This is a superficial form of pemphigus and accounts for 10% of all cases. It is characterized by recurrent crops of flaccid bullae that easily rupture (Nikolsky's sign) leading to shallow erosions and erythematous plaques. Unlike pemphigus, oral mucosal involvement is rare. The disease occurs on the face and trunk but may spread to large portions of the body. Rarely, lesions may resemble dermatitis herpetiformis, a variant known as pemphigus herpetiformis.
Like pemphigus, there is an association with other autoimmune disorders including lupus, bullous pemphigoid, thymoma, myasthenia gravis, lymphoma, Grave's disease, and IgA nephropathy. Offending drugs include ACE inhibitors, penicillamine, gold, pyritinol, rifampicin, thiamazole, and tiopronin. It is the most common form of pemphigus that occurs with the use of penicillamine occurring in as many as 10% of patients taking the drug for prolonged periods.
There is an interesting infectious variant, termed endemic pemphigus foliaceus or fogo selavagem. It is discussed in the outline below.
The pathologist must distinguish this disease from other disorders having acantholysis, including Grover's disease. The clinical presentation is helpful but if doubt remains, DIF is definitive. Bullous impetigo contain bacteria within the blister cavity.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/Immunohistochemistry/Electron Microscopy Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
CHARACTERIZATION ENDEMIC TYPES COLUMBIA
Detection of mercury and other undetermined materials in skin biopsies of endemic pemphigus foliaceus.
Abreu Velez AM, Warfvinge G, Herrera WL, Abreu Velez CE, Montoya M F, Hardy DM, Bollag WB, Hashimoto K.
Institute of Molecular Medicine and Genetic, Medical College of Georgia, Augusta, GA 30912-2630, USA.
Am J Dermatopathol. 2003 Oct;25(5):384-91. Abstract quote
A novel variant of endemic pemphigus foliaceus (EPF) was described among individuals in an area surrounding El Bagre, Colombia, South America. The population in this rural mining community is exposed to high environmental levels of mercury, used for gold extraction, as well as other minerals, metalloids, and trace elements (e.g., quartz, rutile, granite, magnetite, and almenite) and ultraviolet radiation.
Fifty control subjects and fifty EPF patients in the endemic area were examined for the presence of mercury in skin biopsies and hair, using autometallographic and mass spectroscopic analyses, respectively. Simultaneously, serum levels of IgE were measured, and cutaneous tests for hypersensitivity reactions were performed. Using autometallography, mercuric sulfides/selenides were detected in 14 of 51 skin biopsies distributed similarly in the control and patient groups. However, significantly higher serum IgE levels and mercury concentrations in hair, urine, and nails were found in patients compared with controls. Microscopic analysis revealed mercuric sulfides/selenides concentrated within and around the sweat gland epithelium, as well as in dendritic cells. Five skin biopsies from EPF patients and five from controls that tested positive for the presence of mercuric sulfides/selenides by autometallography were randomly selected for electron microscopic analysis.
This analysis revealed a mixed electron-dense and electron-light material closely associated with desmosomes in patients. However, there were intracellular vesicles containing an amalgam of electron-dense and electron-light materials only in the EPF patients. Thus, EPF-affected individuals are exposed to high levels of environmental mercuric sulfides/selenides and other elements.
This is the first study reporting mercuric sulfides/selenides in skin biopsies from people living in a focus of EPF, and these compounds may play a role in the pathogenesis of autoimmunity.
A unique form of endemic pemphigus in northern Colombia.
Abreu-Velez AM, Hashimoto T, Bollag WB, Tobon Arroyave S, Abreu-Velez CE, Londono ML, Montoya F, Beutner EH.
Institute of Molecular Medicine and Genetics, Medical College of Georgia, GA 30912, USA.
J Am Acad Dermatol. 2003 Oct;49(4):599-608. Abstract quote
BACKGROUND: Endemic forms of pemphigus are a unique group of autoimmune diseases that represent opportunities to study interactions of the environment and genetics with the immune system. The restriction to relatively well-defined regions of South and Central America and perhaps Africa characterizes these diseases.
OBJECTIVES: The aims of this study were to confirm the endemic nature of a new type of autoimmune disease occurring in a mining town in northeastern Colombia in the El Bagre area, to characterize it, and to compare it with other forms of endemic pemphigus.
METHODS: A 10-year prospective, controlled epidemiologic, humanitarian, and immunologic fieldwork case-control survey was performed in El Bagre, Colombia.
RESULTS: Our work revealed that this disease is endemic in rural areas surrounding El Bagre. The disease appeared in 4.7% of middle-aged and older men and postmenopausal women from these rural areas. This disease differs from previously described forms of endemic pemphigus. It shares some heterogeneous immunoreactivity with paraneoplastic pemphigus but is not associated with malignant tumors. The disease resembles Senear-Usher syndrome (pemphigus and lupus) but occurs endemically either with a localized stable clinical course or in a systemic form. This systemic form may affect organs other than skin and is characterized by episodic relapses and poor prognosis in comparison with the localized form.
CONCLUSION: We have confirmed endemic pemphigus foliaceus in El Bagre as an autoimmune disease that shares features with Senear-Usher syndrome but occurs in an endemic fashion. Heterogeneous antigenic reactivity is observed as in paraneoplastic pemphigus but with no evidence of association with neoplasia. In addition, constant exogenous antigenic stimulation and a genetic predisposition may be required in the pathogenesis of this disease.
Analyses of autoantigens in a new form of endemic pemphigus foliaceus in Colombia.
Abreu-Velez AM, Beutner EH, Montoya F, Bollag WB, Hashimoto T.
Institute of Molecular Medicine and Genetics, Medical College of Georgia, GA 30912, USA.
J Am Acad Dermatol. 2003 Oct;49(4):609-14 Abstract quote.
BACKGROUND: We previously described a new focus of endemic pemphigus foliaceus in rural areas of El Bagre, Colombia, with clinical and direct immunofluorescence characteristics of pemphigus erythematosus.
OBJECTIVE: The aim of this study was to characterize autoantigen profiles for 34 serum samples obtained from patients with this condition.
METHODS: Immunofluorescence, various immunoblot analyses with different antigen sources and detection methods, and immunoprecipitation were performed.
RESULTS: Immunofluorescence with the use of human skin sections showed IgG autoantibodies against keratinocyte cell surfaces in all 34 serum samples. Some samples also showed weak reactivity with the basement membrane zone. The results of immunoblot and immunoprecipitation analysis indicated that all sera had antibodies reactive with desmoglein 1, the pemphigus foliaceus antigen. In addition, in various immunoblot assays, many sera reacted with several other proteins with molecular weights of 250 kd, 210 kd, and 190 kd, which appear to correspond to desmoplakin I, envoplakin, and periplakin, respectively.
CONCLUSION: This endemic pemphigus disease in El Bagre showed immunologic features similar to pemphigus foliaceus or erythematosus. In addition, paraneoplastic pemphigus-like reactivity with various epidermal antigens was detected.
Fogo selvagem Endemic in certain regions of Brazil, where there are more than 15,000 registered cases
Endemic within the states of Goiás, Mato Grosso do Sul, Paraná, São Paulo, and Minas Gerais
PATHOGENESIS CHARACTERIZATION Autoantibodies Circulating autoantibodies to epidermal polypeptides of 260 kD, 160 kD, and 85 kD are present. The 85 kD protein is the adherence junction molecule plakoglobin while the 160 kD protein is desmoglein I, a desmosomal core protein. The antibody levels correlate with the activity of the disease. Fogo selvagem
J Invest Dermatol 1986;87:197-201.
N Engl J Med 1989;320:1463-9
Predominant disease autoantibodies, present in all patients, are of the IgG4 subclass
These autoantibodies are directed against the desmosomal cadherin desmoglein 1, a 160-kd glycoprotein.
Black fly Simulium nigrimanum Immunopathologic characterization of the tissue response in endemic pemphigus foliaceus (fogo selvagem)
J Am Acad Dermatol 2001;44:446-50
Twenty biopsy specimens of lesional and perilesional skin were analyzed by immunohistochemical techniques. The panel of monoclonal antibodies consisted of CD8, CD4, CD1a, HLA-DR, IL-2R, LFA-1, ICAM-1, and PAN-B
Results: The semiquantitative analysis of the cell population revealed a predominance of CD4 T lymphocytes in the tissue response of perilesional and lesional skin. The population of epidermal Langerhans cells was decreased in lesional skin when compared with the perilesional skin, whereas CD1a+ dermal dendritic cells predominated in lesional skin. Keratinocyte expression of ICAM-1 and HLA-DR was negative in both lesional and perilesional skin.
Conclusion: The overall results suggest the participation of the cell-mediated immunity in endemic pemphigus foliaceus (fogo selvagem). The lack of keratinocyte ICAM-1 expression may be related to the pattern of cytokines secreted by the CD4+ T cells of the tissue reaction in fogo selvagem.
DISEASE ASSOCIATIONS CHARACTERIZATION PEMPHIGUS VULGARIS
Shift in clinical features, histologic findings and antigen profiles from pemphigus vulgaris to pemphigus foliaceus--two case studies.
Kawana S, Hashimoto T, Nishikawa T, Nishiyama S.
Division of Dermatology, St. Luke's International Hospital, Tokyo, Japan
Dermatology 1994;189 Suppl 1:57-9 Abstract quote
We investigated antigen profiles of the sera from 2 cases of pemphigus vulgaris (PV) who subsequently developed pemphigus foliaceus (PF).
Immunoblotting was carried out using normal human epidermal extracts as the antigen source. The sera during PV reacted exclusively with the 130-kD PV antigen and the sera during PF exclusively with the 150-kD antigen.
Therefore, dermatologic, histologic and immunohistologic findings before and after this transition were clearly shown related to changes in serum reactivity with pemphigus antigens.
Clinical and Serological Transition From Pemphigus Vulgaris to Pemphigus Foliaceus Demonstrated by Desmoglein ELISA System
Yukiko Tsuji, MD; Toshimitsu Kawashima, MD, PhD; Koichi Yokota, MD, PhD; Yasuki Tateish, MD; Yuki Tomita, MD; Tetsuri Matsumura, MD, PhD; Hiroshi Shimizu, MD, PhD
Arch Dermatol 2002;138:95 Abstract quote
Several cases in which the disease course has undergone a transition from pemphigus vulgaris (PV) to pemphigus foliaceus (PF) or vice versa have been reported in the literature. The disease transition in these cases was determined by means of clinical and histopathological observations and immunoblot analysis.
To our knowledge, the case described herein represents the first report to clearly demonstrate the serological transition from mucous PV to mucocutaneous PV to PF using a desmoglein (Dsg) enzyme-linked immunosorbent assay (ELISA) system.
Pemphigus foliaceus developing after metastasis of cutaneous squamous cell carcinoma to regional lymph nodes
Makoto Inaoki, MD
Kenzo Kaji, MD
Shinobu Furuse, MD
Akihide Fujimoto, MD
Nahoko Komatsu, MD
Minoru Takata, MD
Kazuhiko Takehara, MD
J Am Acad Dermatol 2001;45:767-70 Abstract quote
We describe a patient in whom pemphigus foliaceus developed after cutaneous squamous cell carcinoma (SCC) metastasized to regional lymph nodes.
Immunologic analysis revealed that production of anti-desmoglein 1 autoantibodies started when SCC metastasized, and the SCC expressed desmoglein 1, suggesting a pathogenic role of metastasized SCC in developing pemphigus foliaceus.
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION General VARIANTS CHILDREN Nonendemic pemphigus foliaceus in children
Denise W. Metry, MD
Adelaide A. Hebert, MD
Robert E. Jordon, MD
J Am Acad Dermatol 2002;46:419-22 Abstract quote
Background: Pemphigus foliaceus is a cutaneous, autoimmune, blistering disease comprising two major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of pemphigus foliaceus is generally a disease of the middle-aged and elderly.
Objective and methods: Because the sporadic form of pemphigus foliaceus rarely affects children, information specific to this unique group is lacking. We describe a 3-year-old boy with the disease and retrospectively review data from 28 past cases.
Results: In comparison to pediatric cases of pemphigus vulgaris, sporadic pemphigus foliaceus in children tends to follow a generally benign course of relatively short duration. However, long-term outcome studies are lacking. A pattern of skin lesions described as arcuate, circinate, or polycyclic appears to be a unique and specific presentation of this disease in children. Occasionally, as in our case, the diagnosis may prove difficult to establish by using routine histology or immunopathology.
Conclusion: The commercial availability of antigen-specific techniques such as enzyme-linked immunosorbent assay for serum desmoglein 1 autoantibody should eliminate delay in diagnosis. Hydroxychloroquine may be another treatment option for those children with photodistributed lesions. Further experience and long-term outcome studies in children are needed to determine whether some medication side effects may outweigh the risks from the disease itself.
Nonendemic pemphigus foliaceus presenting as fatal bullous exfoliative erythroderma.
Nousari HC, Moresi M, Klapper M, Anhalt GJ.
Department of Dermatology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Cutis 2001 Mar;67(3):251-2 Abstract quote
Pemphigus foliaceus is a cutaneous autoimmune blistering disease that is characterized by lower morbidity and mortality than those observed in pemphigus vulgaris or paraneoplastic pemphigus. However, erythrodermic forms of the endemic variant of pemphigus foliaceus have been associated with a higher mortality.
We report a case of nonendemic pemphigus foliaceus that presented as fatal bullous exfoliative erythroderma, and thus, we will emphasize the inclusion of this entity in the differential diagnosis and the use of skin direct immunofluorescence in the evaluation of patients with erythroderma.
FOGO SELVAGEM Fogo Selvagem
(Endemic Pemphigus foliaceus)
J Am Acad Dermatol 1989;20:657-69.
FS differs from classical pemphigus foliaceus (Cazenave) by the age of those affected, by geographic distribution, and by the presence of familial cases in genetically related persons
Clinical manifestations, the histologic findings, and the immunopathologic features are similar in these forms of pemphigus foliaceus
TRANSPLACENTAL PASSAGE Transplacental passage of maternal pemphigus foliaceus antibodies to fetus
(J Am Acad Dermatol 2000;43:1130-4.)
Neonate with PF was born when the mother had widespread skin disease; the normal newborn was born when the mother was in partial remission.
The titers of PF autoantibodies were higher in the mother's serum and the cord serum of the baby with PF than in the mother during partial remission and the unaffected baby. The mother and affected baby had autoantibodies to desmoglein 1.
Furthermore, cord blood from the baby with PF induced skin disease when injected into mice.
In this case, maternal PF was associated with neonatal PF when the titers of maternal anti-desmoglein 1 autoantibodies were elevated. The cutaneous disease in neonatal PF is due to anti-desmoglein 1 autoantibodies.
HISTOLOGICAL TYPES CHARACTERIZATION General Subcorneal blister with acantholysis associated with fibrin and neutrophils. There may be acantholysis involving the granular layer as well. Direct immunofluorescence (DIF) reveals intercellular IgG and C3 in normal and affected skin. VARIANTS IgA pemphigus or IgA intraepidermal pustular dermatosis If IgA is prominent by DIF, some investigators have used the term
SPECIAL STUDIES/IMMUNOHISTOCHEMISTRY CHARACTERIZATION ELECTRON MICROSCOPY
Ultrastructural aspects of mucosas in endemic pemphigus foliaceus.
Guedes AC, Rotta O, Leite HV, Leite VH.
School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
Arch Dermatol 2002 Jul;138(7):949-54 Abstract quote
OBJECTIVE: To investigate whether ultrastructural changes present in clinically normal oral mucosa could occur in the mucosas of patients with endemic pemphigus foliaceus (EPF) or fogo selvagem (wildfire).
PATIENTS: Surgical biopsy specimens were taken from the foreskin of 8 patients with EPF and 3 control subjects, the uterine cervix and vaginal wall of 9 patients with EPF and 2 controls, and the oral mucosa of 5 patients with EPF and 4 controls. The patients received a clinical and histopathologic diagnosis of EPF and all had clinically normal oral and genital mucosas.
RESULTS: In the patients with EPF, widening of the intercellular spaces and distended, elongated cytoplasmic projections, the tips of which contained desmosomes and were sometimes disassembled, were evident in all 4 regions studied. At the periphery of the spinous cells, cytoplasmic vesicles apparently containing intact or fragments of desmosomes or half-desmosomes were seen.
CONCLUSIONS: The ultrastructural lesions found in the mucosas studied are similar to those previously described in the literature for the oral mucosa of patients with EPF. In the cases of EPF, even though the desmosomal changes occurred in all epithelial layers, blisters did not occur in the mucosas by possible coexpression of desmoglein 1 and desmoglein 3.
PROGNOSIS AND TREATMENT CHARACTERIZATION TREATMENT GENERAL
Treatment of pemphigus vulgaris and pemphigus foliaceus: experience with 71 patients over a 20 year period.
Fernandes NC, Perez M.
Departamento de Clinica Medica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, RJ, Brasil.
Rev Inst Med Trop Sao Paulo 2001 Jan-Feb;43(1):33-6 Abstract quote
Forty one cases of pemphigus vulgaris and thirty cases of pemphigus foliaceus were investigated at Hospital Universitario Clementino Fraga Filho from 1978 to 1999. They were divided into two treatment groups: one group received up to 100 mg of oral prednisone daily and the other group received >120 mg daily. The dose up to 100 mg provided good initial control of pemphigus vulgaris and pemphigus foliaceus and did not increase the mortality rate associated to disease. The dose >120 mg induced higher morbidity.
These data allowed us to establish a regimen of oral prednisone (1-2 mg/kg/daily) with maximum of 120 mg daily in the treatment of pemphigus vulgaris and pemphigus foliaceus.
Oral cyclophosphamide for treatment of pemphigus vulgaris and foliaceus.
Cummins DL, Mimouni D, Anhalt GJ, Nousari CH.
Department of Dermatology, Johns Hopkins University, School of Medicine, Baltimore, MS 21205, USA.
J Am Acad Dermatol. 2003 Aug;49(2):276-80 Abstract quote
BACKGROUND: Cyclophosphamide is an alkylating adjuvant used in refractory cases of pemphigus.
OBJECTIVE: We sought to evaluate the effectiveness and safety of oral cyclophosphamide in the treatment of patients with pemphigus vulgaris (PV) and pemphigus foliaceus (PF) with refractory disease.
PATIENTS: We studied 23 patients with pemphigus (20 with PV; 3 with PF) who failed to achieve clinical remissions with the use of prednisone and antimetabolites.
RESULTS: Complete remission was achieved in 17 patients with PV and 2 with PF. A total of 3 patients with PV failed therapy. A partial remission was achieved in 1 patient with PF. The treatment was administered for a median duration of 17 months with a follow-up period of 27 months. The median time to complete remission was 8.5 months. A total of 9 patients who were severely affected received concomitant plasma exchange. Adverse reactions included 5 cases of hematuria, 6 nonlife-threatening infections, and the development of transitional cell carcinoma of the bladder 15 years after discontinuation of cyclophosphamide in 1 patient. No death was associated with cyclophosphamide treatment.
CONCLUSION: Oral cyclophosphamide is an effective adjuvant in the treatment of severe and refractory PV and PF, but requires close monitoring.
Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy
A. Razzaque Ahmed, MD
Naveed Sami, MD
J Am Acad Dermatol 2002;46:42-9 Abstract quote
Background: Pemphigus foliaceus (PF) is a chronic autoimmune blistering skin disease that is commonly treated with oral corticosteroids and immunosuppressive therapy. In some patients, PF can be refractory to treatment and the resultant side effects of prolonged immune suppression can be potentially fatal. Alternative therapies are needed.
Objective: The purpose of this study is to report treatment outcomes with IVIg therapy in 11 patients with severe PF refractory to prednisone and other immunosuppressive therapy.
Methods: Selection criteria included documentation of a biopsy and immunopathology in 11 patients who were resistant to treatment or experienced side effects to conventional therapy. IVIg was administered according to a defined protocol. The parameters used to assess clinical response to IVIg included time observed for effective control of disease, duration of IVIg maintenance therapy, total duration of IVIg, number of IVIg cycles, systemic drug therapy, and the frequency of recurrences and relapses. The pre-IVIg and post-IVIg data were statistically analyzed by means of the SAS UNIVARIATE and 2-sided Wilcoxon sign rank and sign tests.
Results: All patients had an effective clinical response and remained in clinical remission for a mean period of 18.6 months after discontinuation of IVIg therapy. Serious side effects from IVIg use were not observed.
Conclusion: IVIg therapy appears to have potential as a biologic alternative agent in inducing and maintaining clinical remissions in patients with PF who are resistant to more standard conventional treatment. IVIg is effective as monotherapy and may be needed for a period of several months to achieve a long-term clinical remission.
Treatment of pemphigus vulgaris and pemphigus foliaceus with mycophenolate mofetil.
Mimouni D, Anhalt GJ, Cummins DL, Kouba DJ, Thorne JE, Nousari HC.
Department of Dermatology, Johns Hopkins University, School of Medicine, Baltimore, Md.
Arch Dermatol. 2003 Jun;139(6):739-42. Abstract quote
BACKGROUND: Mycophenolate mofetil is increasingly being used as a corticosteroid-sparing agent in immunosuppressive regimens.
OBJECTIVE: To elucidate the effectiveness of mycophenolate as adjuvant therapy in the treatment of both pemphigus vulgaris and pemphigus foliaceus.
DESIGN: Historical prospective study.
SETTING: University hospital.Patients The study included 42 consecutive patients with pemphigus (31 with pemphigus vulgaris and 11 with pemphigus foliaceus) who had relapses during prednisone taper or had clinically significant adverse effects from previous drug therapy.
RESULTS: Remission was achieved in 22 (71%) and 5 (45%) of patients with pemphgus vulgaris and pemphigus foliaceus, respectively. Partial remission was achieved in 1 (3%) and 4 (36%), respectively. The median time to achieve complete remission was 9 months (range, 1-13 months). The treatment was administered for a median of 22 months, and the median follow-up period was 22 months. Seventy-seven percent of patients had no adverse effect. Two patients had side effects severe enough to necessitate discontinuation of treatment, one because of symptomatic but reversible neutropenia and the other because of nausea.
Conclusion Mycophenolate is an effective and safe adjuvant in the treatment of both pemphigus vulgaris and pemphigus foliaceus.
Weedon D. Weedon's Skin Pathology. Churchill Livingstone. 1997.
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