Britishjournal of Dermatology (1979} 100, 441.
Coexistence of bullous pemphigoid and pemphigus foliaceus CHRISTINE I.HARRINGTON AND I.B.SNEDDON Rupert Haliam Department of Dermatology, Hallamshire Hospital, GIosscp Road, Sheffield Accepted for publication 31 July 1978
SUMMARY
A patient with bullous pemphigoid developed pemphigus foliaceus 5 years later. Mixed bullous diseases are rare and this is the first reported case of coexisting bullous pemphigoid and pemphigus foliaceus.
CASE HISTORY
A 62-year-old shipping manager was seen in March 1973 with a 3 week history of a generalized eruption. Examination showed erythematous raised plaques mainly on the trunk and legs and within a few days large tense blisters appeared on the urticarial areas (Fig. i). Apart from a history of mild psoriasis on the shins for 10 years there was no other significant feature in his past. The histology of a lesion on his right arm showed a large sub-epidermal bulla with numerous eosinophils in the dermis. The appearance conformed with pemphigoid. A positive indirect immunofluorescence test for basement membrane zone antibodies in a titre of i /80 was present in the patient's serum and appeared to confirm the diagnosis. Direct immunofluorescence on the skin was not performed. The blistering eruption was controlled with prednisolone phosphate but it was noted that a dose of 60 mg daily was needed and in June 1973 azathioprine 50 mg daily was added as the prednisotene dosage was reduced. By July 1973 his sldn was clear and he had stopped the azathioprine as it made him feel sick. He was maintained on prednisolone 7-5 mg daily. In February 1974 the eruption recurred with a figurate erythema and small bullae at the edge of the erythematous zones. A temporary increase in prednisolone to 30 mg daily controlled the eruption and maintenance therapy of 5 mg daily was resumed. In August 1975 he developed a recurrence of gyrate erythema which necessitated another rise in the dosage of predinsolone to 20 mg daily but during 1976 he was well on 5 mg alternate days. In January 1977 he suffered another recurrence of erthema and bullae and was reinvestigated at that time. Indirect immunofluorescence was positive for skin basement membrane but negative for inter0007-0963/79/0400-0441 $02.00 © 1979 British Association of Dermatologists
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C.I.Harrington and I.B.Sneddon
FIGURE I. The tense bullae of bullous pemphigoid. March 1973.
FIGURE 2, The eruption of pemphigus foliaceus. March 1978.
Bullous pemphigoid and pemphigus foliaceus
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cellular antibodies. Antinuclear factor and all other antibodies such as mitochondrial, gastric parietal cells, smooth muscle and thyroglobulin were negative. A biopsy was again consistent with pemphigoid. Both involved and uninvolved skin showed globular deposits of IgM in the papillary dermis and C3 was deposited on the basement membrane zone. His HLA type was Ai, A9, B12 and BW15. He then remained well on 7-5 mg prednisolone throughout 1977. In March 1978 scales appeared around his neck and the patient considered that it was his psoriasis returning but the scales rapidly spread over his trunk and he was admitted to hospital as an emergency on 4 April. Examination showed classical pemphigus foliaceus (Fig. 2) over his trunk and limbs with scattered intact superficial bullae on the face, hands and feet. His mucous membranes were unaffected. A section of a blister from the back showed intercellular staining for IgG and an intraepidermal cleft (Fig. 3). Biopsy of a blister from the chin showed a subepidermal bulla with basement membrane staining for IgG and C3 (Fig. 4). These findings suggested a diagnosis of concomitant pemphigus foliaceus and pemphigoid. The patient's serum was positive only for skin basement membrane zone antibody in a titre of i in 20, the maximum done in our laboratory. Prednisolone 20 mg daily and locally applied Betnovate ointment improved the pemphigus foliaceus within a week but he continued to show gyrate erythema of
FIGURE 3. Direct immunofluorescence showing a high intra-epidermal cleft and intercellular staining for IgG.
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C.I.Harrington and I.B.Sneddon
FIGURE 4. Direct immunofluorescence showing basement membrane staining for IgG.
pemphigoid type and methotrexate 25 mg daily was added to his treatment. This failed to produce any improvement and dapsone 50 mg daily was substituted. After starting dapsone, the skin slowly became free of lesions and he remains free on prednisolone 20 mg and dapsone 50 mg daily. DISCUSSION
It is well recognized that some patients present with a bullous eruption which appears to be a mixture of two disorders though observation and repeated biopsies will, in most instances, establish a definite single diagnosis (Jablonska et al., 1975). The subject of mixed bullous diseases which appear to cross the borderhne between dermatitis herpetiformis and pemphigus has been reviewed by Knight, Black & Delaney (1976). They described nine patients who showed eosinophilic spongiosis, in six of whom pemphigus antibodies were found. Bullous pemphigoid (van der Meer, 1969), pemphigus vulgaris (Barranco, 1974; Floden & Gcntele, 1955; von Doepfmer, 1961) and pemphigus foliaceus (Barranco, 1974; Winkelmann & Roth, i960; Sneddon & Church, 1967) have all presented with a primary eruption resembling dermatitis herpetiformis. Co-existence of dermatitis herpetiformis and pemphigus vulgaris (Emmerson & Wilson Jones, 1968; De Memo & Grover, 1973), dermatitis herpetiformis and bullous pemphigoid (Honcyman et al., 1972) and pemphigus vulgaris and bullous pemphigoid (Chorzelski et al., 1974) have all been described. The present case differs from those previously reported in having two separate phases: the first, pemphigoid with characteristic clinical and histological features and the second, pemphigus foliaceus, separated by a number of years. There are also many examples of the co-existence of two autoimmune disorders occurring in the same patient, pemphigus erythematosus and myasthenia gravis
Bullous pemphigoid and pemphigus foliaceus
445
(Beutner et ai, 1968), pemphigus and lupus erythematosus (Chorzelski, Jablonska & Blaszczyk, 1968; Jordon et al., 1969), pernicious anaemia with pemphigus (Mackie, Saikia & Morley, 1973) and pemphigoid (Obasi & Savin, 1977), and pemphigoid with rheumatoid arthritis (Cullen et al., 1978). We believe that on clinical and immunological grounds our patient suffered from pemphigoid and pemphigus foliaceus in succession and then simultaneously. In our opinion the co-existence of two bullous disorders in this patient represents two auto-immune disorders involving different levels of the skin.
REFERENCES BARBANCO, P . (1974) Mixed builous disease. Archives of Dermatology, n o , 221. BEUTNER, E.H. CHORZELSKI, T.P., HALE, W.L. & HAUSMANOWA-PHTNISEUICZ, I. (1968) Auto-immunity in con-
current myasthenia gravis and pemphigus erythematosus. Journal of the American Medical Association, 203, 845. CULLEN, J.P., ANDERSON, T.F., CHANDA, J.J. & TAYLOR, W.B. (1978) Bullous pemphigoid and other disorders
associated with auto-immune phenomena. Archives of Dermatology, 114, 245. CHORZELSKI, T.P., JABLONSKA, S. & BLASZCZYK, M . (1968) Immunopathological investigations in the Senear-
Usher syndrome. Coexistence of pemphigus with lupus erythematosus. British Journal of Dermatology, 80,2i r. CHORZELSKI, T.P., MACIEJOWSKI, E., JABLONSKA, S., D E MENTO, F.J., GROVER, R.W., HOLUBAR, K . & BEUTNER,
E.H. (1974) Coexistence of pemphigus and pemphigoid. Archives of Dermatology, 109, 849. DE MENTO, F.J. & GROVER, R.W. (1973) Acantholytic herpettform dermatitis. Archives of Dermatology, 107, 883. EMMERSON, R.W. & WILSON JONES, E, (1968) Eosinophilic spongiosis in pemphigus. Archives of Dermatology, 97, 252. FLODEN, C.H. & GENTELE, H . (1955) A case of clinically typical dermatitis herpetiformis (Duhring) presenting acantholysis. Acta dermato-venereologica, 35, 128. HONEYMAN, J.F., HONEYMAN, A., LOBITZ, W.C. & STORRS, K.J. (1972) The enigma of bullous pemphigoid
and dermatitis herpetiformis. Archives of Dermatology, 106, 21. JABLONSKA, S., CHORZELSKI, T.P., BEUTNER, E.H. & CHORZELSKA, J. (1975) Herpetiform pemphigus, a variable
pattern of pemphigus. Internatio?ial Journal of Dermatology, 16, 353. JORDON, R.E., MULLER, S.A., HALE, W.L. & BEUTNER, E.H. (1969) Butlous pemphigoid associated with systemic lupus erythematosus. Archives of Dermatology, 99, 17. KNIGHT, A.G., BLACK, M.M. & DELANEY, T.J. (1976) Eosinophilic spongiosis. Clinical and Experimental Dermatology, I, 141. MACKIE, R.M., SAIKIA, N.K. & MORLEV, W . N . (1973) A case of pemphigus in association with Addisonian pernicious anaemia. British Journal of Dermatology, 88, 139. OBASI, O.E. & SAVIN, J.A. (1977) Pemphigoid and pernicious anaemia. British Medical Journal, ii, 1458. SNEDDON, I.B. & CHURCH, R.E. (1967) Pemphigus foliaceus presenting as dermatitis herpetiformis. Acia dermatovenereologica, 6, 440. VAN DER MEER, J.B. (1969) Granular deposits of immunoglobulins in the skin of patients with dermatitis herpetiformis. An immunofiuorescent study. British Journal of Dermatology, 81, 493. VON DOEPFMER, R. (1961) Uber eine nosologisch ungeklarte bullose Dermatose. (Pemphigus chronicus vulgaris oder Dermatitis herpetiformis Duhring). Hautarzt, 12, 452. WINKELMANN, R.K. & ROTH, H.L. (i960) Dermatitis herpetiformis with acantholysis or pemphigus with response to sulphonamides. Archives of Dermatology, 82, 385.
Coexistence of bullous pemphigoid and pemphigus foliaceus CHRISTINE I.HARRINGTON AND I.B.SNEDDON Rupert Haliam Department of Dermatology, Hallamshire Hospital, GIosscp Road, Sheffield Accepted for publication 31 July 1978
SUMMARY
A patient with bullous pemphigoid developed pemphigus foliaceus 5 years later. Mixed bullous diseases are rare and this is the first reported case of coexisting bullous pemphigoid and pemphigus foliaceus.
CASE HISTORY
A 62-year-old shipping manager was seen in March 1973 with a 3 week history of a generalized eruption. Examination showed erythematous raised plaques mainly on the trunk and legs and within a few days large tense blisters appeared on the urticarial areas (Fig. i). Apart from a history of mild psoriasis on the shins for 10 years there was no other significant feature in his past. The histology of a lesion on his right arm showed a large sub-epidermal bulla with numerous eosinophils in the dermis. The appearance conformed with pemphigoid. A positive indirect immunofluorescence test for basement membrane zone antibodies in a titre of i /80 was present in the patient's serum and appeared to confirm the diagnosis. Direct immunofluorescence on the skin was not performed. The blistering eruption was controlled with prednisolone phosphate but it was noted that a dose of 60 mg daily was needed and in June 1973 azathioprine 50 mg daily was added as the prednisotene dosage was reduced. By July 1973 his sldn was clear and he had stopped the azathioprine as it made him feel sick. He was maintained on prednisolone 7-5 mg daily. In February 1974 the eruption recurred with a figurate erythema and small bullae at the edge of the erythematous zones. A temporary increase in prednisolone to 30 mg daily controlled the eruption and maintenance therapy of 5 mg daily was resumed. In August 1975 he developed a recurrence of gyrate erythema which necessitated another rise in the dosage of predinsolone to 20 mg daily but during 1976 he was well on 5 mg alternate days. In January 1977 he suffered another recurrence of erthema and bullae and was reinvestigated at that time. Indirect immunofluorescence was positive for skin basement membrane but negative for inter0007-0963/79/0400-0441 $02.00 © 1979 British Association of Dermatologists
441
442
C.I.Harrington and I.B.Sneddon
FIGURE I. The tense bullae of bullous pemphigoid. March 1973.
FIGURE 2, The eruption of pemphigus foliaceus. March 1978.
Bullous pemphigoid and pemphigus foliaceus
443
cellular antibodies. Antinuclear factor and all other antibodies such as mitochondrial, gastric parietal cells, smooth muscle and thyroglobulin were negative. A biopsy was again consistent with pemphigoid. Both involved and uninvolved skin showed globular deposits of IgM in the papillary dermis and C3 was deposited on the basement membrane zone. His HLA type was Ai, A9, B12 and BW15. He then remained well on 7-5 mg prednisolone throughout 1977. In March 1978 scales appeared around his neck and the patient considered that it was his psoriasis returning but the scales rapidly spread over his trunk and he was admitted to hospital as an emergency on 4 April. Examination showed classical pemphigus foliaceus (Fig. 2) over his trunk and limbs with scattered intact superficial bullae on the face, hands and feet. His mucous membranes were unaffected. A section of a blister from the back showed intercellular staining for IgG and an intraepidermal cleft (Fig. 3). Biopsy of a blister from the chin showed a subepidermal bulla with basement membrane staining for IgG and C3 (Fig. 4). These findings suggested a diagnosis of concomitant pemphigus foliaceus and pemphigoid. The patient's serum was positive only for skin basement membrane zone antibody in a titre of i in 20, the maximum done in our laboratory. Prednisolone 20 mg daily and locally applied Betnovate ointment improved the pemphigus foliaceus within a week but he continued to show gyrate erythema of
FIGURE 3. Direct immunofluorescence showing a high intra-epidermal cleft and intercellular staining for IgG.
444
C.I.Harrington and I.B.Sneddon
FIGURE 4. Direct immunofluorescence showing basement membrane staining for IgG.
pemphigoid type and methotrexate 25 mg daily was added to his treatment. This failed to produce any improvement and dapsone 50 mg daily was substituted. After starting dapsone, the skin slowly became free of lesions and he remains free on prednisolone 20 mg and dapsone 50 mg daily. DISCUSSION
It is well recognized that some patients present with a bullous eruption which appears to be a mixture of two disorders though observation and repeated biopsies will, in most instances, establish a definite single diagnosis (Jablonska et al., 1975). The subject of mixed bullous diseases which appear to cross the borderhne between dermatitis herpetiformis and pemphigus has been reviewed by Knight, Black & Delaney (1976). They described nine patients who showed eosinophilic spongiosis, in six of whom pemphigus antibodies were found. Bullous pemphigoid (van der Meer, 1969), pemphigus vulgaris (Barranco, 1974; Floden & Gcntele, 1955; von Doepfmer, 1961) and pemphigus foliaceus (Barranco, 1974; Winkelmann & Roth, i960; Sneddon & Church, 1967) have all presented with a primary eruption resembling dermatitis herpetiformis. Co-existence of dermatitis herpetiformis and pemphigus vulgaris (Emmerson & Wilson Jones, 1968; De Memo & Grover, 1973), dermatitis herpetiformis and bullous pemphigoid (Honcyman et al., 1972) and pemphigus vulgaris and bullous pemphigoid (Chorzelski et al., 1974) have all been described. The present case differs from those previously reported in having two separate phases: the first, pemphigoid with characteristic clinical and histological features and the second, pemphigus foliaceus, separated by a number of years. There are also many examples of the co-existence of two autoimmune disorders occurring in the same patient, pemphigus erythematosus and myasthenia gravis
Bullous pemphigoid and pemphigus foliaceus
445
(Beutner et ai, 1968), pemphigus and lupus erythematosus (Chorzelski, Jablonska & Blaszczyk, 1968; Jordon et al., 1969), pernicious anaemia with pemphigus (Mackie, Saikia & Morley, 1973) and pemphigoid (Obasi & Savin, 1977), and pemphigoid with rheumatoid arthritis (Cullen et al., 1978). We believe that on clinical and immunological grounds our patient suffered from pemphigoid and pemphigus foliaceus in succession and then simultaneously. In our opinion the co-existence of two bullous disorders in this patient represents two auto-immune disorders involving different levels of the skin.
REFERENCES BARBANCO, P . (1974) Mixed builous disease. Archives of Dermatology, n o , 221. BEUTNER, E.H. CHORZELSKI, T.P., HALE, W.L. & HAUSMANOWA-PHTNISEUICZ, I. (1968) Auto-immunity in con-
current myasthenia gravis and pemphigus erythematosus. Journal of the American Medical Association, 203, 845. CULLEN, J.P., ANDERSON, T.F., CHANDA, J.J. & TAYLOR, W.B. (1978) Bullous pemphigoid and other disorders
associated with auto-immune phenomena. Archives of Dermatology, 114, 245. CHORZELSKI, T.P., JABLONSKA, S. & BLASZCZYK, M . (1968) Immunopathological investigations in the Senear-
Usher syndrome. Coexistence of pemphigus with lupus erythematosus. British Journal of Dermatology, 80,2i r. CHORZELSKI, T.P., MACIEJOWSKI, E., JABLONSKA, S., D E MENTO, F.J., GROVER, R.W., HOLUBAR, K . & BEUTNER,
E.H. (1974) Coexistence of pemphigus and pemphigoid. Archives of Dermatology, 109, 849. DE MENTO, F.J. & GROVER, R.W. (1973) Acantholytic herpettform dermatitis. Archives of Dermatology, 107, 883. EMMERSON, R.W. & WILSON JONES, E, (1968) Eosinophilic spongiosis in pemphigus. Archives of Dermatology, 97, 252. FLODEN, C.H. & GENTELE, H . (1955) A case of clinically typical dermatitis herpetiformis (Duhring) presenting acantholysis. Acta dermato-venereologica, 35, 128. HONEYMAN, J.F., HONEYMAN, A., LOBITZ, W.C. & STORRS, K.J. (1972) The enigma of bullous pemphigoid
and dermatitis herpetiformis. Archives of Dermatology, 106, 21. JABLONSKA, S., CHORZELSKI, T.P., BEUTNER, E.H. & CHORZELSKA, J. (1975) Herpetiform pemphigus, a variable
pattern of pemphigus. Internatio?ial Journal of Dermatology, 16, 353. JORDON, R.E., MULLER, S.A., HALE, W.L. & BEUTNER, E.H. (1969) Butlous pemphigoid associated with systemic lupus erythematosus. Archives of Dermatology, 99, 17. KNIGHT, A.G., BLACK, M.M. & DELANEY, T.J. (1976) Eosinophilic spongiosis. Clinical and Experimental Dermatology, I, 141. MACKIE, R.M., SAIKIA, N.K. & MORLEV, W . N . (1973) A case of pemphigus in association with Addisonian pernicious anaemia. British Journal of Dermatology, 88, 139. OBASI, O.E. & SAVIN, J.A. (1977) Pemphigoid and pernicious anaemia. British Medical Journal, ii, 1458. SNEDDON, I.B. & CHURCH, R.E. (1967) Pemphigus foliaceus presenting as dermatitis herpetiformis. Acia dermatovenereologica, 6, 440. VAN DER MEER, J.B. (1969) Granular deposits of immunoglobulins in the skin of patients with dermatitis herpetiformis. An immunofiuorescent study. British Journal of Dermatology, 81, 493. VON DOEPFMER, R. (1961) Uber eine nosologisch ungeklarte bullose Dermatose. (Pemphigus chronicus vulgaris oder Dermatitis herpetiformis Duhring). Hautarzt, 12, 452. WINKELMANN, R.K. & ROTH, H.L. (i960) Dermatitis herpetiformis with acantholysis or pemphigus with response to sulphonamides. Archives of Dermatology, 82, 385.
