Gabriela Petrof

Fibroblast cell therapy enhances initial healing in recessive dystrophic epidermolysis bullosa wounds: results of a randomized, vehicle-controlled trial.

Fibroblast cell therapy can modify disease biology in recessive dystrophic epidermolysis bullosa (RDEB) although whether it improves wound healing is not clear.

Desmosomal genodermatoses: Desmosomal genodermatoses

Desmosomes are intercellular junctions that contribute to cell–cell adhesion, signalling, development and differentiation in various tissues, including the skin. Composed of a network of transmembranous and intracellular plaque proteins, pathogenic autosomal dominant or recessive mutations have been reported in 10 different desmosomal genes, resulting in a spectrum of phenotypes variably affecting skin, hair and heart. This review summarizes the molecular pathology and phenotypes that predominantly affect the skin/hair. Recent desmosomal genodermatoses described include lethal congenital epidermolysis bullosa (plakoglobin), cardiomyopathy with alopecia and palmoplantar keratoderma (plakoglobin), hypotrichosis with scalp vesicles (desmocollin 3), and generalized peeling skin disease (corneodesmosin). Understanding the range of clinical phenotypes in combination with knowledge of the inherent desmosome gene mutation(s) is helpful in managing and counselling patients, as well as providing insight into the biological function of specific components of desmosomes in skin and other tissues.

Potential of Systemic Allogeneic Mesenchymal Stromal Cell Therapy for Children with Recessive Dystrophic Epidermolysis Bullosa

TO THE EDITOR The skin fragility disorder, recessive dystrophic epidermolysis bullosa (RDEB) results from mutations in COL7A1, leading to reduced or absent type VII collagen (C7) and defective anchoring fibrils at the dermal–epidermal junction (Fine et al., 2014). Currently, there is no cure, and most individuals develop lifeshortening squamous cell carcinomas (Fine and Mellerio, 2009). RDEB also has a major health economic burden; wound dressings for a 10-year-old child can cost

A systematic review of the literature on the treatment of pityriasis rubra pilaris type 1 with TNF-antagonists

680 per day (Kirkorian et al., 2014), which equates to 4

Epithelial Inflammation Resulting from an Inherited Loss-of-Function Mutation in EGFR

250,000 annually. Reported clinical trials of cell-based therapies for RDEB comprise intradermal allogeneic fibroblasts (Petrof et al., 2013; Venugopal et al., 2013), bone marrow transplantation (Wagner et al., 2010), intradermal bone marrow– derived mesenchymal stromal cells (BM-MSCs) (Conget et al., 2010), and intravenous BM-MSCs in RDEB adults (El-Darouti et al., 2013; abstract only). Ex vivo COL7A1 keratinocyte gene therapy is also being evaluated (Siprashvili et al., 2014). MSCs are heterogeneous cells that undergo self-renewal or differentiate into mesenchymal lineages (Caplan, 1991). MSCs also have non-progenitor functions in immune regulation, cell growth, and tissue repair (Phinney and Prockop, 2007; Chen et al., 2008). Nevertheless, healing is not associated with large numbers of therapeutic MSCs in injured tissues, suggesting that paracrine benefits may modulate inflammatory and immune responses (Baraniak and McDevitt, 2010). Our interest focuses on the potential of intravenous allogeneic BM-MSCs to help people living with RDEB. Ten children were included in the clinical trial and are detailed in Supplementary Table S1 online, with the trial protocol shown in Supplementary Figure S1 online. The trial was approved by the UK Medicines and Healthcare Products Regulatory Agency, with EudraCT number: 2012-001394-87; the UK National Research Ethics Committee London-Bloomsbury provided ethics approval (Ref:12/LO/1258), and the trial was registered prospectively with www. controlled-trials.com ISRCTN46615946. Written informed consent was obtained for each subject. Inclusion/exclusion criteria are presented in Supplementary Table S2 online, and study interventions are listed in Supplementary Table S3 online. Details of the BM-MSCs are provided in Supplementary Table S4 online. Each participant received three intravenous infusions of BM-MSCs (day 0, 7, and 28; each dose 1–3×10 cells kg) with no HLA matching or pre-conditioning. With regard to safety, there were 163 adverse events (AEs; Supplementary Tables S5–S7 online). Initially, two serious AEs, esophageal dilatation and skin infection, were reported but were subsequently downgraded (protocol version 4.0, 1 August 2014), as they were considered to be complications of RDEB and not the cells. Indeed, 127/163 (78%) of AEs were either unlikely or not related to the BM-MSCs. Concerning the severity of MSCrelated AEs, there were two severe events of DMSO odor, although odor was noted following 28/30 infusions (lasting up to 48 hours). Mild nausea occurred during two infusions, and abdominal pain and bradycardia were observed during two other infusions; all resolved within 15 minutes without treatment or hemodynamic compromise. No AEs resulted in discontinuation of MSCs. Laboratory assessments did not reveal any adverse impact of the BM-MSCs on renal, liver, or bone marrow function. Anti-C7 antibodies were detected by ELISA at baseline in 9/10 participants, but no sera bound to the dermal–epidermal junction by indirect immunofluorescence microscopy. Following MSCs, there were no changes in ELISA or indirect immunofluorescence microscopy data (Supplementary Table S8 online). Collectively, the tolerance data appear encouraging, although it should be noted that a zero event rate for a serious AE in just 10 patients is compatible with an upper 95% confidence interval of over 30%. With regard to secondary outcome measures, the data are summarized in Supplementary Table S9 online. Skin biopsies revealed no increase in C7 and no new anchoring fibrils at day 60. Fluorescence in situ hybridization analysis did not show donor-cell chimerism. Birmingham epidermolysis bullosa severity score (BEBSS) and global severity score questionnaires were completed for all the 10 participants (Supplementary Figures S2 and S3 online). Mean parentreported pain score was lower at 60 days than at baseline (mean difference: −5.5 points; 95% confidence interval (CI): LETTERS TO THE EDITOR

Activating CARD14 mutations are associated with generalized pustular psoriasis but rarely account for familial recurrence in psoriasis vulgaris

Background  Adult pityriasis rubra pilaris (PRP) type 1 is a rare chronic papulosquamous disorder with clinical and histological parallels with psoriasis. Treatment is challenging and recent case reports suggest a potential role for tumour necrosis factor (TNF) antagonists.

Mutations in GRHL2 Result in an Autosomal-Recessive Ectodermal Dysplasia Syndrome

Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283G>A; p.Gly428Asp) in a male infant with life-long inflammation affecting the skin, bowel and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules – similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient’s skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died aged 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues.

Infliximab for the treatment of psoriasis in the U.K.: 9 years’ experience of infusion reactions at a single centre

Caspase recruitment family member 14 (CARD14, also known as CARMA2), is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis. Follow-up studies, however, have been limited, so that it is not clear to what extent CARD14 alleles account for the above conditions. Here, we sought to address this question by carrying out a systematic CARD14 analysis in an extended patient cohort (n=416). We observed no disease alleles in subjects with familial PV (n=159), erythrodermic psoriasis (n=23), acral pustular psoriasis (n=100), or sporadic PRP (n=29). Conversely, our analysis of 105 individuals with generalized pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) that causes constitutive CARD14 oligomerization and shows a significant association with GPP in Asian populations (P=8.4×10(-5); odds ratio=6.4). These data indicate that the analysis of CARD14 mutations could help stratify pustular psoriasis cohorts but would be mostly uninformative in the context of psoriasis and sporadic PRP.

Cell Therapy in Dermatology

Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. Haploinsufficiency for GRHL2 has been implicated in autosomal-dominant deafness, but mutations have not yet been associated with any skin pathology. We investigated two unrelated Kuwaiti families in which a total of six individuals have had lifelong ectodermal defects. The clinical features comprised nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. In addition, three individuals had sensorineural deafness, and three had bronchial asthma. Taken together, the features were consistent with an unusual autosomal-recessive ectodermal dysplasia syndrome. Because of consanguinity in both families, we used whole-exome sequencing to search for novel homozygous DNA variants and found GRHL2 mutations common to both families: affected subjects in one family were homozygous for c.1192T>C (p.Tyr398His) in exon 9, and subjects in the other family were homozygous for c.1445T>A (p.Ile482Lys) in exon 11. Immortalized keratinocytes (p.Ile482Lys) showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2. Whole-skin transcriptomic analysis (p.Ile482Lys) disclosed changes in genes implicated in networks of cell-cell and cell-matrix adhesion. Our clinical findings of an autosomal-recessive ectodermal dysplasia syndrome provide insight into the role of GRHL2 in skin development, homeostasis, and human disease.

Serum levels of high mobility group box 1 correlate with disease severity in recessive dystrophic epidermolysis bullosa

Background  Infliximab is an antitumour necrosis factor‐α chimeric monoclonal antibody that is an established treatment for severe chronic plaque psoriasis. The recommended administration of a 2‐h infusion followed by 2 h of monitoring is practised due to the potential occurrence of infusion reactions. However, accelerated infusions and shortened monitoring periods are used in patients with rheumatological disorders and inflammatory bowel disease without an increase in adverse events.