Cow’s milk protein allergy as a model of food allergy in children with inherited epidermolysis bullosa

Squamous cell carcinoma and junctional epidermolysis bullosa

Background: Inherited epidermolysis bullosa (EB) refers to a group of rare inherited disorders characterized by severe damage of skin and in most patients — the gastrointestinal mucosa, what leads to a violation of skin and mucosal barrier properties in relation to allergens. However, the issues of food sensitization and food allergy in this category of patients have not been studied, and the study of this problem is important.Aim: To evaluate the clinical manifestations of food allergy (FA) and IgE-response to food proteins in children with EB.Methods: 82 patients with EB aged from 2 months to 16 years were entered this open non-randomized observational prospective study, including 20 patients with simple form of EB and 62 patients with dystrophic form of EB. We analyzed allergic history and clinical manifestations of the FA in all the patients. Every patient in this study underwent of determination of the concentration of total serum IgE and specific serum IgE to the most important food allergens, as well as to mixtures of household allergens in some cases (UniCAP System, Phadia AB). Results: Skin lesion in patients with EB masks allergic skin manifestations, causing a hypodiagnosis of the FA in this category of patients, which in turn leads to erroneous organization of nutritional support. FA (clinical manifestations) was identified in 20.7% of children with EB (in 10% of cases with simple form of EB and in 24.2% — in patients with dystrophic form of EB). Products containing cow’s milk protein, cereals, and eggs were identified as etiologic factors of FA in most cases. In the group of children with comorbidity FA and EB high and very high levels of total IgE (1000 kUA / l) were detected most frequently. The main cause-significant allergens are cow’s milk proteins, cereals, eggs. Conclusions: Comorbidity with FA is high in patients with dystrophic form of EB. The main cause-significant allergens are cow’s milk proteins, cereals, eggs.

BACKGROUND: Inherited epidermolysis bullosa is a severe orphan hereditary disease with a predominant lesion of the skin and mucous membranes. The study of the comorbid background, including food allergies, remains an urgent issue, given the difficulties that often arise in the treatment and formation of the diet in this category of patients.
 AIM: to assess the frequency and nature of food allergies in children with inherited epidermolysis bullosa.
 MATERIALS AND METHODS: An open single-center randomized observational retrospective and prospective study included 165 patients aged 2 months to 17 years with an inherited epidermolysis bullosa. All patients were evaluated for an allergic history, determination of the levels of total IgE and allergen-specific serum IgE to the most significant food allergens (UniCAP System, Thermo Fisher Scientific), if necessary, a diagnostic elimination diet and diagnostic product administration were prescribed, based on the data obtained, the diagnosis of food allergy was confirmed or excluded.
 RESULTS: Among children suffering from inherited epidermolysis bullosa, confirmed food allergy was 13.9% of cases (in 13.4% in the group of children with dystrophic form of the disease, 15.2% in the group of children with a simple form of the disease). The main manifestations of food allergy in this cohort of patients were skin symptoms. Cows milk proteins were the most frequent etiological factor of food allergy (78.3%). Most children with food allergies had a high level of total IgE (87.5%). In children with non-IgE mediated form, high levels of total IgE were detected in 25% of cases, while these children were characterized by a severe course of the underlying disease or the presence of concomitant atopic dermatitis. Burdened heredity for allergic diseases turned out to be more typical for children with an IgE-mediated form of food allergy from the group of simple epidermolysis bullosa.
 CONCLUSION: Early detection of food allergies in children with inherited epidermolysis bullosa, as an aggravating factor in the course of the underlying disease, is necessary to optimize the tactics of dietary support for patients with inherited epidermolysis bullosa.

Background: inherited epidermolysis bullosa is a group of genetic skin disorders caused by mutations in genes encoding structural proteins of epidermis and dermo-epidermal junction. Clinical manifestations are characterized by spontaneous or trauma-induced skin and/or mucosal blistering, and extensive wounds. Cell therapy is considered to be a perspective therapeutic approach in improving wound healing process.
 Aims: to assess safety and efficacy of human skin equivalent in the treatment of inherited epidermolysis bullosa patients
 Materials and methods: 7 patients (5 female and 2 male subjects from the age of 20 to 55) with inherited epidermolysis bullosa with different clinical subtypes were enrolled in the study: 3 patients with intermediate recessive dystrophic epidermolysis bullosa, 2 patients with severe recessive dystrophic epidermolysis bullosa, 1 patient with dominant dystrophic epidermolysis bullosa and 1 patient with junctional epidermolysis bullosa. Transplantation of composite allogeneic living skin equivalent comprising allogeneic keratinocytes and fibroblasts in low concentration (5 mg/ml) embedded within a type I collagen gel matrix was performed. The living skin equivalent was developed at N.K. Koltsov Institute of Developmental Biology. 19 erosions and ulcers with a surface area between 0,4 cm2 and 120 cm2 were evaluated. At day 14 clinical assessment was performed. To assess level of expression immunofluorescence antigen mapping was used.
 Results: at day 14 complete erosion closure was achieved in 10 (53%) erosions. 4 (21%) erosions reduced in size 75%. Size reduction between 25% and 75% was shown in a single (5%) case. No clinical efficacy was demonstrated in 4 (21%) cases. Collagen VII expression increased comparing to baseline level and accompanied clinical improvement.
 Conclusions: the obtained data showed clinical efficacy of topical treatment with living skin equivalent, although no statistically significant difference was seen between living skin equivalent and atraumatic non-adhesive dressings.
 Keywords: inherited epidermolysis bullosa, junctional epidermolysis bullosa, recessive dystrophic epidermolysis bullosa, erosions, healing, topical treatment.

BackgroundInherited epidermolysis bullosa (EB) is a group of skin diseases characterized by blistering of the skin and mucous membranes.There are four major types of EB (EB simplex, junctional EB, dystrophic EB and Kindler syndrome) caused by different gene mutations. Dystrophic EB is derived from mutations in the type VII collagen gene (COL7A1), encoding a protein which is the predominant component of the anchoring fibrils at the dermal-epidermal junction.For the first time in literature, we have evaluated the presence of anti-skin autoantibodies in a wider cohort of patients suffering from inherited EB and ascertained whether they may be a marker of disease activity.MethodsSera from patients with inherited EB, 17 with recessive dystrophic EB (RDEB), 10 with EB simplex (EBS) were analysed. As much as 20 patients with pemphigus vulgaris, 21 patients with bullous pemphigoid and 20 healthy subjects were used as controls.Anti-skin autoantibodies were tested in all samples with the Indirect Immunofluorescence (IIF) method and the currently available ELISA method in order to detect anti-type VII collagen, anti-BP180 and anti-BP230 autoantibodies.ResultsThe mean concentrations of anti-type VII collagen autoantibodies titres, anti-BP180 and anti-BP230 autoantibodies were statistically higher in RDEB patients than in EBS patients.The sensitivity and specificity of the anti-type VII collagen ELISA test were 88.2% and 96.7%. The Birmingham Epidermolysis Bullosa Severity score, which is used to evaluate the severity of the disease, correlated with anti-skin autoantibodies titres.ConclusionsThe precise pathogenic role of circulating anti-skin autoantibodies in RDEB is unclear. There is a higher prevalence of both anti-type VII collagen and other autoantibodies in patients with RDEB, but their presence can be interpreted as an epiphenomenon.

Inherited epidermolysis bullosa is a group of genetic diseases characterized by skin fragility and blistering on the skin and mucous membranes in response to minimal trauma. Epidermolysis bullosa is clinically and genetically very heterogeneous, being classified into four main types according to the layer of skin in which blistering occurs: epidermolysis bullosa simplex (intraepidermal), junctional epidermolysis bullosa (within the lamina lucida of the basement membrane), dystrophic epidermolysis bullosa (below the basement membrane), and Kindler epidermolysis bullosa (mixed skin cleavage pattern). Furthermore, epidermolysis bullosa is stratified into several subtypes, which consider the clinical characteristics, the distribution of the blisters, and the severity of cutaneous and extracutaneous signs. Pathogenic variants in at least 16 genes that encode proteins essential for the integrity and adhesion of skin layers have already been associated with different subtypes of epidermolysis bullosa. The marked heterogeneity of the disease, which includes phenotypes with a broad spectrum of severity and many causal genes, hinders its classification and diagnosis. For this reason, dermatologists and geneticists regularly review and update the classification criteria. This review aimed to update the state of the art on inherited epidermolysis bullosa, with a special focus on the associated clinical and genetic aspects, presenting data from the most recent reclassification consensus, published in 2020.

Cause-Specific Risks of Childhood Death in Inherited Epidermolysis Bullosa

Congenital epidermolysis bullosa refers to orphan (rare – no more than 10 cases per 100,000 population) diseases. In the Russian Federation, its prevalence rate in 2016 was 3,9 per 1 million population. The objective was to study the clinical and genetic characteristics, prevalence, and family history of сongenital epidermolysis bullosa patients in the Republic of Dagestan. The clinical picture, features of the course and family history of 127 patients with the diagnosis of сongenital epidermolysis bullosa living in the Republic of Dagestan were studied, and the type and subtype of the disease were verified. In 12 patients, the genetic nature of сongenital epidermolysis bullosa was confirmed by full-exomal DNA sequencing. According to the severity of сongenital epidermolysis bullosa, patients were divided into four groups. Most of them were in the group with mild to moderate severity: Weber – Cockayne сongenital epidermolysis bullosa – 53 (41,73 ± 4,38%, n = 127) and Dowling – Mear herpetiform – 11 (8,66 ± 2,5%, n = 127), dominant dystrophic congenital epidermolysis bullosa – 3 (2,36 ± 1,35%, n = 127) and recessive generalized non – mutating dystrophic congenital epidermolysis bullosa – 1 (0,79 ± 0,79%, n = 127), borderline dystrophic congenital epidermolysis bullosa – 8 (6,3 ± 2,16%, n = 127), and Kindler syndrome – 1 (0,79 ± 0,79%, n = 127). Patients with generalized recessive dystrophic congenital epidermolysis bullosa were included in the group with severe or very severe course-7 (5,51 ± 2,07%, n = 127) and 21 (16,54 ± 3,32%, n = 127), respectively. More than half of the cases of congenital epidermolysis bullosa in the Republic of Dagestan (63,78 ± 4,26%) were children, up to 6,3 ± 2,16% were aged from 56 to 63 years, which required a differentiated approach in their management. The majority of patients with recessive dystrophic congenital epidermolysis bullosa and borderline dystrophic congenital epidermolysis bullosa had closely related parental marriages, which was most typical for 12 districts of the Republic.

Epidermolysis bullosa (EB) is a rare disorder characterized by inherited skin adhesion defects with abnormal disruption of the epidermal–dermal junction in response to mechanical trauma. Our aim was to investigate a set of cytokine levels in serum samples from patients suffering from epidermolysis bullosa simplex (EBS), dystrophic epidermolysis bullosa (DEB), and healthy controls (HCs), exploring their potential correlations with antiskin autoantibody titers and disease activity. Forty patients afferent to the Dermatological Ward of Bari City Hospital and 9 HCs were enrolled and subdivided according to the dystrophic (DEB) and simplex forms (EBS). We found a significant increase in interleukin (IL)-1β plasmatic levels of DEB (P = 0.0224) and EBS (P = 0.0465) patients compared to HCs; IL-6 levels were significantly higher in DEB than in EBS patients (P = 0.0004) or HCs (P = 0.0474); IL-2 levels were significantly increased in DEB compared with EBS (P = 0.0428). Plasmatic tumor necrosis factor-β and interferon-γ were higher in DEB patients than in HCs (P = 0.0448 and 0.0229). Conversely, tumor necrosis factor-α was significantly decreased in DEB (P = 0.0034). IL-5 correlated with anti-BP180 (r = −0.5018, P = 0.0338), anti-BP230 (r = −0.6097, P = 0.0122), and anticollagen VII (r = −0.5166, P = 0.0405) autoantibodies; interferon-γ correlated with anti-BP180 (r = 0.9633, P < 0.0001), anti-BP230 (r = 0.9071, P < 0.0001), and anticollagen VII (r = 0.8619, P = 0.0045) autoantibodies. Score of disease severity was significantly correlated with IL-6 (r = 0.6941, P = 0.029) and IL-12 (r = 0.5503, P = 0.0272). The present study supports that EB might be considered a systemic inflammatory disease rather than a skin-limited disorder; clinical disease activity scores could be also integrated by laboratory data such as IL-6 and IL-12 dosage; biotherapies targeting specific cytokine networks probably represent a way to go in the future.

Inherited epidermolysis bullosa (EB) is a group of genodermatoses with considerable clinical and genetic heterogeneity. Clinical diagnosis of the EB subtypes is frequently imprecise and requires confirmation with genetic testing. There is still limited study using genetic testing to identify EB subtypes in Indonesia. This study aims to identify the pathogenic variants of inherited EB patients at the Department of Dermatology and Venereology, Universitas Padjadjaran-Dr Hasan Sadikin General Hospital in Bandung, West Java, Indonesia and to describe the correlation between the phenotype and genotype of our patients. Twelve patients clinically diagnosed with EB were included in this study. Genetic testing was performed in collaboration with KK Women's and Children's Hospital, Singapore. Pathogenic variants were identified in the COL7A1 gene in seven patients, namely Dominant Dystrophic EB (DDEB) with mutation types c.5945G>T, c.6218G>A, Recessive Dystrophic EB (RDEB) c.2005C>T, c.6081dup, c.1268C>T, c.1784C>T which are all known mutations. Novel mutations were found in the COL7A1 gene in two patients namely DDEB c.6253G>T and RDEB c.6740C>T. Two EB Simplex (EBS) patients showed mutation KRT14 gene as c.356T>C, c.373C>T which are known mutation. In addition, a novel mutation in LAMA3 gene c.2649del was found in one Junctional EB (JEB) patient. The molecular diagnoses of 12 Indonesian EB patients were identified, of which three were novel pathogenic variants. Concordance between the initial clinical diagnosis and genetic testing was only 33%. This demonstrated the importance of early genetic testing for accurate diagnosis, prognostication, management and genetic counselling.

BackgroundInherited epidermolysis bullosa (EB) comprises a highly heterogeneous group of rare diseases characterized by exacerbated skin and/or mucosal fragility and blister formation after minor mechanical trauma. Level of cleavage in the skin, clinical features with immunofluorescence antigen mapping and/or electron microscopy examination of a skin biopsy and/or gene involved, type(s) of mutation present and sometimes specific mutation(s), allow to define the EB type and subtype. This family of genodermatoses exposes patients to several complications, cutaneous squamous cell carcinoma (cSCC) being the most severe of them.ObjectiveThe aim of this systematic review was to document patients with EB who developed cSCC.MethodsA systematic literature search was performed, from inception to March 2014, using Medline, Embase, Cochrane and ClinicalTrials.gov databases. Only articles published in English and French were selected. The diagnosis of EB had to be confirmed by EM and/or IFM and/or mutation analysis, while cSCC had to be confirmed by histological analysis.ResultsOf 167 references in the original search, 69 relevant articles were identified, representing 117 cases. cSCCs were identified in all types of EB, though predominantly in recessive dystrophic EB (RDEB) forms (81 cases (69.2 %)). The median age at diagnosis was 36 years old (interquartile range (IQR), 27-48 years and range, 6-71 years) for all forms. Of those with measurements in the literature (88 cases (75.2 %)), tumor size was greater than 2 centimeters in 52 cases (59.1 %). The histopathological characteristics were specified in 88 cases (75.2 %) and well-differentiated forms predominated (73.9 %). No conclusion could be drawn on the choice of surgical treatment or the management in advanced forms.LimitationsThis study was retrospective and statistical analysis was not included due to various biases. This study design did not allow to infer prevalence, nor EB subtype risk for cSCC occurrence.ConclusionsOur study correlated with historical data shows that most of the cSCCs occurred in subjects with the RDEB subtype, however reports also show that cSCCs can present in any patients with EB. The first signs of cSCC developed at a younger age in EB patients than in non-EB patients. Interestingly, the cSCC duration, before its diagnosis, was shorter in individuals with RDEB than with junctional EB (JEB) and dominant dystrophic EB (DDEB).This study further emphasizes the importance of regular monitoring of EB patients, particularly with the RDEB subtype as they developed cSCC at a younger age.

Eye involvement in inherited epidermolysis bullosa: Experience of the National Epidermolysis Bullosa Registry

Dear Editors, Inherited epidermolysis bullosa (EB) is a group of genodermatoses characterized by skin blistering, caused by mutations in different genes encoding proteins of the dermo-epidermal junction zone.1, 2 Disease severity ranges from localized subtypes with blisters restricted to acral regions, to severe subtypes with generalized blistering and subsequent scarring or atrophy of the skin. Patients with dystrophic EB pruriginosa (DEBp) suffer from highly pruritic papules and nodules, either localized on the lower legs, or disseminated, clinically resembling prurigo or lichenoid skin disorders.1 Pruritus appears to be a major issue for patients with EB and not only for those suffering from DEBp.3, 4 Specifically, more than 90% of individuals with dystrophic EB (DEB) and junctional EB (JEB), and around 70% of patients with EB simplex reported distressing pruritus with overall itch scores comparable with those of atopic dermatitis.4 The problems caused by itch are sleep disturbance and newly induced blisters due to scratching.4 An immune dysregulation is suggested by the presence of increased cytokines and IgE levels in these individuals.5 A recent publication highlighted a skewed Th2 immunological phenotype in DEBp.6 Subsequent reports described reduction of itch upon treatment with dupilumab, a monoclonal antibody blocking the interleukin 4 (IL4) receptor, in at least 13 cases of DEBp (Table 1).7-10 Dupilumab has been approved for treatment of atopic dermatitis and prurigo nodularis, and efficient off-label use of dupilumab has been described for several other dermatological indications.11 It appears to be highly efficient in treating pruritus of various etiologies, even without history of atopy.11, 12 Here we report on the outcomes of dupilumab treatment in a cohort of 13 patients (6 female, 7 men; mean age 29 years, min 6, max 78 years) with different EB subtypes, all suffering from severe pruritus. The EB subtypes were as follows: one case had EB simplex with plectin deficiency, two had intermediate JEB with laminin 332 deficiency, four had recessive DEB and six had dominant DEB. All patients had itch scores of above 7 (median 8; visual analogue score from 1–10). Itch, which caused new blisters due to scratching, was their most burdensome symptom. IgE levels were increased only in four of eight patients for whom this information was available (median 59 U/ml). Most patients had received different antipruritic treatments such as topical steroids of class II–IV, calcineurin inhibitors and/or antihistamines, or methotrexate combined with several rounds of UV treatments (patient 12), without any significant improvement (Table 1). We employed dupilumab with a loading dosage of 600 mg s.c., followed by 300 mg every 2 weeks. Eleven patients showed a rapid improvement of itch with subsequent amelioration of the underlying EB (Figure 1 and Table 1). The median itch VAS level after treatment decreased to 3. For example, patient 6 showed a significant reduction, both of itch, from VAS 10 before to 2 after dupilumab, and skin blistering. An increase of the intervals between injections to 4 weeks led to a worsening of his skin condition and the necessity of resuming treatment every 2 weeks. Although patient 1 experienced an initial improvement of the symptoms, the skin blistering worsened after the second dupilumab injection and the treatment was discontinued. Patient 13 had an episode of generalized pustular extremely itchy skin eruptions accompanied by fatigue after the second injection of dupilumab and treatment was discontinued. She refused a diagnostic skin biopsy. These lesions responded to systemic prednisolone, combined with topical treatment with class IV steroids. In our cohort, 11 of 13 patients perceived a benefit from treatment with dupilumab, irrespective of their EB subtype or age, suggesting that a broader spectrum of EB patients may benefit from this drug. Dupilumab was tolerated well by most, but not all, patients, while unspecific skin reactions occurred in two patients, leading to treatment discontinuation. Patients who tolerated dupilumab well experienced a significant improvement in skin condition, and they reported better sleep and improved quality of life. None of the patients showed signs of conjunctivitis. Our report shows that targeting Th2 inflammation with dupilumab is a valuable symptom-relief therapy for patients with all types of EB who suffer from severe, intractable pruritus. We thank the patients and their families. We also thank our fellow colleagues from the Department of Dermatology in Freiburg, who also took care of the patients presented here. Open access funding enabled and organized by Projekt DEAL. Nine.

Introduction. Inherited epidermolysis bullosa belongs to the group of severe rare hereditary mechanobullous diseases. Often, the skin pathological process is difficult to treat, which leads to a decrease in the quality of life of such patients. The mechanism of development of transcutaneous sensitization in this category of patients is not excluded. This issue remains a very relevant area for study, given the characteristic nutritional deficiency and the difficulties that arise in the formation of the diet.The aim: to assess the frequency of occurrence and characteristics of food sensitization in children with epidermolysis bullosa.Materials and methods: the group included 164 children with epidermolysis bullosa (45 with rapid detection and 119 with dystrophic). For all patients, an assessment of the risk of an allergic history, determination of the total level of IgE and specific IgE of blood serum to the most significant food allergens (UniCAP system, Thermo Fisher Scientific). Results: food sensitization was detected in 34.1 % of children with epidermolysis bullosa (in 38.7 % of cases with dystrophic and in 24.4 % with a simple form of epidermolysis bullosa). Among the manifestations of food allergy in both groups, skin symptoms were more common. The most common etiological factors were products containing cow’s milk protein, eggs, and cereals. In the group of children with comorbid food allergies and epidermolysis bullosa, high and extremely high levels of total IgE were most common.Conclusion: a high frequency of food sensitization in patients with epidermolysis bullosa, was shown, which is important not only from a scientific, but also from a practical point of view. Given the nutritional deficiency characteristic of this disease, the complexity of nutritional support, the presence of comorbid food allergies should be taken into account when recommending nutrition and selecting therapeutic products for this category of patients.

GENITOURINARY COMPLICATIONS OF INHERITED EPIDERMOLYSIS BULLOSA: EXPERIENCE OF THE NATIONAL EPIDERMYLOSIS BULLOSA REGISTRY AND REVIEW OF THE LITERATURE