Management of Type 2 Inflammation in Atopic Dermatitis - Episode 9
An overview of the three JAK inhibitor therapies available for the management of atopic dermatitis.
Peter A. Lio, MD: That brings us to our other new class, the JAK inhibitors. We have 3 available in the United States: 2 orals, upadacitinib [Rinvoq] and abrocitinib [Cibinqo]; and 1 topical, ruxolitinib. I like to tell the story of JAK inhibitors as if we’re following a relay race, a messaging cascade. One cell sends its cytokine to another cell, which binds to the cell surface receptor. That’s where our biologics are working—at the cytokine level, like tralokinumab, or at the receptor level, like dupilumab. When that binds, the receptor undergoes a conformational change. It transmits that message through the cell membrane inside the cell. That allows for dimerization of the JAK enzymes, which activate STAT, which goes into the nucleus. These guys are small molecules. They get into the cell and bind to JAK and affect JAK’s ability to continue that cascade. They’re really powerful.
The most striking thing about JAK inhibitors is their speed. Their speed of onset is remarkable. Frankly, it’s steroid-like. Within hours, you can start to see changes in the patients. Despite their incredible efficacy in terms of death and onset, they have more safety concerns than some biologic agents.
Dr Feldman, how do you think about them? As an allergist, you might not have as much exposure to these, but I’d love to hear your perception of them. Then I can go into a little more. As a dermatologist, I’m using them a lot already, but I respect that they have only dermatology indications.
Matt Feldman, MD: They have only dermatology indications, but I’d be interested to know if they have other indications down the line. There are even some case reports in patients who were in the phase 3 clinical trials for JAK inhibitors who were able to come off their asthma medication, were monitored with lung function analysis, and saw lung function improvement.
As you said, they’re almost steroid-like. They’re very quick. They’re very anti-inflammatory, but they’re promiscuous. Even a specific JAK1 inhibitor has intracellular transmitters after the signal from cell to cell that has been sent via cytokine and received via receptor. JAK1 is involved in interfering responses. JAK1 is involved in IL-6 responses. It’s impacting not just the type 2 inflammatory cascade.
As we’ve been discussing throughout this whole talk, atopic dermatitis is quite heterogeneous. For the more severe and chronic lesions, particularly in adults, you may have more of a polymorphic or pleiotropic inflammatory environment, so hitting more receptors might get you a better response. The problem is that you also potentially have more adverse effects. It’s a delicate balance. We’re going to get into this a little, in terms of sequencing our dosing strategies or our therapeutics in what we would choose: first, second, or third line.
Having a conversation with our patients about oral vs injection is important, but these therapies aren’t equivalent in terms of risk profile. We need to delve into the rapidity of the effect, the potential possible more potent improvement with the JAK inhibitors, but then some of the downsides as well in terms of infection, cytopenias, clot, etc.
Peter A. Lio, MD: Beautifully said. That was poetic. I loved when you said it was promiscuous. That’s a great way to think about it. They are, to some degree. We know there’s some selectivity, especially to the ones we’re talking about. There are more pan-JAK inhibitors. These are allegedly more selective, in particular for JAK1, but you’re right.
Matt Feldman, MD: That’s the point. They’re selective to JAK1, but JAK1 is involved in not just type 2 inflammatory responses.
Peter A. Lio, MD: Exactly. Great point. The JAK system is deep. It’s deep in the code of the computer, so you’re tinkering with some heavy stuff.
Transcript edited for clarity.