This webinar was recorded on October 19, 2023
Atopic dermatitis and eczema are often used interchangeably but there are subtle differences between the conditions. Learn how they are different and how atopic dermatitis can be treated with topical therapies, systemic therapies, biologic therapies, and JAK inhibitors.
- Clint Dunn, MD
Children’s Hospital of the King’s Daughters
Dr. Dunn is a board-certified physician in pediatrics and allergy/immunology. He trained at CHKD for his pediatric residency and fell in love with the specialty of allergy and immunology after working in the allergy division at CHKD. He moved to the Pacific Northwest after that and was thrilled at the recent opportunity to return to CHKD. He sees the full spectrum of conditions, including asthma, eczema, food allergies, hives, swelling, immunodeficiency, and immune dysregulation. He strives to incorporate evidence-based recommendations in evaluating and managing allergic and immunologic diseases.Dr. Dunn and his family are thrilled to grow roots in this community. Outside of medicine, he enjoys being outdoors, hiking, and exploring with his family. On his days off, he will likely be found cooking or baking and enjoying the science behind food and nutrition.
CNE for nurses, and CRCE’s for Respiratory Therapists is available through Allergy & Asthma Network’s Online Learning HQ
CME is available through ACAAI for this webinar.
Sponsored by the American College of Allergy, Asthma and Immunology
Transcript: While this transcript is believed to be accurate, errors sometimes occur. It remains your responsibility to evaluate the accuracy and completeness of the information in this transcript. This transcript is not intended to substitute for professional medical advice.
Lynda Mitchell: Hello everybody, thank you for being here, we will just wait a minute while people join us and then get started. Welcome everybody, we are going to get started in just a minute, maybe. We will wait for some more people to join us and then get going. I will go ahead and get started. Today’s topic is atopic dermatitis, JAK inhibitors and eczema. They are often used interchangeably but there is a subtle difference. Learn how they are different and how atopic dermatitis can be treated. It’s my pleasure to introduce Dr. Clint Dunn. He is a board-certified allergist in pediatrics and allergy and immunology. He trained at Children’s Hospital of the King’s Daughters for his pediatric residency and fell in love with the specialty of allergy and immunology after working in the allergy division at CHKD. He moved to the Pacific Northwest after that to work and was thrilled at the opportunity to return to Children’s Hospital of the King’s Daughters. He sees a whole spectrum of conditions, including asthma, eczema, allergies, hives, immunodeficiency, and immune dysregulation. He strives to incorporate evidence-based recommendations in evaluating and managing allergic and immunological conditions. Thank you for being here today, Dr. Dunn, I will turn it over to you.
Dr. Clint Dunn: My name is Dr. Dunn, and we will be talking through JAK inhibitors and systemic therapies for atopic dermatitis. These are my disclosures; none are pertinent to the lecture. Hopefully by the end we will be able to describe the fundamental features of atopic dermatitis, explain the treatment options in the ideal patient for each therapy as we go along. It’s important to start, anytime you start talking about diseases and therapies from a provider standpoint to understand the basics of the disease.
Just like Lynda said, a lot of the time eczema and atopic dermatitis are thrown together are mentioned in the same sentence. There is a difference and I’m going to be as specific as possible. Eczema is a general term for a description of the skin that means it’s itchy and dry, and there are many subsets of eczema, atopic dermatitis being the most common subset. You’ll see it called atopic dermatitis or atopic eczema. Atopic dermatitis is a complex disease. It’s an inflammatory condition of the skin which can affect the whole body and it starts with a skin barrier dysfunction, which for genetic reasons and environmental factors, causes a dysfunction in the outside layer of the skin that will increase the trans-epidermal water loss across the skin barrier and signal that it is under attack and needs help to try to help itself to call attention to the location and itch. That starts a cycle that perpetuates the singling downstream to call the immune system into the skin and cause dysregulation of the skin and the skin barrier and a dysbiotic change of the skin microbiome towards different bacterial species.
And because of the complexity, t’s important for us to treat across the spectrum as far as atopic dermatitis goes. Some more background as far as epidemiological data, 13% of children are affected by atopic dermatitis and 7% of adults. Most of them have an onset of symptoms prior to five years of age. 70% of patients have remission by adolescence but that remission does kind of differ for each individual. There is an equal distribution with different genders and different races and ethnicities. And because of the differences in the skin texture and makeup, there is spectrum of severity from mild to moderate to severe disease to location where some people it’s only in the creases, or some people is more head to toe. There are phenotypes that underlie the skin changes, and molecular changes which cause inflammation. It’s important to understand when you are talking about therapies that there is a progression with atopic dermatitis, where it starts as a skin barrier dysfunction , and then does progress to involve multiple disease states, including asthma, food allergies and rhinitis. It does not have to be a linear progression to asthma to allergic rhinitis, but it can skip options and show itself in different things.
I love this picture. This is from a lecture given during my training, it’s something that has stuck with me. Eczema, atopic eczema, is the itch that rashes. It starts at the skin barrier, where there is dysfunction in the skin barrier in the stratum corneum or at the skin cells where the cells don’t click together correctly. They are further apart because the tendrils that help hide this consultant are missing or defective. That leads to water loss and starts an intensely itchy process which progresses from there.
I would not be doing my job adequately if I was not going to talk about pathophysiology. There are different phases of atopic dermatitis, and that’s why it’s been harder to design specific therapies for it. There are acute phases of atopic dermatitis and chronic phases. Whenever there’s immune dysregulation, it’s a cascade where it starts the domino falling that progresses down to signal for help from the impaired skin barrier down to where it needs help. Then it skews that information as it progresses towards an allergic endo type that will perpetuate itself to then cause other allergic diseases and impairment of the skin. It progresses after a stretch of time from an acute to a chronic disease. When we talk about therapeutics, we will dive into some of these mechanisms that we think about for both acute and chronic diseases or acute or chronic atopic dermatitis. So that we know how to take care of them.
It’s important to say that this is something that is a big topic in atopic dermatitis, it is different for each ethnicity, it’s not one-size-fits-all, that you can actually approach each individual across ethnicities and say this is the only way there are similarities in the inflammation that is seen, there are similarities in the cell types seen, but the extent that you actually see the dysfunction and the thickness of the skin. In the barrier proteins that are affected is different for children or pediatric atopic dermatitis as well as individuals who are of Caucasian descent or of Asian descent or of African American descent. So instead of having a one size fits all we really have to be much more targeted into how we treat this disease state. It is a systemic disease that can cause many, many implications and it’s not just allergic, there are many different underlying changes. You can see we number them based off of the type of lymphocyte that is affected. There is a TH 22. In some people there’s TH 17, which is thought to be more of a regulatory aspect and we will talk through different aspects.
The major point of the talk is to talk about the JAK molecules that we think about, I will mention here the JAK signaling. When you actually look at the cytokines are kind of the signals from the skin that it needs help to call for the immune system to the party. Those signaling mechanisms have to start from one position and go to the next cell. For that progression you have to have a domino falling down, it starts as a ball that lends into a receptor or kind of into a glove and that signals through. The vast majority of our cytokines, whether inflammatory or allergic or different pathophysiology, that we think of every disease is signaled from a cellular standpoint, the messenger signal through what are called Janus kinase receptors. They are named after the Roman god Janu of the two phases because it requires two signals come together. And then those two signals on the inside, which are kind of what you see at the bottom. They’re kind of on the left side that talked about the different tracks that perpetuates the signal to the nucleus to cause transcription or causes to them to make proteins that have further implications. When we look at what medicines we are going to try to treat with, it’s important that we know the different kinds of Janus kinase signaling mechanisms. There are two different processes but uur immune system has a level of redundancy where it can affect itself in different ways, in which molecules we recruit. We have to find a delicate balance of decreasing the allergic cells but not affecting immunological function. That’s one of the biggest things we are paying attention to.
Anytime we talk about atopic dermatitis, we have to talk about the basics. The basics really do start with a skin hydration issue. I told you that it is a skin barrier dysfunction that leads to transepidermal water loss. The skin’s porous and more open and just like a sponge that dries out, we have to restore moisture. If you ask 10 different dermatologists, 10 different allergist immunologists, you will get 10 different answers on the appropriate way of going. But ultimately, it is a hydration standpoint where we make sure we focus on what we are doing from a bathing perspective, from an emollient or moisturization perspective, and that we avoid irritants and allergens that cause them.
The mainstay of therapy for atopic dermatitis is topical corticosteroids. Those have a lot of utilization and are the most commonly used therapies. They get a bad rap. They are ranked from 1-7, strongest to weakest. Every single guideline that we look at from the American Academy of Dermatology, as well as the American Academy of Allergy Asthma and Immunology and American College of Allergy Asthma and Immunology strongly recommends the use of topical steroids in different potency strengths. It’s important to understand as a provider where we are applying them, how long we use them, and what is the underlying skin texture we’re applying to. I’m not going to use the same strength on the face as I am going to use on unexposed skin or skin that actually kind of folds over each other. There are different ways of approaching it. There is acute therapy for acute flares where you have to calm down the inflammation in the skin. But then also if it has transitioned from an inflammatory disease to a chronic disease, you don’t treat that same way. There’s a different approach as to how frequently to use it. There is acute maintenance using it twice a day until the skin clears and then of different potency strengths and then backing off to maintenance with some mid to low potency steroid. There is evidence to support maintenance use for areas that are chronically inflamed and keeping that area clean by using more consistently to help that. But making sure we don’t find the adverse side which is related to too strong of use to thin the skin or causing strain or stretching the connective tissue. We want to find that delicate balance of not overdoing it and that is one of the hardest aspects with topical steroids.
The next most common medicine is the topical calcineurin inhibitors. These are steroid sparing agents. There’s three available options as they are approved down to two years old. The two medications are pimecrolimus and tacrolimus, approved at two different strengths for the latter, .03% approved down to two years old, .01% at 16 years old. The higher tacrolimus is more potent than pimecrolimus but that is more potent than the lower tacrolumus dose. They are equal whenever we compare them. They are equal to mid to low potency topical steroids, and they do have the ability to be used interchangeably. They have the benefit that they don’t have the same side effects of topical steroids with lightening of the skin or anything. The most common adverse effect is burning. A lot of patients will complain especially if it is used on warm or open skin or if it is used where they are first trying to heal the skin. There are mitigation things we could talk about such as not using it when you come out of the bath, the skin is more supple. If the skin is warmer, it can cause you more problems. If you use it continuously and frequently, the stinging sensation does go down and it can be mitigated by chilling the product for a little bit before you use it. It does have a black box warning. The calcineurin inhibitors in oral forms in higher doses were used as immunosuppressants, so there is a risk of cancer and a big meta analysis showed even kids down to two years of age. There’s a slight increased risk compared to the general population for lymphoma that we are still trying to figure out but it doesn’t look like it’s a substantially bigger risk. But the black box warning is there so we do have to talk about it. It is safe, they are effective, even for long-term use.
The other topical medicine is crisaborole which is a topical PDE4 inhibitor. This one is approved down to three years of age, and for those users who are afraid of topical steroids we can use that. It’s better for more mild atopic dermatitis as a steroid sparing agent because it is not as strong as the topical steroids. But this one really stings. That’s the most common reason people stop using it. You can mitigate a little bit by continued use or by using it cold, but that is the most common reason it was discontinued on most of my patients.
The new player is ruxolitinib, the first of the topical Janus kinase inhibitors. We’ll talk about the oral medications in a little bit. The topical JAK inhibitors that came out in 2021 as a cream, approved for 12 years and above. It is still being studied in younger individuals and it has similar effectiveness. The risk is that it gets systemically absorbed so anytime you put something on the skin, there is some level of absorption through the skin, which is why we are cautious with our ultra potent topical steroids. The topical JAK inhibitors have a risk of absorption as well. So we try not to have continuous use past four weeks. Try to use it on less than 20% of the body surface area to limit how much you are actually using. It has a similar efficacy. It kind of compares to the mid potency topical steroids and it has a steroid sparing agent so it’s a great option. It is expensive right now. And there is a Class Specific Warning for JAK inhibitors for risk of cancer, major cardiovascular events, and thromboembolic events.
Those are the topical medicines. We are going to dive into systemic therapies that I wanted to make sure we talked about, that is the goal of this talk, you can’t talk about this without addressing that. The main question I asked myself all the time and most providers should be asking themselves is when is topical not enough? When do I have to treat the whole disease? We talked about atopic dermatitis, it’s not just isolated, it’s a skin barrier issue. It’s not just one little spot on the skin. These are guidelines that were published and saying when we should be considering it. If its persistent diffuse or locally severe AD with impact on quality of life despite an adequate trial of high-quality topical therapies. We need to assess whether they are actually using it, and that they are filling from the pharmacy and not having adverse events that is limiting their use and we’ve ruled out other disease alternatives for eczema that we can actually approach their skin, so we actually can make sure that we are treating the right disease. That is one thing that we are trying to do a better job of doing.
I’m not going to have enough time in 45 minutes, an hour, to talk about the investigation into biomarkers so we can personalize our decisions for ideal therapy, but that is in the works. We are learning that this is a disease state that affects each individual slightly differently, and if you ask us 5, 10, 20 years down the road we might have a different answer as far as the best medicine to use.
When I talk about systemic therapies, I always explained that there are only a couple of head-to-head comparisons. There is not a lot of drug A versus drug B and drug A is the best thing so it’s important to compare the studies and their efficacy. When we talk about systemic therapies, there are couple of things that we always talk about, which is important terminology to use, which is how do they work in the standardized scoring systems. Scoring for atopic dermatitis is the Eczema Area and Severity Index (EASI) which is utilized the most often and is the validated investigator global assessment. Those are starting from how much healthy body surface area and how much is inflamed in that specific area. We want these numbers to be as close to zero as possible. We look at how they change from starting a therapy. You will talk about EASI 75, EASI and then a number. That number really is a percentage decrease. 50%, that’s an EASI score. 75 is a 75 percent reduction in their EASI. The last thing I will talk about is Peak Pruritis Numerical Rating Scale or the Worst Pruritis Numerical Rating Scale which is a really good measure of how itchy the skin is for our patients.
I’m going to start with biologics and then talk about JAK inhibitors. I’m going to put this slide up again and draw our attention to the blue and white bubbles in this diagram. When we look at the inflammation that starts from the skin barrier coming down, you see those numbers and letters, they are TSLP, IL-25, IL-33. Those are signaling down to our immune system to our helper T cells that are skewed toward allergy or TH-22 cells. They are going to make certain cytokines of certain signals that are going to drive inflammation whether that is IL-31 or IL-23 which skews our allergy antibody producing cells or B cells to make IGE or to recruit our end effector cells like our eosinophils to actually cause us problems. And so when we talk about the medication we use, we target two different pathways to calm down and we really pay a lot of attention to IL-4 and IL-13.
The medicine that has been approved the longest is dupilumab. and was approved in 2017. It’s approved down to age six months. It’s an interleukin 4 receptor alpha monoclonal antibody. It’s a subcutaneous administration at home with a loading dose twice the maintenance dose, based off age and weight. We usually use either 200 or 300 milligrams every two to four weeks after the loading dose and it is something that can be done at home. A lot of biologics we actually have to do it in the office. This one can be done at home and it treats multiple diseases, not just atopic dermatitis but chronic rhinosinusitis, nasal polyps and eosinophilic esophagitis. The indications are starting to grow. It’s kind of been the gold standard for the longest time and the most widely talked about.
When you actually look at it, I’m going to focus on each study and the long-term study. So the left study is the initial phase three trial, the middle is the 6-11-year-olds, and then the right six month and above study, and the bottom right is the four-year long-term study. All of them had a big improvement in atopic dermatitis. In adults, by 16 weeks, they have a 75% reduction in their EASI score, and 40% had a validated investigator global assessment that their skin was clear or almost clear. It was studied as its own therapy, without topical steroids or any other therapies whatsoever, as well as an adjunct or an add on and that’s how it was approved. It was approved as an add on therapy for people who have failed topical therapies. When you look at it for each age, it looks like it has benefit for everybody. So in the adults in just 16 weeks, 50% of patients reached EASI 75, then in the younger kids six to 11 years old, 80% of patients reached an EASI 75. By the end of their 16-week treatment, 50% of kids that were younger, they looked at different doses weekly, every two to four weeks for younger kids to try and find the right dose. When you actually look at it, it works across all ages and its pretty similar as far as the reduction goes. It’s a very effective medicine. And it works quickly, within four months. On the long-term, that lower right side, it keeps working. You see that they progressively get better. The top bar is the EASI of 75, the bottom is EASI 90, and the green is 100% clearance. Through four years they have an EASI 100, completely clear skin in 75% of patients, which is remarkable as far as the disease state. It has been a game changer for our management of atopic dermatitis.
When we talk about dupilamab, the ideal patient to use it on is one with comorbidities like asthma or rhinosinusitis. It can really help with all of them, treating multiple diseases. It is a great option because it hits across the spectrum and it has the benefit to patients, treating one with multiple things. They have to have it injected at home, so they just have to have the capability, and it’s approved down to six months old. As a pediatrician by background, I’m always concerned about anything that goes down to six months of life without vaccine data. We don’t know how that interacts with live vaccines, that’s a contraindication right now. We are looking at it in adult vaccines. There are couple of studies have looked at people that have responded in other countries to the yellow fever vaccine, and they are looking like it is not changed. But it is something that we don’t have a great answer on and that is something we don’t fully know yet.
I did not talk about the side effects. The most adverse event is injection site irritation, so when you are actually doing the injection, the site can be painful. The ocular side effect is the most specific to atopic dermatitis. It doesn’t happen in other diseases, but it does in atopic dermatitis. They get a non-infectious inflammatory conjunctival virus and is expressed as dry eyes. For some people it can aggravated. And we have to be involved with ophthalmology colleagues and distribute eyedrops to moisten and lubricate the eyes. We had to stop them from treating with this, and some could keep going. It requires a whole team to come together and treat, so if it’s an adverse event and they have bad conjunctivitis, it’s may not be the right medicine for them.
The next one is tralokinumab and is in that same pathway, it blocks IL-4 IL-13, both cytokines as converges at the receptor, smaller locations, similar pathways, it was approved for adults at the end of 2021, and it’s approved at 18 years of age, it’s only approved for atopic dermatitis, it does not have any other indications. It is being studied in younger kids, and it will have a benefit that while it has the same dosing structure at the onset, you can space it out. Whereas the previous medication is two weeks consistently, this is done differently. Their studies were called the ECZTRA studies, and they had a second extending study on it. They wanted to figure out whether it was working or not. There is a great reduction in patients who use tralokinumab, and they showed with or without topical steroids that there was a benefit. And to the extent they had an exchange benefit after they were able to space it out. And they even went a step further and when they stopped the medicine some patients actually had sustained improvement multiple months after stopping the medicine. So it has the potential for disease modification and patients are on less medicine. It’s an interesting medication that bears some promise.
The ideal patient, at least right now, it’s being studied in younger people but adult patients with severe atopic dermatitis who failed topical therapy because it was approved as an adjunct therapy. They are comfortable with injections and doing them at home and have the capability after 16 weeks to space it out to actually continue on. It’s a really interesting promise. It’s the same risk for conjunctivitis, and they have similar rates to dupilumab, and there were people who were previously on that and switched over and they had similar benefits. We are still learning which one is the right one to use, and long-term data was only approved in 2021 and there publishing long-term data. The the same question on vaccines as dupilumab. There aren’t as many live vaccines in adults as there are kids so that will be an interesting question.
The main purpose of the lecture is JAK inhibitors. When we talk about cytokines, sit as a ball into a glove and then signals as a domino downstream into the cell to cause production from our nucleus to actually make proteins. That singling starts everything at the base of that receptor are the Janus kinase signals and are different for each cytokine in each different receptor. And they’re different for each disease state. Our infectious cytokines that we call TH 1 that’s kind of more of a bacterial infection signaling those ones do use the same kind of JAK inhibitors to the same kind of JAK signaling, but they do combine slightly different states like downstream signal transducers. We have the combined ones which one of these will be the right one as far as what we are going to inhibit. When we should look at inhibitors, we have to know which JAK do they inhibit to know which disease will be good for which patients.
I’m going to talk about the elephant in the room, this is important for doctors to talk about. Anytime you see pharmaceutical talks may have a litany of side effects where they talk too fast for anyone to understand. There is a Black Box warning for all JAK inhibitors. They carried a risk of cardiovascular events, cancer, thromboembolism, serious infections, and herpes zoster. All of that was based on studies of patients with rheumatoid arthritis and it compared them to patients who were on an anti-TNF medicine. It’s a different disease state, so we have to know it is a different inhibitor, so we are extrapolating it to an entire class of medicines based off of one medicine that has many different targets pathways. We have to know if we are comparing apples to apples or apples to oranges. In the long-term data for tofacitinib, which is a three-and-a-half-year study where they compared the rates for tofacitinib to the anti TNF medicines in patients with rheumatoid arthritis. There was a higher rate of major cardiovascular events, a higher rate of cancer, venous thromboembolism and serious infections like herpes zoster. I’m not going to deny it was there, it was there. Most of those were related to risk factors. Whenever we talk about our JAK inhibitors, either topical or oral, we have to what risk factors are. And it does seem like along with other risk factors for major cardiovascular events or for cancers or for venous thromboembolisms, age over 50, smoking history, hypertension, hyperlipidemia, family history of coronary artery disease, or medications that increase the risk. And it’s important for use to know how the studies were designed because that will affect how we need to interpret it, because you have a selective bias. That is going to be important when we interpret their data, we need to know what their bias was because some studies were designed differently and it removed that sampling if they don’t have the risk. And so for topical ruxolitinib longer-term studies, not the shorter-term studies, did have one myocardial infarction to cerebral accident, cerebrovascular and three thrombo embolic events that weren’t related to the medicines. It was in the earlier treatment course and they did have risk factors. But they were in the study so we can’t deny it. I was looking through the literature previously to make sure I wasn’t missing anything but they haven’t had one severe adverse event in AD and we’ll talk about why I think that is the case. And then Upadacitinib did have some major cardiovascular and venous thromboembolism events that were linked to different drugs. And so the recommendation is to talk about it to make sure we are finding the right patient. And then there is a risk for herpes zoster. So if you have a risk factor for herpes zoster to make sure the we vaccinate before.
It does require lab testing. You can’t do that without knowing what you’re doing. You have to screen your patients. You have to do a test to make sure that they do not have tuberculosis, or smoldering, underlying hepatitis B or hepatitis C, which is going to be different in kids versus an adult, it’s something we need to know. We need to know what their baseline blood counts are and baseline liver function. We need to know if females are pregnant because we don’t have pregnancy data. There are cutoffs that we would avoid because it can cause some cytopenias or some low blood counts and changes in platelets or the production for bone marrow. And so we’re thinking through what’s the best way and then we have to follow people on it. So right now, the recommendation is after you start a medicine, four weeks after you start, you repeat your CBC, or if you increase the dose, you repeat it and then check the lipid panel for weeks or in 12 weeks.
Let’s talk about all of them. Let’s go through each of them individually, and talk about them, and which one is better. So abrocitinib was approved in adults 18 and above in 2022, and it is currently approved in the United States for 12 years and older. It is only approved for atopic dermatitis, no other indications. It is a selective JAK inhibitor, only targeting the JAK one pathway. It has three doses, 50 mg, 100 mg or 200 mg. They recommend that you start at 100 milligrams unless you are on a medication that can inhibit the metabolism, or you have renal impairment. That is why labs are important before we start. In certain medicines, like antifungal medicines, or pump inhibitors or antidepressants like SSRIs and antivirals, those can increase the drug levels so you have to be cautious with these patients. I’m going to say this again, and I think we need to talk about it, you need to be monitoring your patients. You cannot start this and just walk away. You have to follow people. You do have to check labs for weeks after you initiate treatment.
The aborcitinib trials were a bit more choosy in the patients they put in it. They selectively — not select we come up when you look at their demographics, their patients were 23-45. Younger population, healthier population, whatever we talk about risk factors, they were allowed to have anybody who can, but that enabled them, their trials were most comparable to the clinical usage for these medicines. And that gave them that facilitative aspect. And they work quick. There is a dose effect, so the 200 milligram is stronger but has more side effects, and the 100 milligrams works and sustains effectiveness. When you look at it, when these medicines first got approved, we stopped talking about the EASI 75, we started talking about EASI 90, and EASI 100. For somebody who’s taking care of atopic dermatitis with a lot of topical medicines, only about 30% of patients will have an EASI 75 on topical medicines. These going to 90 % or 100% reduction in eczema was astounding to me. When you look at the studies, 8%-10% of patients, by 12 weeks, will have completely clear skin. Almost one third will have no itch whatsoever within the first 1-2 weeks of taking these medicines. Really, it’s one of the best medicines. It targets the pathway really well because it actually targets some of the cytokines directly at the neurons. It is a really, really strong potent medicine.
The most common adverse events were upper respiratory symptoms, so congestion and sore throats. Some abdominal pains and headaches and acne and cytopenia nausea at higher doses. And that did get better at lower doses, and you can always drop them down. The most common was risk for infections increased. We talked about this during the pandemic, how is this going to affect those immunosuppressed but there is an increased risk for infections and herpes. It does carry a Black Box warning though there were none reported in the phase 3 or in extension studies. But the population was youngers. Whenever you look at their demographics, they were healthier, they didn’t have risk factors. They are probably most comparable to what we are using from a clinical standpoint, real-world trials, what it compares to in the real world. If I choose a drug for this population, the younger and the healthier might be the most comparable to say how this is actually how it could work.
It’s approved 12 years and older, it’s an oral medicine, these are oral inhibitors. For those with itch as the major symptom it works fast. It is contraindicated to pregnancy, we don’t know about breast-feeding, we are trying to figure that out and avoid live vaccines. I put something here with generalizability concerns, a lot of trials tend to skew towards certain populations and have not always had the most diverse participation so it’s important to note when you are comparing things.
I know we are in the last little bit, and I’m going to talk faster. This is the other oral JAK inhibitor, upadacitinib, approved for 12 years and older for atopic dermatitis and being studied younger. This does have additional indications for psoriatic arthritis, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis and a lot of autoimmune conditions. It is higher affinity but not selective. It was bound at the signaling mechanism, and it does not get to claim the selective aspect. It comes in two different doses, 15 and 30 milligrams, we recommend starting with the lower and you can always increase if they’re over 60 kilos, over 40 kilograms or at 80 pounds and they are less than 65 years old. You have to do drug monitoring prior so you have to get a blood count and liver electrolytes. You have to get renal function, check hepatitis B and C and a pregnancy test. Repeat your labs at 4 and 12 weeks with a CBC and lipid panel after initiation or when you increase the dose.
Now look at their trials. They work quickly. Within four weeks, two thirds of patients, or three fourths of patients have a higher dose, dose response to reduction in their EASI score 75 within 4 weeks. And there was a dose response to 30 milligrams, but they work and the itch improved within the first week. It extended out to 52 weeks and showed that 50% to 60% of patients on the lower dose and 72% of patients have a higher dose sustain the benefit. And then there was 40% to 60% of patients reached EASI 90 and 10% to 24% for the 30 mg reached an EASI 100 with sustained benefit out to a year with the same kind of benefits for their itch. The middle panel is 16 weeks.
From a safety standpoint, it has similar adverse effects to aborcitinib. It does have acne risk factors, nasal pharyngitis or upper respiratory tract symptoms, has some nausea, headaches, some creatine phosphate, phosphate kinase elevation. The most common serious adverse event was herpes infections, either herpes zoster or herpes labialis. They did not take all comers. They had a bit of a broader spectrum. They did allow patients to have had a history of major adverse cardiovascular events and venous thromboembolism. They had events that occurred. They had two patients at the lower dose with a cardiovascular event, two venous thromboembolism, 9 cancers. There was one death in the older population– a guy over the age of 65, he had obesity, diabetes and hypertension, and hypercholesterolemia. There were risk factors there. But he died while on the drug and it is important to talk about this. And to figure out what is the right population. So they’ve gone back and they’ve looked at their pooled analysis for atopic dermatitis, rheumatoid arthritis, ulcerative colitis and they have studied it out for patient years and what kind of risk factors there are and it looks like the major adverse cardiovascular events and thromboembolism are less than one event per 100 patient years. And the main malignancy rates are low as well. The herpes zoster rates are a little bit higher than expected. It poses risks, and we have to think about it.
And it’s an oral administration for 12 years and older, if your patient has major symptom, it’s an interesting option. And you have to limit risk factors. You have to talk through who is the right patient to put it on and who to actually use it on and it is very similar.
I would love to say that I have a ton of head-to-head data to compare which is best. Each of the individual JAK inhibitors, compared to dupilumab, the cream of the crop at the time, they were compared to themselves, and we will talk about each one in turn. They only did a 16-week study. Both of them actually work faster. They worked quicker, they had a shorter time to effect, and an improvement in their EASI score quicker than dupilumab. You aren’t getting a suboptimal medication but it does kind of make us ask the question of short term goals vs long term treatment. We have had a lot of meta-analysis looking at it, the first one published was in 2020, before they were approved and there was only data for one of them, and dupilumab was more effective. You have to choose which one is your priority for safety and effectiveness. And then several doses were about equal, and that was better than the lower dose of several of them, and it descended progressively where the highest safety was dupilumab, and the rest were on the right-hand side.
I will take questions, I am sorry, I want to crank through, so we don’t keep you longer than the timeframe. So, the research is very exciting. When I was looking at it a month ago and when I was looking at it yesterday, there are over 200 currently active phase one through phase one through phase four trials for atopic dermatitis. Of those, 30 of them have started in the last month. It is a promising time to be taking care of patients with atopic dermatitis and it is a disease we are trying to get better therapies and better options for patients. When we talk about the skin, these are the medicines that have been tried or are being tried in eczema. They are looking at different pathways. I will talk about the big players and the closest to approval if I had to guess, but they are looking from the skin side out all the way down to the itch, which once effects B cells, which one effects helper T cells, which one helps with the microbiota and which one will help in each individual case.
The first ones start on the outside layer of the skin kind of coming inside which are the barrier therapies. We’ve looked at TSLPs, anti IL-25. None of them reach clinical significance in trials so those have been pulled back even though they are working in other disease states. Anti TLSP been approved for asthma but one of the big ones that has been looked at is the itch signaling. So IL-31 is different. There is a reason we don’t use antihistamines as much for atopic dermatitis because the itch is driven through the nerves and signals to call attention to that spot. IL-31 signals through this and that is why this particular Janus receptor can help with itch related symptoms. So there’s a monoclonal antibody that’s looking at IL-31 called nemolizumab. Phase 2b showed improvement in pruritus scores but weren’t statistically significant but they work well when your symptoms are itch-driven and you can’t establish good topical therapies, it can help restore that skin barrier for patients responsive to topical steroids but the itch keeps them up. That is an interesting player to watch, either as monotherapy or as an adjunct down alive.
The one I thought was closest, and I would have said a month ago was closest to coming out is lebrikizumab. It’s an IL-13 monoclonal antibody, and it was rejected from FDA approval due to manufacturing issues. The medicine works, event the FDA said it works. The phase two and phase three data shows that it works out through 14 weeks, it has a lot of benefit, but there were trip ups in the manufacturing processes so the company needs to fix things and reapply before it is able to get approved in atopic dermatitis.
They are working on biosimilars to dupilumab. And those are being studied at two and four weeks to figure out which one is best. Those are on the early side, phase one, and they are trying to do with that, and the study has shown that it works. OX 40, this is the signals that recruit the T cells to come back to the skin and bring them back, they are supposed to be here to check the skin and make cytokines, there is a lock and key mechanism, the pathway signaling allergy cells are supposed to be here and we’re looking at different medicines that target that. There’s rocatinlimab and amlitelimab, these are the presentation cells and the helper T cells respectively. They are being looked at in these trials. The reason we brought those up is because they are interesting, when we dose them, you should benefit while you’re on them, and if you stop them, you have continued benefit for up to six months. You treat them three months, they’re good for a total of nine months. Which is kind of interesting. It tells you that if you can hit reset and break that cycle and establish care you can help guide patients better.
There are two other JAK inhibitors, it’s a topical preparation for a JAK inhibitor approved outside the United States and on par with others as far as topical inhibitors, its broad-based instead of specific. It does not appear to have an absorbence risk, and that will be talked about eventually here. The other one is a JAK 1-2 inhibitor, it’s mainly JAK one, JAK one-two can be involved in other inflammatory conditions, and it makes us worried, and that’s approved in Japan and for rheumatoid arthritis in the United States, not approved for atopic dermatitis. There are two different doses. There is a dose response as far as the higher dose seems to be more effective. There was moderate effectiveness, but they had headaches and upper respiratory tract infections.
That was a whirlwind talk for an hour, but the key takeaway is atopic dermatitis is very complex. We need people more focused on how we can actually take care of the skin and what we can do, what are some of the real-world pieces of data as far as the best option, and having conversations with providers about what is best for their preferences. Is it speed? Is it safety, oral, injectable, what do we think about? And we have multiple medications with seven-year data, and we want to try to find the right medicine and follow it over time because we need to know what it is in the long term, and the future is incredibly bright. For the first time in a long time, for a disease that we have only had topical medicines, this is a disease that we finally can actually help with. So that’s all of my citations, a whole lot. I’m going to take time to answer any questions.
Lynda Mitchell: Wow, Dr. Clint Dunn, thank you so much for that incredibly detailed look at all of the treatments on the radar now for atopic dermatitis and coming online. I was involved in a study back in 2017, before dupilimab, and it was rather bleak and hopeless for people suffering with moderate to severe atopic dermatitis. And now the future is so bright that there are now solutions to allow these folks to not suffer, and these are children. Children are having such a hard time. It was just heartbreaking. It’s just a wonderful, bright and optimistic kind of story you’re painting here. There’s so many options. Hopefully atopic dermatitis won’t be a thing to worry about, because of that. I know that we are really coming up on 5:30, that went really quickly. I want to give everybody a quick bit of information. Our next webinar is going to be Holidays with Food Allergies with Dr. Mike Pistner and Emergency Planning for Children with Asthma and Anaphylaxis on November 29th. Look for a follow-up in the in a few days with additional information about atopic dermatitis that you will find helpful. We have a lot of educational resources about that. It is 5:30 and I know some of you have to drop off. But, Dr. Dunn, can you stay another five minutes or so to answer questions? Anybody who has to leave, thank you very much for being here, we will go ahead and answer some questions. The first one is, is dupilumab a continuous therapy?
Dr. Clint Dunn: That is something that we are trying to figure out. We don’t know. We know from preliminary data from the long term studies that there are couple different trajectories and we don’t know which people go into which trajectory. Some people it hits reset and they come off of it and they don’t see any problems. Some patients are more mild and some patients are severe. It can be used as a continuous therapy, and it has been studied in that way. In the phase three trials they looked at the frequency and said that the weekly was more effective than every two weeks, which is why they went with every two weeks in adults. But nobody has been looking at what the ideal point is to stop these medicines other than what I told you about with the pathways and where they space out the dose. That is probably the number one question we are all asking ourselves. From an allergy standpoint. When can we stop these?
Lynda Mitchell: OK, great. The JAK inhibitors and Biologics will be prescription only, correct?
Dr. Clint Dunn: Right now, they are.
Lynda Mitchell: What other questions we have, bear with me. One of the things that I learned was that there were different immune pathways for acute vs chronic atopic dermatitis, thank you for teaching me about that. And that it is modulated by different cytokines, that is interesting. When you’re dealing with skin color, you brought up that interesting slide, does that sort of also guide your treatment recommendations and your recommendations?
Dr. Clint Dunn: The easy answer is right now we are more blunt in the way that we approach. A lot of these pathways can be inhibited by multiple of the pathways and it can affect it. I think that once we have a better way of identifying which biomarkers are there at the onset, even though we can make ita generalized statement about how skin color behaves, individual behavior is personalized. And so we talk about the melting pot that is the United States, where there is some level of multi-ethnicity in every individual, that can skew data. The easy answer is it does not change what I am doing right now. Some of it is limited by the individual and what pathway is driving them and what comorbidities they have.
Lynda Mitchell: Regarding dupilumab, you don’t think about this happening, but how often doesn’t it happen that somebody is refractory with conjunctivitis that you have to stop it?
Dr. Clint Dunn: There are couple of strategies you can do, and it works better when you are working in conjunction with an ophthalmologist on how to calm down irritation in the eyes, but also, keeping you on the medicine. You notice sometimes they are spacing out the dose and taking time to do the dose, there are patients that I have observed, and the studies will say up to 10% of patients will have conjunctivitis symptoms but not all will have to discontinue. It might resolve, you don’t have to do anything, you will just treat through.
Lynda Mitchell: I’m a mom, so when I think of a pill versus an injectable, the JAK has the black box warnings, so how does that conversation go, especially with conversations about children on these medications?
Dr. Clint Dunn: That is one where as a pediatric allergist, front and center as far as my heart. I want to address the elephant in the room, I do so whenever I recommend any of these different processes, pediatric patients are going to prefer an oral medicine over an injectable every day of the week. And talking to parents, the child is not going to think about what their cardiovascular risk factors are whenever they get over the age of 55, but mom is. I have an open and honest discussion and I make sure I ask what are the risk factors, and I have a handful of patients that decide to go with the oral JAK inhibitors, and they’re happy with it. I always try to make sure I disclose everything, and I talk thorugh to see if these are the risk factors, and what is your risk factor.
Lynda Mitchell: I’m trying to see, I think that was all of the questions. I’m curious, because they’re different phenotypes of eczema, is there a rubric that you go through in order to make that decision with conversation with patients, or is that still sort of a work in progress?
Dr. Clint Dunn: I am a big believer in making sure that I am assessing adherence and I am assessing what the irritations are to the skin. How often do they use soap, what kind do they use, does it have fragrance. Teenagers don’t like to use moisturizers, and are there ways to use different preparations so the people who don’t like that greasy feeling with ointments, cream would be a better option. Right now, as far as systemic therapies are concerned, it is dictated by what hurdles you have to jump through to get something approved. There are going to be those aspects, but traditionally, if I have somebody who has failed a topical corticosteroid that is medium to high potency and has taken the topical inhibitors or the steroids or the JAK inhibitors, I start talking about systemic therapy. And I try to bring that discussion in earlier before thinking about it even a step ahead of that encounter and talking directly about it so that I can make sure I kind of do my due diligence and have them read about it. Because it’s hard in a moment where you feel like you need to start therapy and you end up having to give the family the time to think about questions and giving them time to ask their questions back to you and saying hey, we did this a month ago, let’s keep talking.
Lynda Mitchell: Well, thank you for answering that question, and thank you for your time and attention and everybody in the audience appreciated you hanging in there. With that, I am just going to thank you for that follow-up them, thank you so much, we really appreciate it. Bye everybody.