Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology

Bullous pemphigoid is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or generalized bullous lesions. In up to 20% of affected patients, bullae may be completely absent, and only excoriations, prurigo-like lesions, eczematous lesions, urticated lesions and/or infiltrated plaques are observed. The disease is significantly associated with neurological disorders. The morbidity of bullous pemphigoid and its impact on quality of life are significant. So far, a limited number of national treatment guidelines have been proposed, but no common European consensus has emerged. Our consensus for the treatment of bullous pemphigoid has been developed under the guidance of the European Dermatology Forum in collaboration with the European Academy of Dermatology and Venereology. It summarizes evidence-based and expert-based recommendations.

A transgenic mouse model that recapitulates the clinical features of both neonatal and adult forms of the skin disease epidermolytic hyperkeratosis

Keratins are the major structural proteins of keratinocytes, which are the most abundant cell type in the mammalian epidermis. Mutations in epidermal keratin genes have been shown to cause severe blistering skin abnormalities. One such disease, epidermolytic hyperkeratosis (EHK), also known as bullous congenital ichthyosiform erythroderma, occurs as a result of mutations in highly conserved regions of keratins K1 and K10. Patients with EHK first exhibit erythroderma with severe blistering, which later is replaced by thick patches of scaly skin. To assess the effect of a mutated K1 gene on skin biology and to produce an animal model for EHK, we removed 60 residues from the 2B segment of HK1 and observed the effects of its expression in the epidermis of transgenic mice. Phenotypes of the resultant mice closely resembled those observed in the human disease, first with epidermal blisters, then later with hyperkeratotic lesions. In neonatal mice homozygous for the transgene, the skin was thicker, with an increased labeling index, and the spinous cells showed a collapse of the keratin filament network around the nuclei, suggesting that a critical concentration of the mutant HK1, over the endogenous MK1, was required to disrupt the structural integrity of the spinous cells. Additionally, footpad epithelium, which is devoid of hair follicles, showed blistering in the spinous layer, suggesting that hair follicles can stabilize or protect the epidermis from trauma. Blisters were not evident in adult mice, but instead they showed a thick, scaly hyperkeratotic skin with increased mitosis, resulting in an increased number of corneocytes and granular cells. Irregularly shaped keratohyalin granules were also observed. To date, this is the only transgenic model to show the typical morphology found in the adult form of EHK.

The IgM anti-desmoglein 1 response distinguishes Brazilian pemphigus foliaceus (Fogo selvagem) from other forms of pemphigus

Fogo selvagern (FS) and pemphigus foliaceus (PF) possess pathogenic IgG anti-desmoglein 1-(Dsg1) autoantibodies. Although PF occurs sporadically, FS is endemic in Limao Verde (LV), Brazil (3.4% prevalence). IgM anti-Dsg1 were detected in 58% FS LV patients (n=31), 19% of FS patients from Hospital-Campo Grande (n=57), 19% from Hospital-Goiania (n=42), 12% from Hospital-Sao Paulo (n=56), 10% of PF patients from United States (n=20), and 0% of PF patients from Japan (n=20). Pemphigus vulgaris (n=40, USA and Japan), bullous pemphigoid (n=40, USA), and healthy donors (n=55, USA) showed negligible percentages of positive sera. High percentages of positive IgM anti-Dsg1 were found in healthy donors from four rural Amerindian populations (42% of 243) as compared with urban donors (14% of 81; P<0.001). More than 50% of healthy donors from LV (n=99, age 5-20 years) possess IgM anti-Dsg1 across ages, whereas IgG-anti-Dsg1 was detected in 2.9% (age 5-10 years), 7.3% (age 11-15 years), and 29% of donors above age 16. IgM anti-Dsg1 epitopes are Ca2+ and carbohydrate-independent. We propose that IgM anti-Dsg1 are common in FS patients in their native environment and uncommon in other pemphigus phenotypes and in FS patients who migrate to urban hospitals. Recurrent environmental antigenic exposure may lead to IgM and IgG responses that trigger TS.

Linear IgA dermatosis induced by pregnancy

Linear IgA disease is a rare autoimmune subepidermal bullous disorder characterized by linear IgA deposits at the epidermal basement membrane zone. According to the literature, in patients who have linear IgA disease and become pregnant, the disease tends to improve. We report a case of linear IgA disease induced by pregnancy, successfully treated with dapsone and prednisone with no adverse effects observed in the patient and her newborns.

Increased Melanocytic Nevi in Patients with Inherited Ichthyoses: Report of a Previously Undescribed Association

Ichthyosis is a heterogeneous cornification disorder. Melanocytic lesions have not been previously described in association with ichthyosis. Their clinical importance lies in the fact that they may simulate melanoma clinically and dermoscopically, as seen in epidermolysis bullosa. The objective of this study was to evaluate the clinical, dermoscopic, and histopathologic features of nevi and lentigines in 16 patients with autosomal recessive congenital ichthyosis-lamellar ichthyosis and non-bullous ichthyosiform congenital erythroderma. Patients underwent general clinical examination dermoscopy. The more suspicious lesions were excised and to histopathologic examination. Most patients (n = 13) reported no personal or familial history of melanoma or atypical nevi. All of the patients had at least five atypical melanocytic lesions. Ten of the 16 patients had at least one atypical nevus or lentigo. This study suggests that increased atypical melanocytic nevi may be a feature of long-standing congenital ichthyoses. Whether this finding is disease-related or a coincidental observation is difficult to ascertain. As an unequivocal discrimination from malignant melanoma in vivo is not always possible, regular clinical follow-up of patients with ichthyosis and increased or unusual nevi is recommended.

Progressive bilateral enophthalmos associated with cerebrospinal shunting

A 22-year-old woman was examined for a complaint of bilateral progressive enophthalmos that had begun after the cerebrospinal fluid shunting procedure 9 years ago. Photographs and CT scans taken before surgery proved that the position of her eyes was normal before surgery. The enophthalmos was so severe that it induced a poor eyelid-globe apposition with trichiasis and superficial keratopathy. CT of the orbits showed that both orbital roofs were arched and displaced toward the anterior cranial fossa. The placement of porous polyethylene sheets on the orbital roofs through a coronal approach corrected the eye position. A literature review indicated that cerebrospinal shuntings are plagued by a variety of complications including bone changes and craniosynostosis. We believe that enophthalmos associated with cerebrospinal fluid shunting results from a rare acquired bony orbital anomaly.

Mast cells and transforming growth factor-beta expression: a possible relationship in the development of porphyria cutanea tarda skin lesions

Background Porphyria cutanea tarda (PCT) is a metabolic disease characterized by vesicles and blisters in sun-exposed areas and scleroderma-like lesions in sun-exposed and non-sun-exposed areas. Mast cells participate in the pathogenesis of bullous diseases and diseases that show sclerosis, including PCT. Moreover, transforming growth factor-beta (TGF-beta) is the main cytokine in the development of tissue sclerosis. The correlation of mast cells and TGF-beta with the lesions of PCT has not been examined, however. The possible role of mast cells and TGF-beta (and the relationship between them) in the development of PCT lesions is discussed. Methods To quantify mast cells and cells expressing TGF-beta in skin samples from patients with PCT and controls, immunohistochemical studies were performed in tissue sections allied to morphometric analyses. Results The numbers of mast cells and cells expressing TGF-beta per square millimiter were increased in the PCT group relative to controls, and there was a direct and significant correlation between the mast cell number and cells expressing TGF-beta in PCT. Conclusions The results suggest that the increased number of mast cells and of cells expressing TGF-beta, as well as their direct correlation, may contribute to the pathogenesis of the skin lesions in PCT.

Endemic Pemphigus foliaceus ("Fogo selvagem"): a series from the Northeastern region of the State of São Paulo, Brazil, 1973-1998

Endemic Pemphigus Foliaceus (EPF) is a bullous autoimmune skin disease whose incidence used to be high in the State of São Paulo (SP), Brazil, during the forties, but has declined thereafter. OBJECTIVES: to report a series of EPF patients from the northeastern region of SP. METHODS: a retrospective study concerning demographic and epidemiological data of patients seen from 1973 to 1998 was conducted at the University Hospital, Faculty of Medicine of Ribeirão Preto, SP. RESULTS: bullous disease was diagnosed in 340 patients, 245 with EPF (72.1%), 9.4 cases per year, 60.4% females, and 70.2% white, 7 to 82 year-old (29.4% in their teens); 46.9% lived in the rural zone. Concerning profession, housewives predominated among women (67.6%) and agricultural workers among men (40.2%). The time of disease was less than 1 year in 62.0% of cases, followed by 1 and 5 years (27%), and more than 5 years for the remaining patients (11%). 36.7% of patients were referred by the Direção Regional de Saúde (DIR) XVIII of Ribeirão Preto, with the largest number of cases being from Ribeirão Preto and Batatais: 33.3% and 23.3%, respectively; 22% from DIR XIII (Franca); 13.5% from DIR VII (Araraquara); 2.9% from DIR IX (Barretos); 4.1% from other DIRs of SP, and 20.8% from other States (16.7% from Minas Gerais). Thirteen (5.3%) patients reported occurrence of the disease in some relative, and 4 (1.6%) in neighbors. CONCLUSIONS: the present data characterize the northeastern region of the state of São Paulo as a remaining endemic focus of EPF.

Mastocytosis: a Rare Case of Anaphylaxis in Paediatric Age and Literature Review

The term “mastocytosis” denotes a heterogeneous group of disorders characterised by abnormal growth and accumulation of mast cells (MC) in one or more organ systems. Symptoms result from MC chemical mediator’s release, pathologic infiltration of neoplastic MC in tissues or both. Multiple molecular, genetic and chromosomal defects seem to contribute to an autonomous growth, but somatic c-kit D816V mutation is more frequently encountered, especially in systemic disease. We present a literature review of mastocytosis and a rare case report of an 18 month-old-girl with a bullous dermatosis, respiratory distress and anaphylaxis, as clinical manifestations of mastocytosis. The developments of accepted classification systems and novel useful markers allowed a re-evaluation and updating of the classification of mastocytosis. In paediatric age cutaneous forms of disease prevail and may regress spontaneously. SM is more frequently diagnosed in adults and is a persistent(clonal) disease of bone marrow. The clinical course in these patients is variable.Today diagnostic criteria for each disease variant are reasonably well defined. There are, however, peculiarities, namely in paediatric age, that makes the diagnostic approach difficult. Systemic disease may pose differential diagnostic problems resulting from multiple organ systems involvement. Coversly, the “unexplained” appearance of those symptoms with no skin lesions should raise the suspicion of MC disease. This case is reported in order to stress the clinical severity and difficult diagnostic approach that paediatric mastocytosis may assume.

Desenvolupament d’un nou model murí humanitzat de pemfigoide ampul•lar obtingut a partir de cèl•lules mare humanes fol·liculars

Resum: El pemfigoid ampul•lar és una malaltia cutània autoimmune. La majoria dels pacients presenten autoanticossos contra proteïnes de la membrana basal de la pell, concretament en contra de la col·làgena XVII, específicament envers el epítop immunodominant, l’NC16A. La patogenicitat dels anticossos ha estat demostrada mitjançant experiments in vitro i in vivo. L’escassa homologia existent entre l’NC16A i el seu homòleg murí (NC14A), ha dificultat l’el·laboració de models animals d’aquesta malaltia. En aquest treball demostrem que el sèrum de pacients amb pemfigoid ampul•lar produeix separació dermo-epidèrmica en pell de ratolí humanitzada obtinguda a partir de cèl•lules mare humanes del provinents fol·licle pil·lós

Characteristics of the cornea and ocular surface in patients with congenital aniridia

We performed complete eye exams on 50 eyes in 25 patients with congenital aniridia. Factors such as age, history of ocular surgery, dry eye score and aesthesiometry results correlated with the degree of aniridia-related keratopathy. Schirmer’s test I in 86.8%, Schirmer’s test II in 94.4% and TFBUT in 83.3% of cases were all normal. Corneal staining was altered in 54.2%, and conjunctival staining was altered in 45.7%. The tear ferning pattern was abnormal in 80%. Conjunctival metaplasia was present in 76.9%.Corneal endothelial cell density was normal. Ultrasonic pachymetry was higher than average in all eyes examined.

Skin problems associated with pegylated liposomal doxorubicin-more than palmoplantar erythrodysesthesia syndrome.

Liposomal pegylated doxorubicin is an encapsulation form of doxorubicin, with an improved pharmacokinetic profile and the ability to selectively accumulate into tumor tissue. As a result, the tolerated dose of the drug can be increased, followed by a reduced incidence of neutropenia and cardiotoxicity in comparison to doxorubucin treatment. However, a common adverse dose-schedule limiting effect of the treatment is palmoplantar erythrodysesthesia syndrome. In this retrospective study we included six patients hospitalised in the University Hospital of Zurich during the last 2 years, in connection with side effects caused by pegylated liposomal doxorubicin. These patients received this chemotherapeutic agent for treatment of various malignancies such as breast cancer, ovarian cancer, mycosis fungoides and cutaneous B-cell lymphoma. Three of six patients in this study developed classical palmoplantar erythrodysesthesia, one developed palmoplantar erythrodysesthesia associated with extensive bullous disease, one developed eruption of lymphocyte recovery syndrome and one developed intertrigo like dermatitis with stomatitis. Pegylated liposomal doxorubicin induces various skin reactions including palmoplantar erythrodysesthesia syndrome. However, the exact clinical presentation might depend on pre-existing skin diseases.

Standardizing the diagnosis of inhalation injury using a descriptive score based on mucosal injury criteria.

INTRODUCTION: Inhalation injury is an important determinant of outcome in patients with major burns. However the diagnostic criteria remain imprecise, preventing objective comparisons of published data. The aims were to evaluate the utility of an inhalation score based on mucosal injury, while assessing separately the oro-pharyngeal sphere (ENT) and tracheobronchial tree (TB) in patients admitted to the ICU with a suspicion of inhalation injury. METHODS: Prospective observational study in 100 patients admitted with suspicion of inhalation injury among 168 consecutive burn admissions to the ICU of a university hospital. Inclusion criteria, endoscopic airway assessment during the first hours. ENT/TB lesion grading was 1: oedema, hyperemia, hypersecretion, 2: bullous mucosal detachment, erosion, exudates, 3: profound ulcers, necrosis. RESULTS: Of the 100 patients (age 42±17 years, burns 23±19%BSA), 79 presented an ENT inhalation injury ≥ENT1 (soot present in 24%): 36 had a tracheobronchial extension, 33 having a grade ≥TB1. Burned vibrissae: 10 patients "without" suffered ENT injury, while 6 patients "with" had no further lesions. Length of mechanical ventilation was strongly associated with the first 24 hrs' fluid resuscitation volume (p<0.0001) and the presence of inhalation injury (p=0.03), while the ICU length of stay was correlated with the %BSA. Soot was associated with prolonged mechanical ventilation (p=0.0115). There was no extubation failure. CONCLUSIONS: The developed inhalation score was simple to use, providing a unified language, and drawing attention to upper airway involvement. Burned vibrissae and suspected history proved to be insufficient diagnostic criteria. Further studies are required to validate the score in a larger population.

Uveitis and juvenile idiopathic arthritis: A cohort study.

OBJECTIVE: Assess the incidence of intraocular inflammation (uveitis) and ocular complications in children with various types of JIA in a single cohort of patients. PATIENTS: Included are 172 children (35 boys and 137 girls) diagnosed with JIA. All underwent thorough initial ophthalmologic examination and were followed for a minimum of 3 years. RESULTS: Of 172 children with JIA, 152 (88.4%) presented with arthritis. Uveitis was detected in 14 of the152 children (9.2%) during the first ophthalmic examination. In 17 additional patients of this group (11.2%), uveitis developed during the follow up period of up to 15 years. Twenty children out of the total of 172 (11.6%) presented initially with uveitis. In children developing uveitis before or along with arthritic manifestations, the ocular disease was chronic with a high rate of secondary complications (band keratopathy, glaucoma, posterior synechiae and cataract). In all affected eyes the initial ocular inflammation was typically confined to the anterior segment. On longer follow up however, most children developed binocular disease and posterior segment involvement. Dense cataract and amblyopia were the major cause of severe visual disabilities. CONCLUSION: Pauciarticular JIA is associated with intraocular inflammation (uveitis) early during the arthritic disease course. The ocular disease course is unpredictable. Therefore education of parents regarding its signs and symptoms is of utmost importance. To preserve functional vision, secondary ocular complications and amblyopia should be avoided.

Induction of p38, tumour necrosis factor-α and RANTES by mechanical stretching of keratinocytes expressing mutant keratin 10R156H.

Background : Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma), characterized by ichthyotic, rippled hyperkeratosis, erythroderma and skin blistering, is a rare autosomal dominant disease caused by mutations in keratin 1 or keratin 10 (K10) genes. A severe phenotype is caused by a missense mutation in a highly conserved arginine residue at position 156 (R156) in K10. Objectives: To analyse molecular pathomechanisms of hyperproliferation and hyperkeratosis, we investigated the defects in mechanosensation and mechanotransduction in keratinocytes carrying the K10R156H mutation. Methods: Differentiated primary human keratinocytes infected with lentiviral vectors carrying wild-type K10 (K10wt) or mutated K10R156H were subjected to 20% isoaxial stretch. Cellular fragility and mechanosensation were studied by analysis of mitogen-activated protein kinase activation and cytokine release. Results: Cultured keratinocytes expressing K10R156H showed keratin aggregate formation at the cell periphery, whereas the filament network in K10wt cells was normal. Under stretching conditions K10R156H keratinocytes exhibited about a twofold higher level of filament collapse compared with steady state. In stretched K10R156H cells, higher p38 activation, higher release of tumour necrosis factor-alpha and RANTES but reduced interleukin-1 beta secretion compared with K10wt cells was observed. Conclusions: These results demonstrate that the R156H mutation in K10 destabilizes the keratin intermediate filament network and affects stress signalling and inflammatory responses to mechanical stretch in differentiated cultured keratinocytes.