A Conversation About JAK Inhibitors in Atopic Dermatitis

“I feel like it’s impossible to keep up with what’s going on because before when it came to atopic dermatitis, we just didn’t have that much to talk about after some of the typical topical steroids. But now we have oral medicals, topical medications, and injectable medications. The armamentarium is so rich,” said Raj Chovatiya, MD, PhD, an assistant professor of dermatology at Northwestern University Feinberg School of Medicine and director of the Center for Eczema and Itch at Northwestern University in Chicago, Illinois.

During a Dermatology Times® DermView webinar series, Chovatiya and Lisa Swanson, MD, FAAD, a pediatric dermatologist at Ada West Dermatology in Meridian, Idaho, discussed how treatment options for atopic dermatitis have changed over the past 5 years and what future expansion might look like with Janus kinase (JAK) inhibitors. Swanson began by stressing how difficult it has been to treat certain inflammatory skin conditions, such as moderate to severe atopic dermatitis, moderate to severe psoriasis, alopecia areata, vitiligo, and hidradenitis suppurativa. Dupilumab (Dupixent; Regeneron Pharmaceuticals, Inc/Sanofi-Aventis US LLC) began to change the treatment landscape 5 years ago and has significantly improved how Swanson now treats her patients with severe atopic dermatitis.

Chovatiya echoed Swanson’s excitement about new treatment options such as topical ruxolitinib (Opzelura; Incyte Corporation), tralokinumab (Adbry; Leo Pharma Inc), upadacitinib (Rinvoq; AbbVie Inc), and abrocitinib (Cibinqo; Pfizer Inc). Chovatiya mentioned that the way dermatologists think about atopic dermatitis has shifted, as previously methotrexate or cyclosporine were used as a treatment option. Now she feels more optimistic about the numerous safe and effective options to choose from, which give patients more flexibility and personalization in their treatment options.

Regarding JAK inhibition and what factors play a role in atopic dermatitis, Chovatiya gave an overview of immune activation, immune dysregulation, and type 2 inflammatory signaling.

“When you think about some of these classic cytokine signals that are important to atopic dermatitis like IL-4, IL-13, IL-31, TSLP, [and] IL-33, these are all proteins that are floating around communicating with cells in the skin and immune cells, both locally and throughout the whole body, signaling a lot of the things that we think about that happen in atopic dermatitis. You really can’t get a protein to float its way into the cells, so you can think about the signaling pathway of JAK [inhibitors] and signal transducer and activator transcription as a relay race intermediary system that translates something from the outside of the cell into something the nucleus can act on with transcription and translation and further pro-inflammatory signals down the line,” said Chovatiya.

Each cytokine plays an important role; for example, IL-4 and IL-3 are associated with itch and barrier dysfunction, and IL-31 is also relevant to itch. TSLP and IL-33 are important early-phase cytokines or alarmins that kick-start actions from an epidermal level. Lastly, IL-22 is important for reactive thickening.

Swanson then moved on to discussing her experience with recently approved treatments for atopic dermatitis, beginning with topical ruxolitinib. According to Swanson, this is the first topical nonsteroid that can have the same or similar efficacy as a topical steroid in terms of speed of onset and overall effectiveness. She also chooses topical ruxolitinib for her patients who may be on the autistic spectrum or have tactile sensitivity because the application is nongreasy and feels acceptable to her patients.

Moving on to upadacitinib and abrocitinib, Swanson pointed out to viewers that the biggest take-home message with these 2 JAK inhibitors is their speed of onset.

“Within hours or within a day or 2, our patients are reporting how much better they feel. A lot of them can hardly believe it. I think a lot of them wonder if they’re experiencing a placebo effect of some kind because how could this be true that this could be working so quickly? And then it keeps working and they’re super happy and they express that joy to us, which makes us so much more joyful in the clinic,” said Swanson.

Chovatiya and Swanson both discussed how, in most cases, the extreme itch is what patients hate the most about having atopic dermatitis. But when dermatologists can use these newer therapy options and itch is the first symptom to subside, many patients hardly care what their skin looks like, they are just happy that they can sleep at night without the extreme itch.

“The rapidity and depth of response for itch may in fact be the one thing we need to think more about when it comes to therapy. And this is really where both topical ruxolitinib, abrocitinib, and upadacitinib really shine” said Chovatiya.

Regarding the safety of JAK inhibitors, Chovatiya gave an overview of why JAK inhibitors have received black box warnings. After the US Food and Drug Administration’s approval of tofacitinib (Xeljanz; Pfizer Inc), a broad JAK inhibitor, the agency wanted to see more data on certain signals that were apparent in the data related to mortality, major adverse cardiovascular events, renal thrombotic events, malignancy, and infections. Once findings were released after analyzing the potential adverse effects of tofacitinib, a black box warning was added to all JAK inhibitors, regardless of whether they were topical or oral.

Swanson encourages dermatologists to not shy away from JAK inhibitors just because of the black box warnings, and rather embrace what these inhibitors can do for their patients. Chovatiya echoed Swanson’s opinion and noted that he tells his patients the biggest risk is not treating their disease and letting it go uncontrolled.

“JAK inhibitors are here to stay, both in their topical and oral forms. They’re going to probably revolutionize the way we treat a lot of different diseases, even beyond atopic dermatitis,” said Chovatiya.

To end their informative discussion, Chovatiya and Swanson reviewed the future treatment landscape of atopic dermatitis and some challenges that may arise. Swanson noted that the past 10 years have been devoted to psoriasis, and she sees the next 10 years being devoted to atopic dermatitis. Swanson looks forward to the coming years and numerous advancements in atopic dermatitis treatment. Chovatiya mentioned that he wants to gain a better understanding of a few topics, including how dermatologists define control with atopic dermatitis, what being well controlled on medication means, and which drugs will be best for suppressing atopic dermatitis flares.

“I hope the future holds that age indications get younger and younger over time with future studies. We have dupilumab down to age 6 months and that’s super great, but I’d love to see some of these newer therapies gradually, over time in a safe way, have lower age indications because there are a lot of [children] that need a little bit more help,” Swanson added.

Reference

1. Chovatiya R, Swanson L. A conversation about JAK inhibitors in atopic dermatitis. Dermatology Times® DermView webinar. November 1, 2022. Accessed November 3, 2022. https://www.dermatologytimes.com/dermview/a-conversation-about-jak-inhibitors-in-atopic-dermatitis