Hailey-Hailey Research Articles

Utilizing Upadacitinib for the Management of Hailey-Hailey Disease

Hailey-Hailey Disease (HHD) is a rare disease associated with mutation of the ATP2C1 gene characterized by skin blistering and erosion. Here, we report a case of a patient with HHD who significantly improved after treatment with upadacitinib. A 55-year-old male with biopsy-confirmed Hailey-Hailey disease presented with a 20-year history of ill-defined, brightly erythematous, painful patches initially on the neck and subsequently involving the penile shaft. Following treatment with 30mg of upadacitinib, the patients neck ulcers gradually re-epithelized. This case adds to the growing body of literature supporting the use of Janus kinase inhibitors as a therapeutic modality for this condition.

Long-term remission of Hailey-Hailey disease by Er:YAG ablative laser therapy.

Hailey-Hailey disease (HHD) is a rare genetic therapy-resistant blistering disease with great disease burden. Treatment is currently focused on symptomatic relief. Er:YAG ablative laser therapy is a therapeutic modality with promising results, though evidence is currently scarce. To analyse the effect of Er:YAG ablative laser therapy on clinical remission of erosive plaques in HHD and on patient's quality of life (QoL). In this observational study eight patients were included and 77 erosive plaques were treated once only by Er:YAG laser and assessed for clinical remission. QoL was evaluated by obtaining Skindex-29 and DLQI questionnaires before laser therapy, 6 weeks and 3 years after laser therapy. Skin biopsies were taken to evaluate the depth of laser ablation. The intercellular distance between keratinocytes, the number of desmosomes and intermediate filament distribution were studied by electron microscopy before and after laser therapy and in clinically uninvolved skin and were compared to subjects without HHD. One single Er:YAG laser ablation to mid-dermis resulted in complete remission of 97.4% of HHD plaques (75/77) after median 38 months (range 7-63 months) and significantly improved QoL. Laser therapy restored the number of desmosomes, decreased intercellular distance and diminished perinuclear retraction of keratin filaments to a level comparable to the patient's clinically uninvolved skin. After laser ablation, the skin showed significantly fewer ultrastructural aberrations compared to the patient's clinically uninvolved skin and rather resembled the skin of healthy control individuals. One single Er:YAG laser treatment resulted in long-term remission of HHD and significantly improved QoL. Our findings support a greater role for ablative laser surgery in the management of this recalcitrant disorder.

Therapeutic agents for Hailey-Hailey disease: A narrative review.

Hailey-Hailey disease (HHD) is an autosomal dominant genetic disorder of keratinocyte adhesion. It occurs due to mutations in ATP2C1, a gene on chromosome 3q21-24 which encodes human secretory pathway Ca2+/Mn2+ ATPase isoform 1, a calcium pump on the Golgi apparatus membrane. Recently, there has been a focus on certain pro-inflammatory cytokines such as IL-6 and IL-8 which play a role in HHD. Various triggers include excessive heat, menstruation, pregnancy, sweating, friction, exposure to sunlight and superficial infections. The therapy of the disorder is better understood by the varied pathogenetic steps and we aimed to comprehensively search for the various medical therapies used in HHD and align them with the existing knowledge on the pathogenesis and delineate them according to their major mode of action.

The use of photodynamic therapy in the management of darier disease and Hailey-Hailey disease: a systematic review.

Darier disease and Hailey-Hailey disease are rare autosomal dominant genodermatoses that negatively impact patient quality of life. In addition, they pose challenges to dermatologists who manage these diseases. There is currently no treatment that reliably induces remission for either disease, leaving patients dependent on symptom management. Oral and topical retinoids are the most commonly used therapies but have numerous side effects that often lead to discontinuation or inability to tolerate long-term treatment (Burge and Wilkinson in J Am Acad Dermatol 27:40-50, 1992). Due to the rarity of these diseases, there are no clinical trials investigating treatment options for the persistent flares patients experience. In light of this, dermatologists have tried various methods used in the management of other inflammatory disorders including photodynamic therapy (PDT). A systematic review was conducted to investigate this treatment option which yielded a total of 12 studies that had reported the use of photodynamic therapy (PDT) as a treatment option for Darier or Hailey-Hailey disease. Though results showed that PDT can induce disease remission for up to several months or years, there are many unanswered questions that need to be addressed before adopting PDT as a leading treatment option for those genodermatoses. In particular, cost, tolerability, and efficacy and safety in patients who are skin of color need to be further studied. Lastly, recommendations on treatment duration, number of sessions, photosensitizing agents, lasers, and continuation or discontinuation of topical and systemic medications need to be appraised before formal recommendations can be made.

Acantholytic Dyskeratoses of the Vulva: Clinicopathologic Characterization of 16 Cases and Review of the Literature.

The vulva and perineum are rarely involved by acantholytic dyskeratoses, including Hailey-Hailey disease, Darier disease, papular acantholytic dyskeratosis of the genitocrural area, acantholytic dyskeratotic acanthoma, and warty dyskeratoma. These entities show broad histomorphologic overlap, generally requiring clinical correlation for definitive classification. This institutional series aims to better characterize vulvar acantholytic dyskeratoses and provide a practical literature review and diagnostic aid for gynecologic pathologists. Our institutional archives contained 16 vulvar acantholytic dyskeratoses diagnosed between 1990 and 2023. Affected patients were 36 to 79 (mean, 58) years old and presented with one or more asymptomatic (n = 9) or pruritic (n = 6) lesions involving the vulva (predominantly the labia majora), with additional perineal involvement in 2. Four patients have known Hailey-Hailey disease. Eleven cases comprised singular, raised, erythematous, or skin-colored papules, measuring 0.2 to 0.6 (mean, 0.3) cm. Two patients had oligofocal (both with known Hailey-Hailey disease) vulvar lesions, and 2 had multifocal vulvar lesions (one with known Hailey-Hailey disease). Histologically, all showed acantholysis and dyskeratoses (abundant in 8, focal in 8, with corps ronds generally more conspicuous than corps grains). Additional features included suprabasal clefting (n = 14), dermal papillomatosis (n = 12), and acanthosis (n = 8). Adnexal involvement was rare (n = 1). No histologic features reliably distinguished sporadic versus syndromic acantholytic dyskeratoses. Sporadic lesions were cured by local excision. Patients with Hailey-Hailey disease were variably responsive to corticosteroids. Neither our series nor the literature indicate a significant correlation between sporadic or syndromic acantholytic dyskeratosis and squamous cell carcinoma. Important differential diagnoses include pemphigus vulgaris and pemphigus vegetans, for which direct immunofluorescence may be performed, when indicated.

Dupilumab as a treatment for a case of benign familial pemphigus

Hailey-Hailey disease (HHD) is an uncommon autosomal dominant genodermatosis characterized by recurrent blistering eruptions primarily affecting intertriginous areas, leading to the formation of eroded, erythematous plaques within flexural skin folds. The condition significantly impairs quality of life due to the frequency of infections, exacerbated by the limited and often ineffective therapeutic options currently available for HHD. In this report, we present a compelling case of HHD successfully treated with dupilumab, highlighting remarkable improvement observed within just two weeks of initiating treatment with this novel therapeutic agent. This promising outcome underscores the potential of dupilumab in managing challenging cases of HHD and warrants further exploration in larger clinical trials.

Treatment of Hailey-Hailey disease with biologics and small molecule inhibitors: a systematic review.

Hailey-Hailey disease (HHD) is a rare genetic dermatosis characterized by recurrent flaccid vesicles and blisters on erythematous skin in friction areas. The disease follows a chronic relapsing course and has a significant psychological and social impact. Currently, there is no standardized therapeutic regimen for HHD, posing a challenge for dermatologists in managing the condition. We performed this systematic review to investigate the therapeutic role of biologics and small molecule inhibitors in the treatment of HHD. A systematic search was conducted of the PubMed, Embase, Web of Science, Scopus, and Cochrane databases from inception to January 1, 2024. A total of 31 HHD patients from 18 articles were included in the analysis. Biologics and small molecule inhibitors, including dupilumab, apremilast, upadacitinib, abrocitinib, adalimumab, and etanercept were evaluated. Most reported cases demonstrated clinical improvement after treatment initiation with few major adverse events. However, some patients experienced recurrences. In conclusion, biologics and small molecule inhibitors may offer a treatment alternative for refractory HHD patients, but further confirmation is necessary through large-scale randomized controlled clinical trials.

Case report: segmental form of Hailey-Hailey disease

The article presents a clinical case of a rare segmental form of familial benign chronic pemphigus with a positive family history. Patient S., born in 2014, complained of unilateral eruptions in the area of the left retroauricular fold, left axilla, inguinal fold and labia majora on the left, plantar surface of the left foot. Eruptions were represented by erythematous foci, single blisters with serous contents, erosions, crusts. For the entire period, the patient was observed with the following diagnoses: microbial eczema, Sneddon-Wilkinson Disease, Inflammatory Linear Verrucose Epidermal Nevus. Due to the long-term relapsing course and ineffective therapy, additional examination methods were carried out – histological and genetic studies. Only after genetic testing, in which a heterozygous mutation of the ATP2C1 gene was revealed, and geneticist’s consultation, the final diagnosis was established – Hailey-Hailey Disease.It is known, that the segmental form is formed as a result of mosaicism, which can be of two types. The term "mosaicism" refers to the presence in an organism of two or more genetically heterogeneous cell populations formed from a genetically homogeneous zygote. The formation of type 1 mosaicism is based on a de novo postzygotic mutation at an early stage of embryogenesis. In turn, type 2 mosaicism develops as a result of a postzygotic mutation against the background of an already existing prezygotic mutation. Determining the type of mosaicism by genetic testing will make it possible to assess the prognosis of the disease and the chance of transmitting this disease to offspring.

Hailey-Hailey Disease: Case Series and Review of Systemic Medications.

Hailey-Hailey disease (HHD) is a rare inherited blistering skin disorder characterized by a chronic relapsing course. While it does not pose a serious threat to the patient's health, the quality of life can change. Unfortunately, there is currently no standard treatment for this condition. In this observational retrospective cohort study, our aim was to discover the demographic characteristics and treatment strategies for managing HHD. In this retrospective cohort study, we documented the demographic, clinical, and histopathological characteristics beside various treatment employed options of patients diagnosed with HHD at Razi Hospital over the past 14 years. A total of 32 patients with HHD were enrolled in the study (15 male and 17 female). The mean age of patients was 50.41 ± 13.15 (22-77) years. The average age of disease onset was 37.31 ± 11.88 (15-60) years. Among the participants, 16 individuals (50%) affirm a positive family history of some kind of pemphigoid blisters. The most common site of disease activity was the inguinal area, observed in 14 patients (33.33%). Histopathological examination discovered the existence of suprabasal acantholysis in all of the specimens. Worthily, direct immunofluorescence analysis showed negative results in all skin biopsies. All patients received topical steroids and either topical or systemic antimicrobial agents. In cases of flares, systemic steroids were the most popular and favorable treatment choice during flares. Indeed, Hailey-Hailey disease, characterized by its chronic inflammatory and rare nature with a relapsing and remitting course, poses a significant challenge for dermatologists. The treatment of HHD has been less than satisfactory and it often presents a challenge and could be misdiagnosed. Among the available treatment options, topical steroids and antimicrobial agents are the most administered therapies.

Treatment of Hailey-Hailey disease with JAK inhibitors.

Treatment of Hailey-Hailey disease with JAK inhibitors.

Significant Improvement of Persistent Hailey-Hailey Disease with Dupilumab: A Case Report

Hailey-Hailey disease is a rare, genetic blistering disease characterized by erythematous, scaly plaques in intertriginous regions such as the axillary, inframammary, and groin regions. The plaques cause discomfort and are difficult to treat. Treatment ranges from topical to systemic and surgical. Despite the variety of treatment options, Hailey-Hailey disease is notoriously difficult to treat with each patient responding uniquely to treatment. There has been evidence of patients with Hailey-Hailey disease experiencing improvement of symptoms with dupilumab injections. Dupilumab has several off-label uses, including allergic contact dermatitis, hand dermatitis, chronic spontaneous urticaria, and alopecia areata, showing promise for its use in dermatology outside of atopic dermatitis and prurigo nodularis. Due to its minimal side effects, dupilumab can be tried for Hailey-Hailey disease with little risk. We present the case of a 37-year-old female with recalcitrant Hailey-Hailey disease who noticed significant improvement on dupilumab.

Successful treatment of Darier's disease with apremilast and review of reported cases.

Darier's disease (DD) is a rare autosomal dominant genetic disorder caused by a mutation in ATP2A2, which encodes calcium (Ca2+) ATPase pumps in the endoplasmic reticulum. In this report, we present the first documented case in Japan successfully treated with apremilast. An 18-year-old female presented with red or brown hyperkeratotic papules and plaques on her head, neck, and chest. Histopathological examination revealed a hyperkeratotic, acanthotic epidermis, along with suprabasal acantholysis characterized by corps ronds and grains. Exome sequencing of DNA from peripheral blood mononuclear cells identified a missense mutation in ATP2A2. Based on the above results, we diagnosed her with DD despite the absence of a family history. Given the effectiveness of apremilast, a phosphodiesterase 4 inhibitor, in treating Hailey-Hailey disease (HHD), a genetically related disorder involving ATPases in epidermal calcium channels, we opted for apremilast therapy. Eight weeks post-initiation, significant improvement was observed in the patient's skin lesions on the head, neck, and chest. In this paper, we discuss the successful treatment of DD and HHD cases with apremilast, providing insights into its therapeutic potential, and offer a comprehensive review.

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.

Successful treatment of recalcitrant severe Hailey-Hailey disease with tofacitinib

Successful treatment of recalcitrant severe Hailey-Hailey disease with tofacitinib

ATP2C1 knockdown induces abnormal expressions of cytoskeletal and tight junction proteins mimicking Hailey-Hailey disease.

Background Hailey-Hailey disease (HHD) is a rare, autosomal dominant, hereditary skin disorder characterised by epidermal acantholysis. The HHD-associated gene ATPase calcium-transporting type 2C member 1 (ATP2C1) encodes the protein secretory pathway Ca2+ ATPase1 (SPCA1), playing a critical role in HHD pathogenesis. Aims We aimed to investigate the effect of ATP2C1 knockdown on keratinocytes that mimicked acantholysis in HHD. Methods Immunohistochemistry (IHC) was employed to evaluate the levels of cytoskeletal and tight junction proteins such as SPCA1, P-cofilin, F-actin, claudins, occludin, and zonula occludens 1 in the skin biopsies of patients with HHD. Subsequently, the expression of these proteins in cultured ATP2C1 knockdown keratinocytes was analysed using Western blotting and immunofluorescence. Furthermore, we assessed the proliferation, apoptosis, and intracellular Ca2+ concentrations in the ATP2C1-knocked keratinocytes. Results The results showed decreased levels of these proteins (SPCA1, P-cofilin, F-actin, claudins, occluding, and zonula occludens 1) in HHD skin lesions. Moreover, their levels decreased in human keratinocytes transfected with ATP2C1 short hairpin RNA, accompanied by morphological acantholysis. Furthermore, the proliferation and apoptosis of the keratinocytes, as well as intracellular calcium concentrations in these cells, were not affected. Limitations The limitations of this study are the absence of animal experiments and the failure to explore the relationship between skeletal and tight junction proteins. Conclusion The present study indicated that ATP2C1 inhibition led to abnormal levels of the cytoskeletal and tight junction proteins in the keratinocytes. Therefore, keratinocytes can mimic HHD-like acantholysis and serve as an in vitro model, helping develop treatment strategies against HHD.

Case Report of Hailey-Hailey Disease Successfully Treated with Topical Roflumilast 0.3% Cream

Hailey-Hailey Disease, also called Benign Familial Pemphigus, is a genetic acantholytic blistering condition that most commonly affects the intertriginous areas. There are many treatments, both on and off label, for the treatment of this life-long, uncomfortable condition. More efficacious treatments are needed. We believe we are the first to report successful treatment with topical roflumilast, a PDE-4 inhibitor. This helps us to further understand and speculate beyond the genetics, other mechanisms of action that trigger this disease.

Clinical case: Hailey-Hailey disease or Darier’s disease?

Clinical case: Hailey-Hailey disease or Darier’s disease?

Claudin-4 Upregulation in Acantholytic and Autoimmune-Mediated Bullous Disorders.

Claudin-4 is a key component of tight junctions, which play an important role in the formation of the epidermal barrier by forming a circumferential network in the granular layer that serves as a gatekeeper of the paracellular pathway. The aim of this study is to illustrate claudin-4 immunohistochemical staining patterns of different blistering disorders. We collected 35 cases, including two Hailey-Hailey disease, one Darier disease, three Grover disease, one acantholytic acanthoma, two warty dyskeratoma, 11 pemphigus vulgaris (PV) including six mucosal PV, and two pemphigus foliaceus. For comparison, we included five cases of normal skin, five eczema, and three bullous pemphigoid cases. Claudin-4 demonstrated weak-to-moderate expression in keratinocytes located in the stratum granulosum, keratinocytes surrounding hair follicles, and adnexal glands. Further, claudin-4 exhibited moderate-to-strong membranous staining in disrupted keratinocytes surrounding and within the acantholytic and bullous areas in 16/22 of the acantholytic cases (not seen in the six cases of mucosal PV) and all three bullous pemphigoids. This finding suggests that claudin-4 is upregulated in these conditions, which may be a compensatory response to the disrupted barrier function. This finding could shed light on the molecular mechanisms underlying disrupted barrier function in blistering disorders, independent of the specific underlying disease mechanism.

Hailey-Hailey Disease is Associated with Diabetes: A Population-based Cohort Study, Clinical Cohort Study, and Pedigree Analysis.

Hailey-Hailey disease is a rare hereditary skin disease caused by mutations in the ATP2C1 gene encoding the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1) protein. Extracutaneous manifestations of Hailey-Hailey disease are plausible but still largely unknown. The aim of this study was to explore the association between Hailey-Hailey disease and diabetes. A population-based cohort study of 347 individuals with Hailey-Hailey disease was performed to assess the risks of type 1 diabetes and type 2 diabetes, using Swedish nationwide registries. Pedigrees from 2 Swedish families with Hailey-Hailey disease were also investigated: 1 with concurrent type 1 diabetes and HLA-DQ3, the other with type 2 diabetes. Lastly, a clinical cohort with 23 individuals with Hailey-Hailey disease and matched healthy controls was evaluated regarding diabetes. In the register data males with Hailey-Hailey disease had a 70% elevated risk of type 2 diabetes, whereas no excess risk among women could be confirmed. In both pedigrees an unusually high inheritance for diabetes was observed. In the clinical cohort, individuals with Hailey-Hailey disease displayed a metabolic phenotype indicative of type 2 diabetes. Hailey-Hailey disease seems to act as a synergistic risk factor for diabetes. This study indicates, for the first time, an association between Hailey-Hailey disease and diabetes and represents human evidence that SPCA1 and the Golgi apparatus may be implicated in diabetes pathophysiology.

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

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). 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. 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. 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. 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.