Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Bullous pemphigoid (BP) 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, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo-like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life. OBJECTIVES AND METHODOLOGY: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included. RESULTS: Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations. CONCLUSIONS: The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice.

European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part I.

This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology (EADV) with a contribution of physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline encompassing a systematic review of the literature until June 2019 in the MEDLINE and EMBASE databases. This first part covers methodology, the clinical definition of MMP, epidemiology, MMP subtypes, immunopathological characteristics, disease assessment and outcome scores. MMP describes a group of autoimmune skin and mucous membrane blistering diseases, characterized by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients' autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the 'Cicatrising Conjunctivitis Assessment Tool' and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course.

A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably transmitted as a dominant trait, which has recently been shown to arise from mutations in keratins 14 and 5 (K14 and K5). We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14. In contrast, linkage with keratin 5 was excluded. The loss of an ionic interaction with keratin 5 is likely to affect K14-K5 heterodimer formation. Our data suggest that this mutation underlies EBS in our family, and that mutations in keratin genes may impair the mechanical integrity of basal keratinocytes in a recessive as well as dominant fashion.

[The persistent sciatic artery aneurysm. A rare and painful buttock mass]. / Anévrisme de l'artère sciatique persistante. Une cause rare de masse fessière douloureuse.

The persistent sciatic artery is a rare cause of painful buttock mass with L5-S1 radicular signs. A 56-year-old man presents a right painful buttock mass with L5-S1 radicular symptoms for 3 years. The surgical exploration found a pulsatile vascular mass like a persistent sciatic artery aneurysm. This vascular pathology is a misunderstood embryogenesis anomaly. The treatment aims to avoid serious complications. This pathology must be known from plastic surgeon.

Transforming growth factor beta1, in the presence of granulocyte/macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells.

Langerhans cells (LCs) are dendritic cells (DCs) that are present in the epidermis, bronchi, and mucosae. Although LCs originate in bone marrow, little is known about their lineage of origin. In this study, we demonstrate that in vitro LCs may originate from monocytes. Adult peripheral blood CD14+ monocytes differentiate into LCs (CD1a+, E-cadherin+, cutaneous lymphocyte-associated antigen+, Birbeck granules+, Lag+) in the presence of granulocyte/macrophage colony-stimulating factor, interleukin 4, and transforming growth factor beta1 (TGF-beta1). This process occurs with virtually no cell proliferation and is not impaired by 30 Gy irradiation. Selection of monocyte subpopulations is ruled out since monocyte-derived DCs can further differentiate into LCs. Our data suggest that in vivo LC differentiation may be induced peripherally, from a nonproliferating myeloid precursor, i.e., the monocyte, in response to a TGF-beta1-rich microenvironment, as found in the skin and epithelia. Therefore, the monocyte may represent a circulating precursor critical to the immune response in vivo.

[Vascular ischemic lesions of the kidney in multiple trauma patients: incidence and management, a report of 7 cases]. / Lésions vasculaires ischémiques rénales chez le polytraumatisé: incidence et prise en charge à propos de 7 cas.

AIMS: Study the incidence, type and outcome of traumatic ischemic arterial lesions of the kidney in multiple trauma patients. MATERIALS AND METHODS: Retrospective study of 500 multiple trauma patients who underwent whole body 64 slice CT Scan (mean age 34 years old, sex ratio 4M/1W, mean ISS 29). RESULTS: There were seven cases of vascular lesions of the left kidney 1.4% of patients (men, median age 25 years old, mean ISS43.9). These were closed traumas with sudden deceleration and dissection of the renal artery trunk in three cases and injury to its branches in four cases with preserved excretion. Three patients died of associated injuries, including one patient who received a stent on D0. One patient underwent a nephrectomy and the three other patients were not treated which did not affect renal function or pressure (follow-up 19 months). CONCLUSION: We found a high incidence of traumatic renal dissection in multiple trauma patients. Multidetector scan appears to provide the best results for the diagnosis of these lesions as well as the many associated lesions resulting in a very poor prognosis for these patients. Treatment is not well defined and management of these lesions is often of secondary importance because of the severity of associated injuries.

InnOscent system: Advancing flavor analysis using an original gas chromatographic analytical device.

Despite continuous advances in analytical and physiological knowledge, the comprehension of an aroma is still a challenge. Gas chromatography coupled to olfactometry (GC-O) is an efficient method to identify and estimate individual potential of odorants, but there is a gap between this individual characterization and the effective contribution of compounds in the mixture, which is due to complex chemical and perceptual interactions. Therefore, recombination and omission experiments are often performed to achieve an understanding of food aromas. In this study, a chromatographic device, developed to facilitate aroma analysis, is presented. It was configured to perform both (1) conventional analyses by GC coupled with a mass spectrometer, olfactometric port(s), and a flame ionization detector (FID), and (2) omission or recombination experiments. This dual capability is due to the singular configuration of the system using an ingenious combination of splitter and Deans switch microfluidics transfer modules, and the existence of multiple outlets. The operational status of the system was tested using a purposely simple mixture of compounds. The similarity of retention times (RT) and FID peak areas obtained for each outlet demonstrates that the multiple outlets of the system are equivalent. The reproducibility of retention times (RT) and FID peak areas obtained in switching and non-switching conditions, also demonstrates the efficiency of switching operations. The validation of the system enables multiple detectors to be connected to the outlets and complementary information can be obtained from the eluate. The connection of recovery disposals to the outlets provides fraction collection and recombination possibilities, which contribute much to the understanding of aroma-aroma interactions. As an illustration of the InnOscent system relevance for the comprehension of more complex aromas, the device was used to study the aroma of a wine made from Cabernet Franc grape variety. An olfactometric profile was efficiently produced with the device configured as a GC-MS coupled to a dual olfactometric port. The main odorant active compounds were identified. The omission approach, carried out with the system on isopropyl- and isobutyl-methoxypyrazines, demonstrates the significant contribution of these compounds to the aroma of the wine studied, despite an individual perception among the weakest of the aromagram. A similar approach can be used to evaluate the contribution of any compound to any aroma. This approach overcomes constraints of current methodologies associated to reconstituted model solutions and paves the way for a better understanding of aroma construction.

[Bullous pemphigoid in young patients: a retrospective study of 74 cases]. / Pemphigoïde du sujet jeune.

INTRODUCTION: Bullous pemphigoid usually affects elderly people. Only a few isolated cases among people younger than 65 years have been reported. OBJECTIVES: Describe the clinical and biological characteristics of patients younger than 60 years suffering from bullous pemphigoid, compare them with the usual characteristics known among elderly people and search for potential pathological associations. PATIENTS AND METHODS: Retrospective, national, multicenter study. Clinical, biological and histological characteristics were recorded with a standardised questionnaire as well as treatments and associated pathologies. RESULTS: Seventy-four cases of bullous pemphigoid diagnosed between June 1970 and March 2002 were analyzed. Mean age at the beginning of the disease was 46 +/- 11.6 years. Further explorations by indirect immunofluorescence of separated skin and/or immuno-electron microscopy and/or immunoblotting were performed for 42 patients (56.8 p. 100). Clinical characteristics among this restricted population were comparable to those found among the 32 other cases. Compared to usual data on bullous pemphigoid in elderly people, we observed a greater proportion of extensive form of disease (75 p. 100), a more frequent head and neck involvement (39.2 p. 100) and an overexpression of anti-BP180 autoantibodies (48 p. 100). Neoplasm was notified for 7 patients (9.5 p. 100), 18 (24.3 p. 100) suffered from a pathology of the basement membrane zone (6 psoriasis, 6 atopic dermatitis and 6 lichen) and 13 from neurological disease, among which 4 were bedridden. Fourty-six patients (62.2 p. 100) received drugs for the long term (mean 2.12 +/- 2.43), 4 patients were treated by PUVAtherapy and 2 by radiotherapy. DISCUSSION: Our results suggest that bullous pemphigoid among young people is more severe and more active than the usual form in the elderly. This particular form could be the result of a higher expression of anti-BP180 autoantibodies, which are considered as a marker of poor prognosis in this disease. We also found a high frequency of pathological associations and physical treatment, all responsible for damage to the basement membrane zone, which can involve auto-immunization against hemidesmosome components.

The major cicatricial pemphigoid antigen is a 180-kD protein that shows immunologic cross-reactivities with the bullous pemphigoid antigen.

Recent studies have shown that sera from patients with cicatricial pemphigoid (CP) contained autoantibodies against epidermal antigens of molecular weight 230 kD and/or 180 kD by immunoblotting, similar to those recognized by bullous pemphigoid (BP) sera. Previous immunoprecipitation studies have shown that BP sera only precipitated the 230-kD antigen. To characterize the CP antigen(s) we tested 10 CP sera, 10 BP sera, and four controls by both immunoprecipitation of radiolabeled cells and immunoblotting of epidermal extracts. For immunoprecipitation, we used 0.5% NP-40 extracts of both normal human keratinocytes and Pam cells. All CP sera precipitated a 180-kD protein that co-migrated with the BP180 antigen precipitated by some individual BP sera. Two of these CP sera also faintly bound a 230-kD protein of similar molecular weight as the major BP230 antigen. CP and BP sera with an immunoblotting pattern of 180 kD immunoprecipitated a co-migrating 180-kD protein. CP sera reacting by immunoblotting with the 230-kD antigen precipitated the 180-kD and/or the 230-kD antigen. In contrast, BP sera reacting with the 230-kD antigen only precipitated this antigen. In further experiments, labeled 0.5% NP-40 extracts from Pam cells were first preabsorbed with a reference BP serum and then immunoprecipitated with CP sera. Under these conditions, CP sera that immunoprecipitated both 180-kD and 230-kD proteins with the standard procedure no longer precipitated these proteins. Our results suggest that a 180-kD protein is the major CP target-antigen that demonstrated immunologic cross-reactivities with the BP180 and the BP230 antigens.

Immunoelectron microscopy in subepidermal autoimmune bullous diseases: a prospective study of IgG and C3 bound in vivo in 32 patients.

Thirty-two patients suffering from subepidermal autoimmune bullous disease were studied prospectively by clinical examination and immunoelectron microscopy. Clinically, 1 patient had herpes gestationnis, 14 typical bullous pemphigoid (BP), 3 epidermolysis acquisita (EBA), 3 cicatricial pemphigoid (CP), and 11 patients overlapping clinical diseases. These 11 patients shared clinical features of BP, EBA, or CP and a clinical diagnosis could not be done safely. Immunoelectron microscopy revealed diaminobenzidine deposits in 20 patients on the epidermal side of dermo-epidermal junction in the lamina lucida as in BP. In 5 patients, deposits located mostly under the anchoring fibril zone, in the floor of a sublamina densa dermoepidermal separation for 2 of them, were consistent with a diagnosis of EBA. In 6 patients, deposits were located mostly in the lamina densa, in the floor of a dermoepidermal separation occurring in the lamina lucida for 3 of them. This suggests that some of these 6 patients had neither EBA or BP, but another autoimmune bullous disease again, an uncharacterized component of dermoepidermal junction located in the lamina densa. Finally, a correlation exists between the sites of IgG and/or C3 components on epidermal or dermal side of dermoepidermal junction and the presence or absence of characteristic clinical features such as scar, milia formation, or mucosal involvement.

Healing of full-thickness cutaneous wounds in the pig. I. Immunohistochemical study of epidermo-dermal junction regeneration.

In order to determine the kinetics of epidermo-dermal junction (EDJ) regeneration during would healing, we studied the regeneration of five EDJ components during reepidermization. Cutaneous wounds (50-mm length, 2-mm width, and 5-mm depth) were produced on the flank area of two pigs and left unsutured. Daily biopsies from day 1 to day 20 were studied by light microscopy on paraffin-embedded sections and by indirect immunofluorescence on cryostat sections using human sera to bullous pemphigoid antigen (BPA) with specificity previously confirmed by indirect immuno-electron microscopy, rabbit antisera to type IV collagen (Coll IV) and to fibronectin, and the monoclonal antibodies (MoAb) 4C 12-8 to laminin and NP-76 to type VII collagen (Coll VII). Histologically, reepidermization started from day 1 and progressed unidirectionally and exclusively from the wound edges. Up to day 9, the distal tips of the neo-epidermal tongues generally extended between the crust and the granulation tissue (GT). They fused on day 10, restoring epidermal continuity. For each EDJ component, the date of appearance (emergence), the spreading under the neo-epidermis tongue (expression), and the morphologic aspect of the labeling were studied. BPA and Coll IV were detected from day 1 to day 20 and found to be expressed all along the neo-EDJ. Fibronectin and laminin were detected from day 1, were present in the proximal and median zones of the neo-EDJ before day 7, up to the distal tip from day 7 to day 9 and were all along the neo-EDJ from day 10 to day 20. Coll VII was only detected from day 3. It was present in the proximal zone on day 3 and day 4, in the proximal and median zones on day 5 and day 6, than all along the neo-EDJ from day 7 to day 20. From day 10, all the labeling characteristics of the five components were found to be similar in the neo-EDJ and in the normal EDJ. With regard to the neo-epidermis progression, we found a synchronism of emergence and expression for BPA and Coll IV, a synchronism of emergence but a delay of expression for fibronectin and laminin and lastly, a delay of emergence and expression for Coll VII. We concluded that BPA and Coll IV could constitute the framework on which the neo-EDJ is progressively built by adjunction of the other components, restitution being obtained just after epidermal continuity is restored.

Cicatricial pemphigoid antigen differs from bullous pemphigoid antigen by its exclusive extracellular localization: a study by indirect immunoelectronmicroscopy.

Several components of the dermal-epidermal junction (DEJ) bear the name of the autoimmune bullous disease in which they are involved. The epidermolysis bullosa acquisita (EBA) antigen, a component of anchoring fibrils, and the bullous pemphigoid (BP) antigen, a component of hemidesmosomes (HD) with a molecular weight of 220-240 kD, have been well characterized. In contrast, there is little data known about the cicatricial pemphigoid (CP) antigen. No differences between CP and BP have been reported when sera of patients were studied by Western immunoblotting. Findings of a study of sera from 8 patients with CP by indirect immunoelectron microscopy (IEM) on normal human skin are reported. Saponin (0.1% 10 mn) was used as a permeabilizing agent of cytomembranes and saponin-treated skin samples were compared to saponin-untreated skin samples. Four sera from patients with BP, one from a patient with EBA, and three from healthy donors served as controls. The CP sera produced a similar staining of DEJ on both saponin-treated and saponin-untreated skin samples: immune deposits were localized over the lamina densa and the lower part of the lamina lucida clearly separated from the cytoplasmic membrane of keratinocytes, in regularly spaced clumps. The BP sera produced an intense staining of DEJ only on saponin-treated skin samples: immune deposits were observed on the cytoplasmic attachment plaque of the HD; on saponin-untreated skin samples, BP sera produced only a faint staining of the extracellular part of HD. Finally, as expected the EBA serum appeared on the lower part of the lamina densa and anchoring fibrils, and no DAB deposits were observed with the serum of healthy donors. This data indicated that CP antigen is different than BP antigen by its exclusive extracellular localization. It may be a component of anchoring filaments.