Dr. Raj Chovatiya discusses the safety and efficacy of dupilumab for atopic dermatitis, asthma, and chronic rhinosinusitis as well as its broad potential for treating other conditions affected by the IL-4/IL-13 signaling pathway.
Raj Chovatiya, MD, PhD, is Assistant Professor and Director of the Center for Eczema and Itch, at Northwestern University Feinberg School of Medicine in Chicago, Illinois.
“With atopic dermatitis, we’re thinking about a pathophysiologic process that has outside-in and inside-out mechanisms. That means that there is a lot related to what’s going on in the environment, the skin barrier, plus the immune system that contribute to pathophysiology of atopic dermatitis,” said Raj Chovatiya, MD, PhD, who presented “Dupilumab: Going Beyond Atopic Dermatitis,” at the Diversity in Dermatology 2022 Conference.
Two signaling molecules in the immune system that are important to inflammation and the acquired barrier disruption seen in atopic dermatitis are interleukin (IL)-4 and IL-13. These are two of the canonical cytokines associated with Th2-mediated immunity, called type 2 inflammation, said Dr. Chovatiya.
“Dupilumab [Dupixent, Sanofi] specifically targets the IL-4 receptor alpha subunit shared by IL-4 and IL-13 and thus blocks their downstream inflammatory signaling.”
For patients with moderate to severe atopic dermatitis, dupilumab improves lesional severity, itch, quality of life, sleep, and skin pain, said Dr. Chovatiya.
“Aside from the clinical improvements that we can see, we know there is a variety of effects on both skin and systemic inflammation. The microbiome of the skin becomes more normalized. Circulating markers of inflammation decrease. We know that the skin barrier itself shows decreased proliferation with decreased markers of inflammation in the skin. Dupilumab is acting in all these ways.”1,2
The FDA has also approved dupilumab as an add-on maintenance treatment for individuals 6 years and older with moderate to severe asthma with eosinophilic phenotype or oral corticosteroid-dependent asthma, as well as for chronic rhinosinusitis with nasal polyposis for individuals 18 and older with inadequately controlled disease, according to Dr. Chovatiya.
“Asthma and rhinosinusitis share a lot of the underlying inflammatory mechanisms of atopic dermatitis. IL-4 and IL-13 are really important in patients with these conditions and drive much of the disease severity. We also know that asthma and chronic rhinosinusitis with nasal polyposis are important comorbidities for patients with atopic dermatitis.”
Future Dupilumab Indications
A number of trials, including phase 3, phase 2 and earlier, are looking at different dupilumab indications, according to Dr. Chovatiya.
“Dermatologically speaking, we’re very close to getting approval for the indication for atopic dermatitis down to 6 months to 5 years of age.”
“There are other studies that are showing promising data for prurigo nodularis and chronic spontaneous urticaria. These are the two dermatologic indications that are the furthest along. Other dermatologic indications that are relatively far along are bullous pemphigoid and other urticarias.”
Prurigo nodularis, which is associated with atopic dermatitis but can occur in the absence of it, can have a similar cutaneous phenotype to atopic dermatitis, said Dr. Chovatiya.
“There are a number of reports in the literature where people with prurigo nodularis … seem to respond pretty well to dupilumab treatment. There is also the LIBERTY-PN PRIME phase 3 trial program that has shown efficacy and endpoints achieved for prurigo nodularis.”3
There are case reports suggesting dupilumab effectively treats hand and foot dermatitis, as well as nummular dermatitis, he said. 4,5
“We know that people can get eczematous outbreaks or just some type of eczema in the context of immunodeficiency. For example, individuals with well-controlled HIV can have eczematous outbreaks, but were excluded from the original phase 3 trials for dupilumab. There are actually some good reports in the literature showing that dupilumab is efficacious and not immunosuppressive in these patients.”6
“Hyper IgE syndrome and CARD 11 deficiency are two rare genetic diseases that have shown promising responses to dupilumab, as well,”7 said Dr. Chovatiya.
In his presentation, Dr. Chovatiya touched on chronic spontaneous urticaria, which he said could also be a future on-label indication for dupilumab.
“We don’t understand the pathogenesis of chronic spontaneous urticaria that well, but dupilumab is helping to unravel that story. Results from the LIBERTY CUPID trial show … that patients treated with dupilumab actually saw significant improvement in itch and urticaria activity with very promising safety results,”8 said Dr. Chovatiya.
“Bullous pemphigoid is another dermatologic disease that has reasonable case report data out there suggesting another use for dupilumab. Anything we can do to eliminate or reduce the use of corticosteroids in this largely older population would be great just because of the number of risks that are associated with chronic corticosteroid use. Dupilumab has been shown to reduce blisters, improve pruritis, and allow for a reduction in immunosuppression medication in dozens of case reports.”9
Alopecia areata, which occurs in about one-third of atopic dermatitis patients and is the most common cause of auto-inflammatory hair loss, has been shown to improve with dupilumab. On the flip side, some case reports actually show new onset hair loss with dupilumab treatment, though hair loss is a rare side effect, according to Dr. Chovatiya.10
Dupilumab dosing studied in prurigo, urticaria, and pemphigoid trials was the same every other week maintenance regimen that dermatologists are very familiar with for atopic dermatitis. Case reports in the literature looking at many of the other indications mentioned have also used a similar dosing regimen, said Dr. Chovatiya.
Still Other Potential Approvals
A non-dermatologic indication for which dupilumab might be approved in 2022 is for treatment of eosinophilic esophagitis, which is a known comorbidity in atopic dermatitis patients, according to Dr. Chovatiya.
“Various types of allergies, keratoconjunctivitis, other eosinophilic diseases like gastritis and gastroenteritis, all are in earlier phases of investigation, and all seem to share an important type 2 inflammatory mechanism.”
Other conditions that anecdotally suggest dupilumab may be helpful include Grover’s disease, granuloma annulare, actinic prurigo, eosinophilic granulomatosis with polyangiitis, lichen amyloidosis, and epidermolysis bullosa pruriginosa, said Dr. Chovatiya.
“It’s really important to understand the mechanism of how dupilumab works and what it’s doing in atopic dermatitis. Dermatologists can then correlate this to a whole host of other diseases that share similar mechanisms. It’s pretty cool to think about the number of different conditions that may all fit under this important IL-4/IL-13 signaling pathway.”
Editor’s comment:
The Dermatology Digest thanks Dr. Chovatiya for his thoughtful and extensive review of the many exciting potential future uses of dupilumab. We believe this article highlights an interesting trend, in that it exemplifies rational investigational drug use based on known mechanisms of action and increasing understanding of disease pathogenesis. For example, any disorder with a predominantly Th2 etiology might be fair game in which to explore dupilumab use because the drug selectively blocks cornerstone Th2 cytokine activity. Still, we urge caution when using drugs off-label. Efficacy of dupilumab administration for all of the disease states enumerated in this feature remain to be verified by appropriately powered, randomized controlled trials. Likewise, while typical atopic dermatitis dupilumab dosages have been used in these exploratory case reports and case studies, that does not mean that we have determined an optimal dosing regimen; dose-ranging studies remain to be performed for each disorder.
Ted Rosen, MD, FAAD, Editor-in-Chief
Disclosures:
Dr. Chovatiya has served as an advisory board member, consultant, and/or investigator for Abbvie, Arcutis, Arena, Bristol Myers Squibb, Dermavant, Incyte, National Eczema Association, Pfizer, Regeneron, Sanofi, and UCB, and speaker for Abbvie, Eli Lilly, Incyte, Pfizer, Regeneron, Sanofi, and UCB.
References:
- Guttman-Yassky E, Bissonnette R, Ungar B, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;143(1):155-172. doi:10.1016/j.jaci.2018.08.022.
- Callewaert C, Nakatsuji T, Knight R, et al. IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis. J Invest Dermatol. 2020;140(1):191-202.e7. doi:10.1016/j.jid.2019.05.024.
- Second positive Phase 3 Dupixent® (dupilumab) trial confirms significant improvements for patients with prurigo nodularis – Sanofi, press release, January 19, 2022. Accessed March 15, 2022.
- Oosterhaven JAF, Voorberg AN, Romeijn GLE, de Bruin-Weller MS, Schuttelaar MLA. Effect of dupilumab on hand eczema in patients with atopic dermatitis: An observational study. J Dermatol. 2019;46(8):680-685. doi:10.1111/1346-8138.14982
- Choi S, Zhu GA, Lewis MA, et al. Dupilumab treatment of nummular dermatitis: A retrospective cohort study. J Am Acad Dermatol. 2020;82(5):1252-1255. doi:10.1016/j.jaad.2019.12.054.]
- Alawadhi A, Karibayeva D, Gottlieb AB. Dupilumab in HIV-positive patients: A case series report of 4 patients. JAAD Case Rep. 2020;6(12):1356-1359. Published 2020 Oct 9. doi:10.1016/j.jdcr.2020.09.023.
- Charvet E, Bourrat E, Hickman G, et al. Efficacy of dupilumab for controlling severe atopic dermatitis with dominant-negative CARD11 variant. Clin Exp Dermatol. 2021;46(7):1334-1335. doi:10.1111/ced.14686.
- Dupixent® (dupilumab) significantly improved itch and hives in patients with chronic spontaneous urticaria, a step forward in demonstrating the role of type 2 inflammation in these patients. Sanofi press release. July 29, 2021. Accessed March 15, 2022. https://www.sanofi.com/en/media-room/press-releases/2021/2021-07-29-07-00-00-2270858
- Abdat R, Waldman RA, de Bedout V, et al. Dupilumab as a novel therapy for bullous pemphigoid: A multicenter case series. J Am Acad Dermatol. 2020;83(1):46-52. doi:10.1016/j.jaad.2020.01.089.
- Cho SK, Craiglow BG. Dupilumab for the treatment of alopecia areata in children with atopic dermatitis. JAADCase Rep. 2021;16:82-85. Published 2021 Jul 27. doi:10.1016/j.jdcr.2021.07.015.