Margaret Bobonich, DNP, FNP-C, DCNP, FAANP

Margaret Bobonich, DNP, FNP-C, DCNP, FAANP: 

What do we do? How can we assist our colleagues in helping them look at one, how do we choose therapies, and when do we collaborate and refer these patients, and what kind of patient education can we provide for these patients?

Well, I think just to kind of bring this all the way back around, first off an accurate diagnosis always leads to successful treatments. So, make the diagnosis. Familiarize yourself with the different presentations of atopic dermatitis and the neonate versus the toddler versus the teen versus the elderly. And I think have a high clinical index of suspicion. If it is coming back, if it is very pruritic, if it’s life-altering, even if it doesn’t look like classic atopic dermatitis, it likely is a phenotypic presentation of that even if it’s not what’s inside your dermatology textbook. So, get the right diagnosis because the right diagnosis will then lead you to begin to move into the more, what I call the empathic side of treating this How is this impacting your life? How would your life change, how are the treatments that you’ve been using working? And so, begin that dialogue with patients and just kind of let them open up a little bit. It doesn’t have to be two-hour long visits for them to really feel like why this is different than other people have seen. Just asking a few questions lets them know that you're into the diagnosis, that you're not just going to run for a cream and send them out the door, and that you can make a difference. And if you don’t have that time to really tell them everything; you're not going to unload everything on the first visit. Tell them about comorbidities, tell them about every single systemic option, you're going to get their acute flare under control with topicals. And then you're going to bring them back in, you're going to earn their trust, you're going to continue to talk to them about it, and then you're going to begin – I’m always introducing non-steroidal options to patients right up front. If I feel like I have to use a topical steroid to calm it down – I may not need to once we get this new topical JAK out but I’m always introducing the idea of us moving off the topical steroids. I don’t use them much but systemics onto these new treatments. So it’s kind of a progressive revelation of talking to them about the disease, what you believe it is, how you want to open up the box and let them know that you know how this impacts you and the family, that we’ve got good treatments out there, we’re going to start off with this, but it’s important for me to see you back because we want to look into other treatments that are on the horizon that can control this for long periods of time without having to lead the anxiety about when am I going to break out next time. 

You know I think you summarized it very well Doug. I think it’s exciting where we’ve been and where we’re going. We don’t have to use systemic agents with these high toxicities that are really rescue agents, like the cyclosporine. We have choices now. And letting the patients know that and one of the interesting things is I’ve heard people say well that’s an injection. But guess what, let’s let our patients make that choice. Let’s give a fair representation of all the treatment options that we have and the ones that are coming because the truth is that an injection may be nothing compared to the quality of life that atopic dermatitis is having on these patients. A lot more to come for us especially our adult, some of the newer agents will be anticipated FDA-approved for adults. Some of the resources you like to give your patients Doug, what are they? 

Well certainly the National Eczema Association, the NEA, I think is an excellent resource with information about clinical trials that we may have mentioned in this presentation, great patient support, practical data that’s there, practical recommendations on bathing and moisturizing. I really, really like the NEA as a great resource. Do you have others? 

Margaret Bobonich, DNP, FNP-C, DCNP, FAANP:

 The National Eczema Foundation is my choice. But I think as far as resources for you as clinicians, I think one of the best ammunitions I would have for you is if you're in primary care or if you're in derm and you're not comfortable with prescribing some of these agents that are here now or the newer ones that we anticipate that will be FDA-approved in the near future, if you're not comfortable, reach out to a local dermatologist or dermatology NPPA and let us help you. One, we’ll help you with that patient and supporting them and getting them the best treatment and optimal outcomes, but also to help you learn about it. We really, really want to support you as colleagues and that’s my suggestion. Any last words Doug? 

 I just want to echo that. You know the study is a few years old, but it showed that only 19 percent of patients with severe atopic dermatitis got referred from primary care to dermatology. I think that’s improved, especially with some of the commercials that have been out about eczema and dupilumab’s campaigns. But we just want to say that this is – our medicine is a collaborative effort. We’re not living in silos here. We want to – we in dermatology want to partner with our primary care providers, we want to partner with our allergy specialists, we want to partner with the folks that are going to help us out too. I want to tell Margaret, you're helping your patients and you're helping yourself because these folks are living with infections, they’re living with scratching, they’re living with anxiety and depression. And we now have treatments out there that can radically change and improve that. So that’s the biggest message of today’s time together is that there is help out there, that we can get these medicines covered by most insurances, and that they can really change patients’ lives. 

 Thank you so much Professor Doug. This is why we call him Professor Doug. And thank you so much. Thank you for watching 

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Experts in dermatology discuss patient education and clinical pearls to assist colleagues in the management of atopic dermatitis.  

Care Collaboration in Atopic Dermatitis 

 Now let’s talk about the JAKs. So, here’s the question. Is a JAK a JAK a JAK. So are they all clumped together Doug?

 Well, I think the answer is no. And the reason is that if you kind of understand what JAKs are you can kind of see why. You know we’re talking about the difference in blocking things outside the cell wall, extracellular blockade of cytokines or receptors versus things you're blocking inside the cell wall or intracellular blockade. And that’s where these janus kinase inhibitors have their impact and their effect. We know that these kinases, which are these tyrosine activated. What happens is that these tyrosine kinases kind of – they phosphorylate ATP and take that phosphate group and attach it to another substance. And in this case it’s this JAK stat pathway, stat meaning these are signal transducers and activators of transcription. And that goes all the way back to like middle school biology where you're reading about how proteins are made. We get the blueprint out of the nucleus, then it comes out of the nuclear pore into cytoplasm and then we go through transcription where these little amino acids stack up and hold hands together and form a protein. 

Well, you can develop inflammatory proteins with inflammatory signals. In the JAKs is what’s driving that process during this disease state. If we can block the receptor from this JAK pathway on the inside of the cell then that’s how we can affect disease. The problem is that so many other cytokines signals are happening through these same pathways. When you begin to move into the JAK world and the three JAKs that are going to come out probably first, which we’ll mention in a second, then you're looking at blocking these pathways, which many other important cytokines may need to go through in order to regulate healthy pathways for us. Because you’ve got four different kinds of JAKs. We’ve got a JAK1, JAK2, JAK3, and then this tyrosine kinase TYK2, T-Y-K2 that are there. And they line up in six different receptors with different pairs. They kind of are paired together. A JAK1, JAK2 at one site, a JAK1, TYK2 at another site, a JAK2 – so you can kind of see how that lines out. Depending on which one you're blocking you may be doing what’s called a pan JAK. You may be blocking all of the JAKs, all of the receptors, which could have more and does have more side effects or you be able to target it in on one. 

These JAKs are not all the same. And these JAKs are very different from the monoclonal antibodies to say because they are considered immunosuppressive. And they do have other, more serious side effects. Let’s talk about that. First off, let’s talk about the pros from the JAKs. They’re oral and they’re not shots. That can be a game-changer if somebody is absolutely needle-phobic. But to take it in the oral side means you have to look at the efficacy and see if the efficacy outweighs the risk of them. And we’ve got, as you know Margaret, if you want to speak to these but we’ve got baricitinib that is already out, already approved for rheumatoid arthritis but we’re expecting the approval for atopic dermatitis to come out soon. We’ve got upadacitinib, already approved for rheumatoid arthritis, already been on the market, not yet approved for atopic dermatitis. We have two that we already have, we’re doing world data on, that are being prescribed by rheumatologists and other providers around the globe for rheumatoid arthritis. We know what these medications and their side effects are. Then we have abrocitinib, which is a JAK1 inhibitor, oral, not yet come to market, it’s not being used for any other indications, and it should come to market as its first indication being for atopic dermatitis. So, you want to go into talking about those more specifically?

 No, I think the most important thing here is first of all is that we have this new class that’s going to be approved for atopic dermatitis. And it’s different than dupilumab. And there will be some screening most likely associated when they are FDA-approved. They're not going to be for children. They're going to be for adults. And I think that’s important. These are great things on the horizon but I think we just have to watch and I think we have to wait. But there are differences. So, a JAK is not a JAK is not a JAK. And so topicals. We talked about the systemic. What about topicals Doug?

 We mentioned our topical JAKs already and the one that we’re excited to receive very soon is the ruxolitinib. So that’s our topical JAK. That’s a JAK1, JAK2 inhibitor that does it topically. And that’s the main one as I mentioned earlier that we’re going to see. But I want to make a clear distinction here. The oral JAK inhibitors we know that these are the people not to use oral JAKs on. If they have a history of severe infections, not going to use an oral JAK. If they have a history of malignancy, if they have a history of thrombosis. These are actually some black box warnings on the two JAKs that are already out being used in rheumatoid arthritis. So, malignancies, severe infections, thrombosis, it could affect renal, liver impact. It’s not great and should not be used in pregnancy or breastfeeding and you may have to adjust your dose. So those are all oral JAK problems. And that’s where you mentioned they have to check blood work on those, and you have to go into those. They’re very fast in their use. They may have some great utility. Some of them have greater clearance data like upadacitinib probably having the best clearance data over baricitinib. But they are medications that we’ll have to wait and see how they’re used. When we move into the topical JAK side, we’re not seeing all these same safety signals, which is what makes those topical JAKs, particularly the ruxolitinib, which we’re going to get first, an attractive offer because it’s different than the topical steroids and it doesn’t carry the safety signals that we see with the oral JAKs. It fits a nice niche, whether it’s going to be just first line and maintenance or added on to a monoclonal antibody or added to anything else that comes along the way.

 Right. And I see that clinicians would be a little bit more comfortable using that topical and putting their toe into the pool of JAKs.

 Right. I mean all of the new oral JAKs – there’s no reason why they cannot be used as first-line systemics but it’s just going to – we’re going to have to wait and see how the data pans out on whether or not that’s really going to be captured as first-line treatments or it’s going to be second line or it’s going to adjunctive. I think we’ll see. We’ll have to wait and watch the experts in our field to kind of begin to weigh in and see how these things are going to be utilized and then how we’re going to utilize them ourselves.

 Thanks Doug. I agree. And I think that these oral JAKs give us an opportunity to kind of boost our armamentarium depending on how they’re FDA-approved, whether we use them as adjunct therapy across all severities, they are non-steroidal, they’re non-injectibles. So I think a lot of clinicians are going to feel much more comfortable going to this topical JAK.

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Margaret Bobonich, DNP, FNP-C, DCNP, FAANP, and Douglas DiRuggiero, DMSc, PA-C, provide insight into the emerging class of JAK inhibitors for atopic dermatitis including their pathophysiology, route of administration, and available clinical evidence.  

Emerging Therapies in Atopic Dermatitis: JAK Inhibitors 

 We have a lot of things that we have used traditionally as well as new pharmacologic therapies that are in the pipeline. So Doug, let’s start with some of the topical therapies.

 Yeah, I think – I just want to mention. The real question I get from folks who refer to me is how do you decide or when I have residents or students rotating with me, how do you decide if you're just going to use topicals or just going to try to use some of the new systemics. And I think that’s kind of an underlying question. If you're going to put people – I think basically with atopic dermatitis treatments, you're looking at two boxes you're going to put folks in. Those that you feel like that are mild that can be treated alone with topicals. Maybe some of these newer ones coming out may even say mild to moderate you may be able to treat with topicals and those that you feel like that are moderate to severe that may need to be systemics. The choice to put someone on a systemic is basically this. Have they failed topicals? There’s no lab work you're going to check, there’s no great algorithm that’s out there right now that says this is when you're going to put someone on a systemic versus not. It’s just basically their severity, their presentation, what they failed in the past, make sure you know why they failed in the past, was it lack of compliance, in order to make that decision. Let’s just stick on that mild to moderate patient where we’re going to use topicals. I’ll start off with talking about what we already have. I kind of think of topicals in four categories. What’s in our back pocket, what’s been around the longest. And that’s our topical corticosteroids. The first one came out topically in 1952. It’s the first trial to really change the whole direction of dermatology having topical corticosteroids. And so, we’ve been using them since that time. They still are the mainstay of treatment in dermatology and in primary care. But you know those are not meant to be long-term because of skin thinning and hypopigmentation, atrophy triad that can happen. We know that calming down flares is important, but they're not good for maintenance therapy. If we move into the next tier, what’s in our front pocket in terms of what’s a little more new. What do we have in hand? Now first of all it’d be the topical calcineurin inhibitors, protopic and elidel. We had a good study come out last year of long-term safety looking at kids over ten years, looking at incidence of potential cancer and this study showed that based on lack of seeing any cancer signals that these medications do not have any significant increased risk of cancer according to this trial, even though there is some black box warnings in using them under the age of two. The other side of non-steroidal topicals is crisaborole. And crisaborole came out a few years ago. It’s a PDE4 inhibitor. We have some new PDE4 inhibitors coming out soon that may have a higher binding effect and rate of clearance. But crisaborole is awesome in that category. We’ve got topical steroids as the old traditional. Then we move into some things that have come out more recently that are things that can be moved towards maintenance therapy or maybe even initial therapy, crisaborole and then your two topical calcineurin inhibitors. 

And then we move into what I consider the new kids on the block, ones that we are about to get into our hands; ones that are going to come to us this year or early part of next year. And when we move into those, we’re talking about topical JAK inhibitors. And I’ll just go ahead and give it some special mention. The topical JAK that’s going to come out I think soon to get into our hands first is ruxolitinib. And this ruxolitinib is a JAK1, JAK2 inhibitor. We can talk about that class in a second just to describe what JAKs are. But this cream has great excitement around it simply because of its EASI scores and EASI is this test where this indicator, this subjective market that we use to look at severity and how much the severity improves. It’s a severity index. Eczema area severity index. And they have EASI scores of 62 percent of patients seeing an EASI 75. That means they get 75 percent improvement. So you're looking at greater than six out of ten are getting a 75 percent improvement with a topical alone. And then they have an EASI 90. I mean that’s 90 percent improvement. Almost 41 percent of those patients are doing that. And they’ve run some trials too looking at head-to-head against a.1 percent triamcinolone and saw that that versus.1 percent triamcinolone with a BID application over eight weeks, how it’s typically studied and how it’ll probably come out. We’ll wait to see what the FDA says on that. But even it was as strong as or maybe even a little better than our triamcinolone without the side effects that we see with topical steroids. This is kind of our exciting new topical JAK that we feel is going to be in our hands very, very soon. Delgocitinib I think is the other one that’s far in the horizon. It’s approved already for atopic dermatitis in Japan, but it looks like they’re only going to go for an indication of hand dermatitis in the United States, and not even an indication for atopic dermatitis. So that’s a second topical JAK that is further down the road but may not even have an impact on our AD population in terms of FDA indication.

 I’m glad you mentioned that Douglas. It’s exciting to have all of these new agents. And the truth is when you have patients who have moderate AD and understanding this is – this last year, this is relapsing. Applying topicals over and over and over is difficult for parents. When they start off with the topical steroid and then they switch over because alternating or rotating is often very helpful and helps eliminate some of those side effects and risks. The problem is is that some of the calcineurin inhibitors or the PDE inhibitors, PDE4 inhibitors can cause a lot of stinging. I find my parents want to keep going back to that topical steroid with those side effects. I really welcome the new topicals that will hopefully provide this new option for our patients that give them both control with less side effects.

 Yeah, it’s going to be great. And it looks like these new topicals, particularly this new topical JAK, ruxolitinib is going to have far less stinging and greater tolerability than the others. We also have a new PDE4, roflumilast that will probably come to market soon as well. It seems to have a higher binding affinity than the original PDE4, crisaborole so its EASI scores are likely going to be higher. And there’s one called tapinarof, which should be coming out. Again, these are things that are an arm’s length away from us right now, not quite imminent but coming soon. That’s a whole new compound, what’s called an aryl hydrocarbon blocker. It’s going to be interesting to see if that AhR. I don’t have any data on it at all to say. But lastly too, which I think is definitely going to come in with high tolerability and maybe even be attractive to our patients who want to use natural products is that we mentioned the skin bio earlier. And this dysbiosis or the shift in different populations from a good mixture, a good diversity of the microbial atmosphere on our skin versus when one particular group overtakes, like staphorias. And using these new topical treatments that are in Phase II and entering Phase III trials, looking at the Roseomonas mucosa and also the staph hominis. 

These are “good” bacteria so to speak that when you apply to the skin in the form of a spray or a mist into the antecubital fossa, into the back of the knees, if you look at these trial designs and it shows tremendous improvement, decreasing itch, improvement in skin barrier function as well. We’ve got a lot of exciting things approaching the microbiome side of skin, approaching the intercellular blockade with JAK inhibitors and PDE4 inhibitors, things that will give us better options than just using the traditional topical steroids.

Experts in dermatology describe the topical treatment landscape of atopic dermatitis: corticosteroids, calcineurin inhibitors, crisaborole, and upcoming topical JAK inhibitors. 

Topical Treatments for Mild to Moderate Atopic Dermatitis 

 Let’s talk about some of the foundational non-pharmacologic treatments that we should be recommending and educating our patients about as well as how do we prevent those flares.

 I mean we know that there are some very practical things that anyone should be educated to do in terms of – we know the skin is hypersensitive and is prone to flaring. A lot of exogenous factors can play into that, even patient sweat, chlorine in the pool, pollution outside has been implicated in studies. A lot of things are known to be triggers for atopic dermatitis. But we certainly want to eliminate as many as we can. So, you want to go with silk or smooth clothing, cotton clothing, nothing wool, nothing scratchy. You want to make sure that you're using detergents that are for – that are allergen-free. We want to use soaps inside the bath that are for dry, sensitive skin that are moisturizing. There is a debate on what to do with bath time. I think most people would say now that if – to bathe or not to bathe. We know that if you don’t bathe that can increase infections particularly in our severe atopic dermatitis patients; if you bathe too much, it can be worsening. I think there’s a balance that has to be there between the – our more severe patients probably shouldn’t be bathing every day or at minimum, every other day in order to decrease staff colonization but the bath time, the water should be tepid. The bath time should be short. You should be moisturizing right afterwards. 

You should be applying your topical medications right afterwards for better absorption. I think there are some issues there. And I would just say lastly too, the issue of moisturizing daily or multiple times during the day is very important for barrier function. Unfortunately, we had some information come out last year, 2020 the BEEP trial, B-E-E-P trial that looked like it’s basically a daily barrier emollients for prevention of eczema or eczema prevention, BEP. And it showed when they put emollients on infants, on newborns within two weeks of age who had a parent with atopic dermatitis and applied emollients every day for the first two years of life decreased their chance of developing eczema. And unfortunately, there wasn’t a statistical difference between those two populations. I think the word is still out on that. I think we’re going to find that daily emulsifying the skin with people who are at high risk will eventually pan out in the larger numbers to show that it is preventive. What do you have to add to that?

 I agree. A couple things I’ll say. One of the things that I love about – I do recommend daily baths for – especially the children for a couple of reasons. First of all, children with atopic dermatitis as well as other skin diseases like psoriasis, people don’t touch these patients. They see open cracks or crusts, or scale and the truth is is that they aren’t touched by people. Their intimacy is decreased as they go into adulthood, and they carry these kinds of papulosquamous diseases. I think it’s an opportunity when we have our children bath time is great. It’s when people can calm down and it’s touch, it’s softening that scale. And then when they do get out, like you mentioned Doug, head to toe those emollients. We love to call it soak and smear. And that is – it’s a great time emotionally to reconnect. So that’s the second thing. The last thing I would say is just reiterating what you mentioned. The risk for infection is so, so important especially with these children. And I think historically some people would recommend bleach baths, which is very – it can be disputed by some and for children who have repeated MRSA infections, but I think the key is going back to let’s prevent the flare and let’s take advantage of not just the foundational aspects of skin care and avoidance of triggers but understanding what pharmacologic options do we have in order to treat those flares.

Margaret Bobonich, DNP, FNP-C, DCNP, FAANP, and Douglas DiRuggiero, DMSc, PA-C discuss best practices in the non-pharmacologic management of atopic dermatitis including elimination of triggers, bathing, and reducing infection risk. 

Margaret Bobonich, DNP, FNP-C, DCNP, FAANP

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