- Email: [email protected]
Can pemphigus vulgaris become pemphigus foliaceus?
Can pemphigus vulgaris become pemphigus foliaceus? Keiji Iwatsuki, MD,a Masahiro Takigawa, MD,a Takashi Hashimoto, MD,b Takeji Nishikawa, MD,b and Mizuho Yamada, MDa
Hamamatsu and Tokyo, Japan Among 31patients withpemphigus, weobserved twowomen withclinical andhistologic features characteristic of pemphigus vulgaris that later became thoseof pemphigus foliaceus. Western blot study indicated thatserum from one patient,when shehadthecutaneous manifestations ofpemphigus foliaceus, contained antibodies reactive with a desmosoma1 antigen, suggestive ofdesmoglein 1,thesame asrecognized bypemphigus foliaceus serum. Thepresent study suggests that two distinct types of pemphigus can occur in the sameperson simultaneously or separately. (J AM ACAD DERMATOL 1991;25:797-800.)
CASE REPORTS
Pemphigus consistsof two distinctivesubsets: the pemphigus vulgaris (PV) type that includes pemphigus vegetans and the pemphigus foliaceus (PF) type with pemphigus erythematosus as a subtype. Although both disorders have acantholytic bullae in the epidermis, PV is distinct from PF because of frequent mucosalinvolvement and suprabasa1 acantholysis. In contrast, PF is characterized by crusted scales on the face and upper trunk with a histologic feature of subcorneal acantholysis.' Recent studies have demonstrated that PV serum precipitates an epidermal antigen complex of 210, 130, and 85 kd, whereas PF serum binds to a complex of 260, 160, 110, and 85 kd polypeptides that includes desmoglein 1.2-7 Despite these definitions, patients with an intermediate state betweenPV and PF have been reported.s 9 However, there has been no detaileddescriptionof a transition from PV to PF and viceversa. This article describestwo women with the clinical and histologic features of PV at the onset of their illness, in whom PF developed after treatment.
Case 1 A 36-year-old woman was first seeninNovember 1980 with recalcitrant oralerosions and bullae onthe trunk of 2months' duration (Fig. 1,A). Abiopsy specimen showed suprabasal acantholytic blister formation (Fig. 1,B). She received prednisolone, 10to 60 mg/day, and was occasionally given azathioprine, 50mg/day, untilJune 1983. During the next 3 months, scaly, crusted lesions occurred onthe cheeks, trunk, andextremities (Fig. 1, C). Oral involvement andbullae were absent. A biopsy specimen showed acantholysis in the upperlayer ofthe follicularepithelium (Fig. I,D). Noacantholysiswasobserved in the suprabasallayer. Direct immunofluorescence demonstrated deposition of IgG and complement C3 in the intercellular spaces of the epidermis. Intercellular IgG class antibodies to the epidermis of guinea pig lip were detected at a dilution of 1:640 in her serum. Topical and systemic corticosteroid therapy produced gradual clearing. Although she continued to receive prednisolone, 2.5to5mg/dayfor morethan6years, scaly erythematous plaques suggestive of PF occasionally developed on the face and trunk.
From the Departmentof Dermatology, Hamamatsu University School of Medicine"; and the Department of Dermatology, KeioUniversity School of Medicine, Tokyo," Accepted for publication June 4, !991. Reprint requests: K. Iwatsuki,MD, Department of Dermatology, Hamamatsu University School of Medicine, 3600 Handacho, Hamamatsu, 431"31, Japan.
Case 2 A 58-year-old woman was seen in December 1980becauseof an eroded lesion onthescalpof6 months' duration (Fig. 2, A). A biopsy specimen showed a suprabasal cleft in the epidermis that contained acantholytic cells (Fig. 2, B). Deposits of IgG and complement C3 were observed in the intercellular spaces of theepidermis and along the basement membrane zone. Indirect immune-
16/1/31412
797
Journal of the American Academy of Dermatology
798 Iwatsuki et al.
Fig. 1. Case 1. Clinical and histologic features. A, Initial bullae. n, Histologic findings show suprabasal acantholysis. C, Scaly erythematous plaques in same patient approximately 3 years after onset of her illness, which showed subcorneal acantholysis at the hair follicle (D). (B and D, Hematoxylin-eosin stain; B, X150; D, XIOO.) fluorescence disclosed the presence of antibodies to the intercellular spaces of guinea pig epidermis at a dilution of 1:40. We could not find circulating antibodies to the basement membrane zone. The diagnosis of PV was made. The lesions improved gradually in response to topical clobetasol-17-propionate ointment. No recurrence was observed until spring 1981. In June 1981, small scaly erythematous plaques began to appear on the trunk and spread to the face 2 months later (Fig. 2, C). Biopsy specimens demonstrated acantholytic bullae in the subcorneal area (Fig. 2, D). No acantholytic change was observed at the suprabasallevel. Direct immunofluorescence showed deposition of IgG and complement C3 in the intercellular spaces and basement membrane zone of the epidermis. No circulating antibodies reactive with the intercellular spaces of the epidermis were detected in her serum. She was diagnosed as having PF. The cutaneous lesion responded to pred-
nisolone, 60 mg and azathioprine, 100 mg daily. No recurrence has been observed for 5 years without treatments.
Western blot analysis Western blot analysis was performed to determine the molecular weights of epidermal antigens recognized by the serum obtained when clinicalfeatures ofPFdeveloped in patient 1. Detergent lysates of the human whole epidermis and the desmosome-rich fraction from cow snouts were separated on 6% gel by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transblotted onto nitrocellulose paper as described elsewhere.' Representative serum samples obtained from patients with typical PV and PF were used as positive controls. The patient's serum reacted with a 150 kd protein of the desmosomal fraction from cow snout, suggestive of desmoglein 1 (Fig. 3). The same reaction band was
Volume 25 Number 5, Part 1 November 1991
Pemphigus vulgaris-pemphigus foliaceus 799
. .. ....
."0 \
~"
.~
Fig. 2. Case 2. Clinical and histologic features. Initial eroded lesion on the scalp (A) shows suprabasal acantholysis (B). Scaly erythema on the face approximately 1 year later (C) associated with subcorneal acantholysis (D). (B and D, Hematoxylin-eosin stain; H, XIOO; D, XI50.) observed by incubation with the control PF serum. However, no reaction was detected against a 130 to 140 kd protein that is reactive with almost all PV sera. According to a previous report 7 that used the same experimental procedure, approximately two thirds ofPF sera bound to the 150 kd antigen in the desmosome-rich fraction and less frequently reacted with the 150 kd protein in the epidermal extract. These results indicate that the patient's serum contained autoantibodies to the PF but not the PV antigen complex.
DISCUSSION
Of 31 patients with pemphigus we have seen in the past 12 years, two who had the clinical and histologic features of PV at the onset of their illness later developed PF.
It has been debated since the 1960s whether some pemphigus patients can have another type of pemphigus.v 9 Previous reports have described patients with unclassified pemphigus who showed clinical features of PF with histologic findings more compatible with PV and vice versa. 8 , 9 In our series, we also observed one patient who had recalcitrant oral erosions and denuded bullae on the trunk, which was clinically suggestive of PV. However, acantholytic changes were observed in the upper or middle epidermis in the biopsy specimen. In these cases, we have to exclude secondary changes such as degeneration and regeneration of the epidermis as pointed out by Lever and Schaumburg-Lever. I In the present cases, however, this possibility is unlikely
800
Journal of the American Academy of Dermatology
Iwatsuki et al.
A
PS
B ~
3
2
1
3
l
DG 1.
(150)r; 135
150 130
I
!
Fig. 3. Reactions of pemphigus sera with extracts from desmosome fraction ofcow snouts (A) and human whole epidermis (B). Lane l: serum from patient 1 reacted with the 150 kd PF antigen only in the desmosomal fraction; lane 2: control PF serum reacted with the 150 kd antigen in both extracts; lane 3: control PV serum that reacts with 135 kd PV antigen in the desmosomal fraction and with the 130 kd PV antigen in the epidermal extract. This serum also bound to the 150 kd PF antigen only in the desmosome sample. PS, Protein staining; DP, desmoplakin; DO, desmoglein.
because both patients had characteristic features of PV initially and of PF later. Unlike typical PF, however, the biopsy specimen from the scaly lesion in the first patient showed elongation of the rete ridges with an acantholytic change at the hair follicles, suggestive of the histologic features of a late phase of PF. In the second case, we considered a diagnosis ofpemphigus erythematosus because deposits of IgG and C3 were observed along the basement membrane zone. The following factors may be responsible for the present cases: (1) The patients had two different pemphigus antibodies simultaneously that were capable of inducing both PV and PF. (2) The patients initially had PV antibodies and later acquired PF antibodies. (3) Although each of the patients had
one of the pemphigus antibodies, the reactivity of the patient's skin changed to induce a different acantholytic pattern. (4) The patients had antibodies that recognized different epitopes than those detected by ordinary pemphigus antibodies. Western blot analysis demonstrated that a serum sample obtained from the patient (case 1), when she had clinical features ofPF, bound to the desmosomal protein of 150 kd, which is reactive with the majority of PF sera." The serum did not bind to a 130 to 140 kd protein reactive with almost all PV sera. These results indicate that, despite the characteristic PV lesions at the onset of her illness, the patient later had PF autoantibodies and thereby developed the cutaneous lesions ofPF. We should also consider the possibility that the patient did not produce her original PV antibodies and acquired PF antibodies later. Unfortunately, the patient's serum obtained at the onset of PV was not available for the present study, so we cannot provide a definite answer. Eyre and Stanley" clearly showed by immunoprecipitation that some PV sera, in addition to containing antibodies to the PV antigens , have antibodies to the PF antigen complex. They suggested a close relation between PV and PF antigen complexes. REFERENCES 1. Lever WF, Schaumburg-Lever G. Pemphigus. In: Histopathology of the skin. 7th ed. Phil adelphia: JB Lippincott, 1990:116-25. 2. Stanley JR, Koulu L, Thivolet C. Distinction between epidermal antigens binding pemphigus vulgaris and pemphigus foliaceus autoantibodies. J Clin Invest 1984;74:313-20. 3. Jones JCR, Yokoo KM , Goldman RD . Further analysis of pemphigus auto antibodies and their use in studies on the heterogeneity, structure, and function of desmosomes. J Cell BioI 1986,102:1109-17. 4. Labib RS, Cam argo S, Futamura S, et aI. Pemphigus foliaceus antigen: characterization of a kera tinocyte envelope associated pool and preparation of a soluble immunoreactive fragment. J Invest Dermatol 1989;93:272-9. 5. Eyre RW, Stanley JR. Human autoantibodies aga inst a desmosomal protein complex with a calcium-sensitive epitope are characteristic of pemphigus foliaceus patients. J Exp Med 1987;165:1719-24. 6. Eyre R W, Stanley JR. Identification of pemphigus vulgaris antigen extracted from normal human epidermis and comparison with pemphigus foliaceus antigens . J Clin Invest 1988;81:807-12. 7. Hashimoto T, Ogawa M, Konohana A, et al. Detection of pemphigus vulgaris and pemphigus foliaceus antigens by immunoblot analysis using different antigen sources. J Invest Dermatol 1990;94:327-31. 8. Perry HO. Pemphigus foliaceus. Arch Dermatol 196\; 83:106-26. 9. Perry HO, Brunst ing LA. Pemphigus foliaceus ; furth er observations. Arch DermatoI1965;91:10-28.
Hamamatsu and Tokyo, Japan Among 31patients withpemphigus, weobserved twowomen withclinical andhistologic features characteristic of pemphigus vulgaris that later became thoseof pemphigus foliaceus. Western blot study indicated thatserum from one patient,when shehadthecutaneous manifestations ofpemphigus foliaceus, contained antibodies reactive with a desmosoma1 antigen, suggestive ofdesmoglein 1,thesame asrecognized bypemphigus foliaceus serum. Thepresent study suggests that two distinct types of pemphigus can occur in the sameperson simultaneously or separately. (J AM ACAD DERMATOL 1991;25:797-800.)
CASE REPORTS
Pemphigus consistsof two distinctivesubsets: the pemphigus vulgaris (PV) type that includes pemphigus vegetans and the pemphigus foliaceus (PF) type with pemphigus erythematosus as a subtype. Although both disorders have acantholytic bullae in the epidermis, PV is distinct from PF because of frequent mucosalinvolvement and suprabasa1 acantholysis. In contrast, PF is characterized by crusted scales on the face and upper trunk with a histologic feature of subcorneal acantholysis.' Recent studies have demonstrated that PV serum precipitates an epidermal antigen complex of 210, 130, and 85 kd, whereas PF serum binds to a complex of 260, 160, 110, and 85 kd polypeptides that includes desmoglein 1.2-7 Despite these definitions, patients with an intermediate state betweenPV and PF have been reported.s 9 However, there has been no detaileddescriptionof a transition from PV to PF and viceversa. This article describestwo women with the clinical and histologic features of PV at the onset of their illness, in whom PF developed after treatment.
Case 1 A 36-year-old woman was first seeninNovember 1980 with recalcitrant oralerosions and bullae onthe trunk of 2months' duration (Fig. 1,A). Abiopsy specimen showed suprabasal acantholytic blister formation (Fig. 1,B). She received prednisolone, 10to 60 mg/day, and was occasionally given azathioprine, 50mg/day, untilJune 1983. During the next 3 months, scaly, crusted lesions occurred onthe cheeks, trunk, andextremities (Fig. 1, C). Oral involvement andbullae were absent. A biopsy specimen showed acantholysis in the upperlayer ofthe follicularepithelium (Fig. I,D). Noacantholysiswasobserved in the suprabasallayer. Direct immunofluorescence demonstrated deposition of IgG and complement C3 in the intercellular spaces of the epidermis. Intercellular IgG class antibodies to the epidermis of guinea pig lip were detected at a dilution of 1:640 in her serum. Topical and systemic corticosteroid therapy produced gradual clearing. Although she continued to receive prednisolone, 2.5to5mg/dayfor morethan6years, scaly erythematous plaques suggestive of PF occasionally developed on the face and trunk.
From the Departmentof Dermatology, Hamamatsu University School of Medicine"; and the Department of Dermatology, KeioUniversity School of Medicine, Tokyo," Accepted for publication June 4, !991. Reprint requests: K. Iwatsuki,MD, Department of Dermatology, Hamamatsu University School of Medicine, 3600 Handacho, Hamamatsu, 431"31, Japan.
Case 2 A 58-year-old woman was seen in December 1980becauseof an eroded lesion onthescalpof6 months' duration (Fig. 2, A). A biopsy specimen showed a suprabasal cleft in the epidermis that contained acantholytic cells (Fig. 2, B). Deposits of IgG and complement C3 were observed in the intercellular spaces of theepidermis and along the basement membrane zone. Indirect immune-
16/1/31412
797
Journal of the American Academy of Dermatology
798 Iwatsuki et al.
Fig. 1. Case 1. Clinical and histologic features. A, Initial bullae. n, Histologic findings show suprabasal acantholysis. C, Scaly erythematous plaques in same patient approximately 3 years after onset of her illness, which showed subcorneal acantholysis at the hair follicle (D). (B and D, Hematoxylin-eosin stain; B, X150; D, XIOO.) fluorescence disclosed the presence of antibodies to the intercellular spaces of guinea pig epidermis at a dilution of 1:40. We could not find circulating antibodies to the basement membrane zone. The diagnosis of PV was made. The lesions improved gradually in response to topical clobetasol-17-propionate ointment. No recurrence was observed until spring 1981. In June 1981, small scaly erythematous plaques began to appear on the trunk and spread to the face 2 months later (Fig. 2, C). Biopsy specimens demonstrated acantholytic bullae in the subcorneal area (Fig. 2, D). No acantholytic change was observed at the suprabasallevel. Direct immunofluorescence showed deposition of IgG and complement C3 in the intercellular spaces and basement membrane zone of the epidermis. No circulating antibodies reactive with the intercellular spaces of the epidermis were detected in her serum. She was diagnosed as having PF. The cutaneous lesion responded to pred-
nisolone, 60 mg and azathioprine, 100 mg daily. No recurrence has been observed for 5 years without treatments.
Western blot analysis Western blot analysis was performed to determine the molecular weights of epidermal antigens recognized by the serum obtained when clinicalfeatures ofPFdeveloped in patient 1. Detergent lysates of the human whole epidermis and the desmosome-rich fraction from cow snouts were separated on 6% gel by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transblotted onto nitrocellulose paper as described elsewhere.' Representative serum samples obtained from patients with typical PV and PF were used as positive controls. The patient's serum reacted with a 150 kd protein of the desmosomal fraction from cow snout, suggestive of desmoglein 1 (Fig. 3). The same reaction band was
Volume 25 Number 5, Part 1 November 1991
Pemphigus vulgaris-pemphigus foliaceus 799
. .. ....
."0 \
~"
.~
Fig. 2. Case 2. Clinical and histologic features. Initial eroded lesion on the scalp (A) shows suprabasal acantholysis (B). Scaly erythema on the face approximately 1 year later (C) associated with subcorneal acantholysis (D). (B and D, Hematoxylin-eosin stain; H, XIOO; D, XI50.) observed by incubation with the control PF serum. However, no reaction was detected against a 130 to 140 kd protein that is reactive with almost all PV sera. According to a previous report 7 that used the same experimental procedure, approximately two thirds ofPF sera bound to the 150 kd antigen in the desmosome-rich fraction and less frequently reacted with the 150 kd protein in the epidermal extract. These results indicate that the patient's serum contained autoantibodies to the PF but not the PV antigen complex.
DISCUSSION
Of 31 patients with pemphigus we have seen in the past 12 years, two who had the clinical and histologic features of PV at the onset of their illness later developed PF.
It has been debated since the 1960s whether some pemphigus patients can have another type of pemphigus.v 9 Previous reports have described patients with unclassified pemphigus who showed clinical features of PF with histologic findings more compatible with PV and vice versa. 8 , 9 In our series, we also observed one patient who had recalcitrant oral erosions and denuded bullae on the trunk, which was clinically suggestive of PV. However, acantholytic changes were observed in the upper or middle epidermis in the biopsy specimen. In these cases, we have to exclude secondary changes such as degeneration and regeneration of the epidermis as pointed out by Lever and Schaumburg-Lever. I In the present cases, however, this possibility is unlikely
800
Journal of the American Academy of Dermatology
Iwatsuki et al.
A
PS
B ~
3
2
1
3
l
DG 1.
(150)r; 135
150 130
I
!
Fig. 3. Reactions of pemphigus sera with extracts from desmosome fraction ofcow snouts (A) and human whole epidermis (B). Lane l: serum from patient 1 reacted with the 150 kd PF antigen only in the desmosomal fraction; lane 2: control PF serum reacted with the 150 kd antigen in both extracts; lane 3: control PV serum that reacts with 135 kd PV antigen in the desmosomal fraction and with the 130 kd PV antigen in the epidermal extract. This serum also bound to the 150 kd PF antigen only in the desmosome sample. PS, Protein staining; DP, desmoplakin; DO, desmoglein.
because both patients had characteristic features of PV initially and of PF later. Unlike typical PF, however, the biopsy specimen from the scaly lesion in the first patient showed elongation of the rete ridges with an acantholytic change at the hair follicles, suggestive of the histologic features of a late phase of PF. In the second case, we considered a diagnosis ofpemphigus erythematosus because deposits of IgG and C3 were observed along the basement membrane zone. The following factors may be responsible for the present cases: (1) The patients had two different pemphigus antibodies simultaneously that were capable of inducing both PV and PF. (2) The patients initially had PV antibodies and later acquired PF antibodies. (3) Although each of the patients had
one of the pemphigus antibodies, the reactivity of the patient's skin changed to induce a different acantholytic pattern. (4) The patients had antibodies that recognized different epitopes than those detected by ordinary pemphigus antibodies. Western blot analysis demonstrated that a serum sample obtained from the patient (case 1), when she had clinical features ofPF, bound to the desmosomal protein of 150 kd, which is reactive with the majority of PF sera." The serum did not bind to a 130 to 140 kd protein reactive with almost all PV sera. These results indicate that, despite the characteristic PV lesions at the onset of her illness, the patient later had PF autoantibodies and thereby developed the cutaneous lesions ofPF. We should also consider the possibility that the patient did not produce her original PV antibodies and acquired PF antibodies later. Unfortunately, the patient's serum obtained at the onset of PV was not available for the present study, so we cannot provide a definite answer. Eyre and Stanley" clearly showed by immunoprecipitation that some PV sera, in addition to containing antibodies to the PV antigens , have antibodies to the PF antigen complex. They suggested a close relation between PV and PF antigen complexes. REFERENCES 1. Lever WF, Schaumburg-Lever G. Pemphigus. In: Histopathology of the skin. 7th ed. Phil adelphia: JB Lippincott, 1990:116-25. 2. Stanley JR, Koulu L, Thivolet C. Distinction between epidermal antigens binding pemphigus vulgaris and pemphigus foliaceus autoantibodies. J Clin Invest 1984;74:313-20. 3. Jones JCR, Yokoo KM , Goldman RD . Further analysis of pemphigus auto antibodies and their use in studies on the heterogeneity, structure, and function of desmosomes. J Cell BioI 1986,102:1109-17. 4. Labib RS, Cam argo S, Futamura S, et aI. Pemphigus foliaceus antigen: characterization of a kera tinocyte envelope associated pool and preparation of a soluble immunoreactive fragment. J Invest Dermatol 1989;93:272-9. 5. Eyre RW, Stanley JR. Human autoantibodies aga inst a desmosomal protein complex with a calcium-sensitive epitope are characteristic of pemphigus foliaceus patients. J Exp Med 1987;165:1719-24. 6. Eyre R W, Stanley JR. Identification of pemphigus vulgaris antigen extracted from normal human epidermis and comparison with pemphigus foliaceus antigens . J Clin Invest 1988;81:807-12. 7. Hashimoto T, Ogawa M, Konohana A, et al. Detection of pemphigus vulgaris and pemphigus foliaceus antigens by immunoblot analysis using different antigen sources. J Invest Dermatol 1990;94:327-31. 8. Perry HO. Pemphigus foliaceus. Arch Dermatol 196\; 83:106-26. 9. Perry HO, Brunst ing LA. Pemphigus foliaceus ; furth er observations. Arch DermatoI1965;91:10-28.