endemic pemphigus foliaceus (fogo selvagem)—1998

Endemic Pemphigus Foliaceus (FogoSelvagem)—1998GUNTER HANS-FILHO, MD Y VALERIA AOKI, MDEVANDRO RIVITTI, MD Y DONALD P. EATON, MDMONG SHANG LIN, MD Y LUIS A. DIAZ, MDTHE COOPERATIVE GROUP ON FOGO SELVAGEM RESEARCH

The clinical, histological and immunological fea-tures of the endemic form of pemphigus folia-ceus (PF), also known as fogo selvagem (FS), are

similar to those patients suffering the nonendemic formof PF seen in North America, Europe, and other parts ofthe world as originally described by Cazenave.1–3 FS isan autoimmune disease that has remarkable features.The disease is characterized by superficial subcornealblisters and pathogenic antiepidermal autoantibodiesthat recognize the desmosomal core glycoproteinknown as desmoglein 1 (dsg1).4 In addition, FS pos-sesses unique epidemiological features, such as a highprevalence of the disease in certain regions of Brazil, anincreased frequency of familial cases, and an increasedfrequency of cases among young adults and children.Commonly, FS patients are poor farmers who live andwork in certain rural areas of Brazil where the disease isendemic. Recently, other endemic foci of PF have beenreported in other South American countries such asColumbia and Tunisia.5–8 Several etiological agents arethought to precipitate FS; however, there is no convinc-ing experimental evidence supporting any of these hy-potheses. The disease is treated with systemic steroids,and in certain cases, with immunosuppressive agents.The prognosis of FS has improved with the use of thesenew therapies.

Clinical Presentation of FS

The clinical presentation of the disease varies somewhatfrom patient to patient.9–12 The primary cutaneous le-sion is a superficial blister, which may be filled withclear fluid or yellowish content resembling lesions ofimpetigo. These lesions rupture easily, leaving superfi-cially denuded areas. Lesions occur in the head and

neck area and then spread acrally. In most patients, thelesions are distributed in sun-exposed skin. In all activeclinical forms of FS, the Nikolsky sign is easily elicited.Mucosal blisters or erosions are not observed, even incases with generalized disease. In the majority of pa-tients the disease begins gradually, with cutaneous le-sions evolving over a period of several weeks ormonths. Rarely, FS can be acute and fulminant, withextensive bullae erupting over a period of 1–3 weeks.Finally, it has been reported that pregnant motherssuffering from FS deliver normal babies.13 The clinicalpresentations are commonly observed in FS are de-scribed below.

Localized Forms of FS (forme fruste)

The lesions may be small vesicles that rupture easily,leaving secondary erosions and crusts. In other pa-tients, the lesions may be erythematous, violaceus orhyperpigmented papules and plaques that are distrib-uted on seborrheic areas of the face and trunk. Some ofthese lesions may be round or oval keratotic plaquesand show a yellow-brown scaly surface. In some pa-tients these localized lesions of FS may resemble thelesions of discoid lupus erythematosus (DLE) (Fig. 1);however, the FS lesions lack follicular prominence (the“carpet tack” sign), epidermal atrophic changes, andthe hypopigmentation observed in DLE lesions.14 Thelocation of FS lesions in sun-exposed areas of skin andthe resemblance of these lesions to DLE lesions hadprompted many clinicians in the past to consider thisform of FS as “Senear-Usher syndrome”;15 however FSpatients, show no evidence of lupus erythematosus onskin biopsies or by serologic studies, and therefore, thisterminology should be avoided.16

According to Brazilian investigators, these localizedlesions of FS may remain unchanged for months oryears; and in an undetermined number of patients,these lesions may undergo spontaneous resolution. Insome patients however, these lesions spread centrifu-gally, involving the trunk and extremities. These lattercases are then categorized as generalized FS.

From the Departments of Dermatology of the Universidade Federal deMato Grosso do Sul, Brazil, Universidade de Sao Paulo, Brazil, MedicalCollege of Wisconsin and the Veterans Administration Medical Center,Milwaukee, Wisconsin, USA University of Nevada-Reno, Nevada, USA.

Address correspondence to Dr. Luis A. Diaz, Department of Dermatol-ogy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwau-kee, WI 53226.

© 1999 by Elsevier Science Inc. All rights reserved. 0738-081X/99/$–see front matter655 Avenue of the Americas, New York, NY 10010 PII S0738-081X(99)00014-0

Generalized Forms of FS6

The generalized forms of FS may fall into 3 distinctclinical syndromes. A bullous-exfoliative form (Fig. 2)includes patients with acute, aggressive disease inwhich there is a predominance of a widespread bullouslesions. In these cases, hyperkeratotic lesions and exfo-liative dermatitis are minor components of the disease.In some of these patients, fever, arthralgias, and generalmalaise are associated with the onset of the vesicular

eruption, but bacteremia or sepsis are not found. Pa-tients with this form of FS may develop life threateningKaposi’s varicelliform eruption, if exposed to the herpessimplex virus. The vesicular lesions are superficial; andin patients with active, untreated disease, many of theblisters will be pustular. On occasion, the vesicles formcircinate or annular patterns, which after rupturing,produce exfoliation resembling tinea imbricata. The sec-ond clinical form of FS includes patients that developtypical exfoliative erythroderma. Other causes of exfo-liative dermatitis must be eliminated before diagnosingFS. In these patients, confluent superficial erosions withcrusting and serum exudate are the prominent featuresof the disease. Superimposed infections such as der-matophytosis, scabies, warts, and so forth, are also re-ported to complicate generalized FS.17 The third form ofFS includes those patients exhibiting generalized kera-totic plaques and nodular lesions, similar to those seenin chronic localized forms of the disease.

Hyperpigmented Forms of FS

Several Brazilian investigators have noted that hyper-pigmentation syndromes are often seen in FS patientsundergoing remission.14 The hyperpigmentation maybe restricted to areas of previous lesions, or they may bediffuse and involve previously unaffected skin. In thepresteroid era, diffuse hyperpigmentation was consid-ered an early indicator of a spontaneous remission orcure of FS (in Portuguese—“aurora da cura”). Theyobserved several patients undergoing clinical remissionthat would experience dramatic changes in their skincolor, that is, Caucasians became like mulattos (mixedCaucasian and black), mulattos became black, and blackpatients acquired a deep grey-blue color.

Histopathology and Ultrastructure of SkinLesions of FS

The histologic hallmark of FS is the presence of anintraepidermal vesicle located in the subcorneal regionof the epidermis. Acantholysis occurs immediatelyabove or below cells of the stratum granulosum. In theclassical acantholytic lesions of FS the stratum corneum

Figure 2. Generalized form of FS in a young woman. Individuallesions are superficial vesicles that become confluent, producinglarge areas of denuded skin. The involved areas are located on theanterior chest (A) and the back of the patient (B). The histology ofthe skin lesions as well as the IF findings were positive for FS.

Figure 3. A skin biopsy from a FS patient shows the typicalsubcorneal vesicle (A). The serum of FS patients containantiepidermal autoantibodies that can be detected by indirect IFprocedures producing titers that correlate with disease activity(B). These autoantibodies are disease-specific.

Figure 1. Localized form of fogo selvagem. The infiltrated,keratotic facial lesions resemble the classic “butterfly rash” seenin patients with lupus erythematosus. This patient had thelocalized form of FS with positive histopathological andimmunofluorescence (IF) studies.

226 HANS-FILHO ET AL. Clinics in Dermatology Y 1999;17:225–235

forms the roof of the vesicle and the stratum spinosumthe floor (Fig. 3A). Some vesicles may be filled withneutrophils, and eosinophillic spongiosis may bepresent in some biopsies.14,18 The verrucous plaquesobserved in the chronic localized forms of FS showacanthosis, hyperkeratosis, parakeratosis, and papillo-matosis.18,19 Acantholysis is also present in these le-sions. In hyperpigmented forms, although there ismelanocytic proliferation within the epidermis and aconsequent increase in epidermal pigment, pigment in-continence with melanin accumulation in dermalphagocytes is the primary abnormality.18

The ultrastructural features of the epidermal lesionsof FS have been well documented.20,21 Although bylight microscopy acantholysis is detected in the subcor-neal regions of the epidermis, by electron microscopyvarious degrees of epidermal cell detachment is de-tected in all layers of the affected epidermis includingthe lateral surfaces of basal cells.20,21 From the basal celllayer the acantholytic process extends outwards towardthe stratum spinosum and granulosum being moreprominent in the upper layers of the stratum spinosum,and the granular layer. During the evolution of theacantholytic process, there is a progressive loss of des-mosomal structures that are associated with perinuclearretraction of tonofilaments and a rounding up of thekeratinocyte.20

Immunological Abnormalities in FS

FS is a classic organ-specific autoimmune disease thatinvolves only the epidermis and is mediated by patho-genic, antiepidermal autoantibodies. In 1964, a group ofinvestigators reported that the sera of these patientscontain autoantibodies directed against epidermal in-tercellular antigens in titers that correlated with theextent and activity of the disease (Fig. 3B).22,23 They alsofound that perilesional epidermis in these patients ex-hibited autoantibodies bound to the surface of detachedkeratinocytes. These autoantibodies belong to the IgGclass, and they are predominantly of the IgG4 sub-class.24 Other autoantibodies, such as antinuclear anti-bodies (ANA), anti-nDNA antibodies or precipitin an-tibodies against Sm, nRNP, SSA/Ro, SSB/La are notdetected in the sera of FS patients.17

FS Autoantibodies Are Pathogenic

A significant contribution in understanding the patho-genesis of the acantholytic lesions of FS has been thedemonstration that the anti-dsg1 produced by thesepatients are indeed pathogenic to the epidermis of ex-perimental animals.4,24,25 Passive transfer of these auto-antibodies into neonatal mice reproduces the clinical,histological, ultrastructural, and immunological find-ings of the human disease in these animals (Fig. 4).4,24–26

FS IgG infused into neonatal mice specifically causes

acantholysis only within the granular cell layer of theepidermis.26 On the contrary, IgG from patients withpemphigus vulgaris (PV) produce suprabasilar acan-tholysis under the same conditions.27 These observa-tions have been recently confirmed using affinity-puri-fied anti-dsg1 (FS autoantibodies) and anti-dsg3 (PVautoantibodies).28,29 These results demonstrate that thelesions produced by passive transfer of FS and PVautoantibodies are as distinct in the animal model asthey are in humans from whom the antibodies areobtained. In view of the success of these experiments, itis curious that neonatal pemphigus (due to placentaltransfer of maternal autoantibodies) has been describedto occur in PV;30,31 but it does not occur in FS, even incases where the mother of the newborn had extensiveand active disease.13 There is only a handful of humanautoimmune diseases in which binding of autoantibod-ies to the target tissue alone have been shown to pro-duce all the features of the disease. The list now in-cludes two rare dermatological diseases, that is FS andPV, in addition to Goodpasture’s syndrome, myasthe-nia gravis, and Lambert-Eaton myasthenic syn-drome.32–34

FS Autoantibodies Recognize the Ectodomain ofDesmoglein 1

It has been demonstrated by immunoprecipitation tech-niques that the sera of patients with PF and PV recog-nized two unique desmosomal glycoproteins known asdsg1 and dsg3, respectively (Fig. 5).35,36 Both antigenshave been cloned and sequenced, and they were shown

Figure 4. The antiepidermal autoantibodies in FS are pathogenicwhen passively transferred to neonatal mice. The animals developsuperficial blisters (A) which are located in the subcorneal regionof the epidermis (B). The human antiepidermal autoantibodies aredetected bound to the site of blister formation by direct IF (C).Whole IgG from FS patients, the F(ab)2 and Fab fragments fromthese FS IgG are all pathogenic. The predominant IgG subclass isIgG4.

Clinics in Dermatology Y 1999;17:225–235 ENDEMIC PEMPHIGUS FOLIACEUS 227

to belong to the cadherin family of cell adhesion mole-cules (CAMs).37–40 Sequence analysis of these moleculesrevealed extensive homology between dsg1 and dsg3and between these molecules and other members of thecadherin family of CAMs, such as E and P cad-herin.37,39,40 Dsg1 and dsg3 are transmembrane glycop-roteins with an ectodomain that contains six putativecalcium binding sites, a transmembrane domain, and anintracellular domain likely to be linked to the cytoskel-eton via desmosomal plaque proteins and catenins. Re-cent studies strongly suggest that the extracellular do-mains of dsg1 and dsg3 contain conformational andCa21-dependent epitopes that are recognized by PF andPV autoantibodies respectively.28,29,41–45 The fact thatthese molecules mediate cell-cell adhesion in the epi-dermis has been recently demonstrated using moleculargenetic technology; for example, dsg3 knockout micewere shown to develop spontaneous erosions and su-prabasilar acantholysis without immunological partici-pation.46

T Cells from FS Patients Recognize Desmoglein 1

We have initiated studies exploring the molecular andcellular mechanisms leading to autoantibody produc-tion in FS.47 Peripheral blood (PB) from ten FS patientswas transported from Brazil to our laboratories andused to test T cell response to dsg1. The viability of PBmononuclear cells isolated from these samples waswithin the normal range (1 to 2 3 106/ml of blood).Using the recombinant dsg1 ectodomain produced bythe baculovirus expression system, T cells from 9 out of

10 FS patients showed a proliferation response (S.I. 53.1–17.8). Furthermore, we found that T cells from thesepatients responded to bacterial dsg1 fusion proteins,but did not proliferate when incubated with other un-related epidermal antigens, such as the BP180 antigen.None of the control T-cell preparations (from sevennormal volunteers and one SLE patient) responded torecombinant dsg1 or bacterial dsg1 fusion proteins.Therefore, these results indicate that T cells from FSpatients specifically responded to dsg1.

As described below, the majority of endemic FS pa-tients express DRB1*0404, 1402, and 1406 alleles. Thesethree HLA alleles contain an identical amino acid se-quence in the third hypervariable region of the b chainwhich is known to govern the binding of presentedantigenic peptides. We have tested the proliferationresponses of FS T cells using a panel of synthetic pep-tides corresponding to sites on the dsg1 ectodomainwhich, based on their amino acid sequence, were pre-dicted to bind to this family of DR molecules. It wasdemonstrated that several of these synthetic peptideswere indeed immunogenic. T cells from normal indi-viduals and a SLE patient showed no response to thesesynthetic dsg1 peptides, suggesting that proliferationresponses of FS T cells is specific. Currently, we havedeveloped T cell lines from two FS patients. Furthercharacterization of FS dsg1 specific T cell clones willhelp to elucidate the role of these cells in the pathogen-esis of FS.

FS Patients Share Unique HLA Alleles

A disproportionate number of FS cases occurs amonggenetically related individuals, which has led to theconclusion that there is a genetic predisposition to thisdisease. Consistent with these observations is the dis-covery that FS patients share specific HLA alleles.48,49

FS has been shown to be associated with a high fre-quency of HLA DR1 and/or HLA DR4 genes.48 In astudy of non-Amerindian populations, a group of in-vestigators identified the DRB1*0102 gene as a suscep-tibility factor for FS [relative risk 5 7.3, p 5 0.002] andDQB1*0201 as a gene that is absent in patients butpresent in unaffected individuals living in endemic ar-eas and, therefore, thought to provide resistance to FS(relative risk 5 0.04, p 5 0.006).49 Another group re-ported that the HLA-DRB1*0102 and HLA-DQB1*0201genes are not associated with FS in Amerindian popu-lations. Instead, 6 out of 10 Xavante Indians with FSshared the HLA DRB1*0404 gene, which was present inonly 5 out of 74 of the Xavante controls, conferring arelative risk of 9.6 (p 5 0.002).50 The DRB1*1402 wasalso increased in Xavante FS patients, but the differencewith controls was not significant. These HLA studieshave been extended to FS patients within another nativeBrazilian population, the Terena Indians at the LimaoVerde Reservation. In this group, FS was associated

Figure 5. Desmoglein1 (dsg1) is a transmembrane desmosomalglycoprotein that belongs to the cadherin family ofcalcium-dependent cell adhesion molecules. The extracellulardomain of this molecule bears the epitopes recognized bypathogenic FS autoantibodies. The diagram shows the expressionof the dsg1 ectodomain in the baculovirus system. The solubleglycopeptide was radiolabelled with iodine-125 (125I) and used forimmunoprecipitation procedures. The panel in the upper rightcorner is an autoradiogram showing a single radiolabelled dsg1band that is immunoprecipitated only by FS sera containinganti-dsg1 autoantibodies.


with DRB1*0404, 1402 and 1406 (p , 0.005, relativerisk 5 14). It is interesting that the amino acid sequenceof residues 67 to 74 of the third hypervariable region ofthe DRB1 gene, that is, LLEQRRAA, is shared byDRB1*0102 (susceptibility gene of non-Amerindian FSpatients) and DRB1*0404, *1402 and *1406, (associatedwith FS in Amerindians). Accordingly, this “sharedepitope”, as described for rheumatoid arthritis, mayconfer susceptibility to FS in individuals exposed to theappropriate environmental etiologic agent(s).51 The in-heritance of HLA genes that predispose the host todevelop FS, thought to be autosomal dominant withincomplete penetrance, may explain the observed fa-milial clustering of FS cases in Xavante and TerenaIndians and in non-Indian groups reported else-where.9,52,53

Molecular Mechanisms of Acantholysis in FS

The molecular mechanisms of acantholysis in FS are notclear. It was first shown in the late 1970s that pemphi-gus IgG (PV and PF) enhances cell detachment of ker-atinocytes in culture. Several hypotheses were pro-posed to explain the mechanism of autoantibody-induced acantholysis. For example, it was suggestedthat complement activation may be relevant in PF ac-antholysis, because lesional epidermis in patientsshows strong C3 deposition on the surface of detachedcells and because addition of complement to culturespreviously treated with PF IgG enhances the detach-ment process.54,55 Others have proposed that pemphi-gus autoantibodies may impair the adhesive function ofthe epidermal antigen bound by these autoantibodies oractivate epidermal proteases such as PA and plasminthat lead to cell detachment.56,57 During the 1980s and1990s, there were some important contributions in thisarea. It is now generally agreed that complement acti-vation does not play a critical role in the acantholyticprocess.58 Additionally, it is well established that theepidermal antigens recognized by PF and PV autoanti-bodies are desmosomal glycoproteins (dsg1 and dsg3)of the cadherin family of CAMs,36,37–40 suggesting thatthe autoantibodies in these patients may alter the ad-hesive function of these CAMs. This line of reasoning isreinforced by studies demonstrating that passive trans-fer of univalent Fab from PV and PF IgG are pathogen-ic.58–60 Simple binding of the extracellular domain ofdsg1 or dsg3 (containing adhesive sites) may be enoughto cause acantholysis.

The role of proteases and PA in pemphigus acanthol-ysis in vitro has been the subject of several recentprovocative reports.61–64 Further, it has also been re-ported that systemic administration of certain proteaseinhibitors, such as aprotinin, can block the pathogenicactivity of PV and PF IgG when tested in the passivetransfer model of pemphigus in mice.65,66 Despite theseencouraging results, our previous studies suggested

that PA activation may not be a relevant event in PVautoantibody-induced acantholysis in the mouse mod-el.67 In this study, PA activity was abolished from theskin of recipient animals by dexamethasone treatment.Despite the fact the epidermal levels of PA were re-duced below detectable levels, the animals continued todevelop extensive epidermal blistering upon receivingintraperitoneal injections of PV IgG. Recently, it hasbeen reported that in epidermal cell cultures that areincubated with PV IgG there is a transient intracellularincrease in phospholipase C (PLC), inositol 1,4,5-triphosphate (IP3) production and increased mobiliza-tion of intracellular calcium.68–69 There is also a con-comitant formation of 1,2 diacylglycerol (DAG), whichis an endogenous activator of protein kinase C (PKC). Itis known that PKC activation is a major step in thesignal transduction pathways of cells undergoinggrowth and differentiation.70 It was also shown that theintracellular events described above in cells treatedwith PV IgG are associated with an increase in PAactivity in these cultures and translocation of PKC iso-forms from the cytosolic pool to the cytoskeleton frac-tion of keratinocytes.69,71,72 These encouraging studiesneed to be confirmed using affinity-purified dsg1 anddsg3 autoantibodies from the sera of patients.

Epidemiological Features of FS

Historically, the first documented cases of FS in Brazilwere cited by Aranha-Campos.52 He described two FScases that appeared in the interior of the state of SaoPaulo in the region of Franca, (currently Riberao Preto)in the second half of the 1800’s. The first was a womansuffering and dying of FS around 1860. The secondpatient showed evidence of this disease in 1880, andunderwent spontaneous remission, dying in 1940 at theage of 90. It is interesting that the region of Francarepresented an outpost for the waves of advancingBrazilian settlers that were just beginning to explore therich lands of the states of Minas Gerais and Goias at thattime. These early descriptions of FS were followed by aseries of reports describing FS in other regions of Bra-zil.73–75

Currently, FS is endemic in certain states of Brazil,that is, Goias, Mato Grosso, Mato Grosso do Sul, MinasGerais, Sao Paulo and Parana, where there were morethan 15,000 registered cases as of 1982.76 Significantly,the frequency of cases in the state of Sao Paulo hasdecreased dramatically over the last 40 years, while thenorthwestern states including Mato Grosso, MatoGrosso do Sul, Goias, Maranhao, Para and Amazonashave been exhibiting a gradual increase in reportedcases.9,52,76 Because the number of cases in the state ofSao Paulo increased markedly during the 1930s, thegovernment of Sao Paulo, in 1938, created the Adhemarde Barros Hospital, which was dedicated to the treat-


ment and rehabilitation of patients with FS.52 At itspeak, the Adhemar de Barros Hospital housed approx-imately 300–400 inpatients. New hospitals for FS pa-tients have opened in Goiania (Goias), and CampoGrande (Mato Grosso do Sul).

Until recently, little was known about the prevalenceof FS among the various groups of Amerindians thatreside in Brazil. In studies that include large series ofpatients, references to Amerindians afflicted with thisdisease were isolated and brief.52,53 In 1967, a group ofinvestigators who were carrying out genetic and an-thropologic studies, first reported an FS-like disease ina Xavante Indian settlement.77 They hypothesized thatthis disorder may represent an autoimmune skin dis-ease, a hypothesis that was strengthened by demon-strating that the sera of these patients contained anti-epidermal autoantibodies.23 Isolated cases of FS inXavante Indians have also been recorded in hospitalsdedicated to treating FS patients located in Goias, MatoGrosso do Sul, and Brasilia.9,52,53 In a recent publication,our group has identified and characterized a new focusof FS in a Xavante reservation located in the eastern partof Mato Grosso state in central Brazil.78,79 A clinical andserological survey confirmed the diagnosis of FS in tenXavante Indians out of a population of approximately740. It has also been documented that non-Indian com-munities located in close proximity to the FS endemicXavante villages also show a high incidence ofFS.9,52,53,76 Based on these and other observations, itwould appear that FS in Xavante and non-Xavanteindividuals is precipitated by the same etiologic agent.

The Terena Amerindians comprise a group of ap-proximately 10,000 individuals segregated into 8 inde-pendent groups that settled in the Midwestern regions

of the state of Mato Grosso do Sul, Brazil (Fig. 6).80 Oneof these Terena settlements, the Limao Verde TerenaReservation, was recently shown by our group to havea particularly high prevalence of FS (2.8% among apopulation of 998). Four of the 29 patients developed FSduring 1994, 1 in 1995, 1 in 1996, and 1 in 1997.81 Overhalf of the FS cases (16 of 29) had at least one closerelative (parent, sibling, aunt/uncle, cousin) with thedisease. The FS cases on the Limao Verde reservationexhibited a nonrandom temporal distribution. The dataindicate that an abrupt increase in the rate of diseaseincidence occurred around 1988. In addition, there ap-peared to be a cyclic pattern to the incidence of FS(temporal clustering), suggesting that the inhabitantswere exposed to pathogenic levels of the factor thatprecipitates FS at intermittent periods. Thus, the LimaoVerde Reservation represents a new focus of FS inwhich the disease exhibits temporal, geographic andfamilial clustering. These results suggest that the envi-ronmental antigen or antigens precipitating FS are en-demic to the Limao Verde reservation.

Our clinical and immunological survey of LimaoVerde has led to the important finding that the produc-tion of antiepidermal autoantibodies can precede dis-ease onset by as much as 2 years. Patient FS-9 (a 12-year-old Terena boy) was identified by our team ofinvestigators by a positive indirect IF result (IgG4 ti-ter 5 1:320) 5 weeks prior to the onset of clinical disease(Fig. 7).81 FS-29 is a Terena patient who was diagnosedduring our most recent field trip, August, 1997 (IgG4titer 1:320). We had obtained serum from this patienttwo years earlier, as part of our general survey. At thattime, the serum was negative by indirect IF; however,we have now shown that both serum samples—thoseobtained in 1994, when this individual was disease free,

Figure 6. The Terena Indian reservation of Limao Verde islocated on the State of Mato Grosso do Sul in Brazil. There areapproximately 1000 inhabitants in this reservation, most of whomare dedicated to farming activities. The prevalence of FS is 3%.New cases are being reported every year. (Hans-Filho, G., et al.An Active Focus of High Prevalence of Fogo Selvagem on anAmerindian Reservation in Brazil. Journal of InvestigativeDermatology 1996;107:68–75. Reprinted by permission ofBlackwell Science, Inc.)

Figure 7. A young patient with FS (FS-9) and his family livingin the Terena reservation of Limao Verde, Brazil. The housingand living conditions of the family are depicted in this picture.Ronildo, patient FS-9, had normal skin examination on March14, 1994, but his serum showed high titers of antiepidermalautoantibodies by indirect IF (1:320). One month later FS-9develop classic generalized FS. A second patient (FS-29) hadnormal skin findings for two years before developing generalizedFS with positive indirect IF titers (1:320); however, FS-29 wasconsistently negative by indirect IF before the onset of FS.


and in 1997, at the time of diagnosis of FS—were capa-ble of immunoprecipitating dsg1. This information sup-ports our contention that early detection of anti-dsg1autoantibodies by sensitive techniques, such as ELISA,may assist us in defining FS in its preclinical stages andin estimating the incubation time of the disease.

The Etiology of FS

There is a number of remarkable epidemiological fea-tures of FS, including the geographic clustering of casesand the disproportionately high number of multiplecases among genetically related family members. Alsonoteworthy is the high frequency of FS cases amongchildren and young adults, and particularly those in thelower socioeconomic strata and/or individuals dedi-cated to farming activities.9,52,53,76 In a series of 2,663cases reported from the state of Goias, 90% of thepatients originated from rural farm lands.53 FS occurs inregions with an altitude between 500 and 800 meters. Itis extremely rare in regions with altitudes below 400meters or above 1,000 meters.52 Patients’ houses areinvariably located within 10 to 15 kilometers of a riveror creek, commonly in the path of the dominant winds,suggesting transmission by a flying vector.9,52,53 Theseand other findings have led Brazilian investigators topostulate that FS is precipitated by exposure to anenvironmental factor.9,52,53

Several independent lines of evidence, including acase-control epidemiologic study, point to an insectvector (black fly, family Simuliidae) as a prime candi-date for the FS precipitating factor.82 This case-controlstudy compared a group of 52 FS patients with 52patients suffering from other dermatoses admitted andfollowed at the hospital for pemphigus (Hospital doPenfigo) in the city of Goiania, state of Goias. Patientsand controls matched 1:1 by age, sex and occupation,were examined by two dermatologists at the time ofadmission and asked to respond to a prepared ques-tionnaire. This questionnaire concerned current andpast (one and five years) exposure to environmentalrisk factors. The following risk factors were assessed:black fly bites, presence of rodents at home, exposure tocereal dust, exposure to fumes or dust released by treeand shrub removal, and exposure to insecticides. Rela-tive risks were estimated from tabulated data by theodds ratio and tested for significance by the chi-squaretest. The 95% confidence interval for the odds ratio wasalso calculated for each of the risk factors. The only riskfactor showing an odds ratio significantly differentfrom one was exposure to simuliid bites (odds ratio: 4.7,p , 0.001). This study reinforces the hypothesis thatchronic exposure to black fly antigens may precipitateIgG4 antibody formation in predisposed individuals.

We have now conducted a survey of the simuliidspecies composition and biting activity within a re-

cently discovered FS focus, the Limao Verde TerenaReservation, and neighboring regions with no reportedFS cases.83 Our objective was to determine whetherblack flies of the FS focus showed unique patterns withrespect to the species present or their relative abun-dance. We collected 9 black fly species in various de-velopmental stages from 12 stream sites during 3 an-nual trips to the FS focus. The black flies showedlongitudinal (upstream-downstream) trends in thepresence of particular species, the total number of spe-cies, total abundance, and relative species abundance.The most prevalent species at the focus, Simulium nigri-manum, dominated the stream sites with highly abun-dant black fly populations. This species was absent or invery low numbers in neighboring valleys and villagesthat did not have cases of FS among the population.

These studies lend support to the hypothesis thatpeople at risk to develop FS are those exposed to bitesof a unique specie of black flies, that is, Simulium nigri-manum, which is endemic to the same areas where FSpatients develop the disease. The black fly may inject anantigenic substance (fly saliva or microbes) which, inthe genetically predisposed host, elicits an antibodyresponse that cross-reacts with epidermal antigens(dsg1) and produces disease. More work is needed inthis interesting area of research.

Finally, the possibility that FS may be precipitated byeither bacterial or viral infections has been entertainedthroughout the history of FS with negative results. It iswell documented that FS is not contagious and trans-mission by body fluids is not a feature of the disease.Isolation of viruses from skin lesions, ultrastructuralstudies of lesional skin, testing FS sera for antibodiesagainst arborvirus common to endemic regions of FS orantibodies against HIV-1 antigens have consistentlyyielded negative results.23,84–86 Other proposed poten-tial etiological agents of endemic FS include nutritionalfactors and ingestion of toxic substances that may bepresent in the water supply consumed by geneticallypredisposed individuals;87,88 however, there is no ex-perimental data to support these hypotheses.

Proposed Classification of FS

For the purpose of reporting epidemiological and clin-ical studies dealing with the endemic form of pemphi-gus foliaceus, we are proposing a set of revisions to apreviously published classification scheme.13 In thisclassification, we consider four types of criteria: clinical,histological, immunological, and epidemiological data.Thus, to establish the diagnosis of classic FS, the patientis evaluated clinically, skin biopsies are examined his-tologically for evidence of subcorneal acantholysis andby direct immunofluorescence (IF) for the presence oftissue-bound IgG, and the patient’s serum is assayed byindirect IF for the presence of circulating antiepidermal


autoantibodies. Other more sensitive and specific diag-nostic assays, such as immunoprecipitation or ELISAwith recombinant dsg1, should be incorporated into thecharacterization of these patients as these tests becomeavailable. Finally, the most difficult criteria of this clas-sification are those related to the epidemiology of FS,which focuses mainly on the geographic origin of thepatient. Nonendemic PF is a disease of urban areasaffecting people that spend most of their daily livesaway from rural, nonurbanized areas. If they are ex-posed to a rural environment for short and sporadicperiods of time, for example, golfing, fishing, or camp-ing, this exposure probably does not play a role in theonset of their disease. In contrast, FS patients are typi-cally poor people that live and work in rural areas ofcertain endemic regions of Brazil (or other countries). Ifthey live or work in urban areas, their housing is usu-ally located on the periphery of a small city or in a smallvillage. Many FS patients are laborers and their rela-tives who live deep in the farmlands. The owners ofthese farmlands often live in urban areas and rarelydevelop FS. Of course, there will be patients in whomthe epidemiological criteria will be difficult to assess—for instance, those individuals who live and work in acity located near an endemic region and who are occa-sionally exposed to the rural environment. Based onthese considerations, we proposed the following classi-fication.

Classification of Fogo Selvagem

Classic FS, Localized FormThe patients exhibit localized lesions of FS and thetypical features of FS by histology and direct IF. Thesera of these patients are negative or show low titers ofFS autoantibodies (,1:20) when tested by routine indi-rect IF techniques. The sera of these patients may yieldpositive results when tested by other highly sensitivetechniques.

Classic FS, Generalized FormThese patients can exhibit any of the clinical features ofthe generalized form of FS and show the typical histo-logical findings of FS. Direct and indirect IF studies arepositive. The titer of autoantibodies in the patients’ serais higher than 1:20.

Probable FS, Localized FormThese patients may show clinical lesions of localized FSwith histological findings of FS, but show negativeindirect and direct IF studies of sera and skin biopsies.Follow-up serological testing by indirect IF, immuno-blotting, immunoprecipitation, or ELISA with recombi-nant dsg1 may be necessary to detect the presence ofanti-dsg1 autoantibodies. Once these autoantibodies aredetected the disease will be reclassified as Classic FS,localized form.

FS Under TreatmentThis group includes FS patients with any of the classicforms of FS who are undergoing therapy.

FS, CuredThese patients show no clinical or immunological evi-dence of disease for more than five years posttherapy.

Acknowledgments

This work was supported in part by U.S. Public HealthService Grants R37-AR32081, R01-AR32599 (L.A.D.) fromthe National Institutes of Health and by a VA Merit ReviewGrant (L.A.D.).

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