M. Hailey-Hailey: hSPCA1 Expression and Skin Structure Upon Laser Therapy

Expression of hSPCA1 and Ultrastructural Analysis of the Skin Before and After Laser Therapy in Hailey-Hailey Disease

Hailey-Hailey disease is a genetic acantholytic dermatosis characterized by continuous erosion of the skin that results in a burning, painful sensation and restricts the patient in daily life. This disorder results from a genetic defect in a calcium pump, i.e. the hSPCA1 pump. Calcium pumps are crucial for the processing of cell-cell adhesion proteins such as E-cadherin, part of desmosomes, the major glue between keratinocytes in skin epidermis. Today therapy is mainly focussed on symptom relief and prevention of secondary infection.

Ablative laser therapy is known to result in a speedy healing of the affected skin site within 2 weeks following laser therapy. The fact that the treated skin site remains clear from this acantholytic disorder in the months/years following ablation, regardless the existence of a germline mutation, suggests that an epigenetic modification occurs in the process of wound healing.

Objective: to (1) study the expression of hSPCA1 in keratinocytes before and after laser therapy and (2) verify the loss of acantholysis by immunohistochemistry and electron microscopy of cell-cell adhesions before and after laser therapy

Study Overview

• Status: Completed
• Conditions: Hailey Hailey Disease
• Intervention / Treatment: Procedure: Skin biopsy

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Valerie Verstraeten, MD PhD; Phone Number: 0031/433877295; Email: valerie.verstraeten@mumc.nl

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6202 AZ
      • Maastricht University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

1.Inclusion criteria

1.1.Hailey-Hailey patients

Inclusion Criteria:

• Clinically diagnosed M. Hailey-Hailey as confirmed by histopathology and/or genetic analysis.
• Indication for ablative laser therapy
• >18 years old
• Informed consent

1.2. Patients without Hailey-Hailey disease

• >18 years old
• Clinically no symptoms of M. Hailey-Hailey
• Informed consent

Exclusion Criteria:

• <18 years old
• Treatment with tetracyclines, topical hormones or oral retinoids within the last 30 days preceding participation
• Lack of informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Hailey-Hailey disease; Patients with Hailey Hailey, diagnosis confirmed by histopathology or genetics, with therapy resistant skin lesions suitable for ablative lasertherapy. Skin biopsy specimens will be taken before and after lasertherapy at three time points. Before treatment: Affected skin 4 mm punch for immunofluorescence and RNA extraction 2 mm for electron microscopy Healthy skin within same anatomical region 4 mm punch for immunofluorescence and RNA extraction Immediately after treatment of the treated area: 2 mm punch for histopathology Six weeks after treatment: Treated skin 4 mm punch for immunofluorescence and RNA extraction 2 mm for electron microscopy 2mm punch biopsy of clinically uninvolved skin of the upper arm for electron microscopy Patients without Hailey-Hailey disease: 2mm punch biopsy of skin of the upper arm for electron microscopy

Procedure: Skin biopsy; Skin biopsy: Tissue samples will be taken by punch biopsy according to the daily routine of the Department of Dermatology of the Maastricht UMC+. Steps: Skin desinfection with chlorhexidine digluconate 1% solution; Local anaesthesia with lidocaine hydrochloride 1%; Biopsy specimens are taken with sterile punch device (disposable biopsy punch delivered by kai medical); Biopsy specimens are retrieved with sterile pincer and cut with sterile blade; Wound is stitched with a single transcutaneous stich using absorbable suture (vicryl 4.0).; Wound will be treated with R/ fusidic acid ointment 3 to 5 times per day for two weeks; In the first week after laser therapy the wound will be covered by R/ Urgotull non-adhesive gauze, R/ Cutisoft cotton non-sterile gauze and R/ Klinipress exsupad absorbing bandage.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hSPCA1 expression	Expression of the hSPCA1 calcium pump in keratinocytes before ablative treatment	Assessed at time point 0 weeks
hSPCA1 expression	Expression of the hSPCA1 calcium pump in keratinocytes after ablative treatment	Assessed 6 weeks after ablative treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expression and localization of desmosomal proteins before and after ablative therapy by immunofluorescence.	Expression and localization of desmosomal proteins before and after ablative therapy by immunofluorescence.	At 0 weeks and 6 weeks after ablative therapy
Ultrastructure of the skin before and after ablative treatment by electron microscopy and comparison to clinically uninvolved skin and skin of patients without Hailey-Hailey disease.	Cell-to-cell adhesion and desmosome ultrastructure before and after ablative treatment by electron microscopy and comparison to clinically uninvolved skin and skin of patients without Hailey-Hailey disease.	At 0 weeks and 6 weeks after ablative therapy

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: Valerie Verstraeten, MD PhD, Maastricht University Medical Center

Publications and helpful links

Helpful Links

• Hailey-Hailey disease and tight junctions: Claudins 1 and 4 are regulated by ATP2C1 gene encoding Ca(2+) /Mn(2+) ATPase SPCA1 in cultured keratinocytes.
• Carbon dioxide laser treatment in Hailey-Hailey disease: a series of 8 patients.
• The coexistence of Darier's disease and Hailey-Hailey disease symptoms.
• Efficacy of erbium:YAG laser ablation in Darier disease and Hailey-Hailey disease.
• Carbon dioxide laser treatment for Hailey-Hailey disease: a retrospective chart review with patient-reported outcomes.
• Laser therapy for the treatment of Hailey-Hailey disease: a systematic review with focus on carbon dioxide laser resurfacing.

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2018
• Primary Completion (Actual): March 15, 2024
• Study Completion (Actual): March 15, 2024

Study Registration Dates

• First Submitted: February 19, 2019
• First Submitted That Met QC Criteria: February 20, 2019
• First Posted (Actual): February 21, 2019

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 18, 2024
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous; Pemphigus, Benign Familial
• Other Study ID Numbers: 64815

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No