Targeting Type 2 Inflammation in Eczema, Prurigo Nodularis, and Urticaria

Dr Jeffrey Cohen discusses how IL-4, IL-13, and IL-31 drive inflammation and itch across eczema, prurigo nodularis, and chronic urticaria. Learn how to select between biologics, JAK inhibitors, and IgE-targeted therapies, manage overlapping type 2 diseases, and apply real-world strategies for sequencing treatment based on clinical features, patient comorbidities, and emerging therapies.

Transcript

My name is Dr Jeffrey Cohen. I'm a dermatologist at the Yale School of Medicine, where I serve as associate professor of dermatology and direct the psoriasis treatment program. It's great to be with you today.

When you see eczema, prurigo nodularis (PN), and urticaria through a type 2 inflammation lens, what shared mechanisms most influence how you treat these patients today?

Dr Cohen: I think the most important thing for us to understand as we visualize these disorders through a type 2 lens is what type 2 immunity is. Type 2 immunity is basically if you think about the allergic access in your body, that's what it is. So you think about eczema, you think about prurigo nodularis, you think about urticaria. All of these share an atopic or an allergic background, and type 2 immunity is characterized really by inflammation of interleukin-4, interleukin-13. These are targets of medications that we use and these are really the heart of type 2 inflammatory disease. When we look at all of these different diseases, they're not the same. The inflammation is not the same, the pathophysiology is not the same, but they all prominently feature this type 2 axis of the immune system. And so when we think about shared pathophysiology commonality between these diseases and how to use the medications at our fingertips to treat them, a lot of times that leads us to thinking about interleukin-4 and interleukin-13 as effective ways to treat all of these disorders, although they are different.

How do IL-4, IL-13, and IL-31 differ in their clinical relevance across these diseases, and how does that influence your choice between newer targeted therapies?

Dr Cohen: When I think about IL-4, IL-13, and IL-31, I divide them really into two main groups. First, IL-4 and IL-13 are really the heart of the inflammation of the T-cells that are expanded in individuals with these type 2 immune disorders, eczema, prurigo, nodularis, and urticaria, chronic urticaria. And so when we treat with a medicine that targets those cytokines, we're really trying to turn off the inflammation. Interleukin-31 is important in this type of inflammation, but really its most prominent role is in itch. That is what you can think of as the itch cytokine, and as we all know, by seeing these patients in the clinic, they are extremely, extremely itchy and for some of them, even beyond the skin lesions or discomfort that they feel in other ways, the itch can be really debilitating. It's distracting during the day. It prevents them from doing the things they want to do. It prevents them from sleeping well at night. They wake up in the middle of the night, they're not well rested. They're scratching all the time. They're self-conscious about this. They may be bleeding with scratching. This is a huge, huge problem. Interleukin-31 sits right at the heart of this, and so by blocking interleukin-31, we're really trying to turn off the itch and that's really how I think about that medication as compared to the interleukin-4 and interleukin-13 blockade that we get with other types of medications.

With IL-4/IL-13, IL-31, IgE, and JAK pathways now targetable, how do you approach selecting the right mechanism for the right patient?

Dr Cohen: This is a crucially important question because we now have lots of good choices for many of these diseases, but thinking about which patient should get which drug is the most important thing that we do, and discussing them with our patients can be challenging because there are lots of choices and we need to really steer the conversation in the right direction. I think each disease has a slightly different thought process, so it makes sense to go through them in kind.

First, atopic dermatitis. Most individuals getting systemic therapy for atopic dermatitis are going to start with an IL-4 IL-13 inhibitor. That is because those medications are very effective. They have a very good safety profile and many of our patients do quite well with them. However, not everybody responds as well as we would want to that medication in that case. The next thing I often reach for is a JAK inhibitor. JAK inhibitors are extraordinarily effective. There are head-to-head clinical trials looking at JAK inhibitors versus dupilumab, and we see that JAK inhibitors specifically upadacitinib outperforms dupilumab. However, JAK inhibitors are a bit more immunosuppressive. They can be issues for people who are smokers who have a history of blood clots, heart attacks because there are safety signals coming from JAK inhibitors in general, not necessarily the ones that we use for atopic dermatitis, but JAK inhibitors generally that it may increase some of this. People with a history of malignancy, current ongoing malignancy. These are reasons why you might have pause to use a JAK inhibitor even though you know that it might be more effective than an injectable IL-4, -13 inhibitor like dupilumab or lebrikizumab or tralokinumab.

Next one, I think about chronic urticaria. I think about this a little bit differently. Firstly, some of those patients do really well with IgE blockade. This is not something that actually has been particularly effective for atopic dermatitis, but for chronic urticaria, it can be. That's a really good treatment option, particularly for patients who have concomitant asthma for which that also works. However, more recently we have approval of dupilumab, an IL-4, -13 inhibitor for chronic urticaria, and actually it also works quite well in the dermatology setting. This is an agent that we are very comfortable with. There's no warning about anaphylaxis, and so you do not have to monitor patients the way you do with omalizumab, an IgE inhibitor, for this condition, and so some people do find it to be more convenient to use. And then a lot of people have both urticaria and eczema for example, or urticaria and asthma for example, and dupilumab can hit multiple of those diseases at the same time, so that can be very helpful as well. Additionally, for chronic urticaria, there are now that are approved, and this is an oral medication that can be quite helpful too.

Finally, when we think about prurigo nodularis, this can be quite a challenging condition to treat and it doesn't always respond well even to our best medications, but dupilumab has been very helpful for this and many patients do quite well on dupilumab and so for me, I often reach there first.

What have we learned from real-world use of dupilumab in PN and chronic spontaneous urticaria that has changed expectations compared with its use in eczema?

Dr Cohen: Dupilumab for atopic dermatitis was a real and continues to be a real game changer. Lots of patients do really, really well with this medication and patients who do well, the response is rapid, the response is dramatic, and people love this medication. They do really well. This is still true for prurigo nodularis and chronic spontaneous urticaria, however, the response is not necessarily quite as quick and the response is not necessarily quite as strong, and so it's important for us to understand in our own minds as dermatologists, but also to talk with our patients about the fact that our expectations may be somewhat different. We don't necessarily expect to see as dramatic a response as quickly in prurigo nodularis or urticaria as we did for atopic dermatitis. The important part of that is that we need to understand that we need to expect that it may take a little longer, it may not work quite as well so that we don't decide that the medication is not working when in fact it is, and so that we can encourage our patients to keep trying and to stay on a medication that is helping them even though it may not be as effective as we may ideally want it to be because these conditions can be challenging and we may not necessarily be able to achieve quite as good of a response as we may want despite our best medications.

IL-31-targeted therapies are reshaping itch management. Where do you see them fitting best compared with broader type 2 blockade?

Dr Cohen: IL-31 is really important for itch and the most important thing to think about is which patients will do the best with an IL-31 inhibitor as opposed to, for example, an IL-4 IL-13 inhibitor. For me, when I see patients who are having itch that is debilitating them, itch that seems to be more than the rash. For example, people sometimes have only a little bit of body surface area. What we might consider to be not the most severe atopic dermatitis but describe totally debilitating itch or prurigo nodularis that did not respond to other medications and they just have such itch that they cannot sleep through the night or do the things that they want to do. Those are the ideal patients for IL-31 blockade. On the other side, I think when people have really high body surface area atopic dermatitis or are just so involved with atopic dermatitis that you think that they need really the most effective atopic dermatitis control, this may not be the best choice for that person because truthfully, the IL-31 inhibitor nemolizumab does not work quite as well as, for example, dupilumab, an IL-4, -13 inhibitor. And so I think that this is really important for us to keep in mind as we try to select the right therapy for the right patient based on what their symptoms are and also how their clinical appearance is in the office.

For patients who fail or plateau on biologic therapy, how do JAK inhibitors fit into your escalation or sequencing strategy?

Dr Cohen: When people flare or plateau on biologic therapies, I think the most important thing to do is first just take a beat and ask yourself what is really going on? For example, if the person has flared well out of control, you may wonder, am I sure I have the right diagnosis? Am I sure I have the right treatment? There's a body of literature around what you might do if someone flares, for example on dupilumab, and that may involve taking a step back and saying, do I need to do a biopsy? Do I need to run some lab tests? Have I missed for example, cutaneous T-cell lymphoma? Did the person actually have psoriasis and I've been treating them for atopic dermatitis the whole time? Something like that. So I think before you do anything and think about the next step in treatment, it's important to just step back, take a breath, and make sure that we're on the same page and everything's going as it should.
Once you've established that, the next question in my mind is, is this a big flare, a big deviation, or is this a small flare or a plateau that we're happy with or a plateau that we're not happy with? If it's a plateau that we're happy with or a small deviation, honestly, sometimes adding a little bit of a topical medication or some other small adjustment like that while leaving them on their systemic therapy can be absolutely acceptable and work very well. Other times you might say our IL-4 IL-13 inhibitor, for example, is just not cutting it, and we need to do something that is more effective, even though the person may be a bit better, for example, on their current regimen, we're not in a place that's acceptable, and in that case, I think thinking about a JAK inhibitor for the appropriate candidate is really helpful and can totally change the game for patients. So when people are either not responsive or not responsive enough or do have a flare and have what we call secondary failure, they stop responding to their IL-4 IL-13 inhibitor, for example. That's the perfect time and the appropriate candidate to reach for JAK inhibitor, and sometimes you can quickly recapture control there, keep the person stable on that medication and have them doing really well going forward on the JAK inhibitor.

How do you manage patients with overlapping type 2 diseases—for example, eczema with chronic urticaria—when choosing systemic therapy?

Dr Cohen: In this case, I think it's important to remember the adage hitting two birds with one stone. Now that we know that many of our treatments do work for multiple things, for example, people who have atopic dermatitis, prurigo nodularis together, people who have atopic dermatitis and chronic urticaria together, it is now possible to choose one agent that is FDA approved for multiple of these things, and this is no different from what we've been doing for years. When we look for example at dupilumab in patients with concomitant atopic dermatitis and asthma or concomitant atopic dermatitis and eosinophilic esophagitis where we've reached for dupilumab as an appropriate treatment for more than one of the conditions they have, and this is the same in skin disease. And to be honest, before these were FDA approved for prurigo nodularis or for chronic urticaria, we saw that our patients with atopic dermatitis on dupilumab and these other conditions had improvement in both their atopic dermatitis and these other concomitant comorbidities. And so we're not surprised to see this, but the fact that the drugs are now FDA approved for this and the fact that we have strong clinical trial data for this just makes us feel more comfortable that we're really adequately addressing all of the patient's skin conditions with potentially the same medication and allows us to talk to patients in a more authoritative way about expecting that they will get better, not only with atopic dermatitis but also with chronic urticaria, when we start dupilumab, for example.

Are there clinical features or biomarkers that help you predict which patients will respond best to specific type 2-targeted treatments?

Dr Cohen: This is something that has really been a holy grail in dermatology. In general, in the house of medicine, there's a lot of discussion about how to personalize treatment. How can we get the right drug into the right patient at the right time? And inflammatory skin disease is no stranger to this. We are doing a lot to try to figure out how to perfectly match a drug to a patient, mainly by looking at clinical features and also looking at the immunological underpinnings of what's going on in an individual's skin when they present with an inflammatory skin disease. Unfortunately, at the moment, we are pretty limited in the type 2 space in terms of having an actual product that we can use to evaluate someone's underlying immunology and think about which medication might be the best for them. This is a very active area of research and for example, in our group, we've done what's called RNA in situ hybridization to look at IL-13 signal in atopic dermatitis biopsies, and it turns out that the more signal you have, the better you respond to dupilumab, and people are doing this with all sorts of different approaches. And so I do believe that one day we will have a very robust way to look at biomarkers, either clinical biomarkers or immunological biomarkers to try to figure out which patients should get which drug and make the trial and error nature of systemic therapy for inflammatory skin disease much less of a problem than it is today. But that's something that I think we'll see in the future and something I hope we see in the future because I think it will benefit our patients and also make our jobs a lot more rewarding by knowing that we're giving the right patient the right medication at the right time.

Looking ahead, which late-stage or emerging type 2 therapies do you think will most meaningfully change dermatology practice in the next few years?

Dr Cohen: This turns out to be a pretty exciting time in the pipeline for type 2 immune disorders. One mechanism that I think we should all have our eyes on is the OX40, OX40 ligand mechanism of action, which will be approved at some point for atopic dermatitis. This is a different way of approaching that type 2 inflammatory process that's underlying atopic dermatitis. And this will be yet another mechanism of action for patients who either don't respond or are not good candidates to the currently available medications. These agents are in pretty late-stage clinical trials, so you can see them in your journals and you can see them at conferences, and I think sometime in the relatively near future we may see some of these available on the market for use. In addition, there are more Bruton tyrosine kinase inhibitors that are being studied for chronic urticaria. There's currently one out right now, and there's also a c-Kit inhibitor that's being studied in clinical trials for chronic urticaria, which I think we'll also eventually potentially see on the market.