Pearls in Psoriasis: Dr Green Talks to Dr Gelfand about CVD in Psoriasis

Joel Gelfand, MD, is one of the pioneering researchers who showed a connection between psoriasis and the risk of cardiovascular disease (CVD). In this podcast, Lawrence Green, MD, interviews Dr Gelfand on the latest research in CVD and psoriasis. Dr Green also discusses the management of psoriasis during the COVID-19 pandemic with Dr Gelfand in part 2.

Dr Gelfand is a professor of dermatology and epidemiology, vice chair of clinical research and medical director of the dermatology clinical studies unit, and the director of the psoriasis and phototherapy treatment center at the University of Pennsylvania Perelman School of Medicine.

Dr Green is the section editor of The Dermatologist’s Psoriasis Center of Excellence, clinical professor of dermatology at George Washington University School of Medicine in Washington, DC, and on the National Psoriasis Foundation Medical Board.

Transcript

Dr Larry Green: Hi, I’m Dr Larry Green, section editor of the Psoriasis Center of Excellence for The Dermatologist and clinical professor of dermatology at George Washington University School of Medicine in Washington, DC. Today, we’re lucky to have Dr Joel Gelfand, who’s gonna to join us for discussion on the latest research in cardiovascular disease and psoriasis.

Dr Gelfand is a professor of dermatology and epidemiology, and the vice chair of clinical research and medical director of the Dermatology Clinic, and the director of the Psoriasis and Phototherapy Treatment Center at the University of Pennsylvania, Perlman School of Medicine.

Joel, thanks for joining us.

Dr Joel Gelfand: It’s great to be here with you, Larry.

Dr Green: Yeah, we’re gonna make this a fun and interactive podcast I hope everyone can benefit from. But we’re gonna to focus, like I said, on psoriasis and cardiovascular disease. I know that’s been your major research interest where you’ve published so much and contributed so much to our knowledge about psoriasis and comorbidities.

So, let’s start. We know psoriasis is known to be associated with an increased risk of cardiovascular disease due to inflammation and shared disease pathways. Have there been any recent developments in the understanding between the mechanisms between psoriasis, inflammation, and cardiovascular disease?

Dr Gelfand: Well, I think, you know, taking a step back, some of the big advances we’ve had recently is having a better understanding of the psoriasis phenotype and how that relates to adverse comorbidity outcomes.

So, in a prospective study we did that found 9000 patients, prospectively, to their general practitioners, we collected data on the patients’ body surface area affected as determined by their primary care doctors. And then, showed that this simple measurement has prognostic implications toward a likelihood of the patient developing, say, diabetes over time or even having mortality over time.

And, so the more severe your skin disease is, the larger your body surface area involvement is, the higher your risk is of having these, you know, serious health outcomes. And, it’s independent of the traditional risk factors that we think about that are measured in a medical record.

So, independent of your body mass index or independent of all other health problems you may be experiencing. And, so that information’s become important for dermatologists recently, and the way this AAD-NPF guidelines around comorbidity management. We really try to focus the dermatologists’ attention on those at highest risk.

So, certainly, for all people with psoriasis, we want to counsel them about the risk of comorbidities and help ensure that get up-to-date on their regular age-appropriate screening of traditional cardiovascular risk factors. But, for those who have more severe disease, maybe they had systemic agents for their psoriasis, phototherapy for their psoriasis, or, importantly, they have a body surface area of more than 10%, these are people that we may want to consider for more aggressive screening of cardiovascular risk factors, more screening for blood pressure, diabetes, hypocholesterolemia, then likely set more stringent targets for managing cholesterol in these patients.

And, similarly, the American College of Cardiology and American Heart Association also issued similar guidance suggesting that people with psoriasis be thought of as having a risk-enhancing condition, and therefore, be considered for earlier use of preventive medications, like statins, to help lower their risk of cardiovascular disease over time.

Dr Green: Joel, do you think age has anything to do with it? Would you counsel someone who, say, who’s 30 and has severe psoriasis the same way you’d counsel someone who’s 60 and has severe psoriasis?

Dr Gelfand: Yeah, so it, the answer’s a little bit trickier, a nuanced question to answer. You know, what we know from the work over the years is that the risk related to psoriasis, the relative risk I should say, is, you know, higher in younger individuals and modulates as people get older.

To some extent, that’s because age is the ultimate cardiovascular risk factor. It tends to take over for other traditional risk factors, whether you have high blood pressure, diabetes, what have you. Over time, age becomes the most important risk factor.

So, the way I think about the age aspect in people with psoriasis is that younger people are at a stage where they need to make lifestyle adjustments that would benefit their cardiovascular health, you know, over the decades to come of their life.

You know, a 25-year-old, for example, it’s pretty unlikely that they’re gonna need to go on a statin to lower the risk of cardiovascular disease. Their 10-year risk of events is gonna be low enough that mainly it’s about screen for risk factors, managing blood pressure, identifying diabetes, and having therapeutic lifestyle changes, exercising regularly, having a healthy diet.

But once a patient gets into their 40s and older, then their baseline risk for cardiovascular events becomes more significant, and even more so when they have psoriasis and when they have traditional cardiovascular risk factors on top of that, like elevated blood pressure, diabetes, elevated cholesterol.

And, so these are individuals where it’s especially important to identify their cardiovascular risk factors, calculate their 10-year risk of an event using one of these online calculators provided by the AHA-ACC.

Then essentially, according to the American Heart Association/American College of Cardiology, if someone’s 10-year risk of having an event is five percent or higher, these are people that you put on moderate intensity statins, something like atorvastatin, for example.

Now, a lot of dermatologists do not feel comfortable doing this. Although it’s fairly straightforward to do, a lot of us may not have the time in our busy practices. So, then the important thing to do is to educate the patient that they need to go back to their primary doctor, need to have their risk of a cardiovascular event calculated, and that if their risk if five% or higher, they should be considered for a statin.

Now medicine’s advancing so rapidly, Larry, and a lot of primary care doctors, you know, aren’t aware of the relationship between psoriasis and cardiovascular disease. And that’s why it’s important for us, as dermatologists to, to educate the primary doctors about this phenomenon so they’re able to follow the latest guidance that’s come out of the ACC and AHA.

Dr Green: Can I have you, Joel...This is all fantastic, and it’s so much information. Can I have you go back a little, and let’s break it down for the doctor in private practice. And we’re seeing someone with severe psoriasis at a different age. Say let’s start with a younger 25-year-old and then the 60-year-old.

Dr Gelfand: Yep.

Dr Green: Then we can assume they have other comorbidities or not, other comorbidities, you know, as you like, but let’s break it down and see what you think it’s best for us to do here in private practice...

Dr Gelfand: Yeah.

Dr Green: ...to deal with these different age groups who have serious psoriasis.

Dr Gelfand: So, a young patient with moderate to severe psoriasis and they’re 30-years-old, the first thing I’d do is assess them for traditional cardiovascular risk factors and behaviors. So, you know, if they’re a smoker, you wanna counsel them on stopping smoking. If they’re obese, you wanna counsel them on the importance of regular exercise, trying to lose weight. And then, their blood pressure should be checked, their cholesterol should be checked, and they should be screened for diabetes. I personally find it easiest to screen for diabetes with a hemoglobin A1C and for the cholesterol check, it doesn’t even have to be fasting, it can be non-fasting and you’ll still get similar information.

And then if they’re, you know, hypertensive or their cholesterol is significantly elevated, then we’d refer them back to their primary doctor for their evaluation and management of those issues. I think a big challenge that we have in our health system is a lot of our younger patients, we, as the dermatologist, may be the only doctor they’re seeing.

And, so if we don’t screen them for their blood pressure, their cholesterol, or for diabetes, it’s unlikely they’re gonna have those things done because they may not be seeing a regular primary care physician because they think they’re otherwise healthy.

Now, a patient who’s older than 40, this is where the guidelines recommend that someone calculate the patient’s 10-year risk of a cardiovascular event. And that’s based on things like whether or not they have hypertension, whether or not they have elevations in their cholesterol, their HDL cholesterol, if they have diabetes, things of that nature; things that are fairly simple to calculate.

But I recognize that for most dermatologists they may not want to get that involved in this management of cardiovascular disease. So, the key thing there would be the patient needs to go back and establish treatment with their primary care doctor and have their risk of cardiovascular disease assessed according to the standard ACC/AHA guidelines.

And, that’s important that primary care doctor know that they current guideline, that we would recommend statins for people in psoriasis at a lower risk profile than someone who doesn’t have psoriasis. And, this is because the models that predict your risk of having an event don’t include the fact that you have psoriasis in it. They’re based on people otherwise healthy.

So, to put this in context, the ACC/AHA recommends that if you have a 10-year of having a major cardiovascular event of 7.5% or higher, then a statin should be considered. For someone with psoriasis or other inflammatory diseases like rheumatoid arthritis, they commend that they consider going on a statin if their 10-year risk is 5% or higher.

And, you know, for a lot of our patients, Larry, it’s likely that many of them are going to have a statin recommended for them. Which as we know, so many of our patient with psoriasis already have high blood pressure or have diabetes. And those things will drive their risk higher as well.

Dr Green: Or overweight.

Dr Gelfand: Exactly, exactly, although overweight is not included in, in the statistical model.

Dr Green: So that’s something else to add that, in terms of counseling, when we counsel our patients.

Dr Gelfand: That’s exactly right. And the way the guidelines think about it, they talk about sort of, you know, our risk enhancers, of which metabolic syndrome is one, obesity is one. So, you need to think about a patient’s psoriasis as sort of loaded with these non-traditional cardiovascular risk factors that previously weren’t accounted for in guidelines because it wasn’t recognized how important they were.

And, now that all this data has emerged, the newest guidelines from the field of cardiology are trying to address these issues by starting statins earlier in these patients.

Dr Green: So, you know, it sounds like, Joel, it’s, especially for the person who’s middle-aged and older with severe psoriasis that we, as the dermatologists, can do some screening, should be doing some screening and education for the patients.

But, we could also be doing some education for the patient’s primary care to make sure that if someone does have a smaller risk than normal for cardiovascular disease, for a cardiovascular event, we can counsel the primary care that patient still should be started on the statin. And that’s something we can do and educate both.

Dr Green: That’s exactly right. We see on the new ACC/AHA guidelines came out end of 2018, early 2019. It’s just hard for people to keep up with all this information. And, so I think what their primary doctors need to know is that psoriasis can sure be a cardiovascular risk enhancer, and therefore, the primary doctor should consider starting a statin earlier in that patient than someone who doesn’t have psoriasis.

Uh, and then the primary care doctor should be then familiar with the ACC/AHA guidelines. It’s a fairly standard-issue guidelines that most people use when deciding on whether or not to start a statin in a patient in the United States.

Dr Green: Let me ask even more. And maybe this is something that is needed if it isn’t there, but this will make it even easier for the private practitioner in dermatology. Are there any current AAD or National Psoriasis Foundation guideline recommendations to do all the things we’re talking about?

Dr Gelfand: That’s exactly right. Yeah, so the AAD/NPF comorbidity guidelines came out in 2019. And they sort of list all of these issues out in the recommendations. So that’s a good source to go to for, you know, studying these issues that we’re discussing here today.

Dr Green: Very good. And that’s a resource they could find on the National Psoriasis’s Foundation website if not the AAD website.

Dr Gelfand: Exactly.

Dr Green: So I’m gonna switch more to ask you questions about treatment in a way.

Dr Gelfand: Mm-hmm.

Dr Green: So ho-, are there any treatments in terms that we know of, are there any things we have just learned about the role of psoriasis treatment in mitigating the risk for cardiovascular disease? Are any biologics showing better efficacy? We read a lot, but it’s sort of conflicting. And, and then what about phototherapy, too? Let’s add that on to biologics.

Dr Gelfand: So, you know, this is such a key area for our field and of critical interest to our patients and, of course, as physicians taking care of these patients. When it comes to prevention, we like to have level A evidence, meaning randomized, placebo-controlled trials proving reduction of events. And we just don’t have that kind of data yet in the field of psoriasis.

Now outside of our field, there’s been a couple of trials that have proved the principle that lowering inflammation can lower cardiovascular events. And so, for example, uh, one trial studied a biologic that blocks interleukin-1 beta. It’s a drug called canakinumab. And, that study demonstrated that you can lower cardiovascular event rates in people who had prior coronary disease.

Another study was recently done in people with a recent myocardial infarction and showed that a drug called colchicine, which we as dermatologists are very familiar with, that that drug also lowered the risk of future cardiovascular events compared to placebo.

So, these two studies are clear proof of principle that treating different parts of inflammation in people with coronary disease could lower the risk of future cardiovascular events.

Now the one drug we use regularly for psoriasis, methotrexate, unfortunately, that trial failed to show any benefit of methotrexate on cardiovascular events in people with high underlying cardiovascular risk. Now that study’s been criticized because when patients were enrolled in it, they weren’t required to have had evidence of systemic inflammation. And essentially, in that large patient population, several thousand patients, the CRPs, on average, were pretty much normal. And, so it was a non-inflamed patient population, and that’s sort of different than what we have in our psoriasis patients where they are inflamed from their psoriasis. So, it’s certainly possible that methotrexate lowers cardiovascular events in our patient population, but that hasn’t been proven yet based on the current trials available.

Now returning to psoriasis trials, me and my close collaborator, Nehal Mehta, have conducted 3 rigorous placebo-controlled trials, they, weighing the effects of treatments like adalimumab, phototherapy, ustekinumab, and IL-17 (in this case secukinumab) on critical markers of cardiovascular disease including aortic vascular inflammation, measured by a PET CT scan. And then key markers in the blood of inflammation, lipid metabolism, and glucose metabolism, or insulin resistance. And, so let me briefly review what we found for our colleagues.

For adalimumab, it had impressive reductions in markers of systemic inflammation that are known to be causally related to cardiovascular disease. Things like interleukin-6 went down. C-reactive s went down. So that was an important benefit, with I think, of TNF inhibition in our patients. Interestingly, we saw no benefit on aortic vascular inflammation from TNF inhibitors or changes in insulin metabolism, glucose metabolism.

Turning to phototherapy, interestingly, we also so fairly powerful reductions in things like IL-6 and C-reactive protein, biomarkers known to be important and causally related to cardiovascular events. Interestingly, phototherapy also improved the lipid profile. It actually improved HDL in a way that would suggest that patients would have better events in the way their HDL particles are being used here by the patient’s blood.

Moving on to ustekinumab, that therapy lowered aortic vascular inflammation compared to placebo at 12 weeks. But beyond that, when we scanned the patients again about 52 weeks later, after starting the drug, we didn’t see persistent improvements in aortic vascular inflammation, suggesting that those findings were somewhat transient.

And then finally, when we studied secukinumab, this paper recently came out, it was pretty much a neutral study. We didn’t find any benefits in cardiovascular markers or any impairments in cardiovascular markers that were clinically important.

And so that’s a lot of information at once. And I think what these studies are telling us is that we still have a lot more to learn about how these therapies work in terms of cardiovascular pathways, as well as their true impacts on cardiovascular events.

Dr Green: Yeah, it’s interesting. In theory, like you mentioned, if we lower the large inflammatory burden load which we seen in people with severe psoriasis with any therapy, it should improve their cardiovascular risk. But we just aren’t there in showing that yet. And, like you said, we don’t know why. Are there any other insights you wanna add about that?

Dr Gelfand: I think this field will continue to move forward. And, you know, the way to definitively answer these questions would be whether or not some of our agents are studied in people with coronary disease, so whether or not we could randomize people with coronary disease to phototherapy or getting ultraviolet light, or a TNF inhibitor or an IL-17, or what have you.

The same way they did those trials with canakinumab or methotrexate or what have you, you know, our therapies do show some promise in in vitro studies and observational data or other types of experiments that perhaps they could have some cardiovascular benefit in patients who are at high risk. And those would be sort of logical ways to sort of prove this issue.

Within the psoriasis population, perhaps a next step may be looking at impacts of these therapies on the actual coronary disease. You know, work that Nehal Mehta has pioneered at NHLBI has really characterized the type of atherosclerosis people with psoriasis has helped clarify that they have a thing called non-calcified burden, which is a type of plaque that has high-risk features and is more likely to result in a death. And, so this may be a more helpful surrogate to study future work that we do.

Dr Green: Yeah, it’s sounds really interesting and a lot going on between what you’re doing and what, uh, Nehal Mehta’s doing. Is there anything else you wanna share with us about cardiovascular disease before I close things up and open up to talk about COVID disease and psoriasis? [Part 2]

Dr Gelfand: It think the main this is, you know, stay tuned. We’re learning a lot more about psoriasis and cardiovascular disease. And the best thing we could do at this point in time is at least make sure our patients’ traditional cardiovascular risk factors, their blood pressure, their diabetes, and their cholesterol are identified and adequately treated.

‘Cause we know today that patients with psoriasis have a high frequency of undiagnosed cardiovascular risk factors. And when they are diagnosed, they are less likely to achieve appropriate control of those risk factors, and this problem’s worse the more severe the skin disease is, which is the exact opposite of what we would hope to see in our patients.

Dr Green: Great. All right. Thanks Joel.