 |
|
|
|
|
|
|
|
|
 |
 |
 |
 |
 |
 |
 |
 |
|
Background
This disease is also known as dermolytic pemphigoid. Unlike epidermolysis bullosa, it is acquired, usually occuring in mid-adult life. These non-inflammatory bullae occur at sites of trauma, especially along the extensor surfaces of the limbs, healing with atrophic scars and milia. The mucous membranes may be involved in 30-50% of cases.
It has been associated with many autoimmune disorders including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple endocrinopatny syndrome, and mixed cryoglobulinemia. Pencillamine and pregnancy may trigger the disease.
The histopathology is a cell-poor subepidermal bulla with some fibrin and scattered inflammatory cells. By the salt-split skin method, IgG antibodies are directed against type VII collagen attached to the dermal blister floor. The roof of the blister has laminin, bullous pemphigoid antigen, and type IV collagen.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS EBA INCIDENCE Rare AGE RANGE-MEDIAN Usually adults
DISEASE ASSOCIATIONS CHARACTERIZATION CROHN'S DISEASE Localized epidermolysis bullosa acquisita of the esophagus in a patient with Crohn's disease.
Schattenkirchner S, Lemann M, Prost C, Caux F, Guigui B, Cadot M, Bertheau P, Grateau C, Heller M.
Centre d'Etudes et de Diagnostic des Maladies Bulleuses, Hopital Saint-Louis, Paris, France.
Am J Gastroenterol 1996 Aug;91(8):1657-9 Abstract quote
Epidermolysis bullosa acquisita is a rare autoimmune subepidermal bullous disease that affects both the skin and mucosae and is frequently associated with Crohn's disease.
We report the case of a 27-yr-old man with Crohn's disease who presented with localized epidermolysis bullosa acquisita of the esophagus, without any other mucosal or cutaneous lesions. The patient was successfully treated with sulfasalazine.
MULTIPLE MYELOMA Epidermolysis bullosa acquisita and multiple myeloma.
Engineer L, Dow EC, Braverman IM, Ahmed AR.
Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine; the Department of Medicine, New England Baptist Hospital, Boston; and the Department of Dermatology, Yale University School of Medicine, New Haven.
J Am Acad Dermatol 2002 Dec;47(6):943-6 Abstract quote The coexistence in the same patient of epidermolysis bullosa acquisita (a rare, autoimmune, acquired mucocutaneous blistering disorder) and multiple myeloma (a plasma cell neoplasm) is extremely uncommon.
We describe a patient in whom both of these diseases occurred simultaneously. Intravenous immunoglobulins were used to treat both diseases.
PHOTOSENSIVITY Epidermolysis bullosa acquisita with ultraviolet radiationsensitivity.
Jappe U, Zillikens D, Bonnekoh B, Gollnick H.
Departments of Dermatology and Venereology, Otto-von-Guericke-University of Magdeburg, Germany; University of Wurzburg, Germany.
Br J Dermatol 2000 Mar;142(3):517-20 Abstract quote
A 37-year-old male patient developed a bullous eruption and erythematous plaques mainly in exposed areas following prolonged sun exposure. In addition, blisters were noted on oral and nasal mucous membranes.
Histopathological examination of a lesional skin biopsy revealed a subepidermal blister. Linear deposition of IgG and C3 at the epidermal basement membrane zone was revealed by direct immunofluorescence microscopy of a perilesional skin biopsy. Indirect immunofluorescence on 1 mol/L salt-split skin showed binding of autoantibodies to the dermal side of the split. Immunoblot analysis of dermal extracts demonstrated that the patient's serum contained IgG antibodies against type VII collagen, whereas no reaction was seen with epidermal extracts or by enzyme-linked immunosorbent assay using a recombinant form of bullous pemphigoid 180. Standardized ultraviolet (UV) radiation provocation induced blistering with both UVA (13.5 J/cm2) and UVB (0. 04 J/cm2) within 24 h clinically and histologically. E
xternal and systemic UV-protective medication and nine cycles of high dosage immunoglobulins given intravenously (1.2 g/kg body weight over 2-3 days every 4 weeks) resulted in the cessation of blister formation. To the best of our knowledge, this is the first report of a case of epidermolysis bullosa acquisita with sensitivity to UV.
PSORIASIS Psoriasis vulgaris coexistent with epidermolysis bullosa acquisita.
Endo Y, Tamura A, Ishikawa O, Miyachi Y, Hashimoto T.
Department of Dermatology, Gunma University School of Medicine, Japan.
Br J Dermatol 1997 Nov;137(5):783-6 Abstract quote
Autoimmune bullous diseases, such as bullous pemphigoid or pemphigus vulgaris, occasionally develop in psoriatic patients. In addition, a novel subepidermal bullous disease with autoantibodies against a lower lamina lucida antigen of 200 kDa has recently been reported in association with psoriasis.
We describe here a patient with psoriasis vulgaris who developed epidermolysis bullosa acquisita (EBA). Direct immunofluorescence revealed linear deposition of IgG and C3 at the basement membrane zone. The patient's serum bound to the dermal side of salt-split normal human skin. However, immunoblot analysis demonstrated that the patient's serum reacted with an EBA antigen of 290 kDa. EBA should be included in the list of autoimmune diseases associated with psoriasis vulgaris.
PATHOGENESIS CHARACTERIZATION COLLAGEN TYPE VII Epitope mapping of type VII collagen. Identification of discrete peptide sequences recognized by sera from patients with acquired epidermolysis bullosa.
Lapiere JC, Woodley DT, Parente MG, Iwasaki T, Wynn KC, Christiano AM, Uitto J.
Department of Dermatology, Jefferson Medical College, Philadelphia, Pennsylvania.
J Clin Invest 1993 Oct;92(4):1831-9 Abstract quote
Epidermolysis bullosa acquisita (EBA) is an acquired blistering skin disease characterized by the presence of IgG autoantibodies that recognize type VII (anchoring fibril) collagen.
In this study, we have mapped the antigenic epitopes within the type VII collagen alpha chain by Western immunoblotting analysis with sera from 19 patients with EBA, using bacterial collagenase- or pepsin-resistant portions of type VII collagen and a panel of 12 recombinant fusion proteins corresponding to approximately 80% of the primary sequence of the alpha 1 (VII) collagen polypeptide. These studies identified four major immunodominant epitopes localized within the amino-terminal, noncollagenous (NC-1) domain.
In addition to EBA, sera from three patients with bullous systemic lupus erythematosus (BSLE) were tested. The pattern of epitopes recognized by these sera were similar to those noted with EBA, suggesting that the same epitopes could serve as autoantigens in both blistering conditions.
In contrast, sera from healthy controls or from patients with unrelated blistering skin diseases did not react with type VII collagen epitopes. Collectively, the results indicate that the immunodominant epitopes in EBA and BSLE lie within the noncollagenous regions of type VII collagen.
The precise role of the circulating autoantibodies in the pathogenesis of these blistering diseases remains to be elucidated. Conceivably, however, such antibodies could disrupt the assembly of type VII collagen into anchoring fibrils and/or interfere with their interactions with other extracellular matrix molecules within the cutaneous basement membrane zone.
A novel variant of acquired epidermolysis bullosa with autoantibodies against the central triple-helical domain of type VII collagen.
Tanaka H, Ishida-Yamamoto A, Hashimoto T, Hiramoto K, Harada T, Kawachi Y, Shimizu H, Tanaka T, Kishiyama K, Hopfner B, Takahashi H, Iizuka H, Bruckner-Tuderman L.
Department of Dermatology, Asahikawa Medical College, Japan
Lab Invest 1997 Dec;77(6):623-32 Abstract quote
Epidermolysis bullosa acquisita and bullous systemic lupus erythematosus are autoimmune bullous disorders, with tissue-bound and circulating autoantibodies reactive with the noncollagenous NC1 domain of type VII collagen (C-VII).
Here, we describe a novel acquired bullous dermatosis with autoantibodies against the triple-helical domain of C-VII. Three patients, all Japanese children, presented with widespread inflammatory tense blisters.
Histologically, subepidermal tissue separation was noted with inflammatory infiltrate in the superficial dermis. Direct immunofluorescence staining revealed linear IgG/C3 deposits along the dermal-epidermal junction. Circulating IgG anti-basement membrane zone autoantibodies stained the dermal side of normal skin separated with 1 M NaCl. Direct and indirect immunoelectron microscopy using colloidal gold labeling showed that patient sera reacted with anchoring fibrils. The gold particles were localized both near the lamina densa and on the central banded portion of the fibrils. The sera reacted with C-VII in immunoblots. Epitope analyses with natural and recombinant fragments of C-VII disclosed that the sera did not recognize the NC1 domain of C-VII, but the central triple-helical domain of this anchoring fibril protein.
Thus, the present probands show a hitherto unrecognized variant of epidermolysis bullosa acquisita, with autoantibodies against epitopes in the collagenous domain of C-VII.
NC1 domain of type VII collagen binds to the beta3 chain of laminin 5 via a unique subdomain within the fibronectin-like repeats.
Chen M, Marinkovich MP, Jones JC, O'Toole EA, Li YY, Woodley DT.
Department of Dermatology, Cell and Molecular Biology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Invest Dermatol 1999 Feb;112(2):177-83 Abstract quote
Type VII collagen, the major component of anchoring fibrils, consists of a central collagenous triple-helical domain flanked by two noncollagenous, globular domains, NC1 and NC2. Approximately 50% of the molecular mass of the molecule is consumed by the NC1 domain.
We previously demonstrated that NC1 binds to various extracellular matrix components including a complex of laminin 5 and laminin 6 (Chen et al, 1997a). In this study, we examined the interaction of NC1 with laminin 5 (a component of anchoring filaments). Both authentic and purified recombinant NC1 bound to human and rat laminin 5 as measured by enzyme-linked immunosorbant assay and by binding of 125I-radiolabeled NC1 to laminin 5-coated wells, but not to laminin 1 or albumin. NC1 bound predominantly to the beta3 chain of laminin 5, but also to the gamma2 chain when examined by a protein overlay assay. The binding of 125I-NC1 to laminin 5 was inhibited by a 50-fold excess of unlabeled NC1 or de-glycosylated NC1, as well as a polyclonal antibody to laminin 5 or a monoclonal antibody to the beta3 chain. In contrast, the NC1-laminin 5 interaction was not affected by a monoclonal antibody to the alpha3 chain. Using NC1 deletion mutant recombinant proteins, a 285 AA (residues 760-1045) subdomain of NC1 was identified as the binding site for laminin 5. IgG from an epidermolysis bullosa acquisita serum containing autoantibodies to epitopes within NC1 that colocalized with the laminin 5 binding site inhibited the binding of NC1 to laminin 5.
Thus, perturbation of the NC1-laminin 5 interaction may contribute to the pathogenesis of epidermolysis bullosa acquisita.
Inflammatory variant of epidermolysis bullosa acquisita with IgG autoantibodies against type VII collagen and laminin alpha3.
Jonkman MF, Schuur J, Dijk F, Heeres K, de Jong MC, van der Meer JB, Yancey KB, Pas HH.
Department of Dermatology, University of Groningen, The Netherlands.
Arch Dermatol 2000 Feb;136(2):227-31 Abstract quote
BACKGROUND: The inflammatory variant of epidermolysis bullosa acquisita (EBA) may clinically closely resemble bullous or cicatricial pemphigoid. Patients with inflammatory EBA have IgG autoantibodies against type VII collagen. Patients with anti-epiligrin cicatricial pemphigoid have IgG autoantibodies against laminin 5.
OBSERVATION: We describe a patient with inflammatory EBA exhibiting nonscarring oral and vaginal involvement. Indirect immunofluorescence using skin substrate lacking an epidermal basement membrane molecule, direct immunoelectron microscopy, immunoblot, and immunoprecipitation studies revealed the simultaneous presence of circulating IgG autoantibodies against type VII collagen and laminin alpha3. A final diagnosis of EBA was based on the sublamina densa level of blister formation.
CONCLUSION: This case illustrates the clinical and immunological overlap between EBA and anti-epiligrin cicatricial pemphigoid, a unique finding that may have developed as a consequence of epitope spreading.
Autoantibodies to type VII collagen have heterogeneous subclass and light chain compositions and their complement-activating capacities do not correlate with the inflammatory clinical phenotype.
Gandhi K, Chen M, Aasi S, Lapiere JC, Woodley DT, Chan LS.
Department of Dermatology, Northwestern University Medical School, Chicago, Illinois 60611-3010, USA.
J Clin Immunol 2000 Nov;20(6):416-23 Abstract quote
Epidermolysis bullosa acquisita and bullous systemic lupus erythematosus are blistering skin diseases characterized by IgG autoantibodies that predominantly target the noncollagenous domain 1 of type VII collagen, a skin basement membrane component. The basic immunologic events leading to the blistering processes in these diseases remains unclear.
We defined the subclass and light chain compositions of the IgG autoantibodies in 15 patients, in order to gain insight into the blistering mechanism. Immunofluorescence correlated the patients' in vivo-bound and circulating antibasement membrane autoantibodies. Four eukaryotic recombinant proteins, including one full-length and three truncated noncollagenous domain 1 proteins generated by sequential deletion of C-terminal amino acids, were used to perform enzyme-linked immunosorbent assay to detect the patients' anti-type VII collagen autoantibodies.
The majority of patients' autoantibodies contained both complement-activating and non-complement-activating IgG subclasses. The presence or absence of complement-activating IgG autoantibody subclasses did not correlate with the inflammatory or noninflammatory clinical phenotype. The majority of tested sera contained both kappa and lambda light chain autoantibodies. All sera that reacted to the full-length noncollagenous domain 1 also reacted to the smallest truncated protein containing the cartilage matrix protein and the first three fibronectinlike repeats.
The patients' anti-type VII collagen autoantibodies, likely to be polyclonal in nature, may contribute to the pathogenesis of the blistering process by both complement-dependent inflammatory injury and complement-independent mechanical disruption of the anchoring function of type VII collagen. The N-terminal region of the noncollagenous domain 1 may contain an important antigenic epitope targeted by the IgG autoantibodies.
The carboxyl terminus of type VII collagen mediates antiparallel dimer formation and constitutes a new antigenic epitope for epidermolysis Bullosa acquisita autoantibodies.
Chen M, Keene DR, Costa FK, Tahk SH, Woodley DT.
Department of Medicine, Division of Dermatology, University of Southern California, Los Angeles, California 90033, USA.
J Biol Chem 2001 Jun 15;276(24):21649-55 Abstract quote
Type VII collagen, the major component of anchoring fibrils, consists of a central collagenous triple-helical domain flanked by two noncollagenous domains, NC1 and NC2. The NC2 domain has been implicated in catalyzing the antiparallel dimer formation of type VII procollagen. In this study, we produced the entire 161 amino acids of the NC2 domain plus 186 amino acids of adjacent collagenous domain (NC2/COL) and purified large quantities of the recombinant NC2/COL protein. Recombinant NC2/COL readily formed disulfide-bonded hexamers, each representing one antiparallel dimer of collagen VII. Removal of the collagenous helical domain from NC2/COL by collagenase digestion abolished the antiparallel dimer formation.
Using site-directed mutagenesis, we found that mutation of either cysteine 2802 or cysteine 2804 alone within the NC2 domain blocked antiparallel dimer formation. In contrast, a single cysteine mutation, 2634, within the collagenous helical domain had no effect. A generated methionine to lysine substitution, M2798K, that is associated with recessive dystrophic epidermolysis bullosa, was unable to form antiparallel dimers. Furthermore, autoantibodies from epidermolysis bullosa acquisita patients also reacted with NC2/COL.
We conclude that NC2 and its adjacent collagenous segment mediate antiparallel dimer formation of collagen VII. Epidermolysis bullosa acquisita autoantibodies bound to this domain may destabilize anchoring fibrils by interfering with antiparallel dimer assembly leading to epidermal-dermal disadherence.
LABORATORY/RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC LABORATORY MARKERS CIRCULATING ANTIBODIES Development of an ELISA for rapid detection of anti-type VII collagen autoantibodies in epidermolysis bullosa acquisita.
Chen M, Chan LS, Cai X, O'Toole EA, Sample JC, Woodley DT.
Department of Dermatology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Invest Dermatol 1997 Jan;108(1):68-72 Abstract quote
Epidermolysis bullosa acquisita (EBA) is an acquired blistering skin disease characterized by the presence of IgG autoantibodies to type VII collagen. EBA autoantibodies recognize four major immunodominant epitopes localized within the amino-terminal, noncollagenous (NC1) domain.
In this study, we developed a rapid, quantitative enzyme-linked immunosorbent assay (ELISA) to detect autoantibody activity against the complete NC1 domain of type VII collagen with the use of an eukaryotic-expressed, recombinant human NC1 antigen. With the ELISA, we tested serum from patients with EBA (n = 24), bullous systemic lupus erythematosus (BSLE) (n = 3), bullous pemphigoid (n = 16), pemphigus (n = 11), and normal controls (n = 12). All EBA and BSLE serum, including four sera that were negative by indirect immunofluorescence, demonstrated reactivity with immobilized NC1 in the ELISA. In contrast, none of the sera from healthy control subjects or patients with unrelated blistering skin diseases reacted with NC1. The EBA sera also reacted with recombinant NC1 by immunoblot analysis but with less sensitivity.
Thus, the newly developed ELISA using recombinant NC1 is a sensitive, specific assay and a useful tool for rapidly screening EBA and BSLE serum.
Epidermolysis bullosa acquisita associated with epidermal-binding circulating antibodies.
Wakelin SH, Bhogal B, Black MM, Allen J, Wojnarowska F, Hashimoto T, Farr PM, Swain AF.
Department of Dermatology, Oxford Radcliffe Hospital, U.K.
Br J Dermatol 1997 Apr;136(4):604-9 Abstract quote
Epidermolysis bullosa acquisita (EBA) is a rare, immunobullous disease, characterized by circulating and tissue-bound antibodies against type VII collagen (C7) of anchoring fibrils in the cutaneous basement membrane zone. These antibodies localize to the dermal aspect of salt-split skin on indirect and direct immunofluorescence (IMF).
We report two patients with clinical features of EBA, in whom circulating IgG antibodies bound to the epidermal aspect of salt-split skin. In both patients direct IMF of salt-split perilesional skin revealed dermal IgG deposits, and direct immunogold immunoelectron microscopy showed antibody deposits in the region of anchoring fibrils. Their serum failed to react with epidermal or dermal extracts on Western immunoblotting. Epidermal-binding antibodies have not been reported previously in association with EBA, and the IMF findings in these cases suggest the development of autoantibodies to additional epidermal-associated antigens.
Target antigen heterogeneity has been reported in most other immunobullous diseases, and may be a hitherto unrecognized feature of EBA.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL VARIANTS CHILDHOOD Epidermolysis bullosa acquisita in childhood.
Callot-Mellot C, Bodemer C, Caux F, Bourgault-Villada I, Fraitag S, Goudie G, Heller M, de Prost Y, Prost C.
Department of Dermatology, Hopital Necker-Enfants Malades, Paris, France.
Arch Dermatol 1997 Sep;133(9):1122-6 Abstract quote
BACKGROUND: Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous disease characterized by the presence of antitype VII collagen antibodies, leading to the formation of bullae in the dermoepidermal junction. This disease is rare in childhood.
OBSERVATIONS: We report 3 new cases of EBA in children. The 3 patients were similar; all 3 children were black, with a clinical phenotype resembling linear IgA bullous disease in children and typical histologic and immunologic features of EBA. In the 3 patients, diagnosis was proven using immune electron microscopy and Western blot analysis, where antitype VII collagen antibodies were demonstrated. Patients 1 and 2 were successfully treated with a combination of prednisone and dapsone. In patient 3, the lesions healed without specific therapy. We found 11 other pediatric cases of EBA in the literature and studied those cases in addition to the cases presented herein to describe the characteristics of EBA in childhood.
CONCLUSIONS: Epidermolysis bullosa acquisita is a rare disease in childhood. Mucosal involvement is frequent and severe. Because the clinical features are misleading, the use of immune electron microscopy and Western blot analysis is essential to making a diagnosis. Treatment with a combination of prednisone and dapsone is often effective. The prognosis in children is better than it is in adult patients.
Epidermolysis bullosa acquisita in childhood.
Su JC, Varigos GA, Dowling J.
Department of Dermatology, Royal Children's Hospital, Parkville, Victoria, Australia.
Australas J Dermatol 1998 Feb;39(1):38-41 Abstract quote
This case report of an 11-year-old girl describes a juvenile form of epidermolysis bullosa acquisita, an autoimmune disease of IgG antibodies to basement membrane type 7 collagen. Our case illustrates an unusually severe, acute inflammatory presentation of this condition with prominent mucosal and constitutional features requiring admission to a paediatric burns unit.
The treatment consisted of supportive topical and systemic agents, prednisolone and dapsone. She responded to dapsone alone and the course of the illness was uneventful.
Epidermolysis bullosa acquisita in childhood--a case mimicking chronic bullous dermatosis of childhood.
Park SB, Cho KH, Youn JL, Hwang DH, Kim SC, Chung JH.
Department of Dermatology, Seoul National University College of Medicine, Korea.
Clin Exp Dermatol 1997 Sep;22(5):220-2 Abstract quote
Epidermolysis bullosa acquisita (EBA) is rarely reported in childhood, but we now describe a 6-year-old Korean girl with the condition. She presented with multiple tense bullae annularly distributed on the perioral, periorbital and genital areas, and was successfully treated with dapsone. The clinical and histological features were similar to those of chronic bullous dermatosis of childhood.
We review seven previously reported childhood EBA cases and contrast their features with those of adult EBA. We suggest that some childhood EBA is different from the adult form and shares features with chronic bullous dermatosis of childhood.
CORNEA Bilateral corneal involvement in epidermolysis bullosa acquisita.
Dantas PE, Nishiwaki-Dantas MC, Seguim MH, Cursino JW.
Department of Ophthalmology, Santa Casa Hospital, Sao Paulo, Brazil.
Cornea 2001 Aug;20(6):664-7 Abstract quote
PURPOSE: To report clinical and laboratory findings of bilateral corneal involvement in a patient with epidermolysis bullosa acquisita.
METHODS: A 25-year-old man with a history of progressive and painless loss of vision in both eyes presented to our service with bilateral corneal involvement: peripheral corneal perforation in one eye and advanced corneal thinning in the other eye. There was concomitant dermatologic bullous disease. Clinical and laboratory exams were analyzed.
RESULTS: The patient was diagnosed as having epidermolysis bullosa acquisita. Therapeutic corneal patch graft and conjunctival resection with cryotherapy were done, with satisfactory results.
CONCLUSION: Bilateral corneal involvement in epidermolysis bullosa acquisita is described. To the best of our knowledge, this is the first description of such a case. Surgical management of the ocular findings associated with systemic therapy with colchicine seems to be a good therapeutic option in the management of this defying disease.
ESOPHAGUS Nonscarring inflammatory epidermolysis bullosa acquisita with esophageal involvement and linear IgG deposits.
Taniuchi K, Inaoki M, Nishimura Y, Mori T, Takehara K.
Department of Dermatology, Kanazawa University School of Medicine, Japan.
J Am Acad Dermatol 1997 Feb;36(2 Pt 2):320-2 Abstract quote
A 24-year-old woman with autoimmune thrombocytopenia and hypothyroidism had an inflammatory bullous eruption in the mouth, face, and trunk that left no milia or scars after healing.
Histologic examination revealed a subepidermal bulla and a neutrophil infiltration. Direct immunofluorescence examination showed deposition of IgG and C3 in the basement membrane zone (BMZ). Indirect immunofluorescence examination with 1M sodium chloride-split skin showed IgG binding to the dermal side. Immunoblot analysis demonstrated IgG autoantibodies reacting with 290 kD dermal protein. We diagnosed this as epidermolysis bullosa acquisita (EBA) with a nonscarring inflammatory feature. Treatment with oral dapsone, 75 mg, and prednisolone, 20 mg, cleared the eruption. Reduction of the prednisolone dosage was associated with multiple erosions in the esophagus. Direct immunofluorescence examination revealed linear deposition of IgG in the esophageal BMZ.
To our knowledge, this is the first report of EBA with esophageal involvement and deposition of IgG in the BMZ of the esophagus.
IgA EBA IgA-epidermolysis bullosa acquisita in a child resulting in blindness.
Caux F, Kirtschig G, Lemarchand-Venencie F, Venencie PY, Hoang-Xuan T, Robin H, Dubertret L, Prost C.
Service de Dermatologie, Hopital Saint-Louis, Paris, France.
Br J Dermatol 1997 Aug;137(2):270-5 Abstract quote
Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal bullous disease characterized by IgG autoantibodies directed against type VII collagen, the major component of anchoring fibrils. The classical phenotype of EBA is a non-inflammatory, mechanobullous disease resembling the dystrophic forms of inherited epidermolysis bullosa. Mucous membrane involvement is frequent but usually mild.
We report a 1-year-old girl suffering from IgA-EBA, who presented with an initial eruption of disseminated urticarial lesions and tense blisters of the skin but subsequently developed severe oral and ocular lesions reminiscent of cicatricial pemphigoid. Direct immunofluorescence of the skin and buccal mucosa revealed linear IgA and C3 at the basement membrane zone (BMZ). IgA anti-BMZ autoantibodies stained the dermal side of salt-split skin by indirect immunofluorescence and recognized a dermal protein of 290 kDa co-migrating with type VII collagen by immunoblotting.
Direct and indirect immunoelectron microscopy revealed IgA deposits overlying the anchoring fibrils. The ocular involvement led to total blindness in spite of intense treatment. This case of childhood IgA-EBA is particularly striking because of the cicatricial pemphigoid phenotype with severe ocular involvement which resulted in blindness. It reinforces the necessity to use modern immunological methods to classify autoimmune bullous diseases in order to allow early and appropriate treatment.
Ocular involvement in IgA-epidermolysis bullosa acquisita.
Bauer JW, Schaeppi H, Metze D, Muss W, Pohla-Gubo G, Hametner R, Ruckhofer J, Grabner G, Hintner H.
Department of Dermatology, General Hospital Salzburg, Salzburg, Austria.
Br J Dermatol 1999 Nov;141(5):887-92 Abstract quote
Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous disease with frequent ocular involvement, but visual loss is rare. In contrast, EBA patients with predominant IgA autoantibodies more frequently develop severe ocular involvement, which tends to be refractory to therapy.
We report two patients with 'IgA-EBA' with ocular involvement. Both initially presented with a generalized bullous disease, and direct immunofluorescence microscopy demonstrated IgA in the basement membrane zone of the skin, and in the conjunctiva and cornea of patient 1. On salt-split patient skin, IgA was found predominantly on the dermal side of the artificial split in both patients.
Direct immunoelectron microscopy demonstrated IgA below the lamina densa in close association with the anchoring fibrils in both patients. In patient 1, who had a prolonged course of the disease, the skin disorder responded well to treatment with cyclosporin, but the ocular involvement ended in bilateral blindness despite repeated surgical treatment. In patient 2, the blister formation and scarring conjunctivitis was stopped by a combination of prednisolone and colchicine.
These patients show that in subepithelial blistering diseases, early delineation of disease nosology is critical to detect subtypes with severe ocular involvement such as 'IgA-EBA'. In addition, colchicine may be a valuable alternative in the treatment of EBA with ocular involvement.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL VARIANTS COMBINED Epidermolysis bullosa acquisita with combined features of bullous pemphigoid and cicatricial pemphigoid.
Wieme N, Lambert J, Moerman M, Geerts ML, Temmerman L, Naeyaert JM.
Department of Dermatology, University of Gent, Belgium.
Dermatology 1999;198(3):310-3 Abstract quote
Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal blistering disease associated with autoantibodies against type VII collagen. The classical or mechanobullous form of EBA is characterized by skin fragility, trauma-induced blisters and erosions with mild mucous membrane involvement and healing with scars. Furthermore, bullous-pemphigoid-like and cicatricial pemphigoid-like features have been described.
We report a patient who developed a bullous skin disease with upper airway obstruction requiring tracheotomy. The diagnosis of EBA was established by immunoblot, showing a band at 290 kD (collagen VII), and NaCl-split skin immunofluorescence (IgG deposition at the floor of the split).
This case presented with clinical features of both bullous pemphigoid and cicatricial pemphigoid which to our knowledge is the first report of such a combination in EBA. The patient also presented tracheal involvement that has never been described either
IgA MEDIATED
IgA-mediated epidermolysis bullosa acquisita: Two cases and review of the literature.Vodegel RM, De Jong MC, Pas HH, Jonkman MF.
Center for Blistering Skin Diseases, Department of Dermatology, Groningen University Hospital.
J Am Acad Dermatol 2002 Dec;47(6):919-25 Abstract quote We describe 2 adult patients with a subepidermal bullous dermatosis with exclusively linear IgA depositions along the epidermal basement membrane zone that were deposited in the sublamina densa zone as witnessed by direct immunoelectron microscopy.
Indirect immunofluorescence microscopy of patients' sera revealed circulating IgA autoantibodies that bound exclusively to the dermal site of salt-split skin substrate. Immunoblot analysis using dermal and keratinocyte extracts were negative. Indirect immunofluorescence microscopy using type VII collagen-deficient skin ("knockout" substrate) showed no IgA binding, whereas linear IgA binding was seen at the epidermal basement membrane zone in normal human skin. The autoantigen in the patients was thus type VII collagen. A diagnosis of IgA-mediated epidermolysis bullosa acquisita (IgA-EBA) was made.
We systematically reviewed the literature of this subset of patients with linear IgA dermatosis on the basis of the following criteria: exclusive binding of serum-IgA to the dermal side of salt-split skin or IgA depositions in the sublamina densa zone by indirect or direct immunoelectron microscopy.
We learned that IgA-EBA is clinically indistinguishable from the classic "lamina-lucida type" linear IgA dermatosis or from the inflammatory type of IgG-mediated epidermolysis bullosa acquisita (IgG-EBA). Only a minority of the patients with IgA-EBA showed milia or scarring or had therapy-resistant ocular symptoms as in the mechanobullous type of IgG-EBA. Most patients with IgA-EBA responded to dapsone therapy.
INFLAMMATORY A case of an inflammatory variant of epidermolysis bullosa acquisita: chronic bullous dermatosis associated with nonscarring mucosal blisters and circulating IgG anti-type-VII-collagen antibody.
Tokuda Y, Amagai M, Yaoita H, Kawachi S, Ito T, Matsuyama I, Tsuchiya S, Saida T.
Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan.
Dermatology 1998;197(1):58-61 Abstract quote
A 42-year-old man showed prominent blistering lesions of the mouth and esophagus in addition to a few bullous lesions of the skin.
Direct immunofluorescence microscopy revealed distinct linear deposition of IgG and C3 at the epidermal basement membrane zone where slight deposition of IgA and IgM was also observed. In direct immunoelectron-microscopic examination, antibody was detected in the sublamina densa of the basement membrane zone. Immunoblot analysis with dermal extracts demonstrated that the patient's serum contained circulating IgG antibodies against the 290-kD protein, which comigrated with type VII collagen. The lesions healed without any scars.
The results of these studies corresponded to the laboratory findings in epidermolysis bullosa acquisita (EBA), although the clinical features were distinct from classic EBA.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE DIRECT IMMUNOFLUORESCENCE Antibodies to 290kd (Collagen type VII) Bullous pemphigoid and epidermolysis bullosa acquisita. Differentiation by fluorescence overlay antigen mapping.
De Jong MC, Bruins S, Heeres K, Jonkman MF, Nieboer C, Boorsma DM, Pas HH, van der Meer JB.
Department of Dermatology, University Hospital, Groningen, The Netherlands.
Arch Dermatol 1996 Feb;132(2):151-7 Abstract quote
BACKGROUND AND DESIGN: From previous studies, we concluded that the fluorescence overlay antigen mapping (FOAM) technique could be of value to the differential diagnosis of the acquired subepidermal bullous skin disorders, bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA). In these diseases, ultrastructural identification of the site of skin-bound IgG deposits at the epidermal basement membrane zone (EBMZ) may be essential to the correct diagnosis. Since ultrastructural studies are more expensive, time-consuming, and less widely available than immunofluorescence, we addressed the question of whether the FOAM technique can reliably identify the site of IgG deposits at the EBMZ, and distinguish BP from EBA. For this purpose, the technique was applied to perilesional skin from seven patients with BP and six with EBA, using computer-aided imaging of red-stained type VII collagen and green-stained IgG, according to previous findings.
RESULTS: Digitized multicolor FOAM images of perilesional skin from patients with BP showed nonoverlap band patterns of green-stained lamina lucida IgG deposits (ultrastructurally proven) and red-stained type VII collagen. By contrast, FOAM images of EBA skin typically showed overlap patterns of green-stained sublamina densa IgG deposits and red-stained type VII collagen. These findings were observed also in skin tissue stored in Michel's transport medium or stored frozen for 15 years.
CONCLUSIONS: The computer-aided FOAM technique may have great potential in distinguishing between IgG deposits above (BP) and just below (EBA) the lamina densa of the EBMZ in skin tissue. The technique is not as simple as saline-split skin methodology but offers more flexibility, and it certainly is quicker and less expensive than electron microscopy. Furthermore, the use of digitized fluorescence images offers improved possibilities for evaluating the various "linear" patterns of immune reactant deposition at the EBMZ in subepidermal bullous autoimmune skin diseases.
'Suction split' as a routine method to differentiate epidermolysis bullosa acquisita from bullous pemphigoid.
Feliciani C, Di Muzio M, Mohammad Pour S, Allegretti T, Amerio P, Toto P, Coscione G, Proietto G, Amerio P.
Department of Dermatology, University G.D'Ann unzio, Chieti, Italy.
J Eur Acad Dermatol Venereol 1998 May;10(3):243-7 Abstract quote
BACKGROUND AND DESIGN: Epidermolysis bullosa acquisita (EBA) and bullous pemphigoid (BP) are diseases with similar clinical, histological, and immunofluorescent findings. Diagnosis requires the use of immunoelectron microscopy, immunoprecipitation or immunoblotting, but in recent years the differential diagnosis has been based on a cheaper technique named salt split skin. This study demonstrates that with a suction blister the fracture is at the same level as that obtained with the sodium split method and that it is also faster and cheaper. Suction blisters on normal skin and autoimmune perilesional bullous lesions, obtained with a hand vacuum pump, were studied by direct immunofluorescence and electron microscopy to evaluate the level of the split on normal suction split skin. Normal human split skin was also used as a substrate for an indirect immunofluorescent study using sera of patients with BP (68 sera), EBA (10 sera) and cicatricial pemphigoid (CP) (16 sera). Direct immunofluorescent examination was also done on perilesional skin after artificial separation obtained with a hand-vacuum pump in patients with the same diseases listed above (32 BP, 11 CP, 6 EBA).
RESULTS: On normal human skin split by suction or sodium chloride (NaCl; 1 mol/l) direct immunofluorescence and electron microscopy demonstrated that the split is at the lamina lucida level. Indirect immunofluorescent study of both normal human skin and perilesional skin split using suction as a substrate showed IgG deposits localized on the floor of the suction blister in all cases of EBA, whereas in over 88% of cases of BP and in over 62% of CP the IgG were localized on the roof. Similar results were obtained with direct immunofluorescence in perilesional skin.
CONCLUSIONS: 'Suction split' represents a simple technique to differentiate EBA from BP. This method provides final response in a few hours compared to at least 1-2 days with the sodium split method. Furthermore, the suction split method is cheaper and the tissue can be re-utilized for molecular biology and immunohistochemical studies.
A case of nonscarring inflammatory epidermolysis bullosa acquisita: characterization of IgG autoantibodies by immunofluorescence, immunoblotting and immunogold electron microscopy.
Honoki K, Muramatsu T, Nakatani C, Iida T, Shirai T.
Department of Dermatology, Nara Medical University, Japan.
J Dermatol 1998 Oct;25(10):666-72 Abstract quote
We report a case of nonscarring inflammatory epidermolysis bullosa acquisita in a 59-year-old Japanese woman.
She developed blisters and erosions on her lip, trunk and extremities. Sodium aurothiomalate was effective for the skin lesions. The patient had been free from bullous skin lesions for the last 13 years and had shown no scarring. Indirect immunofluorescence (IF) study on 1 M NaCl-split skin revealed IgG autoantibodies against the dermal side of the split skin. Immunoblotting using normal human dermal extracts disclosed IgG autoantibodies reactive with the 290 and 145 kD antigens. Circulating IgG autoantibodies were deposited on the lamina densa by immunoelectron microscopy. IF mapping using several antibodies for the components of the basement membrane zone revealed blister formation at the lamina densa.
These results suggest that the cleavage at the lamina lucida does not necessarily exclude the diagnosis of EBA and that the definite diagnosis of EBA should be confirmed by immunoblotting or immunoelectron microscopic study.
INDIRECT IMMUNUFLUORESCENCE
Anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita: Differentiation by use of indirect immunofluorescence microscopy.Vodegel RM, De Jong MC, Pas HH, Yancey KB, Jonkman MF.
Departments of Dermatology, Groningen University Hospital and Medical College of Wisconsin.
J Am Acad Dermatol 2003 Apr;48(4):542-7 Abstract quote Binding of autoantibodies to laminin 5 and type VII collagen causes anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita, respectively.
Differentiation between these two dermal-binding autoimmune bullous dermatoses is not yet possible by indirect immunofluorescence microscopy. In this study we tested whether two recently described immunofluorescence techniques, "knockout" skin substrate and fluorescent overlay antigen mapping, can differentiate between anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita. A total of 10 sera were tested: 4 with antilaminin 5, and 6 with antitype VII collagen autoantibodies, as characterized by either immunoblot or immunoprecipitation analysis.Differentiation between anti-epiligrin cicatricial pemphigoid and epidermolysis bullosa acquisita was possible in all 10 sera by indirect immunofluorescence using either knockout skin substrate or fluorescent overlay antigen mapping technique.
ELECTRON MICROSCOPY Epidermolysis bullosa acquisita: ultrastructural and immunological studies.
Yaoita H, Briggaman RA, Lawley TJ, Provost TT, Katz SI.
J Invest Dermatol 1981 Apr;76(4):288-92 Abstract quote
Four patients with epidermolysis bullosa acquisita were investigated using immunofluorescence, routine electron microscopic and immunoelectron microscopic techniques. Immunofluorescence studies demonstrated linear immunoglobulin and complement deposition along the dermal-epidermal junction.
These findings are similar to those seen in skin of patients with bullous pemphigoid. Immunoelectron microscopic studies demonstrated that the immunoreactants were localized below the subbasal lamina-anchoring fibril zone of the basement membrane, thereby clearly distinguishing the immunopathology of epidermolysis bullosa acquisita from that seen in bullous pemphigoid.
Indirect immunoelectron microscopic findings suggest that epidermal basal cells of affected patients may secrete the dermal substances to which the antibodies bind.
Epidermolysis bullosa acquisita: report of a case with comparison of immunogold electron microscopy using pre- and postembedding labelling.
Ishiko A, Hashimoto T, Shimizu H, Nishikawa T.
Department of Dermatology, Keio University School of Medicine, Japan.
Br J Dermatol 1996 Jan;134(1):147-51 Abstract quote
A patient with epidermolysis bullosa acquisita (EBA), who has been diagnosed as having bullous pemphigoid for 7 years, is reported.
By immunoblotting, both the latest serum and a 4-year-stored serum sample of the patient, were shown to react with the 290-kDa EBA antigen or type VII collagen, but not with bullous pemphigoid antigens. Pre-embedding immunogold electron microscopy demonstrated that the serum bound to the 'anchoring plaque' and to both ends of the anchoring fibrils in the fashion reported previously. In contrast, postembedding immunoelectron microscopy showed binding mainly to the lamina densa.
These results indicate that EBA antigens are localized mainly at the lamina densa. Further studies are necessary for confirmation.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES GENERAL Epidermolysis bullosa: variability of expression of cicatricial pemphigoid, bullous pemphigoid, and epidermolysis bullosa acquisita antigens in clinically uninvolved skin.
Fine JD.
J Invest Dermatol 1985 Jul;85(1):47-9 Abstract quote
Indirect immunofluorescence was performed on skin from 13 patients with epidermolysis bullosa (EB) (simplex, 6; junctional, 2; dystrophic, 5) to compare the expression of 3 basement membrane components, bullous pemphigoid (BP) antigen, cicatricial pemphigoid (CP) antigen, and epidermolysis bullosa acquisita (EBA) antigen, in clinically uninvolved tissue.
In addition, expression of laminin, type IV collagen, and KF-1 antigen was also evaluated. Whereas laminin, type IV collagen, and KF-1 antigen were each detectable in EB skin in a manner identical to that previously reported, marked variability was noted in the expression of BP, CP, and EBA antigens. However, no correlation was noted comparing lack of expression of any one of these latter antigens with either of the remaining two.
Of these 3 antigens, BP antigen was the least often detectable, particularly in skin from patients with EB simplex. The lack of detectable BP antigen in EB simplex skin appeared to correlate with more extensive disease involvement and/or younger patient age.
These findings may, therefore, limit the usefulness of BP serum in immunofluorescence mapping. Additionally, the disparity in expression of basement membrane antigens defined by BP and CP sera suggests that BP antigen and CP antigen are distinct entities.
BULLOUS PEMPHIGOID Differences in direct immunofluorescence staining patterns in epidermolysis bullosa acquisita and bullous pemphigoid.
Smoller BR, Woodley DT.
Department of Dermatology, Stanford University Medical Center, CA 94305.
J Am Acad Dermatol 1992 Nov;27(5 Pt 1):674-8 Abstract quote
BACKGROUND: Both bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA) are characterized by linear IgG deposits along the basement membrane zone (BMZ). Although these diseases can be distinguished by special tests, the staining pattern on direct immunofluorescence (DIF) is identical.
OBJECTIVE: The purpose of the present study was to reevaluate DIF as a diagnostic tool in differentiating EBA from BP.
METHODS: We performed DIF studies on biopsy specimens from eight consecutive patients with EBA and 18 consecutive patients with BP.
RESULTS: In five of eight cases of EBA, C3 deposition was essentially absent. IgG was the predominant class of immunoglobulins in the deposits and was present along the BMZ in all eight cases. C3 was present in 17 of 18 cases of BP. IgG was the predominant immunoglobulin present in 15 of these 18.
CONCLUSION: Patients with EBA are more likely to have linear IgG staining along the BMZ without concomitant C3 deposition than are patients with BP. This difference may be a function of the ability of the autoantibodies to fix complement.
CICATRICIAL PEMPHIGOID Anti-epiligrin cicatricial pemphigoid: a case associated with gastric carcinoma and features resembling epidermolysis bullosa acquisita.
Fujimoto W, Ishida-Yamamoto A, Hsu R, Nagao Y, Iizuka H, Yancey KB, Arata J.
Department of Dermatology, Okayama University Medical School, Shikata, Japan.
Br J Dermatol 1998 Oct;139(4):682-7 Abstract quote
A 48-year-old woman with anti-epiligrin cicatricial pemphigoid (CP) who showed clinical features resembling epidermolysis bullosa acquisita was found to have adenocarcinoma of the stomach.
Histological examination of lesional skin demonstrated a subepidermal blister. Direct immunofluorescence microscopy of perilesional skin revealed linear deposits of IgG and C3 at the basement membrane zone. The patient's serum contained IgG autoantibodies that bound to the dermal side of 1 mol/L NaCl-split normal human skin as determined by indirect immunofluorescence microscopy, and the lamina lucida as determined by indirect immunoelectron microscopy. The patient's serum immunoprecipitated laminin-5 from extracts and media of biosynthetically radiolabelled human keratinocytes. Immunoblot studies showed that the patient's autoantibodies specifically bound the alpha3 subunit of this laminin isoform.
Fragility of the skin and bullous lesions disappeared after total gastrectomy, but soon reappeared possibly in association with metastatic disease in a lymph node. The possibility that anti-epiligrin CP may develop paraneoplastically in some patients is discussed.
LINEAR IgA DISEASE Linear IgA disease with clinical and immunopathological features of epidermolysis bullosa acquisita.
Mutasim DF, Cummings MP.
Department of Dermatology, University of Cincinnati, Ohio 45267-0523, USA.
Pediatr Dermatol 1997 Jul-Aug;14(4):303-6 Abstract quote
A 10-year-old boy had a 3-month history of urticarial plaques and vesicles. Histologic and immunofluorescence testing confirmed the diagnosis of linear IgA disease. Immunoelectron microscopy revealed IgA deposits in the sublamina densa area similar to those seen in epidermolysis bullosa acquisita.
Milia developed after resolution of the lesions, similar to lesions of epidermolysis bullosa acquisita.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Salt split skin assay-Normal skin incubated with 1M NaCl which separates the epidermis from dermis. The epidermal half contains the upper lamina lucida, hemidesmosomes, and BP antigen. The dermal half contains laminin 5, lamina densa, and anchoring fibrils.
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscopeSurgical Pathology Report
Examine an actual biopsy report to understand what each section meansSpecial Stains
Understand the tools the pathologist utilizes to aid in the diagnosisHow Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurateGot Path?
Recent teaching cases and lectures presented in conferences
Last Updated April 27, 2005
Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.
Copyright © The Doctor's Doctor