JAK Inhibitors and AD

EP: 1.The Burden of AD on Pediatric and Adult Patients

EP: 2.Symptoms and Severity of AD

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EP: 3.JAK Inhibitors and AD

EP: 4.Topical Therapy Landscape for AD

EP: 5.Important Topical Therapy Considerations for AD

EP: 6.Body Surface Area and AD

EP: 7.Topical Creams Are Important in Atopic Dermatitis Treatment

EP: 8.Breaking the AD Cycle

EP: 9.Prospective Therapies for AD

Transcript

Shawn Kwatra, MD: We focus on itch and pruritus, in general, since they're obviously very common afflictions in our atopic dermatitis patients. Can you comment a little bit about the JAK-STAT pathway in atopic dermatitis and inflammation? We've been learning more about that. We first learned about IL-4 and IL-13, IL-31, and then, JAK-STAT. What are your thoughts?

Peter Lio, MD, FAAD: It's been such a journey because we're learning that the itch of atopic dermatitis really is so fascinating to see how the understanding has changed. Now, we understand that a lot of those inflammatory cytokines are not just inflammatory; some of those cytokines are direct drivers of itch. We know IL-4 and 13 seem to be able to stimulate IL-31, the master itch cytokine, binding those nerve endings. The lesson that hasn't permeated the whole world yet, is that in general, this is not a histamine mediated itch. We have all of these patients, legions of them on antihistamines, which sometimes for other reasons, if you have seasonal allergy, and certainly if you use a first generation, you want to knock somebody out with that soporific effect, so that makes sense. But, some people take cetirizine every day and they say, “Should I be keeping on this?” And I'll say, “Well, if you don't have any other allergies, why don't we try stopping it because this probably isn't doing much for your itch.” Most of my patients taking it just for that putative itch, they say, “Yeah, it wasn't. It doesn't do anything.” I'm like, “Good, let's just get you off of some of these medicines because this pathway is so different.” That's where the JAK-STAT pathway comes in. We've learned that a lot of these inflammatory cytokines share the next step in the relay race. They bind to their cell surface receptors, IL-4, IL-13, and even some of the interferon ones. TSLP probably is part of this whole story, as well the alarmins, and then, when they bind, inside of the cell is the JAK and STAT enzymes and they can trigger nuclear change. Particularly it sounds like JAK-1 and JAK-2 are kind of the big ones that we are interested in. If we can block that, or slow that signal down, then in a way, we can kind of take out a number of cytokines or modulate against a number of relevant cytokines at the same time instead of just targeting them individually. This is effective because we have things that can target even something just like IL-13 that has a powerful effect on itch and inflammation but imagine if we could do it a little bit more broadly.

Shawn Kwatra, MD: Absolutely. I love your point about histaminergic vs nonhistaminergic itch. You hit the nail on the head. There's been this belief that antihistamines are great for any forms of itch, but apart from chronic spontaneous urticaria or hives, many of these classical conditions that we treat with antihistamines actually aren't the right pathway, like you mentioned. There was a study showing that nonsedating antihistamines, so Claritin and Zyrtec don’t do much at all. We know the itch has some of a placebo effect, some of the sedating antihistamines like Benadryl or Hydroxyzine, and agents like that. There's a study showing that they can activate areas of the brain via fMRI imaging that are associated with scratch relief. It seems like there might be mechanisms centrally, apart from making someone super tired, that may be a mechanism though which it works, but we know that if you're taking an agent, which is super sedating, I worry about the effects on mental status and long-term effects like dementia. There've even been some studies showing that if you take a low dose nonsedating antihistamine for several years, it could increase your risk. I agree with you. JAK inhibitors in this target pathway are very interesting. In 2017, we know that we had this revolutionary moment with dupilumab getting approved and for us, IL-4 and IL-13 took their place in atopic dermatitis history as being very important mediators. Now, what we're also seeing is that IL-31 is key for itch induction, but not just IL-31; IL-22 is another important mediator. Some studies are finding, especially in different patient populations like African Americans, that they can be elevated. One of the reasons why I think that there is a role for JAK-STAT in atopic dermatitis is because in addition to this neural itch relay, it also covers a little bit of the heterogeneity in the disease because atopic dermatitis, as we both know, can present dramatically different. I've been so astonished. I don't know if you've been astonished Peter, but just seeing a patient with eczema in the classical flexural areas. Then, seeing, say, an Asian patient who often times has psoriasis like scaling. Then, seeing an African American or Black patient with these papules and bumps and even papular eczema or even sometimes prurigo-like nodules. Knowing that heterogeneity and what we see also translates to molecular heterogeneity in terms of the cytokines.

Peter Lio, MD, FAAD: I love it and I agree, and I feel like, not only do we see different presentations across different groups, across different individuals even within the same group, but even on the same patient. Sometimes, they'll have dyshidrotic eczema on their hands, nummular stuff going on the legs and thick like areas. There's so many different layers and I do think that are probably multiple diseases within this. Once we get these biomarkers figured out, we're going to be saying, “Oh, we clumped all these together,” but they have many similar pathophysiologic themes, they rhyme with each other, but we are going to hopefully one day be able to get personalized or precision medicine enough to say, “Gosh, the reason this didn't do so well on this patient is because this is really a little bit different, we should be using x, y, or z, as opposed to this other approach.”

Shawn Kwatra, MD: Absolutely.

Transcript edited for clarity.