JAK inhibitors: A new player for hard-to-treat skin conditions

[Chrissie Mackins-Crabtree] Oh, Gina, thank you. My absolute pleasure. It’s fun to try something new, and it’s always lovely to be with you.

[Gina Furnival] Well, I think today’s episode is definitely one for you to join. I know you personally spend a lot of time working on the educational content that you see on our websites, touchIMMUNOLOGY and touchDERMATOLOGY.

[Chrissie Mackins-Crabtree] So I have encountered this innovation in several of our activities, most recently relating to ulcerative colitis and prurigo nodularis. I can’t really think of many medical innovations that have, and continue to have, such a broad therapeutic impact.

[Gina Furnival] So very true. I think that leads me nicely to introducing our topic today and turning our focus to Janus kinase inhibitors, or JAK inhibitors as they’re more commonly known. Now today’s guest knows a great, great deal about this class of medication. So without further delay, please join me in sending a warm welcome to our guest today, Dr Bill Damsky. Bill, how are you today?

[Bill Damsky] I’m great. Thanks for having me.

[Gina Furnival] Our absolute pleasure. I think it’s fair to say that over the years, your investigations have paved the way for some really innovative treatments. For example, your focus on JAK inhibitors and how they could be used in dermatology has been particularly groundbreaking. For those that may not be aware, what is a JAK inhibitor, and how do they work?

[Bill Damsky] Yeah. So JAK inhibitors are oral small molecule kinase inhibitors. So they’re, pills, essentially. And it’s important to know that there are four JAK proteins. So JAK1, JAK2, JAK3, and TYK2. And JAK proteins control the activity of cytokines. So there’s greater than 50 cytokines that use this pathway. And cytokines, as many probably know, are small molecules that the immune system and other tissues use to communicate with each other, and they’re often upregulated in the setting of inflammation.

Most of the cytokines that use the JAK-STAT pathway rely entirely on the JAK proteins for signal transduction, and they don’t have their own intrinsic kinase activity. And so JAK inhibitors can simply be thought of as cytokine blockers. And depending on the specificity of the JAK inhibitor, whether it’s inhibiting JAK1 and JAK2 or JAK1 alone or JAK1, JAK2, and JAK3, you can imagine that you’d affect a large number of cytokines.

And so that’s really how they work, and I think that’s why they’ve been so useful in dermatology as well as other specialties.

[Gina Furnival] So for the first JAK inhibitor, it was investigated in 2000, I think, in haematology, and then later in RA in the field of rheumatology. Is that right?

That’s correct. Yep. Ruxolitinib. Yep.

[Gina Furnival] So what led you to investigate then the potential of this treatment in dermatology?

[Bill Damsky] Yeah. It’s a good question, and one that I like to talk about. So I was a dermatology resident at Yale from 2014 to 2017. And at that time, there was another dermatologist at Yale. He was named Brett King, who was beginning to use JAK inhibitors, initially in patients with alopecia areata, which is an inflammatory hair-loss condition. And this was based on some really nice work from Angela Cristiano and Raphael Clynes in New York, showing that this particular form of hair loss depended on JAK-STAT dependent cytokines. And by using a JAK inhibitor, could be reversed.

Dr King was, you know, very insightful in that he thought, well, you know, this works in alopecia areata. Alopecia is so hard to treat. What about some of our other inflammatory skin diseases that are also really hard to treat? Would this work there?

And I was kinda lucky to be in the right place at the right time with the right skill set. And, Dr King and I found that JAK inhibitors really showed pretty impressive efficacy in a large number of skin diseases that are inflammatory, which were difficult to treat: so sarcoidosis and granuloma annulare, are two granuloma skin diseases, which we’ll talk about more, atopic dermatitis, lichen planus, erythema multiforme to name a few.

And so it’s been sort of fun to identify dermatoses or inflammatory skin diseases that we think the JAK-STAT pathway is important and, through our work together, sort of generate at least proof-of-concept data that this was a reasonable treatment strategy for these patients.

[Gina Furnival] So the other potential of JAK inhibitors was really first realized in alopecia, as you mentioned, your research quickly moved into their potential in treating other hard-to-treat skin conditions. Could you tell us a bit more about your research then into using JAK inhibitors to treat these other conditions, and what drove you in this direction?

Yeah. I mean, I would say that we’re mostly focused on the granuloma skin diseases, sarcoidosis and granuloma annulare. So just tell you a little bit more about those. 

Sarcoidosis is an inflammatory disease that most commonly involves the lungs. About a third of patients have it in their skin. Really, any organ can be involved. It’s a pretty heterogeneous disease. The only FDA-approved therapy for sarcoidosis is prednisone or another glucocorticoid-related therapy, which just isn’t good enough because there are so many side effects from these medications.And what we found was that JAK inhibition can be effective in patients with sarcoidosis. It’s a really tough disease to have when it evolves the skin – it often involves the face; it can lead to scarring. It’s just a real problem. We don’t have a lot of great medications to offer patients. And so when my career was sort of unfolding, I really felt passionate about sarcoidosis. This is a disease that affects, in the US, predominantly black, African-American individuals, individuals from a lower socioeconomic status. And I just really felt that need and felt drawn to serve that particular indication.

And so that’s kinda where my focus has been. But it was fun to be involved in the use of JAK inhibitors in so many different skin diseases. And by using them in multiple skin diseases, and in the laboratory studying the immunologic changes that happen in the skin of these patients, it was really sort of, just informative to be used in so many different situations where our understanding of the immunology and how it’s manipulated could be compared across many diseases.

[Chrissie Mackins-Crabtree] That’s fantastic. So looking more broadly at dermatology, I know there’s been many exciting developments over the last kind of 20 years due to increased understanding of the underlying disease process and identifying new targets. So can you tell us why you believe JAK inhibitors represent that significant innovation in dermatology?

[Bill Damsky] Yeah. Thanks. I mean, really, the simple answer is that we can offer treatment to patients that we were never able to offer treatment to before.

JAK inhibitors are unique. I talked about their ability to inhibit cytokines. So they inhibit cytokines. That’s not unique necessarily. A lot of biologics inhibit cytokines.

But they’re really good at inhibiting interferon gamma, which is hard to target with existing biologics and other medications. And they often block multiple cytokines at a time. So you can imagine if you’re blocking interferon gamma and IL-15 and a few other cytokines, it’s sort of that, you know, shared inhibition can really shut down immune response quickly and effectively. And so I think it’s really that ability to inhibit interferon gamma and other cytokines, and the ability to treat patients that we’ve never really been able to effectively treat before.

So alopecia areata, vitiligo, patients with the atopic dermatitis that fail standard therapies, lichen planus… There’s some really exciting data under dermatomyositis, now hidradenitis suppurativa, our work in sarcoidosis and granuloma annulare. Really, the list goes on. So it’s really changing everything in dermatology.

[Chrissie Mackins-Crabtree] It’s really exciting.

Just to talk about the other side of things. So I know, historically, there’s been some controversy in terms of the safety of JAK inhibitors.

So I think most of that was based on studies in rheumatoid arthritis.

Can you tell us a little bit about those black box warnings that I think apply across the class, and what your take is?

[Bill Damsky] So the box warnings are the most important thing to know about these medicines. We know they’re effective, but we need to know when to use them appropriately and when not to use them. So the box warnings, in particular relate to malignancy, thrombosis or clotting, major adverse cardiovascular events and infection.

Most of the best long-term data that we have with JAK inhibitors comes from use of tofacitinib, which is an older JAK inhibitor in patients with rheumatoid arthritis. But the patients that were enrolled in this long-term monitoring study were patients that had cardiovascular risk factors at baseline. They also took a different medication called methotrexate. They often were also taking prednisone. These are medications that by themselves can have side effects.

And that’s really where these black box warning labels come from, is from that study of tofacitinib in rheumatoid arthritis. So probably the biggest question in dermatology is, how can we take the data from that study and use it to advise our patients that don’t have rheumatoid arthritis and don’t have cardiovascular risk factors and maybe are younger and not taking these other medications, like, how do we counsel them on what their risk is? And, ultimately, we just need long term studies in our dermatology indications, and those are happening, and those will be really important to see. 

When I’m thinking about starting a patient on a JAK inhibitor, I just view it as shared decision making. So we talk about the risk factors, what we know, what we don’t know, how the medication and their risk factors might apply to their situation, how the patient might have relief they’ve never had before from their skin condition, and that generally, these medications are well tolerated and, you know, significant adverse events are are very rare. But it’s a shared decision. So some patients are comfortable with that. Some patients aren’t. And we kind of just work through it on a case-to-case basis.

[Gina Furnival] How about affordability and accessibility? Can that represent a challenge for this class of medication?

There’s no perfect answer to this, but here in the US, insurance companies often don’t like to cover JAK inhibitors. It can be challenging to get for patients. We often have to appeal and write, you know, insurance appeal letters.

But often there’s no reasonable other option, and patients have failed things which are in the literature but just haven’t worked from them. And so, I think as we get more data and more studies, I hope access to these medications will increase because that’s just a practical challenge that we face.

[Chrissie Mackins-Crabtree] Absolutely.

So I think there are maybe 10 JAK inhibitors that are currently FDA-approved. Which dermatological conditions have an approved, JAK inhibitor option? And am I right in thinking that there are different formulations?

[Bill Damsky] You’re exactly right. So in dermatology, as things stand now, we have two FDA-approved, in the US, inhibitors for alopecia areata. So baricitinib and ritlecitinib. Ritlecitinib is an interesting drug in that it’s primarily a JAK3 inhibitor, which is unique.

As you’re alluding to, we have a topical JAK inhibitor, which is approved atopic dermatitis and vitiligo, and that’s ruxolitinib cream. Ruxolitinib was, again, one of these very early JAK inhibitors that will sort of transition to a topical formulation.

There’s two oral JAK inhibitors for atopic dermatitis. So abrocitinib and upadacitinib.

Deucravacitinib is really interesting. It’s a TYK2 allosteric inhibitor, so it works a little bit different than the other JAK inhibitors, which don’t tend to have potent TYK2 activity and work on the kinase site and not the allosteric site. That’s approved for psoriasis. It’s being studied in other things. 

And then as much as it relates to dermatology, psoriatic arthritis has a couple approvals. So tofacitinib and upadacitinib are also approved for psoriatic arthritis. That’s sort of the landscape as it stands today in terms of approvals, but there’s a lot happening.

[Chrissie Mackins-Crabtree] I was going to say, are there any imminent approvals that you see?

[Bill Damsky] Yeah. I think we probably will have another drug in alopecia areata soon. There’s a lot of sight excitement in JAK inhibitors, for dermatomyositis or hidradenitis suppurativa. And so I think these probably will be, you know, as much as I know, approved.

It’s hard to know exactly what happens behind the scenes, but the data looks good. But, really, I think over the next 5 or 10 years, there’s going to just be an explosion of JAK inhibitors in dermatology, both in terms of new drugs, and new indications. And, some of these newer indications, I think we’re going to see FDA approvals for, and this is down the road, for diseases where we’ve never had FDA approvals before. So, like, granuloma annulare, cutaneous sarcoidosis are some of the ones that I’m interested in, but it’s going to be a lot of different diseases; lichen planus, persistent erythema multiforme. The list is very long.

[Gina Furnival] Wow. They sound like a miracle drug, don’t they? Working out everything. So you’ve already mentioned, obviously, the future, the imminent future, the next five years, and you’ve mentioned these new JAK inhibitors that are potentially coming through. Are they different from the ones we have now? Are they a different type of selectivity?

[Bill Damsky] Yes. So it’s a really great question, and I think it’s a really important question and one that the field in general doesn’t have a great answer to. So I remember with the safety data with tofacitinib, which is a pretty broad JAK inhibitor, so JAK1, JAK3, JAK2, the thinking is that the newer JAK inhibitors, which are more targeted, so, like, JAK1 specific or TYK2 specific or JAK3 specific, I think the expectation there is that being more targeted is safer.

But, really, at the end of the day, we still don’t really understand the actual molecular mechanism of why patients are getting thrombosis, why patients are having major adverse cardiovascular events. And so I think it’s an assumption that the more targeted therapies will be safer, maybe in a different population than the rheumatoid arthritis studies. But until we really understand the mechanism by which those rare side effects are happening, I think it’s going to be hard to know one way or the other. And I think related to that, these medications are often marketed as being very specific or being specific and differentiated in some way. So, like, JAK1 specific or JAK3 specific or TYK2 specific.

And a lot of that’s based on in vitro studies, which obviously are important in defining activity. But I think understanding that sort of marketed specificity with what we’re actually seeing in patients and activity in patients with disease, and how that relates to these adverse events, I mean, those are, I think, really essential questions moving forward, that we just don’t have an update on at this point.

[Gina Furnival] Yeah. Indeed. So, obviously, you’re considering could we be more selective with the targets. But is there anything else anyone’s looking into in terms of managing any of the side effects or challenges with the treatment?

Yeah. There’s no good guidelines on this. You can imagine, just let’s take thrombosis. Maybe we should not have patients taking oral contraceptives, which can be sort of pro-thrombogenic.

Maybe we should be screening patients for, you know, hypercoagulable states. Otherwise, maybe we should be treating them with anticoagulants if they are at high risk. And these are a lot of the conversations that are happening, but haven’t really entered practice in any way that’s definable, or certainly, you know, consistent from practice to practice, but they are, conversations that are happening. But I really think just understanding in the lab why these side effects are occasionally happening will be really important. Until we understand why they’re happening, what the mechanism is, it’s going to be hard to do anything about it.

[Chrissie Mackins-Crabtree] It’s a super exciting time, and it sounds like there is massive potential. So we’re very much looking forward to seeing how JAK inhibitors can improve lives for other dermatological conditions going forward.

[Gina Furnival] Absolutely. I think they clearly had a huge impact, and will continue to do so in many fields, I’d say, beyond dermatology and also in rarer diseases, which is something everyone’s always, well I’m always interested in hearing about. So Bill, thank you so much for joining us today and telling us about this. It’s been great to be able to speak to you. Someone who’s actually been at the forefront and been involved in understanding the mechanisms of how JAK inhibitors can work and can be used safely. So thanks for being here.

Yeah. It’s a pleasure talking.

[Gina Furnival] Now before you go, please don’t forget, if you’ve enjoyed today’s episode, we’d love you to subscribe.

[Chrissie Mackins-Crabtree] We’d genuinely really love to hear from you. So please take a moment to go to LinkedIn and search for Touch Medical Media and follow our podcast series by going to Podbean and searching for Visionary Voices insights from healthcare professionals.

[Gina Furnival] Well, that’s it for today. As always, thank you for listening, and see you all again soon.