Epidermolysis Bullosa Acquisita: The 2019 Update

Abstract

Epidermolysis bullosa acquisita (EBA) is an orphan autoimmune disease. Patients with EBA suffer from chronic inflammation as well as blistering and scarring of the skin and mucous membranes. Current treatment options rely on non-specific immunosuppression, which in many cases, does not lead to a remission of treatment. Hence, novel treatment options are urgently needed for the care of EBA patients. During the past decade, decisive clinical observations, and frequent use of pre-clinical model systems have tremendously increased our understanding of EBA pathogenesis. Herein, we review all of the aspects of EBA, starting with a detailed description of epidemiology, clinical presentation, diagnosis, and current treatment options. Of note, pattern analysis via direct immunofluorescence microscopy of a perilesional skin lesion and novel serological test systems have significantly facilitated diagnosis of the disease. Next, a state-of the art review of the current understanding of EBA pathogenesis, emerging treatments and future perspectives is provided. Based on pre-clinical model systems, cytokines and kinases are among the most promising therapeutic targets, whereas high doses of IgG (IVIG) and the anti-CD20 antibody rituximab are among the most promising "established" EBA therapeutics. We also aim to raise awareness of EBA, as well as initiate basic and clinical research in this field, to further improve the already improved but still unsatisfactory conditions for those diagnosed with this condition.

Keywords: animal models; diagnosis; epidermolysis bullosa acquisita; pathogenesis; treatment.

Figure 1

Diagram of different clinical forms of EBA. LAD, linear IgA disease. MMP, mucous membrane pemphigoid; EBA, epidermolysis bullosa acquisita; MM-EBA, mucous membrane EBA.

Figure 2

Different clinical forms of EBA. All patients were documented at the first visit in a center for auto-immune bullous disease. (Left) Patient with a classical/mechanobullous form of EBA: lesions are preferably localized to the extensor skin surfaces and trauma-prone sites, i.e., dorsal hands knees elbows and ankles. Tense or flaccid bullous lesions are surrounded by non-inflamed skin; erosions are covered or not by crusts; one erosion with angular contours had been induced by adhesive plaster; old lesions have healed with milium formation and/or are atrophic papery scar. (Middle) Patient with a BP-like form of EBA, with little blistering: urticarial plaques with small or large bullous lesions as in BP, but location of lesions on extensor areas of limbs, hands and scalp, and scars and extensor areas of the face (not shown) and limbs (atypical for BP). (Right) Patient with a BP-like form of EBA, with extensive blistering: bullous lesions and erosions on erythematous skin in flexural areas of limbs (tight and arm) as in BP but also bullous lesions and erosions on normal skin and involvement of extensor area of the limbs and scalp, atypical for a BP involvement of the scalp (not shown) and both flexural and extensor areas of limbs extremities with bullous lesions and erosions on erythematous but also normal skin. The tongue and the lips are the most frequent sites of mucosal lesions in all EBA variants. Other mucosal lesions (not shown) are possible regardless of the variant of EBA The involvement of nasal and buccal mucous membrane are visible in all EBA variants.

Figure 3

Standard histology. (Left) Histological study of lesional skin biopsies in a patient with a classical/mechanobullous form of EBA, subepidermal cleavage without dermal infiltrate; bottom, milium cyst in the dermis. (Middle) Patient with a BP-like form of EBA, subepidermal cleavage with fibrin in the blister cavity and mild dermal infiltrate. Bottom, Neutrophils along the dermo-epidermal junction (Right) Patient with a BP-like form of EBA, one intraepidermal bullous lesion and one subepidermal bullous lesion with dense infiltrate in its cavity prolonged by a cleft in the hair follicle; bottom, a dermal papillary microabcesse of neutrophils.

Figure 4

Diagnosis of EBA by direct immunofluorescence. (A) All pemphigoid variants are characterized by linear deposition of immunoglobulins and/or complement along the epidermal basement membrane zone. Serration pattern can be separated in an n-serrated pattern (blistering diseases with binding above the lamina densa with antibodies against hemidesmosomal components, e.g., BP, pemphigoid gestationis, mucous membrane pemphigoid, anti-p200 pemphigoid, and anti-laminin 332 pemphigoid, exept MM-EBA) and a u-serrated pattern (sublamina densa binding diseases caused by autoantibodies against COL7, e.g., EBA and bullous SLE). (B) In some cases, it is not possible to determine the serration pattern, especially in mucosal biopsies. In these cases, the level of the deposition of antibodies can be determined by fluorescent overlay antigen mapping (FOAM). FOAM is a technique that is based on the possibility of visualizing a targeted antigen relative to a topographic marker. For instance, using red staining, it is used for BP180 as a topographic reference marker, and green staining is used for IgA deposits. In the case of IgA-EBA, separate patterns of IgA deposits (green) and BP180 (red) can be observed with red staining on the dermal side.

Figure 5

Pathogenesis of EBA. (1) Genetic factors and the skin microbiome promote a tolerance loss. (2) This phenomenon is mediated by the interaction of APCs with autoreactive B and T cells, leading to clonal expansion and differentiation into plasma cells. Autoantibodies against COL7 are released into the blood circulation and effector organs. (3) During inflammation, galactosylation of antibodies may differ. High galactosylation of IgG is crucial for these anti-inflammatory properties, whereas low galactosylation is pro-inflammatory. (4) Binding of autoantibodies to DEJ in the skin induces complement deposition, pro-inflammatory cytokine and mediator release and subsequently leukocyte extravasation. (5) Immune complexes bind in a Fc-dependent manner to neutrophils and induce a signaling cascade leading to activation, including the (6) release of ROS and matrix metalloproteases. In addition to neutrophils, other cell types are involved in split formation, as shown for monocytes/macrophages, NKT and γδ T cells. By contrast, T_reg cells have an inhibitory effect on EBA progression. (7) Resolution of autoantibody-induced tissue injury. T_reg, regulatory T cell; NKT, natural killer cell; C, complement; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; LTB4, leukotriene B4; PDE4, phosphodiesterase 4; ROS, reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; MMPs, matrix metalloproteinases; APC, antigen-presenting cell; CD, cluster of differentiation; SYK, spleen tyrosine kinase; Lyn, tyrosine-Protein Kinase Lyn; HSP, heat shock protein; AKT, protein kinase B; NCF1, neutrophil cytosolic factor 1; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; HCK, tyrosine-protein kinase HCK; FGR, tyrosine-protein kinase FGR; RORα, retinoid-related orphan receptor-alpha; BLT1, leukotriene B4 receptor 1; LTB4, leukotriene B4.