Targeting Psoriasis: Understanding the Latest Treatments for Moderate to Severe Disease

With a range of treatments available to treat moderate to severe psoriasis, it can be tough to navigate the landscape. Kara Gooding, MMS, PA-C and Joe Gorelick, MSN, FNP-C provide updates on pathogenesis and the latest treatments. Plus, Jayme Heim, MSN, FNP-BC addresses the diagnosis of CSU and Ted Rosen, MD talks about the challenges of diagnosing STIs. 

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Transcript

This transcript is provided as a courtesy. It has not been edited for accuracy.

Welcome to the Dermalorian Podcast from the Dermatology Education Foundation. The Dermalorian Podcast is an independent program made possible with support from UCB. More than seven and a half million Americans are affected by psoriasis, according to the National Psoriasis Foundation. Over more than two decades, as the biologic revolution has reshaped patient care, we have learned a lot about the pathogenesis of this inflammatory skin disease and witnessed approval of new treatments, but keeping track can be a challenge.
In this episode of the Dermalorian Podcast, dermatology physician assistant Kara Gooding and dermatology nurse practitioner, Joe Gorelick offer context for understanding psoriasis and using the newest treatments.Kara Gooding:

We know in our psoriasis patients there are intrinsic factors like genetics that drive psoriasis and extrinsic factors as well. Those are things like smoking, alcoholism, infections, stress, and many other things that can lead to a trigger for their psoriasis. When that trigger occurs, your innate immune cells become activated, so your macrophages, plasmacytoid dendritic cells and your natural T cells become activated, and I'll back up just for a minute.
There's three really main players and I think it simplifies it a little bit if you look at it that way. You have your dendritic cells, your helper T cells, and your keratinocytes. And so we look at, okay, how do the different players play a role in this pathogenesis? When you have that trigger develop, your innate immune cells will then secrete things like TNF-alpha, that we're all very familiar with, Interferon-gamma, Interferon-alpha, IL-1 beta, that is going to stimulate your myeloid dendritic cells to become activated. Then your lymph nodes will then secrete IL-12 as well as IL-23. IL-12 upregulates the TH-1 pathway, which we now know plays a little bit more of a minor role in the pathogenesis of psoriasis. IL-23 is activated, and that will upregulate both the TH-22 pathway, which again plays a little bit more of a minor role, but the major player is the TH-17 pathway, that will then secrete IL-17, IL-22, as well as more TNF-alpha.
All of this combined is going to cause this inflammatory cascade to develop where we see skin thickening, erythema and keratinocyte proliferation and the development of psoriasis plaques. And of course it gets into a vicious feedback loop. Let's take a look and see where the drugs that we currently have approved, which we now have 12 biologics, which is quite amazing. Where do they fit into this pathogenesis? So first we'll focus on the anti-TNF therapies. Enbrel or Etanercept was the first one that was approved. This actually was approved for psoriatic arthritis first back in the late nineties when I started in dermatology and then became our first drug approved for psoriasis in the early two thousands. As you can see here, all of the TNF inhibitors are approved for both psoriasis and psoriatic arthritis. Enbrel is not a monoclonal antibody, it's actually a fusion protein that consists of the extracellular portion of the human p75 TNF receptor linked to the FC portion of the IgG1, it binds to both TNF-alpha and TNF-beta.
Adalimumab is a human IgG1 monoclonal antibody that specifically binds to TNF-alpha. Remicade is a chimeric IgG1 monoclonal antibody, also binds to TNF-alpha. And then Certolizumab is a little bit different. It is a pegulated anti-TNF biologic for the IL-12 and IL-23 therapies. IL-12, we have one drug that is an anti-12 and anti-23 therapy and that is Ustekinumab. It is a human IgG1 monoclonal antibody that binds with specificity to the p40 protein subunit used by both IL-12 and IL-23. And it also is approved for psoriasis as well as psoriatic arthritis. And then we look at our IL-23 inhibitors, we have three of them guselkumab, tildrakizumab and rizinkizumab, the only one that is not approved for both psoriasis and psoriatic arthritis is tildrakizumab. And then last is our four anti-IL-17 therapies, so secukinumab, ixekizumab, brodalumab, and bimekizumab.Joe Gorelick:

It's almost 5,000 patient years of experience with bimekizumab-exposed patients. The dosing is super straightforward. Each dose consists of 320 milligrams. That's two injections. So each dose is given at baseline, there's a dose, then there's one additional dose at four weeks, eight weeks, 12 weeks, 16 weeks. After that load, you go to every eight weeks unless you're over 120 kilograms. In that case, you can go every four weeks. Now we have a really great understanding of the pathways that are important in psoriasis. Initially there were broader targets like TNF-alpha inhibition and the TH-1 pathway, but it's become very clear that the predominant pathway for psoriasis that drives this disease is a TH-17 pathway. There's absolutely no doubt, and the inflammatory mediators that are specific to psoriasis that are seen in highest concentrations are IL-17A and IL-17F. So the IL-17s don't roll by themselves, they pair up into dimers.
When you look at a plaque of psoriasis, you'll see IL-17A and IL-17F prevalently. But to cause inflammation and drive an inflammatory pathway, they have to be dimerized so they can bind to their receptor site extracellularly. And when that happens and you have elevated levels of A and F, you have disease. And so the treatment of psoriasis is going to be aimed at decreasing these levels of elevated pro-inflammatory mediators. You can do this in lots of different ways. You can mop up or bind IL-17 directly. You could also block the receptor site and those molecules are available commercially in the United States. And also you can inhibit IL-23 activity and decrease the amount of IL-17 that's produced that way as well. One of the theories behind decreasing inflammation is mopping up IL-17 that comes from the IL-23 pathway, but also IL-17A and IL-17F are also produced independently from other sources.
So in binding it directly theoretically, you could mop up those additional sources as well. You can see the very specific mechanism of action that selectively targets IL-17A and IL-17F. So when targeting both A and F, you can mop up all the dimers that bind to the receptor sites that drive inflammation. If you target specifically just IL-17A, you'll miss the IL-FF homo-dimer. You'll mop up very well IL-17AA homo-dimer and IL-17AF hetero-dimer, but there will still be free-floating IL-17FF that can drive inflammation. So specific to the mechanism of action of Bimzelx, you're mopping up all three of these dimers and decreasing the activation at that receptor site so you can decrease inflammation as manifested in our patients with decreases in the level of disease.
We'll look at some clinical trials and look at measurements that quantify the reduction in their disease, the PASI scores. A PASI 90 is representing a 90% reduction in the baseline PASI score. And what you're looking at here is four head-to-head trials with Bimzelx versus Secukinumab in BE RADIANT, where you have Bimzelx versus placebo in the BE READY, and Bimzelx versus Ustekinumab in the BE VIVID, in the BE SURE trial you have Bimzelx versus Adalimumab. When I look across all three of these individual trials at just week four, what I'm seeing is a very consistent ability of this particular agent to achieve a 90% reduction in the baseline PASI score. This is after one dose. If you think about PASI 90, a 90% reduction in baseline PASI score can be translated to a significant improvement in a patient's quality of life, which can unmask their ability to perform social functions, interact with friends, and go to work without having to hide their disease. It is a tremendous improvement, almost eliminating the disease.
It's not completely clear, but PASI 90 is a very high bar and it's nice to see across four separate trials, they have a consistent reduction of around 40%. This is after just one dose, so these patients were dosed at baseline, and then when you saw them back at the one-month point, the four-week point, they were achieving this 40% reduction plus in their PASI score, and you compare it head-to-head fashion versus Secukinumab, Ustekinumab that are both very effective agents in psoriasis. You can see a direct head-to-head comparison at week 16 where Bimzelx demonstrated clear statistical superiority versus all of those agents at week 16. And again, the consistency between the trials, 85 plus percent of patients had a 90% reduction in their baseline PASI score at week 16. The calculation of this data is done by the most stringent statistical analysis possible, which adds more credence and value to those numbers at week 16.Speaker 1:

We'll get back to a discussion of safety in a moment. But first, there has been a lot of attention on chronic spontaneous urticaria or CSU lately, but what precisely is the condition? In this episode's Dermalorian Derm Decoder, nurse practitioner, Jayme Heim, provides some insights.Jayme Heim:

More females than males have chronic spontaneous urticaria, but both are very confused and they're both very upset. A, they're having intense pruritus and B, they don't know why this is happening to them. When we diagnose chronic spontaneous urticaria, they have to have the urticaria, which is happening for at least six weeks period of time. If it is not six weeks period of time, just a couple of weeks, it's just episodic. But to have CSU it has to be six weeks period of time, it can not only involve the urticaria, but also those patients sometimes they can have the angioedema that go along with that. Patients usually are between the ages of 20 and 40.Speaker 1:

Let's get back to Joe Gorelick as he discusses safety of IL-17A and F inhibition.Joe Gorelick:

What about the package insert? This is a brand new biologic, you've got to do your homework, you've got to read the label. Is there something different here? Do we need to change our behavior in prescribing Bimzelx versus prescribing the biologics that we have available before it? Actually, you do not. The package insert is incredibly clear. There's no black box warning. There are some call-outs in the package insert that do not affect our prescribing or our monitoring. They talk about comorbid conditions that we see in our patients that have psoriasis. Just like that we have discussions with our patients about comorbidities, and we're going to talk about those specifically we'll talk about comorbidity for mood and depression, and also non-alcoholic fatty liver disease, which can result in psoriatic patients having elevated liver functions.
In the clinical trials, this is the label that's showing us the incidences of the adverse events of interest. And you see this across all of the biologics and what we're looking for in a specific class, which is an IL-17 inhibition is inflammatory bowel disease such as ulcerative colitis and Crohn's disease. We know that at baseline, our psoriatic population has an increased risk at developing inflammatory bowel disease. So the IL-17 inhibitors in their label talks about potential risk for exacerbations or inducing it. What you can see, very clean low percentages for Bimzelx through the first 16 weeks and in the long-term data, no elevation. Infections is a call-out for all biologics prior to initiating therapy. We want to make sure our patients are healthy and 0.3% of patients versus patients in placebo. And then all comers in the long-term hundred-year data, very low incidence of serious infections.
MACE events, again, very low, no signals here. Non-melanoma skin cancers or malignancies less than 1% in this patient population. Very reassuring. No incidence of serious hypersensitivity reactions. And then this is an injection, so you do have injection site reaction, but it's very low, less than 3%, and then over 100 years, looking at that, it's less than 2%. When you modify or normalize the levels of IL-17, you can run the risk of creating opportunistic infections such as yeast infections, because there's a population of patients that do not have IL-17, and they cannot protect themselves from yeast and they have to be chronically treated with antifungals. So there's a signal for candida that's seen, so it's important to talk to all patients when you're initiating therapy about yeast in particular, thrush and what to look out for. And if that happens, what do you do?
I mean, we're in dermatology, we can handle thrush, and the standard practice would be to give them a prescription of fluconazole to take 100 or 200 milligrams a day for about a week, and that usually takes care of it. What they saw in the clinical trials was that the oral candidiasis rates were low. They usually happened within the first 16 weeks, and patients that had it were treated, did not discontinue therapy, and they didn't tend to have recurrences over time. Suicidal ideation is listed in the package insert. And remember, for our patients that have psoriasis, depression is one of the primary comorbidities of the disease. Also, in previous agents that are approved in the United States, the receptor blocker, an IL-17 receptor blocker, there were in the label suicides. And so in labels that we've seen that have come to market since that particular agent, it's likely that this will be a class warning. In this particular clinical trial, there was only one, and it was during the long-term extension at day 718, and it was very clearly adjudicated that this was not due to the medication, so it's in their label.
You talk about it, make sure your patients know that it's in there because they may go home and read it and say, "Hey, you didn't mention that. I'm on medication, I've had some issues with depression." So it's important to proactively bring it up, but it doesn't appear that this medication in any way is a causal agent for mood or specifically with suicide. And then in the label, there's also a mention of liver function testing. Well, I think most all of us screen patients with a comprehensive metabolic panel prior to initiating therapy for psoriasis. And a lot of our patients with psoriasis at baseline actually do have elevated liver functions because metabolic syndrome, non-alcoholic fatty liver disease appears to be a very high prevalence for patients that have psoriasis. And so likely, this is what we're seeing with this call out for liver function tests. And it's a reminder, make sure you screen your patients prior to initiating therapy, but there's no call out and there's no required additional monitoring for liver function over time.Speaker 1:

Now it's time for our Dermalorian clinical clip. As recently reported on the DEF blog, there is evidence that younger Americans would prefer access to at-home STI screening. This could be important as STI rates continue to climb in the United States. Dermatologist Dr. Ted Rosen provides an update.Dr. Ted Rosen:

There are now about two and a half million new cases of sexually transmitted diseases a year in the United States. That is more cases of STD than there are new cases of diabetes diagnosed in the US every year. This is an epidemic and a lot of them manifest on the skin. It's very important for dermatologists in particular to recognize the primary lesion, a SHANG-kur, and all the various manifestations of secondary syphilis. Remember that hair loss can be the presenting sign of secondary syphilis in 3% to 7% of patients. SHANG-kur's can be off the genitalia in 5% of patients with syphilis. And the rash of secondary syphilis often presents in very atypical areas. You need to know what's going on in your specific state and city because there are some places where syphilis is extremely prevalent, and therefore, you're at high likelihood of seeing that. Remember that both primary and secondary syphilis resolve spontaneously, so if we miss our chance to make that diagnosis, we've missed a chance to prevent progression of the disease later in life.Speaker 1:

Dr. Rosen is a popular faculty member for the DEF Essential Resource Meeting or DERM. In case you missed it, DEF recently announced the educational theme for the DERM 2025 Conference to be held July 23rd to 26, 2025 at Encore At Wynn in Las Vegas. Consider joining us as we catch the big wave of innovation and education at an educational beach party. More information is available at dermnppa.org/Derm2025. Thanks for joining us for this episode of the Dermalorian podcast. The podcast is an independent program made possible with support from UCB. It is produced for DEF by Physician Resources. We'll see you next month.