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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.

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.

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.

Adjuvant immunosuppressive drugs are widely used to minimize corticosteroid-related adverse effects in the short-term and long-term management of cautoimmune bullous diseases. In bullous pemphigoid and pemphigus vulgaris, azathioprine and mycophenolate mofetil seem to be equally effective when used in combination with oral corticosteroids, but mycophenolate mofetil is less myelosuppressive and hepatotoxic. Due to a better safety profile, mycophenolate mofetil or enteric-coated mycophenolate sodium may gradually replace azathioprine as the first-line adjuvant of choice in the treatment of moderate to severe autoimmune bullous diseases, including epidermolysis bullosa acquisita and cicatricial pemphigoid. Cyclophosphamide still has a place in the treatment of severe relapsing autoimmune bullous diseases. Continuous oral cyclophosphamide provides optimal immunosuppression, but it also produces the highest cumulative dose. Several pulsed cyclophosphamide regimens have, therefore, been developed and are reported to be effective in severe forms of pemphigus. Randomized controlled studies are needed to compare the efficacy and safety of cyclophosphamide with newer treatment options, such as rituximab and immunoapheresis, and to define optimal dose ranges and duration of available immunosuppressive treatments in different stages of autoimmune bullous diseases.

Mucous membrane pemphigoid, a heterogeneous group of autoimmune blistering diseases, affects primarily the mucous membranes. Although oral and ocular mucosae can both be affected in a given patient, patients with involvement restricted to oral mucosae tend to have a benign outcome, whereas those with ocular disease commonly face treatment resistance, resulting in scarring and blindness. Diagnosis requires direct immunofluorescence microscopy to demonstrate a linear deposition of immunoglobulin (Ig) G or IgA, or complement component 3 (C3), at the epithelial basement membrane. Although the target antigens vary, subsets of patients affected exclusively by oral and ocular mucosal diseases have autoantibodies targeting α-6 and β-4 integrins, respectively.

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

Antiepiligrin cicatricial pemphigoid (AECP) is a chronic autoimmune subepidermal blistering disease characterized by clinical features of cicatricial pemphigoid and circulating IgG antibasement membrane autoantibodies directed against laminin 332. There is growing evidence of an increased relative risk for solid cancers and lymphomas in AECP patients, especially in the 1 st year after the onset of blisters. However, it is difficult to distinguish patients with initially skin-predominant AECP from similar findings of epidermolysis bullosa acquisita merely based on clinical, histopathologic, and immuno-pathologic examinations. This is a report on a case of AECP confirmed by indirect immunofluorescence of type VII collagen- and laminin 332-deficient skin as substrates to differentiate it from epidermolysis bullosa acquisita.

Autoimmune blistering diseases are a significant cause of morbidity and mortality in the elderly population. Given the advancing age of the population, the incidence of these disorders, particularly bullous pemphigoid, is expected to rise. This contribution reviews autoimmune immunobullous disorders of particular relevance in the elderly population. These include bullous pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, pemphigus, paraneoplastic pemphigus, and linear immunoglobulin A bullous dermatosis. Because therapy and management of individual immunobullous dermatoses differ, establishing the diagnosis is often critically important. An overall approach to bullous diseases in the elderly, as well as key clinical features, appropriate diagnostic tests, microscopic findings, immunofluorescence microscopy patterns, and molecular targets for select disorders are reviewed. Elucidation of antigenic targets at the molecular level has allowed for development of serum enzyme-linked immunofluorescence assays, which have enhanced diagnostic accuracy for several autoimmune blistering disorders. Given the relative rarity of these diseases, large randomized trials evaluating efficacy of various treatments are few, and therapy for most immunobullous disorders in the elderly has not been standardized. Despite this, appropriate therapeutic considerations for each condition are presented and the evidence for them is reviewed.

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

Background Antiepiligrin cicatricial pemphigoid is a mucosal-predominant subepidermal blistering disease associated with an increased relative risk of cancer. In contrast to prior reports showing that anti-laminin (L)-332 autoantibodies are a reliable marker for patients with antiepiligrin cicatricial pemphigoid, a recent report suggested that as many as 40% of patients with bullous pemphigoid (BP) have IgG reactive with this laminin isoform. Objective We sought to determine whether patients with BP possess circulating IgG anti-L-332 autoantibodies. Methods Sera from 100 adults with BP were analyzed by indirect immunofluorescence testing of intact skin, immunoblot studies of human keratinocyte (HK) extracts, and a new L-332 enzyme-linked immunosorbent assay. Sera showing reactivity suggestive of anti-L-332 autoantibodies in these assays were further analyzed in immunoblot studies of HK extracellular matrix and immunoprecipitation studies of biosynthetically radiolabeled HK extracts. Results IgG from all patients with BP bound intact epidermal basement membrane by indirect immunofluorescence microscopy and immunoblotted bullous pemphigoid antigen-1, -2, or both in HK extracts. None of these sera immunoblotted L-332 in HK extracts, although 13 did score above the cut point of a new IgG 4 L-332 enzyme-linked immunosorbent assay (sensitivity = 0.91, specificity=0.98, Youden index=0.89). Further analysis of sera from these 13 patients found: (1) all had IgG that bound the epidermal side of 1 mol/L NaCl split skin by indirect immunofluorescence microscopy; (2) none immunoblotted L-332 purified from HK extracellular matrix; and (3) none immunoprecipitated L-332 from biosynthetically radiolabeled HK extracts. Limitations The basis of false-positive enzyme-linked immunosorbent assay determinations for anti-L-332 IgG among patients with BP is unknown. Conclusion Anti-L-332 autoantibodies remain a reliable marker for patients with antiepiligrin cicatricial pemphigoid.

Background Many complications have been reported after orf infection, including lymphadenopathy, secondary bacterial infection, and erythema multiforme. Rare associations with papulovesicular eruptions, including a bullous pemphigoid-like eruption, have also been described. Objectives Our purpose was to clinically, histologically, and immunologically characterize two cases of orf-induced blistering disease, and to determine whether this condition represented a novel disease entity distinct from known immunobullous diseases. Methods Two patients were clinically described and skin biopsy specimens were collected for routine histology, direct immunofluorescence studies, and polymerase chain reaction analysis to detect orf viral DNA. Patients' sera were assessed for autoantibodies by indirect immunofluorescence studies using normal-appearing human salt-split skin, by Western blot analysis using keratinocyte extracts, dermal extracts, and recombinant type VII collagen, and immunoprecipitation studies of extracts from biosynthetically radiolabeled human keratinocytes. Results Two distinctive cases of severe, diffuse blistering eruptions after orf infection are described. In one patient, orf virus DNA was detected in the inciting orf lesion, but not in blistered skin, ruling out disseminated orf infection as a cause of the blisters. In both cases, histology revealed subepidermal blisters with mixed inflammatory cell infiltrates containing neutrophils and eosinophils, direct immunofluorescence microscopy studies demonstrated IgG and C3 deposited at the dermoepidermal junctions of perilesional skin, and indirect immunofluorescence studies demonstrated circulating antibasement membrane IgG that bound the dermal side of salt-split skin. Extensive immunoblot and immunoprecipitation studies failed to reveal a consistent, identifiable autoantigen. Limitations We describe only two cases. The autoantigen recognized by circulating autoantibodies was not identified. Conclusions Orf-induced immunobullous disease is a unique disease entity that is clinically and immunologically distinct from bullous pemphigoid, epidermolysis bullosa acquisita, and other known immunobullous conditions.

Cicatricial pemphigoid (CP), also known as mucous membrane pemphigoid, is an autoimmune vesiculobullous disease occurring mostly in elderly people and seldom occurring in individuals under the age of 20 years. It predominantly affects the mucosal surfaces, primarily the oral and conjunctival mucosa. Uncommonly, the upper aerodigestive tract is involved, which can lead to life-threatening complications. We present the case of an 18-year-old girl with desquamative gingivitis and severe laryngeal webbing and stenosis, caused by cicatricial pemphigoid. Airway management necessitated a tracheostomy and additional surgical procedure. The clinical, diagnostic, and therapeutic features of this disease are discussed, focusing on the oral and unique laryngeal manifestations.

Anti-epiligrin cicatricial pemphigoid (AECP) is a chronic, autoimmune, subepidermal blistering disease characterized by circulating anti-basement membrane autoantibodies to laminin 5. Recent studies have shown that patients with this form of cicatricial pemphigoid have an increased relative risk for malignant solid tumors. The mechanism underlying this association of AECP and cancer is unknown, but there is accumulating evidence that laminin 5 plays a central role. In this article we report a patient with AECP and co-associated cutaneous T cell lymphoma and summarize all to date reported cases of AECP associated with malignancies. In addition we provide a review of the biology of laminin 5 and its potential role in cancer development.

Subepidermal autoimmune bullous diseases (SABD) are some autoimmune skin diseases that can present in a variety of forms and can be a challenging disease to treat. An overview of the different forms of SABD are discussed including bullous pemphigoid (BP), epidermolysis bullosa acquisita (EBA), cicatricial pemphigoid (CP), bullous systemic lupus erythematosus (BSLE), and Anti-p200 pemphigoid. Emphasis on recent advancement is presented. In recent years, improved knowledge of the mechanisms of intercellular and cell-matrix adhesion has led to better understanding of the blistering process in some SABD. Defects of such structures cause the subepidermal bullous diseases and have also led to the discovery of new diseases (e.g. anti-p200-pemphigoid). Recent studies have outlined the important role of autoantibodies, mast cell lymphocytes and their cytokines in pathogenesis of SABD.

Background Hyperplastic granular gingivitis or “strawberry gingivitis” is a rare manifestation of Wegener's granulomatosis (WG), but it is nearly pathognomonic for this multisystem autoimmune vasculitis. The dentist may be the first health care professional to see patients with symptoms and findings of this condition. Early diagnosis and treatment is the most important factor in the management of this potentially fatal disease. Methods The authors present three case reports that demonstrate the disease spectrum and conducted a literature review focused on current understanding of this disease. Results The first patient had only the classic gingival manifestations of the disease. The second patient had simultaneous typical gingival lesions, as well as dermatologic findings. The third patient had an atypical oral presentation of aphthous ulcers and erythematous gingiva, as well as respiratory and genital involvement. Reaching a definitive diagnosis sometimes is challenging owing to the subtle onset of the disease and variable clinical and laboratory findings. Conclusion and Clinical Implications Clinicians should be familiar with the broad variety of oral and systemic components of WG, as well as strategies to facilitate prompt disease recognition and to provide continued oral health care to these medically complex patients.

We report on a 24-year-old, male Ugandan patient with a 2-week history of itchy papules, vesicles, erosions, and crusts distributed on the entire body, accompanied by minor erosions on the palate, tongue, and lower lip. Conjunctivae and genital mucosa were not involved. Circulating IgG and IgA autoantibodies were found against recombinant full-length BP180, BP180 4575, and the C-terminus of BP230. In addition, IgG reactivity was observed against the 16th noncollagenous region of the BP180 ectodomain, the cell-derived soluble ectodomain of BP180 (linear IgA disease antigen 1), and the alpha3 and gamma2 chains of laminin 5. No reactivity was detected with type VII collagen, alpha6beta4 integrin, and the p200 protein. Oral prednisolone and dapsone led to clearance of lesions that mostly healed with scarring and milia formation. Here, we describe a scarring mucocutaneous variant of an autoimmune blistering skin disorder that extends the current clinical and immunopathologic spectrum of this group of diseases.

Bullous diseases of the oral cavity cause painful erosion. They must be distinguished from aphthae and vesicles which may have a similar presentation. Acute, chronic and congenital conditions are recognized. Acute lesions may involve a polymorphous oral erhythema which has an polymorphous erythematous presentation or toxidermia (Stevens-Johnson syndrome, Lyell syndrome, fixed pigmented erythema). Examination of the skin and history taking are the keys to diagnosis. Patients with chronic bullous diseases may have a congenital condition (bullous epidermolysis or lymphangioma) suggested by the age at onset and the clinical presentation. Acquired chronic bullous diseases include lichen planus and autoimmune bullous diseases. Careful examination is essential to identify mucosal or cutaneous involvement and to obtain a biopsy for histological examination. Search for antibodies deposited in the perilesional mucosa is necessary. Chronic erosive gingivitis is a frequent presentation. Most of the patients have cicatricial pemphigoid, lichen planus, and more rarely pemphigus. The pinch sign is highly discriminative to differentiate the cause of this syndrome. Symptomatic treatment of bullous lesions of the oral cavity include adapted diet and correct and early use of antalgesics.

Background Anti-epiligrin cicatricial pemphigoid (AECP) is a subepidermal blistering disease characterized by circulating anti-basement membrane autoantibodies to laminin 5. Objective To evaluate the relative sensitivity of immunoblotting and immunoprecipitation techniques for the detection of anti-laminin 5 antibodies, comparative studies using reference laminin 5 antiserum as well as sera from patients with AECP, other immunobullous diseases, and normal volunteers were performed. Methods Equivalent amounts of protein from five different substrates were studied by immunoblotting; immunoprecipitation experiments examined biosynthetically radiolabeled human keratinocyte (HK) extracts. Results HK extracellular matrix (ECM) was the most sensitive substrate for detection of antibodies to laminin 5; extracts of HKs, A-431 cells and HaCat cells represented alternative test substrates (though the later required higher amounts of protein input). Sera from patients with AECP immunoblotted laminin 5 in HK ECM at end titers exceeding those identified in indirect immunofluorescence microscopy studies of 1 M NaCl split skin. Immunoprecipitation studies found that a 10,000-fold dilution of reference laminin 5 antiserum retained the ability to identify laminin 5. Maximal dilutions of sera from AECP patients retaining the ability to immunoprecipitate laminin 5 ranged from 500 to 5,000. Conclusion Immunoprecipitation was the most sensitive technique for detection of anti-laminin 5 antibodies, while immunoblotting of HK ECM or HK extracts represented practical alternatives.

We describe a novel autoimmune disease characterized by severe subepidermal bullous eruption and crescentic glomerulonephritis with autoantibodies directed against the noncollagenous domain of the alpha5 and alpha6 chains of type IV collagen. Biopsy of perilesional skin revealed a subepidermal blister with marked polymorphonuclear infiltrate with linear deposits of IgA and C3. Light microscopy of a kidney biopsy specimen revealed a crescentic glomerulonephritis, and immunofluorescence microscopy showed linear basement membrane staining for IgA (3+), C3 (1+), and IgG (1+). No electron-dense deposits were observed by transmission electron microscopy. The patient's autoantibodies reacted with normal human skin and kidney: IgA (3+) and IgG (1+) antibodies stained the basement membrane zones of skin, renal glomerulus, and some tubules. The identity of the target antigen was determined by immunochemical analyses of candidate antigens using the patient's autoantibodies. The patient's IgA and IgG autoantibodies reacted with a 185- to 190-kDa antigen from a human dermal extract that was distinguished from the other dermal or epidermal antigens, including the 145- to 290-kDa (type VII collagen) epidermolysis bullosa acquisita antigen, the 165- to 200-kDa alpha3 laminin mucous membrane cicatricial pemphigoid antigen, and the 230-kDa and the 180-kDa bullous pemphigoid antigens. Patient's IgA and IgG autoantibodies further reacted with the alpha5(IV) and weakly with the alpha6(IV) chains of type IV collagen by Western blot and ELISA. This report expands the repertoire of bullous skin disorders and provides an explanation for the association of anti-type IV collagen autoantibodies and glomerulonephritis with subepidermal blisters.

Pemphigoid gestationis (PG) is an autoimmune pregnancy-associated subepidermal blistering disease. It usually affects skin and, rarely, mucous membranes. In the vast majority of patients with PG, the autoimmune response is directed to the membrane-proximal NC16A domain of the 180-kd bullous pemphigoid (BP) antigen (BP180) and is mediated by IgG1 and IgG3 autoantibodies. We report the case of a patient with PG associated with extensive lesions on oral mucous membranes. Immunoblotting studies demonstrated the presence of circulating IgA autoantibodies in the patient's serum that were exclusively directed to a 49 amino acid stretch on the C-terminal portion of the BP180 ectodomain located 800 amino acids downstream from NC16A. This C-terminal stretch of BP180 has previously been demonstrated to localize to the lamina lucida/lamina densa interface and to be recognized by IgG and IgA antibodies in a subgroup of patients with cicatricial pemphigoid as well as by IgG autoantibodies in some BP sera. Our patient's lesions healed without scarring within 6 weeks after delivery of a healthy child. The findings in this patient extend the clinical and immunopathologic spectrum of PG. (J Am Acad Dermatol 2002;47:780-4.)

Bullous pemphigoid (BP), pemphigoid (herpes) gestationis (PG), cicatricial pemphigoid (CP), and lichen planus pemphigoides (LPP) are autoimmune subepidermal bullous diseases that are characterized by circulating autoantibodies to the transmembrane hemidesmosomal protein BP180/type XVII collagen. Previous studies demonstrated that the majority of patients with BP, PG, and LPP show antibodies to an immunodominant, membrane-proximal non-collagenous domain (NC16A) on the extracellular portion of BP180. By the use of non-overlapping peptides of the NC16A domain, we previously demonstrated that autoantibodies from BP and PG patients mainly react with epitopes clustered within the N-terminus of this immunodominant site of BP180; antibodies from patients with LPP also recognized the C-terminal portion of NC16A. However, some of these results had been obtained indirectly by preadsorption studies. The aim of the present study was to analyze the fine specificity of IgG autoantibodies to NC16A in sera from patients with CP and to compare their reactivity with antibodies from BP, PG, and LPP patients using a series of new overlapping fragments covering the entire NC16A domain. We confirm that BP and PG sera mainly react with N-terminal epitopes of NC16A, whereas sera from patients with LPP also bind to C-terminal portions, of this domain. Interestingly, out of ten patients with CP, the sera of seven reacted with NC16A; within NC16A, these sera bound to both C-terminal fragments and an N-terminal epitope right next to the cell membrane. Our data demonstrate a heterogeneous binding pattern of autoantibodies to BP180 NC16A in patients with CP.

Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid (CP), is an autoimmune mucocutaneous, blistering disease which can lead to blindness and/or death from sudden asphyxiation, secondary to a scarring process. Conventional therapy for the treatment of MMP consists of high-dose systemic corticosteroids and/or immunosuppressive agents. Some patients do not respond to these treatments and develop multiple serious side effects, which can be potentially fatal. In such patients, alternative treatment modalities are needed. This study presents the use of intravenous immunoglobulin (IVIg) therapy in 15 patients with severe MMP whose disease was nonresponsive to the prolonged use of high-dose systemic corticosteroids and immunosuppressive agents and who developed multiple side effects to them. All 15 patients received an IVIg dose of 1-2 g/kg/cycle. The following objective parameters were used to assess the clinical outcome pre- and post-IVIg therapy: number of side effects, frequencies of recurrences and relapses, duration and total dosage of prednisone therapy, and the quality of life. The differences in these variables between the pre- and post-IVIg data were statistically analyzed using the SAS UNIVARIATE software running the two-sided Wilcoxon signed-rank and sign tests. A statistically significant difference was observed between pre- and post-IVIg therapy data when comparing the aforementioned variables. All 15 patients had an effective clinical response, were able to discontinue previous systemic therapies, and eventually achieved a prolonged clinical remission. IVIg improved the quality of life in all 15 patients and demonstrated a steroid-sparing effect. No serious side effects were observed. IVIg therapy is a safe and effective alternative modality in the treatment of patients with nonresponsive and progressive MMP and can induce a sustained clinical remission.

The accurate diagnosis of bullous and other immune diseases of the skin requires evaluation of clinical, histologic, and immunofluorescence findings. Immunofluorescence testing is invaluable in confirming a diagnosis that is suspected by clinical or histologic examination. This is especially true in subepidermal bullous diseases that often have overlap in the clinical and histologic findings. Direct immunofluorescence is performed on perilesional skin for patients with bullous diseases and lesional skin for patients with connective tissue diseases and vasculitis. (J Am Acad Dermatol 2001;45:803-22.) Learning objective: At the completion of this learning activity, participants should be familiar with the ideal method of obtaining immunofluorescence testing for the diagnosis of immune skin diseases and be aware of the value and limitations of immunofluorescence studies.

Autoimmune blistering skin diseases (ABSD) represent a group of heterogeneous mucocutaneous blistering diseases characterized by the deposition within the tissues of autoantibodies recognizing specific molecules involved in the cohesion between epidermal cells or between epidermis and the dermis. Intraepidermal ABSD include the various forms of pemphigus, pemphigus vulgaris (PV), pemphigus vegetans (PVE), pemphigus foliaceus (PF), drug-induced pemphigus (DIP), paraneoplastic pemphigus (PNP), and immunoglobulin A pemphigus (IgA-P).1 Diseases due to autoimmune dermal-epidermal dysadhesion (subepidermal ABSD) include mainly bullous pemphigoid (BP), pemphigoid gestationis (PG), cicatricial pemphigoid (CP), epidermolysis bullosa acquisita (EBA), and bullous systemic lupus erythematosus.2 The diagnosis of these diseases relies on clinical, histological, and immunopathological criteria. Immunopathological features are of paramount importance for the diagnosis, and historically have allowed the distinction between several of these entities that were too often misdiagnosed before the advent of immunofluorescence microscopy. The autoantibodies characteristic of ABSD can be detected by appropriate techniques, either within the tissues where they are deposited or within the serum. In this chapter I review the contribution of immunofluorescence microscopy for the serological diagnosis of ABSD, commonly referred to as “indirect immunofluorescence.”

Interleukin (IL-)1 is an important mediator of inflammatory responses and plays an important role in the pathogenesis of various autoimmune diseases. Cicatricial pemphigoid (CP) is a multisystem autoimmune inflammatory disease. We have studied the role of IL-1 in its pathogenesis. We have investigated the serum levels of IL-1 components (IL-1alpha, IL-1beta, and IL-1Ra), and determined the role of intravenous immunoglobulin (IVIg) therapy in patients with CP. Serum levels of IL-1alpha and beta were significantly higher in untreated patients with active disease compared to levels in patients in prolonged clinical remission and normal human controls (P0.0001). The serum levels of IL-1Ra were higher in patients in prolonged clinical remission compared to patients with active disease (P=0.002). Hence elevated levels of IL-1alpha and beta and low levels of IL-1Ra correlate with disease activity. The levels of IL-1alpha and beta were statistically significantly higher in sera of CP patients with active disease pre-IVIg therapy compared to post-IVIg therapy (P0.0001). Statistically significantly higher levels of IL-1Ra were present in post-IVIg treatment serum samples when compared to levels in pre-IVIg treatment (P0.0001). In the in vitro experiments, the levels of IL-1alpha and beta produced by the peripheral blood mononuclear cells (PBMC) isolated from patients before IVIg therapy were significantly higher when compared to the PBMC isolated from post-IVIg patients (P0.0001). Significantly higher levels of IL-1Ra were observed in the supernatants of PBMC collected from pre-IVIg patients and cultured with exogenously added IVIg, when compared to the levels of PBMC to which IVIg was not added (P0.0001). IL-1 may be an important cytokine involved in the pathogenesis of CP. The regulation of IL-1 could be one of the mechanisms, amongst others, by which IVIg may exert its beneficial effect in the treatment of CP.

Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid, is a rare vesiculobullous disease of mucosal tissues, which involves the oral, ocular, and other mucous membranes. We have studied a group of patients with histologically and immunopathologically proven pemphigoid disease involving predominantly the conjunctiva and oral mucosa in addition to other mucosae. The purpose of our study was to (i) demonstrate the specific binding of autoantibodies present in the sera of patients with MMP to normal human oral mucosa by indirect immunofluorescence (IIF) and (ii) to study the role of these autoantibodies in the pathogenesis of subepithelial blister formation using normal human buccal mucosa in organ culture. Serum and IgG fractions from MMP patients showed homogeneous smooth linear binding along the basement membrane zone (BMZ) of the normal buccal mucosa on IIF. Serum from pemphigus vulgaris patients showed intercellular or keratinocyte cell surface staining. BMZ separation developed at 48 h after incubation of normal human buccal mucosa in organ culture, with serum or IgG from patients with MMP but not after addition of normal human serum. Addition of pemphigus vulgaris serum to the in vitro culture of normal human buccal mucosa showed acantholysis. This preliminary report suggests that circulating autoantibodies may have an important role in the pathogenesis of MMP. This in vitro organ culture model will facilitate enhancing our understanding of various molecular events during the process of blister formation in MMP and in the study of other mucosal diseases.

Collagen XVII/BP180, an epidermal adhesion molecule, exists as a full-length transmembrane protein and as a soluble 120-kd ectodomain that is shed from the keratinocyte surface by furin-mediated proteolysis. Despite a number of studies on autoantibody targets in blistering skin diseases, it has remained unclear whether the physiologically shed ectodomain of collagen XVII plays a role as an autoantigen. Here we isolated the authentic, soluble form of human collagen XVII and showed that it is an autoantigen recognized by IgG and IgA autoantibodies in different blistering skin diseases and is, in some cases, the preferential target. The ectodomain was isolated from the epidermis, keratinocyte media, amniotic fluid, and pemphigoid blister fluid, and autoantibodies affinity-purified with this ectodomain bound to the proximal surface of the epidermis in normal skin but not in collagen XVII-deficient skin. The antibody reactivity was not dependent on the native conformation or the N-glycosylation of the soluble ectodomain, but was abolished by collagenase treatment. Sera of 81 patients with a clinically active blistering skin disease were reacted with full-length collagen XVII, the authentic soluble ectodomain, and recombinant fragments. In bullous and cicatricial pemphigoid, IgG reactive with full-length collagen XVII also recognized the soluble ectodomain. In linear IgA dermatosis and chronic bullous dermatosis of childhood, IgA targeted the soluble ectodomain more efficiently than the full-length protein. The use of recombinant fragments demonstrated that epitopes were present in several noncollagenous and collagenous subdomains of the molecule, and that a significant portion of the sera targeted Col15 domain, a hitherto unrecognized epitope region.

The autoimmune vesiculobullous diseases of the skin and mucous membranes are a fascinating group of diseases characterized by blisters of the skin and mucous membranes. These diseases are among the most intriguing, well-characterized, and potentially serious skin diseases known. In recent years, there has been major progress made in the understanding of their pathophysiology, in the development of new diagnostic techniques and of new therapeutic approaches. These advances have placed the autoimmune blistering diseases of the skin and mucous membranes at the forefront of dermatologic advances in the late twentieth century. This article discusses several of the most important autoimmune blistering disease, including bullous pemphigoid, mucous membrane pemphigoid (formerly known as cicatricial pemphigoid), epidermolysis bullosa acquisita, linear IgA bullous dermatosis, pemphigus and paraneoplastic pemphigus, with particular emphasis on the use of new and emerging therapeutic approaches.

Objective To report the effects of intravenous immunoglobulin treatment of ten patients with progressive ocular cicatricial pemphigoid who did not respond to conventional immunomodulatory regimens. Design Noncomparative, interventional case series. Participants Ten patients with biopsy-proven progressive cicatricial pemphigoid affecting the eyes who did not respond adequately to other local and systemic immunosuppressive treatment regimens. Intervention Intravenous infusions of pooled human immunoglobulin, 2 to 3 g/kg body weight/cycle, divided over 3 days, and repeated every 2 to 6 weeks. Main outcome measures Reduction in conjunctival inflammation, prevention of progression of subepithelial conjunctival fibrosis, improvement in ocular symptoms (discomfort, photophobia), improved visual acuity, reduction in extraocular mucosal lesions. Results Clinical deterioration was arrested and resolution of chronic conjunctivitis was documented in all ten patients. Maximum therapeutic effect was observed and maintained after a minimum of 4 cycles of therapy; three patients required 12 cycles before disease control. The duration of therapy in these ten patients has been 16 to 23 months (mean, 19.3 months) with no treatment-induced side effects. Extraocular mucosal lesion resolution has occurred in all but one patient. Visual acuity has stabilized or improved in all ten patients, and subjective complaints of discomfort and photophobia have decreased in all patients. Conclusions Intravenous immunoglobulin immunomodulatory therapy can be a safe and effective therapy for otherwise treatment-resistant ocular cicatricial pemphigoid.

Pemphigoid is a group of bullous diseases that have a diversified morphologic presentation and affect the skin, oral mucosa, and other mucosal membranes, alone or in combination. In the literature, the condition has been subclassified into bullous pemphigoid and cicatricial pemphigoid (mucous membrane pemphigoid) on the basis of the primary organ of involvement. In addition to the clinical presentation and a subepithelial vesicle or bullae on routine histologic analysis, the diagnosis is based on direct and indirect immunofluorescence studies. Recent investigations indicate that different clinical groups of patients with pemphigoid produce autoantibodies to different molecules within the basement membrane zone. Based on these recent observations and a review of the literature, a viewpoint is presented that not all patients with cicatricial pemphigoid should be grouped together. Rather, they should be classified into subgroups-ocular, oral, etc-on the basis of the clinical phenotype and long-term follow-up. Such a division will facilitate the provision of appropriate and relevant treatment plans; if the clinical course changes, the diagnosis can be adjusted. This strategy will prevent patients with disease limited to the oral cavity from receiving systemic drugs or agents that may be more harmful than beneficial.

Lichen planus pemphigoides is an autoimmune subepidermal blistering disease. The finding of immunoglobulin G antibodies directed against the basement membrane zone differentiates it from bullous lichen planus. The aim of this study was to identify the target antigen of lichen planus pemphigoides autoantibodies. Sera from lichen planus pemphigoides patients (n = 4) stained the epidermal side of NaCl-split human skin in a pattern indistinguishable from that produced by bullous pemphigoid sera. In bullous pemphigoid, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. We previously demonstrated that bullous pemphigoid sera predominantly react with a set of four epitopes (MCW-0 through MCW-3) clustered within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, lichen planus pemphigoides sera were also strongly reactive with recombinant bullous pemphigoid 180 NC16A. The lichen planus pemphigoides epitopes were further mapped using a series of overlapping recombinant segments of the NC16A domain. All lichen planus pemphigoides sera reacted with amino acids 46-59 of domain NC16A, a protein segment that was previously shown to be unreactive with bullous pemphigoid sera. Two lichen planus pemphigoides sera, in addition, reacted with the immunodominant antigenic region associated with bullous pemphigoid. In conclusion, there are now five bullous diseases that are associated with an autoimmune response to BP180: bullous pemphigoid; pemphigoid/herpes gestationis; cicatricial pemphigoid; linear immunoglobulin A disease; and lichen planus pemphigoides. In addition, we have identified a novel epitope within the BP180 NC16A domain, designated MCW-4, that appears to be uniquely recognized by sera from patients with lichen planus pemphigoides.

Objective To determine whether ocular cicatricial pemphigoid (OCP) may represent a distinct immunopathologic disease when it is pure ocular cicatricial pemphigoid (POCP) (e.g., only confined to the conjunctiva) or when it is associated with skin or extraocular mucous membrane lesions or both (OCP + ). Design Prospective, immunologic, and immunopathologic study with special emphasis on direct immunoelectron microscopy. Participants Six patients with POCP and seven patients with OCP + . Intervention After informed consent was obtained, a conjunctival biopsy was performed in all patients. Skin and extraocular mucosa biopsy specimens were harvested in selected cases only. Main outcome measures Results of direct immunofluorescence and direct immunoelectron microscopy without freezing on conjunctival and skin biopsy specimens, indirect immunofluorescence, and Western immunoblotting analysis were analyzed. Results Results of direct immunoelectron microscopic examination of the conjunctiva showed the presence of immune deposits in the upper lamina lucida of the basement membrane zone in the six patients with POCP, whereas the immune reactants were located in the lower part of the lamina lucida and in the lamina densa of the basement membrane zone (conjunctiva, buccal mucosa, and skin) in the seven patients with OCP + . Direct immunofluorescence was positive in the biopsy specimens of three patients with POCP (50%) and the seven patients with OCP + (100%). Results of indirect immunofluorescence study showed circulating autoantibody levels only in two patients with OCP + , and results of Western immunoblot analysis were negative. Conclusions Results of direct immunoelectron microscopic examination of the conjunctiva support the hypothesis that POCP may be a disease entity distinct from mucocutaneous cicatricial pemphigoid.

diopathic” bullous pemphigoid (BP), by definition, is a chronic subepidermal vesiculobullous disease mediated by autoantibodies toward antigens located in the hemidesmosomes and lamina lucida of the dermo-epidermal junction. Druginduced BP, respectively, is a term introduced to designate those cases presenting clinical, histologic, and immunopathologic features identical or closely similar to those in idiopathic disease, but induced by systemic ingestion or local use of certain drugs. Nowadays, it is well known that multiple exogeneous and endogeneous factors, namely a great number of medications, are capable of damaging the dermoepidermal junction, giving rise to a heterogeneous spectrum of subepidermal blistering diseases: fixed-drug eruption, erythema multiforme and Stevens-Johnson syndrome, sporadic porphyria and pseudoporphyria, bullous and cicatricial pemphigoid, and linear IgA-bullous dermatosis. Differentiating among these defined entities and discovering potential drug origin are major challenges in dermatologic practice. There are, however, various controversies concerning the incidence and even the actual existence of drug-induced pemphigoid. First, preceding the introduction of contemporaneous immunopathologic criteria for the diagnosis of autoimmune subepidermal bullous diseases, several cases of drug-induced pemphigoid should have been underdiagnosed. In 1951, Lever1 set the histologic criteria for distinguishing pemphigoid from other bullous diseases. In 1967, Jordon et al2 revealed by immunofluorescence (IF) studies the presence of anti-basement membrane zone (BMZ) antibodies, which remained diagnostic criteria for pemphigoid until it was shown in the early 1970s that epidermolysis bullosa acquisita (EBA) yields similar IF features.3 Both diseases were later reliably differentiated by the ultrastructural location of immune deposits, ie, hemidesmosomes and upper lamina lucida in BP,4 and the sublamina densa region in EBA,3 respectively. In cicatricial pemphigoid (CP), immune deposits were predominantly found to occupy the lower part of the lamina lucida.5 Further, by means of immunoprecipitation and Western blotting, the two major antigens precipitated by anti-BMZ antibodies in pemphigoid were identified and partially characterized as 230-kD BP antigen (BPAG1, BP-230) and 180-kD BP antigen (BPAG2, BP-180);6,7 the latter was also identified as the antigen in CP. Recently, it has been shown that autoantibodies in BP and CP recognize distinct sites of BP-180, which may explain the clinical heterogeneity of both disorders.8 Despite this extensive research, only a few studies have dealt with identification of antigens involved in the drug-induced forms of the subepidermal autoimmune blistering diseases. Another source of skepticism represents the fact that idiopathic BP is primarily a disease of elderly people who are often treated for diverse reasons, and with more than one medication. Two recent multicenter case-controlled epidemiologic studies analyzed the number and spectrum of drugs used on a long-term basis by BP patients.9,10 The results showed that in the patient group, the average number of medications used was 3.5 versus 2 in the control group; moreover, no statistically significant association was found with furosemide, a “classic” culprit for drug-induced BP. During the last decade both the number of published reports on drug-induced pemphigoid and the spectrum of the incriminated agents have continuously increased. Despite significant advances in understanding the heterogeneous group of subepidermal bullous diseases, many problems still await to be resolved regarding the role of medications in inducing this precise pathology of the BMZ. Causative Role of Systemic Drugs

Objective. Cicatricial pemphigoid (CP) is an autoimmune blistering disease characterized by anti-basement membrane zone (BMZ) antibodies with a varied heterogeneous clinical spectrum. We sought to characterize a subset of patients with disease limited to the oral cavity. Study Design. Twenty-nine random patients with vesiculobullous disease limited to the oral cavity were studied. We identified patients by clinical criteria, the presence of subepidermal/subepithelial bullae on routine histopathologic study, and deposition of IgG, complement, or both on the BMZ of perilesional tissue by immunopathological studies. Treatment included local and systemic therapies. Patients were monitored for a mean period of 6.7 years (range, 3.5 to 11 years). Results. The female/male ratio was 4.8:1. Patients with limited or minimal disease received local therapy only. In patients with extensive or severe disease, the use of dapsone yielded significant clinical improvement. Long-term follow-up showed that patients with severe disease treated with dapsone followed a clinical course similar to that in patients with minimal disease. Conclusions. Oral pemphigoid is a distinct clinical subset of CP. Overall it has a relatively benign course compared with that in patients with CP involving the oral cavity and other mucosae and the skin. Patients with minimal disease respond satisfactorily to topical therapy. Patients with severe and extensive disease benefit from dapsone therapy. In most patients the clinical course is prolonged and treatment is required for several months; in our study the mean treatment period was 42 months (range, 24 to 78 months). All the patients in this study went into clinical remission and remained in remission on cessation of therapy. No other mucosae or the skin were involved during the follow-up period.

Cicatricial conjunctivitis may be a sequel to systemic disorders (eg, Stevens-Johnson syndrome, cicatricial pemphigoid) or local disorders such as chemical burns. The cicatrisation is often associated with corneal epithelial changes that cause visual loss. These have been attributed to encroachment of the conjunctival epithelium over the cornea. However, the epithelial anomalies are poorly understood. We investigated the corneal epithelial changes in cicatricial conjunctivitis with an immunohistochemical study of intermediate filaments in normal and pathological specimens. Our results show that the normal corneal epithelium is immunoreactive for cytokeratin 3 (CK 3) but not cytokeratin 19 (CK 19), whereas normal conjunctival epithelium is CK 3 negative and CK 19 positive. Conjunctiva artificially transposed over the cornea (after therapeutic conjunctival flap reconstruction) retained the normal pattern of conjunctival cytokeratin expression (CK 3 negative, CK 19 positive). Conversely, the entire corneal epithelium exhibited the normal cytokeratin pattern (CK 3 positive, CK 19 negative) in 82% of Stevens-Johnson, 80% of cicatricial pemphigoid, and 69% of chemical burns specimens. The findings suggest that conjunctival encroachment is not responsible for the changes at the corneal surface in cicatricial conjunctivitis and that the abnormal corneal epithelium is derived from native corneal cells in these diseases.

This review will describe adult onset mucocutaneous/autoimmune diseases that involve defects in cell-to-cell, cell-to-matrix, or cell-to-basement membrane adhesion. Included in this group are pemphigus, cicatricial pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, and bullous systemic lupus erythematous. Detection and treatment of blistering disorders that manifest early in the oral cavity may prevent widespread involvement of skin. During the past few years, targets of autoantibodies have been clarified and new targets have been identified, allowing better understanding of the pathophysiology involved in these diseases. New information about more effective regimens with fewer side effects has also been obtained, presenting new treatment options. Clinical manifestations and management of these disorders will be described as well as histopathologic, ultrastructural, and immunopathologic studies that distinguish each disorder and facilitate diagnosis and treatment.

This study characterized the specific reactivity, IgG subclass, and complement fixing ability of anti-laminin-5 IgG from 12 patients with anti-epiligrin cicatricial pemphigoid. Circulating IgG from all patients bound the dermal side of 1 M NaCl split skin, immunoprecipitated laminin-5 produced by biosynthetically radiolabeled human keratinocytes, and (in 10 of 12 cases) immunoblotted the laminin-α3 subunit. Analysis of the distribution of IgG subclasses in these patients' circulating anti-laminin-5 autoantibodies by semiquantitative indirect immunofluorescence microscopy using the HP series of subclass-specific monoclonal antibodies revealed: (i) IgG 4 predominant autoantibodies in seven of 11 sera; (ii) IgG 1 and IgG 2 at substantially lower levels in a smaller number of sera; and (iii) no specific IgG 3 anti-laminin-5 autoantibodies in any patients. The same IgG 4 -dominant profile of anti-laminin-5 autoantibodies was found in enzyme-linked immunosorbent assay studies of purified human laminin 5. Direct immunofluorescence microscopy of six skin biopsies from three patients found that IgG 4 was also the predominant subclass of IgG in epidermal basement membranes in situ . Consistent with these findings, sera from 11 of 11 patients with anti-laminin-5 IgG autoantibodies did not fix C3 to epidermal basement membranes in vitro . These immunochemical studies suggest that complement activation does not play a major role in the pathophysiology of this disease and that subepidermal blisters in these patients may develop via a direct effect of anti-laminin-5 IgG itself.

The BP180 antigen is a hemidesmosomal glycoprotein that is recognized by autoantibodies associated with three autoimmune disorders, bullous pemphigoid (BP), herpes gestationis (HG), and cicatricial pemphigoid (CP). BP and HG sera have been shown to recognize a common extracellular site located near the membrane-spanning domain of this protein, whereas CP sera react predominantly with a distinct site near the C terminus. In the current study, the main immunogenic sites on the BP180 ectodomain were ultrastructurally localized using six BP sera, four CP sera, and two rabbit antisera. The immunolocalization pattern of BP sera was largely restricted to the upper lamina lucida region immediately subjacent to the epidermal hemidesmosome and closely resembled that of a rabbit antiserum directed against the NC16A (membrane-proximal) domain of BP180. CP sera, on the other hand, exhibited a lower lamina lucida/lamina densa labeling pattern that was strikingly similar to that of rabbit antibodies to the BP180 C-terminal region. Finally, antibodies to the BP180 C-terminal region co-localized with an anti–laminin-5 antibody in the anchoring filament zone. These findings strongly suggest that the BP180 extracellular domain exists in an extended conformation, with the C terminus of this protein projecting into the lamina densa. These data support the hypothesis that BP180 contributes to the structure and function of the anchoring filaments. Differences in the ultrastructural mapping of BP and CP autoantibodies appear to correlate with epitope mapping data, which, together, may help to explain the clinical heterogeneity observed in this group of bullous disorders.

We characterized basement membrane zone (BMZ) autoantigens targeted by autoantibodies (AAb) from patients with cicatricial pemphigoid. Serum from a patient with severe oral cicatricial pemphigoid contained IgG anti-BMZ AAb. The AAb labeled a lower BMZ component on salt-split skin and localized to the lower lamina lucida/lamina densa by direct and indirect immunoelectron microscopy (HEM) but did not label blood vessels. The AAb did not react with EHS laminin-1 and type IV collagen, pepsinized human type IV collagen, recombinant entactin, or NC1 domain of type VII collagen by dot blotting and western blotting. We focused our studies on the laminin family, as laminin-5 was identified as an autoantigen in cicatricial pemphigoid. Culture-conditioned media from normal keratinocytes (containing laminin-6 and laminin-5) and JEB keratinocytes (containing laminin-6 but not laminin-5) were studied by western blotting. Under nonreducing conditions, the patient's AAb recognized a 600-kDa protein (laminin-6) intensely and a 400-kDa protein (laminin-5) weakly in normal keratinocyte medium even though abundant laminin-5 was present. In JEB keratinocyte medium, however, the 600-kDa protein (laminin-6) alone was recognized by the patient's AAb. The AAb also immunolabeled BMZ of JEB skin that lacked laminin-5. The AAb from this patient and two other patients with anti-laminin-5 cicatricial pemphigoid immunoprecipitated both laminin-6 an4 laminin-5. Taken together, the results of IEM, non-reducing western blotting, immunoprecipitation, and JEB skin BMZ immunolabeling indicate that laminin-6, as well as laminin-5, is identified by the AAb from a subset of cicatricial pemphigoid patients. We propose the name “anti-laminin cicatricial pemphigoid” for this subset.

Sup-epidermal blisters which may be congenital or acquired form a heterogeneous group of conditions. Although they have variable aetiologies, there is considerable histological overlap. As a consequence, they often represent a source of considerable diagnostic difficulty. This difficulty sometimes reflects, at least in part, an attempt by the pathologist to interpret the histological features in isolation. Diagnostic dermatopathology depends upon careful clinicopathological correlation and this is of particular importance to the evaluation of bullous dermatoses. In addition to clinical and histopathological findings a routine assessment of such lesions should also include input from direct and indirect immunofluorescence investigations. On occasion ultrastructural, immunoelectron microscopic and molecular biological techniques will prove necessary before a final diagnosis can be made. In this review, the auto-immune sub-epidermal blistering diseases comprising bullous pemphigoid, cicatricial pemphigoid, herpes (pemphigoid) gestationis, inflammatory epidermolysis bullosa acquisita, linear IgA disease and bullous systemic erythematosus are considered. Dermatitis herpetiformis is also included. In addition to discussing the clinical appearance, histological features and differential diagnoses, emphasis is placed on the role of split skin immunofluorescence and Western immunoblot analysis in the evaluation of these acquired, inflammatory immunologically mediated variants.

Autoimmune bullous diseases are a group of blistering diseases characterized by in vivo bound and circulating autoantibodies directed against components of epithelia. They can be divided histologically into two main groups based on the location of the cleavage plane in the epithelia—intraepithelial for the pemphigus group and subepithelial for the group of subepithelial blistering diseases. These two groups of diseases can also be distinguished by the types of molecules that serve as target antigens. Autoantibodies associated with the pemphigus group react with protein constituents of the desmosome, a cell structure that functions in cell-cell adhesion, whereas the autoimmune response in the subepithelial group is directed against components of the basement membrane zone (BMZ). Both groups of bullous diseases are composed of multiple disease entities that are distinguishable at the clinical, histological, and immunological levels. This article focuses on ocular manifestations of autoimmune subepithelial blistering diseases. The diseases that fall into this category are listed in Table 1. They include cicatricial pemphigoid (CP), the prototypic disease with the most severe ocular involvement, epidermolysis bullosa acquisita (EBA), and linear IgA disease (LAD). This article describes the clinical, histological, and immunopathological findings, with an emphasis on ocular involvement. Pathogenesis and treatment are also discussed. Pemphigus vulgaris and paraneoplastic pemphigus, which are defined by an intraepithelial cleavage, and bullous pemphigoid (BP) and dermatitis herpetiformis, which are rarely associated with ocular lesions, are not covered.

The successful therapeutic use of D-penicillamine (DPA) has been hindered by its many adverse effects. Autoimmune bullous syndromes are among the less common adverse DPA reactions; they are not dose dependent and appear late in the treatment of diseases of altered immunity, most often rheumatoid arthritis. The majority of the DPA-induced bullous syndromes belong to the pemphigus spectrum, usually pemphigus foliaceus or erythematosus, have a lower prevalence of demonstrable tissue-fixed or circulating antibodies than spontaneously occurring pemphigus, display abnormal direct immunofluorescent patterns, and have a generally favorable prognosis. However, many cases do exhibit a full-blown chronic disease, unaffected by DPA withdrawal. DPA-induced cicatricial pemphigoid is a severe disease of both mucous and cutaneous involvement with a prognosis similar to the spontaneous disease. Cases of DPA-induced epidermolysis bullosa acquisita and DPA-induced bullous pemphigoid were not sufficiently substantiated by immunofluorescence or immunoprecipitation criteria.

Background: Circulating IgG anti-basement membrane autoantibodies from patients with subepidermal bullous diseases can be categorized on the basis of their pattern of reactivity against 1 mol/L sodium chloride (NaCl)-split skin. Objective: The purpose of this study was to define by immunochemical techniques the specific antigen(s) targeted by IgG autoantibodies from a group of patients with subepidermal blistering diseases and then (1) prospectively determine which side(s) of 1 mol/L NaCl-split skin is (are) bound by these patients' autoantibodies, (2) compare the sensitivity of intact and 1 mol/L NaCl-split skin for the detection of these autoantibodies; and (3) devise a practical method to distinguish patients with antiepiligrin cicatricial pemphigoid from those with other subepidermal blistering diseases. Methods: Investigative techniques included direct and indirect immunofluorescence microscopy, immunoprecipitation studies, and immunoblotting. Results: These studies identified 14 patients whose sera immunoprecipitate bullous pemphigoid antigens 1, 2, or both. These patients' circulating IgG anti-basement membrane autoantibodies bind the epidermal ( n = 11), epidermal and dermal ( n = 2), or dermal ( n = 1) sides of 1 mol/L NaCl-split skin by indirect immunofluorescence microscopy. In contrast, IgG from all patients with autoantibodies directed against type VII collagen ( n = 5) or epiligrin ( n = 6) bind only the dermal side of 1 mol/L NaCl-split skin. In all but one patient in this series, 1 mol/L NaCl-split skin proved to be a more sensitive test substrate than intact human skin for detection of circulating IgG anti-basement membrane autoantibodies. Patients with antiepiligrin cicatricial pemphigoid were distinguished from other patients in that their circulating autoantibodies bound epidermal basement membrane in the skin of primates but not small mammals. Conclusion: NaCl-split skin (1 mol/L) of various species is a sensitive and practical indirect immunofluorescence microscopy test substrate for the evaluation of patients with IgG anti-basement membrane autoantibodies and evaluation of subepidermal bullous diseases.