our study.
I think personally that the combination biologics are going to be a big wave of the future, and primarily, Stan, because of data that were shown at this ACR meeting from several different countries. The longevity of an anti-TNF agent in PsA is a matter of a year or two. When patients switch to other agents, rapidly within a very short period of time, you have secondary nonresponse. Patients are cycling through these agents very rapidly. We're now running into situations where, despite the fact that 15 drugs have been approved by the FDA for PsA, we have patients who are not responding. I think that combinations are something we need to look at carefully. I can't predict the future and how well this will go, but I suspect that it will be a very good way to treat this disease because of the multiple domains of involvement that patients have.
Cohen: That's very interesting and exciting. The old guys like me still have our concerns back from the days of anakinra, etanercept, abatacept, and TNF inhibitors, but you're right: There are multiple domains and multiple cytokines and it's a little younger population, even though they have their own slew of comorbidities. We all have patients with refractory disease, and we need to know how to handle it.
This has been very helpful, Chris. You've got a lot going on. I hope you have some time to relax, but the studies that you have designed with your colleagues are exciting and we look forward to the results. So thanks for spending a few minutes with me today.
Ritchlin: Thank you, Stan, I enjoyed it.
Cohen: Today we talked about basic research efforts and exciting clinical trials that are ongoing that Dr Ritchlin is involved with. I want to thank everyone for joining us. This is Dr Stan Cohen for InDiscussion.
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Resources
DC-STAMP: A Key Regulator in Osteoclast Differentiation
Tumor Necrosis Factor Inhibitors
Prevention of Psoriatic Arthritis: The Next Frontier
Ultrasound Power Doppler and Gray Scale Joint Inflammation: What They Reveal in Rheumatoid Arthritis
Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift
Etanercept in the Treatment of Psoriatic Arthritis and Psoriasis: A Randomised Trial
Disease Modifying Anti-Rheumatic Drugs (DMARD)
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Cite this: Breakthroughs in Basic Research for Psoriatic Arthritis - Medscape - Apr 25, 2023.
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