Which Comes First – Cardiovascular Disease or Psoriasis?

Guy: Hello and welcome to Psound Bytes™. My name is Dr. Guy Eakin and I'll be your moderator for this episode of the National Psoriasis Foundation Psound Bytes podcast. So we're going to speak today about a health issue that's relevant to everyone who has psoriasis or psoriatic arthritis. We're going to be talking about cardiovascular disease. By way of introduction, I am the Chief Scientific and Medical Officer at the National Psoriasis Foundation and I have the pleasure of working with a number of world-renowned health care providers and researchers who are leading the way towards a greater understanding of psoriatic disease and that includes related health issues. All this with the goal of development of clinical behaviors that ultimately improve health outcomes for people with psoriatic disease. Joining me today is a renowned dermatologist, Dr. Joel Gelfand. He is the James J Leyden Professor of Dermatology and Epidemiology at the University of Pennsylvania's Perelman School of Medicine. There he's directing the Psoriasis and Phototherapy Treatment Center, and he holds the title of Vice Chair of Clinical Research and the Medical Director of the Center for Clinical Sciences in Dermatology. Dr. Gelfand is also a member of the National Psoriasis Foundation Scientific Advisory Committee and, for over two decades, Dr. Gelfand has been involved in research identifying the connection between cardiovascular risks and psoriatic disease. He's currently leading the NPF-funded research project, the CP3, or the Prevention of Cardiovascular Disease and Mortality in Patients with Psoriasis and Psoriatic Arthritis Research Study which we're going to hear a little bit more about today. 

So welcome Dr. Gelfand. I'd like to start our discussion by going back maybe 20 years to the initial draw for you to investigate this connection between cardiovascular disease and psoriasis. How did that happen? What got you started?

Dr. Gelfand: Guy, this is a great question. When I was a medical student at Harvard, I got interested in dermatology kind of late and when I got interested in the field, I started reading a lot about the various diseases that were interesting to me and I sort of got interested in psoriasis and ended up coming across some of the older literature related to psoriasis and cardiovascular disease and it sort of struck me as really interesting. And those were always studies that came out probably in 1970s, didn't use modern epidemiological techniques, but found enough information to suggest, well maybe psoriasis is related to cardiovascular disease. That literature sort of died for decades. And then when I was starting my career an article came out in the New England Journal of Medicine by a guy named Göran Hansson. Göran is a scientist at the Karolinska Institute in Sweden, and he's also known for being on the committee that awards the Nobel Prizes. So he's a good guy to know, and Göran published an article in New England Journal of Medicine explaining the inflammatory pathophysiology of atherosclerosis and cardiovascular events.  And that cartoon in his article in the New England Journal of Medicine, looked exactly like the cartoon we were using at the time to explain the pathophysiology of psoriasis, and that was a major light bulb goes off moment. Already I had some understanding that there was some relationship out there from prior studies, but now it's many years forward we finally started understanding the immunological basis of these two seemingly unrelated diseases. And then at the same time, there were major advances in the field of medical informatics, something that we sort of take for granted now. But in the United Kingdom, they were using medical records, electronic medical records since the 1980s and started using them for research in the 1990s. So I was fortunate to be at University of Pennsylvania, where our scientists were very much involved in validating these medical record systems for medical scientific studies. I did the initial work to validate that, in fact, in this medical record system in UK, you could validly identify people with psoriasis. And once I had that information, others had already validated that you could accurately identify people who had a heart attacks and strokes and validate, and also accurately define the cardiovascular risk factors. And then I was able to do what was by far the largest study ever in people with psoriasis. Well over 100,000 patients, longitudinal follow-up looking at the risk of myocardial infarction. In these patients compared to patients who are seeing the same doctors during the same time period, yet adjusting for other cardiovascular risk factors, and we were able to basically show for the first time in a large-scale epidemiological study that people with psoriasis have a higher risk of myocardial infarction, independent of traditional risk factors. And this risk is more significant in those who have more severe disease and we published this in JAMA and that was a landmark publication at the time.

Guy: So you've talked about a couple types of cardiovascular disease that are those risks. But is there anything related to the severity of psoriasis as a risk factor for development of those diseases?

Dr. Gelfand: Yeah, absolutely. So in our earlier work and work done by others, we define severity of psoriasis based on what therapies people received. So if someone receives, say methotrexate or phototherapy, we would say you know this person probably has moderate-to-severe psoriasis and they didn't receive those therapies we would say, well, maybe they have more mild psoriasis. And that approach generally has shown that those who get treatments consistent with more moderate to severe disease have higher risks of things like diabetes, heart attacks, stroke, premature mortality, end stage kidney disease and these risks are higher in that group than those who we defined as mild psoriasis. Now there are problems with that approach because it doesn't really give us an insight of what their body surface area was like. How objectively active their disease was. More recently, we did perspective studies that we started in 2009, have been publishing on in the last couple of years, where we use the same electronic medical record system United Kingdom and sent surveys to general practitioners, a doctor who’s taking care of these patients. And since these doctors have volunteered to help us participate in research and get compensated for filling out surveys the response rates were very high, over 95% of the doctors filled out their surveys. And so from this information, we knew what the general practitioners thought, the body surface area affected by psoriasis was, which patients had their diagnosis confirmed by a dermatologist, things of that nature. And from that we've been able to show that as a body surface area increases, so too is the increase for things like diabetes, all-cause mortality, and cardiovascular events. Others more recently in Sweden have shown that the PASI score also is predictive of major cardiovascular events. That as a PASI score increases so too does the risk of having cardiovascular events. So this is pretty strong evidence of what we call a dose response. The more severe the skin disease is, the more likely it seems that patients are to develop these major cardiometabolic health problems and it tends to be independent of the traditional risk factors, independent of their body mass index, or their blood pressure, or their cholesterol or things of that nature.

Guy:  I've been struck by one of the statistics that I've read in your work that's says patients with 30% BSA are more likely to experience a major CV event than actually to develop, for instance, melanoma. Let’s go a little deeper, a little bit more molecular. What are you thinking is the driving connection between this vascular dysfunction and psoriasis?

Dr. Gelfand: Yeah.

Guy: One of my understandings from your work is that the communication between these organ systems can be bidirectional. I’m just curious what you mean by that.

Dr. Gelfand: Yeah, so let me just explain a little bit more about what we mean by the comparison of risk of cardiovascular disease related to psoriasis compared to melanoma. So basically someone who has moderate to severe psoriasis is about 30 times more likely to develop a major cardiovascular event in the following year somehow related to their psoriasis above and beyond their risk factors for cardiovascular disease, than they are to develop a melanoma in that following year. And this is something we sort of calculated and presented to clinicians just so dermatologist’s understand why this is clinically important. Most dermatologists understand it's important to do a skin check on patients to look for skin cancer and melanoma, especially in those people who have risk factors for these things. But they are not so likely to check blood pressure in someone with psoriasis or check for diabetes or check cholesterol. And so what we know that in people with psoriasis that by identifying and controlling modifiable cardiovascular risk factors, blood pressure, cholesterol, diabetes, we know we could likely lower the risk of morbidity/mortality substantially. The second part of your question is really what are the connections between psoriasis and cardiovascular disease? They're multifactorial, as many pathways that lead from having the skin disease to developing cardiovascular problem.  Some of them are shared genetics. More recent studies have suggested that the genes people inherit that cause coronary artery disease that patients who inherit those genes are more likely to develop psoriasis. And so this type of analysis suggests that if you have atherosclerosis or coronary artery disease, it may cause you to develop psoriasis over time. Other scientists have shown the reverse of that. The genetics related to psoriasis seem to be related to risk of developing cardiovascular disease. That suggested relationship can be, bidirectional. Now when we come back into humans, human populations now and you follow people longitudinally, what we could definitively say is that patients have skin psoriasis. They don't have known cardiovascular disease. They haven't had a heart attack or stroke. And when you follow them over time, they have a higher risk of those problems compared to people without psoriasis. Now, does that definitely mean that psoriasis came first and then cardiovascular disease? Hard to know for sure. It's possible people may have had asymptomatic atherosclerosis. And then they develop psoriasis and that accelerates things and ultimately leads to higher rates of events. My best guess based on the current data is that the arrow goes in both directions. Having atherosclerotic disease can likely trigger or aggravate psoriasis. Having psoriasis likely can trigger or aggravate, develop an atherosclerotic disease, heart attacks and strokes.

Guy: So the idea of these longitudinal studies is fascinating. And you're talking about risk over time. But if you look at any incremental moment in those longitudinal studies, does the amount of time that you've lived with the psoriasis diagnosis or as you were saying perhaps a cardiovascular disease diagnosis, does that have any influence on the development in the context of psoriasis of the vascular inflammation?

Dr. Gelfand: Yeah, you know, this is a great question, Guy, and it's not so easy to answer. But our best understanding from data published to date is that the longer duration you have with psoriasis, the higher your risk of having cardiovascular complications. And I think that's more sort of data from patients that tells us that this is a real connection that we have a dose response as I explained earlier, we have biologic plausibility - reasons why we think this is occurring, and certainly having longer standing disease being weighed a higher risk is another part of like a dose response if you think about it. And so I think that from a patient perspective, really what this means is that when you have a rash on your skin like psoriasis, it is the skin talking to us. It's saying, well, my skin is inflamed. Other things maybe going on internally that need to be looked into.

Guy: OK well, let's look at it for a moment from the standpoint of the cardiologist. We know that the American College of Cardiology, the American Heart Association that they have included psoriasis as a proinflammatory disease or risk enhancer in the CVD risk calculators that they've set up. How do dermatologists look at the flip side of that? What do US Clinical Guidelines for Psoriasis Treatment recommend to help identify and manage cardiovascular risk in patients with psoriasis?

Dr. Gelfand: First of all it's interesting. Those guidelines to the American College of Cardiology, American Heart Association that came out in 2018-2019, that was a landmark statement. It was the first time a specialty organization defines psoriasis as having health consequences relevant to their specialty, right? That they defined psoriasis as a cardiovascular risk enhancer. Similar to diseases like rheumatoid arthritis for example. And there are other cardiovascular risk enhancers too, like metabolic syndrome and obesity, which we know are very common in people with psoriatic disease as well. So, it's interesting at the same time or similar time that when those guidelines came out from American College of Cardiology, American Heart Association, the American Academy of Dermatology and National Psoriasis Foundation came out with their joint guidelines, also for the first time, speaking to the role of the dermatologist in identifying comorbidities in a skin disease, in this case, psoriasis. And really, what those guidelines spoke to was similar to what we talked about earlier that basically it's important for a dermatologist one to educate the patient that having a rash like psoriasis, a chronic inflammatory skin condition can put them at higher risk of other health consequences, specifically things like psoriatic arthritis, diabetes, cardiovascular issues. So it's the patients are aware of these connections. And then they should encourage the patient to undergo age appropriate screening for cardiovascular risk factors or just initiate those screenings from their own office because it's very easy for us to do. Especially, you know, when we're putting a patient on a systemic medication, we're often getting blood work anyway. So it's easy enough to check cholesterol if that hasn't been done in the last four to five years, to check for diabetes using hemoglobin A1C if that hasn't been done in the last three years or so. And to check a blood pressure in the office. And when these things are done and we know this from a variety of other research studies, some done by my groups, some done by my colleagues in the United Kingdom, we know that patients with psoriasis have a lot of undiagnosed and untreated cardiovascular risk factors that more likely to have high blood pressure, have elevations of cholesterol, have diabetes, and these things don't have symptoms. Patients don't know it. By the time they have symptoms, they could be very, very ill or potentially have lethal consequences. So it's really important to do these simple age-appropriate cardiovascular risk factor screenings in our patients.

Guy: We've gone over some of the aspects of the landmarks and history and talked a lot about high risks that are associated with psoriasis particularly with respect to cardiovascular disease. Let's talk a little bit about what can be done to either reduce those associated risks or treat the patients for the complications that might be occurring. So with that increased risk of cardiovascular disease, is it logical to assume that the use of systemic therapies or biological therapies for psoriasis are going to lower the risk of major cardiovascular vascular disease events?

Dr. Gelfand: I think it's very likely that is the case. As a physician-scientist, we like to have perfect data to tell patients what we know for certain. And in this case, perfect data would be these large-scale placebo control trials, usually involving thousands of patients followed for four or five years. We just don't have that level of data in the field of psoriasis for the treatments we use on their ability to lower cardiovascular risk. We do have a variety of other forms of evidence, observational data of patients, as well as placebo-controlled trials looking at biomarkers in the blood. And what we could say from that data, it does seem like treating psoriasis successfully will lower the risk of major health problems over time, including cardiovascular events and mortality. That's where the data point to although they are imperfect and more work needs to be done so we can be certain of these issues. Certainly we know for our patients that when psoriasis is active it has all sorts of impacts on people's health and wellbeing. It can cause a lot of stress. It can make it difficult to exercise and be physically active. Both of those things could cause cardiovascular problems, right? So just by clearing the psoriasis and helping people live fuller, healthier lives, that alone is likely to lead to better health outcomes. Given we know the burden that psoriasis places on patients, but that's not enough Guy. If we clear someone's skin, their skin is 100% clear, yet they have untreated hypertension, untreated diabetes, untreated hyperlipidemia those things will continue to progress and can cause cardiovascular disease and other health problems. And so we have to think about the problem holistically, right? We need to clear the skin. We need to improve the joint function so the patient will have a fuller, healthier life. We need to identify these risk factors that comingle with psoriasis so commonly, and make sure they're treated and help the patient move towards a healthier diet, regular exercise, being a little more active, and that's a real holistic plan for helping patients achieve better health outcomes overall. 

Guy: Sure. I appreciate you mentioning the modifiable risk factors that the patient themselves can be involved in. Are there other activities when a dermatologist is working to reduce cardiovascular risks in their patients with psoriasis? Do the psoriasis patients themselves have other roles in supporting those dermatologists and helping to manage that cardiovascular risk? Maybe even in clinic? So if they're engaged in their healthy diet, they're engaged in exercise. Is there anything else that they can be doing to support you?

Dr. Gelfand: Well, I think this is the challenge of modern healthcare. Most patients experiences, it's hard to get in with a dermatologist. When they get in with their dermatologist it tends to be a very quick appointment. And so it could be hard to really, fully get the attention a patient needs to understand these issues and to know what needs to be done medically to lower their risk. And I think for this reason, we've been leading some research funded by National Psoriasis Foundation, really important research, to test a centralized care coordination model. And to take a step back, care coordination models are very well accepted in United States as being proven to help patients get better outcomes. We know that. Let's say a patient sees their primary care doctor and they have depression and diabetes, a care coordinator, not a physician, but maybe a nurse or someone with some medical training who helps the patient connect with the people that manage diabetes and the people who manage mental health, the patient could get better outcomes both in their mood and in their diabetes. OK, so we're doing something different though, so that the challenge we have with dermatologists or rheumatologists, is that we're in specialty care. How do we help the patient understand the broader health implications of their skin and joint disease? And then help them connect back to primary care to manage these risks and that's where a care coordination model comes into play. So the idea here would be that the dermatologist or rheumatologist educates the patients about cardiovascular risk and initiates screenings as we recommend per guidelines. But then, if those labs come back abnormal, they would let the patient know “OK, your cholesterol is abnormal or your glucose is abnormal or your blood pressure is high. Why don't you see your primary doctor and also let's talk to the Care Coordinator who's someone that resides at the National Psoriasis Foundation”. So it's a shared virtual resource. The patient could then talk to the Care Coordinator at National Psoriasis Foundation who could walk them through what's going on here. This is what we sort of did on this podcast, explain to them how psoriasis relates to the risk of cardiovascular disease. Calculate their risk of having a heart attack or stroke based on that blood pressure, their cholesterol, and other variables that play a role in cardiovascular disease. And then let them know what the guidelines of care suggest from the American College of Cardiology, American Heart Association for what someone who has psoriatic disease should do based on what their predicted risk is, and that may be a healthy diet. Things like the Mediterranean diet lowers people's risks. Getting moderate intensity exercise on a more regular basis. Managing stress, but also in many cases, people may also need medical therapy. Pills by mouth to help with cholesterol, if there’s diabetes that often needs medications to manage that as well. If there's blood pressure that’s elevated that may also need to be managed medically. But then connect them back to their primary care doctor with everything laid out with what the guidelines say because not all primary care doctors are up to date on this issue. They may not be aware that psoriasis is a risk factor for cardiovascular problems over time. And so having this guidance for them from the American College of Cardiology, American Heart Association helps the primary care doctor then work with the patient to ensure that they're getting the best medical advice currently available.

Guy: Right, and so you've given the setup for what we call together the CP3 or the Prevention of Cardiovascular Disease and Mortality in Patients with Psoriasis and Psoriatic Arthritis Research study. So, we're gonna call it CP3. You've given us the setup for it and it's a program that, like you said, we work closely together at the National Psoriasis Foundation with your team and extended across many other sites. But I know we've recently finished the first phase together in the pilot study. I'm hoping you could share with the listeners what the results were of that pilot study and what you're learning about the model of care that you just described.

Dr. Gelfand: Yeah, so this is something that we're developing a new approach here. So we did a pilot study first just to make sure that we were on the right target. That this was useful for patients. That the materials were developed were understandable and helpful. And the pilot was very successful. We enrolled 85 patients at 4 sites across the United States, two dermatology, two rheumatology sites. And the first thing we notice is that patients really take seriously what their dermatologists, rheumatologists says when we explain to them how psoriatic disease relates to cardiovascular problems. And over 90% of these patients in our initial pilot went ahead and got their blood work done and did their blood pressure checks at home to help understand what their risk of cardiovascular disease is.  And we identified about a third of patients had previously unknown, undiagnosed, significant risk of cardiovascular events that needed medical management. So stated another way, if it wasn't for this pilot study, about a third of these patients that walked into the office would not know they're walking around with risk factors, have to be treated to lower risk of having heart attacks and strokes. We also found that patients overwhelmingly, nearly 90% of patients thought that this model of talking to a care coordinator virtually at the National Psoriasis Foundation was totally doable for them and acceptable and helpful. So that was really a good part of this finding as well. And then we find for the patients who are at higher risk that those who pursued the recommendations that were suggested that they really strongly reversed their risk of having cardiovascular events over time. And that's ultimately what our goal is here.  One is to help the dermatologists, rheumatologists better identify cardiovascular risk factors in patients. So the patient knows what their risk is and their educated about what they may need to do. And then the patient could be fully informed to make a choice that fits with their own personal health goals and priorities in terms of how they want to pursue the recommendations that come out from the American College of Cardiology, American Heart Association.

Guy: Well, we know each other pretty well at this point. I'm gonna put you on the spot just a little bit. So given the results of this pilot study and you're a scientist, you're always going to go by the data. But I’m curious if there's any recommendation, you're comfortable making now, while we wait on completion of that second phase of the study, either for patients or for the care teams?

Dr. Gelfand: Yeah. Well, I think that everything we're doing Guy is basically standard of care.  Things that should be happening in clinical practice anyway, but creating an additional model that really is supportive of patients and clinicians, the care coordination. Absent people not being a part of study right now, so they're not able to plug into the care coordination model that we have, they should be still doing these things in clinical practice. In fact, in my own clinical practice, I collaborate with a prevention cardiologist and one thing I would encourage my colleagues who may be listening to this is just the way we told you - if you're a dermatologist, you should be working with a rheumatologist to collaborate on care when necessary with people with psoriasis or if you’re a rheumatologist should be working with dermatologists, to collaborate on care, when you need to for people with skin psoriasis. So too we probably all should have a preventive cardiologist that we work with, with these patients. So that way when we educate the patients and screen for risk factors or things were abnormal, we have a clinician who's knowledgeable about how to help our patients achieve better cardiovascular outcomes because this is a rapidly moving field Guy and there's so much that can be done now for patients noninvasively to understand what their risk is either through blood tests or certain types of imaging procedures that are done or offered to patients and new medications to help people, improve their metabolic syndrome, improve their weight if they’re very overweight, lower their cholesterol to safe ranges. There's a lot of things that can be done to help people. And so I encourage my colleagues now is that they should go ahead and educate and screen, but then have a colleague that they could then recommend the patient to see and follow up so that way the patients fully plugged in to getting the best care possible.

Guy: Oh absolutely and I wanna turn back just a moment to acknowledging that this is a research study and it probably feels like a very different type of research study than maybe what patients who might be listening might conceptualize of research as being. So it might feel pretty approachable and I'm wondering if somebody's listening and wants to be a part of the CP3 study or wants their healthcare provider to become involved in the study. What should they do?

Dr. Gelfand: Yeah, first of all, we've been involved with the National Psoriasis Foundation for many years now on patient centered clinical research studies and we have experience where patients who have heard these podcasts or are members of the National Psoriasis Foundation have gone out and talked to their dermatologist and said I'd like you to be a part of this study.  And by all means, this is the type of study that's embedded in routine patient care. It's very pragmatic and practical and easy to do. And so if there's people out there that's got to be United States, because this type of work, it's got to be the United States, but if there’s patients out there who are listening to this and would like to be involved in this type of work, they should speak to their dermatologist and have their dermatologist reach out to the National Psoriasis Foundation. Maybe your team can provide the website that the National Psoriasis Foundation created for the CP3 program so patients know how to reach us. And we'd love to get more clinicians around the United States engaged in this type of work.

Guy: We will absolutely put that URL at the end of this podcast. And of course, it's available online at psoriasis.org. Well I want to be acknowledging of your time today and I want to thank you Joel for being here to discuss psoriasis and cardiovascular disease and sharing the highlights of the CP3 study that we're so excited about. But I'm going to give the last word to you and ask if you have any closing comments you'd like to share with the listeners.

Dr. Gelfand: Well, I just have to say how grateful I am to National Psoriasis Foundation who’s really one of the most successful patient advocacy organizations out there. And they make a huge difference in the world for patients living with psoriatic disease. And the current work that we're engaged in with NPF is really just another shining example of how the NPF really wants to help people live longer, healthier lives with psoriatic disease. And so I encourage people get involved with the NPF. Come join our walks when they're in your community. Get involved as a volunteer. I think nothing helps people overcome the challenges of chronic disease like having a sense of community and other people out there who understand what you're going through. And it's also a great place to get educated about the treatments we have available, how to live a healthier life. It really is a great resource for people. So that would be my final wish if I could make one for this podcast.

Guy: That's very gracious of you. And we're very proud of the work that the National Psoriasis Foundation is able to do. But we all exist in an ecosystem and we're here to help work with members of our clinical teams as well as the patient community to make lives easier for everybody involved but particularly on behalf of those patients out there. So I'm looking forward to seeing further results from the CP3 project and thank you very much, Joel.  We look forward to working with you again in the future.

Dr. Gelfand: My pleasure.

Guy: For our listeners, you can continue to learn more about cardiovascular disease and other comorbidities, as well as the research provided by the National Psoriasis Foundation by subscribing to our Advance newsletter, and you can do that at psoriasis.org/subscribe. You can also get to the CP3 study at psoriasis.org/cp3. And finally, we'd like to thank our sponsor, Bristol Myers Squibb for their support of this Psound Bytes™ episode.