Search Results (11)

Background/Objectives: Hailey–Hailey disease (HHD) is an uncommon genodermatosis with autosomal dominant inheritance caused by loss-of-function mutations in the ATP2C1 gene, which lead to disruption in keratinocyte adhesion and intraepidermal acantholysis. The chronic nature of the disease, its frequent recurrences and the lack of specific treatment pose real challenges in the long-term management of these patients. Recent studies have evaluated the effect of dupilumab, a human monoclonal antibody that blocks interleukin-4 and -13 receptor in refractory HHD, with very promising results. The aim of this study was to review the published data on the use of dupilumab for the treatment of HHD, to present our own experience in the field, and to discuss the mechanisms underlying dupilumab’s beneficial effects in HHD and the future treatment perspectives. Methods: A search of the medical literature on the use of dupilumab in the treatment of HHD was conducted. The terms “Hailey–Hailey disease”, “benign familial pemphigus”, “benign chronic pemphigus”, and “dupilumab” were searched across multiple databases (Medline, Chrocane Library, EMBASE) from inception until 30 September 2024. Results: To date, six manuscripts describing 11 refractory HHD cases treated with dupilumab have been published. All the patients experienced significant clinical improvement. The authors reported sustained disease quiescence in seven patients (64%), monitored for 5 to 24 months. None of the patients experienced adverse effects related to dupilumab. To the existing evidence, we add a new case of recalcitrant HHD successfully treated with dupilumab. Conclusions: Mounting evidence indicates dupilumab as a safe and efficient therapeutic alternative in patients with severe, refractory HHD. However, the long-term efficacy of dupilumab and the optimal therapeutic regimen for HHD are yet to be determined. Full article

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. Full article

The chemical milieu, microbiota composition, and immune activity show prominent differences in distinct healthy skin areas. The objective of the current study was to compare the major permeability barrier components (stratum corneum and tight junction (TJ)), investigate the distribution of (corneo)desmosomes and TJs, and measure barrier function in healthy sebaceous gland-rich (SGR), apocrine gland-rich (AGR), and gland-poor (GP) skin regions. Molecules involved in cornified envelope (CE) formation, desquamation, and (corneo)desmosome and TJ organization were investigated at the mRNA and protein levels using qRT-PCR and immunohistochemistry. The distribution of junction structures was visualized using confocal microscopy. Transepidermal water loss (TEWL) functional measurements were also performed. CE intracellular structural components were similarly expressed in gland-rich (SGR and AGR) and GP areas. In contrast, significantly lower extracellular protein levels of (corneo)desmosomes (DSG1 and CDSN) and TJs (OCLN and CLDN1) were detected in SGR/AGR areas compared to GP areas. In parallel, kallikrein proteases were significantly higher in gland-rich regions. Moreover, gland-rich areas were characterized by prominently disorganized junction structures ((corneo)desmosomes and TJs) and significantly higher TEWL levels compared to GP skin, which exhibited a regular distribution of junction structures. According to our findings, the permeability barrier of our skin is not uniform. Gland-rich areas are characterized by weaker permeability barrier features compared with GP regions. These findings have important clinical relevance and may explain the preferred localization of acantholytic skin diseases on gland-rich skin regions (e.g., Pemphigus foliaceus, Darier’s disease, and Hailey–Hailey disease). Full article

We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis—e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey–Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)—vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor). Full article

Botulinum toxin is a superfamily of neurotoxins produced by the bacterium Clostridium Botulinum with well-established efficacy and safety profile in focal idiopathic hyperhidrosis. Recently, botulinum toxins have also been used in many other skin diseases, in off label regimen. The objective of this manuscript is to review and analyze the main therapeutic applications of botulinum toxins in skin diseases. A systematic review of the published data was conducted, following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Botulinum toxins present several label and off-label indications of interest for dermatologists. The best-reported evidence concerns focal idiopathic hyperhidrosis, Raynaud phenomenon, suppurative hidradenitis, Hailey–Hailey disease, epidermolysis bullosa simplex Weber–Cockayne type, Darier’s disease, pachyonychia congenita, aquagenic keratoderma, alopecia, psoriasis, notalgia paresthetica, facial erythema and flushing, and oily skin. Further clinical trials are still needed to better understand the real efficacy and safety of these applications and to standardize injection and doses protocols for off label applications. Full article

A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. The lesion was successfully treated by repeated laser ablation of the affected epidermis. Over the course of three years, the dog additionally developed three dermal nodules of up to 4 cm in diameter that were excised and healed without complications. Histology of the excised tissue revealed multiple infundibular cysts extending from the upper dermis to the subcutis. The cysts were lined by squamous epithelium, which presented with abundant acantholysis of suprabasal keratinocytes. Infundibular cysts represent a novel finding not previously reported in Darier patients. Whole genome sequencing of the affected dog was performed, and the functional candidate genes for Darier disease (ATP2A2) and Hailey-Hailey disease (ATP2C1) were investigated. The analysis revealed a heterozygous SINE insertion into the ATP2A2 gene, at the end of intron 14, close to the boundary of exon 15. Analysis of the ATP2A2 mRNA from skin of the affected dog demonstrated a splicing defect and marked allelic imbalance, suggesting nonsense-mediated decay of the resulting aberrant transcripts. As Darier disease in humans is caused by haploinsufficiency of ATP2A2, our genetic findings are in agreement with the clinical and histopathological data and support the diagnosis of canine Darier disease. Full article

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. Full article

Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn’s disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. In a dosing range at less than 1 μg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. A dosing range between 1 μg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed. Full article

The term orthodisease defines human disorders in which the pathogenic gene has orthologs in model organism genomes. Yeasts have been instrumental for gaining insights into the molecular basis of many human disorders, particularly those resulting from impaired cellular metabolism. We and others have used yeasts as a model system to study the molecular basis of Hailey-Hailey disease (HHD), a human blistering skin disorder caused by haploinsufficiency of the gene ATP2C1 the orthologous of the yeast gene PMR1. We observed that K. lactis cells defective for PMR1 gene share several biological similarities with HHD derived keratinocytes. Based on the conservation of ATP2C1/PMR1 function from yeast to human, here we used a yeast-based assay to screen for molecules able to influence the pleiotropy associated with PMR1 deletion. We identified six compounds, Kaempferol, Indirubin, Lappaconite, Cyclocytidine, Azomycin and Nalidixic Acid that induced different major shape phenotypes in K. lactis. These include mitochondrial and the cell-wall morphology-related phenotypes. Interestingly, a secondary assay in mammalian cells confirmed activity for Kaempferol. Indeed, this compound was also active on human keratinocytes depleted of ATP2C1 function by siRNA-treatment used as an in-vitro model of HHD. We found that Kaempferol was a potent NRF2 regulator, strongly inducing its expression and its downstream target NQO1. In addition, Kaempferol could decrease oxidative stress of ATP2C1 defective keratinocytes, characterized by reduced NRF2-expression. Our results indicated that the activation of these pathways might provide protection to the HHD-skin cells. As oxidative stress plays pivotal roles in promoting the skin lesions of Hailey-Hailey, the NRF2 pathway could be a viable therapeutic target for HHD. Full article

The ATP2C1 gene encodes for the secretory pathway calcium (Ca²⁺)-ATPase pump (SPCA1), which localizes along the secretory pathway, mainly in the trans-Golgi. The loss of one ATP2C1 allele causes Hailey-Hailey disease in humans but not mice. Examining differences in genomic organization between mouse and human we speculate that the overlap between ATP2C1 and ASTE1 genes only in humans could explain this different response to ATP2C1 dysregulation. We propose that ASTE1, overlapping with ATP2C1 in humans, affects alternative splicing, and potentially protein expression of the latter. If dysregulated, the composition of the SPCA1 isoform pool could diverge from the physiological status, affecting cytosolic Ca²⁺-signaling, and in turn perturbing cell division, leading to cell death or to neoplastic transformation. Full article

Rare diseases (RD) are characterized by low prevalence and affect not more than five individuals per 10,000 in the European population; they are a large and heterogeneous group of disorders including more than 7,000 conditions and often involve all organs and tissues, with several clinical subtypes within the same disease. Very often information concerning either diagnosis and/or prognosis on many RD is insufficient. microRNAs are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level by either degrading or blocking translation of messenger RNA targets. Recently, microRNA expression patterns of body fluids underscored their potential as noninvasive biomarkers for various diseases. The role of microRNAs as potential biomarkers has become particularly attractive. The identification of disease-related microRNAs is essential for understanding the pathogenesis of diseases at the molecular level, and is critical for designing specific molecular tools for diagnosis, treatment and prevention. Computational analysis of microRNA-disease associations is an important complementary means for prioritizing microRNAs for further experimental examination. In this article, we explored the added value of miRs as biomarkers in a selected panel of RD hitting different tissues/systems at different life stages, but sharing the need of better biomarkers for diagnostic and prognostic purposes. Full article