Treatment Of Epidermolysis Bullosa Acquisita Research Articles

Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is a muco-cutaneous autoimmune disease characterized and caused by autoantibodies targeting type VII collagen (COL7). The treatment of EBA is notoriously difficult, with a median time to remission of 9 months. In preclinical EBA models, we previously discovered that depletion of regulatory T cells (Treg) enhances autoantibody-induced, neutrophil-mediated inflammation and blistering. Increased EBA severity in Treg-depleted mice was accompanied by an increased cutaneous expression of interferon gamma (IFN-γ). The functional relevance of IFN-γ in EBA pathogenesis had been unknown. Given that emapalumab, an anti-IFN-γ antibody, is approved for primary hemophagocytic lymphohistiocytosis patients, we sought to assess the therapeutic potential of IFN-γ inhibition in EBA. Specifically, we evaluated if IFN-γ inhibition has modulatory effects on skin inflammation in a pre-clinical EBA model, based on the transfer of COL7 antibodies into mice. Compared to isotype control antibody, anti-IFN-γ treatment significantly reduced clinical disease manifestation in experimental EBA. Clinical improvement was associated with a reduced dermal infiltrate, especially Ly6G+ neutrophils. On the molecular level, we noted few changes. Apart from reduced CXCL1 serum concentrations, which has been demonstrated to promote skin inflammation in EBA, the expression of cytokines was unaltered in the serum and skin following IFN-γ blockade. This validates IFN-γ as a potential therapeutic target in EBA, and possibly other diseases with a similar pathogenesis, such as bullous pemphigoid and mucous membrane pemphigoid.

Epidermolysis Bullosa Acquisita-Current and Emerging Treatments.

Epidermolysis bullosa acquisita (EBA) is a rare chronic autoimmune subepidermal blistering disease of the skin and mucous membranes, usually beginning in adulthood. EBA is induced by autoantibodies to type VII collagen, a major component of anchoring fibrils in the dermal-epidermal junction (DEJ). The binding of autoantibodies to type-VII collagen subsequently leads to the detachment of the epidermis and the formation of mucocutaneous blisters. EBA has two major clinical subtypes: the mechanobullous and inflammatory variants. The classic mechanobullous variant presentation consists of skin fragility, bullae with minimal clinical or histological inflammation, erosions in acral distribution that heal with scarring, and milia formation. The inflammatory variant is challenging to differentiate from other autoimmune bullous diseases, most commonly bullous pemphigoid (BP) but also mucous membrane pemphigoid (MMP), Brunsting-Perry pemphigoid, and linear IgA dermatosis. Due to its recalcitrance conventional treatment of epidermolysis bullosa acquisita is shown to be demanding. Here we discuss novel therapeutic strategies that have emerged and which could potentially improve the quality of life in patients with EBA.

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal–epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous diseases.

Colchicine: an ancient drug with novel applications.

Colchicine is a treatment for gout that has been used for more than a millennium. It is the treatment of choice for familial Mediterranean fever and its associated complication, amyloidosis. The 2009 U.S. Food and Drug Administration approval of colchicine as a new drug had research consequences. Recent investigations with large cohorts of patients with gout who have been taking colchicine for years have demonstrated novel applications within oncology, immunology, cardiology and dermatology. Some emerging dermatological uses include the treatment of epidermolysis bullosa acquisita, leucocytoclastic vasculitis, aphthous stomatitis and others. In this work we relate the history and the new horizon of this ancient medicine.

PDE4 Inhibition as Potential Treatment of Epidermolysis Bullosa Acquisita

Pemphigoid diseases such as epidermolysis bullosa acquisita (EBA) may be difficult to treat. In pemphigoid diseases, mucocutaneous blistering is caused by autoantibodies to hemidesmosomal antigens; in EBA the autoantigen is type VII collagen. Despite growing insights into pemphigoid disease pathogenesis, corticosteroids are still a mainstay of treatment. In experimental EBA, myeloid cell activation is a key event leading to blistering. Activation of these cells depends on phosphodiesterase (PDE) 4. We therefore evaluated the potential for PDE4 inhibition in EBA: PDE4 was highly expressed in inflammatory cells and in the epidermis of patients compared with healthy skin samples. PDE4 inhibitors rolipram, roflumilast, and roflumilast N-oxide prevented the release of immune complex-induced reactive oxygen species from polymorphonuclear leukocytes and separation of the dermal-epidermal junction of skin incubated with antibodies to collagen type VII and polymorphonuclear leukocytes. The PDE4 inhibitors also impaired CD62L shedding and decreased CD11b expression on immune complex-stimulated polymorphonuclear leukocytes. For invivo validation, experimental EBA was induced in mice by transfer of anti-collagen type VII IgG or immunization with collagen type VII. Roflumilast dose-dependently reduced blistering in antibody transfer-induced EBA and also hindered disease progression in immunization-induced EBA. PDE4 inhibition emerges as a new treatment modality for EBA and possibly other neutrophil-driven pemphigoid diseases.

Clinical Presentation, Pathogenesis, Diagnosis, and Treatment of Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is a chronic mucocutaneous autoimmune skin blistering disease. The pathogenic relevance of autoantibodies targeting type VII collagen (COL7) has been well-documented. Therefore, EBA is a prototypical autoimmune disease with a well-characterized pathogenic relevance of autoantibody binding to the target antigen. EBA is a rare disease with an incidence of 0.2 new cases per million and per year. The current treatment of EBA relies on general immunosuppressive therapy, which does not lead to remission in all cases. Therefore, there is a high, so far unmet medical need for the development of novel therapeutic options. During the last 10 years, several novel in vitro and in vivo models of EBA have been established. These models demonstrated a critical role of the genetic background, T cells, and cytokines for mediating the loss of tolerance towards COL7. Neutrophils, complement activation, Fc gamma receptor engagement, cytokines, several molecules involved in cell signaling, release of reactive oxygen species, and matrix metalloproteinases are crucial for autoantibody-induced tissue injury in EBA. Based on this growing understanding of the diseases' pathogenesis, several potential novel therapeutic targets have emerged. In this review, the clinical presentation, pathogenesis, diagnosis, and current treatment options for EBA are discussed in detail.

Epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune subepidermal bullous disease with clinical features similar to the genetic form of dystrophic epidermolysis bullosa. EBA is characterized by the presence of autoantibodies against type VII collagen which is a major component of the anchoring fibrils at the dermal-epidermal junction. EBA can be divided into two main clinical types; mechanobullous and inflammatory EBA. Mechanobullous EBA, referred to as classic EBA, presents with skin fragility, blisters and dystrophic changes on trauma-prone areas. Inflammatory EBA resembles other autoimmune subepidermal bullous diseases. Compelling evidence from mouse models supports a pathogenic role of autoantibodies against type VII collagen in EBA. Treatment of EBA is often unsatisfactory. The most widely used systemic treatment is corticosteroids. Colchicine and dapsone have been reported to be good treatment modalities when combined with corticosteroids. Some intractable cases of EBA have successfully been treated with intravenous immunoglobulin or rituximab.

抗 VII 型コラーゲン抗体価の経時的測定が有用であった後天性表皮水疱症の 1 例

抗 VII 型コラーゲン抗体価の経時的測定が有用であった後天性表皮水疱症の 1 例

Epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is a rare, acquired, chronic subepidermal bullous disease of the skin and mucosa characterized by autoantibodies to type VII collagen (C7) structures, a major component of anchoring fibrils, which attach the epidermis to the dermis. EBA patients have tissue-bound and circulating antitype C7 autoantibodies that attack type C7 and result in a reduction or perturbation of normally functioning anchoring fibrils. Patients with EBA have skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These immunoglobulin G antitype C7 antibodies are pathogenic, because when they are injected into mice, the mice develop an EBA-like blistering disease. In addition to the classical mechanobullous presentation, EBA also has several other distinct clinical syndromes similar to bullous pemphigoid, Brunsting-Perry pemphigoid, or cicatricial pemphigoid. Although treatment for EBA is often unsatisfactory, some therapeutic success has been achieved with colchicine, dapsone, plasmapheresis, photopheresis, infliximab, and intravenous immunoglobulin.

Successful treatment of epidermolysis bullosa acquisita with rituximab therapy

The Journal of DermatologyVolume 39, Issue 5 p. 477-479 LETTER TO THE EDITOR Successful treatment of epidermolysis bullosa acquisita with rituximab therapy Jong Hoon KIM, Jong Hoon KIM Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, KoreaSearch for more papers by this authorSang Eun LEE, Sang Eun LEE Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, KoreaSearch for more papers by this authorSoo-Chan KIM, Soo-Chan KIM Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, KoreaSearch for more papers by this author Jong Hoon KIM, Jong Hoon KIM Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, KoreaSearch for more papers by this authorSang Eun LEE, Sang Eun LEE Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, KoreaSearch for more papers by this authorSoo-Chan KIM, Soo-Chan KIM Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, KoreaSearch for more papers by this author First published: 02 October 2011 https://doi.org/10.1111/j.1346-8138.2011.01360.xCitations: 19 Soo-Chan Kim, M.D., Ph.D., Department of Dermatology, Yonsei University College of Medicine, Gangnam Severance Hospital, 712 Eonjuro, Gangnam-gu, Seoul 135-720, Korea. Email: [email protected] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume39, Issue5May 2012Pages 477-479 RelatedInformation

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

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. 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. 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. 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. 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.

Current concepts in the treatment of epidermolysis bullosa acquisita

Introduction: Long-term remission in EBA patients is difficult to achieve. Patients who are resistant or develop side effects to conventional immunosuppressive therapy (CIST) have been treated with several other agents.Areas covered: This review focuses on the clinical outcome in patients treated with a single drug or combination, and determines if long-term remission can be induced. Data on 71 patients was analyzed. There are no controlled trials. The regimens used included dapsone, colchicine, mesalazine, cyclosporine, mycophenolic acid, intravenous immunoglobulin, rituximab, daclizumab, extracorporeal photochemotherapy, and plasmapheresis. An algorithm on treating a patient has been presented.Expert opinion: The use of CIST, especially in wide spread and recalcitrant patients, usually does not produce a prolonged clinical remission and can have hazardous side effects. Intravenous immunoglobulin, rituximab and immunoadsorption have been successfully used in some, but the benefits from their use may require additional studies. The immediate future holds much promise for the development of a specific ELISA which may facilitate the early diagnosis of EBA. As the population ages, it is likely that the number of patients will increase and newer biological agents may emerge that may have a better clinical outcome. One of the challenges is to produce “targeted therapies”.

Épidermolyse bulleuse acquise

Epidermolysis bullosa acquisita (EBA) is a rare autoimmune subepidermal bullous disease with autoimmunity to the type VII collagen which is the major component of anchoring fibrils. Clinical manifestations of the classical EBA include skin fragility, blisters over the trauma-prone surfaces and milium cysts. Other presentations of EBA have been reported: mucosal predominant appearance reminiscent of cicatricial pemphigoid, bullous pemphigoid-like presentation and IgA-EBA. Making a definitive diagnosis of EBA could be difficult because specialized tests available in only some laboratories are necessary to confirm the clinical suspicion: immunoelectron microscopy demonstrating immune deposits on anchoring fibrils and immunoblotting or enzyme-linked immunosorbent assay (Elisa) detecting autoantibodies recognizing the type VII collagen. EBA frequently is associated with Crohn's disease and an inflammatory bowel disease must be ruled out in patients with EBA and abdominal manifestations. EBA potentially is serious, has usually a chronical evolution and is difficult to treat.There are no guidelines for treatment of EBA, which is adapted to clinical severity and include dapsone, cyclosporine and rituximab.

Epidermolysis bullosa acquisita: What’s new?

Type VII collagen is an adhesion molecule of the extracellular matrix in epithelial basement membranes, and the main constituent of anchoring fibrils at the dermal-epidermal junction (DEJ). Autoimmunity against this protein is causing the rare organ-specific epidermolysis bullosa acquisita (EBA). EBA is a rare acquired, heterogeneous, chronic blistering disease of skin disease of skin and mucous membranes characterized by subepidermal blisters and tissue-bound as well as circulating autoantibodies to the DEJ. EBA has several distinct clinical presentations with other subepidermal bullous diseases, such as mainly dystrophic epidermolysis bullosa or bullous pemphigoid. The circulating immunoglobulin G autoantibodies for EBA react with a 290-kDa dermal protein, type VII collagen, as detected by immunoblot analysis using dermal extracts. The pathogenicity of these autoantibodies has been demonstrated by experimental animal models, in which anti-type VII collagen antibodies injected into a mouse produced an EBA-like blistering disease in the animal. EBA cases often require high doses of systemic corticosteroids and a variety of immunosuppressants. Although treatment for EBA is frequently difficult and unsatisfactory, some therapeutic success has been reported with colchicine, dapsone, infliximab and i.v. immunoglobulin. In this review, we will focus on recent progress in our understanding of the clinical manifestations, the etiopathogenesis as well as the management of EBA.

Succès de l’association rituximab–corticoïdes généraux dans le traitement d’une épidermolyse bulleuse acquise récalcitrante

Epidermolysis bullosa acquisita (EBA) is a rare autoimmune subepidermal blistering disease; it is potentially serious and is often refractory to conventional treatments, including corticosteroids. We report a new case of successful treatment of EBA using rituximab (anti-CD20 antibody) without relapse after 1 year of follow-up.A 76-year-old man was seen for blisters of the skin and mucosa, atrophic scars and milia on areas of friction. The diagnosis of EBA was made on the basis of histological and immunohistochemical criteria. The patient was unsuccessfully treated with topical steroids, dapsone, topical tacrolimus, systemic steroids, mycophenolate mofetil, doxycycline and methotrexate. Four weekly infusions of rituximab of 375 mg/m(2) body area were performed, combined with systemic steroids: they proved beneficial within 3 weeks, with a noticeable improvement and no further blisters at 7 months. After 1 year of follow-up, the skin disease is still stable with 5 mg/day of prednisone alone being given.This is the eighth reported case of treatment of EBA with rituximab and the sixth successful therapeutic outcome, with good steroid sparing effect and undeniable improvement in quality of life within several months and good tolerability at 12 months of follow-up. This treatment may be proposed early in cases of EBA refractory to conventional treatments. However, clinical observation is necessary to study potential long-term adverse effects.

Epidermolysis bullosa acquisita: concise review and practical considerations

Introduction Epidermolysis bullosa acquisita (EBA) is a cutaneous subepi-dermal autoimmune blistering disorder (CSEAIBD) that resultsfrom the effects of IgG autoantibodies directed against the145-kDa noncollagenous amino-terminal (NC-1) domain ofcollagen VII, a major component of anchoring fibrils (Fig. 1).

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.

Rituximab in the treatment of epidermolysis bullosa acquisita

Rituximab in the treatment of epidermolysis bullosa acquisita

Treatment of epidermolysis bullosa acquisita with the humanized anti-Tac mAb daclizumab.

Epidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal blistering disease characterized by IgG anti-basement membrane autoantibodies to collagen VII. Since autoantibody formation in EBA patients is thought to be T-cell-dependent, the degree of T cell activation in three patients (all males, ages 33-44 years) was assessed by quantitation of soluble Tac, a fragment of the alpha-subunit of the high-affinity IL-2 receptor (CD25). Soluble Tac levels in all patients were elevated [highest random values, 2430, 920, and 560 IU/ml (normal range, 112-502)]. Based on such findings, these patients were treated with the humanized murine monoclonal anti-Tac antibody daclizumab (1 mg/kg, 6-12 iv treatments at 2- to 4-week intervals). All patients had a significant, rapid, and persistent decrease in lymphocyte CD25 expression. Though a moderate decrease in lymphocyte expression of 7G7, an IL-2 receptor epitope not bound by daclizumab, was noted, stable levels of CD3 cells and in vitro saturation studies indicated that daclizumab effectively bound CD25 and did not promote clearance of such cells from peripheral blood. There were no complications and no patient developed antibodies against daclizumab. While no apparent clinical benefit was seen in two patients with dermolytic disease, one patient with inflammatory EBA had a favorable response. While on daclizumab, this patient stopped prednisone, significantly reduced dapsone, and improved clinically. Furthermore, his disease flared when treatment was stopped, and resumption of daclizumab again effected improvement within 2 weeks. Daclizumab therapy is safe and well tolerated in EBA patients. It may be effective as a corticosteroid sparing agent in patients with inflammatory EBA.

Emerging treatment for epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is a rare, chronic, subepidermal, mucocutaneous blistering disease characterized by skin fragility and spontaneous as well as trauma-induced blisters that heal with scar formation and milia. Treatment is often frustrating because conventional therapy with corticosteroids and immunosuppressive agents frequently does not result in significant clinical improvement. We review the conventional treatment of EBA and critically analyze the literature on various adjuvants and therapeutic modalities that have recently been used. These include cyclosporine, colchicine, plasmapheresis, extracorporeal photochemotherapy, and intravenous gammaglobulins. Although the data are preliminary, they suggest that intravenous immunoglobulins may be a promising treatment modality for resistant, nonresponsive, or refractory EBA. The use of intravenous immunoglobulins results in significant improvement of skin and mucosal lesions, and it is quite safe, with minimal side effects. (J Am Acad Dermatol 2001;44:818-28.)