Navigating the Latest Therapeutic Options

Dermatologists’ armamentarium for treating atopic dermatitis (AD) continues to expand, with the most recent focused update to the American Academy of Dermatology (AAD) guidelines on the use of topical and systemic therapies for the management of AD now including strong recommendations for the use of tapinarof cream, roflumilast cream, lebrikizumab, and nemolizumab with concomitant topical therapy.¹ The guidelines had already included strong recommendations for two other biologics (dupilumab and tralokinumab), three systemic JAK inhibitors (upadacitinib, abrocitinib, and baricitinib), and four other topical therapies (topical corticosteroids, topical calcineurin inhibitors, crisaborole ointment, and ruxolitinib cream).¹ The guidelines also make conditional recommendations for the use of immunosuppressants methotrexate, azathioprine, cyclosporine, and mycophenolate mofetil, as well as for the use of phototherapy.¹

Of course, maximizing the positive impact of this array of therapeutic options depends on clinicians understanding when each option is most appropriate. Practical Dermatology Editorial Board member Raj Chovatiya, MD, PhD, MSCI, FAAD, discusses the most important points.

WHAT SYMPTOMS AND SIGNS DO YOU LOOK FOR DURING AN INITIAL EXAMINATION TO TRY TO DETERMINE WHICH THERAPY TO START A PATIENT ON FOR AD?

With atopic dermatitis, some skin signs and symptoms are more common than others. Typically, we’re talking about signs of cutaneous inflammation as the classic skin signs; this would be redness, scaling, lichenification, scratch marks, or even swelling, and then the key symptom is itch. There are other symptoms that patients can experience that are pretty common—skin pain, mental health symptoms, even sleep symptoms. The bottom line is that it is a holistic evaluation. For most of the medications available, we have data for multiple parameters of not only these skin signs, but also quality of life. Generally speaking, there are some differences from therapy to therapy, such as how quickly they might relieve itch or improve lesions, or how deep that response might be. That can be something that you use. Beyond that, however, the key is looking at the whole patient from head to toe.

HOW MUCH OF THE DECISION DEPENDS ON PATIENT PREFERENCE, WHETHER IT’S ORAL VS INJECTION VS TOPICAL, RELUCTANCE WITH BLACK BOX WARNINGS, ETC?

Shared decision making is so important. You can’t really make a good decision without understanding how the patient ranks and values preferences. Atopic dermatitis is a clinically diagnosed and assessed disease that doesn’t necessarily have a magical test where a swab or a blood test can determine severity and ideal treatment. All things being equal, most of our treatments are theoretically appropriate, depending on what the patient is looking for. Broadly speaking, some people might just be topical patients who will never want a systemic therapy, even if their disease is extensive or severe. You want patients to follow through on treatment. Some people are just not willing to tolerate certain routes of administration. Safety concerns, even if they’re minimal, might be a no-go for some people as well. In my practice, we really try to evaluate what the patient is looking for, what’s important to them in terms of specifics about efficacy and in terms of their itch. Are there certain trade-offs related to safety they’re willing or unwilling to make? Is there a certain preference on round of administration or other parameters about how fast something might work, how regularly they have to use the medication itself, long-term elements of control? For a typical moderate-to-severe AD patient, any one of our four currently approved biologics and two oral therapies could be a possibility and you really need to talk to them to understand how exactly each would fit with what they want.

WHAT FACTORS CAN MAKE A CASE OF ATOPIC DERMATITIS MORE CHALLENGING TO DIAGNOSE OR TREAT?

Atopic dermatitis is definitely not one-size-fits-all. It can affect patients differently based on how it presents. One big one that we’re really focusing on in current research and the next generation of therapies and trials is certain locations on the body. We know about head and neck atopic dermatitis, and facial dermatitis is a really tough one because there’s so much constant exposure to environmental components and personal products and it doesn’t necessarily respond as well as other parts of the body to atopic dermatitis therapies. Hands and feet are challenging for similar reasons; we know hands have a lot of other background factors on a day-to-day basis in terms of friction pressure, rubbing topical products, handwashing background, atopic dermatitis itself, so they don’t always necessarily respond the way that we want to in terms of our current atopic dermatitis therapies as well.

There are other considerations, too. Some people might be more itchy and have fewer skin lesions covering their whole body, and others may not be entirely itchy and have more dominance in terms of their lesions. People might have more symptomatic complaints that are in line with pain as opposed to itch. Most trial criteria, though, for getting a drug approved really requires someone to fit certain categories of having relatively extensive and severe disease so maybe an untapped area is understanding people who don’t necessarily check those boxes but are not getting control with their current therapeutic options.

WHEN YOU CONSIDER COMBINATION THERAPY, OTHER THAN COST WHAT DRAWBACKS KEEP YOU FROM ALWAYS ERRING ON THE SIDE OF USING MORE OPTIONS IN COMBINATION?

Combination therapy is definitely something that happens in the real world. We see it more with a topical and a systemic agent, which is just inherently a lot easier. It’s probably a little trickier with some of our newer topical therapies and some of our systemics, given insurance- and cost-related reasons, but we do it all the time with topical steroids and different injectable medications, or an oral and an injectable medication together. Now, what are the benefits versus potential concerns? We haven’t studied most of these treatments in combination with one another. Some of them have labeling, particularly the oral JAK inhibitors, recommending not combining them with systemic immunosuppressive agents or biologic agents. Our topical JAK inhibitor carries a similar warning. The biologics don’t necessarily specify that, but a lot of that is because we just don’t have bona fide Phase 3 and beyond clinical trial programs to suggest that there isn’t any tradeoff in terms of efficacy and safety. Now, the advantage is that some of these treatments work through different mechanisms of action, and we know that even with our best therapies, there are still people that don’t get 100% skin clearance and 100% itch improvement, or have other symptoms that are still not resolved. Potentially, there could be an additive effect from using two different mechanisms of action. I’m not sure how much of that will ever happen in the real world to lead us to a conclusion, but the next generation of trials are looking at a lot of bispecific treatments—essentially, antibodies that are either single molecules or in combination to recognize multiple targets.

ARE TRADITIONAL MOISTURIZERS STILL IMPORTANT IN THIS ERA OF ADVANCED THERAPEUTICS?

Great question. They remain the baseline therapy, pretty much, in every guideline set around the world in every country, just given the amount of data we have about really good barrier care. With atopic dermatitis, we think about certain modules of dysregulation. The skin barrier is not optimal. There’s dysregulation of the immune system. The microbiome is somewhat dysregulated. The cutaneous nervous system is somewhat dysregulated, too. As a result, a lot of our really successful treatments approved in recent years are primarily directed toward correcting the immune component of the disease, and they tend to secondarily have a beneficial effect across a lot of these other modules—the nerves, dysbiosis, even the skin barrier itself. We haven’t had much success in direct barrier-directed therapies that correct other elements of the disease, so as of now, moisturization is still the gold standard for directly affecting the skin barrier, trying to help repair some of the issues that happen in the epidermis that can drive the disease state itself. In most of our clinical trials, patients are expected to moisturize, oftentimes twice daily, so we don’t actually have biologic and oral medication data in the absence of moisturizers. We do know as well that patients with very mild disease or maybe very subclinical disease can get away with just moisturization, avoiding triggers, and being really good about bathing. Even with a lot of fancy stuff, moisturizers and emollients are still an important part of our counseling for all of our patients.

WITH ALL THAT IS NOW UNDERSTOOD ABOUT THE JAK STAT PATHWAY, IL-4, IL-13, IL-22, IL-31, ETC, IS THERE MUCH LEFT TO LEARN ABOUT THE PATHOPHYSIOLOGY OF AD?

We still have a big distance to go, even though we’ve made up a lot of ground in the last decade-plus. People often look to a disease state that saw a real seismic shift in terms of how we manage it, psoriasis; in a couple of decades, we’ve developed a number of treatments that can very selectively improve patients to the point of getting almost totally clear very quickly, sustainably, and durably without much safety trade-off. Atopic dermatitis is far more heterogeneous, so single targets are often unlikely to get somebody to the point of 100% clearance and 100% itch improvement every single time. That means that we still don’t have a really good grasp on what’s the right treatment for the right patient. Are there really important clinically indicative endotypes that should allow me to drive why I choose a particular treatment? That hasn’t come out yet. We do know that, based on what we’ve learned about the type 2 inflammatory pathway, cytokines like IL-4, IL-13, and IL-31 tend to be important in most patients, but even the drugs that target those pathways directly don’t get the majority of people to 90% to 100% skin clearance. Even with oral Janus kinase inhibitors, same deal. There is a lot more to understand in terms of different potential targets, both at the same level of the current targets or looking farther upstream or earlier in the initiation of the inflammation and the disease process. Or, is it a matter of combining different types of mechanisms together? We don’t really know the answer to that question, so that’s why the next decade of trials are designed to look at upstream molecules, checkpoint molecules, co-stimulatory molecules, combining different cytokine targets together, and other enzymes that we haven’t thought about targeting as it relates to the skin barrier.

IF THAT’S WHAT THE PIPELINE LOOKS LIKE, WHAT REAL-WORLD DATA WOULD YOU LIKE TO SEE IN RESEARCH ON EXISTING THERAPEUTICS?

The big thing that we’re still lacking is understanding why some patients continue to persist on therapies that may not necessarily be getting them to their treatment goals. What is the psyche behind switching? Now that we have so many options, we know that not everybody will get to an optimal target with one therapy, but we know that often the first therapy you end up choosing is the one that you end up sticking with, so what drives that choice and how should we be sequencing our therapies to have the best possible response? The real world will at least dictate a bit of that to help us understand. We have an idea that people tend to favor drugs that have been around longer, but how do people move to additional choices? Is there a class that seems to be more associated with a certain type of patient versus another, and how exactly does that look? This idea of combination is one that we’re starting to see a bit of in terms of cases; will that be a more common phenomenon or will it be very isolated?

Safety is always something people care about, and long-term safety in the real world is always nice to see. With our biologics, we’ve learned a lot about them, but there is more to learn. For example, some of the rare side effects associated with dupilumab never really came out in clinical trials, and it took real-world data to be able to catch some of those. Some of those ended up with label updates for the drug well after it was approved. As we have more time with all these medications, we might similarly find things like that that just weren’t picked up early in the process. 

The bottom line is, as the space gets increasingly crowded, you will never be able to do a clinical trial to understand how to sequence our therapies, so we need to almost democratize that with data to see exactly how people are using these and what patterns, combinations, or sequences seem to be the most optimal for our patients. 

Reference

1. Davis DMR, Frazer-Green L, ET AL. Focused update: Guidelines of care for the management of atopic dermatitis in adults. J Am Acad Dermatol. 2025;93(3):745.e1-745.e7. doi: 10.1016/j.jaad.2025.05.1386. Epub 2025 Jun 17.