Dual diagnosis of Pemphigus and pemphigoid. Retrospective review of thirty cases in the literature.

BACKGROUND: Pemphigus and pemphigoid are two distinct groups of autoimmune blistering diseases. There are many reports of the simultaneous presence of clinical and serological features of both diseases in the same patient. OBJECTIVE: This study is a retrospective review of the present literature on reports of patients with features of both pemphigus and pemphigoid. We recommend that these patients be considered as having a dual diagnosis. METHODS: A review of the English language, peer-reviewed literature was conducted on patients described with features of pemphigus and pemphigoid. Available data on clinical profile, histology, immunopathology, treatment, follow-up and outcome were studied in 30 patients. They were divided into three groups: (1) bullous pemphigoid and pemphigus vulgaris, (2) mucous membrane or cicatricial pemphigoid and pemphigus vulgaris and (3) bullous pemphigoid and pemphigus foliaceus. RESULTS: In all three groups, most patients had a clinical phenotype resembling both diseases. In 17 patients with bullous pemphigoid and pemphigus vulgaris, 83% had a skin biopsy consistent with bullous pemphigoid, 70% had direct immunofluorescence studies typical of bullous pemphigoid and sera of 83% had antibodies typical of pemphigus vulgaris on indirect immunofluorescence. In 10 patients with mucous membrane or cicatricial pemphigoid and pemphigus vulgaris, a histology of mucous membrane pemphigoid was reported in 60% of the patients, direct immunofluorescence studies typical of mucous membrane pemphigoid were reported in 70% of the patients and in 80%, autoantibodies characteristic of pemphigus vulgaris were observed. In 3 patients with bullous pemphigoid and pemphigus foliaceus, the histologies were consistent with bullous pemphigoid, direct immunofluorescence was typical of pemphigus foliaceus and their sera had both autoantibodies. The majority of the 30 patients required long-term high-dose corticosteroids and immunosuppressive agents to control their disease. Three patients with bullous pemphigoid and pemphigus vulgaris (18%) died due to effects of prolonged immunosuppression. CONCLUSION: We characterize a group of patients who have clinical, histological and immunopathological features of bullous or mucous membrane or cicatricial pemphigoid with serological features of pemphigus. These patients did not achieve a prolonged clinical remission by conventional therapy. It is possible that early identification of these patients may improve their prognosis.     

Specific detection of anti-cell surface antibodies in herpes gestationis sera

Abstract We examined 42 herpes gestationis sera with immunofluorescence of normal human skin sections, and found that anti-keratinocyte cell surface antibodies were detected specifically in 10 herpes gestationis sera. The diagnosis of these herpes gestationis cases was confirmed by detecting antibodies against the 180 kD bullous pemphigoid antigen with immunoblotting of its fusion protein. The results of immunoadsorption assay using baculoproteins of both pemphigus vulgaris and pemphigus foliaceus antigens indicated that the herpes gestalionis sera did not recognize common pemphigus antigens. Immunoblotting of human epidermal extracts and immunofluorescence of various tissues also suggested that the sera did not recognize any other desmosomal components or paraneoplastic pemphigus antigens. The significance of this reactivity is unclear. However, because no control bullous pemphigoid sera showed this reactivity, it may suggest a different pathophysiology between herpes gestationis and bullous pemphigoid.     

Eosinophilic spongiosis

This report gives an account of nine patients, all females, with the histological finding of eosinophilic spongiosis. Six of them had positive intercellular antibodies on direct immunofluorescence but only two had circulating pemphigus antibodies. The clinical presentations of those with proven pemphigus resembled bullous pemphigoid in one, dermatitis herpetiformis in another, whereas the remainder were more typical of pemphigus foliaceus or vulgaris. Three patients had negative immunofluorescence. They may still develop pemphigus or alternatively could have some unclassifiable bullous dermatosis.     

Occult Herpes Simplex Virus Colonization of Bullous Dermatitides

Background: Acantholytic disorders, including pemphigus vulgaris, chronic benign familial pemphigus (Hailey-Hailey disease, superficial pemphigus), Darier disease, and Grover transient acantholytic dermatosis, as well as other vesiculo-bullous disorders, including bullous pemphigoid, epidermolysis bullosa, and atopic dermatitis, are prone to florid infections by herpes simplex virus (HSV)-I and -II, and, more rarely, by varicellazoster virus (VZV). As these infections are difficult to recognize clinically and histologically, their frequency remains unknown. A possible occult viral colonization has never been documented in these disorders. The manner in which the primary bullous disorders are contaminated by herpesviridae remains unclear. Objective: To retrospectively assess the possible presence of HSV and VZV in a series of biopsies of acantholytic disorders and bullous pemphigoid. Method: The typical α-herpesviridae-related cytopathic signs were searched for by conventional microscopy in skin biopsies of patients with bullous pemphigoid (n = 20), pemphigus vulgaris (n = 19), Darier disease (n = 18), chronic benign familial pemphigus (n = 3), and Grover transient acantholytic dermatosis (n = 3). Immunohistochemistry (IHC) targeted specific HSV-I, HSV-II, and VZV antigens. Polymerase chain reaction (PCR) was used for detecting HSV- and VZV-specific DNA sequences. Results: No cytopathic signs suggestive of HSV or VZV infection were detected. However, IHC revealed HSV antigens in Darier disease (1/18, HSV-I), Grover transient acantholytic dermatosis (1/3, HSV-I), pemphigus vulgaris (1/19, HSV-I), and bullous pemphigoid (2/20, HSV-I and HSV-II). In these IHC-positive cases, PCR amplified specific HSV primers in Darier disease (1/18), pemphigus vulgaris (1/19), and bullous pemphigoid (1/20). VZV antigens and nucleic acids were never identified. The HSV antigens were nearly always restricted to the upper part of the granular layer and thus differed from the usual HSV distribution during cutaneous infection. Negative and positive controls yielded consistently positive and negative results, respectively. Conclusion: This report shows for the first time that clinically and histologically occult HSV colonization may occur in Darier disease, Grover transient acantholytic disease, pemphigus vulgaris, and bullous pemphigoid. Given the frequent use of immunosuppressive treatments for primary bullous disorders, greater awareness of HSV colonization and infection is recommended in these patients.     

Combined bullous pemphigoid and pemphigus vulgaris in an 18‐year‐old female

We present a case of an 18‐year‐old female with clinical, histological and immunopathological features of overlapping pemphigus vulgaris and bullous pemphigoid. This case is unique both in the context of the distinctive hybrid nature of the bullous disorder and the young age of onset. An initial biopsy showed a combined pemphigus pattern histologically and a dominant pemphigoid pattern by immunofluorescence, hence posing a diagnostic conundrum. A subsequent biopsy however confirmed a combined pemphigus and pemphigoid pattern both in the context of the light microscopic findings and by immunofluorescence. The pathophysiologic basis of this distinctive hybrid dermatosis along with the other reported cases of overlapping pemphigus and pemphigoid are reviewed. Rossi A, Reszko A, Leach J, Magro CM. Combined bullous pemphigoid and pemphigus vulgaris in an 18‐year‐old female.     

Serum plakophilin‐3 autoreactivity in paraneoplastic pemphigus

Summary Background Paraneoplastic pemphigus (PNP) is a malignancy‐associated autoimmune disease in which circulating autoantibodies recognize various polypeptides that constitute the desmosomes and hemidesmosomes of epithelial structures. Objectives To determine whether PNP is associated with autoreactivity against the armadillo‐repeat‐containing plakophilin‐3 (PKP3) protein. Methods HEK293 cells were transiently transfected with either a pEF6/myc‐His or a pEGFP‐N2 construct, both encoding human PKP3 (protein products of 85 kDa and 115 kDa, respectively). Protein lysates were made in Laemmli buffer. The proteins were separated by gel electrophoresis, transferred to filters and probed with five PNP sera, four pemphigus vulgaris sera, two pemphigus foliaceus sera, five bullous pemphigoid sera, one cicatricial pemphigoid serum and one linear IgA dermatosis serum. A mouse monoclonal anti‐PKP3 antibody raised against a 20‐amino acid peptide of human PKP3 was used as a positive control. Results Autoreactivity against both 85‐kDa and 115‐kDa recombinant PKP3 protein products was detected in all five PNP sera and in one pemphigus vulgaris serum. None of the sera of patients with basement membrane zone bullous diseases reacted with the PKP3 protein products. The presence of autoantibodies against PKP3 in PNP sera was subsequently confirmed in human epidermal lysate blots. Conclusions This is the first report of PKP3 reactivity in bullous disorders, which was present in all the PNP sera tested. The presence of PKP3 reactivity in one patient with pemphigus vulgaris is not unexpected as the desmosome is also targeted in this disease.     

A study of benign chronic bullous dermatosis of childhood and comparison with dermatitis herpetiformis and bullous pemphigoid occurring in childhood

Eighteen patients with benign chronic bullous dermatosis of childhood were studied and the findings compared with those of dermatitis herpetiformis (twenty-two cases) and bullous pemphigoid (five cases) beginning in childhood. The patients with benign chronic bullous dermatosis of childhood had a moderately pruritic bullous eruption with maximal involvement of the pelvic and perioral regions which tended to occur at an earlier age than either dermatitis herpetiformis or bullous pemphigoid. In contrast to dermatitis herpetiformis one-third of the cases with benign chronic bullous dermaiosis of childhood went into remission. Evidence of coeliac disease was only found in the dermatitis herpetiformis group. Surprisingly both diseases shared HLA-B8. A linear BMZ band of IgA was detected on direct immunofluorescence in all but one of the cases with benign chronic bullous dermatosis of childhood and circulating antibodies were detectable in two-thirds. Routine histopathology was of little value in distinguishing between benign chronic bullous dermaiosis of childhood and dermatitis herpetiformis or bullous pemphigoid. Several paradoxes have yet to be explained before it can be determined whether benign chronic bullous dermatosis of childhood is a variant of dermatitis herpetiformis or linear IgA disease.     

Evaluation of the usefulness of immunofluorescence on Tzanck smears in pemphigus as an aid to diagnosis

Direct immunofluorescence was done on smears taken from 38 cases of bullous dermatoses and oral ulceration. 16 of these had pemphigus. All of the pemphigus cases had positive Tzanck smears and fluorescence of individual acantholytic cells and/or intercellular fluorescence of sheets of cells. Other bullous dermatoses showed no acantholysis or fluorescence. Smears from a series of oral lesions (mainly aphthous ulcers) showed intercellular fluorescence of sheets of cells similar to pemphigus. Therefore smear immunofluorescence cannot be reliably used as a diagnostic test in oral pemphigus.     

Reliability of cytodiagnosis in oral pemphigus vulgaris. A study of 30 cases

The aim of this study was to verify the reliability of the Tzanck test, performed by both traditional cytomorphology and the direct immunofluorescence technique, in diagnosis of oral pemphigus vulgaris. Cytologic smears were obtained from oral erosions of thirty patients with well ascertained pemphigus vulgaris. Control smears were taken from thirty patients affected by various other diseases of oral mucosa and from thirty healthy subjects. Cytologic diagnosis of oral pemphigus was based upon significant findings of acantholytic cells by cytomorphology, and of epithelial cells with pericellular deposition of IgG (which persisted after cytocentrifugation) by direct immunofluorescence. The cytomorphological test gave positive results in twenty-eight patients with pemphigus and in one patient with herpetic stomatitis, and negative results in all other cases. The immunocytologic test gave positive results in all patients with pemphigus, and negative results in all controls. These findings indicate that the cytomorphological test may be a useful method for screening oral pemphigus, while the immunocytologic test may provide a reliable method for definitive diagnosis.     

UV light-induced linear IgA dermatosis

Various exogenous factors (eg, drugs, dietary antigens, trauma, infections, radiographs, and UV radiation) are known to induce or aggravate skin diseases. UV radiation in particular is known to induce or aggravate the autoimmune bullous diseases of pemphigus foliaceus, pemphigus vulgaris, and bullous pemphigoid. Its role in linear IgA dermatosis, however, is not well recognized. We report the second case of linear IgA dermatosis induced by intense sun exposure in which blistering was induced by UVA radiation. Furthermore, a review of the literature on photoinduced autoimmune bullous diseases and the wavelengths responsible for the induction of blistering is presented and several proposed mechanisms of action for the blister induction, including release or unmasking of antigens, promotion of antibody fixation by UV radiation, and launching of an inflammatory process, are discussed. We conclude that linear IgA dermatosis should be added to the list of autoimmune bullous diseases induced and/or aggravated by UV radiation.     

Linear IgA Bullous Dermatosis of Childhood with Autoantibodies to a 230 kDa Epidermal Antigen

Abstract: Linear IgA bullous dermatosis (LABD) is an autoimmune, subepidermal disease defined on the basis of direct immunofluorescence findings. However, more recent techniques used to study bullous dermatoses suggest that LABD may be heterogeneous. A patient with LABD of childhood (chronic benign disease of childhood, CBDC) was studied by indirect immunofluorescence on salt-split skin and by Western blot in an attempt to characterize the involved autoantigen. This young girl's periorificial (mouth, genitalia), erythematovesicular lesions were diagnosed initially as herpes simplex. Histologic examination revealed eosinophilic spongiosis, suggesting the diagnosis of an autoimmune blistering disease. Direct immunofluorescence showed an exclusive linear IgA deposit at the dermoepidermal junction. Indirect immunofluorescence revealed circulating IgA autoantibodies that reacted with the epidermal side of saltsplit skin; these reacted by Western blot with a 230 kDa epidermal antigen, as in bullous pemphigoid. This case, fulfilling the diagnostic clinical and direct immunofluorescence criteria for LABD/CBDC, seems to represent IgA bullous pemphigoid. It further underscores the nosologic heterogeneity of LABD, which probably includes, apart from bullous pemphigoid, epidermolysis bullosa acquisita and cicatricial pemphigoid.     

Varicella-zoster virus (VZV) and alpha 1 antitrypsin: a fatal outcome in a patient affected by endemic pemphigus foliaceus

Background Herpes virus infections are well known infectious complications of pemphigus and bullous pemphigoid. We describe pathologic findings utilizing autopsy tissue from several organs from a patient affected by a new variant of endemic pemphigus in El Bagre, Colombia, South America. Case report We describe a patient by a new variant of endemic pemphigus foliaceus from El Bagre that was receiving high‐dosage immunosuppressants when hospitalized and died suddenly following contact with a second patient affected by chicken pox. Materials and methods We performed studies utilizing hematoxylin and eosin, immunohistochemistry, and direct immunofluorescence techniques on tissues from several organs. Results We detected the presence of varicella zoster virus, as well as strong positivity for α‐1 antitrypsin in the heart, kidneys, spleen, liver, skin, brain, lungs, pancreas, small and large intestines, and skeletal muscle. In regard to structural damage in the kidney and heart, we believe the observed damage is associated with the presence of autoantibodies to these organs, since both of them are rich in plakins and El Bagre‐EPF patients present significant antibodies to plakin molecules. Conclusion In patients with endemic pemphigus foliaceus, we recommend complete isolation of the patient when receiving high dosages of systemic immunosuppressive agents. We further suggest the clinical possibility of a synergistic, fatal interaction between active pemphigus foliaceus, varicella zoster virus, herpes simplex virus, immunosuppressive agents, and a systemic activation of α‐1 antitrypsin. Thus, we suggest adequate bed spacing, barrier nursing, and preventative testing for α‐1 antitrypsin activation are warranted in these patients to address these complications.     

Adjuvant high-dose intravenous gammaglobulin in the treatment of pemphigus and bullous pemphigoid: experience in six patients

At present, initial high-dose prednisone is the treatment of choice for patients with pemphigus and bullous pemphigoid. To reduce the risks associated with long-term corticosteroid treatment, other immunosuppressants are often given as steroid-sparing agents. Occasionally, the dose of steroids cannot be reduced. In this study, we report six patients with pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid, in whom the daily corticosteroid dose could only be tapered to acceptable, effective, maintenance levels following treatment with high-dose intravenous gammaglobulin.     

Blistering diseases in the mature patient

Autoimmune blistering diseases (AIBD) are a group of chronic diseases affecting the skin and mucous membranes, with different presentation, clinical course, histologic and immunopathologic findings, and different therapeutic approach. Blisters develop as a result of autoantibodies directed against distinct adhesion structures within desmosomes or within the basement membrane zone. The most common AIBD that develops in the elderly is bullous pemphigoid (previously also named “pemphigoid senilis”), but mature patients can also present with other AIBD as mucous membrane pemphigoid, epidermolysis bullosa acquisita, paraneoplastic pemphigus, pemphigus vulgaris, pemphigus foliaceus, linear IgA dermatosis, and dermatitis herpetiformis. There are no differences in treatment approach to mature patients with AIBD, but due to more common comorbidities, systemic therapy should be given with more caution and control, and due to distorted skin integrity in the aged skin, the safety concerns are increased with the long-term use of any topical medication.     

Comparative scanning electron microscopy of bullous diseases

The purpose of this study is to compare scanning electron microscopy findings of the blister roof in three distinct bullous diseases: one intraepidermal acantholytic (pemphigus foliaceus); one due to hemidesmosomal dysfunction (bullous pemphigoid); and one secondary to anchoring fibril dysfunction - type VII collagen (dystrophic epidermolysis bullosa). In pemphigus foliaceus, acantholytic phenomena were readily demonstrated. In bullous pemphigoid, the epidermis had a solid aspect. In dystrophic epidermolysis bullosa a net was seen in the blister roof.     

Successful treatment of autoimmune bullous diseases with a combination therapy of ciclosporin and corticosteroid

Three patients with autoimmune bullous diseases, pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid, were treated with a combination therapy of ciclosporin and corticosteroid. These patients responded to systemic low-dose prednisolone (or dexamethasone) and low-dose ciclosporin therapy; the result was prolonged complete remission. The addition of low-dose ciclosporin may produce enhanced clinical effects of steroid therapy without increasing any significant side effects.     

Coexistence of pemphigus foliaceus and bullous pemphigoid. Demonstration of autoantibodies that bind to both the pemphigus foliaceus antigen complex and the bullous pemphigoid antigen

Pemphigus and bullous pemphigoid are autoimmune blistering diseases of the skin characterized by circulating autoantibodies directed against the keratinocyte cell surface and the epidermal basement membrane zone, respectively. The coexistence of pemphigus and bullous pemphigoid is very uncommon. We describe a patient with pemphigus foliaceus who later developed bullous pemphigoid and show, by means of immunoprecipitation studies utilizing both cultured keratinocytes and suction blister epidermis, that our patient had circulating autoantibodies directed against both the pemphigus foliaceus antigen complex and the bullous pemphigoid antigen. This report is the first to demonstrate the coexistence of pemphigus foliaceus and bullous pemphigoid at the molecular level.     

Penicillamine-induced pemphigus foliaceus-like dermatosis. A case with unusual features, successfully treated by plasmapheresis

A case of a severe, widespread bullous dermatosis clinically resembling pemphigus foliaceus occurred during treatment with penicillamine hydrochloride in a patient with rheumatoid arthritis. Histologically, the disease showed changes compatible with pemphigus vulgaris as well as with a bullous drug eruption. Treatment by plasmapheresis proved to be effective in controlling the disease.     

80例大疱性皮肤病组织病理及直接免疫荧光结果分析

目的：探讨组织病理及直接免疫荧光检查对大疱性皮肤病的诊断意义。方法：对80例大疱性皮肤病患者的皮损进行组织病理检查,并采用鼠抗人免疫球蛋白（IgG,IgM,IgA）及补体C3进行直接免疫荧光检查,对结果进行回顾性分析。结果：本组患者自身免疫性大疱性皮肤病占60.00%,以天疱疮和类天疱疮为主,非自身免疫性大疱性皮肤病以大疱性表皮松解症及大疱性多形红斑多见,不同类型的大疱性皮肤病组织病理及免疫荧光具有特征性。结论：组织病理及直接免疫荧光检查对大疱性皮肤病的诊断、鉴别诊断、治疗、预后判断具有重要的意义。     

Comparison of detection of varicella-zoster virus by the Tzanck smear, direct immunofluorescence with a monoclonal antibody, and virus isolation

A study comparing direct immunofluorescence assay using a new monoclonal antibody specific for a varicella-zoster virus glycoprotein complex, the Tzanck smear, and virus isolation for detection of varicella-zoster virus in 56 patients with clinically apparent herpes zoster is presented. Of 47 patients with clinical herpes zoster and with cultures negative for herpes simplex virus, 30 (64%) had positive Tzanck smears, direct immunofluorescence assay results were positive in 26 (55%), and cultures were positive in only 12 (26%). Both direct immunofluorescence assay and the Tzanck smear were found to be superior to culture technics; however, direct immunofluorescence assay was found to have greater specificity.