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A 72-year-old male presented with scarring alopecia on the scalp vertex, multiple crusted plaques on the hairline, and a history of vesicular eruption on the face. The scalp showed crusted plaques with loss of follicular ostia. No follicular pustules or compound follicles were present. An initial transverse scalp biopsy showed perifollicular neutrophils, lymphocytes, and plasma cells along with dermal fibrosis. Focal epidermal/dermal and follicular/adventitial dermal clefts were apparent but were thought to be secondary to fibrosis, and the biopsy was interpreted to represent a neutrophil-mediated cicatricial alopecia. Concurrently, direct immunofluorescence (DIF) analysis demonstrated linear junctional deposition of IgG and C3. A repeat scalp biopsy revealed more prominent epidermal/dermal clefts, fibrosis, mixed infiltrate with neutrophils, lymphocytes, histiocytes and plasma cells and prominent follicular/adventitial dermal clefts with perifollicular neutrophils. Given the combination of clefts, perijunctional neutrophils, and positive DIF findings, it became clear that this eruption represented the Brunsting-Perry variant of cicatricial pemphigoid. Here, we illustrated that a neutrophil-rich form of cicatricial pemphigoid can masquerade as a neutrophil-mediated scarring alopecia. In evaluating a specimen suspected to be a neutrophil-mediated scarring alopecia, one should be alert to the presence of subepidermal and perifollicular clefting, and consider cicatricial pemphigoid. This article is protected by copyright. All rights reserved.

Although relatively uncommon, autoimmune bullous diseases carry the risk of increased mortality and can significantly impact quality of life. This group of diseases is broad and encompasses subepidermal conditions like bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis, and linear IgA bullous dermatosis, as well as intraepidermal conditions like pemphigus and its variants. The pathophysiology of each condition is incompletely understood but broadly involves the formation of autoantibodies targeting skin adhesion proteins, a process which relies on a complex interplay between a dysregulated immune system, genetic predisposition, and environmental factors. We review the impact of nutrition on pathogenesis, clinical course, and treatment of various autoimmune bullous diseases.

Brunsting-Perry pemphigoid (BPP), a variant of cicatricial pemphigoid, is an autoimmune disease characterized by tense, pruritic bullae with subsequent atrophic scar formation. BPP, which most commonly affects older men, is characterized by preferential cutaneous involvement of the head, face, and neck, with rare mucosal involvement.1,2 The pathogenesis of BPP involves an autoantibody-mediated attack on the epidermal basement membrane. Specifically, autoantibodies targeting laminin 332, type VII collagen, and BP180 have been identified.2,3 In BPP, autoreactive IgG targets these basement membrane proteins with subsequent deposition of C3 complement,4 which is visualized by direct immunofluorescence. This autoimmune cascade continues with local recruitment of lymphocytes and other inflammatory mediators, resulting in a lymphocytic infiltrate with significant eosinophilia that is characteristic of BPP.5 As seen on histologic examination, this inflammatory process results in obliteration of the epidermal attachment to the basement membrane, with subsequent formation of bullae in the newly created space between the basement membrane and the epidermis. Treatment of BPP is often challenging because of the advanced age and comorbidities of the patients. As a variant of cicatricial pemphigoid, mild cases of BPP may be treated with potent topical corticosteroids, whereas moderate-to-severe disease typically requires systemic therapy with immunosuppressive drugs such as prednisone, azathioprine, mycophenolate mofetil, and cyclophosphamide.6 These systemic therapies carry increased risks of adverse effects, including infection and malignancy. This case presents the use of dupilumab, a monoclonal antibody that blocks the actions of interleukin 4 (IL-4) and interleukin 13 (IL-13), to treat BPP. Dupilumab has been proven safe and efficacious for the treatment of atopic dermatitis, asthma, and chronic sinusitis with nasal polyposis.7 It has shown immunologically that secretion of IL-4 and IL-13 by helper T cells results in immune activation, increasing IgE production by B cells and recruiting eosinophils to sites of inflammation. IL-4 and IL-13 have also been identified as potent mediators of tissue fibrosis.8 In BPP, lymphocytosis with eosinophilia, elevated levels of basement membrane IgG, and tissue scarring with fibrosis are essential to disease pathogenesis, presenting a probable mechanism of the action of dupilumab therapy in BPP.

Pterygium is an irreversible scarring of the nail matrix resulting in a split nail. The deformity is most often post-traumatic, though it can be the end result of aggressive inflammatory diseases involving the nail matrix like nail lichen planus, graft versus host disease, or autoimmune bullous disorders like cicatricial pemphigoid. It is thought to be a result of lymphocytic inflammation-mediated damage to the nail matrix, initiating a fibrotic process which slowly fuses the nail fold with the nail matrix and bed, destroying the nail plate. We report an interesting observation in a series of patients of various ages with nail and/or skin psoriasis, and trachyonychia associated with pterygium formation in multiple nails. Insidious progression to anonychia was also observed despite initiating adequate treatment. This report highlights the potential of irreversible nail damage occurring in reportedly benign nail conditions like psoriasis and trachyonychia, emphasizing the need for early recognition and aggressive management in such cases.

An 80-year-old woman with a history of mucous membrane pemphigoid (MMP) was referred for laryngopharyngeal progression. Flexible nasolaryngoscopy (FN) revealed severe swelling of the supraglottic mucosa, ulcerations of the epiglottis, and significant laryngeal scarring and stenosis that was concerning for need for tracheotomy in the near future. Three weeks of conventional therapy yielded no improvement, so the patient underwent two infusions of rituximab, leading to disease remission and avoidance of tracheotomy. Although numerous treatment modalities for MMP are described in the literature, reports describing successful treatment of laryngeal involvement with rituximab are limited and either failed to spare the patient from surgical intervention or make no mention of it. To our knowledge, our case is the first that specifically denotes the patient being spared a possibly imminent procedure by treatment with rituximab.

Desquamative gingivitis is a clinical finding with several potential etiologies. Among the most common are oral lichen planus, cicatricial pemphigoid, and pemphigus vulgaris, though various other differential diagnoses exist. The presence of desquamative gingivitis often results in poor oral hygiene, which can have downstream consequences, including periodontitis and tooth loss. Though certain mucosal findings may be suggestive of a particular diagnosis, a thorough history, physical examination, and appropriate dermato- and immunopathologic assessment is necessary for narrowing this broad differential diagnosis. This article offers a comprehensive review on the subject, including how to differentiate between the different underlying causes and the best methods for diagnosis (eg, how best to obtain mucosal biopsy specimens). In addition, there is minimal information in the dermatology literature on evaluation of oral hygiene and the consequences of poor oral hygiene not only on disease activity but also overall health. Knowledge on appropriate oral cavity inspection and evaluation of dental hygiene is lacking, and this continuing medical education series discusses methods to evaluate for these consequences so that the dermatologist can be better equipped in managing these patients and recognizing complications early on.

Brunsting-Perry type pemphigoid (BPP) is a rare subepidermal blistering disease and a cause of secondary cicatricial alopecia. It was originally described by Brunsting and Perry in 1957 as a rare variant of cicatricial pemphigoid, characterized by bullous lesions limited to the head, neck, scalp, and upper trunk with mild or no mucosal involvement. We report 2 cases of BPP cicatricial alopecia with histopathology of subepidermal blister formation, different clinical presentation, and different salt-split test results. One patient had features of bullous pemphigoid (BP) with important oral mucosal involvement (not yet reported in the literature), and the second patient had typical features of epidermolysis bullosa acquisita (EBA). The secondary cicatricial alopecia may be due to different antigens associated with either BP or EBA. The phenomenon of epitope spreading could explain the association between 2 distinctive bullous diseases in the same patient, justifying the divergent findings of the immunofluorescence. The specific target antigen of BPP is yet to be defined.

Mucous membrane pemphigoid has been documented previously in only 19 patients under the age of 20 years. We report a 14-year-old female who had erosions of the oral, ocular, anal and genital mucosa, congestion, hoarseness of voice, dysphagia, and recurrent cough. Symblepharon formation in both eyes necessitated surgical correction. Biopsy of tissue from a solitary cutaneous lesion demonstrated a subepidermal bulla. Direct immunofluorescence showed the deposition of IgG in linear pattern along the dermoepidermal junction. Therapy was begun, consisting of prednisolone at 1 mg/kg/day, in combination with dapsone at 2 mg/kg/day. Azathioprine was added later for control of the disease. The patient showed good clinical response.

The autoimmune bullous dermatoses discussed in this chapter are the consequence of defects at or near the basement membrane zone. At the light microscopy level, the subepidermal bullous dermatoses can generally be classified based upon the predominant type of inflammatory cells within the blister space: cell-poor, eosinophils, neutrophils, or lymphocytes. The pauci-inflammatory group includes epidermolysis bullosa (EB) and porphyria cutanea tarda. Using transmission electron microscopy, EB are further classified into four major types (EB simplex, junctional EB, dystrophic EB, and Kindler syndrome) according to the plane of the cleavage. Entities with predominance of eosinophils within the blister space include bullous pemphigoid, mucous membrane pemphigoid/cicatricial pemphigoid, and pemphigoid gestationis. Those containing mainly neutrophils are linear IgA disease, anti-laminin gamma-1 pemphigoid, epidermolysis bullosa acquisita, bullous lupus erythematosus, and dermatitis herpetiformis. Lymphocytes are prominent in lichen planus pemphigoid. Due to overlapping histologic features, direct immunofluorescence (DIF) studies are necessary to distinguish various entities. Of those with similar DIF findings, indirect immunofluorescence (IIF) studies performed on sodium chloride split skin are essential to determine the location of the antigens. In the setting of similar IIF findings as noted in EBA and anti-laminin gamma-1 pemphigoid, immunoblot is needed to confirm the diagnosis.

Brunsting-Perry pemphigoid is a rare autoimmune blistering skin disease. Similar to nonmelanoma skin cancers, Brunsting-Perry pemphigoid has a predilection for the head and neck. Herein, a case of solitary Brunsting-Perry pemphigoid treated as cutaneous squamous cell carcinoma (SCC) with subsequent excision is reported.

Bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) are rare chronic autoimmune disorders characterized by subepidermal blistering. For the United States, there is a limited amount of studies in BP and MMP that address disease demographics and clinical data. In order to more comprehensively examine disease demographics and clinical factors, we performed a retrospective analysis of patient-reported data of 138 BP and 165 MMP patients enrolled in the International Pemphigus & Pemphigoid Foundation (IPPF) disease registry from 2010–2016. Patient-reported data was compared to Physician/Investigator reported data generated in our own local patient population (Western New York; 19 BP and 43 MMP patients). We confirm a female predominance in BP (M:F ratio 1:2.1) and MMP (M:F ratio 1:4.3), and a late onset within the 6th decade of life (average age at diagnosis, 59.1 ± 17.5 years for BP and 54.8 ± 11.2 years for MMP). MMP patients were significantly more likely to have a delay in diagnosis >12 months than BP patients (38 vs. 21%, respectively). Similar to other autoimmune conditions, a large number of BP (34%) and MMP (35%) patients present with other co-existing autoimmune disorders, with the most common being thyroid disease for both groups. Increased illness activity was paralleled by an increase in severe limitations of daily activities. The vast majority of of both BP and MMP patients received high intensity immunosuppression (49%). However, the majority of BP patients reported therapy with prednisone combined with other immunosuppressants (40%), while the majority of MMP patients received immunosuppressants other than prednisone (55%). With the exception of age at diagnosis, the clinical and demographic findings from both the national and local datasets were largely consistent with each other, and support those reported in other countries.

Background: Mucous membrane pemphigoid (MMP) is a heterogeneous group of blistering disorders affecting the mucosae with or without skin involvement, characterized by the presence of autoantibodies to components of the basement membrane zone, including the bullous pemphigoid antigen BP180 and β4 integrin. Current literature has shown that a minority of patients present circulating antibodies to laminin-332 and this population seems to be associated with a relatively high risk of malignancy. Objective: To present our personal case series of patients with MMP-associated malignancy from a dermatology university hospital. Methods: Twenty-two patients affected by MMP were seen in the period between 2001 and 2016; in 4 patients (18%) an associated cancer was detected. Results: These patients were 2 men and 2 women, with a mean age of 69.7 years (range, 48-83). The associated malignancies included a breast cancer, a pancreatic adenocarcinoma, a metastatic laryngeal carcinoma, and a hepatic carcinoma. All patients had negative results for both BP180 and laminin-332 autoantibodies. Conclusion: We confirm that MMP patients have a relatively high possibility of developing a solid cancer, but the autoantibody detection is not mandatory and is probably correlated with the severity of the disease.

This article aims to present a report of an atypical clinical presentation of a plasma cell gingivitis (PCG) case with unusual skin lesions. PCG is a rare benign inflammatory condition which can be classified into Type 4 hypersensitivity reaction. It occurs due to reaction to unknown antigen, often flavoring agents or spices found in chewing gums, toothpastes and lozenges. Histologically, the lesion shows dense plasma cells infiltrate in the connective tissue. Early diagnosis of PCG is essential to differentiate from variety of conditions, namely, leukemia, HIV infection, discoid lupus erythematosus, atrophic lichen planus, desquamative gingivitis, or cicatricial pemphigoid which must be differentiated through hematologic and serologic testing. In this article, we will discuss a case of PCG with unusual skin lesions.

Clinical case of patient with rashes on mucous membrane of oral cavity with severe pain, edema, redness, deformation of eyelids on both eyes and decreased visual acuity is presented. After examination by several specialists (dentist, ophthalmologist and dermatologist) cicatricial pemphigoid with primary lesion of eyes was diagnosed. Authors point out doctors on danger of serious complications of this disease, which demand active involvement of doctors of other specialties.

Background. Plasma cell gingivitis (PCG) is a rare condition of the gingiva, characterized histopathologically by infiltration of plasma cells in connective tissue. Hypersensitivity reaction due to antigen is considered as primary etiological factor. Case Presentation. The present case is of an 18-year-old male patient suffering from gingival enlargement along with cheilitis. Histopathological and immunohistochemistry of tissue revealed lesion as plasma cell gingivitis. After gingivectomy, the follow up of the patient was done for 8 months. Gradual reduction of lip swelling was observed after gingivectomy during subsequent visits. Conclusion. Early diagnosis is essential as plasma cell gingivitis has similar pathologic changes seen clinically as in leukemia, multiple myeloma, discoid lupus erythematosus, atrophic lichen planus, desquamative gingivitis, or cicatricial pemphigoid which must be differentiated through hematologic examination.

Plasma cell gingivitis (PCG) is a rare lesion found on the attached and free gingiva, often extending to the mucogingival junction. Clinically, PCG can appear as sharply delineated erythematous lesions which can be accompanied by edema. We present a case of PCG in a 13 year old female patient which clinically presented as generalized desquamative gingivitis involving the facial aspects of the attached and marginal gingiva that persisted despite substituting to a non flavored dentifrice and failure to elicit any suspected drug or food allergies. Dermatologic patch testing proved positive for Iodopropynyl Butylcarbamate (IPBC), a water based preservative or biocide used in personal care products. Microscopically, there was an intense inflammatory infiltrate in the lamina propria composed predominantly of mature plasma cells. Immunohistochemistry and in situ hybridization showed marked unrestricted cytoplasmic positivity for kappa and lambda light chains. IPBC is used in personal care products comprising lip balms, moisturizers, sunscreens, concealers and body washes due to its effectiveness at preventing fungal growth in topical products. The maximum level for safe use in leave on products is 0.1% but cosmetic products continue to use 10 times more than the safe levels. In the differential spectrum it is pertinent to discriminate erosive lichen planus, cicatricial pemphigoid, acute leukemia, HIV infection clinically; multiple myeloma and plasmacytoma histologically. Our case highlights the importance of patch testing for IPBC allergies in the oral mucosa. IPBC can lead to sensitization and contact dermatitis due to prolonged exposure; as its use in cosmetics continues to rise, and it is difficult to completely eliminate exposure to products containing IPBC especially in the context of teenaged girls and adult female patients.

Linear immunoglobulin A (IgA) dermatosis (LAD) is a rare autoimmune disorder that presents as a vesiculo-bullous lesion with cutaneous manifestations, but rare oral mucosal involvement. Here we discuss a case of a vesiculobullous lesion with severe oral and ocular mucosal involvement mimicking pemphigoid with histopathological evidence of subepithelial blisters. Direct immunofluorescence (DIF) confirmed the lesion as LAD of adult variant, although with atypical clinical features.

Secondary acquired lacrimal duct obstructions or SALDO is a term used to define all the secondary causes of lacrimal obstructions [1–4]. It essentially means that the specific cause of obstructions could be zeroed in on, and therapies targeting the cause may result in relief from obstructions. Bartley GB et al. [1–4] described five categories of secondary obstructions, namely, infectious, inflammatory, traumatic, mechanical, and neoplastic with numerous etiologies for each category. Most of the traumatic and neoplastic etiologies have been covered under specific chapters in this Atlas. Inflammatory SALDO can include endogenous etiologies like Stevens-Johnson syndrome, cicatricial pemphigoid, sarcoidosis, and Wegener’s granulomatosis. Exogenous etiologies include burns, allergies, use of eye drops like antiviral, radiotherapy, and certain chemotherapeutic agents like 5-fluorouracil, paclitaxel, and radioactive iodine (I-131) [4–5]. The term mechanical refers to a lacrimal passage physically obstructed anywhere along its entire course by specific agents. These could be endogenous factors like dacryoliths and migrated punctal plugs or exogenous factors like conjunctivochalasis, sinus mucocele, or caruncular masses. The general principle of treatment for a SALDO is to remove the causative factor or to minimize its influence.

IMPORTANCE: Pneumocystis pneumonia (PCP) is a potentially lethal opportunistic infection that primary prophylaxis can help prevent. The risk of prophylactic therapy must be weighed against the incidence of PCP in the patient population. Prophylaxis most frequently involves trimethoprim-suIfamethoxazole, with second-line therapies, including atovaquone, dapsone, and pentamide. The indication for prophylaxis in immunocompromised patients without HIV is less well defined. Previously, an incidence of at least 3.5% has been proposed as a cutoff to justify prophylaxis.OBJECTIVE: To assess the incidence of PCP in patients with autoimmune blistering diseases receiving no routine prophylaxis.DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of patient medical records to determine the incidence of PCP infections. The multicenter study was performed at tertiary care centers that provide care for patients with autoimmune blistering disease in Germany, Italy, Singapore, Israel, and the Netherlands. Patients had a confirmed diagnosis of pemphigus vulgaris/foliaceus, bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid/cicatricial pemphigoid, or anti-p200 pemphigoid.MAIN OUTCOMES AND MEASURES: To determine the incidence of PCP defined as patients with the International Classification of Diseases, Ninth Revision (ICD-9), code 136.3, for PCP or free text documentation of PCP occurring based on characteristic radiographic findings with elevated lactate dehydrogenase, or hospitalization for pneumonia with bronchioalveolar lavage demonstrating Pneumocystis jiroveci on confirmatory stains.& para;& para;RESULTS A total of 801 patients with autoimmune blistering diseases were included in this study; their mean (SD) age was 66.5 (17.6) years, and a total of 465 (58%) were female. Only 1 patient developed PCP, resulting in an incidence rate of 0.1%, This incidence significantly fell below the recommended threshold of 3.5% (0.1% vs 3.5%, chi(2)(1) = 27.0; P CONCLUSIONS AND RELEVANCE: Routine Pneumocystis prophylaxis for patients with autoimmune blistering diseases does not seem to be warranted. Patients with autoimmune blistering disease seem to have a lower risk of PCP than the general population of immunosuppressed dermatology patients. Risks of routine prophylaxis include hyperkalemia, hypoglycemia, photosensitivity, thrombocytopenia, and more rare adverse reactions.

The aim of this paper is to gain better understanding of the ocular manifestations of multiple system atrophy (MSA), a neurodegenerative disorder rarely studied in terms of its ophthalmologic features. We performed a retrospective case series (1/1/05–12/31/14) to search for patients seen at Mayo Clinic, Rochester, MN, who had mention of MSA in the medical record and an eye examination, which yielded 285 cases. Of the 285, we identified 39 cases of true MSA. Each of these 39 patients was further reviewed for ocular abnormalities potentially related to MSA. Ocular findings potentially attributable to MSA were found in 64% of patients. Most common were dry eye (N = 14), conjugate eye movement abnormalities (N = 13), and ocular misalignment (N = 7). One patient had dry eye and monocular diplopia from trichiasis due to cicatricial pemphigoid, one had bilateral optic atrophy, and one had Adie’s tonic pupil. Conjugate eye movement abnormalities (33%) and ocular misalignment (18%) were more common in patients with MSA-C. Patients with ocular findings, excluding dry eye, had a significantly shorter lifespan from time of initial neurologic symptoms to death. Our study confirms conjugate eye movement abnormalities and misalignment are common ocular findings in patients with MSA. Bilateral optic atrophy and cicatricial pemphigoid are possibly attributable to the disease. Ocular manifestations in MSA predict a poor prognosis as these patients have a significantly shorter lifespan. Therefore, we recommend patients with MSA have a comprehensive neuro-ophthalmologic exam at time of diagnosis, and thereafter, to screen for eye findings that may indicate a shorter lifespan.

S Journal of the American Academy of Dermatology Q. Desquamative gingivitis is not a disease sui generis but is a reaction pattern. The cause must be ascertained by tissue study. Desquamative gingivitis may be an early presentation of mucous membrane pemphigoid or of other blistering diseases such as pemphigus. Over time, about one half of patients with desquamative gingivitis will develop extragingivaI disease. R. Benign mucous membrane pemphigoid is neither benign (it may cause blindness) nor limited to the mucosa (it may involve the skin). Some prefer to call the disease cicatricial pemphig·oid. Cicatricial pemphigoid responds nicely to dapsone and/or sulfapyridine therapy in the majority of patients. Ketoconazole metamorphosis: An antimicrobial becomes an endocrine drug Stevens DA: Arch Intern Med 145:813-815, 1985 In addition to its antifungal activity, ketoconazole reduces androgen and adrenocorticoid synthesis. The drug has been found useful in treatment of prostatic carcinoma and hyperadrenalism and is under study in breast cancer. Italso reduces serum cholesterol. J. G. S. The effects of a shampoo containing zinc pyrithione on the control of dandruff Marks R, Pearse AD, Walker AP: Br J Dermatol 112:415-422, 1985 In a comparison study of zinc pyrithione shampoo with its base in the same patient, forty-eight patients were studied. Despite the progressive reduction in dandruff on the sides of the head treated with the zinc pyrithione shampoo, there were no significant differences in the labeling index and mean epidermal thickness on the two sides, whereas there was a significant reduction in the number of periodic acid-Schiff staining organisms but not in the number of gram-positive staining organisms. The authors suggest that the improvement in clinical dandruff correlates better with the reduction in numbers of yeast microorganisms in the· scalp area. J. G. S. Steroid sulphatase deficiency in patients initially diagnosed as ichthyosis vulgaris or recessive Xlinked ichthyosis Yoshiike T, Matsui T, Ogawa H: Br J Dermatol 112:431-433, 1985 Steroid sulphatase assay of plantar callus and peripheral leukocytes was carried out on five patients with ichthyosis vulgaris and sixteen cases of recessive X-linked ichthyosis. When deficiency of steroid sulphatase was used as a pathognomonic feature of recessive X-linked ichthyosis, it was found that some cases initially resembling ichthyosis vulgaris were actually recessive X-linked ichthyosis, although it was unlikely that a case initially diagnosed as recessive X-linked ichthyosis will prove to be ichthyosis vulgaris by steroid sulphatase assay. J. G. S.

Cicatricial pemphigoid is a chronic autoimmune blistering disease in which autoantibodies are produced against the basement membrane zone (BMZ). A 65-year-old black man was referred by the dermatology clinic to our oral diagnostic clinic, complaining of a lip painful ulcer with 2 years of evolution. There was a previous biopsy, but the histopathologic analysis was inconclusive. Oral examination revealed an ulcer covered by a pseudomembrane on the lower lip measuring 2 cm. He had no other lesions. The hypotheses were pemphigus vulgaris, squamous cell carcinoma associated with actinic cheilitis, and actinic prurigo. An incisional biopsy was performed, and the histopathologic analysis revealed cicatricial pemphigoid. Indirect immunofluorescence showed linear deposits of IgG, IgA, IgM, and C3 along the BMZ. The use of topical and systemic corticoids associated with low-level laser therapy provided a complete remission of the lesion in 3 months. The patient is being followed-up for 1 month without recurrence.

Immune-mediated diseases frequently affect oral mucosa, which may often be the first site of clinical manifestation. In this review, we describe the most important oral lesions related to inflammatory disorders and present their management and novel therapies. The review is based on an open PubMed literature search from 1980 to 2012 with relevant keywords. Pemphigus vulgaris, oral lichen planus, cicatricial pemphigoid, erythema multiforme, Stevens-Johnson syndrome, systemic lupus erythematosus, Sjögren's syndrome, and linear IgA dermatosis are the immune-mediated diseases with oral manifestations discussed. Etiology is unknown in most of these diseases, but recently some of them have been found to share common genes. Modern treatment of these diseases is based on drugs that interfere along the pathogenic mechanisms instead of the still commonly used palliative measures. However, the immunomodulatory drugs may also cause oral side effects, complicating the clinical picture. Therefore, consulting dental or oral medicine specialists can be necessary in some cases with various immune-mediated diseases.

Uncommon bullous skin disorders including mucous membrane pemphigoid can sometimes involve the esophageal mucosa, but are not thought to be associated with esophageal neoplasia. A 57-year-old Caucasian woman with a history of refractory painful oral ulceration due to mucous membrane pemphigoid was found to have esophageal mucous membrane pemphigoid when her dysphagia and acid reflux symptoms were investigated. Repeated endoscopies with esophageal dilatation were performed for her recurrent stricturing esophageal mucous membrane pemphigoid. Five years after esophageal involvement was diagnosed, she developed squamous cell carcinoma of the oesophagus. Chronic inflammation of the squamous esophageal mucosal lining may explain the development of esophageal squamous cell carcinoma in esophageal mucous membrane pemphigoid. Gastroenterologists, endoscopists and dermatologists should be mindful of esophageal involvement in mucous membrane pemphigoid and a possible link with esophageal cancer.

As doenças bolhosas autoimunes incluem dois grandes grupos: aquelas que resultam de autoanticorpos contra proteínas dos desmossomas e as que estão associadas a autoanticorpos contra componentes moleculares da membrana basal. Dentro do primeiro grupo vamos abordar o pênfigo vulgar, o pênfigo foliáceo, o pênfigo paraneoplásico e o pênfigo por IgA. No segundo grupo, falamos do penfigóide bolhoso, do penfigóide cicatricial e do penfigóide gestacional. Para cada uma destas patologias, é descrita a etiologia, a fisiopatologia e as manifestações clínicas. Posteriormente aprofundam-se os tópicos do diagnóstico, tratamento e prognóstico destas sete doenças em conjunto.

Autoimmune mucocutaneous blistering diseases (ABDs) represent a group of conditions that manifest with blisters on the skin and/or mucous membranes. Bullous pemphigoid (BP) is the most common autoimmune mucocutaneous blistering disease. In BP, the location of the blisters is subepidermal and the oral involvement is rare. Variants of BP have been described, including pemphigoid vegetans; however, this disease is not completely characterized. The majority of ABDs have blisters and/or vesicles, that are often pruritic, and manifest autoantibodies to diverse proteins. These proteins include 1) hemidesmosomal plaque proteins(ie, BP230, plectins), 2) transmembrane proteins such as BP180 and α6β4-integrin, which are connected via laminin 332 to type VII collagen and 3) currently uncharacterized 105 kDa and 200 kDa molecules. Other ABDs include drug-induced linear IgA disease, bullous systemic lupus erythematosus (BSLE), dermatitis herpetiformis (DH), cicatricial pemphigoid (CP; also termed mucous membrane pemphigoid), lichen planus pemphigoides (LPP), pemphigoid gestationis (PG), herpes gestationis(HG), chronic bullous dermatosis of childhood (CBDC) and the localized forms of CP, such as Brunsting-Perry pemphigoid. The diagnosis of ABDs requires clinical data; skin biopsies (in 10% buffered formalin) for hematoxylin and eosin (H&E) examination and skin biopsies(in Michel’s transport medium) for direct immunofluorescence (DIF). In many ABDs, the histopathologic findings demonstrate a subepidermal vesicle or bulla with a luminal inflammatory infiltrate of neutrophils, eosinophils and/or lymphocytes. In many ABDs, an extensive perivascular and interstitial inflammatory infiltrate is also noted subjacent to the blister in the upper dermis. Normal skin adjacent to an ABD plaque is often excellent for DIF results. Many ABD biopsies reveal autoantibody deposition at the lesional basement membrane zone (BMZ); IgG, IgM, IgA, other immunoglobulins, complement components and fibrinogen may be detected. Indirect immunofluorescence (IIF) yields antibody titer data; the titers usually correlate with disease activity and with ELISA. Linear epitopes are commonly studied by using an immunoblotting (IB) assay. Topical and systemic corticosteroids remain as mainstays of therapy in ABDs; however, multiple other immunosupressors and/or “steroid sparing agents” such as azathioprine have been demonstrated to be of therapeutic value. In the IgA mediated dermatoses, dapsone is often helpful; in addition, liver and blood testing (including G6PD levels) is indicated. The prognosis depends on each case; rapid diagnosis avoids complications and assists in maintaining a good quality of life for each patient.

Autoimmune bullous skin diseases (ABDs) are uncommon, potentially fatal diseases of skin and mucous membranes which are associated with deposits of autoantibodies and complement against distinct molecules of the epidermis and dermal/epidermal basement membrane zone (BMZ). These autoantibodies lead to a loss in skin molecular integrity, which manifests clinically as formation of blisters or erosions. In pemphigus vulgaris, loss of adhesion occurs within the epidermis. The pioneering work of Ernst H. Beutner, Ph.D. and Robert E. Jordon, M.D. confirmed the autoimmune nature of these diseases. Walter F. Lever, M.D. contributed significantly to our understanding of the histopathologic features of these diseases. Walter Lever, M.D. and Ken Hashimoto, M.D. contributed electron microscopic studies of these diseases, especially in pemphigus vulgaris and bullous pemphigoid. In bullous pemphigoid (BP), linear IgA bullous dermatosis, epidermolysis bullosa acquisita (EBA) and dermatitis herpetiformis (DH), loss of adhesion takes place within or underneath the BMZ. Classic EBA demonstrates extensive skin fragility; DH is commonly associated with gluten-sensitive enteropathy, and manifests clinically with pruritic papulovesicles on the extensor surfaces of the extremities and the lumbosacral area. The clinical spectrum of bullous pemphigoid includes tense blisters, urticarial plaques, and prurigo-like eczematous lesions. Pemphigoid gestationis mostly occurs during the last trimester of pregnancy, and mucous membrane pemphigoid primarily involves the oral mucosa and conjunctivae and leads to scarring. Linear IgA bullous dermatosis manifests with tense blisters in a „cluster of jewels”-like pattern in childhood (chronic bullous disease of childhood) and is more clinically heterogeneous in adulthood. Many of the autoantigens in these disorders are known and have been well characterized. ABDs may be influenced by both genetic and exogenous factors. The diagnoses of ABDs is based on histology of lesional skin and direct immunofluorescence (DIF) of perilesional skin, as well as by serologic confirmation of autoantibodies by indirect immunofluorescence (IIF) and recombinant autoantigens. The titers of the autoantibodies may correlate with the disease severity, and can be measured by indirect immunofluorescence and by ELISA testing. Therapeutically, systemic treatment with glucocorticoids is combined with immunosuppressive adjuvants which allow for fast reduction of systemic steroids. A prospective clinical trial in pemphigus showed that adjuvant treatment with azathioprine, mycophenolate mofetil and cyclophosphamide led to a significant reduction of the cumulative dose of systemic steroids until complete clinical remission was achieved. In bullous pemphigoid, topical treatment with clobetasol can help to accomplish a clinical remission without the major side effects seen with systemic steroids. Also, therapeutic depletion of B lymphocytes by rituximab has considerably improved the overall prognosis of pemphigus. Nurses and other paramedical personal caring for patients with these disorders play a critical role in improving the quality of life of the patients and their families. The patients need to be continuously evaluated to avoid secondary infections, especially if they have long term immuosupressive treatment. Abbreviations and acronyms: Bullous pemphigoid (BP), immunohistochemistry (IHC), direct and indirect immunofluorescence (DIF and IIF), hematoxylin and eosin (H&E), antibody (Ab), basement membrane zone (BMZ), intercellular staining between epidermal keratinocytes (ICS), pemphigus vulgaris (PV), cicatricial pemphigoid (CP), subcorneal pustular dermatosis (SCPD), dermatitis herpetiformis (DH), sodium dodecyl sulfate (SDS), SDS polyacrylamide gel electrophoresis(SDS-PAGE), autoimmune blistering skin diseases (ABDs), fogo selvagem (FS), endemic pemphigus foliaceus in El-Bagre, Colombia (El Bagre-EPF), desmogleins 1 and 3 (Dsg1 and Dsg3), nonkeratinizing squamous metaplasia (SM).

La Pemphigoide cicatricielle est une dermatose bulleuse sous épithéliale qui atteint essentiellement les muqueuses avec une évolution cicatricielle. Il s'agit d'un homme de 66 ans hospitalisé pour gingivite érosive avec dysphagie, dyspnée et flou visuel. L'examen dermatologique retrouvait des lésions érosives du palais et du pharynx. L'examen ophtalmologique notait des symblépharons, un ectropion et une cataracte bilatérale. La biopsie gingivale avait montré un décollement nécrotique de l'épithélium buccal. L'immunofluorescence directe notait un dépôt linéaire d'Immunoglobuline A à la jonction dermo-épidermique. L'Immunofluorescence indirecte était revenue négative. Le diagnostic de pemphigoide cicatricielle était confirmé. Le Transit oeso-gastro-duodénal a objectivé une double sténose de l'œsophage. L'endoscopie nasale, pharyngée et bronchique retrouvait des ulcérations de l'épiglotte, de l'hypopharynx, du pharynx et de l'arbre bronchique. Le patient a bénéficié d'un bolus de Solumedrol relayé par la Prednisone à la dose de 0.5mg/Kg/j associé à la Disulone à la dose de 100mg/j. L'évolution était favorable au début mais s'est compliquée après 2 mois d'une aggravation de la dysphagie et de la sténose oesophagienne. Notre observation est très particulière par la survenue d'une Pemphigoide cicatricielle chez un sujet de sexe masculin ayant un tableau grave en rapport avec l'extension des lésions à toutes les muqueuses conjonctivale, buccale, nasale, œsophagienne et même bronchique associée à une immunofluorescence directe faite d'un dépôt d'IgA uniquement.

The subepidermal immunobullous diseases bullous pemphigoid (BP), cicatricial pemphigoid (CP), pemphigoid gestationis (PG) and linear IgA disease (LAD) are characterized by circulating and in vivo deposition of antibodies to antigens in the cutaneous basement membrane zone (BMZ). Indirect immunofluorescence (IMF) of serum is a routine diagnostic test to detect circulating BMZ antibodies in these diseases. We have compared the titres of IgG and IgA and their subclasses, also of IgM and IgE BMZ antibodies in serum and aspirated blister fluid in 35 adult patients with subepidermal immunobullous diseases: BP (n = 30), PG (n = 2), CP (n = 1), and LAD (n = 2), by indirect IMF on intact and salt-split skin. The antibody titre in blister fluid was the same or one dilution less than serum in most cases and there was no significant difference between these results (P > 0.05). IgG1 and IgG4 were the predominant subclasses in both blister fluid and serum in BP. Indirect IMF of serum and blister fluid was also carried out on trypsinized epidermal cells in a subgroup of patients with BP (n = 19). Typical polar fluorescence was obtained in all 14 cases which had positive indirect IMF on intact and split skin. Our findings demonstrate that blister fluid can be used as an alternative to serum for indirect IMF in subepidermal immunobullous diseases. This avoids the need for venesection and has a practical application in children and those with poor venous access.

Summary Cicatricial pemphigoid is a rare subepidermal blistering disease, mainly of elderly women, that primarily involves mucous membranes. Oral, ocular or genital mucous membranes are most frequently involved and skin involvement is less frequent. We report a case of Cicatricial pemphigoid with extensive cutaneous involvement, including unusual bilateral palmar involvement. Clinical improvement has been achieved with a combination of topical steroids, oral nicotinamide and tetracycline.

BACKGROUND: Class I human leucocyte antigens (HLA) -A, -B, -Cw and class II HLA-DRB1, -DQB1 alleles were determined in 131 British Caucasian patients with mucous membrane pemphigoid (MMP) using serological and DNA-based methods. OBJECTIVES: To analyse the class I and II alleles expressed in well-defined clinical and immunopathological subgroups of MMP, in order to establish whether specific alleles or haplotypes might in part explain disease susceptibility, clinical sites of involvement or disease severity. METHODS: Subgroups of patients were analysed according to the following clinical criteria: age of onset, sex, sites of clinical involvement (oral, ocular, skin, nasal, genital, pharyngeal, oesophageal, laryngeal, perianal), disease severity and history of autoimmune disease. Subgroups were also analysed according to the following immunopathological criteria: autoantibody profile, the presence of circulating antibasement membrane IgG or IgA antibodies and the detection of target basement membrane zone (BMZ) antigens (BP230 and BP180) by IgG autoantibodies. RESULTS: Class I HLA typing showed no significant disease or subgroup associations. Class II DRB1 typing showed a significantly increased allelic frequency in MMP vs. controls for DRB1*11 (RR = 2.08, Pc < 0.0000056). For DQB1, MMP vs. controls, there was a significantly increased allelic frequency for DQB1*0301 (Pc < 0.00000028) in both males and females; all clinical sites of involvement, with the exception of laryngeal, oesophageal and perianal sites and in patients with detectable circulating anti-BMZ IgG compared with those negative for IgG (P < 0.0096, Pc < 0.019). A positive trend was noted in patients with ocular involvement compared with no ocular involvement and in patients with a clinical score > or = 10 compared with < 10. We found no difference in DQB1*0301 allele frequency between subgroups with or without BP180 or BP230 target antigens. Haplotype frequencies showed an increase in DRB1*04, DQB1*0301 (Pc < 0.000066) and DRB1*11, DQB1*0301 (Pc < 0.000002) among patients compared with controls. CONCLUSIONS: The DQB1*0301 allele confers a predisposition to all subgroups of MMP and may have a role in T-cell recognition of basement membrane antigens, resulting in the production of anti-BMZ IgG autoantibodies. The positive trend between increased allelic expression of DQB1*0301 in patients with ocular disease and in those with a higher clinical score, further suggests a role for this allele in disease severity.

Summary Cicatricial pemphigoid is a rare autoimmune blistering disease of the elderly. It predominantly affects the mucosae, causing pain and scarring. The target antigen is within the lamina lucida of the basement membrane zone. Potential complications of systemic steroid and other immunosuppressive therapy have prompted trials of other means of treatment. We describe a series of seven patients treated with minocycline, six of whom derived sustained alleviation of orodynia. Four patients developed hyperpigmentation, and two complained of gastrointestinal discomfort which necessitated cessation of minocycline. Complete steroid withdrawal was achieved in two cases. Neither the disease progression nor the response to treatment was influenced by the immunoglobulin isotype or titre. The role of minocycline as a useful adjunct to therapy is discussed.

Autoimmune blistering diseases are a heterogeneous group of disorders that mostly affect the skin and mucous membranes. Occasionally, other organ systems may be involved, depending on the unique pathophysiology of each disease. Cicatricial pemphigoid, pemphigus vulgaris, and paraneoplastic pemphigus are distinct entities, but all have the potential to have cutaneous and ocular involvement. Awareness and early recognition of ocular involvement in these diseases is important given the increased risk for vision loss and blindness with delay in management. Several skin diseases may be associated with involvement of the external eye. The most common autoimmune diseases are cicatricial pemphigoid, pemphigus vulgaris, and paraneoplastic pemphigus.

In immunobullous disease, the host immune system disrupts adhesive interactions in the skin, typically leading to clinical blister formation. The pathophysiology of these diseases has been an active area of investigation. The mechanisms by which these disorders lead to loss of adhesion are variable and disease dependent; however, general principles have been described. The term ‘‘subepidermal blistering disease’’ applies to several disorders that share the clinical appearance of vesicles and bulla, the histologic finding of subepidermal blistering, and in situ deposition of autoantibodies at the dermal–epidermal junction. This group of diseases includes bullous pemphigoid (BP), cicatricial pemphigoid, herpes gestationis, dermatitis herpetiformis, linear IgA disease, lichen planus pemphigoides, epidermolysis bullosa acquisita (EBA), and bullous systemic lupus erythematosus. Intraepidermal blistering diseases are characterized by acantholysis, loss of adhesion between adjacent epidermal keratinocytes, and deposition of immunoreactants at the keratinocyte cell membrane. The protypical intraepidermal autoimmune blistering diseases are pemphigus vulgaris (PV) and pemphigus foliaceus (PF). The autoimmune nature of these disorders began to be appreciated in the late 1960s when Jordon and Beutner used immunofluorescent techniques to demonstrate that BP patients have circulating and tissue-bound autoantibodies directed against antigens of the basement membrane zone. Use of these autoantibodies as a screening tool facilitated the identification of the target autoantigens. Using such an approach, Stanley et al. (1981, 1988) first characterized BP antigens at the molecular level and cloned the BP230 cDNA. Subsequently, cDNAs encoding BP180 (the autoantigen for BP, cicatricial pemphigoid, herpes gestationis, lichen planus pemphigoides, and linear IgA disease), laminin 5 (the autoantigen for cicatricial pemphigoid), and type VII collagen (the autoantigen for EBA and bullous systemic lupus erythematosus) were also cloned and characterized.