Advances in the Management of Atopic Dermatitis - Episode 6

An Overview of JAK Inhibition in Atopic Dermatitis

October 14, 2021
Lawrence Eichenfield, MD

,
Raj Chovatiya, MD, PhD

,
Leon Kircik, MD

,
Peter Lio, MD

,
Elizabeth Swanson, MD

Shared insight on the available JAK inhibitors for atopic dermatitis, both topical and systemic.

Transcript:

Lawrence Eichenfield, MD: It’s a good time for us to transition to newer treatments. We’re going to discuss JAK inhibitors in atopic dermatitis. I’m going to take the lead and discuss the mechanism of JAK inhibitors. First, what are we talking about? Depending on when you finished medical school, if it wasn’t within the last few years, you probably didn’t hear much about the JAK-STAT pathway. It’s relatively new in the scheme of things and knowledge that there was this insight on important mediators of inflammation. Essentially, these are important mediators of inflammation in the skin.

The JAK-STAT pathway is essentially a pathway that’s important in cell signaling. What sits at the top of the cells are receptors that are essentially mediated by these enzymes. These enzymes are part of these nonreceptor kinases, and there are 4 of them: JAK1, JAK2, JAK3, and type 2. No one knows what happened to type 1. These come up in different combinations as these intracellular receptors, and they’re important because they modulate downstream signaling of inflammatory cytokines that are important in the pathogenesis of atopic dermatitis. They also influence itch. We often have these diagrams of the JAK-STAT pathway sitting at the bottom of a receptor that’s sitting in the cell. When the JAKs get activated, they enable docking of STATs, which then essentially do their thing and impact gene transcription inside the cells. Because of that, if you impact or interrupt STAT activation, there can be an anti-inflammatory effect.

Now we have targeted therapies that are essentially targeting JAK1, JAK2, or the different combinations. In targeting different parts of JAKs, you’re influencing some of the cytokines that influence atopic dermatitis; for instance, IL-4; IL-13; IL-31, the so-called itch cytokine; and TSLP [thymic stromal lymphopoietin]. When we talk about different agents that have been developed vs topical ruxolitinib, which is a JAK1/2, so it’s formulated as a topical inhibitor of JAK1/2 compared with topical tofacitinib, which is a pan-JAK inhibitor. The relative selectivity of the different JAKs is partially what will influence both its efficacy and potential adverse-effect profile, especially when we get outside the topicals and move into systemic.

That’s a good enough overview to know how these fit in. We’ll be discussing the drugs that are just about in our hands, like topical ruxolitinib, which is a JAK1/2, but we’ll also talk about systemic abrocitinib, baricitinib, and upadacitinib, which are being developed as oral JAK inhibitors. Lisa, what’s your sense about some of the features of JAK inhibitors that might make them unique in atopic dermatitis practice?

Elizabeth Swanson, MD: I’m really excited for these medicines. I’m ready to go JAK to the future. It’s really exciting. They’re unique. It’s a unique mechanism of action for us that we’re just getting more familiar with. I’m so excited for their approval. It will give us a topical nonsteroidal with pretty good efficacy. It’s really exciting to have a good topical nonsteroidal that’s going to help us a whole lot in treating our patients, and then the oral medications to treat systemically without the necessity of an injection, which will be appealing to a lot of folks.

This will be particularly good for our patients with atopic dermatitis who might also have vitiligo or alopecia areata. They’ll do very well with these JAK inhibitors. It will also be a brave new frontier of considering a systemic agent on an as-needed basis. That’s part of the plan for the marketing of the oral JAKs, that you wouldn’t necessarily have to keep a patient on it all the time. You could treat as needed for flare-ups and things like that. That’s unique to our world. When we think of systemic therapy, we typically think of keeping people on it. It will also be exciting for patients who either haven’t cleared on a medicine like Dupixent or have had adverse effects like the head and neck dermatitis, bad conjunctivitis, or the psoriasiform eruptions that we occasionally see with Dupixent. These JAK inhibitors will be a nice alternative for them.

Lawrence Eichenfield, MD: Any other comments from the crew?

Leon Kircik, MD: I’m as excited as Lisa, but I’m also I’m concerned about possible adverse events with the oral JAKs. Not the topical but the oral JAKs. I’m cautiously optimistic.

Lawrence Eichenfield, MD: We’ll come back to those issues with the oral JAKs in more detail. Raj, we’re talking about JAK inhibitors and whether they all have the same effect. What’s your sense of how they compare in terms of the route and frequency of administration? How’s your consciousness about the relationship of oral vs topical?

Raj Chovatiya, MD, PhD: As you mentioned that there’s varying selectivity across each JAK inhibitor, which influences a lot of what we talk about in terms of efficacy and sometimes the safety signals. As far as topical ruxolitinib goes, in the phase 3 trial data, this is a 1.5% cream used twice daily. It’s a JAK1/2 selective. In terms of the oral agents, baricitinib, abrocitinib, and upadacitinib were studied with flexible dosing, so a lower dose and a higher dose. Baricitinib is more JAK1/2 selective, whereas abrocitinib and upadacitinib are more JAK1 selective. All of them would be a single daily dosing. With ruxolitinib, a twice-daily dosing was looked at.

It’s difficult to compare across trials for obvious reasons, especially because ruxolitinib was studied in patients with mild to moderate atopic dermatitis. The oral JAK inhibitors were used in patients with more moderate to severe disease, but it seems like the oral agents are seemingly more potent than the topical agent, maybe unsurprisingly. In particular within the oral agents, JAK1 selectivity seems to be associated with higher efficacy, but in general across all the clinical domains we think about with atopic dermatitis, the data seem to suggest that they all act on eczema severity, itch seemingly fairly quickly, and quality of life. Even subgroup analyses on age, race, and ethnicity seem to have very similar findings as well.

Lawrence Eichenfield, MD: Great comments. I neglected to give the signpost of the selectivity of drugs that we’ll be discussing. I mentioned that ruxolitinib targets JAK1/2, and then 2 of the orals, abrocitinib and upadacitinib, are relatively selective JAK1s, and baricitinib is a little less selective. It’s a selective 1/2 with moderate activity against type 2 and significantly less against JAK3. For most of us, it’s going to take a lot of repetitions to get that right. It’s probably more important when the drug is ready for us to learn what that drug is like and the efficacy, safety, and tolerance that goes with each of them. Then we’ll be learning the differential mechanism as we move on.

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Transcript edited for clarity.

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