New Research Evaluates Ablative CO₂ Laser Therapy for Refractory Hailey–Hailey Disease

To address a knowledge gap in the study of Hailey–Hailey disease (HHD), researchers evaluated the efficacy and molecular rationale of CO₂ laser therapy.¹ The treatment was found to be effective after 6 months, with additional pathophysiological research suggesting that IL-17–mediated inflammation is a key driver of disease activity.

Background

HHD is a rare autosomal dominant acantholytic disorder caused by mutations in ATP2C1, which encodes the Golgi calcium pump SPCA1. This loss of SPCA1 disrupts epidermal calcium homeostasis and desmosomal assembly, producing fragile keratinocyte adhesion, recurrent erosions, and painful intertriginous plaques.²

Most therapies—topical corticosteroids, antibiotics, immunomodulators, and botulinum toxin—provide only transient symptomatic relief. CO₂ laser ablation has emerged as an effective option for localized, refractory disease, but its biological mechanism has been unclear. This trial provides the first transcriptomic evidence explaining how CO₂ laser induces durable remission in HHD.

Study Design

This prospective controlled cohort study included 10 participants with genetically and histologically confirmed, bilateral HHD, who were treated at Clínica Universidad de Navarra, a tertiary dermatology center in Pamplona, Spain. Patients had long-standing, treatment-refractory disease involving sites like the groin, perineum, axillae, and genitals. Each patient underwent ablative CO₂ laser treatment on 1 affected side using standardized parameters of 10,600 nm wavelength and 3 passes to the papillary dermis. The contralateral side served as a control for molecular comparisons.

To further understand why laser-treated skin behaves differently, the authors obtained paired 4-mm punch biopsies from affected and unaffected skin before treatment, and from laser-treated and adjacent untreated skin 6 months later. RNA was extracted and analyzed using Affymetrix microarrays, followed by qPCR validation of key genes. This design allowed direct comparison between healthy skin, lesional HHD skin, and previously lesional skin after laser therapy.

Results

The mean affected area decreased from 65 cm² at baseline to 6 cm² at 6 months, with further reduction to 4 cm² and 3 cm² at 12 and 24 months, respectively (p < 0.002). Importantly, no recurrences developed within treated areas during follow-up, although 3 patients developed new peripheral lesions, consistent with the systemic nature of the disease. Pigmentary changes were common, but no pathological scarring occurred, and only 1 transient local infection was observed.

Additionally, after the CO₂ laser treatment, the gene expression profile of previously affected skin shifted toward that of healthy epidermis. Expression of ATP2A2 remained unchanged, indicating that the laser effect was not mediated through this pathway but rather through modulation of the ATP2C1-dependent system and downstream inflammation. Additional findings include:

• ATP2C1 expression increased, suggesting partial restoration of SPCA1-dependent calcium handling.
• Proliferation and keratinization genes declined, indicating normalization of epidermal differentiation.
• Inflammatory and Th17-associated genes (S100A7, S100A9, S100A12, LCN2, PI3) were significantly reduced.
• DEFB103A, a defensin involved in barrier repair, was paradoxically increased, potentially supporting epithelial integrity.

Clinical Implications

These findings suggest that HHD lesions are maintained by a self-reinforcing loop: reduced ATP2C1 leads to acantholysis, which compromises the barrier, allowing microbial penetration and triggering IL-17–dominant inflammation that further drives keratinocyte hyperproliferation and structural instability. CO₂ laser likely ablates diseased epidermis, allowing re-epithelialization from follicular stem cells and adjacent keratinocytes, which—even though genetically mutated—can express higher levels of ATP2C1 and re-establish a more normal calcium gradient. The accompanying reduction in Th17-associated inflammation restores epidermal homeostasis. The authors of the study hope that this research will help to create optimized procedural strategies and rational biologic therapies for this genodermatosis.

References

1. Antoñanzas J, España A, Gorostidi A, et al. Molecular Changes Induced by Carbon Dioxide Laser in Hailey-Hailey Disease: A Potential Mechanism Underlying Treatment Efficacy. Int J Dermatol. Published online January 7, 2026. doi:10.1111/ijd.70229

2. Shibata A, Sugiura K, Kimura U, Takamori K, Akiyama M. A novel ATP2C1 early truncation mutation suggests haploinsufficiency as a pathogenic mechanism in a patient with Hailey-Hailey disease. Acta Derm Venereol. 2013;93(6):719-720. doi:10.2340/00015555-1551