Mechanism of action and treatment selection for AD in patients with colored skin

Neal Bhatia, MD: I’ll put 2 of you on the spot. I will ask you, Omar, to give me the synopsis of the mechanism of action [MOA] of organic products. Angela, I’m going to ask you the same question about JAK. [Janus kinase] inhibitors. Omar, you go first. I’m the average Joe patient coming in, or I’m the average Joe dermatologist at 1 of your lectures. How would you describe the mode of action of biological products?

Omar Noor, MD, FAAD: With regard to biologics, and with regard to atopic dermatitis, we have identified that in the immune system, in its simplest form, there is a Th1 and Th2 phenotype of patients. The Th1 phenotype is more related to psoriasis, with cytokines associated with psoriasis. The Th2 phenotype has cytokines associated with atopic dermatitis. Diving deeper into these different cytokines that produce the inflammation that we see with eczema, we see IL-4, IL-13, TSLP, and IL-31. I grew up with pharmaceutical industries creating target drugs, which later gave me a greater appreciation for the immune system. IL-4 and IL-13 are specifically implicated in different eczema factors, whether class B switching or antimicrobial peptides, increasing the risk of staph infections in our patients atopic. Beyond, beyond producing inflammation, these IL-4 and IL-13 are also involved in barrier breakdown. When we target these cytokines with biologics like dupilumab, tralokinumab, and future biologics coming to market, we can minimize the immune system’s response to these cytokines and their downstream effect. This is essentially how we minimize the phenotype of these atopic patients and how that translates into clinical practice.

Neal Bhatia, MD: It’s excellent. This sheds light on the targeting of immune mechanisms and where things stand, in terms of coverage or tracking 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 topical ruxolitinib as well. I didn’t want to overlook that. I want to hear your progress on how we went from crisaborole and tacrolimus to topical ruxolitinib and obviously how the 12 year upadacitinib indication is helpful. Give us the practical details with some of these descriptors.

Angela Lamb, MD: The first thing is to understand 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, modulate and up-regulate some of the phenotype that we see in atopic dermatitis. You see the lichenification, you see the itch, and you see this whole itch-scratch cycle. The beautiful thing about these JAK inhibitors is that they come in and block that pathway. They practically prevent the formation of these cytokines at the nuclear level. It all flows. What makes JAK inhibitors so different is that they block the whole process, and that’s why you see some of these adverse effects, because several of the more non-specific ones inhibit B and T cell proliferation This is why we see some of the hematopoietic side effects. I find them incredibly exciting, and it all comes down to that pathway and JAK-STAT output in the core.

Neal Bhatia, MD: It fits perfectly with one of my favorite analogies: turning off the tap or cleaning up the mess, because you’re stopping the process in its tracks to some extent. This is something you can talk to parents about. You tell them we’re going to try to prevent this from happening. Even though you don’t want to put this in the context of prevention and cure, you mean 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 hot topics or systemic agents that we talked about that would be a barrier to talking to different racial groups or different ethnic groups? We touched on that, but now we 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 that. Is there anything else we should focus on? Omar, I’m going to ask you the same thing: is there anything else we’re missing?

Angela Lamb, MD: For some of the newer ones, most important is this idea that you absolutely have to do lab checks. What I liked about dupilumab is what you just basically said: there are potential side effects, but no lab. As soon as you start telling people that we may need to check your lipids, we’ll make sure you don’t have TB [tuberculosis], we need to check your liver, it may discourage people. These are harder conversations to have. When I talk to patients or when I do decision trees in my mind about which one to choose, it’s often patients I know well. Frankly, I’m swayed by who will be more discouraged by an injection once in a while versus a pill – every day, not an injection, but some labs. With these conversations, while I think 1 may work better, the potential side effects are definitely things I need to think about.

Neal Bhatia, MD: It’s quite encompassing. Playing defense is what we do pretty much all day, so it would be nice to get past that and get some things done. Omar, how would you answer that same question?

Omar Noor, MD, FAAD: This discussion is important because it lets us know, as Angela mentioned earlier, that not everyone is the same. People ask me all the time, “What is the first drug you use and why?” I tell everyone that there is no first med algorithm; each person is different. I’m not a vending machine, am I? If a patient comes in with atopic dermatitis, I don’t just put A6 and you get the first drug, then if that drug fails, you get the second drug. This is not the world we live in. Everyone is built differently. Every situation is different. A lot of things come into play. There are patient preferences and cultural biases that we’ve talked about. There are genetic susceptibilities that patients will do better with 1 drug over the other.

By having this discussion about patients with skin of color, we increase our knowledge and education to target patients for better treatment. Unfortunately, at this time, we cannot be as specific about which drug brown patients will respond to, white patients will respond to, or black patients will respond to. There is no such thing; however, we are working towards this goal. What I want my patients to know when choosing a drug for them is my level of comfort with that drug in the patients I’ve used it on – what I’ve learned to see in my patients through a multitude of skin types, and what to 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 comes down to better communication, which plays a big role.

Neal Bhatia, MD: It is a good example. It reminds me a lot of how we talk to darker skinned people about sunscreen. Everyone has a preconceived idea: “I don’t need to do this. I am already dark. It does not mean anything. We don’t want to take apples and oranges out of the discussion of whoever is lighter or darker. Rather, it is about addressing the process. Let’s think about the fundamentals and get what’s under the hood with all of this. I come back to this analogy about the cost of not treating patients. You need to talk to them about the cost of not treating all facets of your disease, be it hydration, anti-itch and all that.

Transcript edited for clarity

Martin E. Berry