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Pathophysiology of Plaque Psoriasis and Targeted Therapies


A panel of experts review the nature of plaque psoriasis and the mechanism of action of several classes of targeted therapy.


Christopher G. Bunick, MD, PhD: Hello, and welcome to this Dermatology Times® Around the Practice video series titled “Perspectives on the Management of Plaque Psoriasis.” I’m Christopher Bunick, an associate professor of dermatology and physician scientist at Yale University Department of Dermatology in New Haven, Connecticut.

Joining me today in this discussion are 3 of my colleagues, including Dr Mark Lebwohl, dean of clinical therapeutics at the Kimberly and Eric J. Waldman Department of Dermatology at the Icahn School of Medicine at Mount Sinai. He’s also president of the New York Dermatological Society, the Manhattan Dermatologic Society, and the New York State Society of Dermatology, as well as chairman of the dermatology section of the New York Academy of Medicine. We’re also joined by Dr Jashin Wu, founder and course director of the San Diego Dermatology Symposium being held March 11-13, 2022; Dermatology Refresher Symposium for Nurse Practitioners and Physician Assistants, April 8-10, 2022; Skin Cancer Symposium and Symposium for Inflammatory Skin Disease, June 10-12, 2022; and the Dermatology Innovation Symposium being held in November 2022. We’re also joined by Dr Helen Torok, medical director of the Trillium Creek Dermatology Center in Medina, Ohio.

In today’s discussion, we’re going to provide an overview of diagnosing plaque psoriasis. We’ll also discuss treatment options for moderate to severe plaque psoriasis and how to approach and address challenges in patient treatment. Let’s get started.

Our first segment is going to focus on an overview of plaque psoriasis. Our first topic is going to be a review of the pathophysiology of plaque psoriasis with some focus on the systemic nature of the disease. Beyond the skin and joints, what’s the evidence of systemic effects of psoriasis, such as on heart disease or other organ systems? Dr Lebwohl, could you please address the pathophysiology of plaque psoriasis?

Mark G. Lebwohl, MD: By all means. It appears that the inflammatory cytokines that are characteristic of plaque psoriasis also contribute to the development of psoriatic arthritis and cardiovascular disease as well as a host of other systemic problems. In fact, there’s very good evidence that initially emerged from registries around the world showing that patients treated with TNF [tumor necrosis factor] blockers ended up having a dramatic reduction in cardiovascular disease. Joel Gelfand first showed that myocardial infarctions were increased in patients with severe psoriasis more than a decade ago in a landmark article that was published in JAMA [Journal of the American Medical Association].

Subsequently, data from registries showed as much as a 50% reduction in heart attacks in patients with psoriasis who had been treated with TNF blockers. Dr Wu, who is on our panel, also demonstrated similar findings in the Kaiser Permanente database. It was shown in several of the registries that other treatments like methotrexate also reduced cardiovascular disease. Perhaps not as much, but still they reduced cardiovascular disease. We don’t have nearly as much registry data with the IL [interleukin]-17 or IL-23 blockers because they are newer, but initial data emerging on the IL-17 blockers, which came out first, is showing some effect on cardiovascular disease. Some very good studies looked at atherosclerotic plaque in patients with psoriasis who had been treated with biologics and hadn’t been treated with biologics. There was a reduction in lipid-rich necrotic core and atherosclerotic plaques in patients on biologics, particularly those on IL-17 blockers.

Christopher G. Bunick, MD, PhD: Dr Lebwohl, with this important information on cardiovascular disease in patients with psoriasis, does this affect how dermatologists and other physicians should be treating patients with psoriasis?

Mark G. Lebwohl, MD: One of the first questions we ask patients who come to us is, “Do you have any joint pains?” Then we should be conducting a search for psoriatic arthritis. If the answer is yes, or it looks like they may have psoriatic arthritis—not even that they do but that they may have psoriatic arthritis—that should influence the selection of biologic therapy. I’d be more inclined to go to an IL-17 blocker or TNF blocker in patients with psoriatic arthritis.

Christopher G. Bunick, MD, PhD: You mentioned TNF alpha, IL-17, and IL-23. Could you take a moment and review some of the pathophysiology behind these cytokines and how they’re connected with being treatment targets in psoriasis?

Mark G. Lebwohl, MD: TNF blockers are a bit more broadly immunosuppressive. I don’t usually go to TNF blockers first anymore because they have boxed warnings, while IL-17 and IL-23 blockers don’t have boxed warnings. The boxed warnings pan out. There’s probably a small increase in malignancies and infections in patients on those drugs, but not on the IL-17 blockers, with the exception of candidal infections, which are pretty minor, and not with the IL-23 blockers.

Having said that, how IL-23 works is it causes upregulation of Th17 cells to create IL-17. IL-17 is the key cytokine in the development of psoriasis, so if you block IL-23, you indirectly block IL-17. What’s more is that when you block IL-23, the Th17 cells either die or hibernate. They seem to wither away. So once you stop an IL-23 blocker, it takes a while for the body to reconstitute those Th17 cells. I believe that’s why we see prolonged remissions after using IL-23 blockers. Of note, they can be given less frequently, so they’re injected every 2 or 3 months, but they’re a little slower.

When you block IL-17, you’re blocking the cytokine that’s immediately responsible for the development of psoriasis. By blocking it, you get a very rapid response. Having said that, though, for at least for the IL-17A blockers—secukinumab and ixekizumab—and brodalumab, which is an IL-17 receptor blocker, the psoriasis seems to come back a little more frequently, so they have to be injected at least once a month to maintain their response. Of note, the newest entry to the IL-17 family is a drug that blocks IL-17A and IL-17F. IL-17A is a very potent inducer of psoriasis. IL-17F might not be as potent an inducer of psoriasis, but it’s more prevalent in psoriatic plaques. It seems that when you block both, you get an additive effect. It’s interesting that the new IL-17A and IL-17F blocker, bimekizumab, is eventually administered as infrequently as every 2 months. We seem to have an added benefit. Not only is it fast, but it also doesn’t have to be given as often.

Christopher G. Bunick, MD, PhD: Thank you for those comments. We’re actually going to come back to bimekizumab later in the discussion. Certainly, with IL-17A and IL-17F, the amount of each in the skin and the amount of synergy between them is an important and interesting topic to discuss. One last question before we go to our next question: Are you aware of any studies or is there any utility in combining or investigating an IL-23 and an IL-17 inhibitor?

Mark G. Lebwohl, MD: If I were going to combine agents, I don’t think I would combine those 2. I’m not aware of any studies combining them. Although I theoretically could see a patient’s psoriasis doing very well with IL-23 and needing IL-17 for the psoriatic arthritis. Guselkumab [Tremfya] has data that it’s effective for psoriatic arthritis, and so do the other IL-23 blockers, risankizumab [Skyrizi] and tildrakizumab [Ilumya]. Guselkumab is already approved for psoriatic arthritis. But so far, it looks like with the dose that is accepted today, which is an every 8 week administration of 100 mg, it might not be as effective as the IL-17 blockers.

Christopher G. Bunick, MD, PhD: Thank you.

Transcript edited for clarity.

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