Japanese guidelines for the management of pemphigoid (including epidermolysis bullosa acquisita)

The pemphigoid group is a category of autoimmune subepidermal blistering diseases in which autoantibodies deposit linearly at the epidermal basement membrane zone (BMZ). The main subtypes of pemphigoid mediated by immunoglobulin G autoantibodies are bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). To establish the first guidelines approved by the Japanese Dermatological Association for the management of pemphigoid diseases, the Committee for Guidelines for the Management of Pemphigoid Diseases (Including EBA) was founded as part of the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labor and Welfare Research Project on Overcoming Intractable Diseases. These guidelines aim to provide current information for the management of BP, MMP and EBA in Japan. Based on evidence, the guidelines summarize the clinical and immunological manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment algorithms and treatment recommendations. Because of the rarity of these diseases, there are few clinical studies with a high degree of evidence, so several parts of these guidelines were established based on the opinions of the Committee. To further optimize these guidelines, periodic revision in line with the new evidence is necessary.     

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.     

Serration pattern analysis for differentiating epidermolysis bullosa acquisita from other pemphigoid diseases

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Inflammatory epidermolysis bullosa acquisita in a 4‐year‐old girl

This study presents a case of linear immunoglobulin A dermatosis‐like epidermolysis bullosa acquisita in a 4‐year‐old girl showing rapid, widespread and inflammatory skin lesions. The diagnosis was confirmed by histopathology, direct and indirect immunofluorescence, various immunoblotting analyses and enzyme‐linked immunosorbent assays. Despite the severe clinical manifestations, the disease was successfully controlled by combination therapy of oral prednisolone and dapsone.     

Remission of recalcitrant epidermolysis bullosa acquisita (EBA) with colchicine monotherapy

A 42-year-old woman with widespread recalcitrant epidermolysis bullosa acquisita (EBA) responded well to colchicine monotherapy after attempts to control her disease with other modalities failed. These included dapsone, tetracycline, prednisolone, and combination of cyclophosphamide/azathioprine with dexamethasone 'pulse therapy'. The useful role of colchicine in controlling some difficult cases of EBA, a therapeutically problematic condition, is stressed.     

获得性大疱性表皮松解症伴宫颈鳞状细胞癌一例

患者女,54岁,因反复眼干涩2年,躯干四肢水疱伴口腔破溃2个月入院.皮肤科检查:鼻腔黏膜破溃结痂、充血.口腔大片浅溃疡,可见有水疱,表层水肿发白,边缘充血,下唇散在小溃疡,双峡颊黏膜水肿,溃疡与舌背相似.肩部、颈部及躯干见红斑周围或红斑上散在少许水疱,疱壁稍紧张,疱壁薄,尼氏征可疑阳性.该例以黏膜为突出表现,临床表现类似于瘢痕性类天疱疮,容易误诊,且皮疹和黏膜损害随着肿瘤的病情而转变.获得性大疱性表皮松解症与Ⅶ胶原有关,可能与恶性肿瘤及鳞状细胞癌有一定的相关性.     

Administration of IgG fraction of epidermolysis bullosa acquisita (EBA) serum into mice

In order to study the pathogenic role of autoantibodies in the serum of EBA patients, we tried to induce EBA lesions in mice by administration of the IgG fraction of EBA serum via the intraperitoneal (i.p.) or subcutaneous (s.c.) routes into neonatal or adult mice. We also tried to induce EBA lesions in fetuses by intravenous (i.v.) injection of EBA serum into pregnant mice. This study demonstrates that IgG fraction of EBA serum injected into neonatal or adult mice, but not into fetal mice, deposits at the epidermo-dermal junction in a linear fashion but fails to induce bullae. The role of EBA serum in the pathogenesis of EBA lesions is discussed.     

Basement membrane antibodies in sera of haematopoietic cell recipients are associated with graft‐versus‐host disease

Background Graft‐versus‐host disease (GvHD) occurs frequently after haematopoietic cell transplantation (HCT). Mucocutaneous lesions of GvHD may mimic bullous autoimmune dermatoses, and 10 cases of concurrent GvHD and a bullous autoimmune disease have been reported in the literature. Objective To determine the frequency of circulating antibodies to the cutaneous basement membrane zone (BMZ) in HCT patients with GvHD in comparison with HCT patients without GvHD, psoriasis patients and healthy controls. Subjects and methods We examined 42 patients with chronic GvHD, 18 HCT patients without GvHD, 11 psoriasis patients and 40 healthy controls, prospectively. Sera were tested by indirect immunofluorescence (IIF) on salt‐split skin, NC16a‐ELISA and immunoblot using keratinocyte extracts. Univariate statistical analyses and logistic regression were performed to assess possible correlations of graft and patient characteristics with the presence of BMZ antibodies. Results Circulating basement membrane zone (BMZ) antibodies were detected in 10/42 (24%) GvHD sera by immunoblot, but not in any of the HCT sera from patients without GvHD (0/18; 0%). The antibodies targeted collagen VII, BP230, collagen XVII/BP180 or p200/laminin γ1. Clinically manifest bullous autoimmune dermatoses (bullous pemphigoid or epidermolysis bullosa acquisita) were found in two GvHD patients. 1/11 (9%) psoriasis sera and 1/40 (2.4%) healthy control sera reacted with collagen XVII or BP230, respectively. Conclusions Circulating BMZ antibodies are significantly associated with chronic GvHD in contrast to uncomplicated HCT. Recurrent mucocutaneous lesions in chronic inflammatory skin disorders may liberate antigens, which may lead to production of BMZ antibodies, particularly in the context of GvHD‐mediated reduced self‐tolerance.     

Clearance rates of circulating and tissue‐bound autoantibodies to type VII collagen in experimental epidermolysis bullosa acquisita

Background Epidermolysis bullosa acquisita (EBA) is a severe autoimmune skin disease characterized by autoantibodies to type VII collagen, the major component of anchoring fibrils. In this and other autoimmune bullous dermatoses, specific autoantibody detection systems are not only of diagnostic use but also allow monitoring of circulating and skin‐bound autoantibodies during the course of the disease. However, little is known about their natural clearance rates in these different compartments. Objectives To study clearance rates of circulating and tissue‐bound autoantibodies to type VII collagen in experimental EBA. Methods Using offspring from mice with experimentally induced EBA, we examined retention times of diaplacentally transmitted autoantibodies to type VII collagen in serum of neonatal mice by enzyme‐linked immunosorbent assay and of immunoreactant deposits in skin by direct immunofluorescence microscopy. Additionally, the pathogenic potential of transmitted autoantibodies was evaluated in descendant mice. Results Immediately after birth, comparable levels of pathogenic antibody concentrations were observed in maternal and neonatal mice. The clearance time of skin‐bound autoantibodies was twice as long as that of circulating autoantibodies (8 and 4 weeks, respectively). Maternofetal transfer of pathogenic autoantibodies produced specific immunopathological (IgG, IgG1, IgG2a/b and complement C3 deposits) but not histological or clinical alterations in skin of offspring mice. Conclusions Although still to be confirmed in humans, our findings add to the knowledge on turnover rates of circulating and skin‐bound autoantibodies in autoimmune bullous dermatoses, which in turn may facilitate a more specific monitoring of these antibodies during the disease course, reduce the need for repeated skin biopsies, and may also be helpful in guiding treatment decisions.     

Case with Brunsting–Perry‐like localized subepidermal blister formations and immunoglobulin G antibodies against unidentified basement membrane zone antigen

Brunsting–Perry type bullous pemphigoid is defined by the blister formation limited to the head and neck, and autoantibodies to type VII collagen are detected in several cases. However, the pathomechanisms and autoantigens in this condition remain unknown. We report a 20‐year‐old female patient with a more than 2‐year history of recurrent tense blisters localized on the face with no distinct atrophic scar formation. The patient had neither extensive sun exposure nor a history suggestive of contact dermatitis. Oral betamethasone was effective on the skin lesions. Histopathology revealed subepidermal blister formation with dermal infiltrates of neutrophils. Although direct and indirect immunofluorescence tests detected immunoglobulin G antibodies to the basement membrane zone (BMZ), no known dermal or epidermal autoantigens were detected in immunoblot analyses. Therefore, this case may be a rare variant of Brunsting–Perry type localized bullous pemphigoid with autoantibodies to an undetermined BMZ antigen.     

Detection of novel LAMA3 mutation in Herlitz junctional epidermolysis bullosa in a Jordanian family

The Herlitz junctional epidermolysis bullosa (H‐JEB) subtype usually presents as a severe lethal inherited variant of epidermolysis bullosa (EB) caused by a homozygous mutation in the genes LAMA3, LMAB3, or LAMAC3. Each gene encodes one of the three chains of heterotrimer laminin‐332 proteins (including the alpha‐3 chain, beta‐3 chain and gamma‐2‐chain) responsible for the adherence of the epidermis to the underlying dermis. The aim of this report is to add to the existing knowledge about EB by describing a novel mutation in a gene responsible for genodermatosis. A case of a Jordanian male neonate, born to healthy, first cousin consanguineous parents, who developed nonhealing blistering skin and mucous membrane lesions, crusted erosions with significant granulation tissue and dystrophic nails immediately after birth is described. The patient was diagnosed as having a novel LAMA3 mutation causing (H‐JEB) by immunofluorescence mapping and molecular analysis. Both parents and this baby's sibling were shown to be heterozygous carriers of the same mutation. Pre‐implantation diagnosis using molecular analysis for subsequent pregnancies in this family is crucial for managing any new pregnancy.     

Anti‐type VII collagen autoantibodies,detected by enzyme‐linked immunosorbent assay,fluctuate in parallel with clinical severity in patients with epidermolysis bullosa acquisita

Epidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal blistering disease caused by autoantibodies against type VII collagen. An enzyme‐linked immunosorbent assay (ELISA) is currently available to detect autoantibodies in EBA. There have been reports suggesting generically that ELISA indices reflect EBA disease severity; however, there is, as yet, no conclusion as to whether ELISA indices fluctuate with disease activity over time in each EBA patient. This study aimed to investigate whether ELISA titers fluctuate with EBA disease activity and to validate the clinical significance of checking ELISA values in EBA by monitoring type VII collagen ELISA titers and disease severity, evaluated in terms of numbers of blisters and erosions as a clinical score, over time in three Japanese patients with EBA. All three cases in this study, which were treated successfully, showed titers of anti‐type VII collagen autoantibodies detected by ELISA that fluctuated in parallel with disease activity. Especially in case 1, we could determine that the expanding erosions were not due to flare‐ups of EBA because the ELISA indices stayed low, although new lesions continued to appear. In fact, control of infection and nutrition helped the lesions to become epithelialized. In conclusion, we found that repeated ELISA measurements are useful in monitoring disease activity and making decisions in EBA treatment plans.     

Case of pemphigoid with immunoglobulin G antibodies to BP180 C‐terminal domain and laminin‐γ1 (p200) developed after pneumococcal vaccination

Pemphigoid cases have been reported in association with vaccination, including pneumococcal vaccination in infants but not in adults. There are also sporadic reports of pemphigoid diseases involving reactions to multiple autoantigens. We herein report a 75‐year‐old Japanese patient with pemphigoid who had immunoglobulin G antibodies to both the BP180 C‐terminal domain and laminin‐γ1 (p200), which developed 1 day after pneumococcal vaccination.     

Refractory bullous pemphigoid leaving numerous milia during recovery

Recovery with milia may occur in bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). Scarring commonly occurs in MMP and EBA. Here, we report a 62‐year‐old man patient with BP, who was left with numerous milia during recovery. The patient had immunoglobulin (Ig)G autoantibodies to the recombinant protein of the BP180‐NC16a domain and the soluble 120‐kDa ectodomain of BP180 (linear IgA bullous dermatosis [LAD]‐1). There are cases of BP with IgG autoantibodies to LAD‐1 and/or the recombinant protein of BP180 C‐terminal domain. Extensive milia formation during recovery may be associated with immunological predisposition and/or improper interaction between hemidesmosomes and the extracellular matrix components.     

Paraneoplastic immunobullous disease with an epidermolysis bullosa acquisita phenotype: two cases demonstrating remission with treatment of gynaecological malignancy

Two cases of paraneoplastic immunobullous disease occurring in women with gynaecological malignancies are reported. Both cases demonstrated mechanobullous mucocutaneous blistering as is typically seen in epidermolysis bullosa acquisita. Their immunopathology, however, favoured a dermal-binding mucous membrane pemphigoid (MMP) (or possibly bullous pemphigoid) for patient 1 and laminin-5 MMP for patient 2. Both patients showed resolution of blistering within 1 year of treatment of their malignancies; uterine and ovarian carcinoma, respectively. These cases are of interest because of their paraneoplastic nature; as well as overlapping clinicoimmunopathological features. In addition, patient 2 is, as far as we are aware, the first report of ovarian-carcinoma-associated laminin-5 MMP.