Protocolo Clínico e Diretrizes Terapêuticas da epidermólise bolhosa hereditária e adquirida / Clinical Protocol and Therapeutic Guidelines for bullous epidermolysis hereditary and acquired

INTRODUÇÃO: A epidermólisebolhosa(EB) é uma condição clínica caracterizada pela presença de bolhas e erosões na pele, e muitas vezes nas mucosas, geralmente após mínimos traumas. A EB pode ter causa genética ou autoimune, e, por conseguinte, é dividida entre as formas epidermólisebolhosa hereditária (EBH) ou epidermólisebolhosaadquirida (EBA), respectivamente. A EBApode acometer pele e mucosas, com diferentes fenótipos, na qual há produção de anticorpos contra o colágeno VII(1). Não há transmissão genética na EBA. APRESENTAÇÃO A proposta de elaboração do Protocolo Clínico e Diretrizes Terapêuticas de Epidermólise Bolhosa Hereditária e Adquirida foi apresentada aos membros do Plenário da CONITEC em sua 82ª Reunião Ordinária, os quais recomendaram favoravelmente ao texto. O Protocolo segue agora para consulta pública a fim de que se considere a visão da sociedade e para que se possa receber as suas valiosas contribuições, que poderão ser tanto de conteúdo científico quanto um relato de experiência. Gostaríamos de saber a sua opinião sobre a proposta como um todo, assim como se há recomendações que poderiam ser diferentes ou mesmo se algum aspecto importante deixou de ser considerado. DELIBERAÇÃO INICIAL: Os membros da CONITEC presentes na 82ª Reunião do Plenário, realizada nos dias 09 e 10 de outubro de 2019, deliberaram para que o tema fosse submetido à consulta pública com recomendação preliminar favorável à publicação deste Protocolo. CONSULTA PÚBLICA: O PCDT de Epidermólise Bolhosa Hereditária e Adquirida foi disponibilizado para consulta pública (CP) no. 60 no período de 12 a 31 de outubro de 2019. Foram 641 manifestações,das quais 618 eram provenientes de pessoa física e 23 de pessoa jurídica.Dentre as contribuições de pessoa física, a participação foi majoritariamente de contribuintes do sexo feminino (74%), branca (72%), entre 25 e 39 anos (51%), proveniente da região sudeste (70%) e familiar, amigo ou cuidador de paciente (41%). A maioria das contribuições julgou a qualidade do PCDT como muito boa (59%), 26% julgaram como boa, 12% como regular e 3% como ruim ou muito ruim. Todas as contribuições da consulta pública foram analisadas, discutidas e respondidas. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 83ª reunião do plenário realizada nos dias 6 e 7 de novembro de 2019, deliberaram, por unanimidade, recomendar a aprovação do Protocolo Clínico e Diretrizes Terapêuticas de Epidermólise Bolhosa Hereditária e Adquirida. O tema será encaminhado para a decisão do Secretário da SCTIE. Foi assinado o Registro de Deliberação nº 487/2019. DECISÃO: PORTARIA CONJUNTA Nº 11, DE 26 DE JUNHO DE 2020. Aprova o Protocolo Clínico e Diretrizes Terapêuticas da Epidermólise Bolhosa Hereditária e Adquirida.

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.

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.

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.

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.

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.

Immune mechanism-targeted treatment of experimental epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous dermatosis characterized by chronic mucocutaneous blistering caused by autoantibodies directed against type VII collagen. EBA causes a high morbidity and is difficult to treat. Model systems have significantly broadened our understanding of EBA pathogenesis, leading to the identification of numerous therapeutic targets. Of these, so far, a few have been evaluated for their therapeutic potential in preclinical models. In mice, EBA can be induced by transfer of anti-type VII collagen antibodies or by immunization with the protein. The latter model, immunization-induced EBA, is ideal to test drugs for their therapeutic efficacy. Here, mice with already established disease can be treated for prolonged periods. Albeit time consuming, results from immunization-induced EBA will pave the way for clinical application in patients. As the key pathogenic principle, that is, autoantibody-induced, leukocyte-mediated tissue injury and inflammation, is shared by other diseases, these findings may have translational applications beyond EBA.

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.

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.

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.

[Long-term use of an endovascular temperature catheter]. / Langzeitanwendung eines intravasalen Temperaturkatheters.

A patient suffering from severe cutaneous graft versus host disease (GvHD) developed generalized epidermolysis and refractory hypothermia. Due to the insufficient effect of traditional rewarming methods, an endovascular temperature catheter was placed via the femoral vein to achieve and maintain normothermia over a period of 31 days. This case shows that an endovascular temperature modulation device primarily made for short-term use may be safe and effective even over weeks and may offer an alternative to other rewarming methods in patients with severe epidermolysis and burns.

Epidermolysis bullosa acquisita: autoimmunity to anchoring fibril collagen.

Epidermolysis bullosa acquisita (EBA) is a rare and acquired autoimmune subepidermal bullous disease of skin and mucosa. EBA includes various distinct clinical manifestations resembling genetic dystrophic epidermolysis bullosa (DEB), Bullous pemphigus, Brunsting-Perry pemphigoid, or cicatricial pemphigoid. These patients have autoantibodies against type VII collagen (C7), an integral component of anchoring fibrils (AFs), which are responsible for attaching the dermis to the epidermis. Destruction or perturbation of the normal functioning AFs clinically results in skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These anti-C7 antibodies are "pathogenic" because when injected into a mouse, the mouse develops an EBA-like blistering disease. Currently, treatment is often unsatisfactory; however, some success has been achieved with colchicine, dapsone, photopheresis, plasmapheresis, infliximab, rituximab, and IVIG.

Model systems duplicating epidermolysis bullosa acquisita: a methodological review.

Epidermolysis bullosa acquisita (EBA) is a chronic mucocutaneous autoimmune skin blistering disease, in which generation of autoantibodies to type VII collagen (COL7) is the key factor for pathogenesis. Much of this current understanding of EBA pathogenesis has been obtained through the development and further application of respective model systems. In vitro model systems of EBA duplicate neutrophil activation by immune complexes of COL7 and anti-COL7 antibodies. Blister induction by anti-COL7 antibodies can be reproduced ex vivo by incubation of cryosections of human skin with anti-COL7 antibodies and neutrophils. Furthermore, EBA can be induced in mice by transfer of human or rabbit anti-COL7 IgG into adult mice, or by immunization of susceptible mouse strains with an immunodominant fragment within the non-collagenous 1 domain of COL7. However, our understanding of EBA pathogenesis is largely limited to mechanisms in autoantibody-induced tissue injury. Furthermore, these model systems of EBA have not been used to a large extent to evaluate the potential of novel treatment options. To foster a broader use of these elaborate model systems to specifically address these open issues, this review focuses on a detailed description of model systems for EBA, which should allow for a broad use of these models. This will hopefully lead to a better understanding of EBA pathogenesis, as well to a benefit in patient care.

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.

Epidermólisis ampollosa adquirida relacionada con el estrés / Acquired epidermolysis bullosa associated with stress

La epidermólisis ampollosa adquirida (EAA) es una enfermedad ampollosa rara, cuyas lesiones se desarrollan sobre piel no inflamada en relación a roces o traumatismos. Presentamos el caso de un varón de 53 años con brotes de ampollas en ambas piernas, probable relacionada con el estrés laboral. El diagnóstico de EAA fue establecido por estudio histológico y el paciente fue tratado con corticoides primero y después con colchicina (AU)

Acquired epidermolysis bullosa is a rare bullous disorder, with lesions in non-inflamed skin in relationship with grazes or traumas. We present the case of a 53 year-old man with blisters in both legs, probably due to an occupational stress. The diagnosis of acquired epidermolysis bullosa was established by histological study and firstly the patient was initially treated with steroids and then with colchicine (AU)