Efficacy and safety of dupilumab in Hailey–Hailey disease: A multicentre cohort study

Hailey–Hailey disease (HHD), now renamed ATP2C1-associated non-syndromic epidermal differentiation disorder (ATP2C1-nEDD), involves inflammatory vesiculobullous lesions in major skin folds, affecting the quality of life (QoL). Limited efficacy of current treatments highlights the need for targeted therapeutic approaches. Targeting IL-4 and IL-13 may modulate calcium dysregulation in keratinocytes, leading to actin fibre disorganization in HHD, thereby improving skin lesions.1, 2 The efficacy and safety of dupilumab (interleukin (IL)-4/13 signalling inhibitor) have been reported in several HHD cases.3-8 This study aimed to evaluate its long-term efficacy and safety in a larger cohort. This multicentre retrospective cohort study (registered under number 2025-50) included patients with HHD treated with dupilumab for at least 6 months. The primary objective was to evaluate the effect of dupilumab at 6 months compared to baseline using the Investigator Global Assessment change (IGA-C) score.9 Patients were classified as non-responders (IGA-C: 0 or +1) or responders (IGA-C: −1, −2 or −3), with good responders defined as those with a score of −2 or −3. Efficacy, defined as the percentage of responders, was analysed with a 95% confidence interval (CI) using the Agresti–Coull method. Due to the limited sample size, statistical subgroup analyses were not performed. Secondary objectives included assessments of safety, QoL, use of analgesics and topical treatments, hospital admissions and long-term efficacy. A total of 20 patients (13 women and 7 men) were included, with a median age of 59 years (IQR: 23.5) (Table 1). All but one patient had severe or very severe disease, long-standing in almost all cases. At baseline, all patients were using topical treatments, primarily corticosteroids, and nine patients (45%) were also taking analgesics. Dupilumab was administered at the standard dose used for atopic dermatitis. At 6 months, 18 patients (90%) responded to treatment, including 14 classified as good responders (Table 1, Figure 1). The mean Dermatology Life Quality Index improved by 15.5 points out of 30 (SD: 8.7). Use of topical treatments decreased in frequency for seven patients (35%) and was discontinued in nine patients (45%). Among the nine patients using analgesics at baseline, use was reduced in 2 (22%) and completely stopped in seven patients (78%). Hospital admissions decreased by 83%. Beyond 6 months (mean treatment duration: 18.4 months; SD: 4.7; range: 11–25 months), 16 of the 18 initial responders maintained full efficacy, while two experienced relapses. No safety signals were observed. Injection site pain occurred in four patients (20%) but resolved in all cases after switching from pen to syringe administration. No cases of conjunctivitis were reported. Our large cohort of patients with HH shows that dupilumab is effective, well tolerated, with sustained efficacy in most patients. However, the study has several limitations, including its retrospective design, potential selection bias due to hospital-based recruitment, the inherently relapsing nature of the disease and the influence of external factors, such as seasonal variations. To date, the efficacy and safety of dupilumab in HHD have been reported in a total of 18 patients in the literature, with variability in treatment duration, follow-up periods, dosing regimens and evaluation methods.3-8 Sustained efficacy was inconsistent across cases. The exact mechanism of dupilumab in HHD is unclear. One theory links skin barrier dysfunction to Th2-driven inflammation. Another suggests IL-4 and IL-13 disrupt calcium balance in keratinocytes via eotaxin 3/CCL26 and receptors CCR3, CCR1 and CCR5.2, 10 Dupilumab may help restore calcium homeostasis by inhibiting these cytokines. In conclusion, this series supports dupilumab as a promising and well-tolerated treatment option for patients with severe HHD. These findings highlight the need for double-blind, randomized controlled trials to confirm efficacy and safety and to support future on-label indications. None. Over the past 5 years, JM-H and MS-F have served as investigators for the DUPILAB and PEDISTAD clinical trials conducted by Sanofi. MS-F has also participated in Sanofi's expert advisory boards. ACB has acted as a speaker for Sanofi. The remaining authors declare no conflicts of interest. As defined in article R1121-1, the protocol complied with the General Data Protection Regulation (GDPR) and conformed to the MR-004 reference methodology. This project was registered with number 2025-50. The patients in this manuscript have given written informed consent to the publication of their case details. The data that support the findings of this study are available from the corresponding author upon reasonable request.