Margaret Bobonich, DNP, FNP-C, DCNP, FAANP, and Douglas DiRuggiero, DMSc, PA-C, provide insight into the emerging class of JAK inhibitors for atopic dermatitis including their pathophysiology, route of administration, and available clinical evidence.
Margaret Bobonich, DNP, FNP-C, DCNP, FAANP: Now let’s talk about the JAKs. So, here’s the question. Is a JAK a JAK a JAK. So are they all clumped together Doug?
Douglas DiRuggiero, DMSc, PA-C: Well, I think the answer is no. And the reason is that if you kind of understand what JAKs are you can kind of see why. You know we’re talking about the difference in blocking things outside the cell wall, extracellular blockade of cytokines or receptors versus things you're blocking inside the cell wall or intracellular blockade. And that’s where these janus kinase inhibitors have their impact and their effect. We know that these kinases, which are these tyrosine activated. What happens is that these tyrosine kinases kind of – they phosphorylate ATP and take that phosphate group and attach it to another substance. And in this case it’s this JAK stat pathway, stat meaning these are signal transducers and activators of transcription. And that goes all the way back to like middle school biology where you're reading about how proteins are made. We get the blueprint out of the nucleus, then it comes out of the nuclear pore into cytoplasm and then we go through transcription where these little amino acids stack up and hold hands together and form a protein.
Well, you can develop inflammatory proteins with inflammatory signals. In the JAKs is what’s driving that process during this disease state. If we can block the receptor from this JAK pathway on the inside of the cell then that’s how we can affect disease. The problem is that so many other cytokines signals are happening through these same pathways. When you begin to move into the JAK world and the three JAKs that are going to come out probably first, which we’ll mention in a second, then you're looking at blocking these pathways, which many other important cytokines may need to go through in order to regulate healthy pathways for us. Because you’ve got four different kinds of JAKs. We’ve got a JAK1, JAK2, JAK3, and then this tyrosine kinase TYK2, T-Y-K2 that are there. And they line up in six different receptors with different pairs. They kind of are paired together. A JAK1, JAK2 at one site, a JAK1, TYK2 at another site, a JAK2 – so you can kind of see how that lines out. Depending on which one you're blocking you may be doing what’s called a pan JAK. You may be blocking all of the JAKs, all of the receptors, which could have more and does have more side effects or you be able to target it in on one.
These JAKs are not all the same. And these JAKs are very different from the monoclonal antibodies to say because they are considered immunosuppressive. And they do have other, more serious side effects. Let’s talk about that. First off, let’s talk about the pros from the JAKs. They’re oral and they’re not shots. That can be a game-changer if somebody is absolutely needle-phobic. But to take it in the oral side means you have to look at the efficacy and see if the efficacy outweighs the risk of them. And we’ve got, as you know Margaret, if you want to speak to these but we’ve got baricitinib that is already out, already approved for rheumatoid arthritis but we’re expecting the approval for atopic dermatitis to come out soon. We’ve got upadacitinib, already approved for rheumatoid arthritis, already been on the market, not yet approved for atopic dermatitis. We have two that we already have, we’re doing world data on, that are being prescribed by rheumatologists and other providers around the globe for rheumatoid arthritis. We know what these medications and their side effects are. Then we have abrocitinib, which is a JAK1 inhibitor, oral, not yet come to market, it’s not being used for any other indications, and it should come to market as its first indication being for atopic dermatitis. So, you want to go into talking about those more specifically?
Margaret Bobonich, DNP, FNP-C, DCNP, FAANP: No, I think the most important thing here is first of all is that we have this new class that’s going to be approved for atopic dermatitis. And it’s different than dupilumab. And there will be some screening most likely associated when they are FDA-approved. They're not going to be for children. They're going to be for adults. And I think that’s important. These are great things on the horizon but I think we just have to watch and I think we have to wait. But there are differences. So, a JAK is not a JAK is not a JAK. And so topicals. We talked about the systemic. What about topicals Doug?
Douglas DiRuggiero, DMSc, PA-C: We mentioned our topical JAKs already and the one that we’re excited to receive very soon is the ruxolitinib. So that’s our topical JAK. That’s a JAK1, JAK2 inhibitor that does it topically. And that’s the main one as I mentioned earlier that we’re going to see. But I want to make a clear distinction here. The oral JAK inhibitors we know that these are the people not to use oral JAKs on. If they have a history of severe infections, not going to use an oral JAK. If they have a history of malignancy, if they have a history of thrombosis. These are actually some black box warnings on the two JAKs that are already out being used in rheumatoid arthritis. So, malignancies, severe infections, thrombosis, it could affect renal, liver impact. It’s not great and should not be used in pregnancy or breastfeeding and you may have to adjust your dose. So those are all oral JAK problems. And that’s where you mentioned they have to check blood work on those, and you have to go into those. They’re very fast in their use. They may have some great utility. Some of them have greater clearance data like upadacitinib probably having the best clearance data over baricitinib. But they are medications that we’ll have to wait and see how they’re used. When we move into the topical JAK side, we’re not seeing all these same safety signals, which is what makes those topical JAKs, particularly the ruxolitinib, which we’re going to get first, an attractive offer because it’s different than the topical steroids and it doesn’t carry the safety signals that we see with the oral JAKs. It fits a nice niche, whether it’s going to be just first line and maintenance or added on to a monoclonal antibody or added to anything else that comes along the way.
Margaret Bobonich, DNP, FNP-C, DCNP, FAANP: Right. And I see that clinicians would be a little bit more comfortable using that topical and putting their toe into the pool of JAKs.
Douglas DiRuggiero, DMSc, PA-C: Right. I mean all of the new oral JAKs – there’s no reason why they cannot be used as first-line systemics but it’s just going to – we’re going to have to wait and see how the data pans out on whether or not that’s really going to be captured as first-line treatments or it’s going to be second line or it’s going to adjunctive. I think we’ll see. We’ll have to wait and watch the experts in our field to kind of begin to weigh in and see how these things are going to be utilized and then how we’re going to utilize them ourselves.
Margaret Bobonich, DNP, FNP-C, DCNP, FAANP: Thanks Doug. I agree. And I think that these oral JAKs give us an opportunity to kind of boost our armamentarium depending on how they’re FDA-approved, whether we use them as adjunct therapy across all severities, they are non-steroidal, they’re non-injectibles. So I think a lot of clinicians are going to feel much more comfortable going to this topical JAK.
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Transcript Edited for Clarity