A unique form of endemic pemphigus in
northern Colombia
Ana Marı́a Abrèu-Velez, MD, PhD,a Takashi Hashimoto, MD,b Wendy B. Bollag, PhD,a
Sergio Tobón Arroyave, DDS,c Clara Eugenia Abrèu-Velez, DDS,c
Martha Luz Londoño, DVM,d Fernando Montoya, MD,e and Ernst H. Beutner, PhDf
Augusta, Georgia; Buffalo, New York; Fukuoka, Japan; and Medellı́n, Colombia
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. (J Am Acad Dermatol 2003;49:599-608.)
T
he prevalence of endemic pemphigus foliaceus (PF) in one relatively well-defined geographic area makes it an excellent natural
model for studying the interactions among genetics,
the immune system, and possible environmental risk
factors in the development of autoimmunity. Endemic PF in South America occurs particularly in
From the Institute of Molecular Medicine and Genetics, Medical
College of Georgiaa; Department of Dermatology, Kurume
University School of Medicine, Fukuokab; Dental School,
University of Antioquia, Medellı́nc; Distribuciones WYM Ltda,
Medellı́nd; Basic Biomedical Science Corporation, University of
Antioquiae; and Department of Microbiology, The State
University of New York, and Beutner Laboratories.f
Funding sources: Grants from the Embassy of Japan in Colombia;
Mineros de Antioquia, S.A.; Instituto Colombiano de Medicina
Tropical as part of the Instituto de Ciencias de la Salud; Universidad de Antioquia; Direccion Seccional de Salud de Antioquia;
and Medical College of Georgia and the National Institutes of
Health (grant no. AR45212). Dr Abrèu-Velez received a scholar-
Abbreviations used:
Dsg1: desmoglein 1
IF:
immunofluorescence
PF:
pemphigus foliaceus
ship from Colciencias, Colombia. Studies at Beutner Laboratories
on monkey esophagus sections were aided by Beutner Laboratories and by National Institutes of Health grant No. RR00163 to
the Oregon Primate Center and by Beutner Laboratories.
Conflict of interest: None identified.
Accepted for publication October 21, 2002.
Reprint requests: Ana Marı́a Abrèu-Velez, Institute of Molecular
Medicine and Genetics, Medical College of Georgia, 1120
Fifteenth St, Augusta, GA 30912. E-mail: [email protected]
mcg.edu.
Copyright © 2003 by the American Academy of Dermatology, Inc.
0190-9622/2003/$30.00 ⫹ 0
doi:10.1067/S0190-9622(03)00851-X
599
600 Abrèu-Velez et al
Brazil, where the disease is known as fogo selvagem.1-12 Endemic PF differs from sporadic PF (Cazanave’s PF) in its geographic distribution, high familial incidence, and age of onset (youth in fogo
selvagem versus adults in the sporadic form of the
disease).1-12
In the early twentieth century, more than
15,000 fogo selvagem cases were reported in Brazil, with a remarkably high incidence in rural areas. The disease occurs often in children, young
people aged 14 to 16 years, and young adults,
with the highest incidence (50%) in the 20- to
30-year-old age group, and affects both sexes
equally.1-12 Most patients are poor, inhabit rural or
suburban areas, and work as homemakers, farmers, or lumberjacks.1-10 In Brazil, fogo selvagem
has disappeared in most previous endemic areas,
and the total number of such cases has notably
decreased. Recently, in a report of a new focus in
Brazil, fogo selvagem patients had epidemiologic
features slightly different from the original descriptions.12,13 A recent study of fogo selvagem in
São Paulo revealed that 60.4% of endemic PF
patients were female, 79.2% were white, their ages
ranged from 7 to 82 years old, and large percentages were in their teens (29%) and living in rural
areas (46.9%).14,15 In 1993, another possible focus
of endemic PF in Tunisia, North Africa, affected
predominantly young women, had no familial
component, and had clinical features resembling
herpetiform pemphigus. However, no fieldwork
confirmed the endemic nature of this PF
focus.16,17
The existence of another possible focus of endemic PF, this time in the South Amazonian and
Orinoquian rain forest of Colombia, was reported
to have features like those in the original reports
of fogo selvagem.18 In addition, the existence of
another probable focus of endemic PF was described in a retrospective 1976-86 study of 21
cases of endemic PF diagnosed in a reference
hospital in Colombia.19,20 Since no dermatologist
visited this possible focus and no field study was
performed, we visited the area to better characterize the disease, to compare this new focus with
other described endemic PF foci, and to confirm
its endemic nature.
MATERIALS AND METHODS
Subjects
For 10 years (1992-2001), an active search was
undertaken to detect endemic PF cases in El Bagre,
a rural village in northeastern Colombia, and the
area surrounding this village, at the northern end of
Colombia’s Central Cordillera, 284 km north of
J AM ACAD DERMATOL
OCTOBER 2003
Medellı́n (Fig 1).21,22 The area around El Bagre is
characterized by fighting among guerrilla, paramilitary, and military forces in disputes over land,
power, money, and narcotics. The population is 41%
American Indian and white (mestizo), 15% white,
14% American Indian and black (zambo), 3% white
and black (mulatto), and 1% American Indian.21,22
We evaluated approximately 6000 people from the
area, examining endemic PF patients, as well as
control volunteers who matched the patients in
terms of age, sex, residence, and work activities.
Controls from the endemic area included people
with or without other dermatoses (Table I).
Laboratory studies
Skin biopsy specimens were taken from endemic
PF–like lesions on each patient and examined histopathologically. Direct immunofluorescence (IF) of
the specimens was performed as previously described.23 Sera from patients were also examined for
the presence of anti– cell surface antibodies by
means of indirect IF with monkey esophagus and
human foreskin sections used as substrates.24 Immunoprecipitation and immunoblot data are detailed in
a separate report.25
Statistical evaluation
Previously codified original data, tabulated in the
Epi-Info program for distribution frequencies and
associations, were graphed with the Harvard Graphics package (Table I). So that we could identify
potential factors associated with disease development, patients and controls also completed a questionnaire. Data were evaluated as blind studies by
two epidemiologists.
RESULTS
Clinical findings
The clinical findings are described in Table I.
Patients showed keratotic follicular skin lesions resembling discoid lupus erythematosus, or the abortive form of fogo selvagem, similar to Senear-Usher
syndrome (Fig 2). The most typical lesions found in
our patients were hyperkeratotic plaques on the
face, chest, and back, referred to as acanthoma. All
active cases also showed conjunctivitis, which was
diagnosed by two ophthalmologists as actinic in
origin (Table I). As in fogo selvagem, oral, nasal,
pharyngeal, genital, and anal mucosae were not
affected. Also as in fogo selvagem, the soles and
palms were not affected by lesions. However, hyperkeratosis was observed on the soles and palms,
and in patients with more than 70% of their skin
affected, these areas showed a pruned appearance.
We found that many persons progressed through
various clinical stages, whereas a few had a stable
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Abrèu-Velez et al 601
Fig 1. Geographic and demographic distribution of the El Bagre municipality in Colombia.
A, Map of Colombia, with the state of Antioquia outlined and shaded. The El Bagre area is
indicated by darker shading and a star. B, Larger map of Antioquia with a star showing El Bagre
and surrounding municipalities of El Bajo Cauca, a political and geographic region of Antioquia that has 137,023 inhabitants, of whom 90,832 live in urban areas and 46,191 in rural areas.
El Bajo Cauca includes Cáceres, Tarazá, Caucasia, Zaragoza, Nechı́, Arboletes, San Juan de
Urabá, and El Bagre.
clinical course. We were unable to utilize chloroquine or hydroxychloroquine and thalidomide, because warfare in the area prohibits their use. Our
treatment strategy involved the use of oral or topical
steroids (we prefer topical ones), antihistamines,
sun-protective clothing, and sun block and dietary
interventions.
Histopathologic findings
Histopathologically, acantholysis in granular layers (a typical feature of PF) was seen only in new,
active, or exacerbated skin lesions (Fig 3). In total,
42.3% of skin biopsies showed the changes typical
of PF. Follicular hyperkeratosis with some dyskeratosis appeared in the granular layer of old lesions.
Chronic dermatitis–like changes with scleroderma-like
alterations (23%), pustule formation (15.4%), lupuslike
features mixed with pemphigus-like changes (29%),
psoriasiform changes (7.7%), and lesions resembling
polymorphic light eruptions also appeared. In addition, skin biopsies in about one fourth of the patients
showed liquefaction or degeneration of the basement
membrane zone, correlating with the clinical lupuslike
appearance seen in 29% of cases.
Laboratory findings
By direct IF, all the skin biopsy specimens obtained from active endemic PF patients revealed
IgG deposition on keratinocyte cell surfaces (Fig
4, A). Also, deposition of IgG, IgA, IgM, and C3 on
the basement membrane zone gave a positive
lupus band test by direct IF in 40% of the endemic
PF cases (Table II and Fig 4, B). Such positive
lupus bands rarely occur in Brazilian fogo selvagem. In addition, the presence of the lupus band
correlated in 100% of the cases with clinical signs
of Senear-Usher syndrome and histopathologic
findings of lupuslike features mixed with pemphigus-like changes. In approximately two thirds of
these patients, basement membrane zone liquefaction was also noted. Tests of 30 serum samples
from El Bagre endemic PF patients and controls
for antinuclear antibody (ANA) with enzymelinked immunosorbent assay kits (Incstar Co, Stillwater, Minn) revealed ANA in one endemic PF and
one control serum. Indirect IF for IgG4 antibodies
revealed prominent intercellular staining (Table
II). These results, as well as the enzyme-linked
immunosorbent assay method for desmoglein 1
602 Abrèu-Velez et al
J AM ACAD DERMATOL
OCTOBER 2003
Table I. Epidemiologic differences between the controls from the endemic area and endemic PF patients,
matched by age, sex, and living conditions.
Subject characteristics
Sex
Male
Female
Presence of same disease
in siblings
Dermatologic diagnosis
Controls (N ⴝ 130)*
Statistical
‡
difference
P ⬍ .0001
85% ⬎6 h/d and including the highest
radiation exposure (10 AM–2 PM).
P ⬍ .05
P ⬍ .0001
Depression (35%)
All cases that showed high clinical
activity
Depression (80%)
Fatigue (30%)
Arthralgia, mainly at knee, ankles,
and vertebral joints (30%)
Fatigue (100%)
Arthralgia, mainly at knee, ankles, and
vertebral joints (90%)
Psoriasis (2%)
Xerotic eczema (2%)
Impetigo (2%)
Eccrine hydrocystoma (1%)
Basal cell skin cancer (3%)
Presence of actinic
conjunctivitis
Presence of systemic
symptoms
†
124 (95%)
6 (5%) (all postmenopausal)
33% of patients affected by endemic PF
have siblings affected by endemic PF
disease.
Clinical form of pemphigus (according
to Viera’s clinical classification for fogo
†
selvagem )
Bullous exfoliative or hyperkeratotic
generalized forms (10%)
Localized form (18%)
Prurigoid-like form (16%)
Clinically inactive (6%)
Senear-Usher–like form (50%)§
Criteria, as described in the text, met
for diagnosis of endemic text, met
for diagnosis of endemic PF (80%)
124 (95%)
6 (5%)
10% of patients affected by atopic
dermatitis have siblings affected
by atopic dermatitis.
Vitiligo (7%)
Atopic dermatitis (4%)
Sun exposure (⬍3, 3–6,
and ⬎6 h)
Endemic PF patients (N ⴝ 130)
Lichen planus (6%)
Postphlebitic syndrome (4%)
Cutaneous amyloidosis (1%)
No apparent dermatologic diseases
(70%)
50% ⬎6 h/d and including the
highest radiation exposure (10 AM
to 2 PM)
None detected
P ⬍ .0001
P ⬍ .0001
P ⬍ .0001
*The control group and the endemic PF (pemphigus Abreu-Manu) group 25 in El Bagre were matched by following a Gaussian distribution.
†
From Viera JP. [Different aspects of Brazilian pemphigus foliaceus]. São Paulo: Empresa Grafica da Revista dos Tribunais; 1948.
‡
The Wilcoxon test was used to determine whether significant differences existed between the two values in each row; illustrated are the
differences. The data were analyzed with Graph Pad Instant Software (San Diego, Calif) and Epi-info 2000 software (Public Health Foundation,
Washington, DC). The following factors examined were not discriminating: history of malarial or gastrointestinal infections or sexually transmitted diseases, dengue, or tuberculosis; cohabitation with domestic animals; living, working, and resting distance to riverbeds; tobacco, marijuana, or liquor habits; exposure to agricultural and jungle vegetation; exposure to rodents, mosquitoes, and snakes during rest or work hours;
basic diet; and percentage of skin compromised (according to Lund and Browder skin burn surface scale).
§
The hyperpigmented form was not considered because of intrinsic racial characteristics in each individual.
(Dsg1) (RhiGene, Chicago, Ill), indicated that
Dsg1 is the major autoantigen in endemic PF from
El Bagre, as it is in Brazilian endemic PF. Most sera
from El Bagre endemic PF patients also reacted
with several other protein bands at immunoblot
and immunoprecipitation analyses.26,27 These
findings are now under investigation.28
Epidemiologic and statistical analysis
During our 10-year surveillance with active
searching, we found 130 patients with endemic PF in
the area surrounding El Bagre. All cases of the dis-
ease started in the rural area around El Bagre, in the
municipality of El Bagre (90%), or in the neighboring
rural areas of the bordering Zaragosa municipality
(10%) (P ⬍ .0001). The majority of endemic PF patients
were men (95.4%) in their middle forties or older, with
a mean age of 50 years; the remainder (6/130, or
4.6%) were postmenopausal women. Ninety-eight
percent were illiterate and poor and performed
outdoor activities such as mining, farming, or forestry. All people living in the rural area lacked
sewage and water systems, as in most rural areas
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Abrèu-Velez et al 603
Fig 2. Clinical features. A, Numerous exfoliative skin lesions and pustules are seen. B, Lesions
are present in the armpits. C, A common clinical trait of people affected by Colombian endemic
PF resembles that of integumentary lupus: a butterfly pattern over malar regions with patchy
hyperpigmented plaques. D, Hyperkeratotic plaques on interscapular areas are present. These
plaques predominate on sagittal areas of seborrheic zones.
of El Bagre; however, both patients and controls
have good personal and home hygiene. Table I
shows an epidemiologic comparison among endemic PF patients and controls. Table II compares
different groups of endemic pemphigus. The
prevalence of 130 endemic PF cases among the
rural population of 5626 is 2.3%. However, since
2586 (46% of the rural population) are at risk (men
604 Abrèu-Velez et al
Fig 3. Light microscopy. A, Histologic study of a papulosquamous lesion reveals subcorneal and intraepidermal
acantholysis with epidermal acanthosis and papillomatosis. B, Histologic study reveals psoriasiform epidermal
acanthosis with subcorneal acantholysis. (A and B, Hematoxylin-eosin stain; original magnifications: A, ⫻4; B,
⫻10).
older than 18 years and postmenopausal women),
the incidence of this disease in the group at risk is
closer to 5%, and our data confirm the endemicity
of this disease in the rural area surrounding El
Bagre. The prevalence of endemic PF in women of
childbearing years was 0.23% (similar to that of
the sporadic form). The prevalence of endemic PF
over 10 years has been stable (about 3 to 10 new
cases per year) with similar mortality. This disease
can be catalogued as chronic, since two thirds of
patients had suffered from the disease for 1 to 30
years. In the rural areas surrounding El Bagre,
Indians, who make up about 1% of the total population, had 10.8% of the cases identified, indicating that the disease is prevalent among this ethnic
group compared with other races (P ⬍ .0001).
Severe complications of El Bagre endemic PF
Presently, about 30 patients have died. The
causes of death we detected included stroke; peri-
J AM ACAD DERMATOL
OCTOBER 2003
Fig 4. Direct immunofluorescence. A, IgG deposits show
typical intercellular staining between keratinocytes in all
cases. When using mouse antihuman IgG, IgM, or IgA,
complex immunofluorescence was observed, consisting
of staining of the basal membrane zone and basal keratinocytes, as well as some intracellular staining. B, C3
complement deposits in the basement membrane area
resemble a lupuslike band.
tonitis of unknown origin; exacerbation of endemic
PF; tuberculosis; renal, liver, and lung failure of
unknown cause; and chickenpox in 3 patients. In
addition, some hospitalized patients had proteinuria, hypoalbuminemia, generalized edema, hematuria, leukocyturia, and frank nephrotic syndrome
indicating possible renal failure. Indeed, chronic
kidney failure with decreased creatinine clearance
was diagnosed in two patients with a lupus band in
the skin and with facial eruptions in a butterfly
distribution over the malar areas and bridge of the
nose. An abrupt death syndrome without apparent
cause was also reported by the relatives of some
patients. Diagnostic autopsies were performed only
in 2 patients who died as the result of complications
from chickenpox. The autopsies in these 2 cases
showed a severe generalized endotheliitis in most
organs. In our experience, the disease activity of
chickenpox (herpesvirus) and tuberculosis is severe
in patients affected by endemic PF. Such patients
show low tolerance to these diseases as is observed
in most Indians. When the patients’ health declines
to a state characteristic of that occurring in sepsis,
Abrèu-Velez et al 605
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Table II. Clinical, epidemiologic, and immunologic features in people affected by different types of endemic PF
Patient characteristics
Clinical findings
Age ranges
Ethnic heritage
Sex
Racial groups
Occupation
Land use
Environmental and
geological
conditions
Presence of
conjunctivitis*
Fogo selvagem
(N > 15,000)1–9,34,39
Endemic pemphigus in
Tunisia (N ⴝ 22)14,15
Endemic pemphigus in El
Bagre (N ⴝ 130)25
Senear-Usher syndrome
(N ⴝ 366)26
Senear-Usher syndrome Senear-Usher syndrome
(pemphigus
(pemphigus
erythematosus) in a
erythematosus) in a
localized form and a
localized form and a
generalized form with generalized form
possible compromise
of other organs in
addition to skin
1st and 2nd decade,
21–37 y
30–70 y
0–9 y (4.6%), 10–19 y
mostly 14–16 y
(31.4%), 20–29 y
(28.6%), 30 y or older
(35.2)
Spanish, Portuguese,
Turkish, Carthaginian, Spanish, American
Spanish, Portuguese,
American Indian,
Roman, French,
Indian, African
American Indian,
African
Phoenician, Arab
African
Men (39.6%)
Women of
Males (95.4%)
Men (45.6%)
Women (60.4%)
childbearing age
Postmenopausal
Women (54.4%)
(70%)
females (4.6%)
Caucasian (about 50%),
White Mediterranean Indian and white (40%), Caucasian (63%),
Negroid (36%),
mixed race (49%),
(100%)
Indian and black
Mongoloid (1%)
Mongoloid (1%)
(35%), Indian (17%),
White and black, or
white (9%)
Agriculture, forestry,
Homemaking
Agriculture, forestry,
Agriculture, forestry,
road construction,
and mining
road construction,
homemaking
homemaking
Arable land (10%),
Palm plantations
Arable land (4%),
Arable land (10%),
permanent crops
permanent crops
permanent crops (5%),
(5%), permanent
(1%), permanent
permanent pastures
pastures (10%), forest
pastures (20%), forest
(10%), forest and
and woodland (35%)
and woodland (30%)
woodland (35%)
Deforestation, soil
Deforestation, soil
In the south, the
Deforestation, soil
damage from overuse
damage from mining
proximity to the
damage from overuse
activities and mercury of pesticides, air
Sahara increases the
of pesticides, air
pollution; rich
and other metal
aridness of the
pollution; rich deposits
deposits of gold,
deposits; rich depolandscape.
of gold, silver, and their
sits of gold, silver, and silver, and their
associated metallic
associated metallic
their associated
minerals and clays
minerals and clays
metallic minerals
Rare†
Not described
In most clinically active Not described
cases
Cont’d on page 606
Pemphigus foliaceus
typical
Herpetiform (and
classic pemphigus)
ICS, Intercellular staining between the keratinocytes; IF, immunofluorescence.
†Proenca Guimares N. Med Cutan Ibero Lat Am 1974;4:291-8.
‡
“Pose of fogo selvagem” includes dwarfism; loss of hair in the scalp, eyebrow, eyelash, or pubic area; ankylosis of the large joints; demineralization of the extremities of the long bones; and endocrinologic and sympathetic alterations.
*
See Arneondola R. Bol Soc Bras Dermatol Sif 1944;19:329. Arch Dermatol 1988;124:1664-8.
§
See de Messias IT, Von Kuster LC, Santamaria J, Kajdacsy-Balla A.
even cyclosporine and conventional high-dose steroids or pulses of methylprednisone are ineffective.
We found many groups of genetically related
patients with endemic PF: for example, siblings,
uncle and nephew, and father and son. These familial cases composed about 30% of our endemic PF
group. Indeed, in about 3000 families in the rural
area surrounding El Bagre, 4.3% have a member in
whom endemic PF has been diagnosed. Familial
cases were most common among Indians, followed
by the zambos; however, no siblings were affected
among the white patients. We also found no en-
606 Abrèu-Velez et al
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Table II. Cont’d
Patient characteristics
Fogo selvagem
(N > 15,000)1–9,34,39
Presence of “Pose of
‡
fogo selvagem”
In about 70% of cases in
presteroid era, and just a
few reported after the
availability of steroids
Familial cases
30%
Location
Rural or suburban
Immunofluorescence IgG4, IgG1, C3
findings
Direct IF (ICS)
IgG4, IgG1, C3, and rarely,
IgA and IgM
Direct IF (basement
membrane zone)
§
5%–10%
Endemic pemphigus in
Tunisia (N ⴝ 22)14,15
Not described
Not reported
Rural
IgA, IgG, C3
IgA, IgG, C3
32% (7 of 22)
demic PF cases in wives, sexual partners, or cohabitants of El Bagre patients or in the group of researchers, indicating the unlikelihood of an infectious
cause. The most important exacerbating factor for this
disease was sun exposure or ultraviolet radiation, followed by high daily temperatures, high humidity,
stress, and low protein intake. No other detectable
differences in predisposing condition were detected.
Clinically this pemphigus seems to affect not only
the skin but also other organs, since many patients
showed various systemic symptoms (Table I), such
as arthritis of the major joints including wrists and
ankles (80%), chronic fatigue (100%), actinic conjunctivitis (100% in the most clinically active cases),
occasional episodes of syncope, dizziness, and corticonuclear cataracts, which are not the type commonly produced after long steroid treatment. In addition, an increase in the prevalence of depression
and arthalgia was also observed. These clinical
symptoms and some preliminary IF studies indicate
autoreactivity against organs in addition to skin. In
preliminary studies, we detected autoantibodies
against the bladder, parietal cells of the stomach and
skeletal, cardiac, and smooth muscle cells and endothelial cells, as well as intracellular organelles
such as mitochondria and endoplasmic reticulum. In
addition, in about one third of the chronic cases, the
skin is tight and firm, with apparent damage to the
endothelium and appendages and increased dermal
collagenization, resembling alterations observed in
scleroderma. However, further studies are required
to determine the extent of autoimmunity in these
patients. In our 10 years of fieldwork, only 3 endemic PF patients have been clinically and immunologically cured. This cure occurred after the patients
moved to colder mountains in the endemic area.
Endemic pemphigus in El
Bagre (N ⴝ 130)25
Senear-Usher syndrome
(N ⴝ 366)26
Not observed, perhaps
owing to the preventive
use of steroids in our
fieldwork studies
30%
Rural
IgG4
Not described
IgG4, IgG1, C3, IgGM,
IgGA, and lupuslike
band
70% (70/100)
IgG, C3
30%
Rural or suburban
IgG, C3
30%–40%
Endemic PF in El Bagre versus known
endemic pemphigus foci in Brazil and Tunisia
In general, in the Brazilian and El Bagre foci, the
patients were poor farmers or lumberjacks, living in
rich geologic areas with extensive mining operations. Another common feature of both fogo selvagem and endemic PF in the El Bagre area is a high
mestizo rate (racial mixes) of American Indians (various ethnic groups), Spanish, Portuguese, and Africans. These two types of endemic PF are distinct in
the gender affected and age of onset. Fogo selvagem
predominantly affects young white females under
age 30, usually with 2 or 3 family members showing
symptoms, and an important endocrine imbalance,
that is, a generalized hypofunctioning of various
endocrine glands, is characteristic. El Bagre endemic
PF appears to differ from Tunisian endemic PF primarily in the profile of affected persons. Table II
summarizes the similarities and the differences
among the 3 forms of endemic PF.
DISCUSSION
Almost a century ago, thousands of cases of fogo
selvagem were reported in Brazil.1-12 However, recently, only small clusters of fogo selvagem have
been reported.13,14 Two settlements of people with
fogo selvagem in Brazil—the Xavante reservation in
Matto Grosso and the Terena reservation of Limao
Verde— have mainly Indian populations and show
slight epidemiologic differences, resembling more
the Cazanaves PF than the fogo selvagem described
a century ago.13,14 Recently, a retrospective epidemiologic study was reported from the northeastern
region of the state of São Paulo in Brazil that determined the most recent prevalence of fogo selvagem.15 This study showed similar results regarding
sex, race, and type of work activity but with a lower
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incidence than that reported a century ago. Interestingly, in 1974, Proenca reported a high incidence of
Senear-Usher syndrome occurring simultaneously in
areas of fogo selvagem but again differing in age,
sex, and race from our cases.26 In the El Bagre
population, we observed an increased rate of vitiligo
and lichen planus in comparison with other rural
areas of Colombia, suggesting perhaps that an environmental factor is also increasing these diseases
simultaneously with endemic PF. For example, it is
known that serum selenium levels might play a role
in triggering vitiligo.29 Thus exposure to such agents
may represent a risk factor in this endemic disease.
In general, Brazilian fogo selvagem shows extensive superficial bullae and erythematous exfoliative
skin lesions on the face and trunk.1-10 Our 10-year
surveillance revealed that endemic PF patients in El
Bagre show similar features but also unique clinical
characteristics (Table II). In addition, our study revealed that endemic pemphigus in El Bagre is epidemiologically and immunologically distinct from
other known types of endemic pemphigus, such as
fogo selvagem and Tunisia endemic PF, although
the endemicity of the Tunisia type has not been
clearly confirmed.16,17 The endemic PF patients in El
Bagre presented unique features in age of onset,
gender, work activities, and the presence of autoantigens in addition to Dsg1, as previously reported.25
These additional autoantibodies may be responsible
for another feature of endemic PF, the hyperkeratosis of the palms and soles. This hyperkeratosis is
similar to the striated form of palmoplantar keratoderma, which results from mutations in desmoplakin, keratin 1, or Dsg1.30-32 Thus, we speculate
that autoantibodies to Dsg1, desmoplakin, or keratin
1 induce this feature of the disease.
More than 40% of endemic PF patients in El Bagre
showed clinical features resembling those of SenearUsher syndrome, such as a high degree of photosensitivity like that observed by Deschamps and
colleagues in Senear-Usher syndrome.33 Clinical and
immunologic studies revealed some additional similarities between our endemic PF patients and those
with Senear-Usher syndrome.34-38 We found a lupus
band–like deposition of immunoglobulins and complement at the basal membrane zone by means of
direct IF in about 40% of El Bagre endemic PF
patients.34-38 Our failure to find elevated ANA in a
small sampling of these patients is consistent with
the findings of Chorzelski, Jablonska, and Blaszczyk36 and our laboratories (unpublished data, 1998).
Most cases of El Bagre endemic PF, or pemphigus
Abreu-Manu,25 have the following clinical features
of the disease: (1) hyperpigmented plaques and
macules mainly on the face and trunk, predominat-
Abrèu-Velez et al 607
ing in the middle of the chest; (2) an erythematous
butterfly-like macular lesion with fine scaling and
erosions on the face; (3) pruriginous or hyperkeratotic patches with crusting mainly on the presternal
and interscapular seborrheic regions and armpits;
(4) occasional scarring and scabbing of the scalp,
resembling a false tinea amiantacea; (5) hyperpigmentation of previous lesions (seen mostly in people showing clinical control); (6) the presence of
pustules around scaling lesions; and (7) an actinic
conjunctivitis–like condition. This last appears
mainly in cases with high clinical and immunologic
activity. Histopathologic changes in lesions of El
Bagre endemic PF most resemble those seen in nonendemic PF. Cases that fulfilled most or all of the
above clinical criteria and produced immunopathologic findings consistent with pemphigus were diagnosed as El Bagre endemic PF. To determine
whether these patients have a systemic compromising condition, further studies are warranted.
We acknowledge Stella Prada de C, MD, Walter Leon
Herrera, MD, Maria Mercedes Yepes, MD, Juan Guillermo
Maldonado, MD, Jorge Botero, MD, Edinson Villa, Fredy
Vélez, MD, Juan Esteban Arroyave, MD, Alex Pabón, MD,
Armando Muñoz, MD, Andres Jaramillo, PhD, Doris Ruiz,
and all co-workers that participated in the visits to El Bagre
for their contribution to this research and humanitarian
program, as well as all those who donated goods for the
patients. We also appreciate those who assisted the endemic PF patients at the Hospital Universitario San Vicente
de Paul in Medellı́n. We extend our thanks to the El Bagre
community, to Hospital Nuestra Señora de El Bagre, and
to the Major Office and Health Jurisdiction in El Bagre. We
also thank Darius Mehregan, MD, of Pinkus Laboratories
for the study of skin biopsy specimens and for the micrographs used in this study. Special thanks go to Marcos
Restrepo, MD, at ICMT for support; to Richard Plunkett,
MD, and Janet Zilliox of Beutner Laboratories for testing
specimens of endemic PF cases and for reading and commenting on this manuscript; and to Dawn Martin for finalizing the manuscript. This article represents a portion of
the PhD thesis of Ana Marı́a Abréu Velez, who received a
scholarship from Colciencias, Colombia, administered by
the Latin American Scholarship Program of American Universities (USA).
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