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Pearls in Psoriasis: Dr Lebwohl on the Changing Field of Topical Therapies

In this episode, Larry Green, MD, interviews Mark Lebwohl, MD, about his career and role in pivotal topical therapy trials. Dr Lebwohl also shares his thoughts on how the field will evolve over the next 10 years.


Dr Lebwohl is the Waldman Professor and Chairman of the Kimberly and Eric J. Waldman Department of Dermatology at the Icahn School of Medicine at Mount Sinai in New York City, NY. 

Dr Green is the section editor of The Dermatologist’s Psoriasis Center of Excellence, clinical professor of dermatology at George Washington University School of Medicine in Washington, DC, and on the National Psoriasis Foundation Medical Board.

Transcript

Dr Larry Green: Welcome everybody to listening to our podcast. My name's Larry Green. I'm section editor of The Dermatologist’s Psoriasis Center of Excellence and clinical professor of dermatology at George Washington University in Washington, DC.

We're very, very fortunate here to have with us on the podcast Dr Mark Lebwohl. Pretty much everyone knows Dr Lebwohl, but he is the Waldman Professor and Chair of the Kimberly and Eric J. Waldman Department of Dermatology, dean for clinical therapeutics at the Icahn School of Medicine at Mount Sinai in New York City.

Mark has served as president previously of the American Academy of Dermatology. He is also chair emeritus of the medical board of the National Psoriasis Foundation and past president of the medical board of the National Psoriasis Foundation.

He currently is on the board of directors for the National Psoriasis Foundation as well. He is the editor of the Dermatology Section of Scientific American Medicine and co‑editor‑in‑chief of SKIN ‑‑ The Journal of Cutaneous Medicine. Mark, it's so great to have you.

Dr Mark Lebwohl: Thank you.

Dr Green: We're going to discuss today a little bit of your career and some of your work in psoriasis, and then we're going to concentrate on the latest work on new topical therapies, which I think is really the new advancing frontier of the treatment of psoriasis. Also, we're going to get your thoughts on the future of this field.

Dr Lebwohl, let me ask you first, what drew you to psoriasis?

Dr Lebwohl: Very interesting. I had a background in internal medicine. I was going to be a cardiologist, and I was also very interested in uremic pruritus. I had never taken a full dermatology elective in medical school, and because I didn't know any dermatology, that was my first elective rotation as a medical resident.

I did a full three years of internal medicine, and I just loved it. One thing led to another, and long story short, when I started as a derm resident, we did need a real phototherapy unit at Mount Sinai. I essentially put together the first phototherapy program for Mount Sina. I thought I was going to be treating uremic pruritus, but of course, what I ended up treating was psoriasis. What I liked about psoriasis, it was very similar to internal medicine because those patients were patients you didn't just see once. It was a chronic condition. You saw them over and over again, so just like hypertension, asthma, and diabetes in internal medicine, you got to know the patients, you got to know their families. It was what I wanted to do.

The other thing is that while back then, we weren't as good at treating psoriasis as we are today. We helped patients a lot, and it was a good feeling. Phototherapy was actually the best thing we had back then. It was safe and effective. We got to see patients three times a week for months and take care of them, make them better, and they were very grateful.

Dr Green: Was this an inpatient unit you set up, or an outpatient, or both?

Dr Lebwohl: No, it was used for both inpatients and outpatients.

Dr Green: I remember back when I was a resident we had an inpatient phototherapy unit that the older dermatologists like us know about that. Now, there's no such thing as an inpatient phototherapy unit. I'm sure the inpatient unit was utilized quite a lot when you were there, when you were a resident and...

[crosstalk]

Dr Lebwohl: We tried as much as possible to do outpatient, but I would say probably a dozen times a year we hospitalized somebody for psoriasis. We gave them the old‑fashioned Goeckerman regimen where we coated them in tar, ran the clock, and then had them come in for light treatments.

Dr Green: I think it's so interesting you started with uremic pruritus, which phototherapy does work for, and it's expanded into psoriasis. Was this the beginning of when phototherapy was really used for psoriasis for you?

Dr Lebwohl: You know, I'm not that old, Larry. [laughs]

Dr Green: You're not as old as Goeckerman, but when it really took off. I know you're not that old, though.

[laughter]

Dr Green: I'm almost as old as you, so no. When it really became commonly used, I don't know when that was. My career, it's always been commonly used. I don't know if that was the change is when you were...

Dr Lebwohl: When you think about it, William Goeckerman introduced phototherapy in 1925. Until methotrexate came out in the 1960s, we had nothing that was systemically effective for psoriasis. UV-B phototherapy took off more because people like Rob Stern and John Parrish, they showed various modifications of phototherapy.

Parrish, of course, was PUVA [psoralen and UV-A], but Rob Stern, with a lot of help from people like John Koo, who are around today, showed that you don't need tar with UV-B to make psoriasis go away. They made it easier and easier to do phototherapy, and then outpatient phototherapy became much more user‑friendly.

Another leap forward occurred with the development of PUVA. I to this day think that Parrish and Fitzpatrick should have gotten a Nobel Prize for that because they were the ones who really brought it to the world.

They did all of the work to refine that, and it's a treatment that still to this day is probably the most effective therapy for cutaneous T‑cell lymphoma. Those guys really deserved Nobel Prizes for that. Then a whole period went by where the next breakthrough was retinoids, which were not that big a breakthrough in psoriasis, and cyclosporine, which was a massive breakthrough in psoriasis but a dangerous drug and not good for long‑term, multiple‑year, long use. The real breakthrough then came with biologics, which was the beginning of the millennium.

Dr Green: Yeah, that really did change everything for severe psoriasis. I think the frontier for topical psoriasis is changing, and we'll get into that in a second. I wanted to ask you one quick question first, just getting on your experience, because everyone, I'm sure, wants to hear about your experience over the years.

You've done pretty much every clinical trial in psoriasis over the last 20, 30 years. What trials have stayed with you and what patients have stayed with you? You really, really helped and made a difference in their lives.

Dr Lebwohl:I think know now are in a much safer place with biologics, but one of the trials that sticks with me the most was an investigator‑initiated trial. I literally had to talk Westwood‑Squibb into funding the continuation trials of this. It was the combination of calcipotriene and halobetasol. There are several pieces to it. Calcipotriene got approved, decently effective; halobetasol, super‑potent steroid. People started to mix things with calcipotriene, and I was smart enough to see early on that anything that was an acid was going to inactivate the calcipotriene.

We actually published that. I wrote the protocol on the manuscript, but I put the chemist, who I loved working with, as first author because I wanted to continue to work with him. I wanted to reward him for helping me so much.

That actually, you could see a boost in sales of halobetasol when we published that because that was the one steroid that was clearly compatible with calcipotriene where many others inactivated it. I wish I had patented that because that led to the development of Dovobet, which we call Taclonex in the [United States], which is the combination of a steroid with calcipotriene.

I do wish I had patented that. We then did the trial. I...

Dr Green: I'm glad you didn't, Mark, by the way, because then we wouldn't have you doing all this clinical research. You'd have been very wealthy, so I'm glad you didn't.

Dr Lebwohl: [laughs] That's true. Then we did the study which showed that...To me, it was a no‑brainer. You use the two drugs together. Actually, when we did that study, when we didn't know they were compatible—we used halobetasol in the evening, calcipotriene in the morning—we showed that that combination was much superior to either one of them used twice a day. I remember sitting and breaking the code. It was investigator‑initiated. Westwood‑Squibb didn't want to fund it. We had to twist their arm to talk them into it. I remember Stu Siskent was the guy, a scientist, very smart man from Westwood‑Squibb, came down from Buffalo the day we broke the code. I'm sitting there, and as each patient's code got broken, he was like...I could have gone, "Yay," because there was a tiny study, and it was statistically significant. That was one of the most exciting studies I did, and it was a topical study.

It just shows you that psoriasis is a disease that, for 80% of patients, is treated topically. Actually, the patients treated with biologics have residual plaques that are also treated topically. Topical therapy is very important for psoriasis.

Dr Green: That's so much great, and that's a great segue for what we're doing, because the calcipotriene/betamethasone is really the way we're moving away from topical steroids or making them more safe. I'm going to ask you about more recent advances in the treatment of topical psoriasis.

Maybe we can talk about calcipotriene/betamethasone cream, which is different than PAD technology, or the calcipotriene/betamethasone foam, the long‑term safety on that. Then there's nonsteroidals that are going to come out, roflumilast and tapinarof.

I can keep going. I'll just let you talk about that, and then we can even get into the future beyond that.

Dr Lebwohl: Sure. I'll start with something that we actually tried to do for years, and finally, I think changes at the FDA...There's a very patient‑friendly dermatology head of the FDA and team around her. For many years, we tried to convince the FDA that topicals are not used for 2 weeks or 4 weeks, they need to be used chronically. Topical steroids, which are the most effective agents we have today, are problematic if you use them long‑term. We believe that there are ways that they can be used safely.

We actually negotiated with the FDA, and the FDA always was encouraging, but they demand so much. Imagine doing a Cortrosyn stimulation test in all the patients every month. It's just basically financially impossible.

Not to mention that means you're giving steroids to the patient every month, injected steroids, or ACTH. Finally, the current FDA approved a protocol that was conducted on the spray foam of calcipotriene and betamethasone dipropionate.

We're combining calcipotriene with a high‑potency steroid. The regimen was to be used daily for 4 weeks, according to the label. Then, departing from the label, twice a week for a year. If there were recurrences, the patients were then put back on daily therapy until the next month, and then again went back to twice a week.

We have yearlong data for the first time that was just accepted, will be published. To no one's surprised, it showed that, when you go up against placebo during the maintenance phase, the twice a week maintenance is very effective.

It prolongs the point until the first relapse. It reduces the number of relapses. Everything about it was a win. It was a well‑done study, and it's going to be published shortly, with fairly dramatic results. I think maintenance therapy with products that, like the spray foam, that contain strong steroids, are finally proven beyond a doubt, I think.

Twist on that is that MC2 has this PAD technology, and that allows medications to penetrate more deeply, and also causes less irritation. They've used that with a number of ingredients. I'm actually very excited, they have a cyclosporine eye drop. There's currently a cyclosporine eye drop on the market, and it's hard to get cyclosporine to penetrate. They were able to get higher concentrations of cyclosporine in their eye drop. They also reduce the sodium lauryl sulfate, which is irritating. If you speak to anyone who's used the current cyclosporine eye drop, it's irritating. They've been able to get away with a higher concentration. It's important for our patients on dupilumab who get conjunctivitis. When you use the current eye drop, it's irritating, and it doesn't work well enough.

I'm very optimistic about the new one for MC2, but they also did it with calcipotriene/betamethasone dipropionate, where they went up against the gel formulation, and they showed that they are superior. While they haven't shown superior to the spray foam, they clearly have identified a technology that simply makes better topical therapies.

I'm excited about that.

Then there are the nonsteroids. Also, we have been talking about other combinations that came out recently. Other breakthroughs are there's a combination with low‑concentration halobetasol and tazarotene that is very effective.

There's a very interesting technology where they showed that using clobetasol at half the concentration is just as effective as the full concentration. Of course, theoretically, we are causing fewer side effects. I believe that that's true.

That's a preparation I also use a good deal. Other innovations, there are ingredients that help enhance the penetration of various topical therapies. Those have taken off as well. The real exciting horizon is the nonsteroids.

Dr Green: You want to talk about those? You talked about how we're teaching the old dog new tricks with the halobetasol/tazarotene and the MC2 product, calcipotriene/betamethasone, which is fantastic, because as the technology advances, we get much better penetration in the skin.

I really think, like you mentioned, the exciting technologies are nonsteroidals that are the way of the future treating psoriasis. Go ahead and lead us through some of that.

Dr Lebwohl: We've had crisaborole for atopic dermatitis, and we published a paper showing that on facial and intertriginous areas, it is very effective for psoriasis as well. We had been using it for a number of years. Well, along comes roflumilast, which approved for a pulmonary indication, and it is a much more powerful phosphodiesterase inhibitor.

Someone was smart enough to put it in a cream which is used once a day. We just published this in the New England Journal of Medicine. Basically, if you use it once a day, it is as effective as a potent steroid for psoriasis.

It is very effective— we're talking about if you use it long enough, numbers showing 90% clear or almost clear—on intertriginous areas. Facial and intertriginous areas are a real problem for us, because steroids cause stretch marks. They cause a rash called perioral dermatitis. They cause cutaneous atrophy, telangiectasia, and around the eyes, they cause cataracts and glaucoma. We don't like using them on facial and intertriginous sites. The agents we've been using until recently have been largely topical calcineurin inhibitors, tacrolimus and pimecrolimus, which are modestly effective.

Calcipotriene is irritating, specifically on the face and intertriginous areas. Tazarotene is pretty irritating, too, so we don't really have much to treat those areas. Roflumilast is very nonirritating and very effective on those areas.

Dr Green: I was going to say, also, since you mentioned it seems to be as effective as a potent topical steroid, also on the rest of the body, too, it seems.

Dr Lebwohl: Yes, and it worked quite well on the rest of the body as well, of course, as effective as a potent topical steroid, so it's safe to use everywhere. Tapinarof, likewise. It's a very effective treatment, and it competes with any topical steroid—dramatically effective, and again, very effective everywhere on the body.

In their trial, they did not separate out the face and intertriginous sites, but investigators will tell you that it worked very well on those sites as well, exactly where we need to use a nonsteroid. Both of these are fairly nonirritating.

Tapinarof had some folliculitis, which was minor, but both agents are going to dramatically add to our armamentarium for psoriasis.

Dr Green: That's great. What do you think about the future beyond nonsteroidals? Do you think there's another path for topical treatment for psoriasis?

Dr Lebwohl: Janus kinase inhibitors are taking off in atopic dermatitis, and they are being studied topically for atopic dermatitis. They're also being studied for vitiligo and for alopecia areata, where they're not quite as effective yet, but there's no question that they will work for psoriasis. Tofacitinib was brought to the FDA for approval for psoriasis orally. It did not get approval for psoriasis, because there were a lot of agents out there that are even more effective and safer at the time, but newer Janus kinase inhibitors are coming out. Certainly, in a cream, I think anyone would consider them to be very safe. I'm sure they will be used topically as well.

Dr Green: That's so interesting. Again, I mentioned how the topical landscape is really changing. I wanted to ask you one question, because everyone, I'm sure, wants to hear from you as someone we all respect for treatment of psoriasis.

Let's forward 10 years to 2030. How do you think the landscape will be different, and we'll be doing things different? How do you think we're going to approach the psoriasis patient?

Dr Lebwohl: Again, in terms of localized disease, I don't think we're going to be treating them systemically. I think we will be treating them with better and better topicals. I think excimer laser, which we use a lot for psoriasis now, has a major place. We didn't talk about lasers.

There are also some home handheld units, like Clarify Medical has this little narrowband UV-B box that you hold while you watch TV. Keep it in place for 6 minutes, and it works pretty well.

I think we're going to have things that are patient‑friendly that can be done at home. Better and better lasers that reduce the number of treatments for patients to be used. I think we'll have better and better topicals in that space.

Dr Green: Yeah. So, so interesting. We're going to wrap up, but I wanted to ask you real quick, for everyone on the, who's listening, do you have any clinical pearls for treating psoriasis you'd like to share with us, something you've learned over the years that is a good trick?

Dr Lebwohl: I have many clinical pearls. A lot of them, of course, apply to biologic therapies and oral therapies. I will say, in the realm of topical therapies, I also have many. There are some ingredients that enhance penetration and efficacy, as well as side effects, of topical psoriasis therapy.

Salicylic acid is one of those agents. A couple of cautions about it. Don't use it on the entire body surface, because it gets absorbed and has side effects. Secondly, if you have a pharmacist compound it for you, call them up and make sure they know what they're doing. Years ago, when we were using a lot of compounded salicylic acid preparations, we actually called the pharmacy after I went to an AAD meeting, and I heard a statistic. Sure enough, half the pharmacists we were using were using aspirin instead of salicylic acid, acetylsalicylic acid, which to the best of my knowledge, doesn't do anything for psoriasis as opposed to salicylic acid. But salicylic acid does make many topical therapies penetrate more. Be careful what you combine things with, though, because for example, salicylic acid on contact immediately inactives 100% of calcipotriene.

I would leave you with that pearl. It's a great ingredient, but be careful when you mix things to make sure that you know what they're doing.

Dr Green: Thanks, Mark. Anything else you want to add, that you think we missed?

Dr Lebwohl: I think we did a pretty comprehensive topical therapy session, so thank you, Larry, for those great questions.

Dr Green: No, thanks for being with us, and thank you, everyone, for listening. Don't forget to submit any comments or questions in the feedback box, which is below here. Thank you all for listening. Thanks, Dr Lebwohl, for being with us. Hopefully, all of you will enjoy the podcast.

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