Navigating the New Era of Systemic Care in Atopic Dermatitis

Join us as Derek Chu, MD, PhD, explores the paradigm shift in treating atopic dermatitis as a systemic, immune-driven disease rather than a localized skin condition. We discuss the updates to the practice parameters including practical guidance on integrating of novel topicals, biologics, and JAK inhibitors into our treatment as well as the upcoming practice parameters on chronic spontaneous urticaria. 

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Transcript

Rebecca Saff, MD, PhD, FAAAAI 0:13

This podcast is the American Academy of Allergy, Asthma & Immunology. I'm your host Dr. Rebecca Saff . Allergy and immunology is a field that's evolving at an incredible pace, and staying current isn't just important, it's essential. This podcast brings you conversations with leading experts to explore the latest advances, challenge how we think about core topics, and ultimately help us deliver the best care to our patients. Atopic dermatitis is one of the most common conditions we manage in clinic, and our growing understanding of type 2 inflammation and skin barrier dysfunction has dramatically improved how we approach diagnosis and management. We've gone from topical steroids as our primary treatment modality to targeted biologics and to small molecules. Today we'll review the latest updates in atopic dermatitis as well as look at the upcoming guidelines in urticaria. Today we welcome Dr. Derek Chu. Dr. Chu is an assistant professor in allergy and clinical immunology in the Department of Medicine at McMaster University. He also holds a joint appointment in the Department of Health Research Methods, Evidence and Impact. He is the chair in allergy of the Canadian Institutes of Health Research. He serves on the Joint Task Force for Allergy Practice Parameters and multiple international initiatives to improve outcomes in allergy immunology. Dr. Chu discussed the atopic dermatitis practice parameters with Dr. Stukus in 2024 and is back to discuss some updates with us. Dr. Chu, thank you so much for taking the time to join us today and welcome to the podcast.

Derek Chu, MD, PhD 1:30

Thanks so much, Rebecca. Looking forward.

Rebecca Saff, MD, PhD, FAAAAI 1:34

So could you tell us a little bit more about yourself and how you got interested in atopic dermatitis?

Derek Chu, MD, PhD 1:39

As you mentioned, I'm an allergist by training and I also do the methodology for the joint task force and practice parameters. And clinically, I also run our challenge unit at McMaster. And consequently, I'm seeing a lot of folks that come in with atopic dermatitis and associated uh diseases, such as suspicion for food allergy. And I also see a lot of those patients just in the general allergy clinic uh in addition. So they're near and dear to my heart, and there have been a lot about um the importance of the need for updated guidance for atopic dermatitis. I had the great pleasure of uh helping develop the first round of the guidelines that we uh published in Annals with the Joint Task Force, and we've been as a commitment to a new initiative called Living Guidelines, that is to say, continuously updated guidelines. We are uh in the midst and just about to release the next update for the Atopic Dermatitis Guidelines as well.

Rebecca Saff, MD, PhD, FAAAAI 2:37

I love that. Can you tell us a little bit more about what living practice parameters means? How often they're planning to review them. Is it the same group, or will do eventually you get to roll off, or are you now a lifetime member?

Derek Chu, MD, PhD 2:49

Well, as the as a methodologist for the joint task force, I'm I'm uh intimately involved with all the guidelines we develop, uh particularly the grade-based guidelines that try to follow the Institute of Medicine recommendations for uh optimal trustworthiness of guidelines as well as explicit methods to uh systematically review the evidence and translate that to actual recommendations. So um, yes, as we are committed to the living component. Living means that it should be continuously updated. In theory, that means any moment, any second, uh new practice changing evidence arises, that it is immediately updated. However, what we are doing is being intentional about not making premature decisions too quickly, being sure that uh we have both the important new evidence and approvals that come out and the experience with it rolling out. And so we are initiating uh both periodic review as well as uh important practice changing triggers for review that would then lead to a new guideline panel recommendation. So for us, we uh were able to package new recommendations for multiple new topicals as well as systemics, and uh, in part from Dave's uh very wide advice, Dr. Stukas's very wide advice from last time, we've also addressed the issue of antihistamines in atopic dermatitis.

Rebecca Saff, MD, PhD, FAAAAI 4:08

Oh, fantastic. Yeah, I think many of us appreciate this idea because sometimes our practice parameters would be 10 years ago, and what we've done, what we do in practice is so different than that, just because the field has evolved so much.

Derek Chu, MD, PhD 4:22

Yeah, so a major initiative that we're trying to do with a joint task force and great gratitude to our parent bodies is trying to shorten that time between new evidence and uh change to guidance. Uh, so we're getting it down, and uh just with the practice parameters coming out in the first iteration coming out in 2024. We initiate that update and have finished them just in uh January, February of this year. And so we are uh right about to issue them for for public comment again.

Rebecca Saff, MD, PhD, FAAAAI 4:50

That's amazing. And it was so much work. So thank you so much for all the work you put into it to give us these guidelines to really help us know how to best manage our patients.

Derek Chu, MD, PhD 4:59

Thanks. And grateful to our membership and and leadership for prioritizing uh getting that guidance out there.

Rebecca Saff, MD, PhD, FAAAAI 5:05

So the current thinking um in atopic dermatitis is that rather than thinking of it as just a skin condition, this is really a systemic immune-driven disease. How does that change our approach to treatment?

Derek Chu, MD, PhD 5:16

Yeah, I think this has multiple implications. So the first that's probably the most widespread is about the importance of the skin to uh being associated with multiple other diseases, and especially with most atopic dermatitis presenting in the first few years of life. We now know and paired also in other joint task force work with food allergy. We just had a big food allergy risk factors paper come out in GMA Pediatrics that shows that eczema, even if mild, is an important risk factor for developing other conditions, most proximately in that atopic march concept uh food allergy, but it's also associated with other conditions, allergic rhinitis, asthma, and so on. And so there's emerging evidence that optimal control early in life is not only important for the eczema itself, but also for developing some of these other comorbidities and complications, both topical treatments and likely potentially some others have shown some preventative early effect on developing other conditions. But then, secondly, by saying that it's not just a skin condition, what we're trying to articulate are some other aspects. That number one, that just because someone doesn't have a rash doesn't mean their eczema is not there. We see very many kids with contact urticaria and and um from introduction to foods and irritant reactions, which may be a sign of underlying untreated uh atopic dermatitis, it also means about the concept of proactive therapy that uh even for our mild to severe patients, just because that skin has returned to what seems to be looking normal, that's underlying inflammation that might be dermal or lower, is still present and has to be addressed. And then in addition, from a broader point of view, what we're trying to say, and that was articulated beautifully in a BMJ paper that we cited near the end of the first guideline, is that it affects more than just the skin. It affects the individual, it affects their sense of well-being as well as the family as a unit. And so what we're trying to talk about is the uh multiple layers of how this condition impacts uh patients and those around them, and how, as clinicians, we need to take a broad approach to addressing all these different factors.

Rebecca Saff, MD, PhD, FAAAAI 7:25

Yeah, no, definitely it affects the family so much, you know, even the development of food allergies and how that will affect their diet, the sleep that we know is an impactful. So all these things that happen are such an impact on just the whole family, not just the patient. So there's lots of newer topical therapies that are now available. So not we don't just have the um topical steroids, the calcinurin inhibitors, we have all these different new medications. How do we incorporate those into our care?

Derek Chu, MD, PhD 7:51

Yeah, that's a it's a great point. So the topical steroids still extremely effective, very well established safety and efficacy profile, and um still important about being certain about what whatever you're treating is the right condition whenever escalating therapy. We had a good practice team that was very clear about uh about that. Um, and topical calciner is extremely safe. We've shown that it's been safe down to the infant age group and that there's no clear association with an increase in malignancy. But these newer ones include things like Topinoroff as well as refluidast. Uh, there are some also new emerging data with crossabrool as a maintenance therapy as well. And of course, we have our topical jacks like Ruxolitonib. So, with um refluidast, uh, has been studied more so in the milder age group uh with a series of randomized trials that have come out that have shown that it is overall efficacious, is closer to like a TCS-5 type role between TCS5 and TCS6, whereas to Pinuroff, a slightly more potent than it that works via the aerol hydrocarbon receptor and is uh more in the moderate uh disease category. They technically studied moderate to severe, but more in the moderate category, and it's also been quite effective as the in the TCS5 range. Now, the main issue behind both of these is that in comparison to uh the topical steroids and topple calcium inhibitors, that they're actually much more expensive. At least good RX prices for what you can take of them at face value, which are you know they could be substantially lower with coupons and so on, are in the range of thousands. So they're they're extremely expensive medications and they come in 60 gram tube sizes. So if 30 grams is an adult application, this is not going to last someone very long. And so they might be used more so in sensitive areas, special um that we may want to avoid topical corticosteroids such as face and folds. They might be used also as a steroid sparing agent in other places where people are frequently applying, or based off patient values and preferences. If cost is not as much of a main factor and there's a strong preference to avoid topical corticosteroids, clinicians have the option of trying to re-or change the way the patient thinks and their values and preferences, something very hard to do, or to try to give the patient options. And this is a critical component to that.

Rebecca Saff, MD, PhD, FAAAAI 10:20

Is there any data on how to combine them with you know topical steroids with the calciner inhibitors and these newer agents to know how we can use them all effectively?

Derek Chu, MD, PhD 10:30

So there have been no big formal randomized trials comparing, say, efficacy of what we would call induction of remission, that first phase of controlling an uncontrolled or a flare of eczema to get it back to a quiescent state or back to remission that have you know directly head-to-head compared combination of say topical steroids plus refumulas or topical steroids plus to pin her off. Though in practice, there's been a lot more experience about trying to combine these. One of them may be uh the more common way about how we think about proactive therapy, uncontrolled disease, the topical steroids, especially increasing in potency, are likely going to be helpful as a jump start if you need to. But you can either use that as an option to jumpstart things, or you can go direct to one of these agents. That being said, the the more potent topical steroids will likely be uh more effective in terms of their potency, and then transition to these other agents as more proactive therapy. Proactive therapy meaning intermittent application, such as two to three times a week, they can be consecutive or non-consecutive days, and best evidence available for topical calciurin inhibitors. That approach will still work with topical corticosteroids, but some people may be less keen to do that. That might be, say, your teenagers that are growing rapidly, or people that are changing in their habitus that might be more prone to stretch uh marks or other discolorations, certain, but the formal studies actually for maintenance as intermittent therapy are best established for TCIs and topical steroids. In practice, it would make sense that Rufolium last and to Pinoroff could also be, and perhaps also the topical jacks, but there is much less formal evidence that have actually addressed that.

Rebecca Saff, MD, PhD, FAAAAI 12:13

So now that we have these systemic therapies available as well, so the biologics, the small molecules, and we know that systemic disease control is so important. How do we balance when to start a systemic therapy versus kind of these more potent topical therapies?

Derek Chu, MD, PhD 12:30

Yeah, so the it really boils down to uh thinking about the whole patient, I think, and making sure that we make it clear to them that you don't need to just kind of have a persistent of only topicals, if really the problem is going to be what their objectives are. And if you're worried about, say, that infant with uh that is struggling with eczema, parents and families are with parent and family and patient are at wit's end, and you're worried about the potential for this being systemic as they introduce foods that they could be developing a lot of these contact and sensitization, then one might lead, yes, to give the option of we could intensify topical treatment, it could be the way to go, but it we are very clear in the guidelines that if uh if someone is moderate severe disease refractor to your best treatment of topicals, then we strongly recommend to go for the systemic agents, starting with the biologics, primarily given their extremely good efficacy and safety profile. So that would be your dupillomap. And in the updates, we've also now shown that Libra Kismap is a very close to dupilumab. Many people may not even be able to distinguish the two, and so you could use dupilumab or librachismap as a strong recommendation. And then the original, we also said a strong recommendation for tralo, so dupilumab, libre, or tralo as kind of your first options, extremely good efficacy and safety. And so those should we will be adding Libre as a new option in addition to the recommendations.

Rebecca Saff, MD, PhD, FAAAAI 13:59

Given these wonderful systemic therapies, it sounds like you know, we think about patient preference, we think about cost, we think about safety. How do we really personalize the systemic therapy for our patient and incorporate all of those parameters when we discuss it?

Derek Chu, MD, PhD 14:12

Yeah, so one of them might be about what people can access, and that can be determined by uh many, many factors. There are some differences regarding dosing of these, but I think the probably my main consideration, at least for now, until we get robust information about biomarkers that will predict response, are going to be comorbidity. So if we're worried about that patient that's gonna be you know developing asthma as well, then or has comorbid asthma or uh nasal polyps, for instance, or even say verticaria now, then people are more likely to favor dupilumab given its known efficacy and safety for these other indications. You're treating more than one condition with the same intervention. If, however, say someone has intolerance to any one, you could switch to another. So I've had a number of patients that have been intolerant to dupilu mab but have been successful on either Libri or trilow or vice versa. Uh, and certainly that's been the experience for a number of experts as well. But then, in addition, or similarly, we also recommended other advanced systemics such as the oral jack inhibitors with appropriate cautions uh regarding their safety, that it can be very helpful for a number of other autoimmune conditions that also come with them, or alopecia that also comes with some of these conditions as well. So, really considering that whole patient approach and understanding can I treat more than one condition with the same intervention and optimize kind of polypharmacy or reduce that chance of polypharmacy, I think is the main way uh we have right now. A lot of great interest in the future about using biomarkers to predict response, but not quite there yet.

Rebecca Saff, MD, PhD, FAAAAI 15:46

Yeah, it'll be so interesting because just I have the same thing. I have patients that have responded to one and not responded to another, and I don't necessarily understand why. Um so I look forward to the era of biomarkers where I can really know that this is likely to be the best treatment for the right patient.

Derek Chu, MD, PhD 16:00

Now, one thing that is coming up is actually a new agent, nemalismab. Now, nemalismab works by a new mechanism uh targeting uh IL-31 and its interaction with the corresponding receptor and onkocin M. And this one is appears to be a dominant itch pathway in eczema. So patients that are treated with nemalismab, their eczema severity may not go down quite as much as dupilumab or tralar or livery, but the itch will go down quite substantially. And so, consequently, nemalismab could be considered as an add-on for some of these agents, considering patient values and premises, cost access, uh all to get them sorted.

Rebecca Saff, MD, PhD, FAAAAI 16:41

We talk about eczema being the itch that rashes, but certainly there are some patients where itch is such a predominant symptom versus others. And so having another medication available that really addresses that, I think, will really add to our arsenal.

Derek Chu, MD, PhD 16:53

Yeah. So it's all about that, again, that personalization, that itch dominant, then bringing it up as that second option for them.

Rebecca Saff, MD, PhD, FAAAAI 16:59

So this is a long-term uh disease that patients really need to manage chronically. How do we help patients with their maintenance regimens when they're feeling much better, they're um they're getting tired of applying all these medications or asking if they can taper off their medications? How do you work through that?

Derek Chu, MD, PhD 17:17

Yeah, so there's uh so in each of our uh documents, we have an implementation guide for each that might be helpful as a document. In addition, written action plans are generally advised. It can be quite helpful to lay those out those steps. And uh for the topicals, for instance, then yes, being on that proactive therapy is often one way to keep control. And then with time and sustained control, then one could taper that from say two, three times a week to one to two times per week or less. And similarly for the biologics, our typical data, our typical approach based off of some data such as solo continue, liberty solo continue, or uh corresponding others for uh Libre and Trellar, that typically if someone is having sustained response, similar to how we might approach the uh familiar with OMLIS map for urticaria, we can then taper it week by week or every two weeks to extend the interval between doses, and if there still remains sustained response, then to taper off. There are a lot of interest in in slowly tapering it off, and and I think it would be a very important to find out long term do these treatments modify the disease uh in some permanent way going forward or some long-term way? I think we're awaiting some, there's some emerging data for that, but we're that the definitive evidence is eagerly awaited.

Rebecca Saff, MD, PhD, FAAAAI 18:36

I know there's a nice paper on spacing out for zopolyps with dupilomab that when people are well controlled, you can get some people out to eight or even 12 weeks, but they still need some maintenance. I mean I think that there's some emerging evidence in atopic dermatitis that that may be true as well, but we don't know which patient will need which interview.

Derek Chu, MD, PhD 18:55

Yeah, I think that goes back to the the need in the future for our also understanding biomarkers.

Rebecca Saff, MD, PhD, FAAAAI 19:00

Yeah. Absolutely. What are some of the practical strategies that you give patients to adhere to kind of these complicated regimens? Do you have, you know, break down an action plan? Um what are some of your tips?

Derek Chu, MD, PhD 19:12

So we we give action plan to all our patients. Uh, and it will it involves, you know, if mild, do this, if more severe, do this as an option. We try as much as possible, and what we recommended is to reduce polypharmacy, keep it as simple as possible, consider the patient's previous treatment history, what they have available, what they can access, what their preferences tend to be, but where it's affecting, on top of, of course, what we said before, make sure that you're not missing any other condition. And then it will say very clearly in that handout what to do to induce remission, how to convert that to your maintenance therapy or your proactive therapy, what exactly is a fingertip unit, and then the standard non-pharmacologic recommend recommendations such as sugar avoidance, exacerbating factor avoidance, as well as please use a moisturizer frequently, fragrance-free and bland. So those are some of the most common ones. And then for the biologics, yeah, we do keep them uh quite up to date in terms of frequency of visits and making sure that uh they're comfortable when and how they can taper. Uh, very much trying to promote that self-agency, but sometimes it requires that written information every single time to uh which we we we try to personalize in terms of we'll create it internally for them uh rather than just rely on uh maybe what's provided by uh the manufacturer.

Rebecca Saff, MD, PhD, FAAAAI 20:32

So just to circle back to triggers that patients have, you know, there are some families we I think as well, I think we're all well aware that we should not test for food allergies in these patients. Um, but there are definitely some families that feel that there are certain food triggers for the kids with atopic dermatitis, and they end up starting to restrict those. How should we manage that when they feel that there is a food that not that they're concerned about an Ig-mediated reaction, but really flare the atopic dermatitis, knowing the risk of Ig-mediated reactions?

Derek Chu, MD, PhD 21:01

I think the issue is about definitive diagnosis ultimately. There's two components that we suspect ultimately at their heart of the issue, which is about reading between the lines of what the patient's seeing to you and getting at what the actual outcome they want is. I think the first one is when someone comes to you and says, I'm worried that food is the issue. Number one, acknowledging, and that's what we showed in the systemac review and the guideline, is that they could be right. There are a proportion of people where you can have exacerbation of eczema, but that's very different from using a food avoidance as a strategy to gain control of eczema. And we now know that has a lot of trade offs which might be ultimately unfavorable, such as the promotion of dominant food allergy, especially when it's young, and across all ages, nutritional issues. And we have many options for treatment. We can certainly treat the eczema. We have so many tools now, but we don't have a mechanism to cure food allergy yet. And so the first issue. Is okay hearing them out and acknowledging them and then addressing how to get control of the eczema in a definitive fashion. The second component is does this person have food allergy? So by history, and by history and so on, you often discern a lot of those issues, but there may be some, such as the those children that have frequent contact dirty care of the face and so on, that might actually suggest food allergy. And for those, the definitive diagnosis is going to be a food challenge. And so in the corresponding food allergy guidelines that are coming out as well, yeah, that may be a common theme. But that but as we've shown in the previous peanut diagnosis practice parameters, most tests, whether they be a history, physical, skin test, blood test, even your ARH2 for peanut allergy, will not get you from say a 50% probability of allergy to 100% confident that they're allergic. And most times, if you even increase your probability of allergy from say 50% to say 80% with a skin test or whatever of a skin test size of 5, 6, 7, the parent may not be comfortable with that to live their life the entire life with that degree of confidence. And so we now know, in addition, early intervention might be important for prevention, in addition. So it's quite crucial that we get the diagnosis right.

Rebecca Saff, MD, PhD, FAAAAI 23:22

It sounds like the food allergy practice parameters are also going to emphasize the need for food challenges to really possibly.

Derek Chu, MD, PhD 23:29

One of the questions is should we screen? Should and how accurate is all the testing? So that's ongoing right now.

Rebecca Saff, MD, PhD, FAAAAI 23:35

Yeah. And one thing we a lot of us really are concerned about is the disparities in atopic dermatitis between different skin colors, um, different skin textures. What is what are some of the things we can do to address this?

Derek Chu, MD, PhD 23:48

So, uh, of course, as physicians, we all uh play a role to advocate for society and for uh optimal clinical care for the population. Uh, but beyond that, uh for individual patients, I think it's quite important. We articulated it a bit and we had great input from our patient partners and about resources available. There are some even through the college, for instance, that address eczema and the skin of color. And it is important to recognize that eczema may present differently. That would is to say that it may not have that, you know, that literal interpretation of the word erythema or red. It may be more violaceous, it might be more gray, it might be more important to look out for more population and the like unification that can appear. And then we also are quite aware that there is an association with worsening uh or worse outcomes, in part it may be due to worse access. So being upfront addressing the issues with you know, providing the what we say in the good practice statement of making sure you have the right diagnosis and moving forward with the basic fundamentals of care, but then also making sure that we're not dismissing or under-reporting that eczema severity so that we don't under-prescribe, say, systemic treatments and so on to get them their best outcomes. I think is quite important. So I think that's probably where I would start. Yeah.

Rebecca Saff, MD, PhD, FAAAAI 25:08

And are there any complicating factors that we really need to be aware of? I know one of the things of the the very beginning of the atopic neumatitis practice is the right diagnosis and the right patient with the right treatment, kind of getting all those rights in order. Are there other things that we should be aware of as we're thinking through this?

Derek Chu, MD, PhD 25:24

Yeah, so for uh perhaps from our lens uh from clinical immunology and allergy, for the very young patient with a very severe disease, looking out for inborn areas of immunity, uh, um, which that practice parameter just came out as well. So big plug for that one to read as well. Um, but for others, there can be looking out for complications such as infectious complications, uh, will be next most common in the young, uh, both bacterial and viral, and at times potentially fungal. In the young, it may be hard to differentiate, especially on the face, sebderm versus atopic. Some of the most recent interventions, such as refluid and molast, are indicated for both, so that can be quite helpful. But then as there's older uh ages, then contact dermatitis becomes more apparent as a potential complicating factor. And then in our uh older age individuals, looking always out for cutaneous T cell lymphomas is going to be quite important. So if there's a rash that's not responding well, it seems to be refractory and fixed, or associated with any systemic symptoms, you have a biopsy of that. And those are probably uh the the basics for looking out for any complications or or differential diagnoses. So keep your keep your mind broad whenever before you intensify any therapy.

Rebecca Saff, MD, PhD, FAAAAI 26:34

Are there any other points in the upcoming updates that you think are important to emphasize that patients that physicians should look out for?

Derek Chu, MD, PhD 26:42

So along the same lines, I mean there, they're uh other than the great new evidence with the new topical systemics, I did bring up the point about uh antihistamines. Antihistamines tend to still be quite commonly prescribed, often for their uh perceived potential benefits for sedation, whether it be second generation or first generation. We have done the first systematic review that has compared all antihistamines from all time and it's synthesized it all together and uh should be coming out quite shortly. But antihistamines remain over-prescribed, is the is the bottom line. And so the new guidelines will recommend to use them in very select scenarios. And in most case scenarios, such as the first generations, uh, is likely to be a little and no benefit and may actually cause harm with sedation leading into the next day, which can impair, along with uncontrolled eczema, sleep and performance and so on. And so, therefore, we have better tools now in our toolbox.

Rebecca Saff, MD, PhD, FAAAAI 27:35

Definitely. Uh, and I think many of us will had in the past tried to escalate the dose to really get on top of the edge, and it just is a different itch with atopic dermatitis than we see with other.

Derek Chu, MD, PhD 27:45

Yeah.

Rebecca Saff, MD, PhD, FAAAAI 27:47

So I'd like to talk a little bit about the chronic spontaneous urticaria guidelines that are coming out. Um, what are some of the important highlights that we should really be aware of?

Derek Chu, MD, PhD 27:54

There are going to be highlights that are um that are gonna be critical. There's there will be some recurrent themes, such as making sure we've got the right diagnosis, but we have systematically examined probably the most important features of urticary care. We've looked through all antihistamines from all time, all systemic agents, including the new small molecule inhibitors. We've looked at topical steroids, we've looked at oral corticosteroids, uh, we've looked at patient values and preferences, all to systematically develop all the statements. So those are right about to come out, and I'd be super keen to get uh public feedback as well as to see them uh implemented. So, one of the uh points is that yes, while antihistamines remain essential, not all antihistamines are the same. So, first generations uh will have those unfavorable trade-offs of uh sedation, and they're not necessarily going to give you added benefits. In fact, actually, uh second generation antihistamines tend to be more efficacious on average uh than the first generations. Both are effective, but second generations even more, plus, they have some potential other benefits about onten of action and duration, and of course, less sedation. But not all second generations are equally non-sedating, such as your satirizine and levosatirazine might be slightly more sedating. Things like laratidine might be more intermediate, and uh things like uh the desluratine might be among the less uh less, particularly for those that have access to uh agents such as Blexin, Blexin available in Canada, I apologize, but that is among the least sedating agents as well. So nothing is the same. Though you can updose, of course, the chance of sedation overall increases. Probably the least sedating uh that would be available would be uh, for instance, fexafhenidine or allegra, which can which is available uh as well. But the main downside to fexaphenidine typically is cost relative to the others. I mean, mostly shouldn't break the bank, but still relative to each other, it can be among the more expensive. For the biologics, uh omalismab, very effective and safe, and we have great information about how to taper and change dosing, but we have at least two new contenders uh for first-line advanced systemic therapies that is dupilomab, uh, which has is now indicated. However, there are some caveats to dupilumab. Number one, not great data for angiodema. So if your patient has angiodema, it might be a factor to consider whether or not uh they actually would be the optimal uh therapy for that patient. Thus far, the angiodema data has has actually shown no major impact to angioedema. And then, secondly, at least uh for the inducible urticareous, less information with dupilumab and inducible urticarous. There was a recent negative trial in Jackie Global that showed that dupilumab did not improve cold urticary outcomes. A lot of considerations around the trial itself, so we await more evidence to see how dupilumab will fare better uh or not for the inducibles. And then we have remibrutinib, your small molecule inhibitors, oral, fast acting effects can be seen within the even the first week, though typically quite clear within the first two to two, three weeks. Very efficacious, but like many other small molecule inhibitors, we await more uh safety data. So, thus far, encouraging. Its main safety event profile has been bleeding, potential increase in minor infections like upper respiratory, but those bleeds tend to be more paticii and bruising bleeding uh episodes rather than major bleeding. And so we that most of the data has come from at most 52 weeks. Some of the data from the randomized portion have been the range of 24 weeks. And so uh we really need to see how this is deployed, but it might be a great option for many patients as well. And then we have a lot of other guidance about how to use the other uh treatments, such as updosing, omalismab, cyclosporin, and all the other ones, all the other conventional immunosuppressives.

Rebecca Saff, MD, PhD, FAAAAI 31:48

One of the other things the guidelines address is how we use adjunctive therapies in addition to the H1 antihistamines. So, how should we think about things like anti-leucotrides and topical steroids when our patients aren't controlled on H1 antihistamines, but we're not quite ready to move to some of these biologics or small molecules?

Derek Chu, MD, PhD 32:03

That's great. Yeah, so the topical steroids, so there have been no systematics in the past. We addressed it, and uh no surprise, the evidence is very low certainty. But we've seen many patients come in uh with topical steroids, even though they have urticaria. At the end of the day, they might actually have some effect, uh, but and we and we're very familiar with their safety profile, but the issue is it boils down to what kind of uricaria do they have? Erticaria, as we know, we classically teach as evanescent and migratory. A systemic acting treatment is gonna make the most sense for most individuals. However, there are some individuals where it's very localized or just a few spots here or there, or maybe an inducible where they are very clearly exactly where it will be localized. A topical might make sense for very select patients if they really prioritize that topical treatment over a systemic. That being said, conversely, for most individuals, they'll likely favor the oral acting antihistamine speed of action, everything like that. The mechanism behind the topicals maybe it's the anti-inflammatory action, but it's probably primarily the vasoconstrictive action. For the anti-leukotrides, like we've updated the systematic crew. There actually was quite a few data out there that's published in Jackie that has shown a modest improvement in urticary activity used as an adjunct, uh, and that's balanced by primarily the box warning. Uh, and so that's a rare potential neuropsychiatric change for our adverse event for patients, so that is important to disclose. Patient comorbidities and their preferences are very important in this circumstance. And what was surprising about the randomized trial evidence is that it did not address angiodema outcomes, whereas there's a lot more kind of clinical experience that suggests using anti-leucotrine either on demand or as an add-on therapy might actually be efficacious for the angiodema. So, given the low certainty for that added benefit, but otherwise the moderate certainty for a very modest improvement in urticaria, balanced by this potential for harm, we're making conditional recommendation generally to not add it in. You have other things to focus on, such as the omalism ab and so on, and the other advanced therapies. But in that select patient where they really place that higher value on the potential added benefit, then it actually might be a good option to add in. And then for the H2s, similarly, the boost is even smaller for the H2s compared to the uh anti leucotrians, might be good for your patient as a bridge if you're trying to get them uncontrolled on that 4x antihistamine, for instance, to start an omelism app in just a few days. Uh, might be good enough for a bridge or intermittent therapy, but by itself, it's unlikely to make a major difference. So it is worth about that cost, that uh feasibility in terms of polypharmacy for them as well.

Rebecca Saff, MD, PhD, FAAAAI 34:59

You mentioned it as a bridge. I think one of the other things that was studied was oral steroids and how to use those in urticaria, because they often get used as a bridge to some of our more systemic therapies.

Derek Chu, MD, PhD 35:10

Yeah, exactly. So the oral corticosteroids, the first one is that for acute flares, it really depends on if you have a patient with urticaria, whether it's the first presentation or your patient that you've had uh um you're managing, but then has an acute flare, how to address that flare management. And what we try to emphasize is follow your action plan for flare management up for your antihistamines, and if it's gonna be something that seems to be a new level of activity, then we have other options for you that are gonna be more efficacious and safer than oracle corticosteroids. So if someone has not already tried increasing their dose of antihistamines for a flare, you probably want to favor that approach rather than adding a pred. There might be some options to prevent repeated visits or healthcare utilization. Uh, taking some maybe tips and tricks from our young uh ones that are coming up with AOM that show up with uh maybe a middle ear effusion, that maybe you you inform them what the optimal plan is going to be and you give them a delayed prescription, just a very small amount of oral corticosteroids, just to try to keep them out of the eMERGE. But emphasize please try to avoid this, it has a lot of side effects. If, however, someone has is flaring severely and has already tried their antihistamines and is you know at their wit's end, maybe they have a viral infection, they just need to get over for a few days, then yeah, prednitzone is certainly uh an option there. But either way, if it's being seen in primary care or even at uh a siologist, consider whether or not this patient needs to see an urticare specialist. That would also apply to potential special scenarios or as a bridge. So special scenarios might include a bridge to advanced therapy where you have a defined start date. We're gonna start to omelism or dupilumab or REMI, but then it's you're waiting for the prior auth or something else, and they're on oral corticosteroids for like weeks or months at a time. That's not a great idea. Uh, we have to keep very close monitoring. And then lastly, other than that, we have much better options now than to use oracorates as maintenance therapy. So we're that's gonna be a strong recommendation to avoid using that because it's many, many down uh downsides for uh its harms.

Rebecca Saff, MD, PhD, FAAAAI 37:20

I think there's more and more evidence for cumulative effective steroids as well. I don't know if that was evaluated when you were looking at the evidence.

Derek Chu, MD, PhD 37:28

Totally agree. So that's this this concept that that chronic OCS means repeated bursts, which is why we want to avoid as much as possible to reduce the need to use OCS for bursts.

Rebecca Saff, MD, PhD, FAAAAI 37:41

And then the one of the most interesting aspects is the inclusion now of patient preferences. So how we in how we look at patients' preferences and values and how that informs our treatment options available and how we we go about that. What did the paper look at in terms of patient preferences?

Derek Chu, MD, PhD 37:57

Yeah, so uh, as part of each one of these systematic reviews and the guidelines, we actually go out to do a systematic review of patient values and preferences, in addition to having patient partners on our guideline panel itself, so that when we're going through each of the recommendations, we review the clinical evidence for efficacy and safety, benefits and harms, as well as the patient values and preferences that might be germane to that decision. So, do they prefer uh in general, how do they perceive benefits versus the trade-off with harms? And generally, patients are willing to tolerate some minor harms and burdens, even including daily therapy, uh, to get rid of this highly bothersome condition or what some people have called the devil's itch. But as that risk of harm and the seriousness of harm increases, then they begin to prioritize safety. If things are equal on average, they would favor, of course, less invasive therapies, as in such as oral or topical, over injections. But putting all these factors into play are what was central to each or each one of our recommendations, such as that's what helped emphasize the reduction of uh oracorposteroids, or in other cases, when to use cyclosporin. So we might be thinking about cyclosporin more as a second-line therapy or as an adjunct in those that are really advanced and refractory. So that's how patient value parameters was central to all our guidelines and what we're hoping to do for all our future guidelines, in addition.

Rebecca Saff, MD, PhD, FAAAAI 39:20

Love that. And certainly there's a lot of evidence that uh quality of life is really impacted by urticaria. I think there was a recent paper that looked at causes of death in patients with urticaria that actually said that um suicide is actually the number one cause of death in these patients because it's such a horrible um disease in terms of impact on your quality of life.

Derek Chu, MD, PhD 39:40

Yeah, that was a great, there's actually a US database study, Trininex database study, I think, uh performed by a German group, the Sherate group. Uh, yes, so this is also part of the reason why in each one of our systematic reviews, it was very clear from our patients and our guideline panel to not only include in the indices of EarDicare activity, but also Eartica related quality of life. And so it was a critical outcome in making all our decisions.

Rebecca Saff, MD, PhD, FAAAAI 40:04

And the importance inclusion of patients on those panels. I think that's fantastic that we have our patients there in the room as we think about how to use the evidence.

Derek Chu, MD, PhD 40:12

Yeah.

Rebecca Saff, MD, PhD, FAAAAI 40:13

Well, great. This is fantastic. I think we have two great guidelines coming out, and the you know, immune deficiency ones just came out, and we have the food allergy ones to look forward to. So much reading for everyone to know how to best treat their patients with the evidence.

Derek Chu, MD, PhD 40:28

Yeah, really, really appreciate the time. And these are extremely exciting and dynamic fields, and uh we're honored at the JTF to be able to help develop guidance for our practice.

Rebecca Saff, MD, PhD, FAAAAI 40:40

Thank you so much.

Derek Chu, MD, PhD 40:41

Thanks so much, Rebecca.

Rebecca Saff, MD, PhD, FAAAAI 40:43

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