Speaker: Dr. Vimal Prajapati, MD, FRCPC, DABD
Objectives: Thank you, Dr. Chuck Lynde and Dermatology Update. You folks put on a great show twice a year every year, and I’m really sad that I couldn’t be there in Vancouver as we’re about to get a snowstorm here in Calgary.
Today we’re going to talk about targeted systemic therapies for adolescents to treat atopic dermatitis. It’s an exciting time to be a dermatologist or even a patient with atopic dermatitis. We have so many amazing treatments available today. In the adult population, we have several approved treatments, and in the adolescent population, we have one approval with more approvals likely to come in the next few years.
Feel free to ask questions in the chat. I am monitoring it for questions. This program has been funded by Sanofi Genzyme.
Today I hope to cover:
- The burden of atopic dermatitis with a focus on adolescents
- Overview of drugs for atopic dermatitis with a focus on Dupilumab
- Mechanism of action, efficacy and safety data in 12 years or older patients, dosage, and administration
- Questions and answers
Impact of Atopic Dermatitis
Atopic dermatitis is the most common chronic inflammatory disease in the pediatric population in industrialized countries. The prevalence is between 5% and 20%, but this is higher in industrialized nations. 80-85% of atopic dermatitis will start before the age of 5, and recent data suggests that there are new-onset patients that are adults – this is a new finding. 10-40% of pediatric cases are moderate to severe.
Importantly, atopic dermatitis has a huge impact not only on the patients but also on the caregivers. I think pediatric patients are burnt out from repeated topical and oral medications over the years, but the adult caregivers are also burnt out. This CLQI score shows that atopic dermatitis has the second-highest impact on the quality of life, only second to cerebral palsy. You can see that the impact is higher than psoriasis and urticaria, listed here. That’s something we have to address when we talk to patients and their families. This is also true for adult patients.
How much does your atopic dermatitis bother you?
I always ask that question and then wait. On average, the patient will give you a 15-second, maybe 90-second explanation. It’s very important to listen to the patients and to hear their stories. Ultimately some of the goals or targets that we have come out in that discussion.
There are multiple dimensions of moderate to severe atopic dermatitis:
- Sleep disturbance
- Mental health issues
- Impact on quality of life
- Other associated conditions
As someone who has a pediatric practice, I see a lot of children. These are multifaceted issues that need to be addressed. Impact on mental health – so anxiety, depression, low self-esteem, all of these can happen. I always ask about the impact of atopic dermatitis on the child’s sleep. There was a study done suggesting that a child may wake up 36 times in a night. If a child isn’t getting adequate sleep, growth hormones aren’t being produced, and they aren’t meeting their height and weight milestones. Asthma and seasonal allergies, we all know, are associated with atopic dermatitis. We can also see eosinophilic esophagitis and chronic nasal rhinitis with nasal polyps, and these are often related to atopic dermatitis.
Atopic dermatitis has a major impact on sleep. If you categorize by age, 44 nights a year are affected if you are between 2-13 years of age. That number goes up to 88 nights for 14-17-year-olds. Categorized by severity, a moderate patient has 33 nights affecting sleep, and with severe disease, that number shoots up to 162 nights. With that many nights of sleep disturbance, it will affect function. Children won’t be able to function well at school. We will often have teachers commenting that they seem uninterested in the subject, but the truth is that they are so tired from lack of quality sleep. Children become fidgety during the day without sleep. This can be interpreted as ADHD, and in fact, there is a link between the two. School attendance is also affected by atopic dermatitis. According to the Eczema Society of Canada, of patients who missed school due to atopic dermatitis, 23% of patients missed more than ten days of school, and 12% missed more than 20 days. So you can see that atopic dermatitis can have a direct impact on performance at school. We can extrapolate this for adults who may have a similar effect on performance at work.
Another issue with the pediatric population is the burden on caretakers. We have many topical treatments such as topical steroids, calcineurin inhibitors, JAK inhibitors, hydrocarbon agonist inhibitors. There are lots of targeted topical treatments coming out in the market. The problem is that compliance isn’t necessarily high while the burden of disease on the family is high. Often we see a breakdown of adherence both on the part of the patient and the caregiver.
We do about 125 atopic dermatitis pediatric patients a week. Frequent follow-ups are ideal as it keeps the family accountable. They know I’m going to scold them if the child’s skin is not clear. We have to follow up frequently to ensure that everyone is following the protocol. Sometimes you know that they aren’t using the topicals, and at that point, you need to move on to other modalities like light therapies or systemic therapies. At that point, families often have a realization. If they are hesitant to use these light or systemic therapies, pediatric patients will usually be more accepting at this point.
A Plethora of Treatments Being Investigated
This is a wonderful slide; it’s very busy, but it shows you that this is an exciting time for dermatologists who treat atopic dermatitis. As you can see in this slide, we have so many targeted treatments available.
This discussion will focus on Dupilumab (IL4Rɑ), which my patients and I call an absolute game-changer for atopic dermatitis. Dupilumab has been amazing for adolescent patients that we have on this medication. They’re all doing wonderful and are super happy with the treatment. There is sometimes fear and needle phobia at the beginning, but that goes away very quickly. When the child and parent realize they are spending way less time on their skin, they are fine with the inconvenience of an injection that takes maybe 5 seconds. Their skin clears up, and their quality of life improves.
We’ve had some patients with eosinophilic esophagitis – I know Dupilumab is being investigated for that condition. We’ve worked with pediatric gastroenterologists, and they were very impressed with the results. Some were skeptical, but after several endoscopies and follow-ups, they found that patients were doing much better. Families were happy, the child was happy, and the other specialists in care were happy. So when we talk about Dupilumab, even though other molecules are coming into the market, this will remain the true treatment for atopy: Asthma, atopic dermatitis, seasonal allergies, and eosinophilic esophagitis. Dupilumab is the standard for those conditions.
Breakdown by targeted interleukins (for detailed discussion watch the video):
IL-4 and IL13:
- They are the main drivers of atopic dermatitis.
- Dupilumab is still the true treatment for the atopic diathesis. It has demonstrated efficacy for asthma in adults, and studies are coming out for children soon. Dupilumab also affects IL-31.
- Tralokinumab and Lebrikizumab are also being investigated.
- IL-31 plays a role with atopic dermatitis, especially with itch. Nemolizumab is being investigated for the adolescent population now.
- TSLPs are thought to be the cytokines responsible for the atopic march. If you can deal with atopic dermatitis early in life, maybe you can prevent asthma and seasonal allergies from developing later.
We have TSLP inhibitors that are being investigated for adults now, and eventually children as well.
- Mepolizumab is an IL-5 inhibitor. Not a lot of success with atopic dermatitis.
- Respirologists use it more than dermatologists.
- IL-17 isn’t a blockbuster but can be beneficial in edge cases where psoriasiform and spongiosis are seen.
I’ve had the most success with Brodalumab. Dr. Jensen Yeung taught me that it blocks IL17C, which is important as well.
- Asian patients with the Th17 phenotype can be a challenging population to treat. The skin looks like atopic dermatitis, but after skin biopsy, using an IL-17 may help.
IL-12 and IL-23, OX4 Ligand and IL-22:
- Some anecdotal evidence that Ustekinumab, an IL-12 and IL-23 inhibitor, works for some atopic dermatitis patients. Again, likely for patients with psoriasis overlap.
- OX4 is being investigated but not clear whether it will be taken to the market at this time.
Fezakinumab, an IL-22 inhibitor, is also being investigated as IL-22 may also play a role in atopic dermatitis.
Small Molecules (18:42)
These are super-targeted, so I’m excited about their potential. Most of the treatments I mentioned in the previous slide are subcutaneous, and a few are intravenous. This slide shows that we have a few oral therapies that are more targeted and coming to the market soon.
I think the JAK inhibitors are going to be very fast. They may replace systemic corticosteroids and also systemic immunosuppressants like Cyclosporine. They will be extremely effective for atopic dermatitis, but the issue is going to be compliance. Any time that we give a tablet in dermatology, we think our patients are listening to us. Most likely, they’re not, and we’re going to have issues with these medications not being taken daily.
- Upadacitinib and Abrocitinib.
JAK 1 and JAK3:
- Tofacitinib has been on the market for some time, and rheumatologists use it.
- I use it, but not for atopic dermatitis. I use it for alopecia areata and vitiligo off-label, and it’s excellent. I’ve had patients with alopecia totalis and alopecia universalis regrow their hair.
- Delgocitinib is mentioned here, but it’s actually a topical therapy that inhibits JAK1, JAK2, JAK3, and TYK2.
- For JAK1, JAK2, and JAK3, we have to monitor cytopenia, dyslipidemia, and elevated serum CK. With JAK2 inhibitors, more hematologic adverse events seem to occur as Baricitinib will show more cytopenias than the JAK1 and JAK 3 specific inhibitors.
- We can adjust dosing once the small molecules are on the market. JAK inhibitors require laboratory test monitoring at baseline and follow-up. With Dupilumab, there is no need for this.
Dupilumab Clinical Trials (22:18)
Sanofi-Genzyme and Regeneron have done a tremendous job with the clinical trial program for atopic dermatitis. They’ve investigated atopic dermatitis, asthma, and chronic rhinitis with nasal polyps.
- Three pivotal trials with 2119 adults for use in atopic dermatitis. Dupilumab was approved in 2017 for this indication in adults. One pivotal trial with 251 adolescents. Approval for adolescents came in 2019.
- There is one pivotal trial with 267 children with severe atopic dermatitis. There is no approval at this time, but we hope to have it soon.
- Dupilumab is not yet approved for asthma in Canada. There are three pivotal trials with 2888 patients 12 years and older.
- There were two pivotal trials with 724 patients for chronic rhinosinusitis with nasal polyposis. Dupilumab was approved in 2020 for this indication.
- Dermatologists have had plenty of experience with Dupilumab as the molecule has been with us for some time.
Over 2700 patients have participated in this study on atopic dermatitis. Let’s focus on the trial for adolescents. In this study, they were using monotherapy with Dupixent 200mg every two weeks.
Efficacy endpoints: Proportion of patients with IGA of 0 or 1 so clear or almost clear at week 16 and week 52. They also need a 2 point improvement from baseline. There’s also EASI-75 and a change in EASI (Eczema Area and Severity Index) and peak pruritus numerical scale as secondary endpoints as well.
Cohort: If you look at this slide, many of these patients enrolled have allergic comorbidities, and these tend to be the patients that are challenging to treat. You can see that this is a high disease burden. They have high EASI scores and have many other problems like asthma, allergic conjunctivitis, and food allergies. The mean time for having the disease was 12 years for adolescents and 28 years for adults. So when we look at the results in this study, it may not look like the success rate is as high as we like, but that’s because we’re looking at a challenging population to treat with a high disease burden.
Efficacy data from the adolescent studies:
- Dupixent was better than placebo – almost three times the number in the placebo treatment required rescue treatment.
- Pruritus went down significantly by week 16. There’s a 48% itch reduction by week 16.
- We see here that Dupixent is effective from both an IGA standpoint but also a peak pruritus standpoint.
- Improvements were seen as early as week 4. Patients in real life will tell you this too – itch went away first. The itch went away quickly, then the redness and flaking, which took a bit longer.
Comparison – adolescent vs. adult:
- You’ll notice that adolescent patients have worse outcomes and we attribute that to adolescent patients generally having more disease burden than the adult population.
- Comparing the data, you can see that the results are similar and comparable between adults and adolescents. While adolescents had less IGA 1 or 0, the difference against placebo is similar, suggesting that most of this is a function of a higher disease burden in adolescents. Same thing with EASI 75.
- These are great photographs. You can see adult patients 1, 2, and 3 see tremendous results. Clear at week 16. The IGA score went from 4 to 2, but this patient wouldn’t reach the primary endpoint (not 1 or 0), but if you were to ask that patient, they would be ecstatic. In real life, we can also add topical therapies so that we can expect better results.
Clinical Trials vs. Real World
- I find that atopic dermatitis sometimes is a bit like hidradenitis suppurativa, where we sometimes need more than three months. We have to give it 6, 9 months, or even a year before we need to start thinking of changing dosage or medication.
- We need to remember to keep things in perspective and compare it to the baseline. Part of the reason that we do EASI scores on everybody, adults, adolescents, or children, we always do EASI, IGAs if they’re on systemic therapies, and body surface area to show patients that no, you are much better.
- Another before and after picture of a patient at 200mg Dupilumab at 16 weeks. You can see a little lichenification, scaling, subtle erythema, but this is someone who would be very happy with the treatment. This individual is someone who did reach IGA 0 or 1, EASI 75, pruritus improved, so that’s a great response.
- This post hoc analysis again shows that we cannot just base our impressions of a certain medication on clinical trial data. We know that in clinical trials, the criteria are stringent. We can only use one medication, and it has to be at a specific dosing frequency, and we can use rescue therapy, but the rescue therapy sometimes impacts how we calculate efficacy data and whether that patient is considered a responder or a non-responder.
- In real life, many of these patients, even though their score is significantly better, may not have received an IGA score of 0 or 1 in clinical trials. These patients would still be super happy – they had a tremendous response in their EASI scores, pruritus. That’s what we have to focus on. Some of these adults not achieving the primary endpoints still had a mean change of 35% in pruritis with Dupixent vs. 9% placebo. Same with the adolescent population, even among those that did not achieve their goals.
- There are several examples with photographs here. There are several examples with photographs here. These patients did not reach their primary endpoints in the clinical trial, but anybody would be happy with the results if you look at the picture.
- Dr. Gulliver just asked a great question: Where is the real-world data? I think there are some registries. I know that there’s a CORRONA study in the US. There are also several SANOFI-funded registries going on, so that’s something to look forward to.
Roughly about 10% of patients in the adult population get conjunctivitis. That seems to be the adverse effect of special interest. The numbers are similar in children. Interestingly enough, I do not see as much conjunctivitis in the pediatric and adolescent population in the real world. In my experience, children seem to respond faster to Dupixent so far. Other reactions listed here – injection-site reactions. I haven’t had many issues with that.
Some patients have been hesitant, but once I explain that you’re going to spend way less money, time, and effort on your skin, both the parents and the child are on board. There was a study showing that applying topical therapy was 19 minutes and 63 minutes per day so if you can go down to 5 seconds with an injection, patients will take that any day. Dr. Lynde also agrees that in the real world, conjunctivitis, while it can happen, we’re finding that it’s not a huge issue or a detriment to keeping the patient on Dupilumab or managing it. I follow my friend Dr. Leo in the United States, who is an expert in atopic dermatitis, so I do loteprednol 0.5% and we do eye drops, corticosteroids, sometimes we give omega 3. Lubricating eye drops – we do send them to ophthalmologists if they have issues.
- HSV can occur, but the rates are low at 3% to 4%.
- Other Herpes viruses are 1% or 2%.
- Dupilumab reduces infections overall as it reduces skin damage. Discontinuation rates are very low due to adverse events. 0% at 16 weeks. 1.8% in the adult population. Patients are doing great.
- The one adverse effect of interest is persistent head and neck dermatitis. I do not see much of this in the adolescent population. I see it in the adult population.
- There are many theories as to why. It could just be atopic dermatitis. It could be contact dermatitis. It could be perioral facial dermatitis. It could be rosacea of some type. Other people have mentioned certain microorganisms playing a role, such as Demodex mites and Malassezia. This has been a real problem in the adult population. I’ve seen this not just with Dupilumab but also with oral JAK inhibitors as well.
- I’ve had the most success dealing with this using Itraconazole in adults and adolescents close to adult age 200mg for 14 days. Some manuscripts suggest four weeks. I’ve had a couple of patients do a skin biopsy. I’ve also used tacrolimus 0.1%. Crisaborole.
- Black tea compresses – When you give a patient treatment, they’re happy, but when you give them something “natural,” they are super happy. Black tea has some antibacterial components in it. We tell patients to wrap black tea steeped in gauze, and it seems to work for many patients.
Questions and Answers
Q: Ketoconazole + hydrocortisone, tacrolimus. What are the main systemics you use in pediatric patients before Dupilumab?
A: If I can get patients started on Dupilumab right away, that’s always best, but some of my patients have been on Methotrexate. That’s probably the number 1 most prescribed systemic in North America. In Europe, Cyclosporine is more commonly used. I do 0.5mg to 1. I try to max out as they need a higher dosage. Some of these children have been on it anywhere from a few months to 5 years as we didn’t have Dupilumab on the market. They were only ever 85% clear, but with Dupilumab and other emerging treatments on the market, we’re now able to make a more targeted approach.
Q: Do you use Cyclosporine?
A: I do use Cyclosporine. Some children I have on Methotrexate and Cyclosporine. I’ll do cyclo at 5mg per kg divided BID and methotrexate at .5 to .7 mg per kg once a week. Once they are clear, I’ll drop the Cyclosporine entirely, or in some individuals, I’ll do a weekend dosing of methotrexate on the weekend so they won’t get a flare-up. Patients across all age groups in the clinical trials had a history of systemic corticosteroid use. I only use this for flare management because the issue is that they all have rebound flare. With Dupilumab, they have way less use of systemic corticosteroids. One note on the risk factors for conjunctivitis, they have higher baseline IgE levels. Maybe we see more conjunctivitis in the adult population for this reason.
Q: Can you transition someone off of Dupilumab and maintain remission?.
A: This is probably the million-dollar question. Right now, none of my adolescent patients and off-label pediatric patients have come off of Dupilumab. It’s been such a game-changer that they’ve stayed on the drug. At some point, if they’re clear after six months or a year, I have dropped the dose. I have not been able to drop Dupilumab for any patients and maintain remission. There was one patient, and I have many patients on Dupilumab, who came off of it because he thought he didn’t see an improvement. Interestingly enough, he had a 96% improvement in his EASI score from his baseline; it was just the concept of doing an injection that bothered him. So he stopped it, and of course, he flared. Over the course of 6 months, his eczema went back to what it was before. I think in the long-term, that’s going to be the question – if we stop it, what proportion of patients maintain it, and I think that’s why we need more real-world data, and if ever these patients grow out of it and what laboratory markers we can have.
Maybe we take it in the summer when it flares. The take-home message is that Dupilumab is available for atopic dermatitis. My clinical experience has been that adolescents do better and faster than in the adult population. They have no complaints about the needle, even in the off-label 12 years of age group. Parents are happy spending less time and money. The nice thing is that there is no laboratory monitoring, no interactions with immunizations, there have been studies on that, and no increased risk of COVID 19.
Lastly, dosage – reminder – adults and adolescents – over 60kg the adult dosing basically. The initial dose of 600mg subcutaneous dosing 300mg every two weeks. In adolescents, less than 60kg, start with the initial dose of 400mg subcutaneous every two weeks and proceed with a 200mg dose every two weeks.
Q: Is there any staining with the black tea?
A: No concerns. I haven’t had any complaints.
Q: Is there any good economic study that is digested by using Dupilumab that you are actually saving money because you don’t have all these time factors, cost of putting the cream on, and so on?
A: I think there are some studies in the United States suggesting that it could reduce economic burden, and hospitalizations are one issue that can be a huge cost on the system. That’s a great point that I think we do need more studies showing the amount of time and money that patients are spending.
Dr. Lynde: I think we need to get the data out to pediatricians and allergists, and GPs recognize that sleep deprivation is terrible in many ways. It’s like a chronic disease. There’s actually a wealth of data for patient burden, caregivers, etc., that was taken into consideration by INES in Quebec because they look at the total utility, not just direct health care cost. That was part of the reason that they approved Dupilumab. Unfortunately, CADIFF only looks at direct health care costs where there’s less data.