Dupilumab treatment of bullous pemphigoid: Hoping for approval on the double

By Warren R. Heymann, MD, FAAD
Jan. 15, 2025
Vol. 7, No. 2

I am quoting myself from the first commentary I wrote about dupilumab nine years ago, before its release. I am delighted that my cautious prediction was wrong — there is no drug that has had a more profound impact on dermatological therapy over the last decade than dupilumab.

The biologic agent is not perfect — no drug is. Over the past decade, I have written about adverse reactions of dupilumab including ocular surface disease, arthritis, dupilumab-associated erythema (which may be due to eczema, rosacea, flushing, or Malassezia), Demodex folliculitis, and its controversial relationship with cutaneous lymphoma. (2,3,4,5)

Dupilumab is a versatile monoclonal antibody that reduces T-helper cell type 2 inflammation by blocking the shared receptor subunit for interleukin 4 and interleukin 13. Although there are only two currently approved dermatologic indications for dupilumab (atopic dermatitis and prurigo nodularis), off-label uses have skyrocketed since its introduction in 2017. Wherever eosinophils are present, a therapeutic report of dupilumab’s effectiveness is sure to follow (bullous pemphigoid, eosinophilic annular erythema, Kimura disease, etc.). (5) This commentary focuses on the use of dupilumab for bullous pemphigoid (BP).

Bullous pemphigoid (BP) is the most common autoimmune bullous disease that primarily affects the elderly population, presenting with bullae, erosions, and urticarial lesions. Extensive pruritus is observed in the majority of patients. (6) Many drugs may induce BP including gliptins, PD-1/PD-L1 inhibitors, loop diuretics, penicillin and derivatives. (7) Pathogenically, Th2 biomarkers correlate with clinical scores, eosinophil counts, and anti-BP180 immunoglobulin G levels. More than 25 years after their initial identification of autoreactive T helper 2 cells against BP180 and BP230 secreting IL-4, IL-5, and IL-13, Borradori and Hertl state that evidence now exists that the tissue damage and pruritus of BP are mediated by type 2 T helper cells and group 2 innate lymphoid cells. This results in the secretion of mainly IgG4 and IgE autoantibodies and potent inflammatory chemokines, such as eotaxin 1 and 3, CCL13, CCLL 24, and CCL1720. The chemokines impact eosinophils, mast cells, and additional innate and adaptive immune responses. (8)

Standard therapy for BP includes ultrapotent topical steroids, systemic steroids, antibiotics (notably doxycycline with niacinamide), and steroid-sparing immunosuppressive agents such as mycophenolate mofetil. “So, with reluctance, prednisone is prescribed, fingers are crossed hoping that the comorbidities don’t go haywire, and that no hips are broken. The steroid-sparing frenzy for the right drug starts on day one of therapy.” (9)

Kaye et al. were the first to report the effective use of dupilumab in BP. Their patient was a man in his 80s whose BP would flare with steroid tapers. His BP cleared within 3 months of dupilumab administration, with undetectable levels of BP180 and BP230 antibodies. (9) Since the initial report, there have been > 250 BP patients in the literature who have received dupilumab therapy. (10)

Miller et al. performed a multicenter, retrospective case series of 30 BP patients who received a loading dose of dupilumab 600 mg, followed by a 300 mg maintenance dose with varying administration frequency tailored to individual patient response. All patients experienced at least some improvement in blister formation and pruritus, with 23 (76.7%) of patients demonstrating either a complete clearance of blistering or marked response. Complete clearance of pruritus or a marked response was noted in 25 (83.3%) of patients. Eight patients were effectively maintained solely on dupilumab. One (3.3%) patient reported an injection site reaction. (11)

Planella-Fontanillas et al performed an ambispective study of 103 BP patients treated with dupilumab. The authors tracked patient progress for at least 4 weeks, assessing drug efficacy and adverse effects. More than half of the patients (53.4%) saw their symptoms completely clear up within 4 weeks, and nearly all (95.7%) had clear skin by 52 weeks. Pruritus decreased by 70.0% in the first 4 weeks and was completely resolved by week 24 for many patients. The use of corticosteroids dropped significantly by over 80% within 52 weeks. Only 12.6% of patients had side-effects (mostly mild joint and muscle aches, conjunctivitis, and psoriasis exacerbation). (12)

Murrell et al. have instituted the LIBERTY-BP ADEPT study, a multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of dupilumab in adults with BP. The primary endpoint is determining the proportion of patients achieving complete remission off steroid therapy at week 36. (13) Although the study has not been published, a press release from Sanofi stated, “In the study, five times more Dupixent patients achieved sustained disease remission compared to those on placebo.” (14)

My own experience mirrors the effectiveness of dupilumab in all forms of BP. I recently had a patient with radiation-induced BP and was delighted to see a case report advocating dupilumab in this circumstance that will (hopefully) allow the patient to continue radiation for her breast cancer. (15) The frustrating aspect is the randomness of getting approval for dupilumab — occasionally, it can be secured, but more often we supply samples to patients in need. Hopefully, the upcoming publication will confirm what dermatologists in the trenches already know — dupilumab is useful for BP either as monotherapy or adjunctive therapy. Once approved, I anticipate that it will become my first-line treatment for BP.

“Our Experts’ Viewpoints” are provided by Dr. David Rosmarin, who is the senior author of the first manuscript describing the use of dupilumab for BP, and by Dr. Dedee Murrell, who is the lead author of the upcoming LIBERTY-BP ADEPT study.

Point to Remember: Case reports and retrospective studies have demonstrated dupilumab’s efficacy in treating bullous pemphigoid. Preliminary data from a prospective trial confirms dupilumab’s therapeutic value. Perhaps approval of dupilumab for bullous pemphigoid is on the horizon.

Our experts’ viewpoints

David Rosmarin, MD, FAAD
Kampen-Norins Scholar & Chair
Department of Dermatology
Indiana University School of Medicine

I appreciate the excellent commentary from Dr. Heymann and agree with his assessment that the use of dupilumab in bullous pemphigoid (BP) represents a promising therapeutic strategy, especially in light of the positive results from the pivotal LIBERTY-BP study. Although full study details are yet to be published, years of case reports and case series have increased confidence that dupilumab may offer significant benefits for BP patients, a group typically characterized by older age and multiple comorbidities. For these patients, who are often already on complex medication regimens, a targeted approach is highly advantageous. Particularly for those with BP triggered by immune checkpoint inhibitors or underlying malignancies, dupilumab presents a worthwhile therapy. In my experience, a good number of patients require more frequent dosing than the approved regimen for atopic dermatitis to achieve adequate disease control, potentially reflecting a higher inflammatory burden.

Further research is needed to determine whether newer anti-IL13 therapies, such as tralokinumab and lebrikizumab, can also be utilized in the treatment of BP. IL-4 plays a key role in class switching from IgG1 to pathogenic IgG4 autoantibodies in BP, raising the question of whether dual targeting, as seen with dupilumab, may offer superior efficacy compared to targeting only IL-13. While Medicare is currently covering dupilumab off-label for the treatment of BP, I hope that with official FDA approval, access to this therapy will improve, allowing for superior care for our patients.

Dedee F. Murrell, MD, FAAD
Professor and Chair, Department of Dermatology, St George Hospital, University of NSW, Sydney, Australia

My view is that dupilumab will also be a “game changer” in BP. It should allow tapering off steroids with far fewer relapses and mitigate the chronic use of steroids, which are the main cause of serious complications in these frail patients.

1. Heymann WR. Dupilumab and the dawn of the biologic era for atopic dermatitis. Dermatology World Insights and Inquiries. August 28, 2016. https://staging.aad.org/dw/dw-insights-and-inquiries/medical-dermatology/dupilumab-and-the-dawn-of-the-biologic-era-for-atopic-dermatitis

2. Heymann WR. Seeing red with dupilumab. Dermatology World Insights and Inquiries. March 1, 2023. https://staging.aad.org/dw/dw-insights-and-inquiries/archive/2023/seeing-red-with-dupilumab

3. Heymann WR. Dupilumab’s growing pains. Dermatology World Insights and Inquiries. January 8, 2020. https://staging.aad.org/dw/dw-insights-and-inquiries/2020-archive/january/dupilumabs-growing-pains

4. Krakowski AC, Senft SC, Heymann WR. Demodex Folliculitis and Recent Dupilumab Administration. Pediatrics. 2021 May;147(5):e2020029520. doi: 10.1542/peds.2020-029520. PMID: 33879520.

5. Heymann WR. Dupilumab's duplicity. J Am Acad Dermatol. 2024 Aug;91(2):249-250. doi: 10.1016/j.jaad.2024.05.041. Epub 2024 May 23. PMID: 38789044.

6. Li J, Chen X, Zhu X, Shang P, Wang M. Serum inflammatory biomarkers associated with disease severity and response to dupilumab treatment in bullous pemphigoid: A cluster analysis. J Dermatol Sci. 2024 Oct;116(1):24-33. doi: 10.1016/j.jdermsci.2024.09.003. Epub 2024 Sep 18. PMID: 39358056.

7. Verheyden MJ, Bilgic A, Murrell DF. A Systematic Review of Drug-Induced Pemphigoid. Acta Derm Venereol. 2020 Aug 17;100(15):adv00224. doi: 10.2340/00015555-3457. PMID: 32176310; PMCID: PMC9207627.

8. Borradori L, Hertl M. Targeting type 2 inflammation in bullous pemphigoid (BP): dupilumab as game changer opens new avenues. Br J Dermatol. 2024 Dec 6:ljae465. doi: 10.1093/bjd/ljae465. Epub ahead of print. PMID: 39657119.

9. Heymann WR. OblIgEd to search for steroid-sparing agents in treating bullous pemphigoid. Dermatoloy World Insights and Inquiries. January 19, 2017. https://staging.aad.org/dw/dw-insights-and-inquiries/medical-dermatology/obliged-to-search-for-steroid-sparing-agents-in-treating-bullous-pemphigoid

10. Kaye A, Gordon SC, Deverapalli SC, Her MJ, Rosmarin D. Dupilumab for the Treatment of Recalcitrant Bullous Pemphigoid. JAMA Dermatol. 2018 Oct 1;154(10):1225-1226. doi: 10.1001/jamadermatol.2018.2526. PMID: 30140849.

11. Miller AC, Temiz LA, Adjei S, Duran MA, Sassmannshausen J, Dominguez A, Thomas C, Schmidt JD, Bernhardt M, Doolittle-Amieva CJ, Moshiri AS, Thompson AJ, Pyoung Kim-Lim P, Mattia AV, Tyring SK. Treatment of Bullous Pemphigoid With Dupilumab: A Case Series of 30 Patients. J Drugs Dermatol. 2024 Jun 1;23(6):e144-e148. doi: 10.36849/JDD.8258. PMID: 38834228.

12. Planella-Fontanillas N, Bosch-Amate X, Jiménez Antón A, Moreno-Vílchez C, Guerrero MG, Del Mar Blanes Martínez M, Ballester Martínez MA, Bassas-Freixas P, Castaño Fernández JL, Estébanez Corrales A, Suarez Fernández R, Santos Alarcón S, Alonso AB, Torrent M, Ballano Ruiz A, Collantes Rodríguez C, España A, Fonseca Capdevila E, Faure IG, Hernández Fernández CP, Melgosa Ramos FJ, Spertino J, Zaragoza Ninet V, Armillas L, Bielsa I, Carrera C, Rafat ME, Fulgencio Barbarin J, Fernandez Vela J, Lova Navarro M, Callizo CM, Martín-Sala S, Ojeda R, Amer MEP, Puigdollers AS, Pujol RM, Podlipnik S, Mascaró JM Jr, Curto-Barredo L. Real-World Evaluation of the Effectiveness and Safety of Dupilumab in Bullous Pemphigoid: An Ambispective Multicenter Case Series. Br J Dermatol. 2024 Oct 17:ljae403. doi: 10.1093/bjd/ljae403. Epub ahead of print. PMID: 39418120.

13. Murrell DF, Joly P, Werth VP, Ujiie H, Worm M, Mangold AR, Avetisova E, Maloney J, Laws E, Mortensen E, Dubost-Brama A, Shabbir A. Study Design of a Phase 2/3 Randomized Controlled Trial of Dupilumab in Adults with Bullous Pemphigoid: LIBERTY-BP ADEPT. Adv Ther. 2024 Jul;41(7):2991-3002. doi: 10.1007/s12325-024-02810-3. Epub 2024 Mar 5. Erratum in: Adv Ther. 2024 Jul;41(7):3014-3015. doi: 10.1007/s12325-024-02886-x. PMID: 38443648; PMCID: PMC11213798.

14. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-11-05-00-00-2944237

15. Wongtada C, Rerknimitr P. Radiotherapy-induced localized bullous pemphigoid with a favorable response to dupilumab. JAAD Case Rep. 2024 Apr 21;48:128-130. doi: 10.1016/j.jdcr.2024.04.013. PMID: 38841519; PMCID: PMC11152609.