Unmet Needs in Darier's Disease from a Patient's Perspective: Lessons Learnt from the German Registry.

The MDHHgermany registry was initiated to characterize the "real-life" situation of affected individuals with Darier's disease (DD; Morbus Darier, MD) and Hailey-Hailey disease (HH), including their treatment and healthcare. To gain deeper insights into medical care of patients with DD, various aspects such as demographics, subjective symptoms, patient satisfaction with medical care, past and current therapies were explored. Patients with diagnosed DD were included. Subjective symptoms such as itch, pain and burning sensation were assessed. Individual therapy goals were recorded and patients assessed previous/current therapies along with satisfaction of medical care and treatment. A total of 55 patients were recruited; 47 patients were eligible for the analysis. Pruritus was rated the most bothersome symptom. Some 42.6% had not received systemic treatment so far or systemic therapies were rated ineffective (32.6%). Most commonly oral retinoids were prescribed, followed by corticosteroids. Patient satisfaction with medical care and treatment proved to be mediocre. This "real-life" data show an alarming unmet need regarding patients' satisfaction with medical care and treatment, evidenced by the reported lack of disease control. Further studies and interventions are needed to improve the spectrum of available therapies. MDHHgermany provides a foundational platform for future clinical trials, epidemiological studies, and pathophysiological analyses.

Patients' perspective, quality of life and treatment goals in Hailey-Hailey disease: Lessons learned from the German National Registry.

BACKGROUND: Hailey-Hailey disease (HHD) remains a difficult-to-treat dermatosis and little is known about the patient's perception of the disease activity, the treatment success and its impact on quality-of-life (QoL). OBJECTIVE: To obtain better understanding of HHD patients' needs regarding their medical condition, financial burden, QoL, subjective well-being and treatment thereof as well as satisfaction to evaluate common treatments' 'real-life' relevance. METHODS: With initiation of the national registry for Darier's disease (DD; Morbus Darier, MD) and Hailey-Hailey disease (HH) MDHHgermany, patients with HHD diagnosis were included starting June 2020. To assess subjective symptoms, patients filled out questionnaires such as the DLQI (dermatological life quality index), numeric rating scale (NRS) for itch, pain and burning sensation, as well as the SWLS (satisfaction with life scale) questionnaire to quantify overall satisfaction in life. Additionally, data on therapies were collected along with the patients' satisfaction of those and their medical care. Furthermore, patients assessed financial aspects and work ability. RESULTS: One hundred and two patients were recruited from dermatology clinics, office-based dermatologists and self-help platforms across Germany between June 2020 and February 2023, 90 were eligible and analysed (mean: 49.91 years, 73.33% females, 26.67% males). 39.77% stated according to the DLQI their life is severely/very severely affected. Satisfaction with life was mediocre. Burning sensation was most pronounced among subjective symptoms (NRS 5.85 ± 2.80). Systemic treatments were rated as ineffective according to 56.92%, 25.56% had never received one. Most prescribed systemic treatments were corticosteroids (73.8%), followed by low-dose naltrexone (LDN) (26.2%), retinoids (15.4%) and antibiotics (13.8%). Satisfaction with medical care was generally low. CONCLUSION: Our 'real-life' data state a major disease burden and impact on the QoL for affected individuals, as well as limited disease control due to inadequate therapies. MDHHgermany can provide insights into improvement of healthcare support with this debilitating disease and improve QoL. In the long term, it aims to provide basis for further clinical trials, epidemiological studies and immunological investigations.

Generalized Hailey-Hailey disease associated with c.2395C>T ATP2C1 gene mutation and fatal outcome.

Hailey-Hailey disease (HHD) is a rare, autosomal dominant genodermatosis caused by a mutation of the ATP2C1 gene and presenting as an erosive dermatosis, particularly in the intertriginous areas. Generalized HHD is a rare variant. We present a case of widespread, recalcitrant HHD in a middle-aged woman with a fatal outcome. No other underlying dermatosis was identified, with the possible exception of drug sensitivity to carbamazepine. Diagnosis of HHD was confirmed by histology and genetic studies which showed a c.2395C>T mutation in the ATP2C1 gene. Concurrent pemphigus was excluded. Cases of generalized HHD are extremely rare and present a challenge in diagnosis and management. Increased awareness of this severe clinical variant is needed to improve quality of care for patients with this form of HHD.

Acute generalized exanthematous pustulosis associated with clindamycin in a patient with Hailey-Hailey disease.

A 61-year-old African-American female with moderately controlled Hailey-Hailey disease (HHD) presents to the emergency department with a rash and fever. One day prior to her presentation, she was started on oral clindamycin for a tooth extraction procedure. Her physical examination shows diffuse erythema on the trunk and extremities with multiple nonfollicular pustules. A punch biopsy of her upper extremity revealed intraepidermal acantholysis, neutrophilic spongiosis, and subcorneal pustules. The perivascular and interstitial superficial dermal infiltrate is mixed and composed of predominantly neutrophils, with lymphocytes and rare eosinophils. These findings suggest a superimposed acute generalized exanthematous pustulosis (AGEP) in the background of HHD. AGEP is a potentially severe cutaneous condition characterized by the abrupt onset of numerous nonfollicular pustules in a background of pruritic edematous erythroderma. To date, only two case reports have described AGEP in patients with HHD. Early diagnosis of AGEP is essential to initiate prompt and aggressive systemic therapy, prompt medication cessation, close monitoring for end-organ damage, and improve overall morbidity and mortality.

Double-Blind, Placebo-Controlled Study of Onabotulinumtoxin A for the Treatment of Hailey-Hailey Disease.

BACKGROUND: Hailey-Hailey disease (HHD) can be treated with topical steroids, antibiotics, and invasive surgical procedures. Since sweating often exacerbates HHD lesions, the use of onabotulinumtoxin A could serve as an adjunctive treatment. OBJECTIVE: The goal of this study was to evaluate the safety and efficacy of onabotulinumtoxin A for the treatment of HHD. METHODS: A double-blind, placebo-controlled single center study was conducted. Six HHD patients who successfully completed this trial in addition to 1 patient who exited early are reported and discussed. Four of these patients received an initial injection of Btx-A and 3 received the placebo initially. RESULTS: All patients except 1 who received an initial or reinjection of Btx-A decreased 2 levels on a 4-point clinical severity scale at weeks 8 or 12 after treatment. Patient 6 received an initial placebo injection and maintained clearance for 6 months, while patients 5 and 7 did not have any improvement in their target lesions after a placebo injection. All patients who received a reinjection of Btx-A at the week 4 follow-up decreased by at least 1 level on the HHD severity scale. CONCLUSION: Btx-A is a safe treatment that is effective for most cases of HHD. The most severe cases of HHD may not respond to Btx-A as sole treatment. J Drugs Dermatol. 2023;22(4): doi:10.36849/JDD.6857 Citation: Saal R, Oldfield C, Bota J, et al. Double-blind, placebo-controlled study of Onabotulinumtoxin A for the treatment of Hailey-Hailey disease. J Drugs Dermatol. 2023;22(4):339-343. doi:10.36849/JDD.6857.

Sequential treatments of Hailey-Hailey disease with photodynamic therapy, botulinum toxin type A and dapsone: A case report.

Hailey-Hailey disease is a rare autosomal dominant chronic recalcitrant blistering genodermatosis involving the intertriginous areas. Therapeutic options are various, depending on the type and size of the lesion, and include topical and systemic corticosteroids, topical and systemic retinoids, and DMARDs, but the only true curative approach is represented by the destruction of the affected areas through different techniques like carbon dioxide laser, photodynamic therapy, electron beam radiotherapy, botulinum toxin type A. We report a case of Hailey-Hailey disease successfully treated with a consequential regimen of PDT, botulinum toxin type A and dapsone.

An enhanced transcutaneous delivery of botulinum toxin for the treatment of Hailey-Hailey disease.

Successful treatment of Hailey-Hailey disease with intradermal botulinum toxin injections has been previously reported. The main disadvantages of this treatment are the excruciating pain and the risk of infections due to the numerous injections. We sought to evaluate the clinical effectiveness and safety profile of a novel approach using an energy-based device (Tixel, Novoxel, and Israel), followed by the topical application of botulinum toxin Type A for the treatment of Hailey-Hailey disease. A retrospective study of all cases of histologically diagnosed cases of Hailey-Hailey disease treated with Tixel device followed by topical application of botulinum toxin between 2018 and 2019 was performed. Epidemiologic, clinical, and treatment data, including effectiveness score and safety, were reviewed. The study included eight patients, of whom seven patients (87.5%) showed good or partial response. No systemic or local adverse effects were reported. There was no difference in effectivity between different body areas. Response to treatment ranged between patients with an average duration of 7.125 months after the second treatment. Tixel treatment followed by topical application of botulinum toxin can be considered in the treatment of Hailey-Hailey disease. This approach is less invasive, less painful, and yet effective as well as safe.

Vulvar Hailey-Hailey disease treated with low-dose naltrexone: case report and literature review.

PURPOSE: To report a case of vulvar familial benign pemphigus, or Hailey-Hailey disease, treated successfully with low-dose naltrexone and to review the current literature. METHODS: We report a case of a 71-year-old white woman with vulvar Hailey-Hailey disease recalcitrant to topical corticosteroids. After treatment with low-dose naltrexone, 3 mg nightly was initiated, the lesions began to heal and 5 months later her skin showed no lesions. A literature review on the use of low-dose naltrexone for Hailey-Hailey disease was performed. We searched the PubMed/MEDLINE databases for previous case reports using the key words ''Pemphigus, Benign Familial'' and ''naltrexone". RESULTS: We found 35 more cases of Hailey-Hailey disease treated with naltrexone, showing promising results, reported until January 2020, with no major adverse effects. CONCLUSION: Low-dose naltrexone may represent a cost-effective and successful treatment modality in nongeneralized Hailey-Hailey disease without serious adverse effects. Future prospective studies are needed to investigate this interesting therapeutic option.

The uses of naltrexone in dermatologic conditions.

BACKGROUND: Naltrexone in standard and reduced doses is efficacious in many inflammatory and acantholytic disorders. OBJECTIVE: We summarized the current data of naltrexone that are relevant to dermatologic practice. METHODS: An English language PubMed literature search was performed using the terms naltrexone, low-dose naltrexone, Hailey-Hailey, psoriasis, lichen planopilaris, alopecia, opioid, opioid receptor, treatment, dermatology, monitoring, side effect, skin, pruritus, cutaneous, acantholytic, and Darier. RESULTS: Opioid receptors are found throughout the skin and affect cell proliferation, migration, and adhesion. µ Opioid receptors have been found in all layers of the epidermis, while δ receptors are concentrated at cell junctions and can reduce desmoglein expression. Typical doses of naltrexone result in continuous binding to receptors. Low doses result in intermittent blockade with increased ligand and receptor expression, potentiating their effect. LIMITATIONS: Our review was restricted to the English language literature. CONCLUSION: Naltrexone affects inflammation, cell adhesion, and keratinocyte proliferation and migration. While low-dose naltrexone has demonstrated efficacy in treating patients with Hailey-Hailey disease, further dose-ranging studies are needed. Data suggest that naltrexone could be helpful in the treatment of pruritus and a variety of inflammatory and acantholytic skin diseases that are refractory to other treatments. At higher doses, liver function tests should be monitored on a periodic basis.

Use of low-dose naltrexone in the treatment of severe Hailey-Hailey disease: One case report.

Hailey-Hailey disease (HHD) or chronic benign familial pemphigus is an autosomal dominant genodermatosis with complete penetrance characterized by painful vesicles, erosions, and macerated intertriginous skin. We present a 66-year-old woman with a personal 35-year history of pruritic recurrent vesicles and erosions in both axillae and inguinal folds. HHD was confirmed by cutaneous biopsy. Past treatments had failed, including topical corticosteroids, antibiotics and oral doxycycline, minocycline, dapsone, and acitretin. Phototherapy and intralesional injection of toxin botulinum A was performed in the axillae. The patient was started on naltrexone 6.25 mg nightly. Six weeks later, complete clearing was observed. At typical doses, naltrexone blocks µ and δ opiod receptors, thereby blocking the union of ß-endorphins at those sites. Paradoxically, at low doses, the partial binding to those receptors leads to a homeostatic increase of opioid receptors and an upregulation of endogenous opioids. Low-dose naltrexone (LDN) may also exert an anti-inflammatory action through its antagonist effect on toll-like receptor 4 found on macrophages. We consider that LDN is an effective and safe alternative for the HHD, representing an important progress in the management of this disease with limited therapeutic options.

Generalized Hailey-Hailey disease with flexural keratotic papules: An interesting presentation and remarkable response with minocycline.

Hailey-Hailey disease is a hereditary blistering disorder characterized by episodic vesicles, pustules, erosions, and maceration mainly in intertriginous areas with generalized eruptions encountered rarely. We present a case of generalized HHD with keratotic papules over flexural areas along with its dermoscopic features; treated successfully with minocycline alone.

Hailey-Hailey disease successfully treated with vitamin D oral supplementation.

Hailey-Hailey disease (HHD) also known as familial benign chronic pemphigus is a rare autosomal dominant genodermatosis. HHD treatment is often not satisfactory and hence, various modalities of treatment have been tried. We describe the case of a 37-year-old woman with a 2 years history of macerated erythematous plaques along with erosions, fissures, and crusts located on axillae and submammary areas, successfully treated with only oral supplementation of vitamin D (800 I.U./die) for 3 months. We reported this case to suggest that oral vitamin D may be enumerated in the various treatments proposed for HHD so far due to its rapid efficacy on skin lesions and symptoms.

Hypotonic, Acidic Oxidizing Solution Containing Hypochlorous Acid (HClO) as a Potential Treatment of Hailey-Hailey Disease.

Hailey-Hailey disease (HHD) is a rare, chronic and recurrent blistering disorder, characterized by erosions occurring primarily in intertriginous regions and histologically by suprabasal acantholysis. Mutation of the Golgi Ca2+-ATPase ATP2C1 has been identified as having a causative role in Hailey-Hailey disease. HHD-derived keratinocytes have increased oxidative-stress that is associated with impaired proliferation and differentiation. Additionally, HHD is characterized by skin lesions that do not heal and by recurrent skin infections, indicating that HHD keratinocytes might not respond well to challenges such as wounding or infection. Hypochlorous acid has been demonstrated in vitro and in vivo to possess properties that rescue both oxidative stress and altered wound repair process. Thus, we investigated the potential effects of a stabilized form of hypochlorous acid (APR-TD012) in an in vitro model of HHD. We found that treatment of ATP2C1-defective keratinocytes with APR-TD012 contributed to upregulation of Nrf2 (nuclear factor (erythroid-derived 2)-like 2). Additionally, APR TD012-treatment restored the defective proliferative capability of siATP2C1-treated keratinocytes. We also found that the APR-TD012 treatment might support wound healing process, due to its ability to modulate the expression of wound healing associated cytokines. These observations suggested that the APR-TD012 might be a potential therapeutic agent for HHD-lesions.

Low-dose naltrexone: a novel treatment for Hailey-Hailey disease.

Hailey-Hailey disease (chronic benign familial pemphigus) is a rare inherited dermatosis typically characterized by erosions at intertriginous sites preceded by minor trauma or stress. We report a case of treatment-resistant Hailey-Hailey disease having failed topical and oral steroids, prophylactic aciclovir and doxycycline, and systemic therapies including dapsone, acitretin and ciclosporin. Low-dose naltrexone 4·5 mg once daily was commenced following an incidental benefit in this patient's similarly affected sister. The clinical and psychological response to date has been considerable.

A Case of Hailey-Hailey Disease Managed With Oral Magnesium Citrate and High-Dose Vitamin D3.

Hailey-Hailey disease, or benign familial pemphigus, is a rare blistering disease originally described in 1939. The disease is due to an autosomal dominant mutation in the ATP2C1 gene on chromosome 3, which encodes for an adenosine triphosphate-dependent calcium pump in the Golgi apparatus whose function is to maintain intercellular calcium homeostasis. Common treatments for Hailey-Hailey disease involve calcineurin inhibitors, topical corticosteroids, topical or systemic antibiotics, topical antifungals, ablative lasers, or botulin toxin. In this case report, we highlight a unique case of Hailey-Hailey disease that was resistant to many conventional therapies and ultimately managed with oral magnesium citrate and high-dose vitamin D3.