Review
NOSOLOGY OF BRAZILIAN PEMPHIGUS FOLIACEUS CHARLES SeVADIIAN. M.D.
From ihf Department ol Dermatology, Baylor College ot Mvdicir^e. Houston, Texas
Brazilian pemphigus foliaceus (BPF) has attracted much attention for its unique place among (he pemphigus group of bullous diseases. Its high incidence and geographic distribution seem to set it apart from European and North American pemphigus foliaceus (NAPF); yet it is still uncertain whether Brazilian pemphigus foliaceus and North American pemphigus foliaceus represent separate entities or the same disease.'
localized or diffuse, and the clinical classification proposed by C. A. Leme'^ (Table 1) reflects the same broad range of clinical settings described for NAPF.** The histopathology of BPF is characterized by subcorneal acantholytic bullae indistinguishable from NAPF. Further evidence for the identity of BPF and NAPF is provided by immunofluorescence studies of the two diseases. Beutner et al., in 1964, demonstrated intercellular immunoglobulin deposition with indirect immunofluorescence (IIF) using the sera of eight pemphigus vulgaris patients.' The significance and accuracy of this test were already confirmed**''* lor NAPF when Furtado et al., presented the first IIF data on BPF at the XIII International Congress of Dermatology in 1967, showing 100% positive results in patients with active disease.'" As in NAPF, the extent of the disease correlated with the antibody titers. More recent studies indicate that in NAPF," in contrast to pemphigus vulgaris, antibodies may preferentially localize to the uppermost stratum malphigii.
History Ca/enave first described pemphigus foliaceus in France in 1844.^ Fogo selvagem ("wild fire") was an early Brazilian slang for a familiar .ind often devastating skin disease, but it was not until 1905 thatCandidoTeixeira suggested that fogo selvagem was a form of pemphigus foliaceus.^ In the exchange of ideas that has followed, a well-established clinical picture of the two diseases has emerged, offering compelling evidence for their physical, histologic and immunologic identity. Clinical and Laboratory Features In the Brazilian literature,'* patients with fogo selvagem are described as having superficial erosions, crusts and occasional llaccid bullae on the upper back, trunk and proximal extremities. The mucous membranes are spared and Nikolsky's sign is often positive. The disease may be aggressive or benign.
Other laboratory tests do not reveal any consistent differences between NAPF and BPF. Reports"*-'^"'^ of a high incidence of nanism, endocrine disturbances, dwarfism.
0011-9059/79/1200/0781 ,'$00.80© Inlemdtional Society of Tropic =il Derm-stoiouy, Inc.
781
782
INTERNATIONAL lOURNAL OF DERMATOLOGY
Table 1.
Claisification
of South American
December 1979
Vol. 18
Pemp/iigus Foliaceus*
LOCALIZED - SENEAR-USHER (PE) FORM FRUSTE OR BENIGN DISSEMINATED
PEMPHIGUS iOLIACtUS
ACUTL ERYTHRODERMIC
GENERALIZED OR MALIGNANT
PROGRESSIVE TYPICAL CHRONIC
REGRESSIVE HERPETIFORM RESISTANT HVPERKERATOTIC PAPILLOMATOUS HYPERPIGMENTED
Adapted from reference 17.
osteoporobis ^md breast atrophy in BPF are often inadequalelvdocLitnentetl and probably relate to the age of onset and the degree of chronic debility. Elevated serum copper"* and anti'Streptolysin titers'^' "* have been reported in some BPF patients, but these have not yet been thoroughly investigated; there are no comparable series in the NAPF literature. Finally, the increased association ot' F-iLA-A10 histocompatibility antigen in NAPF"*-^" has not been studied in the Brazilian variety. Clinical Course Some debate also surrounds the clinical course of BPF, with case descriptions often giving the impression of a more severe disease than NAPF.' In Lever's series of 30 nonsteroid-treated North American pemphigus foliaceus patients, the rate of spontaneous remission was 23%."^ Three reports on BPF give the comparable figures of 19 to 26%.'^•^^•^••^ The mortality rate in Lever's patients related strongly to age (14% in patients under 50 years of age, but 100% in patients over 50), and that in non-steroid-treated BPF
was 29 to 43%.^'"'^^ In both types of pemphigus foliaceus, steroids are highly effective in controlling the disease and reducing mortality. Epidemiology Pemphigus foliaceus is at least five times as prevalent in Brazil as it is in North America. While the exact incidence ot NAPF is not known and no large-scale epidemiologic studies have been published, a reasonable estimate may be derived from the incidence of pemphigus vulgaris (approximately 1.1 x lO"'')-''divided by the ratio of pemphigus vulgaris to pemphigus foiiaceus in unselected large series such as Lever's summary of pemphigus cases seen at Massachusetts General Hospital between 1937 and 1949 (36 pemphigus vulgaris cases: 32 pemphigus toliaceus cases)."^ This (approximately 1 x 10"**) compares with an estimated 600 to 700 cases of PF in Brazil per year or an incidence of 4.6-6.4 X 10-*^. The endemic nature of BPF is striking when the incidence is considered by geographic
No. 10
BRAZILIAN PEMPHIGUS FOLIACEUS
location. A nationwide, carefully designed epidemiologic study by Proen^a and Ribeiro--" in 1976 gives the number of cases ot' pemphigus foliaceus over a twelve-month period in each of Brazil's 26 states. The highest incidence by state reaches approximately 50 X 10"^ in Goias, with the greatest concentration of cases occurring in rural communities of the central woodlands. Many investigators have observed a decreasing incidence in areas of advancing urbanization and industrialization and an increasing incidence in newly settled territories," This phenomenon is evidenced by the great decline in the number of cases in Sao Paulo, where the hlospital Adhemar de Barros was built in 1940 strictly for the care of BPF patients, and by the growing incidence of cases in Goias and MinasGerais,^''wherea large influx of settlers is occurring. Vieira" speculates that an exogenous factor such as an insect-vectored
783
Sevari/ian
virus could account for the geographic distribution of BPF; he suggests the planaltoborrachudo (Simulium pruinosum), a biting fly, as a likely vector because its habitat corresponds to the distribution of BPF cases and because other members of the genus are known vectors of onchocerciasis.^'* There is no other evidence supporting this theory. In the English literature, data on the geographic distribution of NAPF are lacking, and ihe unproven assumption has been that it is uniform across North America. Thus, like many other skin disorders, NAPF still awaits a detailed epidemiologic profile. Age, Sex and Racial Incidence
BPF is primarily a disease of adolescents and young adults. This long-established view was reaffirmed by the study of Proen^a and Ribeiro,-' who cite 464 new cases registered
0 Age in years FJfi, I. A(ie-Jn< idence in BPF, Adapted Inini References J4 and 2^5, Number of ( ases iif SAPF-' population by af>r,-'' Mean A^V— 51) years.
perccnl
INTERNATIONAL lOURNAL (5F DERMATOLOGY
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to
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0)
1 30,
784
iJ
(0 0)
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December 1979
Vol, 18
during the period from June 1, 1973 to May 31, 1974, Figure 1 shows the age incidence of BPF in the study and the percentage of population by age in Brazil, There is an obvious peak risk at ages 16 to 18 and an equally significant low risk in childhood. Two hundred of the 464 patients (43%) are under 25 years of age. There is no comparable study in the English literature; the largest is a series from the Mayo Clinic which summarizes 74 cases of NAPF (including pemphigus erythematosus) seen between 1919 and 1963.^^'^" Figure 2 demonstrates that NAPF affects mainly middle-aged adults with no predilection for adolescents (90% of patients are over 25 years old). The incidence by sex of BPF was originally reported to be about 2:1 female to male'"; however, more recently investigators report the incidence to be about equal,^' and the Mayo series shows no notable difference in NAPF (54% female to 46% male). The racial distribution of BPF cases is diffuse; it affects both indigenous natives and European and African immigrants. The notable exceptions are Orientals who populate the rural farmlands in large numbers and rarely seem to be affected. None of the 464 patients in the Proen^a and Ribeiro series was Oriental, and in two other series totaling 4,713 BPF cases, only 38 were Oriental.^^ The English literature alludes to a predilection among Jews for pemphigus foliaceus, although not as strong as for pemphigus vulgaris.^
CM Heredity The Brazilian literature suggests that familial cases of BPF are common.^^-^^ A 10% incidence is generally thought to occur.^^ According to Proen^a, 55 of 464 patients (11%) reported that other family members were affected with the same disease, in all but two of these 55 cases, the family members were blood relatives. In contrast, the English literature offers but a single example of the familial occurrence of NAPF (a father and son in Galveston).^'
No. 10
BRAZILIAN PEMPHICU5 EOLIACEUS
Origin Metabolic, biochemical, viral and autoimmune theories have been advanced to explain the pathogenesis of pemphigus vulgaris and pemphigus foliaceus. None has been fully acceptable, and they are well reviewed elsewhere.*^ The Brazilian literature emphasizes the viral concept of pathogenesis but recognizes that no infectious agent has been reproducibly isolated from BPF patients.^^•''^ Regarding the insect-vectored virus proposed by Vieira, serum antibodies to known arboviruses have not supported their rote in the disease.^^ A recent report of interest indicates that serum copper levels are elevated in BPF and that d-penicillamine therapy in ten patients was accompanied by clinical mprovement and lowering of the serum copper.'^ Although penicillamine is implicated as a cause of some cases of pemphigus foliaceus,••'^ this finding, if confirmed, should generate renewed interest in the role of trace metals in this disease, particularly in view of our new understanding of acrodermatitis enteropathica.
Sevadiian
785
pathogenesis of BPF,'^ and the commonly held view is that an unidentified virus, probably insect-vectored, alters tissue antigenicity and provokes autoantibody formation. It is difficult to reconcile every feature peculiar to BPF with the hypothesis that NAPF and BPF are the same disease. Differences in the genome between Brazil and North America should not account for the geographic concentrations of BPE and its peak incidence in adolescence. Yet the physical, histologic and immunologic features, as well as the natural history and therapeutic response of BPF, are for all practical purposes identical to NAPF. This suggests (analogous to erythema multiforme) that pemphigus foliaceus is a syndrome in which an identical clinical presentation may be evoked by varying stimuli, thus affecting separate subsets of the population in different environmental settings. The idea that several pathogenetic mechanisms may lead to the pemphigus foliaceus syndrome is compatible with what is known of the two diseases and accommodates the two major conceptions of pemphigus foliaceus. Perhaps future studies Interpreted in light of this possibility will yield a more precise understanding of pemphigus foliaceus.
In the English literature, most recent studies cn the pathogenesis of NAPF deal with the autoimmune theory;^^'''''-'''* however, the etiologic significance of pemphigus antibodies has not been established and the list of non-pemphigus conditions in which they have been found is increasing.^^ This has led Kreysel and Memmesheimer to conclude that the autoimmune concept of blister formation in pemphigus Is dubious.^^
Acknowledgment
Conclusion
The author acknowledges the contribution to this artit l e of Weslwood Pharmateuticalb, Buffalo, New York,
Current concepts of the nature of NAPF and BPF are largely speculative. Perhaps the predominant view of the pathogenesis of NAPF is that hereditary and immunologic factors dtjtermine a predisposition to the formation o' disease-causing autoantibodies (to altered or normal intercellular antigen or crossreacting with the same). Among Brazilian authorities there is a strong belief that exogenous factors are involved in the
Drug Name d-penicilljmine: Cuprimine
References 1, Ramos e Silva, ],: Ideias gerais sobre o pent'igo SulAmericano: seu historico no Brazil conteitua^ao iitual do grupo penfigo. Rev, Bras, Med, 2(5:611, 1971, 2, Cazenave, P.: Pemphigus (hronique general: forme rare du pemphigus foliace, Ann. Mai. Peau 1:208, 18443. Pupo, |. de Aguiar: Aspectos originais do penfigo folijceo no Brasil. Ann, Bras, Dermatol. 46:53. 1971,
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INTERNATIONAL lOURNAL OF DERMATOLOGY
4. Vieira, ]., Fonzari, M,, and Goldman, L-: Some recent studies in Brazilian pemphigus. Am, |. Trop. Med, 3:868, 1954. 5. Leme, C. A.: Penfigo foliaceo: ctiopatogenia, sintomatologia e diagnostico. O Hospital 65:201, 1964. 6. Lever, W. F.: Pemphigus and Pemphigoid. Springfield, Charles C Thomas, 1965. 7. Bcutner, E. H., and lordon, R. E.: Demonstration of skin antibodies in sera of pemphigus vulgaris patients hy immunofluorescent staining. Proc. Soc. Exp, Biol. Med. 117:505, 1964. 8. Kano, K., Beutner, E. H,, and Milgrnm, F.: Humoral antibodies in sera of patients with bullnus skin diseases. Proc. Soc. Exp. Biol. Med, 127:355, 1978, 9. Peck, M, D., Osserman, K. E., Weiner, L. B., Lefkovits. A,, and Osserman, R. S.: Studies in hullous diseases. Immunofluorescenl serologic tests. N. fcngl. i. Med. 279:951, 1968. 10. Proen(,a, N. G., and Rivitti, E.: Antiepithelial antibodies in Brazilian pemphigus foliaceus. Inl. |. Dermatol. 16:799. 1977, 11. Byslryn, |-C., Abel, E,, and DeFeo, C: Pemphigus toliaceiis subcorneal interceullar antibodies of unique specificity. Arch. Dermatol. 110:857, 1974. 12. Proenga, N. G,, et al.: Azoospermia caused by South American pemphigus foliaceus. Apropos of a case study. Rev. Inst. Med. Trop. Sao Paulo 20: i()7, 1978. 13. Rezendc, S. T.: Pendgo foliaceo. Rev. Bras. Med. 24:61, 1967. 14. Perry, H, O.: Fogo selvagem (Pemphigus foliaceus). In: Clinical Dermatology- Edited by Demis, et al. Hagerstown, Harper & Row, 1977, p. 1. 15- Counter, C. E.: The disease called "wild fire." Arch. Dermatol. 80:391, 1959. 16. Gamarski, |., and Auad, T.: D-penicilamina no pentigo foliaceo Sul-Americano. Rev. Inst, Med, Trop. Sdo Paulo 19:1.58, 1977. 17. Leme, C. A.: Penfigo foliaceo no Brasil—doen^a de auloagressao, O Hospital 76:583, 1969. 18. Rivitti, E. A., Camargo, M. E., Castro, R. M., and Sampaio, S. A. P,: Use ot methotrexate to treat pemphigus foliaceus. Int. |. Dermatol. 12:119, 1973, 19. Krain, L. S., Terasaki, P- 1., Newcomer, V, C, and Mickey, M. R.: Increased frequency of HL-A10 in pemphigus vulgaris. Arch, Dermalol. 108:803, 1973. 20. Hashimoto, K,, Yoshuharu, M., Nakata, S-, and Matsuyama, M.: HLA-AIO in pemphigus among Kipanese. Arch. Dermalol. 1IJ:1518, 1977.
December 1979
Vol. 16
21. Vieira, |. P.: Pemphigus foliaceus (fogo selvagem). Arch. Dermatol. Syphilol. 41:858, 1940, 22. Brown, M. W,: Fogo selvagem (pemphigus foliaceus). AMA Arch. Dermatol. Svphilol. 69:589, 1954. 23. Krain, L. S., and Bierman, S, M,: Pemphigus vulgaris and internal malignancy. Cancer 33:1091, 1974. 24. Proen^a, N. G., and Ribeiro, A. G.: Aspectos epidemiofogicos do penfigo foiiaceo no Brasil. Rev. Assoc. Med, Bras. 22:281, 1976. 25. Ldcaz, C- S., Baruzzi, R. G., and Siqueira, W. )r.Introdu^ao a Geografia Med ica do Brasil, Edited by E. Blucher, Sao Paulo, Universidade de Sao Paulo, 1972, p. 427. 26. Beutner, E. H., Chorzelski, T, P,, and lordon, R. E.: Autosensitization in Pemphigus and Bullous Pemphigoid. Springfield, Charles C Thomas, 1970. 27. Vieira, 1. P.: Algumas pesquisas sobre o "fogo selvagem" no estado de Sao Paulo. Conferencia realizada na Academia Nacional de Medicina, 1941. Bras. Med. 33:561, 1941. 28. Leme C. A.: Penfigo foliaceo brasileiro. Visao atual de sua patogenia em face dos recentes estudos imunologicos. Rev. Assoc. Med. Bras. 19:71, 1973. 29. Perry, H, O.: Pemphigus fotiaceus. Arch. Dermatol. 83:52, 1961. 30. Perry, H, O., and Brunsting, L, A.: Pemphigus foliaceus. Arch. Dermalol. 91:10, 1965. 31. Voelter, W. W., Newell, G. B., Schwartz, S. L., Bean, S. F., and Mullins, |. F.: Familial occurrence of pemphigus foliaceu';. Arch. Dermatol, 108:93, 1973. 32. Angulo, I- ).: Attempts to isolate a virus from pemphigus foliaceuh cases, AMA Arch. Dermatol. Svphilol. 69:472, 1954. 33. Sams, W. M., and lordon, R. E,: Pemphigus antibodies: their role in disease. |. Invest. Dermatol. 56:474, 1971. 34. Beutner, E. H., Chorzelski, T. P,, larzabek, M-, Wood, G., Leme, C. A,, and Bier, O.: Studies in immunodermatology I. Int. Arch. Allergy 42:545, 1972. 35. Tuffant-lli, D. L.: Pemphigus. Clin. Pharm. Ther. 16:974, 1974. 36 Krevsel, H-W., and Memmesheimer, A. R.: is pemphigus an autoimmune disease;' Br. |. Dermatol, 85:519, 1971. 37. Kristensen, |. K., and Wadskov, S.: Penicillammeinduced pemphigus fnliaceus. Acta Derma. Venerol, 57:69. 1977.
G-l Symptoms
Gastroitntestitnal symptoms due to anitbiotic therapy ratnge from mild abdominal discomfort to severe life-threatening colitis. Numerous drugs, including ciindamycin, lincomycin, tetracycline, chloramphenicol, cephalosporin, penicillin, and ampicillin, have been implicated. Ampicillin is associated with change in bowel habits and pseudomembranous colitis (P.M.C.),—Toffler. R. B.. Pingoud, E. G.,and Burrell, M. I.: Acute colitis related to penicillin and penicillin derivatives. Lancet 2:707, 1978.
NOSOLOGY OF BRAZILIAN PEMPHIGUS FOLIACEUS CHARLES SeVADIIAN. M.D.
From ihf Department ol Dermatology, Baylor College ot Mvdicir^e. Houston, Texas
Brazilian pemphigus foliaceus (BPF) has attracted much attention for its unique place among (he pemphigus group of bullous diseases. Its high incidence and geographic distribution seem to set it apart from European and North American pemphigus foliaceus (NAPF); yet it is still uncertain whether Brazilian pemphigus foliaceus and North American pemphigus foliaceus represent separate entities or the same disease.'
localized or diffuse, and the clinical classification proposed by C. A. Leme'^ (Table 1) reflects the same broad range of clinical settings described for NAPF.** The histopathology of BPF is characterized by subcorneal acantholytic bullae indistinguishable from NAPF. Further evidence for the identity of BPF and NAPF is provided by immunofluorescence studies of the two diseases. Beutner et al., in 1964, demonstrated intercellular immunoglobulin deposition with indirect immunofluorescence (IIF) using the sera of eight pemphigus vulgaris patients.' The significance and accuracy of this test were already confirmed**''* lor NAPF when Furtado et al., presented the first IIF data on BPF at the XIII International Congress of Dermatology in 1967, showing 100% positive results in patients with active disease.'" As in NAPF, the extent of the disease correlated with the antibody titers. More recent studies indicate that in NAPF," in contrast to pemphigus vulgaris, antibodies may preferentially localize to the uppermost stratum malphigii.
History Ca/enave first described pemphigus foliaceus in France in 1844.^ Fogo selvagem ("wild fire") was an early Brazilian slang for a familiar .ind often devastating skin disease, but it was not until 1905 thatCandidoTeixeira suggested that fogo selvagem was a form of pemphigus foliaceus.^ In the exchange of ideas that has followed, a well-established clinical picture of the two diseases has emerged, offering compelling evidence for their physical, histologic and immunologic identity. Clinical and Laboratory Features In the Brazilian literature,'* patients with fogo selvagem are described as having superficial erosions, crusts and occasional llaccid bullae on the upper back, trunk and proximal extremities. The mucous membranes are spared and Nikolsky's sign is often positive. The disease may be aggressive or benign.
Other laboratory tests do not reveal any consistent differences between NAPF and BPF. Reports"*-'^"'^ of a high incidence of nanism, endocrine disturbances, dwarfism.
0011-9059/79/1200/0781 ,'$00.80© Inlemdtional Society of Tropic =il Derm-stoiouy, Inc.
781
782
INTERNATIONAL lOURNAL OF DERMATOLOGY
Table 1.
Claisification
of South American
December 1979
Vol. 18
Pemp/iigus Foliaceus*
LOCALIZED - SENEAR-USHER (PE) FORM FRUSTE OR BENIGN DISSEMINATED
PEMPHIGUS iOLIACtUS
ACUTL ERYTHRODERMIC
GENERALIZED OR MALIGNANT
PROGRESSIVE TYPICAL CHRONIC
REGRESSIVE HERPETIFORM RESISTANT HVPERKERATOTIC PAPILLOMATOUS HYPERPIGMENTED
Adapted from reference 17.
osteoporobis ^md breast atrophy in BPF are often inadequalelvdocLitnentetl and probably relate to the age of onset and the degree of chronic debility. Elevated serum copper"* and anti'Streptolysin titers'^' "* have been reported in some BPF patients, but these have not yet been thoroughly investigated; there are no comparable series in the NAPF literature. Finally, the increased association ot' F-iLA-A10 histocompatibility antigen in NAPF"*-^" has not been studied in the Brazilian variety. Clinical Course Some debate also surrounds the clinical course of BPF, with case descriptions often giving the impression of a more severe disease than NAPF.' In Lever's series of 30 nonsteroid-treated North American pemphigus foliaceus patients, the rate of spontaneous remission was 23%."^ Three reports on BPF give the comparable figures of 19 to 26%.'^•^^•^••^ The mortality rate in Lever's patients related strongly to age (14% in patients under 50 years of age, but 100% in patients over 50), and that in non-steroid-treated BPF
was 29 to 43%.^'"'^^ In both types of pemphigus foliaceus, steroids are highly effective in controlling the disease and reducing mortality. Epidemiology Pemphigus foliaceus is at least five times as prevalent in Brazil as it is in North America. While the exact incidence ot NAPF is not known and no large-scale epidemiologic studies have been published, a reasonable estimate may be derived from the incidence of pemphigus vulgaris (approximately 1.1 x lO"'')-''divided by the ratio of pemphigus vulgaris to pemphigus foiiaceus in unselected large series such as Lever's summary of pemphigus cases seen at Massachusetts General Hospital between 1937 and 1949 (36 pemphigus vulgaris cases: 32 pemphigus toliaceus cases)."^ This (approximately 1 x 10"**) compares with an estimated 600 to 700 cases of PF in Brazil per year or an incidence of 4.6-6.4 X 10-*^. The endemic nature of BPF is striking when the incidence is considered by geographic
No. 10
BRAZILIAN PEMPHIGUS FOLIACEUS
location. A nationwide, carefully designed epidemiologic study by Proen^a and Ribeiro--" in 1976 gives the number of cases ot' pemphigus foliaceus over a twelve-month period in each of Brazil's 26 states. The highest incidence by state reaches approximately 50 X 10"^ in Goias, with the greatest concentration of cases occurring in rural communities of the central woodlands. Many investigators have observed a decreasing incidence in areas of advancing urbanization and industrialization and an increasing incidence in newly settled territories," This phenomenon is evidenced by the great decline in the number of cases in Sao Paulo, where the hlospital Adhemar de Barros was built in 1940 strictly for the care of BPF patients, and by the growing incidence of cases in Goias and MinasGerais,^''wherea large influx of settlers is occurring. Vieira" speculates that an exogenous factor such as an insect-vectored
783
Sevari/ian
virus could account for the geographic distribution of BPF; he suggests the planaltoborrachudo (Simulium pruinosum), a biting fly, as a likely vector because its habitat corresponds to the distribution of BPF cases and because other members of the genus are known vectors of onchocerciasis.^'* There is no other evidence supporting this theory. In the English literature, data on the geographic distribution of NAPF are lacking, and ihe unproven assumption has been that it is uniform across North America. Thus, like many other skin disorders, NAPF still awaits a detailed epidemiologic profile. Age, Sex and Racial Incidence
BPF is primarily a disease of adolescents and young adults. This long-established view was reaffirmed by the study of Proen^a and Ribeiro,-' who cite 464 new cases registered
0 Age in years FJfi, I. A(ie-Jn< idence in BPF, Adapted Inini References J4 and 2^5, Number of ( ases iif SAPF-' population by af>r,-'' Mean A^V— 51) years.
perccnl
INTERNATIONAL lOURNAL (5F DERMATOLOGY
o 00 00 00
•o
o
Si u
CO
E OJ LL.
o
to
o
0)
1 30,
784
iJ
(0 0)
0)
o CO
o
c fN
December 1979
Vol, 18
during the period from June 1, 1973 to May 31, 1974, Figure 1 shows the age incidence of BPF in the study and the percentage of population by age in Brazil, There is an obvious peak risk at ages 16 to 18 and an equally significant low risk in childhood. Two hundred of the 464 patients (43%) are under 25 years of age. There is no comparable study in the English literature; the largest is a series from the Mayo Clinic which summarizes 74 cases of NAPF (including pemphigus erythematosus) seen between 1919 and 1963.^^'^" Figure 2 demonstrates that NAPF affects mainly middle-aged adults with no predilection for adolescents (90% of patients are over 25 years old). The incidence by sex of BPF was originally reported to be about 2:1 female to male'"; however, more recently investigators report the incidence to be about equal,^' and the Mayo series shows no notable difference in NAPF (54% female to 46% male). The racial distribution of BPF cases is diffuse; it affects both indigenous natives and European and African immigrants. The notable exceptions are Orientals who populate the rural farmlands in large numbers and rarely seem to be affected. None of the 464 patients in the Proen^a and Ribeiro series was Oriental, and in two other series totaling 4,713 BPF cases, only 38 were Oriental.^^ The English literature alludes to a predilection among Jews for pemphigus foliaceus, although not as strong as for pemphigus vulgaris.^
CM Heredity The Brazilian literature suggests that familial cases of BPF are common.^^-^^ A 10% incidence is generally thought to occur.^^ According to Proen^a, 55 of 464 patients (11%) reported that other family members were affected with the same disease, in all but two of these 55 cases, the family members were blood relatives. In contrast, the English literature offers but a single example of the familial occurrence of NAPF (a father and son in Galveston).^'
No. 10
BRAZILIAN PEMPHICU5 EOLIACEUS
Origin Metabolic, biochemical, viral and autoimmune theories have been advanced to explain the pathogenesis of pemphigus vulgaris and pemphigus foliaceus. None has been fully acceptable, and they are well reviewed elsewhere.*^ The Brazilian literature emphasizes the viral concept of pathogenesis but recognizes that no infectious agent has been reproducibly isolated from BPF patients.^^•''^ Regarding the insect-vectored virus proposed by Vieira, serum antibodies to known arboviruses have not supported their rote in the disease.^^ A recent report of interest indicates that serum copper levels are elevated in BPF and that d-penicillamine therapy in ten patients was accompanied by clinical mprovement and lowering of the serum copper.'^ Although penicillamine is implicated as a cause of some cases of pemphigus foliaceus,••'^ this finding, if confirmed, should generate renewed interest in the role of trace metals in this disease, particularly in view of our new understanding of acrodermatitis enteropathica.
Sevadiian
785
pathogenesis of BPF,'^ and the commonly held view is that an unidentified virus, probably insect-vectored, alters tissue antigenicity and provokes autoantibody formation. It is difficult to reconcile every feature peculiar to BPF with the hypothesis that NAPF and BPF are the same disease. Differences in the genome between Brazil and North America should not account for the geographic concentrations of BPE and its peak incidence in adolescence. Yet the physical, histologic and immunologic features, as well as the natural history and therapeutic response of BPF, are for all practical purposes identical to NAPF. This suggests (analogous to erythema multiforme) that pemphigus foliaceus is a syndrome in which an identical clinical presentation may be evoked by varying stimuli, thus affecting separate subsets of the population in different environmental settings. The idea that several pathogenetic mechanisms may lead to the pemphigus foliaceus syndrome is compatible with what is known of the two diseases and accommodates the two major conceptions of pemphigus foliaceus. Perhaps future studies Interpreted in light of this possibility will yield a more precise understanding of pemphigus foliaceus.
In the English literature, most recent studies cn the pathogenesis of NAPF deal with the autoimmune theory;^^'''''-'''* however, the etiologic significance of pemphigus antibodies has not been established and the list of non-pemphigus conditions in which they have been found is increasing.^^ This has led Kreysel and Memmesheimer to conclude that the autoimmune concept of blister formation in pemphigus Is dubious.^^
Acknowledgment
Conclusion
The author acknowledges the contribution to this artit l e of Weslwood Pharmateuticalb, Buffalo, New York,
Current concepts of the nature of NAPF and BPF are largely speculative. Perhaps the predominant view of the pathogenesis of NAPF is that hereditary and immunologic factors dtjtermine a predisposition to the formation o' disease-causing autoantibodies (to altered or normal intercellular antigen or crossreacting with the same). Among Brazilian authorities there is a strong belief that exogenous factors are involved in the
Drug Name d-penicilljmine: Cuprimine
References 1, Ramos e Silva, ],: Ideias gerais sobre o pent'igo SulAmericano: seu historico no Brazil conteitua^ao iitual do grupo penfigo. Rev, Bras, Med, 2(5:611, 1971, 2, Cazenave, P.: Pemphigus (hronique general: forme rare du pemphigus foliace, Ann. Mai. Peau 1:208, 18443. Pupo, |. de Aguiar: Aspectos originais do penfigo folijceo no Brasil. Ann, Bras, Dermatol. 46:53. 1971,
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4. Vieira, ]., Fonzari, M,, and Goldman, L-: Some recent studies in Brazilian pemphigus. Am, |. Trop. Med, 3:868, 1954. 5. Leme, C. A.: Penfigo foliaceo: ctiopatogenia, sintomatologia e diagnostico. O Hospital 65:201, 1964. 6. Lever, W. F.: Pemphigus and Pemphigoid. Springfield, Charles C Thomas, 1965. 7. Bcutner, E. H., and lordon, R. E.: Demonstration of skin antibodies in sera of pemphigus vulgaris patients hy immunofluorescent staining. Proc. Soc. Exp, Biol. Med. 117:505, 1964. 8. Kano, K., Beutner, E. H,, and Milgrnm, F.: Humoral antibodies in sera of patients with bullnus skin diseases. Proc. Soc. Exp. Biol. Med, 127:355, 1978, 9. Peck, M, D., Osserman, K. E., Weiner, L. B., Lefkovits. A,, and Osserman, R. S.: Studies in hullous diseases. Immunofluorescenl serologic tests. N. fcngl. i. Med. 279:951, 1968. 10. Proen(,a, N. G., and Rivitti, E.: Antiepithelial antibodies in Brazilian pemphigus foliaceus. Inl. |. Dermatol. 16:799. 1977, 11. Byslryn, |-C., Abel, E,, and DeFeo, C: Pemphigus toliaceiis subcorneal interceullar antibodies of unique specificity. Arch. Dermatol. 110:857, 1974. 12. Proenga, N. G,, et al.: Azoospermia caused by South American pemphigus foliaceus. Apropos of a case study. Rev. Inst. Med. Trop. Sao Paulo 20: i()7, 1978. 13. Rezendc, S. T.: Pendgo foliaceo. Rev. Bras. Med. 24:61, 1967. 14. Perry, H, O.: Fogo selvagem (Pemphigus foliaceus). In: Clinical Dermatology- Edited by Demis, et al. Hagerstown, Harper & Row, 1977, p. 1. 15- Counter, C. E.: The disease called "wild fire." Arch. Dermatol. 80:391, 1959. 16. Gamarski, |., and Auad, T.: D-penicilamina no pentigo foliaceo Sul-Americano. Rev. Inst, Med, Trop. Sdo Paulo 19:1.58, 1977. 17. Leme, C. A.: Penfigo foliaceo no Brasil—doen^a de auloagressao, O Hospital 76:583, 1969. 18. Rivitti, E. A., Camargo, M. E., Castro, R. M., and Sampaio, S. A. P,: Use ot methotrexate to treat pemphigus foliaceus. Int. |. Dermatol. 12:119, 1973, 19. Krain, L. S., Terasaki, P- 1., Newcomer, V, C, and Mickey, M. R.: Increased frequency of HL-A10 in pemphigus vulgaris. Arch, Dermalol. 108:803, 1973. 20. Hashimoto, K,, Yoshuharu, M., Nakata, S-, and Matsuyama, M.: HLA-AIO in pemphigus among Kipanese. Arch. Dermalol. 1IJ:1518, 1977.
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21. Vieira, |. P.: Pemphigus foliaceus (fogo selvagem). Arch. Dermatol. Syphilol. 41:858, 1940, 22. Brown, M. W,: Fogo selvagem (pemphigus foliaceus). AMA Arch. Dermatol. Svphilol. 69:589, 1954. 23. Krain, L. S., and Bierman, S, M,: Pemphigus vulgaris and internal malignancy. Cancer 33:1091, 1974. 24. Proen^a, N. G., and Ribeiro, A. G.: Aspectos epidemiofogicos do penfigo foiiaceo no Brasil. Rev. Assoc. Med, Bras. 22:281, 1976. 25. Ldcaz, C- S., Baruzzi, R. G., and Siqueira, W. )r.Introdu^ao a Geografia Med ica do Brasil, Edited by E. Blucher, Sao Paulo, Universidade de Sao Paulo, 1972, p. 427. 26. Beutner, E. H., Chorzelski, T, P,, and lordon, R. E.: Autosensitization in Pemphigus and Bullous Pemphigoid. Springfield, Charles C Thomas, 1970. 27. Vieira, 1. P.: Algumas pesquisas sobre o "fogo selvagem" no estado de Sao Paulo. Conferencia realizada na Academia Nacional de Medicina, 1941. Bras. Med. 33:561, 1941. 28. Leme C. A.: Penfigo foliaceo brasileiro. Visao atual de sua patogenia em face dos recentes estudos imunologicos. Rev. Assoc. Med. Bras. 19:71, 1973. 29. Perry, H, O.: Pemphigus fotiaceus. Arch. Dermatol. 83:52, 1961. 30. Perry, H, O., and Brunsting, L, A.: Pemphigus foliaceus. Arch. Dermalol. 91:10, 1965. 31. Voelter, W. W., Newell, G. B., Schwartz, S. L., Bean, S. F., and Mullins, |. F.: Familial occurrence of pemphigus foliaceu';. Arch. Dermatol, 108:93, 1973. 32. Angulo, I- ).: Attempts to isolate a virus from pemphigus foliaceuh cases, AMA Arch. Dermatol. Svphilol. 69:472, 1954. 33. Sams, W. M., and lordon, R. E,: Pemphigus antibodies: their role in disease. |. Invest. Dermatol. 56:474, 1971. 34. Beutner, E. H., Chorzelski, T. P,, larzabek, M-, Wood, G., Leme, C. A,, and Bier, O.: Studies in immunodermatology I. Int. Arch. Allergy 42:545, 1972. 35. Tuffant-lli, D. L.: Pemphigus. Clin. Pharm. Ther. 16:974, 1974. 36 Krevsel, H-W., and Memmesheimer, A. R.: is pemphigus an autoimmune disease;' Br. |. Dermatol, 85:519, 1971. 37. Kristensen, |. K., and Wadskov, S.: Penicillammeinduced pemphigus fnliaceus. Acta Derma. Venerol, 57:69. 1977.
G-l Symptoms
Gastroitntestitnal symptoms due to anitbiotic therapy ratnge from mild abdominal discomfort to severe life-threatening colitis. Numerous drugs, including ciindamycin, lincomycin, tetracycline, chloramphenicol, cephalosporin, penicillin, and ampicillin, have been implicated. Ampicillin is associated with change in bowel habits and pseudomembranous colitis (P.M.C.),—Toffler. R. B.. Pingoud, E. G.,and Burrell, M. I.: Acute colitis related to penicillin and penicillin derivatives. Lancet 2:707, 1978.
