Drs Noor and Lamb discuss mechanisms of action of biologics and JAK inhibitors and the importance of patient communication while selecting AD treatments.
Neal Bhatia, MD: I’m going to put you 2 on the spot. I’m going to ask you, Omar, to give me the synopsis of the mechanism of action [MOA] of biologics. Angela, I’m going to give you the same question for JAK [Janus kinase] inhibitors. Omar, you go first. I’m the average Joe patient who comes in, or I’m the average Joe dermatologist at 1 of your lectures. How would you describe the MOA of the biologics?
Omar Noor, MD, FAAD: When it comes to the biologics, and when it comes to atopic dermatitis, we’ve identified that in the immune system, in its simplest form, there’s a Th1 and a Th2 phenotype of patients. The Th1 phenotype is more psoriasis related, with cytokines associated with psoriasis. The Th2 phenotype has cytokines associated with atopic dermatitis. When diving deeper into these different cytokines that are producing the inflammation we see with eczema, we see IL-4, IL-13, TSLP, and IL-31. I’ve grown up with pharmaceutical industries creating medications to targets, which has then allowed me to better appreciate the immune system. IL-4 and IL-13 are specifically involved in different factors of eczema, whether it’s B-cell class switching or antimicrobial peptides, increasing the risk of staph infections in our atopic patients. Beyond that, beyond producing the inflammation, these IL-4 and IL-13 are also involved in barrier disruption. When we target these cytokines with biologics like dupilumab, tralokinumab, and future biologics that come to the market, we can minimize the immune system’s response to these cytokines and their downstream effect. That’s essentially how we’re minimizing the phenotype of these atopic patients and how it translates into clinical practice.
Neal Bhatia, MD: That’s excellent. It brings into the light the targeting of the immune mechanisms and where things are at, in terms of blanketing vs going after the process.
Omar Noor, MD, FAAD: Right.
Neal Bhatia, MD: Angela, I’ll give you the same charge for the JAK inhibitors. Feel free to include the topical ruxolitinib also. I didn’t mean to overlook that. I want to hear your progression of how we’ve gone form crisaborole and tacrolimus to topical ruxolitinib and obviously how the 12-year-old upadacitinib indication is helpful. Give us the nuts and bolts with some of those descriptors.
Angela Lamb, MD: The first thing is understanding the JAK-STAT [signal transducer and activator of transcription] pathway and how the interleukins that bind to those, where you don’t have the JAK inhibitors, upmodulate and regulate some of the phenotype we see in atopic dermatitis. You see the lichenification, you see the itching, and you see that whole itch-scratch cycle. What’s beautiful about these JAK inhibitors is they go in and block that pathway. They pretty much prevent the formation of those cytokines at the nuclear level. That all trickles down. What makes the JAK inhibitors so different is that they block the whole process, and that’s why you see some of those adverse effects, because several of the more nonspecific ones inhibit the B-cell and T-cell proliferation. That’s why we see some of the hematopoietic adverse effects. I find them incredibly exciting, and it all comes down to that JAK-STAT pathway and production in the nucleus.
Neal Bhatia, MD: That fits right into 1 of my favorite analogies: turning off the faucet vs mopping up the mess, because you’re stopping the process in its tracks to some degree. That’s something you can talk to parents about. You tell them we’re going to try to prevent what’s coming. Even though you don’t want to put it into a context of prevention and a cure, you want to say we’re trying to stop the process rather than just the result.
Angela Lamb, MD: Exactly.
Neal Bhatia, MD: Based on that, Angela, is there anything about any of the topicals or the systemic agents we talked about that would be a barrier in talking about with different racial groups or different ethnic groups? We touched on that, but now we’ve put the MOA in there.
Angela Lamb, MD: Sure.
Neal Bhatia, MD: You mentioned filaggrin. You mentioned some of the other issues that go along with this. Is there anything else that we should be focusing on? Omar, I’ll ask you the same thing: is there anything else we’re missing?
Angela Lamb, MD: For some of the newer ones, the biggest is this idea that you definitely have to do lab checks. What I liked about dupilumab was what you just basically said: there are some potential adverse effects but no labs. The minute you start telling people we may have to check your lipids—we’re going to make sure you don’t have TB [tuberculosis], we have to check your liver—that can throw people off. Those are harder conversations to have. When I talk to patients or when I’m doing decision trees in my mind about which 1 to select, these are often patients I know well. Frankly, I’m influenced by which person is going to be more put off by an injection every so often vs a pill—daily, no injection, but some labs. With those conversations, even if I think 1 may work better, the potential side effects are definitely things I have to think about.
Neal Bhatia, MD: That’s pretty encompassing. Playing defense is what we do pretty much all day, so it would be nice to get past that and get some things through. Omar, how would you take on that same question?
Omar Noor, MD, FAAD: This discussion is important because it’s allowing us to know, as Angela referred to earlier, that not every person is the same. People ask me all the time, “What’s the first medication you use, and why?” I tell everyone there’s no first-medication algorithm; every person is different. I’m not a vending machine, right? If a patient comes in with atopic dermatitis, I don’t just put in A6 and you get the first medication, and then if that medication fails, you get the second medication. That’s not the world that we live in. Everyone is built differently. Every situation is different. A lot of things go into it. There are patient preferences and cultural biases that we talked about. There are genetic susceptibilities that patients will do better with 1 medication vs the other.
By having this discussion about skin-of-color patients, we increase our knowledge and our education to target patients into better treatment. Unfortunately, at this moment in time, we can’t be so specific to say what medication brown patients will respond to, White patients will respond to, or Black patients will respond to. That doesn’t exist; however, we’re working to that goal. What I want my patients to know when I choose a medication for them is my comfort level with that medicine in patients I’ve used it on—what I’ve grown to see in my patients through a multitude of skin types, and what they should expect to see. When they understand that in a very communicative way, they can appreciate what I think is going to happen and then we go from there. It gets back to better communication, which plays a large role.
Neal Bhatia, MD: That’s a good example. It reminds me a lot of how we talk to people with darker skin types about sunscreen. Everyone has a preconceived notion:” I don’t need to do that. I’m already dark.” That doesn’t mean a thing. We don’t want to take apples and oranges away from the discussion of anyone who’s lighter or darker. It’s more about getting to the process. Let’s think about the fundamentals and get what’s under the hood with all that. I go back to that analogy about the cost of not treating patients. You have to talk to them about the cost of not treating all facets of your disease, whether it’s the moisturizing, the anti-itching, and everything else that goes with it.
Transcript Edited for Clarity