In this video, Dr Chovatiya provides valuable insights into the science behind JAK inhibitors, their evolving history, and the diverse applications across dermatologic conditions such as psoriasis, atopic dermatitis, vitiligo, and alopecia areata.

Raj Chovatiya, MD, PhD, is an assistant professor of dermatology at the Northwestern University Feinberg School of Medicine in Chicago, IL, where he also directs the Eczema and Itch Clinic.

Transcript:

What are the latest updates in JAK inhibitors used to treat inflammatory skin diseases (ie psoriasis, atopic dermatitis, etc.)?

Dr Raj Chovatiya: My name is Dr. Raj Chovatiya, I'm a board-certified dermatologist based at Chicago, Illinois. And a huge love for talking about all things immunology and dermatology, and JAK inhibitors have really been one of the most fun and exciting ways that we've seen the science come to the real bedside for a lot of our diseases. And JAK inhibitors are really the forefront of that revolution. So JAK inhibitors essentially are a way that you can inhibit a really conserved important signaling program that is a part of a lot of different disease states. And to me, really some of the most exciting things that have happened include updates and medications that we have and new medications as well. So just very briefly touching on the whole space, in the case of atopic dermatitis, we have three JAK inhibitors to choose from, a topical JAK inhibitor called ruxolitinib. Some of the coolest data I've seen there involves itch improvement within minutes actually.

So there was recently presented data that showed even within about 15 minutes, statistically significant improvement in itch, which is really amazing thinking about the burden our patients face. In the case of upadacitinib, we really have a long-term clinical enterprise of safety across multiple different indications. Upadacitinib is really racking them up across the rheumatology and GI space as well. And so it's probably one of the best examples we have about thinking about safety across a lot of different diseases. In the case of abrocitinib, there's some really nice data that probably hasn't been presented nearly enough that actually is a really good example of what happens if you start somebody out on biologic therapy. And then if they don't respond appropriately, transition them over to an oral JAK inhibitor and watch them respond, which really gives us a good idea of what might be going on in the real world.

Now in the case of vitiligo, we have one JAK inhibitor currently, this is topical ruxolitinib also approved for atopic dermatitis. And one of the coolest pieces of data we've seen for vitiligo is extension data going to a year and beyond, which is really showing us that the longer you treat continuously, the better that people seem to do. Proven that vitiligo behaves very differently than diseases like atopic dermatitis or psoriasis. Now speaking of psoriasis, we have one JAK inhibitor, technically speaking, that currently is available. This one is an oral allosteric inhibitor of TYK2, which is one of the four JAK proteins. Now, this one's a little different because it doesn't bear the same boxed warning the others do in part related to mechanism, even though TYK2 is technically considered one of the four JAK proteins, it's exciting to not have to talk about a box warning with patients number one, but number two, it's really cool to have an oral option that actually has efficacy in the level of biologic therapy.

And there's some really nice recent data showing some modeling, looking at historical TNF-alpha inhibitor data and looking at oral TYK2 inhibitor data to suggest that you're actually having some better long-term responses as well. Now the final disease state I'll touch on is alopecia areata, where we have two JAK inhibitors. One, baricitinib, we've had for about one year now, and we have some really cool data that shows that for individuals that are long-term doing really well, if we drop them down to a lower dose, they might be able to actually maintain their responses. But if you end up discontinuing therapy altogether, individuals tend to bounce back to where they were suggesting that long-term treatment and modulation is necessary. Our newest JAK inhibitor is ritlecitinib, and this one is a mixed JAK3 and TEC Inhibitor, a slightly different signaling pathway. But I'll stick with just the top line results here. Very exciting meeting the primary endpoint of improvement in SALT scores for alopecia, and this one now offering us a chance to treat adolescents in addition to adults.

What combination therapies are available with the use of JAK Inhibitors?

Dr Raj Chovatiya: With JAK inhibitors, we have usually fairly wordy labels that suggest what we can and can't do based on what the FDA might want. And so one of the things in general with JAK inhibitors is because they haven't necessarily been studied in the context of big gun immunosuppressants and many other concurrent medications, you oftentimes have limits based on label. So most of them have been studied potentially with concurrent topical corticosteroids, particularly in the case of your atopic dermatitis drugs. But for most of the others, they were generally studied as monotherapy. Now speaking just from real world experience, we know in dermatology our treatment paradigms are oftentimes stepwise and additive, so people are oftentimes on concurrent therapies as well. I'd say in the atopic dermatitis and psoriasis world, very common for people to be using topical corticosteroids. And for the occasional rare really difficult patient, you may potentially need two systemic therapies as well. In the case of vitiligo, obviously topical corticosteroids could potentially be used adjunctively with a topical JAK inhibitor, but not something that's probably done quite as commonly unless you have a really extensive body surface area.

In the case of alopecia areata, oftentimes people are probably doing concurrent topical corticosteroids or injectable top steroids as well alongside JAK inhibitors. But by and large, based on label, usually the recommendation is not to be mixing other immunosuppressive medications.

How can physicians determine if JAK inhibitors are the best line of treatment for their patients with psoriasis, atopic dermatitis, or other inflammatory skin diseases?

Dr Raj Chovatiya: We are lucky in this era of inflammatory skin disease treatment that we have so many options and that list is going to continue growing. So I would be making a huge overstatement if I said every patient is the perfect patient for JAK inhibitors. And I think that it's important for us to understand, number one, what are the treatment options for each individual disease? Number two, what is the patient preference? I put that above all because we really need to understand, number one, is this somebody that even wants a medication that has this balance of efficacy, safety, and other characteristics, oral dosing, et cetera? And then three, understanding is this going to be the best trade-offs of efficacy and safety for a particular patient?

So, for some of the oral molecules, for somebody that might be older, have a variety of comorbidities, potentially histories of infectious, malignant, or venous thrombotic events that may not be your best patient. But for some of the diseases that really have no other treatments like alopecia areata or vitiligo, this is probably going to be your first line. And the safety does suggest that even we do have boxed warnings, they may not necessarily be super applicable to this population. And so I think that it's just a case by case individual discussion.

What additional tips and insights would you like to share with your colleagues regarding your session for Fall Clinical on JAK inhibitors?

Dr Raj Chovatiya: This is one of the most fun sessions I've had a chance to put together because I really got a chance to delve into a little bit of the history of JAK inhibition and a little bit of the actual immunology. And I think that we normally oftentimes want to think about scientific mechanism only as it relates to the exact purpose of treatment. And I think with JAK inhibitors, if you understand a little bit about how they evolved, how our understanding evolved, and what sort of very important role they play in a lot of different signaling pathways, you begin to appreciate why this is really an exciting area to target across multiple disease spaces. And just looking at primary endpoints and phase three data isn't going to really drive that point home. So I think that to really understand, appreciate, and think about the role JAK inhibitors are going to play in immunologic disease, you have to take it back a bit to the basics. And that's hopefully what I'm going to get across in my session at Fall Clinical.