Advancements in the Pathophysiology of Psoriatic Arthritis

Disclaimer (00:00 – 00:24)

• This is an educational program sponsored by UCB
• The information contained within this podcast is for your educational purposes only and is not intended to be medical advice
• The guest speakers have been compensated for the presentation of this educational information
• Healthcare providers should exercise their professional judgment when treating their own patients

Introduction (00:25 – 01:55)

Dr Christopher Ritchlin

Hello. I want to welcome you to this podcast entitled, Advancements In The Pathophysiology of Psoriatic Arthritis or PsA. The goals of the podcast are to provide an overview of the key advancements in the understanding of the pathobiology of PsA in addition to the molecular mechanisms implicated in the pathogenesis of PsA. I am Christopher Ritchlin. I am a professor of medicine at the University of Rochester Medical School. And I'm in the Department of Rheumatology and the Center for Musculoskeletal Research. My expertise is in the areas of rheumatology and dermatology with a special focus on psoriatic arthritis. We would like to provide a high-level outline of the discussion by calling out that the podcast will focus on epidemiology and progression of PsA, tissue types impacted in PsA, and cell types and molecular mechanisms involved in the pathobiology of PsA. I would like to introduce my guest expert today, Dr. Dominique Baeten. Dominique.

Dr Dominique Baeten

Thank you very much, uh, Chris. Um, happy to be here and work with you on this podcast. My name is Dominique Baeten. I'm a rheumatologist. I worked a long time in academia. I'm still professor of rheumatology at the University of Amsterdam in the Netherlands. About six years ago, I joined UCB Pharma where I'm currently leading the research in immunology and inflammation. My actual title is Head of the Immunology therapeutic area at UCB. Looking forward to the discussion with you, Chris.

Epidemiology and Disease Course of PsA (01:56 – 08:49)

Dr Christopher Ritchlin

Thank you. Dominique, let's talk about epidemiology and disease course of psoriatic arthritis. Approximately 1.5 million adults in the US who have been diagnosed with PsA, and we know that 30% of patients with psoriasis will develop PsA. Could you provide a brief overview of PsA including the disease course and associated comorbidities?

Dr Dominique Baeten

Yes, Chris. Uh, let's maybe start with, rheumatological manifestations. As we all know, psoriatic arthritis can affect the joints, the peripheral joints in different patterns. Sometimes it affects small joints like the hands and the toes, sometimes large joints. Interesting for psoriatic arthritis: it's not only the arthritis itself. Very often, we see also enthesitis occurring in these patients. And in up to 40%, we see, also, axial disease occurring in these patients. Now, the challenge, Chris, in terms of disease course is, when you see a patient early on, it's very, very difficult to predict whether he or she will become polyarticular or more destructive or more bone formation or will get axial disease, yes or no. So predicting that disease course is very difficult.

Now, if we move to the skin, as you indicated, it occurs very often in patients with psoriasis. And in fact, in up to 90% of cases, you have the psoriasis, the skin psoriasis first, and then you develop the arthritis. Very few cases where it's the opposite. So that's a little bit of golden rule in disease course: first the skin, then the joints. And another rule, I suppose, is, it's rare to see pure, axial disease, often you have peripheral and axial disease. Does that fit with your experience, Chris?

Dr Christopher Ritchlin

It does, very much so. I think the holy grail in psoriatic arthritis research right now, as you know, Dominique, is for us to try and develop biomarkers that will help us determine which patients are more likely to get oligoarticular, polyarticular, or erosive disease, or those with bone-forming phenotypes. Moreover, we're working very hard, as were many other groups, to try and find biomarkers, whether that be imaging or serum or other, that will help us determine which psoriasis patients are more likely to develop PsA so that we can intervene early to either attenuate or prevent the onset of arthritis. The other area that's really critical in psoriatic arthritis are comorbidities. Can you describe some of these for us, Dominique?

Dr Dominique Baeten

Sure, let's focus, maybe, on three types of comorbidities. Where I want to start is cardiovascular disease. It's a comorbidity of many of our chronic inflammatory diseases, but also, it's occurring in psoriatic arthritis. And approximately, it's the same as we see in rheumatoid. So I think we can, translate what we've learned in rheumatoid in terms of trying to detect and mitigate risk factors for cardiovascular disease also in our patients with psoriatic arthritis.

Second, psoriatic arthritis belongs to spondyloarthritis, and we have the typical comorbidities of spondyloarthritis. I mentioned two here, uveitis and IBD, or to be more precise, Crohn's Disease and ulcerative colitis. So uveitis occurs in 10 to 20 percent of patients with psoriatic arthritis, and it's approximately the same for IBD.

And then, the third and final comorbidity I want to flag is osteoporosis. It's often one we forget but we need to be mindful of. Of course, it occurs more in post-menopausal women than in other patients, but can also occur in men and at a younger age. So just as for cardiovascular disease, uh, being aware of it, monitoring it, and mitigating the risk factors is quite essential for our patients.

Dr Christopher Ritchlin

Thank you, Dominique. And despite the fact that we've had therapeutic advancements in psoriatic arthritis, there are still unmet needs that exist for our patients with PsA. And because we don't have a biomarker of the disease like we have with rheumatoid arthritis or lupus, diagnosis is really dependent on clinician and patient awareness. And many of our patients, as you know, come from either primary care or dermatology, so there's been a lot of effort to educate them about this disease. And this is vital because we know that early diagnosis can have a major impact on decreasing the impact of the disease on the patient, both short and long term. So, Dominique, could you discuss the genetic features associated with PsA?

Dr Dominique Baeten

Thank you, Chris, fascinating question. Let's start with the most well-known genetic risk factors, which are the association with MHC class 1 molecules. For skin psoriasis, we know, of course, the association with HLA-C*06, which is very strong. We also see that in psoriatic arthritis, but it's lower than in pure skin psoriasis. Even some people suggested that it would be a little bit more protective.

And then, we have the classical HLA-B27 associated with ankylosing spondylitis and other spondyloarthritis which we see also increased in these patients with psoriatic arthritis. Now that's the theory. What does it mean in clinical practice? It's intriguing to see that patients who have HLA-B27 have a much shorter time interval between the skin symptoms and the first joint symptoms, on average, 1 year, whereas patients who have C06 have a much longer interval, up to 10 years. So that indicates that these factors can influence the evolution of skin to joints.

And then, the other aspect is that we know that up to 40% of patients with psoriasis or psoriatic arthritis have a family history of psoriasis or psoriatic arthritis, and there one of the fascinating studies published, I think, a couple of years ago, Chris, was that if you want to predict who, with psoriasis, will develop psoriatic arthritis, that family history of psoriatic arthritis might be important. But if I recollect correctly, Chris, I'm not sure this data had been reproduced in other cohorts.

Dr Christopher Ritchlin

Yes. This is such an important question. You know, there are these risk factors that have been identified: scalp psoriasis, nail disease, severity of psoriasis, and of course, family history, as you appropriately pointed out. I think, though, when you put this in a multivariate model to calculate the likelihood of PsA, we're still far from achieving that goal.

The other point that I wanna make is about the interval that you mentioned between the onset of skin and joint disease. Recent data from two registries indicate that older age of onset of psoriasis is associated with a shorter interval to development of PsA, which is kind of surprising, but an interesting finding, and one that, I think, we have to keep in mind.

Impact of PsA on Specific Tissues (08:50 – 12:44)

Dr Christopher Ritchlin

Dominique, let's now turn to the impact of PsA on specific tissues. We know that systemic inflammation localized at various sites throughout the body, including the skin and joints, leads to different manifestations of PsA. Can you discuss how inflammation impacts specific tissues resulting in the clinical manifestations you discussed earlier?

Dr Dominique Baeten

Sure, Chris, let's start, maybe, with the skin because that's the organ where we can most easily take biopsies and describe exactly what we see. When you do that in patients with psoriatic arthritis, you see the prototypical lesions of psoriasis. So that includes hyperproliferation of the keratinocytes leading to skin thickening and then leading to plaques. You also see infiltration with different kinds of inflammatory cells including neutrophils in the epidermis and dermis.

The other organ we've studied in quite some detail is the synovial tissue, again, because we're able to take biopsies and study them. Now, there are two aspects here. One, we see a couple of generic features of synovial tissue inflammation such as hyperplasia of the superficial layer of the synovial tissue as we see in rheumatoid as well. But there are also some specific features in psoriatic arthritis. One is the infiltration, again, with neutrophils. And another one to mention is a very pronounced neovascularization of the tissue. So interesting to think then, and we'll come to it later, Chris, what drives these processes.

Now, there are also tissues where we don't know a lot. One is the enthesis, for the simple reason that it's not easy to take biopsies from a human enthesitis. So our information is limited to what we see with imaging like MRI and/or what we can mimic in animal models. And basically, the same holds true for axial disease where we know that we have enthesitis, axial enthesitis. We know we have, also, pronounced osteitis in the spine. That's the pure inflammation part of the story, Chris.

There's another part which is very important, but you are the expert, so I want to ask you the question: how does that relate, then, to structural damage in terms of cartilage, bone erosion, and ultimately, also, bone formation?

Dr Christopher Ritchlin

Thanks, Dominique. The challenge in PsA is that the bone and cartilage disease is complex. So unlike rheumatoid arthritis, which is largely an erosive disease with repair that is not adequate, in psoriatic arthritis, frequently, you have the co-occurrence of bone erosion and new bone formation. And this new bone formation and erosion can occur not only in the peripheral skeleton, but also the axial skeleton. Moreover, uh, as Dennis McGonagle has shown, when you look at the enthesis, you can see areas of erosion, and right adjacent to it, new bone formation, in and around entheseal insertion points. So it's a fascinating process that we're only now beginning to understand. I wondered what your thoughts were on a recent manuscript published by Ursula Fearon and Doug Veale that looked at single-cell transcriptomics in psoriatic synovial tissue and found there to be a very strong presence of B cells.

Dr Dominique Baeten

Correct, Chris. A fascinating paper, if you look at what cells are present in the inflamed synovial tissue, it's a wide variety of inflammatory cells, including B cells. The issue in this type of work is always, then, to translate description to function and to really assess what are these B cells doing there. Are they contributing to the inflammation, and if so, how do they do that?

So it's really fascinating to follow up on that work from the group from Doug Veale and see what the function of these B cells might be.

Dr Christopher Ritchlin

I fully agree. Thanks, Dominique.

Cell Types Involved in the Pathobiology of PsA (12:45 – 16:31)

Dr Christopher Ritchlin

Let's turn to cell types involved in the pathobiology of PsA. As we just discussed, there's an elevated inflammatory burden in the synovial tissue of patients with PsA. This inflammation is driven by both adaptive and innate immune mechanisms. Can you briefly expand upon the types of cells involved in this inflammatory response?

Dr Dominique Baeten

Chris, if I may, I will take a historical perspective here on the cell types. Originally, people have been fascinated by this link with MHC class 1 molecules and therefore assume that they should involve T lymphocytes and especially CD8+, cytotoxic T lymphocytes, however, at the time, and with the techniques we had at the time to identify these CD8 cells and describe what they are, what they do, how they contribute. Then there was another tendency, and it was to look at the absence of autoantibodies, the absence to response to some treatments, suggesting to people that the adaptive immune system may not be that important. And then combined with the features we described previously, Chris, for instance, the neutrophil synovial tissue, the other side of the debate was, "Well, it's these innate cells that are super important." Now, recently, I think we have rebalanced this debate in two very important scientific observations that contribute to that.

First, many scientists have now described a specialized subset of CD8 T cells which are present in tissues. We call these tissue-resident memory T cells. And they have been described in the skin of patients with psoriasis and in the synovial tissue of patients with psoriatic arthritis. These cells do not circulate all the time - they are tissue-resident - but we know sometimes they can recirculate. And some people even suggest that they may originate in the skin and then, later on, recirculate to the joint to cause joint inflammation.

The second recent scientific observation is related to what we call innate lymphoid cells. These are lymphoid cells, but with innate characteristics. And one, uh, very important subset of these cells - we call them ILC3s - are dependent on IL-23 and produce cytokines like IL-17 that may drive inflammation as well. So I think these two observations have rebalanced that debate between acquired immune cells or innate immune cells and forces us to focus on the specific cell subsets that are present in the synovial tissue or the other inflamed tissue in patients with psoriatic arthritis.

Dr Christopher Ritchlin

Dominique that is a great summary of the rebalance of the T lymphocytes and the innate cells and the pathobiology of PsA. One of the more recent manuscripts from David Masopust's Lab who studies T resident memory cells in a number of different settings has found that these T resident memory cells can actually, move out of their tissues and go back to the lymph nodes. Exactly how they do that is not exactly clear, but I think it raises the point that you also mentioned, and that is the possibility that these T resident memory cells could migrate from the skin tissue into the synovium. And I think that's something we're all very interested in trying to determine because that might give us a clue, once again, as to what are the markers in the skin that might tell us which patients could develop arthritis.

Molecular Mechanisms in the Pathobiology of PsA (16:32 – 19:05)

Dr Christopher Ritchlin

Dominique, let's discuss molecular mechanisms and the pathobiology of PsA. As you previously noted, inflammatory cytokines are important in the pathobiology of psoriatic arthritis. Many pro- inflammatory cytokines have been implicated in the pathogenesis of PsA including TNF, IL-17, and IL- 23. Moreover, the IL-17/IL-23 axis, and IL-12/IL-23 axis are important contributors to the inflammatory response. Could you please describe each of these key mechanisms?

Dr Dominique Baeten

Let's start with TNF alpha, Chris. We know TNF alpha for a long time in different diseases including psoriatic arthritis. It's a very strong pro-inflammatory cytokine which is expressed in the inflamed joints and in the inflamed skin of patients with psoriatic arthritis. It's produced by a variety of cells. T cells, innate immune cells, as we discussed, such as macrophages, but even tissue cells can produce it, and it plays a role both in skin and joint inflammation. The second one is IL-6, which is also very strong pro-inflammatory cytokine, which signaling is mediated by JAK1, JAK2. And IL-6 is doing a lot of different things. Between others, it stimulates the activation of Th17 cells and the production and the production of IL-17 in the joints. If we move, then, to IL-12 and IL-23, these are two closely related cytokines. And in fact, they share one subunit we call p40, which is part both of IL-12 and IL-23. The other part of IL-23 which is unique to IL-23 is p19.

Now, we know that IL-12 is mainly important to drive T helper 1 cells, where IL-23 is very important to drive T helper 17 cells. However, let's also not forget, Chris, that there are reports indicating that IL-23 had other activities beyond driving Th17 cells. For instance, it can activate macrophages, and therefore have other downstream effects in the inflammatory cascade in psoriatic arthritis. And then, finally, let's move to the IL-17s. As indicated, both IL-6 and IL-23 can activate Th17 cells to produce IL- 17s.

The Role of IL-17 in PsA (19:05 – 21:32)

Dr Christopher Ritchlin

Dominique, let's talk about the role of IL-17 in PsA. Can you describe the IL-17 biology?

Dr Dominique Baeten

First important comment here, Chris, is, when we discuss IL-17, we discuss a family of cytokines. There are six different family members. And here, IL-17A and IL-17F share a lot of homology between each other. They also form heterodimers and use the same receptor.

Now, both cytokines are produced by Th17 cells, and we discussed before the T cells are critically dependent on IL-23 for their production of IL-17. But both IL-17A and IL-17F are also produced by innate cells like gamma delta T cells and the previously mentioned ILC3. And we discussed also that, in this case, it's not critically dependent on IL-23, but it can be driven by cytokines like IL-18 and IL-1 family members.

Now, once produced, both these cytokines use receptors in a variety of cells, immune cells, and stromal cells, to induce an inflammatory response. It's important to realize here, Chris, that IL-17A and F in itself, in isolation, are not very strong. But when they're in a milieu with other pro-inflammatory cytokines like TNF, then they really lead to a very strong pro-inflammatory response. So they can cooperate with different autocytokines to drive, locally, the inflammation in the joints and in the skin.

Dr Christopher Ritchlin

Thank you, Dominique. Uh, I was under the impression that gamma delta T cells are important in certain psoriatic arthritis animal models, but have they been described in human psoriatic synovium?

Dr Dominique Baeten

A very good point, Chris. Indeed, the role of gamma delta T cells in IL-17 biology is based on animal studies. Which exact cell type, then, contributes in human tissue? Is it ILC3s? Should we consider MAIT cells, other cells? Remains to be further investigated, absolutely. I think the point here is that we should look broader than only T cells, but also these innate lymphoid cells.

Dr Christopher Ritchlin

Fully agree. Thanks.

The IL-23/IL-17 Axis (21:33 – 22:35)

Dr Christopher Ritchlin

Let's discuss another important topic, the IL-23/IL-17 axis in PsA. Dominique, you've mentioned that the IL-17/IL-23 axis is important when discussing what has been learned about the pathobiology of PsA. Could you please provide an overview for us of the IL-17/IL-23 pathway?

Dr Dominique Baeten

Yes, Chris. As discussed, it's very clear that IL-23, which is produced by antigen-presenting cells, including dendritic cells, activates and drives T helper 17 cells and that these cells produce both IL-17A and F, and that both IL-17A and F then synergize with other cytokines to drive both the inflammation and the pathological structural lesion we see in psoriatic arthritis. However, Chris, just as a reminder, we also indicated that IL-17A and F can be produced by a mechanism independent of IL-23, especially by innate lymphoid cells.

Summary (22:36 – 24:33)

Dr Christopher Ritchlin

So, Dominique, to briefly summarize disease mechanisms in PsA, we have discussed that pathways leading to skin, joint, and bone manifestations in PsA are non-linear and very complex. There are interactions between tissue-specific resident cells as well as immune cells of both the adaptive and the innate immune response.

Moreover, complex inflammatory signaling cascades induce inflammation that result in bone remodeling and synovitis, and also, as you discussed, enthesitis.

So, Dominique, this has been a really great discussion on the pathobiology of PsA. We are now in an era where we're gonna be able to really interrogate cell-cell interactions through really novel technologies including spatial transcriptomics and single-cell RNA-seq. And I know that in the next few years, we're gonna have a much greater understanding of the key events that underlie synovitis and, of course, psoriasis in the skin as well. And so what are your thoughts, and final conclusion about this important topic?

Dr Dominique Baeten

Yes, Chris. This has been a really interesting journey. Not only today, in this podcast, but I think for you and me over the last 25 years. We've learned a lot, but we've mainly learned a lot of the complexity of this disease. Different tissues affected; different cells contributing; different pro-inflammatory cytokines all playing their role. So yes, much more to discover in the next couple of years. Fortunately, better and better technologies to discover it. So I think we've only lived part of the journey, Chris, and I'm looking forward to the second part.

Dr Christopher Ritchlin

Yes, Dominique. I'm also looking forward to the next 25 years. And I want to thank you, and I want to thank the listeners.