Serum autoantibody reactivity in bullous pemphigoid is associated with neuropsychiatric disorders and the use of antidiabetics and antipsychotics: a large, prospective cohort study.

BACKGROUND: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed. OBJECTIVE: To determine associations of autoantibody reactivities with comorbidities and concomitant medication. METHODS: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed. RESULTS: An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine. CONCLUSION: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.

International validation of the Bullous Pemphigoid Disease Area Index severity score and calculation of cut-off values for defining mild, moderate and severe types of bullous pemphigoid.

BACKGROUND: The Bullous Pemphigoid Disease Area Index (BPDAI) score has been proposed to provide an objective measure of bullous pemphigoid (BP) activity. OBJECTIVES: The objective of this study was to calculate BPDAI cut-off values defining mild, moderate and severe BP. We also aimed to assess the interrater reliability and correlation with the number of daily new blisters, and anti-BP180 and anti-BP230 antibodies. METHODS: Severity scores were recorded by two blinded investigators. Anti-BP180 and anti-BP230 antibodies were measured using an enzyme-linked immunosorbent assay (ELISA). Cut-off values defining mild, moderate and severe subgroups were calculated based on the 25th and 75th percentiles of the BPDAI score. RESULTS: In total, 285 patients with BP were enrolled from 50 dermatology departments in Europe. Median BPDAI activity was 37·5 points (range 0-164). Cut-off values corresponding to the first and third quartiles of the BPDAI score were 20 and 57, respectively; thus, these values were used to define mild (≤ 19), moderate (≥ 20 and ≤ 56) and severe (≥ 57) BP. The median BPDAI score for patients with ≤ 10 daily new blisters was 26 [interquartile range (IQR) 17-45], and for patients with > 10 daily new blisters the median score was 55 (IQR 39-82). The BPDAI intraclass correlation coefficient measured at baseline was 0·97 and remained higher than 0·90 up to month 6. The improvement in the BPDAI score was correlated with the absolute decrease in anti-BP180 ELISA value (Spearman's rank r = 0·34, P < 0·004), but not with anti-BP230 antibodies (r = 0·17, P = 0·15). CONCLUSIONS: This study suggests cut-off values of 20-57 for BPDAI to distinguish mild, moderate and severe BP, and confirms that it is a robust tool to assess BP severity precisely.

Natural history of growth and anaemia in children with epidermolysis bullosa: a retrospective cohort study.

BACKGROUND: Impaired growth and anaemia are major extracutaneous complications of epidermolysis bullosa (EB), but data on their development are lacking. OBJECTIVES: To determine the clinical course of growth and anaemia in children with EB and clarify the impact of nutritional compromise, inflammation and genetic factors. METHODS: A retrospective study was conducted of 200 children, 157 with recessive dystrophic EB (RDEB) and 43 with junctional EB (JEB)-generalized intermediate, followed at the main referral centre in Germany. Growth charts were calculated using the modified LMS method and were correlated with parameters of anaemia, nutrition, inflammation and the molecular defect in a linear model. RESULTS: In our cohort of patients with RDEB, weight impairment started at 12-18 months old; by the age of 10 years, 50% showed wasting. The predicted median weight at age 20 years was 35·2 kg for men and 40·1 kg for women. In JEB, growth resembled that of healthy children. Anaemia was present from the second year of life onwards in RDEB and JEB. Low levels of haemoglobin, iron, vitamin D, zinc and albumin, high levels of C-reactive protein, and absence of collagen VII correlated significantly with low weight in RDEB. No correlation was observed in JEB. CONCLUSIONS: The results highlight that nutritional compromise occurs early in children with RDEB and therefore may require interventions as of the first year or two of life. What's already known about this topic? Children with epidermolysis bullosa (EB) suffer from failure to thrive and anaemia as major extracutaneous complications. The course of growth and the development of anaemia in EB are poorly characterized. What does this study add? A molecularly well characterized cohort of 200 children with EB was followed with regard to anthropometrics, anaemia and inflammation. We demonstrate early onset of growth failure and anaemia, most pronounced in the subset of recessive dystrophic EB. Awareness of early growth delay and nutritional deficiencies will improve EB care in daily practice.

Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies.

Monoallelic desmoglein 1 mutations have been known for many years to cause striate palmoplantar keratoderma, but only recently, biallelic loss-of-function mutations were associated with a new disorder, designated as SAM syndrome (comprising severe dermatitis, multiple allergies and metabolic wasting) in two consanguineous families. We report on a new case from a third independent family with the homozygous nonsense mutation, c.2659C>T, p.R887* in exon 15 of DSG1 (desmoglein 1 gene). This mutation led to mRNA decay and loss of expression of desmoglein 1. The clinical phenotype consisted of severe palmoplantar keratoderma, dermatitis and multiple allergies. In contrast to the previous cases, malabsorption, hypoalbuminaemia, developmental delay, hypotrichosis or severe recurrent infections were not observed.

[The many facets of inherited skin fragility]. / Multiple Facetten der genetisch bedingten Hautfragilität.

The inherited skin fragility encompasses a heterogeneous group of disorders, collectively designated as epidermolysis bullosa, characterized by recurrent mechanically induced blisters, erosions or wounds. The spectrum of clinical manifestations is broad, as well as the molecular background. Besides the skin, mucosal membranes and other organs can be affected. In real-world practice, patients with mild genetic skin fragility usually do not require medical care and often remain underdiagnosed. In contrast, the well-defined severe EB subtypes are recognized based on typical clinical features. The molecular diagnostics is usually performed in order to allow genetic counselling and prenatal diagnosis. Besides wound care and careful management of the disease complications, new experimental targeted therapies are being developed. New very rare forms of inherited skin fragility have been identified with modern sequencing methods.

Phenotypic spectrum of epidermolysis bullosa associated with α6ß4 integrin mutations.

BACKGROUND: Integrin α6ß4 is a transmembrane receptor and a key component of the hemidesmosome anchoring complex. It is involved in cell-matrix adhesion and signalling in various tissues. Mutations in the ITGA6 and ITGB4 genes coding for α6ß4 integrin compromise dermal-epidermal adhesion and are associated with skin blistering and pyloric atresia (PA), a disorder known as epidermolysis bullosa with PA (EB-PA). OBJECTIVES: To elucidate the molecular pathology of skin fragility in eight cases, disclose the underlying ITGA6 and ITGB4 mutations and study genotype-phenotype correlations. METHODS: DNA was isolated from ethylenediaminetetraacetic acid-blood samples, and the coding exons and exon-intron boundaries of ITGA6 and ITGB4 were amplified by polymerase chain reaction (PCR), and directly sequenced. Skin samples were submitted to immunofluorescence mapping with antibodies to adhesion proteins of the dermal-epidermal junction. Primary keratinocytes were isolated, and used for RNA and protein extraction, reverse transcription PCR and immunoblotting. Ultrastructural analysis of the skin was performed in one patient. RESULTS: We disclose 10 novel mutations, one in ITGA6 and nine in ITGB4. Skin cleavage was either intraepidermal or junctional. Lethal outcome and PA correlated with loss-of-function mutations in two cases. Solely mild skin involvement was associated with deletion of the C-terminus of ß4 integrin. Combinations of missense, nonsense or frameshift mutations caused severe urinary tract involvement in addition to skin fragility in five cases. CONCLUSIONS: The present study reveals novel ITGA6 and ITGB4 gene mutations and supports previous reports showing that the phenotype may lack PA and be limited to skin and nail involvement. In four out of six cases of EB-PA, life expectancy was not impaired. A high frequency of urinary tract involvement was found in this study, and represented the main cause of morbidity. Low levels of ß4 integrin expression were compatible with hemidesmosomal integrity and a mild skin phenotype.

Molecular therapies for epidermolysis bullosa.

Inherited epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of disorders manifesting with blisters and erosions of skin and mucous membranes in response to minor mechanical trauma. More than 1500 mutations in 17 different genes underlie more than 30 different EB subtypes. To date, the treatment is symptomatic aiming mainly to support wound healing and solve complications, and patients with severe subtypes, with chronic, life-long skin fragility have high, unmet medical needs. During the last years, many experimental therapeutic studies for EB have been initiated in cell culture systems, animal models or pilot clinical trials, making use of gene correction, RNA reprogramming, protein replacement or therapeutic stem cells. Although gene therapy was the first to be applied in patients, the focus now moved towards protein and cell-based therapies. However, the approach is extremely complex; not only in technical terms, but also in the way the chronic disease, its progression and its complications can be amended in the long term. Therapeutic efficacy, as well as unexpected outcomes must be carefully monitored.

Forty-two novel COL7A1 mutations and the role of a frequent single nucleotide polymorphism in the MMP1 promoter in modulation of disease severity in a large European dystrophic epidermolysis bullosa cohort.

BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a severe genetic skin blistering disorder caused by mutations in the gene COL7A1, encoding collagen VII. Recently, the MMP1 promoter single nucleotide polymorphism (SNP) rs1799750, designated as 1G 2G, was shown to be involved in modulation of disease severity in patients with recessive DEB (RDEB), and was proposed as a genetic modifier. OBJECTIVES: To identify the molecular basis of DEB in 103 individuals and to replicate the results of the MMP1 promoter SNP analysis in an independent patient group, as verification is necessary in such a rare and heterogeneous disorder. METHODS: To determine the molecular basis of the disease, we performed COL7A1 mutation screening, reverse transcription-polymerase chain reaction (PCR) and real-time quantitative PCR. The status of the MMP1 SNP was analysed by PCR and restriction enzyme digestion and verified by sequencing. RESULTS: We disclosed 42 novel COL7A1 mutations, including the first large genomic deletion of 4 kb affecting only the COL7A1 gene, and three apparently silent mutations affecting splicing. Even though the frequency of the high-risk allele was increased in patients with RDEB, no statistically significant correlation between disease severity and genotype could be made. Also, no correlation was observed with development of squamous cell carcinoma, a severe complication of DEB. CONCLUSIONS: Taken together, the results suggest that the MMP1 SNP is not the sole disease modifier in different forms of DEB, and other genetic and environmental factors contribute to the clinical phenotype.