Breaking Down JAKs and TYKs

JAKi pathway

Image courtesy of DermNetZ

During her session “Let’s Get JAK’d and TYK’d,” Kristine Kucera, PA-C, MPAS, DHS, presented a detailed breakdown of the JAK-STAT pathway, the JAK family, small molecule therapies that inhibit JAK proteins, and more. Kucera, a physician assistant at Bare Dermatology in Dallas, Texas, emphasized to attendees the importance of understanding the JAK-STAT pathway and the different dermatology therapies in the JAK family.

The JAK-STAT pathway, or the Janus kinase signal transducer and activator of transcription signaling pathway, is “regarded as one of the central communication nodes in the cell function,” according to Kucera. The JAK-STAT pathway is part of a rapid membrane-to-nucleus signaling module that plays a key role in immune function. Dysregulation of the JAK-STAT pathway is associated with several types of cancers and autoimmune conditions. JAK1, JAK2, JAK3, and TYK2 make up the JAK family. According to Kucera, the connection between JAK and STAT started in 1992, with 7 members of the STAT family that all communicate with each other.

In a quick breakdown of the JAK family:

• JAK1: Works in pair with TYK2, JAK2, and JAK3
• JAK2: Works in pair with itself, TYK2, and JAK1
• JAK3: Works in pair with JAK1
• TYK2: Works in pair with JAK1 and JAK2

Currently available small molecule therapies in dermatology that inhibit JAK proteins include ruxolitinib cream 1.5%, upadacitinib (15mg and 30 mg orally), abrocitinib (100mg and 200mg orally), baricitinib (2mg or 4mg orally), deucravacitinib (6mg orally), and ritlecitinib (50mg orally).

For a more specific breakdown of the JAK family, Kucera provided the following JAK inhibitor list:

• Selective JAK1: abrocitinib, upadacitinib
• JAK1/JAK2: Baricitinib, ruxolitinib
• JAK1/JAK2/JAK3: tofacitinib
• JAK3/TEC kinase: ritlecitinib
• Selective TYK2: deucravacitinib

There are also many JAK inhibitors that are being evaluated for off-label use currently, including oral tofacitinib for psoriasis and vitiligo, topical ruxolitinib for alopecia areata and psoriasis, baricitinib for psoriasis and vitiligo, and upadacitinib for hidradenitis suppurativa.

“Soon, we’re going to see all of these indications hopefully coming through. So, to treat all of these inflammatory conditions that we see on a daily basis, you’re going to need to learn to get comfortable with these medications,” Kucera told attendees.

Kucera also touched on boxed warnings in JAK inhibitors due to the ORAL surveillance trial of tofacitinib. She urged attendees to be aware of the risks, but to also be prepared to openly talk about Boxed Warnings with patients to explain that yes there are risks, but that should not inhibit the use of all JAK inhibitors.

To help clinicians feel more comfortable with JAK inhibitors, Kucera encouraged everyone to keep up with data in the latest journals, listen to online dermatology podcasts, attend in-person and online conferences to network with key opinion leaders, chat with colleagues, and speak to the medical science teams of the various pharmaceutical companies.

Reference

Kucera K. Let’s get JAK’d and TYK’d. Presented at: 2023 Inflammatory Disease Summit; October 19, 2023; Las Vegas, NV.