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Rapid response of IgA pemphigus of subcorneal pustular dermatosis type to treatment with isotretinoin
Rapid response of IgA pemphigus of subcorneal pustular dermatosis type to treatment with isotretinoin Claus Gruss, MD,a Detlef Zillikens, MD,b Takashi Hashimoto, MD,c Masayuki Amagai, MD,d Maximilian Kroiß, MD,a Thomas Vogt, MD,a Michael Landthaler, MD,a and Wilhelm Stolz, MDa Regensburg and Würzburg, Germany, and Kurume and Keio, Japan Diagnosing IgA pemphigus and distinguishing between its 2 subtypes, intraepidermal neutrophilic IgA dermatosis type and subcorneal pustular dermatosis type, is important because treatment of IgA pemphigus has to be different from treatment of other blistering autoimmune dermatoses. We present a patient with subcorneal pustular dermatosis type of IgA pemphigus who rapidly responded to systemic treatment with isotretinoin. Specific diagnosis was established by detecting IgA serum activity to desmocollin 1 by indirect immunofluorescence microscopy on unfixed COS7 cells transfected with desmocollin 1. No IgA or IgG serum reactivity was found to recombinant forms of desmogleins 1 and 3 by an antigen-specific enzyme-linked immunosorbent assay. The disease was not effectively controlled by conventional therapeutic regimens. Systemic treatment with isotretinoin 20 mg daily led to complete clearance of skin lesions within 3 weeks. Assaying IgA serum reactivity to desmocollin 1, desmoglein 1, and desmoglein 3 as a valuable method for establishing the diagnosis and differentiating the 2 subtypes of IgA pemphigus. Isotretinoin was an effective drug in the treatment of subcorneal pustular dermatosis type of IgA pemphigus in this patient. (J Am Acad Dermatol 2000;43:923-6.)
I
n 1982 Wallach et al1 described a patient with a subcorneal pustular dermatosis and monoclonal IgA deposits in the subcorneal zone of the epidermis. Subsequently, multiple similar cases were reported using a variety of different names.2,3 Although various terms have been used for these conditions, including intraepidermal IgA pustulosis4 and intercellular IgA vesiculo-pustular dermatosis,5 we will use the most simple term, IgA pemphigus, throughout this report. IgA pemphigus is characterized by depositions of IgA autoantibodies at epidermal cell surfaces and has been classified into 2 distinct subtypes: intraepidermal neutrophilic IgA dermatosis (IEN type) and subcorneal pustular dermatosis (SPD
This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Departments of Dermatology, Universities of Regensburga and Würzburg,b Germany; and Departments of Dermatology, Universities of Kurumec and Keio,d Japan. Reprint requests: Claus Gruss, MD, Department of Dermatology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany. E-mail: claus.gruss@klinik. uni-regensburg.de Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/4/104002 doi:10.1067/mjd.2000.104002
type).4,6 Clinically, both subtypes of IgA pemphigus present with small blisters and pustules overlaying well-circumscribed erythemas. Histopathologically, a subcorneal pustule (with slight acantholysis in some cases) is seen in the SPD type7 and a pustule formation in the entire epidermis in the IEN type.8 Desmocollin 1, a desmosomal component located primarily in the upper epidermis, has recently been identified as the target antigen of the SPD type. In contrast, in the IEN type, no reactivity of autoantibodies with desmocollin 1, 2, and 3 has been found9; whereas, desmogleins 1 and 3 were suggested as putative target antigens of this disease in single case reports (Table I).10-12 Establishing the exact diagnosis of IgA pemphigus is important because of the different types of therapeutic management. Unlike IgG pemphigus, IgA bullous dermatoses are often not effectively controlled by steroids alone.4,13 In addition, the 2 subtypes of IgA pemphigus differ in therapeutic responsiveness (Table I).4,7,14 For treatment of IgA pemphigus, dapsone, prednisolone, sulfapyridine, etretinate, colchicine, and PUVA have been used but are ineffective in controlling the disease in some cases.4,7 In this study, we describe the successful treatment of a patient with the SPD type of IgA pemphigus with isotretinoin. 923
924 Gruss et al
J AM ACAD DERMATOL NOVEMBER 2000
Fig 1. Left axilla with small flaccid pustules and superficial crusts before initiation of treatment.
Fig 2. Histopathology of lesional skin biopsy. Pustule with neutrophils and few acantholytic cells. (Hematoxylineosin stain; original magnification, ×200.)
Table I. Target antigens, dermatohistopathology, and treatment regimens of the 2 subtypes of IgA pemphigus Type of IgA pemphigus
Target antigen
Histopathology
Subcorneal pustular dermatosis (SPD)
Desmocollin 1
Subcorneal pustule (slight acantholysis in some cases)
Intraepidermal neutrophilic IgA dermatosis (IEN)
Unknown, desmogleins 1 and 3 were suggested in single case reports
Pustule formation in the entire epidermis
Treatment
Dapsone,* prednisolone, colchicine, etretinate, PUVA, sulfapyridine, isotretinoin† Dapsone,* prednisolone, colchicine, antihistamine
*Drug of choice. †Present report.
CASE REPORT A 65-year-old white man with no familial or personal history of skin diseases presented with a blistering eruption that he had for 4 months. On admission, small flaccid pustules and erosions were seen predominantly on the neck and the trunk. The pustules were initially tense but quickly became flaccid, and evolved into dry, scaly, superficial crusts. Within a period of several days, new pustular lesions
appeared over the axillae and groins (Fig 1). Mucous membranes were not involved. Histologic examination of a biopsy specimen from a pustule revealed focal subcorneal clefts with slight acanthosis and polymorphonuclear leukocytes in the blister cavity (Fig 2). Direct immunofluorescence microscopy of perilesional skin was obtained at 2 different occasions. Both times, intercellular deposits of IgA were found predominantly in the upper epidermis (Fig
J AM ACAD DERMATOL VOLUME 43, NUMBER 5
3). No IgG, IgM, or C3 deposits were detected. Indirect immunofluorescence microscopy was performed on monkey and guinea pig esophagi, as well as on normal human skin sections, but revealed no circulating IgA of IgG autoantibodies. However, by indirect immunofluorescence microscopy on unfixed COS7 cells transfected with desmocollin 1, IgA autoantibodies to the cell surface were detected in the patient’s serum; whereas the serum of a healthy control subject was negative (not shown). Immunoblot analysis of epidermal extracts was performed as described previously15 but revealed no specific IgA or IgG reactivity in the patient’s serum. In addition, the serum was assayed for IgA and IgG reactivity with recombinant forms of desmogleins 1 and 3 using a recently reported antigen-specific enzyme-linked immunosorbent assay,16 but no reactivity was detected. Further investigations, including extensive laboratory investigations, glucose-6-dehydrogenase levels, chest x-ray films, abdominal ultrasound, gastroscopy, and colonoscopy, were normal. The patient was treated with oral prednisolone 100 mg orally once a day, but he continued to develop new blisters. After 5 days, dapsone was added, initially 50 mg/d, and 2 days later the dosage was increased to 100 mg/d. This treatment regimen stopped the progression of the disease and oral corticosteroids were tapered and subsequently stopped. However, 1 week after initiation of dapsone, the patient developed fatigue, nausea, fever, and malaise. Laboratory studies demonstrated signs of toxic liver dysfunction, with elevated serum levels of bilirubin, serum glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase, and dapsone was discontinued. Within several days after discontinuation of dapsone, a widespread eruption of blisters recurred. Subsequently, isotretinoin 20 mg once a day was initiated. Within 4 days, this treatment led to a striking improvement of skin lesions, and lesions disappeared completely within the following 3 weeks. No side effects of isotretinoin were observed, and no relapse occurred at this dosage over the following 6 months. At the end of this time, indirect immunofluorescence microscopy on unfixed COS7 cells transfected with desmocollin 1 demonstrated a decreased labeling, but IgA autoantibodies to the cell surface could still be detected in the patient’s serum. Treatment of isotretinoin was tapered to 10 mg once a day and the disease is still controlled at this dosage.
DISCUSSION The diagnosis of blistering diseases with intraepidermal IgA deposits is important because of the therapeutic management required. Unlike IgG pem-
Gruss et al 925
Fig 3. Direct immunofluorescence microscopy of perilesional skin biopsy specimen. Intercellular deposition of IgA predominantly in upper layers of the epidermis. (Hematoxylin-eosin stain; original magnification, ×400.)
phigus, IgA-mediated bullous dermatoses are often not effectively controlled by steroids, and even the 2 subtypes of IgA pemphigus, ie, the SPD and the IEN type, may respond differently to treatment.4,7,14 Immunoelectron microscopic studies found IgA deposits within the intercellular spaces accumulating in the region of desmosomes in the upper epidermis in the SPD type of IgA pemphigus.17,18 In the IEN type, however, IgA deposits were found localized uniformly in the intercellular spaces along the keratinocyte membrane, predominantly in the stratum spinosum.3,12,18 By indirect immunofluorescence on COS7 cells transfected with desmocollin 1, our patient’s serum showed IgA autoantibodies to this protein. In contrast, no IgA or IgG reactivity was found with desmoglein 1 and desmoglein 3. Therefore, together with the clinical and histopathologic findings, the patient was diagnosed as having the SPD type of IgA pemphigus. For treatment of both types of IgA pemphigus, dapsone is commonly the drug of choice, but it may have to be discontinued because of systemic side effects.3 Furthermore, both types of IgA pemphigus have been described to respond to topical and systemic steroids and colchicine. In addition, treatments with etretinate, PUVA, and sulfapyridine have been successfully used for the subcorneal pustular dermatosis type of IgA pemphigus (SPD); whereas only antihistamines have been described as additional therapeutic modality for the intraepidermal neutrophilic dermatosis type of IgA pemphigus (IEN). All treatment modalities have been described to control disease for a period, either alone or in various combinations with each other,3,7,14 and are delineated in Table I. However, some cases fail to respond to all currently known therapeutic modalities, especially if dapsone has to be discontinued because
926 Gruss et al
of systemic side effects.4,7 In our case, isotretinoin led to a complete clearance of skin disease within 3 weeks, and no relapse has been observed over the following 9 months. The exact mode of action of retinoids and sulfones in the treatment of IgA-mediated dermatoses is unknown. However, their interaction with neutrophils seems to be of importance. Unlike the histopathologic finding of typical IgG-mediated pemphigus, which is characterized by an eosinophilic infiltration, IgA-mediated dermatoses such as IgA pemphigus, dermatitis herpetiformis, and linear IgA bullous dermatosis demonstrate prominent neutrophilic infiltrations. The specific binding site for the IgA-Fc receptor (CD89) at the constant domain of human IgA distal to the hinge region19 is thought to provide resistance to protease digestion, thus allowing for efficient binding of neutrophils, and may be responsible for the prominent neutrophilic infiltration as well as for the concomitantly induced acantholysis in IgA pemphigus.19,20 Antiinflammatory drugs such as retinoids may interrupt this pathogenetic process, because they inhibit migration of neutrophils and monocytes, thereby repressing accumulation of neutrophils and their destructive actions at the antigen binding site. Isotretinoin is especially postulated to produce significant antiinflammatory effects by the inhibition of monocyte and neutrophil chemotaxis across biologic barriers.21 We present a case of subcorneal pustular dermatosis type of IgA pemphigus that rapidly responded to treatment with isotretinoin. Further clinical studies are needed to evaluate the effectiveness of isotretinoin in treatment of this disease and its value, compared with other therapeutic regimens. Our report also elucidates the importance of an exact diagnosis because the treatment of IgA pemphigus has to be different from the treatment of other blistering autoimmune dermatoses. Isotretinoin might also be of therapeutic value in other conditions with pronounced involvement of neutrophils. REFERENCES 1. Wallach D, Cottenot F, Pelbois G, Cavelier B, Didierjean L, Saurat JH. Subcorneal pustular dermatosis and monoclonal IgA. Br J Dermatol 1982;107:229-34. 2. Hodak E, David M, Ingber A, Rotem A, Hazaz B, Shamai-Lubovitz O, et al. The clinical and histopathological spectrum of IgApemphigus—report of two cases. Clin Exp Dermatol 1990; 15:433-7. 3. Kim SC, Won JH, Chung J, Bang DS. IgA pemphigus: report of a case with immunoelectron localization of bound IgA in the skin. J Am Acad Dermatol 1996;34:852-4. 4. Wallach D. Intraepidermal IgA pustulosis. J Am Acad Dermatol 1992;27:993-1000.
J AM ACAD DERMATOL NOVEMBER 2000
5. Iwatsuki K, Hashimoto T, Ebihara T, Teraki Y, Nishikawa T, et al. Intercellular IgA vesiculo-pustular dermatosis and related disorders: diversity of IgA anti-intercellular autoantibodies. Eur J Dermatol 1993;3:7-11. 6. Supapannachart N, Mutaism DF. The distribution of IgA pemphigus antigen in human skin and the role of IgA anti-cell surface antibodies in the introduction of intraepidermal acantholysis. Arch Dermatol 1993;129:605-8. 7. Beutner EH, Chorzelski TP, Wilson RM, Kumar V, Michel B, Helm F, et al. IgA pemphigus foliaceus: report of two cases and a review of the literature. J Am Acad Dermatol 1989;20:89-97. 8. Ebihara T, Hashimoto T, Iwatsuki K, Takigawa M, Ando M, Ohkawara A, et al. Autoantigens for IgA anti-intercellular antibodies of intercellular IgA vesiculopustular dermatosis. J Invest Dermatol 1991;97:742-5. 9. Hashimoto T, Kiyokawa C, Mori O, Miyasato M, Chidgey MA, Garrod DR, et al. Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 1997;109:127-31. 10. Wang J, Kwon J, Ding X, Fairley JA, Woodley DT, Chan LS. Nonsecretory IgA1 autoantibodies targeting desmosomal component desmoglein 3 in intraepidermal neutrophilic IgA dermatosis. Am J Pathol 1997;150:1901-7. 11. Karpati S, Amagai M, Li LW, Dochmowski D, Hashimoto T, Horvath A. Identification of desmoglein1 as autoantigen in a patient with intraepidermal neutrophilic type of IgA pemphigus. Exp Dermatol 2000;9:224-8. 12. Prost C, Intrator L, Wechsler J, Lebbe C, Bagot M, Roujeau JC, et al. IgA autoantibodies bind to pemphigus vulgaris antigen in a case of intraepidermal neutrophilic IgA dermatosis. J Am Acad Dermatol 1991;25:846-8. 13. Zillikens D, Miller K, Hartmann AA, Burg G. IgA pemphigus foliaceus: a case report. Dermatologica 1990;181:304-7. 14. Inazumi T, Kikuchi A, Hanyaku H, Hashimoto T, Nishikawa T. Intercellular IgA vesiculopustular dermatosis: an additional case and a review of the literature. Eur J Dermatol 1997;7:503-7. 15. Zillikens D, Kawahara Y, Ishiko A, Shimizu H, Mayer J, Rank CV, et al. A novel subepidermal blistering disease with autoantibodies to a 200-kDa antigen of the basement membrane zone. J Invest Dermatol 1996;106:1333-8. 16. Ishii K, Amagai M, Hall RP, Hashimoto T, Takayanagi A, Gamou S, et al. Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J Immunol 1997;159:2010-7. 17. Stolz W, Bieber T, Meurer M. Is the atypical neutrophilic dermatosis with subcorneal IgA deposits a variant of pemphigus foliaceus. Br J Dermatol 1989;121:276-9. 18. Akiyama M, Hashimoto T, Sugiura M, Nishikawa T. Ultrastructural localization of autoantigens of intercellular IgA vesiculopustular dermatosis in cultuted human squamous cell carcinoma cells. Arch Dermatol Res 1992;284:371-3. 19. Carayannopoulos L, Hexham JM, Capra JD. Localization of the binding site for monocyte IgA-Fc receptor (CD89) to the domains boundary Cγ2 and Cγ3 in human IgA1. J Exp Med 1996;183:1579-86. 20. Weisbart RH, Kacena A, Schuh A, Golde DW. GM-CSF induces human neutrophilic IgA-mediated phagocytosis by an IgA Fc receptor activation mechanism. Nature 1988;332:647-8. 21. Norris DA, Osborn R, Robinson W, Tonnesen MG. Isotretinoin produces significant inhibition of monocyte and neutrophil chemotaxis in vivo in patients with cystic acne. J Invest Dermatol 1987;89:38-43.
I
n 1982 Wallach et al1 described a patient with a subcorneal pustular dermatosis and monoclonal IgA deposits in the subcorneal zone of the epidermis. Subsequently, multiple similar cases were reported using a variety of different names.2,3 Although various terms have been used for these conditions, including intraepidermal IgA pustulosis4 and intercellular IgA vesiculo-pustular dermatosis,5 we will use the most simple term, IgA pemphigus, throughout this report. IgA pemphigus is characterized by depositions of IgA autoantibodies at epidermal cell surfaces and has been classified into 2 distinct subtypes: intraepidermal neutrophilic IgA dermatosis (IEN type) and subcorneal pustular dermatosis (SPD
This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Departments of Dermatology, Universities of Regensburga and Würzburg,b Germany; and Departments of Dermatology, Universities of Kurumec and Keio,d Japan. Reprint requests: Claus Gruss, MD, Department of Dermatology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany. E-mail: claus.gruss@klinik. uni-regensburg.de Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/4/104002 doi:10.1067/mjd.2000.104002
type).4,6 Clinically, both subtypes of IgA pemphigus present with small blisters and pustules overlaying well-circumscribed erythemas. Histopathologically, a subcorneal pustule (with slight acantholysis in some cases) is seen in the SPD type7 and a pustule formation in the entire epidermis in the IEN type.8 Desmocollin 1, a desmosomal component located primarily in the upper epidermis, has recently been identified as the target antigen of the SPD type. In contrast, in the IEN type, no reactivity of autoantibodies with desmocollin 1, 2, and 3 has been found9; whereas, desmogleins 1 and 3 were suggested as putative target antigens of this disease in single case reports (Table I).10-12 Establishing the exact diagnosis of IgA pemphigus is important because of the different types of therapeutic management. Unlike IgG pemphigus, IgA bullous dermatoses are often not effectively controlled by steroids alone.4,13 In addition, the 2 subtypes of IgA pemphigus differ in therapeutic responsiveness (Table I).4,7,14 For treatment of IgA pemphigus, dapsone, prednisolone, sulfapyridine, etretinate, colchicine, and PUVA have been used but are ineffective in controlling the disease in some cases.4,7 In this study, we describe the successful treatment of a patient with the SPD type of IgA pemphigus with isotretinoin. 923
924 Gruss et al
J AM ACAD DERMATOL NOVEMBER 2000
Fig 1. Left axilla with small flaccid pustules and superficial crusts before initiation of treatment.
Fig 2. Histopathology of lesional skin biopsy. Pustule with neutrophils and few acantholytic cells. (Hematoxylineosin stain; original magnification, ×200.)
Table I. Target antigens, dermatohistopathology, and treatment regimens of the 2 subtypes of IgA pemphigus Type of IgA pemphigus
Target antigen
Histopathology
Subcorneal pustular dermatosis (SPD)
Desmocollin 1
Subcorneal pustule (slight acantholysis in some cases)
Intraepidermal neutrophilic IgA dermatosis (IEN)
Unknown, desmogleins 1 and 3 were suggested in single case reports
Pustule formation in the entire epidermis
Treatment
Dapsone,* prednisolone, colchicine, etretinate, PUVA, sulfapyridine, isotretinoin† Dapsone,* prednisolone, colchicine, antihistamine
*Drug of choice. †Present report.
CASE REPORT A 65-year-old white man with no familial or personal history of skin diseases presented with a blistering eruption that he had for 4 months. On admission, small flaccid pustules and erosions were seen predominantly on the neck and the trunk. The pustules were initially tense but quickly became flaccid, and evolved into dry, scaly, superficial crusts. Within a period of several days, new pustular lesions
appeared over the axillae and groins (Fig 1). Mucous membranes were not involved. Histologic examination of a biopsy specimen from a pustule revealed focal subcorneal clefts with slight acanthosis and polymorphonuclear leukocytes in the blister cavity (Fig 2). Direct immunofluorescence microscopy of perilesional skin was obtained at 2 different occasions. Both times, intercellular deposits of IgA were found predominantly in the upper epidermis (Fig
J AM ACAD DERMATOL VOLUME 43, NUMBER 5
3). No IgG, IgM, or C3 deposits were detected. Indirect immunofluorescence microscopy was performed on monkey and guinea pig esophagi, as well as on normal human skin sections, but revealed no circulating IgA of IgG autoantibodies. However, by indirect immunofluorescence microscopy on unfixed COS7 cells transfected with desmocollin 1, IgA autoantibodies to the cell surface were detected in the patient’s serum; whereas the serum of a healthy control subject was negative (not shown). Immunoblot analysis of epidermal extracts was performed as described previously15 but revealed no specific IgA or IgG reactivity in the patient’s serum. In addition, the serum was assayed for IgA and IgG reactivity with recombinant forms of desmogleins 1 and 3 using a recently reported antigen-specific enzyme-linked immunosorbent assay,16 but no reactivity was detected. Further investigations, including extensive laboratory investigations, glucose-6-dehydrogenase levels, chest x-ray films, abdominal ultrasound, gastroscopy, and colonoscopy, were normal. The patient was treated with oral prednisolone 100 mg orally once a day, but he continued to develop new blisters. After 5 days, dapsone was added, initially 50 mg/d, and 2 days later the dosage was increased to 100 mg/d. This treatment regimen stopped the progression of the disease and oral corticosteroids were tapered and subsequently stopped. However, 1 week after initiation of dapsone, the patient developed fatigue, nausea, fever, and malaise. Laboratory studies demonstrated signs of toxic liver dysfunction, with elevated serum levels of bilirubin, serum glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase, and dapsone was discontinued. Within several days after discontinuation of dapsone, a widespread eruption of blisters recurred. Subsequently, isotretinoin 20 mg once a day was initiated. Within 4 days, this treatment led to a striking improvement of skin lesions, and lesions disappeared completely within the following 3 weeks. No side effects of isotretinoin were observed, and no relapse occurred at this dosage over the following 6 months. At the end of this time, indirect immunofluorescence microscopy on unfixed COS7 cells transfected with desmocollin 1 demonstrated a decreased labeling, but IgA autoantibodies to the cell surface could still be detected in the patient’s serum. Treatment of isotretinoin was tapered to 10 mg once a day and the disease is still controlled at this dosage.
DISCUSSION The diagnosis of blistering diseases with intraepidermal IgA deposits is important because of the therapeutic management required. Unlike IgG pem-
Gruss et al 925
Fig 3. Direct immunofluorescence microscopy of perilesional skin biopsy specimen. Intercellular deposition of IgA predominantly in upper layers of the epidermis. (Hematoxylin-eosin stain; original magnification, ×400.)
phigus, IgA-mediated bullous dermatoses are often not effectively controlled by steroids, and even the 2 subtypes of IgA pemphigus, ie, the SPD and the IEN type, may respond differently to treatment.4,7,14 Immunoelectron microscopic studies found IgA deposits within the intercellular spaces accumulating in the region of desmosomes in the upper epidermis in the SPD type of IgA pemphigus.17,18 In the IEN type, however, IgA deposits were found localized uniformly in the intercellular spaces along the keratinocyte membrane, predominantly in the stratum spinosum.3,12,18 By indirect immunofluorescence on COS7 cells transfected with desmocollin 1, our patient’s serum showed IgA autoantibodies to this protein. In contrast, no IgA or IgG reactivity was found with desmoglein 1 and desmoglein 3. Therefore, together with the clinical and histopathologic findings, the patient was diagnosed as having the SPD type of IgA pemphigus. For treatment of both types of IgA pemphigus, dapsone is commonly the drug of choice, but it may have to be discontinued because of systemic side effects.3 Furthermore, both types of IgA pemphigus have been described to respond to topical and systemic steroids and colchicine. In addition, treatments with etretinate, PUVA, and sulfapyridine have been successfully used for the subcorneal pustular dermatosis type of IgA pemphigus (SPD); whereas only antihistamines have been described as additional therapeutic modality for the intraepidermal neutrophilic dermatosis type of IgA pemphigus (IEN). All treatment modalities have been described to control disease for a period, either alone or in various combinations with each other,3,7,14 and are delineated in Table I. However, some cases fail to respond to all currently known therapeutic modalities, especially if dapsone has to be discontinued because
926 Gruss et al
of systemic side effects.4,7 In our case, isotretinoin led to a complete clearance of skin disease within 3 weeks, and no relapse has been observed over the following 9 months. The exact mode of action of retinoids and sulfones in the treatment of IgA-mediated dermatoses is unknown. However, their interaction with neutrophils seems to be of importance. Unlike the histopathologic finding of typical IgG-mediated pemphigus, which is characterized by an eosinophilic infiltration, IgA-mediated dermatoses such as IgA pemphigus, dermatitis herpetiformis, and linear IgA bullous dermatosis demonstrate prominent neutrophilic infiltrations. The specific binding site for the IgA-Fc receptor (CD89) at the constant domain of human IgA distal to the hinge region19 is thought to provide resistance to protease digestion, thus allowing for efficient binding of neutrophils, and may be responsible for the prominent neutrophilic infiltration as well as for the concomitantly induced acantholysis in IgA pemphigus.19,20 Antiinflammatory drugs such as retinoids may interrupt this pathogenetic process, because they inhibit migration of neutrophils and monocytes, thereby repressing accumulation of neutrophils and their destructive actions at the antigen binding site. Isotretinoin is especially postulated to produce significant antiinflammatory effects by the inhibition of monocyte and neutrophil chemotaxis across biologic barriers.21 We present a case of subcorneal pustular dermatosis type of IgA pemphigus that rapidly responded to treatment with isotretinoin. Further clinical studies are needed to evaluate the effectiveness of isotretinoin in treatment of this disease and its value, compared with other therapeutic regimens. Our report also elucidates the importance of an exact diagnosis because the treatment of IgA pemphigus has to be different from the treatment of other blistering autoimmune dermatoses. Isotretinoin might also be of therapeutic value in other conditions with pronounced involvement of neutrophils. REFERENCES 1. Wallach D, Cottenot F, Pelbois G, Cavelier B, Didierjean L, Saurat JH. Subcorneal pustular dermatosis and monoclonal IgA. Br J Dermatol 1982;107:229-34. 2. Hodak E, David M, Ingber A, Rotem A, Hazaz B, Shamai-Lubovitz O, et al. The clinical and histopathological spectrum of IgApemphigus—report of two cases. Clin Exp Dermatol 1990; 15:433-7. 3. Kim SC, Won JH, Chung J, Bang DS. IgA pemphigus: report of a case with immunoelectron localization of bound IgA in the skin. J Am Acad Dermatol 1996;34:852-4. 4. Wallach D. Intraepidermal IgA pustulosis. J Am Acad Dermatol 1992;27:993-1000.
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5. Iwatsuki K, Hashimoto T, Ebihara T, Teraki Y, Nishikawa T, et al. Intercellular IgA vesiculo-pustular dermatosis and related disorders: diversity of IgA anti-intercellular autoantibodies. Eur J Dermatol 1993;3:7-11. 6. Supapannachart N, Mutaism DF. The distribution of IgA pemphigus antigen in human skin and the role of IgA anti-cell surface antibodies in the introduction of intraepidermal acantholysis. Arch Dermatol 1993;129:605-8. 7. Beutner EH, Chorzelski TP, Wilson RM, Kumar V, Michel B, Helm F, et al. IgA pemphigus foliaceus: report of two cases and a review of the literature. J Am Acad Dermatol 1989;20:89-97. 8. Ebihara T, Hashimoto T, Iwatsuki K, Takigawa M, Ando M, Ohkawara A, et al. Autoantigens for IgA anti-intercellular antibodies of intercellular IgA vesiculopustular dermatosis. J Invest Dermatol 1991;97:742-5. 9. Hashimoto T, Kiyokawa C, Mori O, Miyasato M, Chidgey MA, Garrod DR, et al. Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 1997;109:127-31. 10. Wang J, Kwon J, Ding X, Fairley JA, Woodley DT, Chan LS. Nonsecretory IgA1 autoantibodies targeting desmosomal component desmoglein 3 in intraepidermal neutrophilic IgA dermatosis. Am J Pathol 1997;150:1901-7. 11. Karpati S, Amagai M, Li LW, Dochmowski D, Hashimoto T, Horvath A. Identification of desmoglein1 as autoantigen in a patient with intraepidermal neutrophilic type of IgA pemphigus. Exp Dermatol 2000;9:224-8. 12. Prost C, Intrator L, Wechsler J, Lebbe C, Bagot M, Roujeau JC, et al. IgA autoantibodies bind to pemphigus vulgaris antigen in a case of intraepidermal neutrophilic IgA dermatosis. J Am Acad Dermatol 1991;25:846-8. 13. Zillikens D, Miller K, Hartmann AA, Burg G. IgA pemphigus foliaceus: a case report. Dermatologica 1990;181:304-7. 14. Inazumi T, Kikuchi A, Hanyaku H, Hashimoto T, Nishikawa T. Intercellular IgA vesiculopustular dermatosis: an additional case and a review of the literature. Eur J Dermatol 1997;7:503-7. 15. Zillikens D, Kawahara Y, Ishiko A, Shimizu H, Mayer J, Rank CV, et al. A novel subepidermal blistering disease with autoantibodies to a 200-kDa antigen of the basement membrane zone. J Invest Dermatol 1996;106:1333-8. 16. Ishii K, Amagai M, Hall RP, Hashimoto T, Takayanagi A, Gamou S, et al. Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J Immunol 1997;159:2010-7. 17. Stolz W, Bieber T, Meurer M. Is the atypical neutrophilic dermatosis with subcorneal IgA deposits a variant of pemphigus foliaceus. Br J Dermatol 1989;121:276-9. 18. Akiyama M, Hashimoto T, Sugiura M, Nishikawa T. Ultrastructural localization of autoantigens of intercellular IgA vesiculopustular dermatosis in cultuted human squamous cell carcinoma cells. Arch Dermatol Res 1992;284:371-3. 19. Carayannopoulos L, Hexham JM, Capra JD. Localization of the binding site for monocyte IgA-Fc receptor (CD89) to the domains boundary Cγ2 and Cγ3 in human IgA1. J Exp Med 1996;183:1579-86. 20. Weisbart RH, Kacena A, Schuh A, Golde DW. GM-CSF induces human neutrophilic IgA-mediated phagocytosis by an IgA Fc receptor activation mechanism. Nature 1988;332:647-8. 21. Norris DA, Osborn R, Robinson W, Tonnesen MG. Isotretinoin produces significant inhibition of monocyte and neutrophil chemotaxis in vivo in patients with cystic acne. J Invest Dermatol 1987;89:38-43.