IL-13 Blockade for Benign Familial Pemphigus

Benign familial pemphigus (BFP), also known as Hailey-Hailey disease or chronic familial pemphigus, is an autosomal dominant genodermatosis caused by an ATP2C1 mutation that disrupts a calcium transporter within cells. Without sufficient intracellular calcium, the bridges between keratinocytes collapse, leading to acantholysis, often in skin folds. Although the incidence is estimated at 1 in 50,000 people,¹ the actual prevalence is likely higher than what the rare incidence suggests because of misdiagnosis and patients not seeking treatment for milder symptoms. So familial pemphigus must be on a dermatologist’s radar.

Don’t let the nomenclature fool you; the effect on quality of life resembles what we see in much more common chronic inflammatory dermatoses, such as hidradenitis suppurativa. Patients chronically experience erosive, macerated plaques and linear, stellate fissuring, with waxing and waning cycles of pain, itch, odor, and drainage, in high-impact areas of the body.² With the right morphology, distribution, and family history, a diagnosis can be made clinically. In clinically ambiguous cases, a punch biopsy showing diffuse intraepidermal acantholysis without much dyskeratosis, overall resembling a dilapidated brick wall, can support the diagnosis.² If other acantholytic disorders, such as keratosis follicularis, remain on the differential diagnoses due to ambiguous clinical morphology and histopathology, commercially available genetic testing can confirm the diagnosis by pinpointing pathogenic variants of the ATP2C1 gene.

Because of the disorder’s rare incidence, large randomized controlled studies are challenging to organize. The level of evidence is limited to case series and retrospective analyses, and there are no FDA-approved options. Many patients require a combination of topicals, systemics, and procedures for symptomatic management and to minimize exacerbators, such as sweat and overlying infections.³ Off-label biologics are increasingly reported, with the largest case series to date for dupilumab.⁴ Here we summarize our recently reported observation of using lebrikizumab for treatment-refractory BFP⁵ and discuss the potential for IL-13 blockade for this chronic, debilitating dermatosis.

Case Summary

A 60-year-old woman presented with decades of macerated plaques studded with stellate erosions on the upper medial thighs and in the right inframammary fold. Her mother and daughter had similar symptoms throughout their adult lives, so in the context of classic clinical findings and the positive family history, we suspected BFP. However, she had received unclear diagnoses from other dermatologists throughout her life, so we also performed a punch biopsy and genetic testing to confirm the diagnosis and build trust with the patient.

Over the years, she had unsuccessfully tried standard treatments for BFP, such as topical corticosteroids and cycles of oral antibiotics. She had also tried newer nonsteroidal topical agents often attempted off-label for inflammatory dermatoses in intertriginous areas, such as tapinarof, roflumilast, and ruxolitinib. In light of recent reports of Th2 pathway inhibition, we started our patient on off-label subcutaneous lebrikizumab at the approved dose for atopic dermatitis. We observed rapid improvement in itch, rash severity, and quality of life at 1 month, with these findings maintained to 5 months to date, even after she transitioned to every-4-week maintenance dosing.⁵

Discussion

The underlying problem in BFP is depletion of intracellular calcium. Consequently, emerging therapies aim to increase calcium availability, enabling keratinocytes to use it more effectively for adhesion.⁶ Recent reports and case series of dupilumab and tralokinumab propose utility in IL-4 and IL-13 blockade.^4,7 IL-4 and IL-13 stimulate a chemokine called eotaxin-3/CCL26, which can inhibit the release of free intracellular calcium and block actin polymerization through chemokine receptors 1 and 5 that are in keratinocytes. Blocking IL-4 and 13 can allow calcium to build up where it needs to be in the cell, likely attenuating calcium dysregulation in keratinocytes by downregulating eotaxin-3 and C-C chemokine receptor type 3.^4,7,8 Additionally, recruitment of eosinophils and basophils is a downstream effect of the chemokines through IL-13, with both cells shown to inhibit intracellular calcium release. Selectively targeting IL-13 with tralokinumab, and now with lebrikizumab, has demonstrated results similar to dupilumab in familial pemphigus.⁷ Notably, this patient experienced rapid improvement of both dermatitis and itch, likely due to decreased hyperexcitability of sensory neurons in addition to restoring the homeostasis of intracellular calcium.⁷ These multiple possible mechanisms illustrate the need for more mechanistic work to better elucidate the observed clinical effects and for larger controlled studies.

Nagasai Adusumilli, MD, MBA, is a chief resident physician in Dermatology at The George Washington University School of Medicine and Health Sciences.

Leonardo Tjahjono, MD, FAAD, is a board-certified dermatologist and assistant professor of Dermatology at the George Washington University School of Medicine.

Adam Friedman, MD, FAAD, is a board-certified dermatologist, professor, and chair of dermatology at The George Washington University School of Medicine & Health Sciences.

References

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2. Hohl DM. Darier disease and Hailey-Hailey disease. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 5th ed. Elsevier; 2025:951-961.
3. Giannopoulou N, Mathot O, Richert B. Treatment algorithm suggestion for Hailey-Hailey disease. J Cutan Med Surg. 2025;29(6):616-626. doi:10.1177/12034754251344213
4. Alzahrani N, Grossman-Kranseler J, Swali R, et al. Hailey-Hailey disease treated with dupilumab: a case series. Br J Dermatol. 2021;185(3):680-682. doi:10.1111/bjd.20475
5. Mummareddy H, Adusumilli NC, Friedman AJ, et al. Benign familial pemphigus treated with lebrikizumab. JAAD Case Rep. Preprint posted online January 13, 2026. doi:10.1016/j.jdcr.2026.01.006
6. Edminister JR, Patel HA, Pixley JN, Huang WW, Jorizzo JL. Improvement of Hailey-Hailey disease with topical cinacalcet, 3%, ointment. JAMA Dermatol. 2023;159(6):669-671. doi:10.1001/jamadermatol.2023.0435
7. Garg KS, Silverberg J, Tjahjono L. Hailey-Hailey disease successfully treated with tralokinumab and literature review of successful treatment with dupilumab. JAAD Case Rep. 2024;52:18-20. doi:10.1016/j.jdcr.2024.07.008
8. Thaci D, Kabashima K, Simpson EL, et al. Efficacy and safety of lebrikizumab in adults with moderate-to-severe atopic dermatitis: a randomized, placebo-controlled phase II trial. Br J Dermatol. 2020;182(3):476-486.

Acknowledgments

Dr Friedman is a speaker and consultant for Eli Lilly and Company. His work with the company did not influence our study. This article has no funding sources. We thank the patient for granting permission to publish this information.