REPORT
NONBULLOUS BULLOUS PEMPHIGOID RONNI WOLF, M.D., JOSEPH OPHIR, M.D., AND EDIT DECHNER, M.D.
Abstract
sis with hyper- and parakeratosis. Examination of many slides of this specimen did not show any bullae or detachment of the epidermis from the dermis. The dermal changes consisted of extensive accumulations of mononuclear cells. The infiltrate was seen around the vessels and in the upper dermis. There were only a few eosinophils.
Three patients had a rare form of bullous pemphigoid, clinically similar to the erythematous type of bullous pemphigoid without vesiculobullous lesions. All the patients displayed immunofluorescence features of bullous pemphigoid. This form of the disease presents a substantial diagnostic problem because it lacks the principal morphologic feature of bullous pemphigoid, namely the vesicles and bullae.
Case 2: A 65-year-old woman was referred to our clinic for evaluation of a pruritic eruption on her extremities, which did not respond to topical therapy with steroid ointments. The patient had undergone a total hysterectomy 12 years previously. The rest of her medical history was unremarkable. She had not been receiving any medication at the time the eruption appeared. Physical examination showed erythematous plaques of various sizes on the extensor surfaces of her extremities and abdomen (Fig. 1). A biopsy specimen of a plaque showed nonspecific changes consisting of mild acanthosis with parakeratosis, vascular dilatation, edema, and mononuclear cellular infiltrate in the upper dermis (Fig. 2). Direct IF examination showed a pattern characteristic of BP, consisting of linear IgG and C3 deposition in the BMZ (Fig. 3). The diagnosis of BP was made and the patient was treated with prednisone 60 mg/day, resulting in clearing of her eruption. Since her eruption reoccurred when the prednisone was reduced below 30 mg/day, azathioprine 100 mg/day was added, and we were able to reduce the prednisone to 10 mg every other day. Reappearance of her ery-
The advent of direct and indirect immunofluorescence testing has broadened the study of the disease entity bullous pemphigoid (BP) and has thrown light on the varying clinical and morphologic features of this disease.^ We describe three patients with a rare form of BP, who present a substantial diagnostic problem since there was no manifestation of bullae or vesicles during the course of their disease. Case Reports Case 1: An 84-year-old woman had a 6-month history of pruritic erythematous plaques involving the extensor surface of the body. She had suffered for 15 years from hemiparesis because of a cerebrovascular accident. The rest of her history was unremarkable. She specifically denied taking any medication during the previous 2 years. Physical examination showed well-defined, large, erythematous, urticarial plaques, predominantly on the extensor surfaces of the extremities. At first, she was treated with topical steroid ointments, and when this treatment proved ineffective, a biopsy and a direct immunofluorescence (IF) examination were performed. The latter revealed linear IgG and C3 basement membrane zone (BMZ) deposition. The diagnosis of BP was made and the patient was treated with prednisone 40 mg/ day, resulting in good control of her disease. After reducing the dose to 25mg/day, she experienced a reoccurrence of her eruption. In a long follow-up, the patient experienced several relapses of her eruption each time the prednisone dose was reduced below 20 mg/day. A biopsy specimen of a plaque showed nonspecific inflammatory changes. The epidermis showed mild acantho-
From the Department of Dermatology, Ichilov Hospital, Tel Aviv Sourasky Medical Center, and the Sackier Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Address for correspondence: Ronni Wolf, M.D., Department of Dermatology, Ichilov Hospital, 6 Weizman Street, Tel Aviv 64239, Israel.
Figure 1.
Patient 2, an erythematous plaque on the the exten-
sor surface of the right arm. 498
Noiibuilous Bullous Pemphigo Wolf, Ophir. and Dochner
thematous, pruritic plaques forced us to increase the dose of prednisone for short periods. A 4-week trial with dapsone alone, 150 mg/day, without any additional therapy, was unsuccessful. Multiple erythematous plaques continued to appear, and we were forced to discontinue the treatment. A biopsy specimen showed mild inflammatory changes. The epidermis was normal except for mild acanthosis. Careful examination of all slides did not reveal any cleavage or blister formation under the epidermis. The dermal changes were slight, consisting of a sparse infiltrate in the
upper dermis and around the blood vessels, composed mainly of mononuclear cells (Fig. 2). Case 3: A 62-year-old man had a 6-month history of a widespread, intensely pruritic eruption, predominantly involving his upper and lower extremities. Examination revealed welldefined erythematous plaques of various size, and erythematous papules. No blisters or bullae were seen. Histologic examination of a biopsy specimen showed a nonspecific picture similar to that seen in patient 2. Direct IF examination showed linear deposition of IgG and C3 along the BMZ. The diagnosis of BP was made, and the patient received treatment with prednisone 60 mg/day and azathioprine 100 mg/day. The pruritus and erythematous lesions disappeared, and the prednisone was reduced to 5 mg/day.
DISCUSSION
Bullous pemphigoid has many clinical variations., including localized pemphigoid," polymorphic pemphigoid,' vesicular pemphigoid,"* pemphigoid vegetans, cicatricial pemphigoid or hyperkeratotic scarring pemphigoid,'•''•'' and pemphigoid nodularis.' All of them, despite their differing presentations, are usually characterized hy a bullous or vesicular component at some time during the course of the disease. The patients descrihed in this report were followed by us for a period of more than 2 years, yet no vesiculobuUous lesions were ever observed. Chorzelski et al.** described a polymorphic or erythematous variant of Bl' many years ago. His patients had large, erythematous, urticarial plaques, and all had bullous lesions during the course of their disease. Immunofluorescence studies were negative in the majority of cases.** Our patients, who had a similar clinical picture, should certainly be classified as having the erythematous type of BP. In contrast to the latter, vesiculobuUous lesions never appeared, although IF features of HP were present. In addition, the clinical course appeared to be more chronic in nature. Dapsone failed to alleviate the symptoms in one of our patients. The question as to whether the present, and similar, cases are indeed variants of BP, or a different entity with similar immunologic patterns, is a moot one. Unfortunately, it cannot be resolved from the available data. It is, however, important to draw attention to this rare form of BP because of the diagnostic problem that it presents. Because the principal morphologic feature of BP is absent, namely the vesicles and bullae, it clinically resembles more closely the configurate erythematous dermatoses than BP.
Figure 2. Histologic findings of a biopsy specimen from patient 2. The epidermis is normal. The dermis contains patches of an inflammatory infiltrate composed of mononuclear cells.
CONCLUSIONS
We are of the opinion that the key to correct diagnosis in these cases is increased awareness on the part of the
Figure 3. Direct immunofluorescence test of patient 2. Linear immunofluorescence is seen along the basement membrane. 499
International Journal of Dermatology Vol, 31. No, 7, July 1992
3.
physician of this unusual manifestation of bullous pemphigoid,, which can easily be confirmed or otherwise by immunologic studies. We believe this to be the major contribution of our report.
4. 5.
REFERENCES
2.
6.
Provost TT, Maize JC, Ahmed AR, et al. Unusual subepidermal bullous diseases with immunologic features of bullous pemphigoid. Arch Dermatol 1979; 115: 156160. Person JR, Rogers RS III, Perry HO. Localized pemphigoid. Br J Dermato! 1976; 95:531-534.
7. 8.
Honeyman JF, Honeyman AR, De la Parra MA, et al. Polymorphic pemphigoid. Arch Dermatol 1979; 115: 423-437. Bean SF, Michel B, Fury N, et ai. Vesicular pemphigoid. Arch Dermatol 1976; 112:1402-1406. Winkelmann RK, Su WP. Pemphigoid vegetans. Arch Dermatol 1979; 115:446-448. Ueda Y, Nahiro K, Seki Y, et al. Pemphigoid vegetans. BrJ Dermatol 1989; 120:449-453. Roenigk RK, Dahl MV. Bullous pemphigoid and prorigo nodularis. J Am Acad Dermatol 1986; 14:944-947. Chorzelski TP, Jablonska S, Beutner EH. Pemphigoid. In: Beutner EH, Chorzelski TP, Bean SF, eds. Immunopathology of the skin. 2nd Ed. New York: Wiley, 1979:243.
Epidermolysis Bullosa Simplex Keratin is an essential component of the epidermis, but attempts to explain scaly dermatoses in terms of abnormal keratinisation have been unrewarding. Psoriasis and pityriasis rubra pilaris are traditionally called disorders of keratinisation, yet there is little evidence that abnormal keratin plays a part in pathogenesis. Although blisters are not usually classified under that heading, we now have surprising evidence that production of abnormal keratin causes the inherited blistering disease, epidermolysis bullosa simplex. There are many types of epidermolysis bullosa. The commonest type, epidermolysis bullosa simplex (EBS), is characterised by the fact that the trauma-induced blistering is due to cytolysis of the epidermal basal cells, as shown by electron microscopy—ie, the split occurs within the cytoplasm. There are several subtypes, even of the simplex form. The Weber-Cockayne type is a mild form, with blisters localised to the hands and feet, whereas the Kobner type, though likewise mild, is more generalised. The Dowling-Meara type is distinguished by its greater severity, and by the presence on electron microscopy of large cytoplasmic clumps of tonofilaments, which are intermediate filaments composed of keratin. Intermediate filaments are proteins that are found in the cytoplasm of virtually all mammalian cells. They all have a similar molecular architecture, with four long helices that are essential for their function. There are several groups of intermediate filaments, of which keratins are the most diverse, there being more than twenty types of keratin in epithelial cells. The keratinous filaments that make up the cytoskeleton of human epidermal cells are formed by the polymerisation of two different keratin molecules—type I (acidic), and type II (basic). Neither type can polymerise on its own, but any type I and type II molecules can unite to form a filamentous dipolymer. From the Lancet. Epidermolysis bullosa simplex: a disorder of keratin. Lancet 1992; 339:29-30. 500
NONBULLOUS BULLOUS PEMPHIGOID RONNI WOLF, M.D., JOSEPH OPHIR, M.D., AND EDIT DECHNER, M.D.
Abstract
sis with hyper- and parakeratosis. Examination of many slides of this specimen did not show any bullae or detachment of the epidermis from the dermis. The dermal changes consisted of extensive accumulations of mononuclear cells. The infiltrate was seen around the vessels and in the upper dermis. There were only a few eosinophils.
Three patients had a rare form of bullous pemphigoid, clinically similar to the erythematous type of bullous pemphigoid without vesiculobullous lesions. All the patients displayed immunofluorescence features of bullous pemphigoid. This form of the disease presents a substantial diagnostic problem because it lacks the principal morphologic feature of bullous pemphigoid, namely the vesicles and bullae.
Case 2: A 65-year-old woman was referred to our clinic for evaluation of a pruritic eruption on her extremities, which did not respond to topical therapy with steroid ointments. The patient had undergone a total hysterectomy 12 years previously. The rest of her medical history was unremarkable. She had not been receiving any medication at the time the eruption appeared. Physical examination showed erythematous plaques of various sizes on the extensor surfaces of her extremities and abdomen (Fig. 1). A biopsy specimen of a plaque showed nonspecific changes consisting of mild acanthosis with parakeratosis, vascular dilatation, edema, and mononuclear cellular infiltrate in the upper dermis (Fig. 2). Direct IF examination showed a pattern characteristic of BP, consisting of linear IgG and C3 deposition in the BMZ (Fig. 3). The diagnosis of BP was made and the patient was treated with prednisone 60 mg/day, resulting in clearing of her eruption. Since her eruption reoccurred when the prednisone was reduced below 30 mg/day, azathioprine 100 mg/day was added, and we were able to reduce the prednisone to 10 mg every other day. Reappearance of her ery-
The advent of direct and indirect immunofluorescence testing has broadened the study of the disease entity bullous pemphigoid (BP) and has thrown light on the varying clinical and morphologic features of this disease.^ We describe three patients with a rare form of BP, who present a substantial diagnostic problem since there was no manifestation of bullae or vesicles during the course of their disease. Case Reports Case 1: An 84-year-old woman had a 6-month history of pruritic erythematous plaques involving the extensor surface of the body. She had suffered for 15 years from hemiparesis because of a cerebrovascular accident. The rest of her history was unremarkable. She specifically denied taking any medication during the previous 2 years. Physical examination showed well-defined, large, erythematous, urticarial plaques, predominantly on the extensor surfaces of the extremities. At first, she was treated with topical steroid ointments, and when this treatment proved ineffective, a biopsy and a direct immunofluorescence (IF) examination were performed. The latter revealed linear IgG and C3 basement membrane zone (BMZ) deposition. The diagnosis of BP was made and the patient was treated with prednisone 40 mg/ day, resulting in good control of her disease. After reducing the dose to 25mg/day, she experienced a reoccurrence of her eruption. In a long follow-up, the patient experienced several relapses of her eruption each time the prednisone dose was reduced below 20 mg/day. A biopsy specimen of a plaque showed nonspecific inflammatory changes. The epidermis showed mild acantho-
From the Department of Dermatology, Ichilov Hospital, Tel Aviv Sourasky Medical Center, and the Sackier Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Address for correspondence: Ronni Wolf, M.D., Department of Dermatology, Ichilov Hospital, 6 Weizman Street, Tel Aviv 64239, Israel.
Figure 1.
Patient 2, an erythematous plaque on the the exten-
sor surface of the right arm. 498
Noiibuilous Bullous Pemphigo Wolf, Ophir. and Dochner
thematous, pruritic plaques forced us to increase the dose of prednisone for short periods. A 4-week trial with dapsone alone, 150 mg/day, without any additional therapy, was unsuccessful. Multiple erythematous plaques continued to appear, and we were forced to discontinue the treatment. A biopsy specimen showed mild inflammatory changes. The epidermis was normal except for mild acanthosis. Careful examination of all slides did not reveal any cleavage or blister formation under the epidermis. The dermal changes were slight, consisting of a sparse infiltrate in the
upper dermis and around the blood vessels, composed mainly of mononuclear cells (Fig. 2). Case 3: A 62-year-old man had a 6-month history of a widespread, intensely pruritic eruption, predominantly involving his upper and lower extremities. Examination revealed welldefined erythematous plaques of various size, and erythematous papules. No blisters or bullae were seen. Histologic examination of a biopsy specimen showed a nonspecific picture similar to that seen in patient 2. Direct IF examination showed linear deposition of IgG and C3 along the BMZ. The diagnosis of BP was made, and the patient received treatment with prednisone 60 mg/day and azathioprine 100 mg/day. The pruritus and erythematous lesions disappeared, and the prednisone was reduced to 5 mg/day.
DISCUSSION
Bullous pemphigoid has many clinical variations., including localized pemphigoid," polymorphic pemphigoid,' vesicular pemphigoid,"* pemphigoid vegetans, cicatricial pemphigoid or hyperkeratotic scarring pemphigoid,'•''•'' and pemphigoid nodularis.' All of them, despite their differing presentations, are usually characterized hy a bullous or vesicular component at some time during the course of the disease. The patients descrihed in this report were followed by us for a period of more than 2 years, yet no vesiculobuUous lesions were ever observed. Chorzelski et al.** described a polymorphic or erythematous variant of Bl' many years ago. His patients had large, erythematous, urticarial plaques, and all had bullous lesions during the course of their disease. Immunofluorescence studies were negative in the majority of cases.** Our patients, who had a similar clinical picture, should certainly be classified as having the erythematous type of BP. In contrast to the latter, vesiculobuUous lesions never appeared, although IF features of HP were present. In addition, the clinical course appeared to be more chronic in nature. Dapsone failed to alleviate the symptoms in one of our patients. The question as to whether the present, and similar, cases are indeed variants of BP, or a different entity with similar immunologic patterns, is a moot one. Unfortunately, it cannot be resolved from the available data. It is, however, important to draw attention to this rare form of BP because of the diagnostic problem that it presents. Because the principal morphologic feature of BP is absent, namely the vesicles and bullae, it clinically resembles more closely the configurate erythematous dermatoses than BP.
Figure 2. Histologic findings of a biopsy specimen from patient 2. The epidermis is normal. The dermis contains patches of an inflammatory infiltrate composed of mononuclear cells.
CONCLUSIONS
We are of the opinion that the key to correct diagnosis in these cases is increased awareness on the part of the
Figure 3. Direct immunofluorescence test of patient 2. Linear immunofluorescence is seen along the basement membrane. 499
International Journal of Dermatology Vol, 31. No, 7, July 1992
3.
physician of this unusual manifestation of bullous pemphigoid,, which can easily be confirmed or otherwise by immunologic studies. We believe this to be the major contribution of our report.
4. 5.
REFERENCES
2.
6.
Provost TT, Maize JC, Ahmed AR, et al. Unusual subepidermal bullous diseases with immunologic features of bullous pemphigoid. Arch Dermatol 1979; 115: 156160. Person JR, Rogers RS III, Perry HO. Localized pemphigoid. Br J Dermato! 1976; 95:531-534.
7. 8.
Honeyman JF, Honeyman AR, De la Parra MA, et al. Polymorphic pemphigoid. Arch Dermatol 1979; 115: 423-437. Bean SF, Michel B, Fury N, et ai. Vesicular pemphigoid. Arch Dermatol 1976; 112:1402-1406. Winkelmann RK, Su WP. Pemphigoid vegetans. Arch Dermatol 1979; 115:446-448. Ueda Y, Nahiro K, Seki Y, et al. Pemphigoid vegetans. BrJ Dermatol 1989; 120:449-453. Roenigk RK, Dahl MV. Bullous pemphigoid and prorigo nodularis. J Am Acad Dermatol 1986; 14:944-947. Chorzelski TP, Jablonska S, Beutner EH. Pemphigoid. In: Beutner EH, Chorzelski TP, Bean SF, eds. Immunopathology of the skin. 2nd Ed. New York: Wiley, 1979:243.
Epidermolysis Bullosa Simplex Keratin is an essential component of the epidermis, but attempts to explain scaly dermatoses in terms of abnormal keratinisation have been unrewarding. Psoriasis and pityriasis rubra pilaris are traditionally called disorders of keratinisation, yet there is little evidence that abnormal keratin plays a part in pathogenesis. Although blisters are not usually classified under that heading, we now have surprising evidence that production of abnormal keratin causes the inherited blistering disease, epidermolysis bullosa simplex. There are many types of epidermolysis bullosa. The commonest type, epidermolysis bullosa simplex (EBS), is characterised by the fact that the trauma-induced blistering is due to cytolysis of the epidermal basal cells, as shown by electron microscopy—ie, the split occurs within the cytoplasm. There are several subtypes, even of the simplex form. The Weber-Cockayne type is a mild form, with blisters localised to the hands and feet, whereas the Kobner type, though likewise mild, is more generalised. The Dowling-Meara type is distinguished by its greater severity, and by the presence on electron microscopy of large cytoplasmic clumps of tonofilaments, which are intermediate filaments composed of keratin. Intermediate filaments are proteins that are found in the cytoplasm of virtually all mammalian cells. They all have a similar molecular architecture, with four long helices that are essential for their function. There are several groups of intermediate filaments, of which keratins are the most diverse, there being more than twenty types of keratin in epithelial cells. The keratinous filaments that make up the cytoskeleton of human epidermal cells are formed by the polymerisation of two different keratin molecules—type I (acidic), and type II (basic). Neither type can polymerise on its own, but any type I and type II molecules can unite to form a filamentous dipolymer. From the Lancet. Epidermolysis bullosa simplex: a disorder of keratin. Lancet 1992; 339:29-30. 500
