Brazilian pemphigus foliaceus

Brazilian pemphigus foliaceus

3 Brazilian Pemphigus Foliaceus Raymundo Martins Castro, M.D., Justin Theodore Roscoe, M.D., and Sebastiao A. Prado Samoaio, M.D. From the Departme...

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Brazilian Pemphigus Foliaceus

Raymundo Martins Castro, M.D., Justin Theodore Roscoe, M.D., and Sebastiao A. Prado Samoaio, M.D.

From the Department of Tropical Medicine and Dermatology, University of Sao Paul0 Faculty of Medicine, Sao Paula. Brazil

Fogo Selvagem (Wildfire) is a cutaneous disease characterized by a specific epidemiology, generalized distribution of bullae followed by an exfoliative erythroderma, and frequently, a grave prognosis, if untreated. Its etiology is unknown and the pathogenesis only partly understood. The histopathologic hallmark is the presence of acantholysis in the superficial layers of the epidermis. The acantholysis is due to the binding of immunoglobulin to the intercellular cement substance of the epidermis.

Histow The first mention of “pemphigus brasiliensis” was made by Francois Boissier de Lacroix (Sauvages) in his Nosologia Methodica.’ He relates the observation made by Father Bougeant in 1730. Ramos e Silva reviewed the description and concluded that it was not the disease currently described as Fogo Selvagem (FS) or pemphigus foliaceus endemicus (PFE).2 An accurate description of the disease first appeared in the beginning of the twentieth century. In 1903, Paes-Leme, in Rio de Janeiro, presented cases that were observed inland, especially in the state of Sao Paulo.3 He erroneously diagnosed his patients as having tokelau. The descriptions, however, were typical of PFE. Most patients came from the region where the native vegetation was being destroyed to cultivate coffee. It is interesting to note that one of the cases was a native Indian from central Brazil. At about the same time, Sequeira observed cases of FS in Bahia, but did not publish his observations. His observations were published by Silva about 40 years 1ater.4 The cases were clinically and epidemiologically similar to those observed by Paes-Leme. Most of the patients were from the state of Bahia where cacao plantations were substituting the native vegetation. Two years after the initial description by Paes-Leme, Teixeira suggested that FS is a form of pemphigus foliaceus.5 The clinical entity was widely discussed at the 1912 Brazilian Medical Congress. A new focus was appearing in the region around the planned city of Belo Horizonte, which had been constructed and inaugurated in 1898. Aleixo pioneered the studies in the area, but 22

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his observations were published by Orsini much later.6mR In the 193Os, due to the large number of cases with this incapacitating and often fatal disease, the health authorities of the state of Sao Paulo built a hospital exclusively for the treatment of FS patients. At present the hospital is being gradually deactivated due to the rapid disappearance of the disease from the area-a result of heavy urbanization (see Epidemiology). The first director of this hospital, Vieira, published several important manuscripts during the 1930s and 1940s describing the clinical manifestations and course of FS.l”ri’ The construction of Goiania in the 1940s transferred the major focus of the disease to central Brazil and led to the construction of a special hospital there. Auad has studied the patients in central Brazil and reported the presence of 4,000 cases.” The problem is very significant in central Brazil and has necessitated the creation of four additional specialized hospitals. In 1970 at the Brazilian Pemphigus Meeting in Goiania, it was estimated that there were at least 10,000 known cases of FS. Since there are an increasing number of settlements in the Amazon region, the disease that was once rare in that areal has now become more frequent and has been observed also among native Indians (Figs. 1A and 16).i4 Pemphigus foliaceus endemicus is not seen exclusively in Brazil.l5,16 Brazilian hospitals register cases from Bolivia and Paraguay. Cases published by Jaimovich and Mazzini17 have features that strongly resemble it. Corder0 and Magnin observed that pemphigus foliaceus in Argentina is similar to FS seen in Brazil.lx The disease was seen in Peruvian Indians by Heimgartner and Heimgartner.‘” London0 in Colombia and Medina in Venezuela have seen patients with features similar to PFE.* Hernandez-Perez reports cases seen in El Salvador and emphasized their resemblance to cases of FS earlier seen in Brazil.‘O Basset69 noted the same similarities in Senegalese patients. A patient from Uganda studies by Lomholt*i appears to have the initial form of PFE. Since the

23

Pemphigus

FIG. 1B. Macular lesions with pigmentary changes in the regressive phase of FS in a native Indian patient. Clinical picture resembles latestage of pinta. (See Fig.

1A, page

34.)

disease occurs in countries other than Brazil and outside South America, the terms Brazilian pemphigus or South American pemphigus foliaceus are inappropriate, and PFE or FS are preferred; however, at the present time, it is still unclear whether PFE and the pemphigus foliaceus described by Cazenave (PFC) are distinct entities. Hence the designations European pemphigus foliaceus and North American pemphigus foliaceus do not seem justified.‘”

EtioDathoaenesis The etiology of FS is unknown. b-hem,olytic have been cultured from pustules, the blood, and the cardiac cavity of patients at autopsy,23 and high ASLO titers have been reported.24q5 The ASLO titers do not correlate with disease activity or severity streptococci

*Personal communication.

Clinics 24

Castro et al.

and do not parallel clinical course. Not infrequently, high ASLO titers persist after clinical recovery. In some patients, even as the anti-ICS antibody titers fall after steroid therapy, the ASLO titers persist.25 Several attempts have been made to demonstrate a viral etiology.2 Lindenberg inoculated serum from PFE patients into rabbits and reproduced the bullae in these animals and attributed the etiology to a virus.28 In a study by Crosti et al.,‘9 a cytopathogenic agent was isolated from the blood of FS patients. This observation has not been confirmed. The formation of bullae in rabbits and monkeys similar to those found in the human disease after infusion of high titers of pemphigus antibodies has been reported.3Op31 In the rabbits, dinitroclorobenzene (l-5%) was applied immediately after the infusion to induce bulla formation. In the monkeys, no topical application of any chemical was necessary, but the injections were repeated up to three times with 3-4-hour intervals.32 The pathogenesis remains unknown. Antibody titers to intercellular cement substance are usually very high.25130 Antibodies to gastric parietal cells, mitochondria, and smooth muscle have been found, while antinuclear antibodies and rheumatoid factor have not been reported.s3 Therefore, it is believed that PFE is an aitoimmune disease.

Epidemiology PFE is readily distinguished from PFC by its distinctive epidemiology.34m37 Some of the significant features of its epidemiology include: (1) the endemic occurrence of FS in certain regions of South America, particularly Brazil; (2) markedly higher incidence in rural areas, being extremely rare in urban centers; (3) a great majority of the patients are children, adolescents, and young adults (In PFC, most patients are mature adults or elderly); (4) a high frequency of several cases in one family; (5) the appearance of PFE in wilderness areas that now are being inhab-

ited; (6) the disappearance of the disease from areas of prior endemicity as the areas become developed.38 The disease is probably not spread by direct inter-human contact, since hospital workers have not been reported to acquire the disease; however, several members of a family living in an endemic site are known to be affected. It is possible that Pavlovsky’s niche theory might be applicable. Accordingly, an individual upon entering the region begins to participate in the epidemiologic cycle. Examples of this would be the appearance of PFE in Belo Horizonte at the turn of the century, north-eastern Parana from 1940-1960, and more recently, in central Brazil after the construction of Brasilia, presently the largest focus of the disease. Most cases of PFE live by the river or nearby. This distribution may be related to the presence of a vector. An arthropod of the genus Simulium. which is know to transmit oncocerchiasis-another endemic disease in Latin America; however, PFE is not seen along the coast, despite the fact that these insects are frequently found there; however, the species are different. Simulium pertinax is found along the coast, and Simulium pruinosum is usually found inland. The geographic distribution of the disease in Brazil is shown in the map (Fig. 2) from the available data.lzCurrently, the incidence of FS is increasing in the northern and western regions of Brazil, while it is steadily declining in the southeastern regions. Information regarding the prevalence and incidence in the northeast or south or from other South American countries is lacking. An interesting pattern of incidence is seen in the state of Sao Paulo. In the 1930s and early 194Os, there were 100 new cases yearly for a population of 8 million. In 1973-1974, only 40 new cases per year were seen for a population that had increased to 20 million. The majority of patients with PFE are young in contrast to the older age group seen in PFC. A statistical study of 2,222 cases12 with regard to age group is shown in Table 1. These observations are similar to other studies of 464 and 506 cases.12~3s~40 In a recent

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DISTRIBUTION

Brazilian Pemphigus

OF FOG0 SELVAGEM RLBIONS- NUMBER OF CASES

FIG. 2. Current map of Brazil indicating the distribution

25

IN BRAZIL

of FS in the various geographic areas

26

Clinics in Dermatology

Castro et al.

P.F.E.

WITHIN

FAMILIES

6’

c%

w

24,

Y?

Pa? 331

30’

29*

2W

27’

v??

%Y 34=

-

s i Ming8

FIG. 3. Incidence

and distribution

261

25’

23*

G

35’

p-’ 37*

36=

u married

of FS or PFE within 20 families

0 diroarod

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TABLE

Brazilian

PemDhiaus

27

1. Distribution of PFE According to Age at Onset of Disease

Age Wars)

Number of Cases

Percentage

of Total Cases

20-30 30-40 40-50 50-60 60-92

125 599 619 421 281 115 62

5.6 27.0 27.9 18.9 12.6 5.2 2.8

Total

2222

100

O-10

1O-20

report, it was observed that only 1.2%of PFE cases occur in the elderly.41 The frequent occurrence of PFE in families is another important epidemiologic characteristic. Fifty-five of 464 patients in one study,40 and 485 of 2,686 patients in another study occurred in members of the same families.‘” This phenomenon is probably related to a genetic predisposition that may or may not be associated with an immunologic defect, rather than inter-human contagion (Figs. 3 and 4). Interestingly it has been observed that anti-ICS antibodies are often present in the sera of healthy, unaffected family members and neighbors of patients. This observation has not been confirmed yet.“” Data showing the distribution by sex, race, and dwelling area at onset of the disease are shown in Table 2. Mongoloids comprise about 1% of the Brazilian population but were not included in

TABLE

2. Epidemiologic

these studies. This appears to be a sampling problem. Proenca has found 38 cases of mongoloids with PFE in the archives of the Sao Paulo Pemphigus Hospital.* The racial distribution is approximately the same as that found in the general rural population of central Brazil. The proportion of rural cases is much greater than that of the general population.12~3g~40The higher incidence in males is probably related to the higher exposure of men to the ecosystem. The differences and similarities between PFE and PFC have been recently emphasized35 and are summarized in Table 3.

Features of PFE* Number of Cases/ Percentage of Total

Sex Male Female

119Y53.6 1035/46.4

Race White Nonwhite

930/41.7 1300/58.2

Dwelling area Rural Urban

2001/89.7 229/l 0.3

*Total cases = 2230.

FIG. 4. Posterior view depicting the backs of a mother and her son with PFE. The son has features of thegeneralized erythrodermic stage, while the mother has hyperkeratotic lesions similar to those seen in Senear-Usher syndrome. *Unpublished

data.

Castro et al.

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TABLE

Clinics in Dermatology

3. Comparison of Fogo Selvagem and Pemphigus Foliaceus of Cazenave’ Endemic Pemphigus Foliaceus (Fooo Selvaaem)

Epidemiology Endemic Increased frequency before years of age Predominant in rural zones with formation of geographic foci Familial cases Alterations of incidence through socioeconomical development in the region Recurrence upon returning to the area where the disease was acquired Clinical aspects Significance of the Senear-Usher syndrome (pemphigus erythematosus) Prospect of survival for untreated patients Treatment Response to moderate doses of corticosteroids, e.g., Metabolic and endocrine alterations Nanism Azoospermia Histopathology and electron microscopy lmmunoelectrommicroscopy Pemphigus antibodies (IIF and DIF) Antiepithelial antibodies inhabitants the areas with FS-foci

Pemphigus Foliaceus of Cazenave

Yes Yes

No No

Yes Yes

No No No

Yes

No

Pre-invasive, frequently develops to generalization One third of the patients survived

Steady stage rarely develops to generalization 7

Very good

Poor

Yes Yes ldential lntitial lesions at the glycocalix Yes

No No -

Yes

Yes

No

of

*Due to these differences, it is probable that PFEand PFC are similar cutaneous responses to partially different antigens, as stated by Holubar (personal communication) and more recently by Sevadjian.22

Natural History and Clinical Aspects The natual history of Fogo Selvagem may present itself in various clinical aspects, depending upon which stage is seen. Four phases can be identified: an initial stage, an invasive stage, a steady-state, and the regression phase. It must be emphasized that mucosal lesions are never observed. The initial stage is also known as the abortive form and is indistinguishable from the Senear-Usher syndrome (pemphigus erythematosus).43 It is characterized by erythematous, squamous, exudative, and crusted lesions, which may appear anywhere on the skin but appear more frequently on the scalp, face, or sternal region (Fig. 5). The patient does not always notice blister forma-

tion. Most patients usually report the appearance of a few grouped lesions that suggest an inexplicable burn. It is this resemblance to a burn that gives the disease the name Wildfire. Nikolsky’s sign can already be elicited from the skin near the lesions. These may be the only manifestations for a period ranging from days to years. The course may then take one of three directions: (1) slow, spontaneous regression with only erythemato-hypopigmented or hyperpigmented macules remaining; (2) maintainence of the pattern of healing lesions and appearance of new lesions, predominantly in seborrheic areas; and (3) sudden generalization that may affect the entire skin. This generalization is known as the invasive phase. Most patients enter it after the first few weeks or months. Regardless of the

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time elapsed, the characteristics are always the same. The bullae, now easily noticed, appear following the metameres, symmetrically and usually in a descendant fashion. The bullae vary from millimeters to several centimeters. They rupture with extreme ease, lasting only for short periods. Large erythematous and exudative areas appear with an abundant formation of scales and crusts. (Figs. 6A and 6B). Should a patient not bathe one day, he can usually fill both hands with the crusty scales that cover his bed. Nikolsky’s sign is always present, especially in the next metamere to be invaded. In a few weeks, the entire skin is involved, and the next stage is reached. The lesions may remain generalized in a steady state for a period ranging from a few months to several years. Rarely does spontaneous regression occur before the end of the first year. The steady state very rarely persists longer than 10 years. The majority of cases remain in the steady state 2-8 years. The most common clinical form during this phase is the herpetiform or bullo-exfoliative.1” 12 Over an initially erythematous and later erythemato-pigmented background, lesions are incessantly formed in areas that merge to form polycyclic figures. Exudation is constant (Fig. 7A). The next most common form is the erythrodermic. The skin is intensely red as in the classic French expression “l’homme rouge.” The abundant desquamation is more farinaceus than foliaceus and forms what the patients call a “moist clay” due to the constant exudation. This form takes longest to heal (Fig. 7B & 7C). The papillomatous variety is the rarest but the most interesting, because few dermatoses resemble it.” The dermal papillae of the entire skin rise 0.51 mm above the normal level of the cutaneous surface. They remain individualized and do not coalesce, and the appearance of the skin resembles a mulberry (Fig. 7C). Indelible alterations of the finger prints have been reported.‘” During this steady state adnexa become altered. Scalp hair, eyebrows, and axillary and pubic hairs may be lost. The nails show transverse ridging and may fall off should

PemtMaus

FIG. 7E. Dorsum of the hand showing the papillomatous variety of the steady also Figs. 7A-D, page 34.).

29

features of state. (See

the hands and feet be involved. The scalp is thickly crusted and palmo-plantar hyperkeratosis occurs. Hyperpigmented macules develop after some years and are a favorable prognostic sign,’ heralding the next stage. The regression phase is characterized by these hyperpigmented macules, progressive clearing, and absence of Nikolsky’s sign. Lesions continue to appear in the remaining areas but exhibit an odd tendency to become hyperkeratotic or even verrucous. The regression occurs in the direction opposite to the invasion. The initially affected areas are usually the last to heal (Figs. 8A and B). The clinical picture seen during regression is usually one of erythemato-squamous or erythemato-keratotic lesions with little exudation located on the scalp, face, and sternal regions. The remaining skin is mottled by hyperpigmentation (leopard skin), with an occasional active lesion. The adnexa return to normal, although the hairs are sparser and finer than before the disease. After a long time, no lesions are seen, and only the leopard skin remains. Often the patient seems to have become darker. The white patient resembles a mulatto: the

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mulatto appears black, and the black patients look bluish. The patient is then considered cured. A relapse is very rare. The clinical course of the disease has been radically modified by the use of systemic corticosteroid. In untreated cases, the initial phase is not accompanied by general symptoms. When the invasive phase begins, it resembles an acute infectious disease. Fever, malaise, headache, muscle pain, chills, anorexia, and weight loss occur. The intensity of the symptoms is directly proportional to the spread of the lesions. It is rare for patients, even those acutely ill, to die before reaching the steady state. The steady state has features typical of chronic diseases: progressive weight loss leading to cachexia (Fig. 9), muscle wasting, ankyloses, bone decalcification, pathological fractures, and a low resistance to infections that may lead to death. Remissions eventually occur in patients who receive supportive care and treatment of complications. In the 194Os, about 35% of the patients achieved a spontaneous remission. Complications were common and often fatal in that era. They were classified as pulmonary (tuberculosis, pneumonia and bronchial pneumonia), cardiac (endocarditis, pericarditis), hepatic (fulminant hepatitis, cirrhosis), renal (diffuse acute glomerulonephritis, subacute glomerulonephritis), nervous(meningitis, meningoencephalitis), intestinal (intractable diarrhea), and general (sepsis). It is reasonable to assume the complications were due to a state of depressed immunity, secondary to the cachexia. Associations with other autoimmune diseases, such as myasthenia gravis, thymoma, systemic lupus erythematosus (SLE), or penicillamine-induced pemphigus as reported for pemphigus vulgaris have not been described in PFE. Pregnancy has been recognized as aggravating or triggering FS.44 Differential Diagnosis The peculiar characteristics of fogo selvagem make the differential diagnosis extreme-

ly simple in relation to other bullous diseases. Pemphigus vulgaris, pemphigus vegetans, and bullous pemphigoid can be excluded since mucosal lesions are usually not seen in FS. The intra-epithelial bulla is acantholytic and Nikolsky’s sign is present, thus differentiating this entity from dermatitis herpetiformis. The erythrodermic phase can be differentiated from other diseases that may present as erythroderma, like psoriasis, seborrheic dermatitis, atopic dermatitis, and lamellar icthyosis. Histopathology Pemphigus foliaceus endemicus cannot be distinguished histopathologically from the pemphigus foliaceus described by Cazenave. The hallmark of the histology is acantholysis. It was first described by Alayon in 194845 and later confirmed by other authors.39p46 This constant and characteristic feature forms a cleft that is located in the granular layer or the upper portion of the squamous cell layer, rarely being found in the middle portion (Fig. 10A). The cleft may develop into a bulla, or the upper epidermis may detach without bulla formation (Fig. 10B). Depending on the level of the cleavage, the roof of the bulla may be constituted only by horny and granular cells, or there may be one or more layers of squamous cells. The floor of the bulla shows a varied number of isolated or grouped acantholytic cells that exhibit loss of intercellular bridges, hyperchromic nuclei, and homogenization of the cytoplasm. Fibrin, neutrophils, and some eosinophils may eventually be found in the blister fluid. In older lesions, the histopathology depends on the clinical aspect and may show acanthosis, papillomatosis, hyperkeratosis, follicular plugging, and parakeratosis, with only occasional evidence of acantholysis at some places in the upper epidermis. The absence of acantholysis makes the histology nonspecific in such cases. Segregation is often observed. In this process, individual or groups of granular and squamous cells separate. Dyskeratotic cells seen in the granular layer are basophilic and shrunken

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TABLE

Brazilian

4. Indirect lmmunofluorescence

31

PemDhiaus

Studies in PFE

Author

Year

Number of Cases

Beutner, et al. Furtado, et al Rivitti Rivitti, et al. Odo. et al.

1967 1967 1972 1973 1980

28 27 35 8 28

along with the presence of clefts, resembling the corps ronds, grains, and a lacunae of Darier’s disease. Melanin may be increased in the epidermis, and melanophores may be found in the dermis. Dermal alterations are discrete. The infiltrate of lymphocytes, neutrophils, and eventually, eosinophils is not characteristic. Capillaries are dilated and a variable degree of edema is seen.

Number Positive

of Cases Negative

27 21 35 a 23

1 6 0 0 5

% of Total 96.4 77.7 100 100 a2 I

material. The desmosomal junctions were irregularly distributed, and the cytoplasmatic projections formed digitations in most cases. Lamellar and cytoplasmatic bodies were found more frequently. These alterations could be related to PFE, since direct immunofluorescence shows IgG in the intercellular spaces of the oral mucosa.

lmmunopathology Electron Microscopy In the earlier studies, the alterations of the tonofilament desmosome complex seen in PFC47 were also observed in cases of PFE.T3 A later study by Sotto showed that the tonofilament-desmosome complex was preserved in various layers of the epidermis.48 The partial or total loss of desmosomes was found only in the area with acantholytic cells. The acantholysis begins by the separation of nonspecific junctions, and only later does the desmosome junction rupture. Tonofibrils were visible as irregular bundles. Dyskeratotic cells showed irregularly arranged tonofibrils, and many had keratohyaline granules. Lamellar bodies were present without alterations, and some mitochondria were swollen. The basal cell layer was not altered, and the adhesion to the basal membrane through the anchoring filaments was intact. The ultrastructural aspects of the oral mucosa in PFE were described by Marcucci.49 He found a widening of the intercellular spaces and dissolution of the intercellular substance that appeared as an irregularly distributed, electron-dense

Anti-intercellular cement substance antibodies demonstrated in pemphigus vulgaris (PV)25~30~50+1have been found in cases of PFE. In PV, circulating, anti-intercellular, cement substance antibodies are found in 79-90X of patients tested, while in PFE, they range from 70-100% as shown in Table 4. Direct immunofluorescence of perilesional skin has been studied in patients with PFE. Deposition of Ig in the epithelial intercellular cements substance demonstrated a pattern similar to that observed in PV. In the majority of cases, IgG is present, but some cases have additional deposition of IgA, IgM, and C. (Figs. 11A and 11B). Table 5 summarizes a recent study of direct immunofluorescence of PFE by Odo.5’ It should be noted that despite the initial phase of PFE being clinically identical to the Senear-Usher syndrome (pemphigus erythematosus), basal membrane zone immunfluorescence, described in Senear-Usher syndrome,j3 has never been seen in FS. Another observation not seen in PFE is the deposition of predominantly IgG in the superficial epidermal layers as described by Bystryn et al. in [email protected] In a recent study of 45 patients

Clhnrcs

I”

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Castro et al.

TABLE

5. Direct lmmunofluorescence in PFE.

Reagent

Number

Studies

of Patients

IgG IgG-C3 IgG-IgM c3 Negative

38 (80.9) 4 ( 8.5) 1 ( 2.1) 1 ( 2.1) 2 ( 2.3)

Total

47 (100)

(%)

in our laboratories, IgG was found in all layers of the epidermis. Five cases of the SenearUsher type did not show any basal membrane zone fluorescence with IgG or IgM. One of these cases did exhibit weak homogeneous discontinuous fluorescence at the BMZ with fibrinogen (unpublished data). Despite the absence of clinical lesions in the oral mucosa and the absence of histopathologic changes on light microscopy, IgG is always deposited in the intercellular cement substance spaces of the oral mucosa in PFE patients.5R The presence of IgG is independent of the clinical severity of the disease and can be seen in both mild and severe forms. No correlation with the titer of circulating anti-ICS antibodies was found. Circulating anti-ICS antibodies were not seen in one of the cases. The third component of the complement (C3) was not found. There are various explanations for the absence of clinical lesions: (1) immunocomplexes are not formed, (2) insufficient amounts of IgG exist locally to trigger the tissue pathogenesis, (3) high turnover of cells in the oral mucosa, and (4) absence of some epidermal factor(s) necessary for pathogenesis at the tissue level. The mucosal epithelium of the esophagus and small intestine were biopsied in six patients.58 All showed IgG in the esophageal mucosa, but no IgG deposition was observed in the epithelium of the small intestine. These findings suggest that the alterations in PFE are localized only to squamous cell epithelium.

Dermatology

lmmunoelectron Microscopy Konrad et al. observed the deposition of IgG in the epidermal intercellular spaces.59 This finding was confirmed by Sotto et a1.,4R and further shown that IgG deposition occurred over the plasma membrane and permeated the desmosomal junction as previously described in pemphigus vulgaris. The initial lesion is located in the glycocalyx, and later, the desmosomes lose their attachment (Fig. 12). Exfoliative CytologY (Tzanck’s test) Grouped or isolated acantholytic cells are found on the smear from the base of a bulla. Such cells are seen in other acantholytic bullous diseases. Other Laboratory Tests Various alterations, probably due to the chronic nature of FS, will not be discussed. The increase ASLO levels and the finding of antibodies to gastric parietal cells, smooth muscle, and mitochondria (but absence of ANA and rheumatoid factor) have been mentioned earlier. Relative or absolute hypergammaglobulinemiaoccurs in most patients and returns to normal levels with treatment.26 Immunoelectrophoresis shows an increase of IgG in most patients, and a few patients have increased IgA and IgM levelsz7 Decreased levels of complement are observed in half the patients studied.52 Circulating as well as paracortical T lymphocytes have been found to be decreased in PFE.5g Endocrine disturbances seem to be related to the age of onset and not to side effects of systemic corticosteroid therapy (Fig. 13).60 Azoospermia has been reported in six patients who developed the disease as chil-

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33

FIG. 12. lmmunoelectromicroscopy of a lesion of PFE showing the intercellular space between two epidermal cells. IgG is seen (arrows) as electron dense material on the cellular membrane of the keratinocytes and permeating the desmosomes (X28,500).

dren and remained untreated for several years. After prolonged systemic steroid therapy, these patients were healed, and five reached normal body size. Investigation of sterility revealed azoospermia. Testicular biopsy was diagnostic for primary hypogonadism in one of these patients.‘jl The relationship between PFE and the histocompatibility antigens (HLA) was studied associaby Patrus,62 who found a significant tion for Bw16 and Aw26, and A24. Patients under two years of age were associated with Bwl6, while older patients were associated with Aw26 and A24. Treatment

There was no effective treatment for fogo selvagem before the availability of systemic

corticosteroids. Left untreated, 26% eventually would be cured, while 40% would die during the first two years, and the remainder would suffer chronically with periodic surges of the disease until death intervened.Ymll Various attempts at topical medication were made. A local treatment program, in which a pitch mixture was applied to the entire body surface, received a certain notoriety. Quinacrine was the first drug to improve the chronic phase of the disease.6X The availability of chemotherapic and antibiotic agents reduced the mortality by controlling the secondary infections that appeared in the acute and chronic phases. The introduction of corticosteroids completely changed the course and prognosis of PFE. Patients with FS respond more quickly and to lower doses of systemic steroids than

Castro et al.

Clinics in Dermatoloav

FIG. 1A (top, left). Lesions in the invasive phase of fovo selvagum in a native Indian patient. (See also Fig. lB, page 23.) FIG. 5A and B (top, center and right). Erythematous scaly lesions on the faces of two young women seen in the initial phase of FS (Senear-Usher syndrome). FIG. 6A and B. Clinical presentation in the invasive phase of FS. The patient in A (center, far left) has the more typical distribution. The patient in B (center, left) has lesions present in a photo-induced distribution. FIG. 7. Clinical presentation of FS during the steady state phase of the disease. The lesions in 7A (center, right) are typical of the bullo-exfoliative variety. The patients in 78 (center, far right) and 7C (bottom, left) have features of the erythrodermic variety of the steady state. The lesions of the face of the child in 70 (bottom, right) and the dorsum of the hand in 7E (page 29) have features of the papillomatous variety of the steady state.

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Pemphigus

35

FIG. 8 (top, leftandright). The anterior (A, left) and posterior(B, right) view of an adult man with FS who is in the regression stage of the disease. FIG. 9 (center, left). Clinical features of extreme cachexia seen in a patient due to chronic illness and poor health care. Such cases were frequently seen in the presteroid era. FIG. 10A and 6. Histopathologic features of PFE. Hematoxylin and eosin stains on biopsy of early lesions. A (center. right) demonstrates an intraepidermal cleft with acantholysis in the superficial malphighian granular layer. B (bottom, left) shows detachment of the superficial epidermis with acantholysis observed at the floor of the of the intracellular cement substance with goat bullae. FIG. 11 (bottom, right). Indirect immunofluorescence anti-human IgG and patient serum.

36

Castro et al.

Clinics in Dermatology

FIG. 13 (top, left). Nanismus. Two children afflicted with FS. The 5year-old on the left has FS of threemonths duration. The shorter boy on the right is 8 years old. He was afflicted with FS at the age of 1% years. Note the significant growth retardation. FIG. 14 A-D. Effect of systemic corticosteroid therapy. A (top, center) demonstrates anterior view of a patient prior to therapy. 6 (top, right) illustrates the posterior view prior to therapy. C and D (bottom left and center) shows the anterior and posterior view (respectively) of the same patient exhibiting dramatic improvement and significant clearing of the lesions. FIG. 15 (bottom right). Effect of intralesional steroid injection for local persistent lesions. The FS lesions were similar on both sides of the face. Note significant clearing of the lesions on the right side after intralesional steroid injections. The left side was not injected.

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PFC or pemphigus vulgaris patients. All preparations of systemic corticosteroids are effective, but the best results are obtained with oral triamcinolone (Fig. 14).64 The following guidelines have been established: (1) the initial dose for an average case is 1.0 mg/kg/day of oral triamcinolone. Once control of the disease is achieved, the dose is gradually reduced to about 0.2 mg/kg/day. This dose is given on alternate days and then only every third or fourth day. The drug is discontinued only after the patient has been without signs of the disease for at least one year. (2) In more severe or unresponsive cases, the initial dose of oral triamcinolone is increased to 1.5 mg/kg/day and reduced as previously discussed. (3) In less severe cases, 0.5 mg/kg/day of oral triamcinolone is used as the initial treatment dose. (4) The initial oral dose of triamcinolone for children is 1.0-2.0 mg/kg/day, according to the clinical severity, and reduced as discussed. (5) Localized recurrent or resistant lesions should not be treated by increasing the dose but rather by intralesional triamcinolone injections(Fig. 15). (6) Recurrences should be treated with an initial dose in accordance to the clinical severity. (7) Prednisone is the next choice, but slightly higher doses than the usual equivalents should be used since it is less effective. Immunosuppressors are not routinely used in PFE because response to corticosteroids is usually satisfactory. Exceptionally resistant

TABLE

PemDhiaus

37

cases requiring high doses of steroids for a long period may merit a trial with immunosuppressors. Methotrexate was used in conjunction with triamcinolone in eight patients.65 Five did not improve, two improved slightly, and one died of bronchial pneumonia. Azathioprine, cyclophosphamide, gold, and sulfones have been used in resistant forms, but results have not been conclusive. The side effects of systemic corticosteroids in 141 patients were studied by Auad et al.68 All patients gained weight. Only five patients that had normal glucose levels prior to treatment developed increased serum glucose levels. Serum sodium and potassium or blood pressure levels did not change significantly during treatment. Osteoporosis is quite common. The remaining side effects are summarized in Table 6. Other complications may arise due to the immunosuppressive effect of either the disease and,‘or the treatment.““,“~,;‘l~~l Sc\el.e forms of Kaposi’s varicelliform eruption \varts. dermatophytes. and scabie?+ (Figs. lfA-D and 17) are frequent skin complications. Mortality has dropped to minimal levels since FS has been treated with steroids. Most deaths occur in the acute invasive phase and in severe cases where the treatment was delayed or in patients who developed secondary infections. A recent seriesof eight autopsies of chronic resistant cases treated

6. Side Effects of Systemic Steroids*

Side Effects

Betamethasone (66 patients) No. (“/a)

Gastralgia Arthalgia Myalgia Insomnia Psychic changes

38 14 10 16 1

(57.5) (21.2) (15.1) (24.2) (1.5)

Cushingoid features (hirsutism, acne, straia, moon face)

41 (62.1)

Prednisolone (47 patients) No. (%) 17 6 4 6

(36.1) (12.7) (8.5) (12.7)

Triamcinolone (28 patients) No. (%) 15 4 5 5

(50) (142) (17.8) (17.8)

1(21)

1(35)

23 (48.9)

7 (25)

*Total number of patients studied = 141; effects studied after 90 days of treatment

38

Clinics in

Castro et al.

Dermatoloav

FIG. 16A-D. Complication of disease and/or therapy in patients with PFE. A (top, left) scabies affecting the extremities and groin. B and C (top, right and center, left) Kaposi’s varicelliform eruption in a child and young adult. D (center, right) dermatophytosis on the forearm and abdomen. FIG.17(bottom). Multiple warts on the face of a young woman.

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with corticosteroids has shown the major causes of death to be disseminated strongyloidiasis and septicemia.‘2 Upon control of initial disease and careful monitoring of systemic steroid dose and clinical recovery, complete regression occurs in most cases. A smail maintenance dose of systemic steroids may be required in some patients. About 95% of the patients with FS remain in remission without any subsequent systemtic

Pemphigus

39

10. Vieira JP. Patologia das impressoes digitais. Rio de Janeiro:

Atheneu,

1943.

11. Vieira JP. Pemphigus foliaceus (fogo selvagem): endemic disease of the state of Sao Paulo. Arch Dermatol Syphilol. 1940:41: 85863. 12. Auad A, Castro RM. Fraga S, Rassi D. Rivitti E, Sampaio SAP. The treatment of Brazilian pemphigus foliaceus. Int J Dermatol. 1979:9: 130-6.

therapy."4,J'

13. Matta A. Da fogo selvagem ou pemphigo ceo. Amazonas Med. 1941;5:5-22.

Acknowledaments

14. Talhari S, Fernandes G. Alecrim WD. Penfigo foliaceo sul americano no Estado do Amazonas. Ann Bras. Dermatol. 1975:50:49-52.

The authors acknowledge Rubens Brando, M.D., A. F. Martins Castro, M.D., Mario Fonzari, M.D., Sebastio Armond, M.D., Miriam Soto, M.D., Herbert Lieske, M.D., and the Archives of the Pemphigus Hospital, Sao Paulo, Brazil provided some of the photographs. References 1. Sauvages

FB, de-Apud von Hebra F, Kaposi M. Lehrbuch der hautkrankheiten. Erlangen: Enke. 1874:659.

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E, Silva J. Que podera ser “pemhigus brasiliensis”de Sauvages? Ann Bras Dermatol Sif. 1948:2X273-9.

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A. Pemphigus chronique general; forme rare de pemphigus foliate; mort; autopsie; alteration du foie. Ann Mal Cutan Syphilol. 1844;1:208-10.

folia-

15. Proenca NG. Castro RM. Geografia medica do penfigo foliaceo sulamericano. Ann Bras Dermatol. 1971:46:253-60. 16. Pupo JA. Aspectos originais do penfigo foliaceo no Brasil. Ann Bras Dermatol. 1971:46: 56-60. 17. Jaimovich L, Mazzini RH. Penfigoverdadeiro en integrantes de una misma familia. Dermatol Ibero-Lat Am. 1971;12:365-71. 18. Jaimovich L. El penfigo foliaceo en Argantina. Apresentado no Radla 6”. Rio de .Janeiro. 1981. 19. Heimgartner E. Heimgartner V. Experienicas en la selva Peruana: leishmaniasis tegumen y penfigo foliaceo brasileno. Med Cutan Ibero-Lat Am. 1976;4:1-6. Med Cutan Ibero-Lat Am. 1976;4:1-6. 20. Hernandez-Perez E. Los penfigos. Analisis 28 cases. Dermatologia 1971:17:46-59. 21. Lomholt G. Dermatology Dermatol. 1972:11:156-67.

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22. Sevadjian C. Nosologyof Brazilian pemphigus foliaceus. Int J Dermatol. 1979:18:781-6. 23. Mourao BM. 0 papel do estreptococo figo foliaceo. Mem Inst Butantan. 141-285.

no pen1943:17:

24. Cisalpino EO. Furtado TA. Cardoso JP. Investigacoes sobre anti-estreptolisina “0” no penfigo foliaceo. Hosp. 1960;58:91-7. 25. Rivitti EA. Electroforese, immunoeletroforese, antiestreptolisina “0” e anticorpos antiepitelio, no penfigo foliaceo su americano. Estudo evolutivo. Tese Faculdadede Medicina da Universidade de Sao Paula, Sao Paula, 1972. 26. Furtado TA. Histopathology foliaceus AMA Arch Dermatol. 27. Ferri

RG. Castro

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SAP. Electrophoretic and immunoelectrophoretic study of the South American pemphigus foliaceus. Rev Inst Trop S Paulo. 1970;12:388-94. 28. Lindenberg A. Quelques recherches tendant a etablir l’etiologie du pemphigus et du psoriasis. Bull Sot Franc Dermatol Syphilol. 1937;44:1956-61.

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International Congress of Aging and Ambiental Factors. Ancona, Italy, 1982. 42. Castro RM, Chorzelski TD, Jablonska S, Marquart F. Antiepithelial antibodies in healthy people living in endemic areas of South American pemphigus foliaceus. Castellania. 1976; 4:111-2.

29. Crosti A, Bellone AG, Gianotti

43. Proenca NG. Pemphigus drome de Senear-Usher). Lat Am. 1974;4:291-8.

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44. Proenca NG. Proenca YM. Guedes M. Gravidez em doentes corn penfigo foliaceo sul-Americano (fogo selvagem). Ann Bras Dermatol. 1979;54:239-44.

F. Isolation of a single pathogenic virus from patients of the pemphigus group. (Preliminary note). G Ital Dermatol Sifilol. 1959;100:229-42.

EH, Prigenzi LA, Hale W, Leme CA, Bier OG. Immuno-fluorescent studies of autoantibodies to intercellular areasof epithelia in Brazilian pemphigus foliaceus. Proc Sot Exp Biol Med. 1968;127:81-6.

31. Wood VW, Beutner

TH, Chorzelski TD. Studies on immunopathology II. Production of pemphigus like lesions by intradermal injection of monkeys with Brazilian pemphigus foliaceus sera. Int Arch Allergy. 1972;42:456.

32. Beutner

E, Wood GW, Chorzelski TD, Leme CA, Bier OG. Producao de lesoes semelhantes as do penfigo foliaceo pela injecao intradermica, em coelhos e macacos, de soros de doentes corn titulo elevado de autoanticorpo. Mem Inst Butanta. 1971;35:79-94.

33. Mendes

E, Castro RM. Autoimmunity in patients with pemphigus foliaceus. Acta Allerg. 1976;31:275-82.

34. Castro RM, Proenca

phigus foliaceus.

N. South American Glaxo. 1973;36:17-30.

pem-

35. Castro

RM, Proenca NP. Aber uhnlichkeiten and unterschiede zwischen dem Brasilianischen “fog0 selvagem” und dem pemphigus foliaceus Cazenave. Hautarzt. 1982;33:574-7.

11

45. Alayon FL. Contribuicao para o estudo dopenfigo foliaceo (fogo selvagem) no Brasil. Rev Med Cirurg S Paulo. 1948;8:13-93. TA. Histopathology of pemphigus 46. Furtado foliaceus. Arch Dermatol. 1959;80:66-71. 47. Wilgram GF, Cawfield JB, Madgic EB. An electron microscopic study of acantholysis and diskeratosis in pemphigus foliaceus. J Invest Dermatol. 1964;43:287. 48. Sotto MN, Shimizu H, Costa JM, Brito T. South American pemphigus foliaceus: electron microscopy and immunoelectron localization of bound immuno-globulin in the skin and mucosa. Br J Dermatol. 1980;102:521-7. ao estudo da ultra 49. Marcucci G. Contribuicao estrutura da mucosa oral em doentes de penfigo foliaceo brasileiro. Tese Faculdade de Odontologia da Universidade de Sao Paulo. Sao Paulo, 1978. 5. Furtado TA, Lima AE, Andrade GO, Seabra 0. Antibodies in pemphigus foliaceus. In: Congressus internationalis dermatologieae, 13”, Munich, 1967 Proceedings. Munich, 1967: 1159.

36. Castro

RM, Proenca N, Cardoso AEC, Sampaio SAP. Endemic trichophytosis in pemphigus foliaceus patients. Mykosen 1970;13:273-5.

37. Proenca

NG, Castro RM. Penfigo foliaceo sulamericano. Rev Hosp Clin Fat Med S Paulo. 1971;26:115-22.

38. Proenca

NG. Declinio do penfigo foliaceo em Sao Paulo. Rev Paul Med. 1977;89:97-100.

39. Minelli

L. Geografia medica do penfigo foliaceo sul-americano no Parana. Ann Bras Dermatol. 1976;51:173-91.

40. Proenca

NG, Ribeiro AG. Aspectos epidemiologos do penfigo foliaceo no Brasil. Rev Ass Med Bras. 1976:22:281-4.

41. Leme LEG, Leme CA, Serro-Azul

LG, Giannini SD, Forti NA, Diament J. Brazilian pemphigus in old people. Presented to the

erythematosus (sinMed Cutan Ibero-

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Proenca NG, Rivitti EA. Antiepithelial antibodies in Brazilian pemphigus foliaceus. Int J Dermatol. 1977;16:799-806.

52. Odo MEY, Rodriaues RL, Miyauchi L. Immunofluorescencia direta em biopsia de pele no penfigo foliaceo. Ann Bras Dermatol. 1981;56: 131-4. 53. Chorzelski

TD, et al. Immunopathologycal investigations in the Senear-Usher syndrome (coexistence of pemphigus and lupus erythematosus) Br J Dermatol. 1968;80:211-7.

54. Jablonska S, et al. Pathogenesis erythematosus. Arch Dermatol 135-40. 55. Bystryn

JC, et al. Absence

of pemphigus Res.1977;258: of intercellular

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antigen in the deep layers of the epidermis in pemphigus foliaceus. J Clin Invest 1978: 61339-48.

41

65. Rivitti EA, Camargo ME, Castro RM, Sampaio SAP. Use of methotrexate to treat pemphigus foliaceus. Int J Dermatol. 1973:12:119-22.

56. Bystrin JC. Abel E, De Feo C. Pemphigus foliaceus: subcorneal intercellular antibodies of unique specificity. Arch Dermatol. 1974;llO: 857-61.

66. Castro RM, Proenca N, Salles-Gomes LD. On the association of some dermatoses with South American pemphigus foliaceus. Int .J Dermatol. 1974;13:271-5.

57. Zilberberg B. Penfigo e dermatite de DuhringBrocq. Contribuicao para o estudo histologico. Arq Dermatol. Sifilol. S. Paula 1955;16:430.

67. Magaldi-Jordao F, Salles-Games LD, Rabello SI. Amorosino A, Angulo JJ. Outbreaks of vaccinia in a pemphigus foliaceus hospital. Arch Dermatol. 1962:85:533.

58. Takahashi MDF. Immunopathologia do penfigo foliaceo sul americano. Estudo por imunofluorescencia direta e imuno fluorescencia direta e immunofluorescencia inderta. TeseFaculda de de Medicina da Universidade de Sao Paulo. Sao Paulo, 1981. 59. Konrad K, String1 G, Holubar K. Ultrastructural localization of in vivo bound immunoglobulin in epidermis of Brazilian pemphigus foliaceus. Br J Dermatol. 1977;96:449-51. 60. Guimaraes JRA. Penfigo foliaceo (fog0 selvagem) e nanisomia. Arch Dermatol Sifilol S Paulo. 1941:5:21-51. 61. Proenca NC;. Moraes X, Neto MP, Prosper0 JD. Azoospermia resultante do penfigo foliaceo sul-americano. A proposito do estudo de urn doente. Rev Inst Med Trop S Paula. 1978; 20:307-l 1. 62. Patrus ORA. Antigenos de histocompatibilidade imunoceomplexos e complemento no penfigo foliaceo. Tese Faculdade de Medicina da Universidade Federal de Minas Gerais. Minas Gerais, 1980. 63. Fonzari M. Apontamentos a terapeutica penfigo foliaceo. Hosp. 1960:57:275-83.

do

64. Reis AP. Guerra HA, Guerra MVN. Linfocitos T e B em penfigo foliaceo sul-americano. Rev Assoc Med Bras. 1976;22:285-8.

Address Paulista Brazil.

68. Auad A. Penfigo foliaceo sul-americano em Goias. Tese Faculdade de Medicina da IJniversidade Federal de Goias. Goiania. 1971. 69

Basset A. Pathologie cutanee de la face noire. Encyclopedic Medico-Chirurgiale. Paris: Flammarion, 1967.

70 Proenca NG, Castro RM. Rivitti EA, SallesGomes LF. Erupcao variceliforme de Kaposi por herpesvirus hominis em doentes de penfigo foliaceo sul-americano. Estudo de 19 doentes. Dermatol Ibero-Am. 1972:14:443-73. 71. Salle+Gomez LS, Rabello SI. Magaldi-Jordao R. Pederneira CAA, Amorosin A. Angulo Jd. Generalized vaccinia in patients with pemphigus foliaceus. Post Grad Med .J. 196339: 86-90. 72. Aki HE, Sotto MN, Sampaio SAP. Penfigos: complicacoesassociadas a terapeutica. Relvisao de necropsias. In: Congress0 brasileiro de dermatologia, 27”. Salvador:Bahia. 1981. 73. Barros C. Ultraestruturada lesao bolhosae do sinal de Nikolsky no penfiao foliaceo. Tese Faculdade de Medicina da.Universidade de Sao Paulo. Sao Paula, 1972. 74.Castro AFM, Fonzari M. Penfigo foliaceoe verrugas. Arch Dermatol Sifilol S Paulo. 1952:15: 9-17.

for correspondence: Raymundo M. Castro, M.D., Department of Dermatology, Escola de Medicina, Faculdade de Medicina da Universidade de Sao Paula, Sao Paulo,