In utero development of epidermolysis bullosa acquisita.

We report the case of an infant born with perioral vesicles that rapidly spread to involve his mouth and the majority of his body. Histopathology, immunofluorescence, and enzyme-linked immunohistochemistry assays confirmed a diagnosis of epidermolysis bullosa acquisita (EBA). His mother had no history of EBA, and serum indirect immunofluorescence was negative. The patient improved rapidly with local wound care and oral dapsone.

Signalling and targeted therapy of inflammatory cells in epidermolysis bullosa acquisita.

Pemphigoid diseases (PDs) are chronic and life-threatening autoimmune diseases of the skin and mucous membranes. PDs are characterized and caused by autoantibodies targeting components of the basement membrane. In the PD epidermolysis bullosa acquisita (EBA), the target autoantigen is type VII collagen. Current treatment options of PD, especially EBA, are limited and are mostly based on systemic immunosuppression. Animal models of PD have greatly advanced our understanding of PD pathogenesis. This has led to the identification of several novel therapeutic targets, including signalling molecules. Herein, the contribution of signalling molecules in the pathogenesis of the PD EBA and the effects of pharmacological targeting of these pathways are reviewed in detail. The p38 MAPK, ERK1/2, AKT, PI3Kß, Hsp90, RORα, PDE4, Src kinases and CARD9 have been demonstrated to be critically involved in EBA pathogenesis. With the advent of new signal transduction inhibitors, we expect that the so far poor prognosis of EBA and other PD will improve significantly in the future.

Nanoparticles prepared from porcine cells support the healing of cutaneous inflammation in mice and wound re-epithelialization in human skin.

Previous reports have demonstrated that cell-derived nanoparticles (CDNPs) composed of bovine or porcine protein complexes exerted therapeutic effects against viral infections and cancer in mice and humans. Based on these observations, we asked whether CDNPs would improve inflammatory skin disorders. To address this, we utilized two distinct mouse models of cutaneous inflammation: the autoimmune skin-blistering disease epidermolysis bullosa acquisita (EBA) as an example of an autoantibody-induced cutaneous inflammation, and Leishmania major (L. major) infection as an example of a pathogen-induced cutaneous inflammation. In both models, we observed that CDNPs increased mRNA expression of the Th2 cytokine IL-4. Clinically, CDNPs decreased inflammation due to EBA and increased L. major-specific IgG1 levels without major effects on infected skin lesions. In addition, CDNPs supported the growth of keratinocytes in human skin cultures. In vitro studies revealed that CDNPs were taken up predominantly by macrophages, leading to a shift towards the expression of anti-inflammatory cytokine genes. Altogether, our data demonstrate that treatment with porcine CDNPs may be a new therapeutic option for the control of autoimmune-mediated inflammatory skin disorders.

Extracorporeal photopheresis for the treatment of autoimmune diseases.

The immune system is tasked with the unique challenge of recognizing foreign pathogens and damaged cells while at the same time preserving and protecting the integrity of "self". When this process fails, severe consequences including cancer and autoimmunity are the end result. Current therapies aimed at treating autoimmune disorders result in generalized immunosuppression and place the patient at increased risk for infection and malignancy. ECP is a potential therapeutic intervention that recapitulates natural physiologic processes of tolerance induction to restore immune homeostasis. Several clinical trials suggest that ECP may be used to treat a broad spectrum of autoimmune diseases.

The successful use of extracorporeal photopheresis in a 12-year-old patient with refractory epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita is a rare autoimmune bullous disease of the mucosa and skin characterized by the presence of anti-collagen VII antibodies at the dermoepidermal junction. Most patients respond to immunosuppressive or antiinflammatory agents, although patients whose condition is refractory to these therapies will require more aggressive treatment. We present a 12-year-old girl with refractory epidermolysis bullosa acquisita who responded to extracorporeal photopheresis.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome associated with neonatal epidermolysis bullosa acquisita.

We report the case of a 2-week-old boy who presented with a vesiculopustular, bullous eruption in the setting of autoimmune enteropathy, hypothyroidism, membranous nephropathy, Coombs-positive hemolytic anemia, and persistent eosinophilia. Immunologic testing revealed a deficiency of FOXP3-expressing regulatory T cells, and a diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome was made. Histologic analysis, immunofluorescence, and enzyme-linked immunosorbent assay confirmed the bullous eruption as epidermolysis bullosa acquisita with associated collagen VII autoantibody production. The skin lesions responded to systemic immunosuppressant therapy and have regressed after allogeneic bone marrow transplantation.

Treatment of epidermolysis bullosa acquisita with intravenous immunoglobulin in patients non-responsive to conventional therapy: clinical outcome and post-treatment long-term follow-up.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal blistering disease that is caused by antibodies binding to type VII collagen within anchoring fibrils. It is rare disease with an incidence of 0.25 cases per 1,000,000 population. OBJECTIVE: The objective of this study is to report the treatment outcomes with intravenous immunoglobulin (IVIg) therapy in 10 patients with severe and widespread EBA non-responsive to conventional therapy. METHODS: Patients were treated according to a protocol published in a Consensus Statement to treat autoimmune mucocutaneous blistering diseases, including EBA with IVIg. A dose of 2 g/kg/cycle was used. RESULTS: Ten patients: four males and six females, all were North American Caucasian. The age at onset varied from 37 to 75 years (mean 57.4). A satisfactory clinical response was observed in all 10 patients. The patients received 16-31 cycles (mean 23.1) of IVIg over a period of 30-52 months (mean 38.8). Once IVIg was initiated, earlier drugs (prednisone, dapsone and others) were gradually withdrawn over a 5-9 month period (mean 7.2). Thereafter, IVIg was used as monotherapy. No serious side-effects were observed. The follow-up period since discontinuation of IVIg varied from 29 to 123 months (mean 53.9). During this follow-up period, recurrence of disease was not observed. CONCLUSION: The data suggest that IVIg can produce a long-term sustained clinical remission in patients with EBA. In the patients, of this study concomitant therapy could be discontinued and IVIg was used as monotherapy.

[Epidermolysis bullosa acquisita: literature review]. / L'épidermolyse bulleuse acquise: revue de la littérature.

INTRODUCTION: Epidermolysis bullosa acquisita (EBA) is the rarest of the autoimmune bullous diseases (AIBD). It is defined as an AIBD secondary to production of antibodies directed against type VII collagen and then binding to anchoring fibrils in the basal membrane zone (BMZ) of the skin and the Malpighian mucosa. AIMS: To evaluate risk factors, different clinical forms and diagnostic methods, and the efficacy of treatments. METHODS: The articles were identified by a search of PubMed and Embase from the initial creation of these databases through to March 2009. We selected generalised reviews and meta-analyses, cases involving unusual and/or serious clinical presentations, studies of immunological tests and homogeneous retrospective series regarding therapy. RESULTS: Of the 206 articles analysed, only two were of an adequate level of proof, with four of intermediate level, and all the others of only low level. EBA affects all age groups (from newborn infants to the very elderly) with a slight predominance in female subjects. Diagnosis must be considered in subjects with black skin of African origin. A drug-induced origin of the disease was reported in 11% of cases of IgA-EBA. Classical EBA (30 to 50% of cases), resembles epidermolysis bullosa hereditaria (EBH), with fragile skin, non-inflammatory bullae, dystrophic scars and milia. Numerous atypical and misleading forms exist. Evocative signs are the presence of mucosal lesions and/or scars. The severity of EBA is determined by the extent of cutaneous lesions, and ophthalmological, ENT and/or oesophageal involvement. Crohn's disease is associated in 25% of cases of EBA. Unequivocal diagnosis is provided by direct immunoelectron microscopy (IEM). Therapeutic efficacy has been reported for dapsone, sulphapyridine and colchicine in milder forms, and for cyclosporine, mycophenolate mofetil, rituximab, intravenous immunoglobulins and extracorporeal photochemotherapy in resistant and severe forms. A number of authors have reported inefficacy of systemic corticosteroids, even in high-dose regimens, with the development of corticosteroid dependence in certain cases. CONCLUSIONS: In the absence of any therapeutic trials, it is difficult to select optimal treatment; however, the benefit/risk ratio of systemic corticosteroid treatment is unfavourable.

Premonitory epidermolysis bullosa acquisita mimicking eyelid dermatitis: successful treatment with rituximab and protein A immunoapheresis.

We report a unique case of a 71-year-old female patient with epidermolysis bullosa acquisita. The patient initially presented with the clinical symptoms of bilateral eyelid dermatitis that occurred several months prior to the development of oral and pharyngeal erosions and blisters. While no contact allergy was found by patch testing, direct immunofluorescence microscopy demonstrated linear deposits of IgG at the basement membrane zone. By indirect immunofluorescence microscopy on human salt-split skin, IgG antibodies bound to the dermal side of the split. Immunoblot analysis showed predominant IgG4 reactivity of the patient's serum with the recombinant non-collagenous-1 domain of type VII collagen. Because of treatment resistance to systemic corticosteroids, dapsone, and colchicine, we initiated a combination treatment of protein A immunoapheresis and rituximab. With this treatment, complete remission was achieved within 4 months. Our case highlights that epidermolysis bullosa acquisita may initially mimic an eyelid dermatitis. Consequently, dermatologists should be aware of this rare differential diagnosis of eyelid dermatitis where a contact allergy or atopic dermatitis is absent.

Remission of severe autoimmune bullous disorders induced by long-term extracorporeal photochemotherapy.

Pemphigus vulgaris (PV) and epidermolysis bullosa acquisita (EBA) sometimes resist treatments. In drug-resistant cases, adjuvant treatment with extracorporeal photochemotherapy (ECP) has been reported to induce remission. However, limited numbers of patients have been reported up to date. Eleven patients with drug-resistant autoimmune bullous diseases have been treated with ECP (8 patients with PV, 3 patients with EBA). The introduction of ECP to systemic therapies of the patients with PV resulted in complete response (CR) after a limited cycle (2-6 cycles) in all, except one patient. Prednisolone doses could be tapered in all patients. ECP resulted in CR in two patients while improvement was partial in one patient with EBA after 3-6 cycles. Our patients demonstrate the efficacy of long-term ECP to be tried in the treatment of aggressive autoimmune bullous disorders. The treatment has produced a remarkable corticosteroid-sparing effect while inducing clinical remission.

Epidermolysis bullosa acquisita: A comprehensive review.

Epidermolysis bullosa acquisita is a rare autoimmune blistering disease which results in vesicle and bullae formation on the skin and erosions on the mucous membranes. EBA is mediated by autoantibodies to collagen VII. Clinically, it can present with numerous phenotypes, though the most common are the mechanobullous and inflammatory variants. Patients with mechanobullous EBA develop non-inflammatory bullae and erosions at sites of trauma while patients with the non-mechanobullous type develop inflammatory lesions which often mimic other blistering conditions including bullous pemphigoid, linear IgA bullous disease, and mucous membrane pemphigoid. Diagnosis is established by having a consistent clinical presentation, DIF, and autoantibodies against collagen VII. In apparent "seronegative" patients, the diagnosis is challenging due to the need for confirmatory tests which are often not routinely accessible outside of the specialized center. In light of EBA's rarity, and lack of any randomized controlled trials, treatment guidelines rely on the small case series presented in the literature. There has been variable success utilizing the arsenal of immunosuppressants and biologics. Development of experimental murine models has facilitated a deeper understanding of EBA's pathogenesis and allows for preclinical testing of numerous novel drug targets predominantly targeting inhibition of neutrophil activation. We herein review the presentation, diagnosis, treatments, and future avenues of research in EBA.

Treatment Update of Autoimmune Blistering Diseases.

The treatment of refractory autoimmune blistering diseases (AIBDs) has always been a challenge. Because randomized controlled trials are lacking, treatment has been based on analysis of anecdotal data. The last 2 decades has seen the use of rituximab become a conventional treatment in the therapeutic armamentarium of AIBDs, leading to its Food and Drug Administration indication for pemphigus vulgaris in 2018. We review the current updated data on the use of rituximab including dosing, protocols, and its role in the algorithm of AIBDs. In addition, we discuss several promising novel emerging therapeutic agents for AIBDs.

Autoimmunity to type VII collagen: epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is an acquired, autoimmune, mechanobullous disease with clinical features reminiscent of genetic dystrophic epidermolysis bullosa (DEB). EBA patients have skin fragility, blisters, scars, and milia formation. DEB is due to a genetic defect in the gene-encoding type VII collagen, which makes anchoring fibrils, structures that attach the epidermis and its underlying basement membrane zone onto the papillary dermis. DEB patients have a decrease in normally functioning anchoring fibrils. EBA patients have the same problem, but their decrease in normally functioning anchoring fibrils is because of an abnormality in their immune system in which they produce anti-type VII collagen antibodies that attack their anchoring fibrils. These IgG anti-type VII collagen antibodies are "pathogenic" because when injected into a mouse, the mouse develops an EBA-like blistering disease. EBA has several distinct clinical presentations. It can present with features similar to DEB. It can also present with features reminiscent of bullous pemphigoid, cicatricial pemphigoid, Brunsting-Perry pemphigoid, or IgA bullous dermatosis. Treatment for EBA is unsatisfactory. Some therapeutic success has been reported with colchichine, dapsone, photopheresis, infliximab, and IVIG.

High-dose intravenous immunoglobulins for the treatment of autoimmune mucocutaneous blistering diseases: evaluation of its use in 19 cases.

BACKGROUND: The mainstay of therapy of autoimmune mucocutaneous blistering diseases has been prolonged high-dose systemic corticosteroids and immunosuppressive agents. Recently, high-dose intravenous immunoglobulin (IVIg) has been employed in selected cases, with excellent results in most of them. OBJECTIVE: We sought to evaluate the outcome of the use of IVIg in patients with autoimmune mucocutaneous blistering diseases refractory to conventional therapy or with contraindications for it. METHODS: We performed a retrospective analysis of clinical response to monthly cycles of IVIg in 19 patients affected with autoimmune mucocutaneous blistering diseases: 10 patients with pemphigus vulgaris (PV), 2 with pemphigus foliaceus (PF), 4 with mucous membrane pemphigoid (MMP), 2 with epidermolysis bullosa acquisita, and one with linear IgA bullous dermatosis. RESULTS: Four (21%) of 19 cases presented a complete response (2 PV, 1 MMP and 1 epidermolysis bullosa acquisita). Five (26%) patients did not respond to the treatment (3 PV, 1 PF, 1 MMP). Ten patients (53%) had a partial response. LIMITATIONS: This was a retrospective noncontrolled study with a heterogeneous group of patients. CONCLUSION: The effectiveness of IVIg was inferior to that previously reported. This difference could be attributed to the preparations employed, the different severity of the disease, or individual responses in each patient dependent on Fc receptor gamma polymorphisms.

Double filtration plasmapheresis can decrease factor XIII Activity.

Factor XIII (FXIII) produces cross-linkages among fibrin molecules within fibrin clots. Its deficiency is related with bleeding diathesis or retardation of wound healing. We report the possibility that intense double filtration plasmapheresis (DFPP) is associated with decreased FXIII activity. Five patients with various primary diagnoses were treated with DFPP and their FXIII activity was measured. Coagulation test results remained almost normal, but FXIII activities declined to less than 20% of their initial value before starting DFPP and 10% after DFPP in most cases. The cases that received intense DFPP therapy exhibited profoundly decreased FXIII activity. The clinical course demonstrated that DFPP caused the FXIII decrease. Fortunately, with careful observation, none of the patients experienced fatal bleeding. Only one case required fresh frozen plasma and an open hemostatic procedure because of prolonged postoperative bleeding. In general, DFPP most efficiently removes substances with the following characteristics: adequate molecular weight; long half-life; and small extravascular distribution volume. The FXIII properties meet all these characteristics. Consequently, we should devote much attention to FXIII activity during DFPP because it cannot be estimated from the usual coagulation tests. Patients who receive DFPP therapy, especially intensified therapy, should have FXIII measured during the course of therapy. Results show that DFPP can decrease FXIII activity. For this reason we recommend the measurement of FXIII when patients receive intense DFPP therapy with albumin replacement.

Autoimmune bullous diseases: diagnosis and management.

Autoimmune bullous diseases are a heterogenous group of diseases characterized by cutaneous and mucosal vesicles and bullae. Diagnosis is based on a combination of clinical, histopathological, and immunofluorescence findings. Current treatment, including vigilant wound care, significantly reduces disease morbidity and mortality.

Elucidating the interplay between IgG-Fc valency and FcγR activation for the design of immune complex inhibitors.

Autoantibody immune complex (IC) activation of Fcγ receptors (FcγRs) is a common pathogenic hallmark of multiple autoimmune diseases. Given that the IC structural features that elicit FcγR activation are poorly understood and the FcγR system is highly complex, few therapeutics can directly block these processes without inadvertently activating the FcγR system. To address these issues, the structure activity relationships of an engineered panel of multivalent Fc constructs were evaluated using sensitive FcγR binding and signaling cellular assays. These studies identified an Fc valency with avid binding to FcγRs but without activation of immune cell effector functions. These observations directed the design of a potent trivalent immunoglobulin G-Fc molecule that broadly inhibited IC-driven processes in a variety of immune cells expressing FcγRs. The Fc trimer, Fc3Y, was highly efficacious in three different animal models of autoimmune diseases. This recombinant molecule may represent an effective therapeutic candidate for FcγR-mediated autoimmune diseases.