Dr Lio discusses features that make JAK inhibitors, including ruxolitinib, abrocitinib, baricitinib, and upadacitinib, attractive in the management of atopic dermatitis.
Peter A. Lio, MD: We know that the inflammatory cascade that we talk about has several little checkpoints, and the way it would go is, between cells they might use a cytokine. So one cell releases a cytokine, let’s take IL-4 [interleukin-4] for example, it comes from one cell and goes across to another cell. On the surface of that cell, there’s a receptor, and that cytokine binds to the receptor. When the receptor binds, it undergoes conformational changes, and those changes actually transmit the fact that it’s been bound through the cell membrane. Because this is outside the cell and there’s the membrane inside the cell, it transmits it. And down inside the cell, there are these little enzymes, they used to be called just another kinase, JAK. Now they’ve kind of “backronymed” them Janus kinase. These guys can dimerize, and then they activate something called STAT [signal transducer and activator of transcription]. STAT is another little enzyme buddy that goes into the nucleus and then changes gene transcription.
The JAK inhibitors, therefore, play an important role in a lot of this inflammatory itch and a lot of cell regulatory aspects. By blocking this, these little molecules, these JAK inhibitors go into the cell, and they can interfere with this dimerization and activation of them, which is really cool. That’s a great thing because they should help with itch, inflammation, and overall disease severity. The negative when we play with the JAK system is that that’s not the only thing it does. It’s not just playing a role in itch in atopic dermatitis. It plays a role in, for example, making new red blood cells, white blood cells, and platelets. You can interfere with other systems sometimes, and that’s the question. A lot of the JAK inhibitors that are now being studied, and the one that’s approved, are relatively selective. We’re trying to target more important ones, but we know this is a relative term. If you use enough of them at a high enough dose, you begin to get some untoward effects. Those adverse effects can be serious for the oral or systemic versions because they already do exist for other diseases.
We actually have a history with these medicines, for example, in rheumatoid arthritis. We know they can cause increased infections because they’re lowering the immune system. There’s an increased risk of cancers or malignancies in the longer term. They also can cause issues with platelets and other blood counts because, again, they’re kind of tinkering with some of these things. We’re trying to find the perfect balance there, and for the right patient, I think they’re going to be transformative, but we want to be very sagacious about how we pick those patients and how we use these medicines.
The JAK inhibitors are really unique because there are a couple of aspects to this class of medicines that’s exciting. First of all, because it’s a small molecule, it can be prepared as an oral therapy, the pills, but also as a topical because it can penetrate very well. It gets into the cells and gets deep, deep, deep into the root of this problem. It can block this JAK activation, which is really important. The second thing is that they work extremely quickly; as a class of medications they work so quickly that it’s pretty astounding. Many of the things we talk about, for example, the conventional immunosuppressants that we might use, like methotrexate off-label, of course, it’s not approved for atopic dermatitis use in the United States—that could take months. Whereas these JAK inhibitors are on the order of hours to days, it’s amazing. What’s also nice is that because they’re a small molecule, they can come in and out of the body very quickly. So we’ve been long thinking, is this something we could use more intermittently? Could you have somebody start it, get much better, and then maybe come off for a while? That we don’t know, but I love the idea that it’s fast on, fast off, and we really can be in and out quickly as opposed to these slower agents.
The other thing about them that’s really exciting is that they come in different types and different dosages. It is also possible that we could be a little more artistic with them. We could use a very strong one to start and then maybe taper down the dosing or the schedule, or maybe even the drug, use a milder one for maintenance. All of this is still so cutting edge, I don’t know, but these are the kinds of things that make them unique and exciting as a class.
Baricitinib, abrocitinib, and upadacitinib, from 3 different companies, those are the oral agents. Then the topical agent we have, just released, is called ruxolitinib. These are their drug names; they all have trade names as well. They are all similar in that they’re the same class. They all fundamentally have the same mechanism of action. But personally, as a clinician, I think it’s a little unfair to lump them completely together because each one is its own drug, even among the 3 oral ones. They have a little different binding selectivity. They have a little different dosing setup. It’s really fascinating. The oral ones, we think, will all be dosed twice daily. Maybe once daily, but it really seems like the plan was for twice daily. The topical one is also a twice daily cream.
All of them are going to probably have the same black box warning, for better or for worse. I was going to say, unfortunately, but I suppose there is a counterargument that we want to be as transparent as possible and educate as well as we can. The hard part as a clinician is that when we ratchet it up to a black box warning, there’s sort of no room for nuance. It’s one of those difficult situations because the patient looks at this and says, “Well, is this as dangerous as me smoking a pack of cigarettes,” which we also have a black box warning on. Is this the same level? The answer is, I don’t know, because we’re not having any gradations and because we’re not using our resources to help us know for a given patient. It becomes a very difficult conversation to have, especially for the topical cream, where it’s literally stated in the warning. All the warnings are about the oral formulations, so it is a very confusing thing to talk to a patient about who is now worried and say, “Well, if you read it, they’re actually not saying this drug at all, they’re talking about a different drug orally.”
This makes our job extremely difficult. It would be like if every time you got into a car, people gave you drag racing danger and precaution warning stuff. You’d say, “Well, I’m just going to work, I’m not drag racing.” Well, you’re in a car and people drag race cars, and it’s extremely dangerous, and you can be decapitated. And it’s like OK, I guess; at some point though are we doing more harm than good? That’s not for me to decide here, that’s for us as a society to come together, and our friends at the FDA to think about clearly if we’re doing more harm than good. The other problem is of course, if we cry wolf a lot, then we don’t have the ability to warn people when there really is something [to warn them about], because we keep escalating.
That being said, the oral medicines will certainly require blood monitoring and initial laboratory tests. We want to check liver, kidneys, blood counts. And probably every month or every few months, we’ll have to keep an eye on things, especially in the beginning. I sense that once things are better, probably we will not have to check as frequently. With the topical version, I don’t expect to have to do any blood work or plan to because as long as we’re using it appropriately and not on a large enough body surface area, which admittedly if you put a lot on, you could absorb it and then have the defacto systemic medicine, that’s real. But if we’re using it appropriately, I’d like to think that we won’t have to do that, and the safety issue should be much smaller. But there’s a lot to unpack there, everything from cardiovascular risks to blood clots, to cancer and malignancy, and also even things like infections or this acne-like eruption that’s been described. We have our work cut out for us.
Transcript edited for clarity.