Emerging drugs for the treatment of epidermolysis bullosa.

INTRODUCTION: Epidermolysis Bullosa (EB) form a heterogeneous group of rare, sometimes life-threatening inherited skin diseases characterized by skin and mucosal blistering after mild trauma from birth. They display a wide range of disease severity, with multiple local and systemic complications with no satisfactory treatment. AREAS COVERED: Approaches aiming to restore the functional expression of the defective protein such as ex vivo and in vivo gene therapy, cell therapies, protein replacement and pharmacological approaches have shown promising results. In addition, improved knowledge of EB pathogenesis has open the way to symptom-relief therapies using repurposed drugs in some forms of EB. EXPERT OPINION: A cure for all forms of EB will remain challenging, but it is anticipated that treatments for EB will rely on precision medicine, involving a combination of complementary approaches. Treatments aiming to restore the function of the defective genes will be combined with symptom-relief therapies to address the specific features of the different forms of EB and each patient complications. A growing number of biotech and pharmaceutical companies have shown an increasing interest in the treatment of EB and as a result, have implemented numerous clinical trials. Therefore, we anticipate the emergence of effective treatments in the near future.

Bart syndrome associated with skeletal deformities: An uncommon case report.

Bart syndrome is a rare genetic disorder characterized by aplasia cutis congenita, epidermolysis bullosa (EB), and nail abnormalities. We reported an unusual case of Bart syndrome associated with skeletal abnormalities and bilateral clubfoot.

Caring for Pediatric Patients With Epidermolysis Bullosa in the Emergency Department.

Epidermolysis bullosa (EB) refers to a heterogeneous group of genetic disorders characterized by epithelial fragility. We provide guidelines for management of pediatric patients with EB in the emergency department based on a review of literature, as well as insights from our own experiences caring for patients with EB. The purpose of the guidelines proposed is prevention of avoidable iatrogenic trauma to the skin and mucosa of patients with EB who are presenting to the emergency department for a variety of reasons.

Pain Quality Assessment Scale for Epidermolysis Bullosa.

Pain is one of the most debilitating symptoms in epidermolysis bullosa (EB) leading to reduced quality of life. Pain in EB comprises both neuropathic and non-neuropathic qualities. An assessment of pain qualities has not formerly been completed in EB. The Pain Quality Assessment Scale (PQAS) is an adjusted version of the validated Neuropathic Pain Scale and includes 20 pain qualities and descriptors. Patients with EB (n = 43) rated the pain qualities in the PQAS on 20 numerical scales and 1 multiple choice question. Pain was experienced by 39 patients (91%). In general, patients with EB experience intense and unpleasant pain on the surface of the skin; the hands and feet are most commonly affected. The subtypes, recessive dystrophic EB and junctional EB reported pain qualities pathognomonic of neuropathic pain. The PQAS adds value to the current practice of global pain intensity scoring in EB.

[Genodermatoses - pathogenesis and molecular diagnostics]. / Genodermatozy ­ patogeneza i diagnostyka molekularna.

Genetically determined skin diseases, genodermatoses, are a group of rare disorders characterized by heterogeneous clinical course, prognosis and complex molecular pathology. In Epidermolysis Bullosa (EB) and Mendelian disorders of cornification (MeDOC) epidermal dysfunction occurs. Mutations in several dozen genes have been identified to be responsible for clinical symptoms of EB and MeDOC, which, in general, include: tendency to blister formation with skin fragility and abnormal keratinization, respectively. However, clinical symptoms of these diseases can be variable and genotype-phenotype correlations are only partially determined. Molecular diagnostics aimed at identification of mutations in affected individuals enables verification of clinical diagnosis, calculation of disease recurrence risk in other family members and, gradually, is also the basis for new therapies development. Nevertheless, even modern molecular technologies allow mutation detection in 80% of patients only. Hence, further, interdisciplinary scientific research are needed in order to increase detection rate and develop effective therapies.

[Inherited epidermolysis bullosa]. / Vrozhdennyi bulleznyi épidermoliz.

OBJECTIVE: To summarize an update on epidermolysis bullosa as a polymorphic group of inherited diseases with a failure of epidermal-dermal integrity. Emphasis is placed on the role of transmission electron microscopy in diagnosis and search directions for new types of the abnormality and its molecular markers. Despite numerous mutations in the genes encoding the components of desmosomes and epithelial basement membrane, the stereotyped manifestations of pathological processes in the group of epidermolysis bullosa have been identified. The paper gives a positive result of cell and gene therapies used by European scientists in the treatment of a 7-year-old child with borderline epidermolysis bullosa, which opens up new prospects for patients with butterfly disease that has long been considered fatal.

Birmingham epidermolysis severity score and vitamin D status are associated with low BMD in children with epidermolysis bullosa.

Bone status impairment represents a complication of generalized forms of epidermolysis bullosa (EB); however, the prevalence and the main determinants of this event in localized forms remain poorly defined. Birmingham epidermolysis bullosa severity (BEBS) score and 25-hydroxyvitamin D levels are strongly associated with low bone mass, suggesting that vitamin D may play a potential beneficial role in bone health. Further longitudinal studies are needed in order to confirm this hypothesis. INTRODUCTION: Bone status impairment represents a complication of generalized forms of EB; thus, we aimed to estimate the prevalence of low bone mass, to examine mineralization differences in various EB subtypes and to identify the most important determinants of bone impairment in children with either generalized or localized EB. METHODS: An observational study of 20 children (11 males; mean age ± standard deviation, 11.7 ± 3.9 years) with EB was performed. Clinical history, physical examination, laboratory studies, X-ray of the left hand and wrist for bone age, and dual energy X-ray absorptiometry scans of the lumbar spine were obtained. Areal bone mineral density (aBMD Z-scores) and bone mineral apparent density were related to the BEBS score. RESULTS: Areal BMD Z-score (mean -1.82 ± 2.33, range, -7.6-1.7) was reduced (<-2 SD) in 8 patients (40%), whereas aBMD Z-score adjusted for bone age was low in 7 patients (35%). BEBS score and 25-hydroxyvitamin D serum levels were the most important elements associated with aBMD (P = 0.0001 and P = 0.016, respectively). A significant correlation between the aBMD Z-score and area of skin damage, insulin-like growth factor-1, C-reactive protein, and sodium serum levels was also found. CONCLUSIONS: Low aBMD can be considered a systemic complication of EB, primarily associated with BEBS score and 25-hydroxyvitamin D levels. Therefore, longitudinal evaluation of bone status is ongoing in these patients to define whether vitamin D supplementation would prevent, or at least reduce, bone status impairment.

Dental implants in patients with oral mucosal diseases - a systematic review.

To reveal dental implants survival rates in patients with oral mucosal diseases: oral lichen planus (OLP), Sjögren's syndrome (SjS), epidermolysis bullosa (EB) and systemic sclerosis (SSc). A systematic literature search using PubMed/Medline and Embase databases, utilising MeSH and search term combinations identified publications on clinical use implant-prosthetic rehabilitation in patients with OLP, SjS, EB, SSc reporting on study design, number, gender and age of patients, follow-up period exceeding 12 months, implant survival rate, published in English between 1980 and May 2015. After a mean observation period (mOP) of 53·9 months (standard deviation [SD] ±18·3), 191 implants in 57 patients with OLP showed a survival rate (SR) of 95·3% (SD ±21·2). For 17 patients with SjS (121 implants, mOP 48·6 ± 28·7 months), 28 patients with EB (165 implants, mOP 38·3 ± 16·9 months) and five patients with SSc (38 implants, mOP 38·3 ± 16·9 months), the respective SR was 91·7 ± 5·97% (SjS), 98·5 ± 2·7% (EB) and 97·4 ± 4·8% (SSc). Heterogeneity of data structure and quality of reporting outcomes did not allow for further comparative data analysis. For implant-prosthetic rehabilitation of patients suffering from OLP, SjS, EB and SSc, no evidence-based treatment guidelines are presently available. However, no strict contraindication for the placement of implants seems to be justified in patients with OLP, SjS, EB nor SSc. Implant survival rates are comparable to those of patients without oral mucosal diseases. Treatment guidelines as for dental implantation in patients with healthy oral mucosa should be followed.

Higher Dental Caries Prevalence and Its Association with Dietary Habits and Physical Limitation in Epidermolysis Bullosa Patients: A Case Control Study.

AIM: Epidermolysis bullosa (EB) represents a highly rare subgroup of skin diseases that affects skin and mucous membrane. The aim of the present study was to assess caries prevalence and its associated factors in EB subjects. Salivary status was also assessed. MATERIALS AND METHODS: Ten subjects with EB who were under supervision were selected (cases) and matched by age and gender with unaffected individuals (controls). Dental caries were recorded using the World Health Organization (WHO) criteria. Oral hygiene and dietary habits were investigated by clinical examination and questionnaires. Both nonstimulated and stimulated saliva were collected and salivary pH, buffering capacity and mouth opening were evaluated. RESULTS: The results showed that the median decay-missing-filled teeth was significantly higher (p = 0.0094) in EB cases 5 (3.9-20.3) than in controls 3 (2-3.25). The groups also differed when food consistency was analyzed. Individuals with EB have a higher intake of soft food. In addition, the median mouth-opening values from cases (0.84-2.84 cm) and controls (4.3-4.9 cm) have shown to be statistically different (p = 0.007). Considering the salivary parameters, none of them showed significant differences among groups. CONCLUSION: Epidermolysis bullosa subjects present higher caries scores and might be related to their physical condition and dietary habits. CLINICAL SIGNIFICANCE: There is a lack of information about oral status in EB subjects. Hence, our findings add useful information regarding the relationship between caries prevalence and associated risk factors in EB subjects.

Electrocardiographic Monitoring in Patients with Epidermolysis Bullosa: A New Proposal.

Epidermolysis bullosa causes serious blistering of the skin even with minor trauma. The use of standard electrodes, tapes, and adhesives is restricted in these patients because it exposes the skin to stretching and shearing forces that cause traumatic blister formation. We propose herein an alternative electrocardiographic monitoring technique to minimize cutaneous trauma.

Prevalence and characterization of pruritus in epidermolysis bullosa.

Qualitative data suggest that pruritus is a burdensome symptom in patients with epidermolysis bullosa (EB), but the prevalence of pruritus in children and adults with EB and factors that contribute to pruritus are unknown. The objective of the current study was to quantitatively identify and to characterize pruritus that EB patients experience using a comprehensive online questionnaire. A questionnaire was developed to evaluate pruritus in all ages and all types of EB. Questions that characterize pruritus were included and factors that aggravate symptoms were investigated. Patients from seven North American EB centers were invited to participate. One hundred forty-six of 216 questionnaires were completed (response rate 68%; 73 male, 73 female; median age 20.0 years). Using a 5-point Likert scale (1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = always), itchiness was the most bothersome EB complication (mean 3.3). The average daily frequency of pruritus increased with self-reported EB severity. Pruritus was most frequent at bedtime (mean 3.8) and interfered with sleep. Factors that aggravated pruritus included healing wounds, dry skin, infected wounds, stress, heat, dryness, and humidity. Pruritus is common in individuals with EB and can be bothersome. Future studies will need to investigate the most effective treatments given to individuals with EB for pruritus.

Effectiveness of saltwater baths in the treatment of epidermolysis bullosa.

Current management of epidermolysis bullosa (EB) focuses on preventing secondary infections--a leading cause of mortality--by regularly cleaning and bandaging blisters and erosions and preventive bandaging of high-friction areas. Unfortunately the baths and showers used to remove bandages and clean the skin are often painful, causing lack of adherence and subsequent increases in infections, pain, and antimicrobial use. This study evaluates the hypothesis that bathing individuals with EB in saltwater is less painful than in normal bath water. The study also explores whether taking saltwater baths reduces infections as measured through skin pruritus, odor, discharge, and nonbathing pain. Participants recruited from the Children's Hospital Colorado Outpatient EB Clinic completed standardized questionnaires assessing the effects of the clinic's saltwater bathing recommendations; the data were analyzed using frequencies and Fisher tests. After starting saltwater baths, patients reported a significant reduction in pain (91%), pain medication use (66%), skin odor (31%), and skin discharge (44%). No significant differences were found with respect to the type of EB, age, length of time using baths, or amount of salt added. Saltwater baths are a noninvasive, low-cost, effective treatment that significantly reduces bathing pain, pain medication use, and some signs of skin infection. This treatment can be recommended to patients with all studied EB types without regard to age, the specific amount of salt used, bathing frequency, or pain level. Given the central role bathing and dressing changes play in the management of EB, the use of saltwater baths can lead to significant improvement in quality of life.

Instrument for scoring clinical outcome of research for epidermolysis bullosa: a consensus-generated clinical research tool.

Epidermolysis bullosa (EB) is a genetic condition characterized by skin fragility and blistering. There is no instrument available for clinical outcome research measurements. Our aim was to develop a comprehensive instrument that is easy to use in the context of interventional studies. Item collection was accomplished using a two-step Delphi Internet survey process for practitioners and qualitative content analysis of patient and family interviews. Items were reduced based on frequency and importance using a 4-point Likert scale and were subject to consensus (>80% agreement) using the nominal group technique. Pilot data testing was performed in 21 consecutive patients attending an EB clinic. The final score, Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa (iscorEB), is a combined score that contains clinician items grouped in five domains (skin, mucosa, organ involvement, laboratory abnormalities, and complications and procedures; maximum score 114) and patient-derived items (pain, itch, functional limitations, sleep, mood, and effect on daily and leisurely activities; maximum score 120). Pilot testing revealed that combined (see below) and subscores were able to differentiate between EB subtypes and degrees of clinical severity (EB simplex 21.7 ± 16.5, junctional EB 28.0 ± 20.7, dystrophic EB 57.3 ± 24.6, p = 0.007; mild 17.3 ± 9.6, moderate 41.0 ± 19.4, and severe 64.5 ± 22.6, p < 0.001). There was high correlation between clinician and patient subscores (correlation coefficient = 0.79, p < 0.001). iscorEB seems to be a sensitive tool in differentiating between EB types and across the clinical spectrum of severity. Further validation studies are needed.

Fragility of epidermis and its consequence in dermatology.

The skin is the largest organ of the body, providing a protective barrier against bacteria, chemicals and physical insults while maintaining homeostasis in the internal environment. Such a barrier function the skin ensures protection against excessive water loss. The skin's immune defence consists of several facets, including immediate, non-specific mechanisms (innate immunity) and delayed, stimulus-specific responses (adaptive immunity), which contribute to fending off a wide range of potentially invasive microorganisms. This article is an overview of all known data about 'fragile skin'. Fragile skin is defined as skin with lower resistance to aggressions. Fragile skin can be classified into four categories up to its origin: physiological fragile skin (age, location), pathological fragile skin (acute and chronic), circumstantial fragile skin (due to environmental extrinsic factors or intrinsic factors such as stress) and iatrogenic fragile skin. This article includes the epidemiologic data, pathologic description of fragile skin with pathophysiological bases (mechanical and immunological role of skin barrier) and clinical description of fragile skin in atopic dermatitis, in acne, in rosacea, in psoriasis, in contact dermatitis and other dermatologic pathologies. This article includes also clinical cases and differential diagnosis of fragile skin (reactive skin) in face in adult population. In conclusion, fragile skin is very frequent worldwide and its prevalence varies between 25% and 52% in Caucasian, African and Asian population.

Hand function and quality of life in children with epidermolysis bullosa.

Patient-reported outcomes are becoming increasingly important to clinical care. Epidermolysis bullosa (EB), a rare genetic skin disorder, can result in severe hand impairment, but parent and patient perceptions of hand function have never been assessed. This study aimed to quantify parent- and patient-reported hand function and assess its relationship with quality of life (QOL) in children with EB. This cross-sectional study included children with EB treated at an interdisciplinary EB center. Hospital records were searched for demographic characteristics and medical history. Eligible families were invited to complete two surveys by mail or telephone. The ABILHAND-Kids questionnaire assessed manual hand ability for 21 functions. The Quality of Life in Epidermolysis Bullosa questionnaire assessed EB-related QOL. Hand function and QOL of various subtypes were compared using Mann-Whitney tests. Seventy-one parents and patients ages 2 to 18 years with EB from 20 states in the United States completed questionnaires. Children with recessive dystrophic EB reported the worst hand function and QOL. Bimanual functions involving finger mobility were the most challenging for all EB subtypes. QOL was highly related to the degree of hand function, being correlated with 20 of the 21 individual hand functions and most associated with the ability to perform unimanual functions. Parent- and patient-reported hand function can be measured in children with EB using the ABILHAND-Kids questionnaire. Hand impairment is strongly associated with worse QOL, probably due to difficulty performing daily activities. The effect of interventions such as hand surgery could be prospectively evaluated using this questionnaire.

A direct method to determine the strength of the dermal-epidermal junction in a mouse model for epidermolysis bullosa.

Epidermolysis bullosa (EB) describes a spectrum of rare, incurable, inherited mechanobullous disorders unified by the fact that they are caused by structural defects in the basement membrane zone which disrupt adhesion between the epidermis and dermis. Mouse models provide valuable tools to define the molecular basis of these diseases and to test novel therapeutic approaches. There is need for rapid, quantitative tests that measure the integrity of dermal-epidermal adhesions in such models. To address this need, we describe a novel quantitative method to determine the mechanical strength of the adhesion between tail skin epidermis and dermis. We show that this test reliably measures the force required to cause dermal-epidermal separation in tails of mice that are genetically predisposed to a form of non-Herlitz Junctional EB which develops as the result of a hypomorphic mutation in the laminin gamma 2 gene (Lamc2(jeb) ). This simple, quantitative method of directly measuring the tensile strength of dermal-epidermal adhesion provides a novel dimension to the pathophysiological screening, evaluation, and therapeutic treatment of mice that may develop progressive forms of EB and potentially other disorders that compromise cutaneous integrity.

A consensus approach to wound care in epidermolysis bullosa.

BACKGROUND: Wound care is the cornerstone of treatment for patients with epidermolysis bullosa (EB); however, there are currently no guidelines to help practitioners care for these patients. OBJECTIVES: The objective of this study was to generate a list of recommendations that will enable practitioners to better care for patients with EB. METHODS: An expert panel generated a list of recommendations based on the best evidence available. The recommendations were translated into a survey, and sent to other EB experts to generate consensus using an online-based modified Delphi method. The list was refined and grouped into themes and specific recommendations. RESULTS: There were 15 respondents (45% response rate), with significant experience in the EB field (>10 years [67%]). Respondents included physicians (67%), nurses (17%), and allied health professionals (7%). There was more than 85% agreement for all the proposed items. These were further refined and grouped into 5 main themes (assessment and management of factors that impair healing, patient-centered concerns, local wound care, development of an individualized care plan, and organizational support) and 17 specific recommendations. LIMITATIONS: There is a paucity of scientific evidence with most recommendations based on expert opinion. CONCLUSIONS: These recommendations will provide practitioners with a framework for caring for these patients. Additional scientific research including effectiveness studies for everyday practice and expert consensus, may further refine these recommendations.

Improvement of renal function in epidermolysis bullosa patients after gluten free diet: two cases.

Epidermolysis bullosa (EB) is a rare inherited genetic disease characterized by an abnormal response of the skin and mucosa to mechanical trauma. Dystrophic EB (DEB) is very often associated with many extra cutaneous complications. Those complications involve either epithelial associated tissues or other organs. In particular, several renal complications have been described for DEB in the recessive form, such as amyloidosis, post-infection glomerulonephritis, upper and lower urinary tract obstruction and IgA-Nephropathy (IgAN). In the cases reported below we have two patients diagnosed with DEB that showed compromised renal function and proteinuria. The switch of the normal diet toward a gluten free diet resulted beneficial for both patients, since renal function was rescued and proteinuria cured. Moreover, a general health status improvement was recognised, given that nutritional condition was ameliorated and bone growing enhanced. Furthermore, in both patients the presence of autoantibodies anti-COL7 indicating an autoimmune form of the disease. Therefore, patients received low doses of betametasone useful to reduce inflammatory state and to control immune system function. In conclusion, our results prompt us to hypothesized that in these patients, due to the fragility of the intestinal mucosa, the absence in the diet of gluten may be beneficial.