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Clinical

Karen M. Winkfield, MD, PhD; Narjust Florez, MD, FASCO; Gilberto de Lima Lopes Junior, MD, MBA, FASCO; Coral Olazagasti, MD; Vonetta M. Williams, MD, PhD

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The needs of the individual patients with atopic dermatitis come basically from the fundamentals. We talk a lot about their living situation, if they’re in a house or apartment, and what potential irritants they’re around, such as pets. Do they have a water softener? Do they have any exposures to other pollutants or irritants? Then we get into daily moisturizing and cleansing, their showering habits. We want to remind them to shower for less than 5 minutes a day with lukewarm water, not hot water. We try to watch for if they’re swimmers or anything else.

Then we’ll ask about foods. There are still very few correlations between foods and food allergies, but we still send them to an allergist if they want to get some testing done. Then you get into some of the other nuances, like scratching. When are they scratching the worst? Is it around bedtime or some other time of day? Are they putting anything on their fingertips to help numb up the skin? Even more so, it’s the experience of what they’ve been on before. Have they been on a lot of antihistamines? Have they used topicals? Have they had many courses of steroids, for example? All of that fits into the determinants of what we’re moving forward with.

Then it gets into some of the essentials, like patients’ age. Obviously, the color of their skin is going to have a lot to do with how much following because we’re going to make sure we’re not still dealing with violaceous erythema that could still be active in darker skin. Then we want to get into kids being helped by their parents. All of that comes into play. A lot of factors come into the discussion topics, as well as what the best options are for the patients.

With JAK [Janus kinase] inhibitors, we were fortunate to be investigators in the trials as they’ve been slowly reaching the market. Abrocitinib [Cibinqo] is for 18 years [old] and up. Upadacitinib [Rinvoq] is for 12 years [old] and up. But abrocitinib is dedicated to atopic dermatitis. It’s a dermatology drug, if you look at it that way. Upadacitinib has a lot of experience in the field in other specialties. They both come with a lot of upside.

The key to the dermatologist for adopting these into practice is the expectation of how fast things will get better, but also when you want to get laboratory tests. You want to check things at baseline, at 4 weeks, then with any dosing change, and also consider some blood tests like lipid check at about 12 weeks. Even more so is the understanding of what can we do top down. We can use steroids. We can use anti-itch lotions. The only thing that seems to be a contraindication is using biologics and JAK inhibitors together. But maybe we’ll learn more about that another day, especially with a topical version. Right now, the incorporation has to be getting past the access issues. Let’s get past the phobias. Let’s get patients better because that’s what’s missing in the market.

Anyone prescribing JAK inhibitors for atopic dermatitis should be aware of some of the potential issues that go along with what has been experienced in the rheumatology world where these indications came from. A lot of them were seen in patients aged 50 and up who were on other immunosuppressants or steroids. The black box warnings were brought to the dermatology space for that. But from what we saw on the trials, most of these medications are very safe. Unfortunately, there were some cases of deep vein thrombosis. There were a few patients with major cardiovascular events. One or 2 had a malignancy develop. More so, the laboratory monitoring of leukopenia and thrombocytopenia are things to watch for, as well as CPK [creatine phosphokinase] elevations, which could manifest as muscle aches. These are things that should be followed and monitored.

With serious adverse events, you obviously want to stop the drug right away. In patients who are of childbearing age, you want to discuss their timeline for having children and stop the drug then. With any serious infection, you want to make sure that the drug is stopped, and the infection is managed. Another issue that comes up is tuberculosis [TB], especially in areas that are endemic to TB or if a patient has a history of latent TB. You want to get those issues covered first. Then make sure to avoid any live vaccines with any of these drugs.

The real-world access is always a problem. It’s a struggle that we all have to deal with, whether you’re in dermatology or another specialty. The key is going to be defending the rationale for therapy, the safety of steroids and immunosuppressants, working off label, and any potential failures from biologics or topicals. The patient profile of someone who’s a good candidate for a topical JAK inhibitor is someone who has areas around the eyelids, intertriginous areas, and surface area that lends itself to being treated. The fatigue of steroids, the opportunity of steroids in some of those places, and the lack of efficacy should be good talking points to get topical JAK inhibitors coming. More so, it’s a matter of painting the picture in terms of who’s a good topical JAK inhibitor candidate.

This transcript has been edited for clarity.

Videos

Dr Bhatia concludes our discussion by outlining what factors physicians should be cognizant of when prescribing therapies to patients with AD.

Video Series

Prescribing AD Therapy: What to Consider

The mechanism of action of a Janus kinase [JAK] inhibitor starts with what a kinase does, which is develop phosphorylation with its target. If you think about the processes needed in cytokine intake and processing into the immune system and how it works, you have to think of the simple steps that are in play: the amortization of the cytokine receptor, the actual binding of the cytokine to that receptor, the docking of the STAT [signal transducer and activator of transcription] protein, then the carriage of that information on the STAT protein to the nucleus. Those several steps are very important. They also involve phosphorous. It’s like the passage of a battery when you think about where that phosphorous comes from. It has to be there to make the receptor come together to allow cytokine binding to allow for the STAT protein to dock and carry the inflammation down as well to go to the nucleus. All of those steps are essential.

When we think about what Janus kinase inhibitors do, they’re very specific to binding that enzyme so that those processes don’t receive that necessary phosphorous and therefore can’t continue. That’s some of the essential equations vs the biologic therapies that are readily available. For example, the interleukin-4 and interleukin-13 receptor blockade by dupilumab [Dupixent] is dupilumab blocking the receptor binding of those cytokines, but it isn’t depleting their population or affecting the cells. It’s just preventing the exertion of interleukin-4 and interleukin-13 to doing their job of making the pathogenesis of atopic dermatitis. Whereas tralokinumab [Adtralza] is going right after interleukin-13 itself. It has a significant impact on the cytokine, basically destroying it rather than going after the receptor. There a lot of variations in the approach. But as you see from all of them, they’re much more targeted and developed to stop the process of the disease rather than just mopping up the mess of inflammation that’s downstream.

We’ve learned [a lot] in the past couple of years with the development of Janus kinase inhibitors, starting with the original molecules, such as tofacitinib [Xeljanz] and a few others that were used in rheumatology and other disciplines. Now we have topical delivery of ruxolitinib [Jakafi] with the ruxolitinib 1.5% cream indicated for atopic dermatitis, which is a great asset. Because for one, it doesn’t have the steroid consequences, so we can use it head to toe. We can use it on the eyelids, in the intertriginous areas and not worry about any atrophic or absorption potential. It’s well suited for that patient who has 3% to 12% body surface area [BSA] affected. But even more so, we can use it with a lot of flexibility because of its speed of onset and the lack of any steroid-type effects.

The best part about what we’re learning about the flexibility of ruxolitinib cream is the long-term safety data, not just at 8 weeks but also at 52 weeks with how patients can use this and basically continue on with their daily lives. They can use it when things flare up and stop it or take holidays as they need to and keep moving. Obviously, there’s development of ruxolitinib cream in other disease states. But when we focus on atopic dermatitis, there are significant advantages obviously over triamcinolone, which has been studied head-to-head. But even more so, it’ll reduce our reliance on steroids. It’ll allows us to use steroids properly but without the consequences or steroid phobia in the world today.

The studies that brought topical ruxolitinib cream to the market were known as TRuE-AD1 and TRuE-AD2. The design was a dose-ranging study where 1.5% cream and .75% cream were studied [twice a day] head-to-head as well as against the vehicle. Remember, in dermatology, we don’t say placebo. We always say vehicle because we want to see the vehicle do something. There was basically a 2:2:1 ratio. Four out of 5 subjects got at least some active treatment in the trial design. But it was standard in terms of who was in the trial. Patients were 12 years of age and older. They all had to have a history of atopic dermatitis. Most of them were mild, but there were some moderate patients. There were a lot of different skin and color types as well as gender and age. But the vast majority were considered moderate. There were a few mild patients as well.

What’s interesting is the average BSA in those trials was about 10%. If you look at the data, they looked at the sprint effect compared with the vehicle of how many patients got better within 2 weeks, at 4 weeks, and then at 8 weeks. There were close to about 53% of the patients in each study by 8 weeks achieving that 2-grade improvement. Those are significant numbers of those who achieved success.

What they found that made an impact was the sprint effect of how fast things were getting better in a lot of patients. The flatter vehicle numbers were obvious in terms of the separation of the trial. But even more so what they found with safety. There’s no atrophogenic potential, so they can use it on different areas. In that 12%, there was nothing that would be considered to be excluded. But even more so, the NRS [numerical rating scale] data. Remember the rating scale numbers? Those who achieved 4-point improvement was also pretty significant. That’s where we’re going to see the test of these patients, how fast they’re going to get better within several days and even up to 8 weeks.

Finally, there was very little in terms of application site reactions, and very little in terms of anything that was of concern for permeation and such. Because everyone is asking you about black box warnings, you have to remember that a lot of these black box warnings were developed in patients with rheumatoid arthritis aged 50 and older on concomitant medications or had significant comorbidity. Those patients unfortunately also had other risks, but it affected the entire class of Janus kinase inhibitors. It’s very important to keep all of that in mind as well.

A dermatology expert highlights the role JAK inhibitors play in AD therapy, from mechanism of action to ruxolitinib and the TrUE AD1 and -2 trials.

The Impact of JAK Inhibitors in AD Treatment

 In dermatology, allergy, and across the board, we look at guidelines as a template and, in many cases, an update of different treatment options. The landscape has changed over the past several years—even decades—from topical therapies alone and immunosuppressives. We’ve gained many targeted therapies over the past several years. We were part of the clinical research trials for dupilumab and many of the Janus kinase inhibitors. Over time, we’ve seen these become part of the mainstream in dermatology in terms of how we’re treating the approach to not only make things go away but keep things away.

Patients still like to treat from the top down. We use steroids to put out fires. We use prednisone tapers as we need to. Topical anti-itch lotions as well as antihistamines are important. We have the cleansing and moisturizing instructions that we provide all the patients through the [American] Academy of Dermatology and our other outlets. If topical therapies aren’t working, we turn to oral and injectable therapies as the next steps, including calcineurin inhibitors and crisaborole, a phosphodiesterase-4 inhibitor. These work well to try to slow down a flare or even intercept it as it’s growing. The JAK inhibitors have given us a lot of opportunities to put things out fast. The biologics have given us opportunity to have staggered dosing of therapies that will work well for the long run with very few safety issues.

It’s going to be a management strategy where you work with the patients and say, “Who’s a topical patient? Who’s an oral patient? Who’s an injectable patient? Are we doing things from the top down as well as inside out?” All those approaches are essential to managing the disease. But if we’re not controlling the itch, we’re not doing our jobs completely.

The past couple of years, the treatment landscape has evolved from just topical therapies and systemic immunosuppressants, which aren’t specific for the disease or even indicated by FDA guidelines or clinical trial work. Drugs like methotrexate are psoriasis drugs and rheumatologic drugs. Cyclosporine is a transplant drug. CellCept [mycophenolate mofetil] is an immunosuppressive drug. But these tend to get used quite a bit for atopic dermatitis, but they don’t affect the same cell lines and even suppress immune responses, which can compromise patient safety.

Now that we have targeted treatment options that go after the cytokines that are involved or the development of cytokine inflammation and inhibiting it with Janus kinase inhibitors, we have many more targeted ways to interrupt the process and stop it in its tracks. I like to use the example of turning off the faucet vs mopping up the mess, because steroids, calcineurin inhibitors, and other immunosuppressives basically go after the amount of inflammation that’s developed, while targeted therapies try to stop it in its tracks from progressing.

Dr Neal Bhatia explains the available treatment options for patients with AD, including their relation to guideline recommendations.

Navigating the AD Treatment Landscape

 In the dermatology clinic, the patient journey [for atopic dermatitis] has been 1 of frustration in seeking resolution, not just treating results. It’s even more so trying to get some relief from itch, which is obviously the biggest symptom complex that goes along with their disease. This can vary from the mildest patients, who have 2% or 3% body surface area covered, to 50% and up.

These are patients who are scratching at stoplights while waiting for it to turn green, scratching in their cubicles at work, or unable to sleep. These patients have slow or very rapid quality-of-life changes depending on the severity. They’re looking for solutions that aren’t just bandages. They’re looking for things that could be more for the long run, and things that are safe in the hands of those who can treat them. We have opportunities with topicals, injectables, and pills. There are a lot of opportunities to make atopic dermatitis a little better controlled. That’s what patients need from the beginning.

The terms atopic dermatitis and eczema are often used interchangeably. But in dermatology we think of eczema as the symptom complex—itching, the breakdown of skin, fissuring, dryness—whereas dermatitis is something more objective. It’s more of the objective findings, like spongiosis changes under the microscope, the inflammatory cascade, erythema, lichenification, excoriation, and the population that make the EASI [Eczema Area and Severity Index] score. Obviously the -itis is inflammation of the skin. Atopic is basically part of atopy. Atopy is part of the Th2 [T helper 2 cells] side of immunity that involves several cell lines.

Even more, we think of asthma to the lungs, allergic rhinitis to the nose, and atopic dermatitis to the skin as part of the atopic triad. All those tend to go either hand in hand, or there may be overlap in some patients. Atopic dermatitis as a whole isn’t something we look at and say, “There’s a flare here and there. Let’s try to manage it.” We have to think in terms of what’s under the hood, how we keep that patient from getting worse, and getting some restoration of quality of life.

There are varied presentations of atopic dermatitis—mild, moderate, and severe. When we think of moderate and severe patients who’ve probably been treated by their primary care physician or somewhere else or have tried and failed over-the-counter medications, where there’s rapidly progressing surface area, we divide moderate and severe by surface area by the [Validated] Investigator [Global] Assessment [scale] or the physician assessment when we’re in the clinic. Even more so, the EASI score is a nice objective way of looking at things.

When you think about patients who have atopic dermatitis on their face, flexural surfaces, extremities, abdomen, or trunk, 1% of the surface area of your body is your palm, so you measure that based on the number of palms. Many would say that 20% and higher is severe, and moderate is 10% to 20%. But there’s also the quality of the plaques, how bad they are in terms of periorbital change, how much itching is involved, the amount of excoriation, and even more so the distribution that goes along with the objective change. Then you throw in the subjective impact of itching and poor sleep, the inability to take off your shirt and hold hands. We have a lot of patients with atopic dermatitis who don’t want to go swimming because they know it hurts. They have issues with showering and bathing. Even more so, there’s the patient who can’t look you in the eye because they’re so fatigued from their disease that they can’t concentrate at school or at work because they can’t sleep. This is where severity has a different kind of impact as well.

Neal Bhatia, MD, provides an overview of atopic dermatitis (AD) and the diagnostic process, as well as how its severity impacts the patient.

Dermatology

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