Betsey Zbyszynski: Welcome everybody. I’d like to welcome you to part two of our two part series of the Future of Itch. We’re lucky to have Dr. Mark Lebwohl and Dr. Brian Kim with us again. And if you both like to briefly give a quick introduction about yourself. I’m sure most of the participants on the phone know who you are, but Dr. Lebwohl, if you’d like to kick it off.
Dr. Mark Lebwohl: Sure. I am Dean for Clinical Therapeutics at Mount Sinai, New York. For 24 years, I was Chair of the Department of Dermatology. And in my stepping down as chair, we have Emma Guttman, who’s a real star and really on the forefront of inflammatory skin disease, chairing the department. And probably the best recruit I had after Emma was Brian Kim, who came in to run our neuroinflammation center at Mount Sinai. He’s been an incredible catch for us.
Betsey Zbyszynski: Great. Thanks. Yeah. And Dr. Kim?
Dr. Brian Kim: Hi. Brian Kim, I’m Vice Chair of Research in the Department of Dermatology here at Mount Sinai, and running the Mark Lebwohl Center for Neuroinflammation and Sensation, which is just coming up. So we are really interested obviously in itch as a major focus.
Betsey Zbyszynski: Yeah. Thank you both so much for joining us again. These webinar series are sponsored by Vial. And I’m Betsey Zbyszynski, I am head of clinical operations at Vial. And for those of you don’t know, Vial is a dermatology organization, we have a clinical site network of dermatologists that run dermatology trials, as well as a CRO division that manages dermatology trials. Now I’m gonna get back to Drs. Kim and Lebwohl. So in our first part, I know there were a couple to topics that we wanted to expand a little bit upon, and we ran out of time. One was about itch protocols. Do you guys wanna expand a little bit about that?
Dr. Mark Lebwohl: The, the traditional one, which is accepted as an FDA endpoint for studies is called the WINRS, Worst Itch Numeric Response Scale. And I have to say you, itch is so subjective, one person’s severe will be another person’s mild. But you say to the patient, zero is no itch, 10 is the worst itch possible, put your pen on this bar from zero to 10 and tell us where you are. And then is it, where you are in the last 24 hours, they, you can put various other specifications on there. And that appears to be accepted and I will say a four point reduction in the WINRS is considered very substantial. A three point reduction is pretty good. But that’s really the endpoint.
Dr. Brian Kim: Yeah. There are a number of different tools like the 5-D, which is more multidimensional. And there are a lot of tools that have been developed. But I think one of the driving aim for itch is that you have to be able to capture it in a simple and tractable way. And really the NRS, it’s just become the gold standard, are there wrinkles to that? There are as we start to understand itch better, there are we also appreciate that the reason why itch is becoming so big in my opinion, is that there was unexpected success in diseases that we considered tractable five years ago, like atopic dermatitis. And my interpretation of what’s happened is that there was unexpected success, particularly in terms of the itch symptoms in patients with atopic dermatitis, and then that shed light on the fact that itch is a real big thing. And patients came out of the woodwork, providers came out of the woodwork and started paying attention to it. And I think that, and then it alerted people to the fact that there are many other itch conditions beyond atopic dermatitis.
Oh, when Dr. Lebwohl mentions a four point NRS reduction as being clinically meaningful I think what we’re trying to say this kind of improvement is gonna translate in the clinic in a meaningful way. It doesn’t mean that we beat out … you can still beat out placebo, right? Without reaching that. And I think these are more complex conversations we have to have because the biggest wins we’ve had in itch were mostly in patients with moderate, if not pretty severe itch. And as someone who treats itch, it’s actually much easier to reach that kind of endpoint and have good results in patients who actually have severe itch. It might sound a counterintuitive if they’re more severe why is it easier? It’s because you can actually improve their itch quite dramatically, and it’d still actually be in the moderate range. So you can go from severe score of 10 to a six, and they’re still having significant itch, but you’ve now hit this clinically meaningful endpoint.
The conversation I’ve been trying to have now is that we actually need to think about itch differently too, from disease to, from one disease to the next. So itch in psoriasis might not be the same as it atopic dermatitis [00:05:00] versus say prurigo nodularis, which now is a hot topic. And we can talk about a, a lot of the reasons for why itch may not be the same across diseases, but I think with better resolution and granularity, we need to understand that, because the way in which itch imprints the and negatively impacts the quality of life can actually differ a bit from disease to disease as well.
Betsey Zbyszynski: Yeah. I understand the difference. If you can improve someone from severe to moderate, that’s a big deal for them, I’m sure. I have a question for protocols too, how do you feel about using devices or wearables capturing it?
Dr. Brian Kim: Yeah. There, there’s been a number of different technologies advance in this area, actigraphy, where you wear something which has some advantages, there are studies that show that it can work. What, non-wearables as well. We’ve actually, I’ve worked with a colleague, Dina Katabi at MIT who’s a world expert on machine learning and artificial intelligence. So we’ve actually used artificial intelligence. So we’ve actually used the technology she invented to actually measure itch by using a wifi device in which the patient actually does in which the patient actually does not wear anything. And there are distinct advantages to that because what we actually found in the course of that study too, is that there are lots of unique ways in which patients actually can scratch. So they might not necessarily use one arm. They might not even just use the, their arms, they might use their legs and they’re not even aware of what they’re doing. ‘Cause most actual, actually itch and scratching behavior is actually pretty unconscious. It’s very much a reflex.
Dr. Mark Lebwohl: Yeah. There, there are devices like if you have an Apple watch, there’s a device that measures your motion of that arm during sleep. So it can estimate, you may be doing something else with the arm, you may be boxing for all I know, but they they will over the course of a night, see how many times you moved your arm as a measure, as a surrogate marker for itch. And that exists. It is not, as I said, the WINRS is the most widely accepted that is not. There are also creative descriptions of a numerical response scale. For example, interferes with, wakes you up once at night, wakes you up twice at night, interferes with your sleep all night, wakes you up every hour, or you scratch every hour. They, those kind of questions that go into descriptors for a numerical response scale. So there are a number of scales, but the WINRS is what’s most widely used.
Dr. Brian Kim: Yeah. And you know, I wanna throw in a little bit more here too, about itch. The other thing is, we put a lot of weight into the objectivity. So if we can measure people scratching, then that- that’s better, ’cause it’s more objective and that’s more quantified. And I would also argue though that’s not necessarily the case. We have patients with atopic dermatitis, children who come in and they’ll actually dig themselves down to ulcers in their lesions and come in with bleeding and everything. And I’ll ask them what their NRS score is, and they’ll say I don’t know, a four, low moderate. And that’s because they’re A, children and then B, they’ve lived it, with it their whole life, so they’ve actually adapted to it. And then I have patients who are more elderly who developed severe itch in their 70s, and they say, “I can’t live like this anymore. I don’t know if I could go on living.” And there are no lesions dug up, they’re not scratching, but they’re not even scratching in front of me. So the idea that objectivity is everything I think with itch is a little bit of a dangerous concept. I don’t think it’s necessarily always true.
But then I’m also gonna mention something else that we learned from the studies where we’re actually measuring itch using this device at night when patients are asleep. So patients actually are asleep, they don’t know they’re scratching, we’re comparing the device to the video and we’re learning all these things. The other thing that we start to notice, ’cause this device can actually pick up on … It’s called Emerald, it can actually pick up on breathing rate, other movements, and you can actually measure or sleep as if they were in a sleep lab because of that. And one interesting observation that came out of it is that the patients don’t necessarily know how much they’re scratching while they’re sleeping. So if they wake up in their morning and you ask them, they don’t necessarily know what happened. Additionally when they were scratching a lot, they were actually putting themselves into a lighter stage of sleep and they didn’t know that either. So I think the morbidity of it also can be much greater than we realized. So it could actually have an effect on sleep, which has a huge effect on your overall health in ways that patients don’t even know and they can’t endorse. So I think there are both, there are, there is value to objective measurements and there’s value to subjective measurements. But I don’t think that one is necessarily more important than the other.
Betsey Zbyszynski: That’s really interesting, the sleep portion, because that can affect everything in their life too. Not only their day-to-day operations, but just overall health, like you said. Thanks Dr. Kim. Another topic that we [00:10:00] just wanted to expand on a little from our first webinar was how do you approach your itch patients when they come to see you?
Dr. Mark Lebwohl: So I’ve heard Brian give a brilliant talk on this. And I will say we’ve had an organized approach to itch and literally everything on our approach you covered Brian, so I’m gonna let you take it.
Dr. Brian Kim: So the first question is why do dermatologists treat itch? Fundamentally actually, itch does not have to be treated by dermatologists it actually spans almost every specialty of medicine. I met with a a hematologist who said, the leukemias and myeloproliferative disorders is such a big problem, so many of these patients itch, there are neurologic causes of it. So there are many specialties in medicine. But the reason why dermatologists in my opinion have to treat itch is because there are so many itches, the most common symptom in dermatology. There’s so many rashes that cause itch, that you, the first kind of bifurcation and is it dermatologic or not? And essentially you need to do a residency in dermatology to make that kind of distinction. It’s very hard for non-dermatologists to say, “Oh, it’s definitely not urticaria, it’s definitely not atopic dermatitis, not allergic contact dermatitis, it’s not scabies.” So that’s the big distinguishing factor.
Once you rule out the dermatologic causes which many dermatologists can do, clinically right away by looking at the patient, then you get into this other category of all other things. And they, these can be neurologic causes of itch and dermatologists will still assess that. But there are also systemic causes of itching that, generally we don’t see that much in the clinic, but you need to make sure isn’t going on. So they don’t have liver failure. They don’t have kidney failure there, isn’t some kind of me metabolic arrangement and some other rare conditions. And as I mentioned, a malignancy, you wanna make sure the patient does not have a lymphoma. They don’t have leukemia. And so there are a host of systemic factors.
So then once do a really good kind of evaluation, what are the things that you’re looking for and how do you distinguish these different things? One of the things you wanna know is a good history, like any good physician. You wanna know the timing, is there a rash associated with the itch? Does the itch actually proceed the rash? That starts to if that’s the case, that starts to hint that there’s more of a neurologic cause of the itch, it’s not necessarily a dermatitis or a rash that causes it. Is it localized or generalized? If it’s more localized, you also think there might be more of an anatomic problem, there might be some kind of a nerve problem that could be driving that. You wanna screen the medications. There are certain medications, antihypertensive medications, and such. I could go into why I don’t think there are necessarily allergies, I think that they are actually physiologic effects of the medication that actually can cause itch.
And then from a history standpoint, you wanna make sure that there isn’t something unusual. Are they losing weight? Are they having fevers or something like that? These are rare instances. You wanna do a really good thorough physical exam. And I say, you have to do a genital exam. And because there are path and amount findings on a genital exam that would immediately tell you, this person has scabies. And scabies, we talked about this last time, it’s missed so much in patients with itch. You really don’t wanna miss it, but, I can’t fault someone if they do. It’s one of the most missed things I think in dermatology.
You’re trying to get at now at the laboratory level, some of the things I’m talking about. You wanna look at their white blood cell count, make sure there isn’t something off there, it’s not low, it’s not high. Low immune deficiency, probably high, you start to worry about certain kinds of leukemias and such. Platelets. The reason why platelets is that one of the most itch associated conditions is a myeloproliferative disorder called polycythemia vera. It’s not, rare, but it’s not crazy rare, we’ve caught it a few times. And then you wanna look at labs, as I mentioned before, to make sure there isn’t something crazy with biliary function, liver function and kidney function. I actually do get chest x-rays on all my patients who’ve had itch for a long time. It’s cheap, it’s easy, we’ve caught enough things.
Now, with the disclaimer that my clinic has a tremendous amount of selection bias. So people who are coming to me have, I have had the good fortune to have had these patients see a lot of other doctors. So I already know what’s been done and what didn’t work. And then I don’t go crazy when it comes to a malignancy workup. Now, everything I’m talking about does tend to freak people out a little bit, ’cause I’ve mentioned cancer a few times, including patients, Cutaneous T-cell lymphoma as a dermatologist, you wanna rule that out. We catch that a lot. But really, we do a good exam like that. And if someone, if there’s an index a suspicion from malignancy, for whatever, a lot of it’s driven by intuition or family history and such, I do follow up with their primary care physician and say, “I wanna, I would rather be a little bit more aggressive with a malignancy surveillance,” is what I say. But I don’t necessarily … I’ve, patients come in with these whole body like CT scans and things like that. I don’t think, that needs to be done. It needs to be directed based on their history physical exam.
So that’s the … I know it’s not straightforward necessarily, but [00:15:00] it has to be very systematic. And if it’s a lot of things, but it’s not crazy if you take a very systematic approach. And generally what I find with itching is it’s actually helpful for me to not try to be creative with the workup lot of pivots. It’s actually better if I just take a very systematic approach and turn my brain off a little bit and say, “Look, I’m just gonna get a good history. I’m gonna stick to this script. And then if all’s negative, then I can turn my brain on again.”
Dr. Mark Lebwohl: Yeah. There, there are very specific items which you can easily forget if you don’t do what Brian says and turn off your brain, you really have to do. And we use a checkoff list. The checkoff list is several pages long and I don’t do it. I, at this point, I, the reason I published it is, I was finding myself, spending half an hour with those patients. Now I give it to my, the resident who’s working with me and I say, “Go through every item on here.” So in the history you have to ask about fever, night sweats, weight loss, because lymphoma’s a common cause of itch. It’s not a common cause, it’s a cause of itch, and it’s uncommon actually but every now and then we pick one up. When you when you do your physical exam, you have to check for lymph nodes, because again, lymphoma is a possibility there.
You wanna feel what the liver and spleen look like because again, an obstructed liver will back up and enlarge the spleen. There are many reason, rationales behind what we do, but you, we put them down on paper and then we go through them systematically, Again, Brian said, check liver check kidney, that’s an early part of it. We do have actual chest x-ray on our list as well. The, but if you, before you get to chest x-ray, if there’s something in the history that suggests or in the physical, that suggests you found the cause you can stop there. There was a wonderful article in the British Journal of Dermatology, it was produced by the British Association of Dermatologists, the BAD and they and they, and I loved the article, ’cause it really outlined in table form, what are the tests you have to follow? And we actually applied that to our patients.
I believe one of our residents, Rosalyn Stanger, did a great job and she … I think it was over 100 patients. And we went and looked at, what do we do differently than was in those guidelines? We had our checkoff list before those guidelines came out. And there were a few things that we found, and I’m gonna just say, I thought that was one of the best articles ever published, but here’s what we found that we do in addition. A drug history was not on the guidelines. ACE inhibitors commonly cause itch. And we actually have a fair number of patients in whom we’ve stopped them, switched to an angiotensin receptor blocker instead of an angiotensin-converting enzyme inhibitor. And they clinically have the act same impact on blood pressure, but the ARBs don’t cause itch, the ACE inhibitors do. And it’s not an allergy, it’s actually dose related. They are kininogen ACE blockers, so they increase kinins and by increasing kinins they cause itch. If you cut the dose in half, they increase kinins less, so it’s a dose related phenomenon, not an allergy.
The other two items that we found differently was we treated everyone presumptively for scabies because it has missed so often. And it’s such an easy treatment, you can give them ivermectin for one day. And if they come back two days later and say, “My itch is gone,” which has happened to us numerous times, we then go and treat everyone in the family, we do all of the steps you take to minimize it’s coming back. And we have a large number of patients in that series, at least 10%. And so we may be wrong, maybe we weren’t treating scabies and it would’ve gone away anyway, but you know what? The patient was very happy.
The third thing that we found to our surprise and a lot of our patients were elderly, was we had a very high frequency of subclinical bullous pemphigoid. So the patients come in itching, we do a biops- routine biopsy and a biopsy for immunofluorescence to find bullous pemphigoid. In some patients, especially ones who are biopsy shot, we might get a BP, 180 and a BP, 230, which are less specific, but also pretty good barometers. Now I’ll just tell you a story of one patient I had. This patient actually, I knew since I was in college and and he was much older than me. He was a, actually a trustee of one of our organizations. And when I became a dermatologist, he came to me as a patient and for years he was itching. And what said to me this guy’s got bullous pemphigoid, is we treated him with ultraviolet light back then. This is before dupilumab was available.
And, with one dose, lowest dose, just burned, developed blisters, which we should have biopsied back then. But I thought, okay, we gave him a burn, but it occurred to me. We gave him so little and we know that ultraviolet light triggers bullous pemphigoid. Now, he went on four year, he did actually get biopsies, now I’m remembering, they were all negative. I don’t remember if we did serologies, but he got biopsies with immunofluorescence all negative. He, five years later came in with classic bullous pemphigoid that was [00:20:00] positive on biopsy and clinically you couldn’t miss it. And so he treated him with traditional treatments for bullous pemphigoid. In that five year period, his itch was so bad that I actually put him on prednisone, which is something I almost never do. And in my mind I was treating bullous pemphigoid and it turned out I was right. So bullous pemphigoid occurred, I think in something like 10% of our elderly patients, and, it is missed all the time. So those are the three items that were not on the British Association of Dermatology list that we have on our workup. And everything else on their workup, I thought was just reinforcing what you should be doing, that actually, most of our colleagues are not doing.
Betsey Zbyszynski: Thanks. Thanks so much. I love the systemic approach. That, that seems very pragmatic. I wanna invite any attendees for our last five minutes with any questions. You can put them in the Q and A section. I do have a question for you guys though. I’ve been seeing a lot of activity in the skin microbiome area, do you see that affecting the future of itch at all?
Dr. Brian Kim: Yeah. The most data is in atopic dermatitis. But there’s a lot of interest in the skin microbiome, but it hasn’t been actually linked to itch in a, very high impact way yet. I think there’s probably a story, the microbiome will work its way into pretty much everything one way or another. But I also think that a lot of itch is also pretty systemic. I don’t think it’s just a skin disease per se. I, I think, so we also, I think still have to really consider the impact on the systemic immune system as well as the gut microbiome as well. Also, all these different itch disorders are pretty different. I think the misconception before was that it’s really just one symptom, but the way in which itch manifests across different diseases is pretty different, and they really are in many ways different diseases depending on how itch comes into play.
The other point I’ll make that Dr. Lebwohl I think was making too, is that it’s not a protocol, it’s not a snapshot protocol, it’s not just a workup and you’re done. Itch is a harbinger of a lot of things. And one of the things it is a clinical marker of is there’s something wrong. I don’t think, fundamentally, I don’t think if you’re super healthy, you’re young, you’re not gonna itch. I think it starts to tell you something’s going wrong. It might be a bone marrow, it might be an organ, it might be your skin. And what it tells me if someone comes in with protracted itch is that you want to work them up, but you also wanna follow them over time. You wanna constantly re-surveil patient, ’cause it’s already put them in a slightly different category that there’s something going on that’s just not quite right.
And that’s why we’ve caught a lot of things, whether it’s cutaneous lymphoma or whether it’s even a diversity of leukemias and things like that. It’s not that it’s so common that this happens, but that these are often elderly patients and something is happening. You just need to be, you just have to be a little bit vigilant and watch them over time. And then things happen. And you find that, oh, they had polycythemia vera and it just hadn’t declared itself quite yet and things like that.
Dr. Mark Lebwohl: So, to answer the microbiome question, staph aureus and atopic dermatitis have been known a long time. And in my mind, my simple mind I don’t think of the staff as causing the atopic dermatitis, but rather the atopic dermatitis presents often with oozing that actually attracts staph aureus. And and and in fact, just this week, an article came out showing that dupilumab, which has zero antibacterial effect reduces staph aureus in the skin of atopic dermatitis patients. Why? Because it gets rid of the atopic dermatitis, which in my mind attracts the staph aureus.
Dr. Brian Kim: Yeah.
Betsey Zbyszynski: Speaking of dupilumab, do you see any hurdles with securing insurance coverage for itch with dupilumab, but there’s an absence of atopic derm?
Dr. Mark Lebwohl: Oh I’m gonna take that one.
John Koo who is a superstar John Koo came up with a concept of the atopic complex. And I participated in the meeting, but this is all John Koo, he deserves all the credit for it. And what he pointed out is that, here we have conditions where we don’t really have a name for pruritus of the elderly. There was a Willan’s pruritus, it was an old name for itching in the elderly. It’s really a waste basket diagnosis, if you can’t make a diagnosis definitively, you call it Willan’s pruritus. But in fact, what we are probably looking at is a subclinical form of atopic dermatitis in older patients. They get older, their skin gets drier, they become more prone to the itching that we associate with atopic dermatitis. And it responds incredibly well to dupilumab, probably also to tralokinumab, which is now approved, and lebrikizumab is coming.
The prurigo nodularis, that’s atopic dermatitis that you scratch too much. And there are many other conditions that fall into the atopic complex. And I believe he’s completely right about that. And we have no trouble getting it approved in New [00:25:00] York. The main barrier has been in other states where step therapy legislation doesn’t exist. And so the insurers don’t wanna pay for an expensive drug, so they’ll actually tell you, “No, you have to first fail cyclosporin, methotrexate CellCept,” other drugs. Those drugs are much more dangerous, and aren’t even approved for atopic dermatitis. And if you persist and fight that, you can win. Before we had step therapy legislation, we were getting dupilumab approved in New York. Since the legislation it’s actually been much easier.
I think that all over the country where they have step therapy legislation, if you simply take the trouble to challenge the denial you’ll be able to do that. The American Academy of Dermatology has a website, aad.org/priorauth, they’ll write the appeal letter for you. It takes 30 seconds for your secretary to generate that letter.
Betsey Zbyszynski: That’s great. Thanks so much. I’m sure that’s really helpful for folks on the call that might be in other states. But we are at the bottom of the hour now, and I wanna thank you both so much. That was really informative. And I hope the attendees on the call enjoyed it too. And we will be recording this, or we are recording this, so it will be available after. And thanks so much Drs. Kim and Lebwohl.
Dr. Mark Lebwohl: Thanks for having us.
Dr. Brian Kim: Thank you.
Vial’s mission is to run clinical trials with faster execution and higher quality in order to bring new therapies to market. Vial has over 70 employees and is based in San Francisco, California. Vial partners with Dermatologists to support their research teams and has created a network of over 35 Dermatology clinics. The Vial network has contributed to over 150 trials for many of the leading sponsors in Dermatology having run trials across common Medical Dermatology indications (Atopic Dermatitis, Psoriasis, Vitiligo, Alopecia Areata, Rosacea, Hidradenitis Suppurativa, Prurigo Nodularis among others) as well as Aesthetic Dermatology indications. The clinic network runs trials from Phase I through Phase IV.