JAAD ONLINE CASE A case of childhood bullous pemphigoid with IgG and IgA autoantibodies to various domains of BP180 To the Editor: Bullous pemphigoid (BP) is an autoimmune blistering disease that predominantly affects older adults and rarely children.1 The target antigens have been studied in a few cases of childhood BP. Diffuse or annular edematous erythemas developed on the trunk and face, and tense bullae developed on the extremities of a 4-month-old male infant with normal parturition (Fig 1, A-D). There were no mucosal lesions. Peripheral eosinophilia (21%) was found. Direct immunofluorescence of skin biopsy sample revealed subepidermal blister and predominant eosinophil infiltration in the superficial dermis, as well as linear deposition of IgG and C3, but not IgA, to epidermal basement membrane zone. Indirect immunofluorescence demonstrated both IgG and IgA antibodies reactive with epidermal side of 1 mol/L NaCl-split normal human skin. Enzymelinked immunosorbent assay showed positive reactivity with BP180 but not with BP230.
LETTERS Immunoblot analyses of various antigen sources were performed for two sera samples obtained either at the first visit or 10 days later. Faint IgG, but not IgA, reactivity with BP180 in normal human epidermal extracts was found only at day 10 (Fig 2, A). Both IgG and IgA antibodies reacted with recombinant protein of BP180 NC16a domain, being stronger at day 10 (Fig 2, B).2 IgG, but not IgA, antibodies reacted with recombinant protein of BP180 C-terminal domain only at day 10 (Fig 2, C ).3 Both IgG and IgA antibodies reacted with the 120-kDa LAD-1 in concentrated HaCaT cell culture supernatants only at day 10, although IgA reactivity was faint (Fig 2, D).4 From the stronger reactivity of IgG antibodies, we diagnosed childhood BP, although concurrence of lamina lucida-type linear IgA bullous dermatosis (LABD) may be considered. Administration of oral prednisolone in combination with intravenous immunoglobulin, followed by diaminodiphenylsulfone, could not suppress development of skin lesions. Subsequently, three courses of intravenous pulse methylprednisolone were administered, resulting in complete remission. No relapse was observed in the following 3 years.
Fig 1. Childhood bullous pemphigoid. Clinical features on the whole body (A), dorsal foot (B), and sole (C), as well as dorsal hand at higher magnification (D). J AM ACAD DERMATOL
JUNE 2014 e129
e130 Letters
J AM ACAD DERMATOL
JUNE 2014
Fig 2. Childhood bullous pemphigoid (BP). Immunoblot analyses. A, In normal human epidermal extracts, IgG antibodies in control pemphigus vulgaris serum (PV) reacted with the 160-kDa Dsg1 and the 130-kDa Dsg3 (lane 1), IgG antibodies in control paraneoplastic pemphigus serum (PNP) reacted with the 210-kDa envoplakin and the 190-kDa periplakin (lane 2), and IgG antibodies in control BP serum reacted with the 230-kDa BP230 and the 180kDa BP180 (lane 3). B, IgG antibodies in control BP serum (lane 1), but not in normal control serum (lane 2), reacted with recombinant protein (RP) of BP180 NC16a domain. C, IgG antibodies in control anti-BP180 type MMP serum (lane 1), but neither IgG (lane 2) nor IgA (lane 3) antibodies in normal control serum, reacted with RP of BP180 C-terminal domain. D, IgA antibodies in control LABD serum (lane 1), but neither IgG (lane 2) nor IgA (lane 3) antibodies in normal control serum, reacted with the 120-kDa LAD-1 in concentrated HaCaT cell culture supernatants. In all analyses, IgG and IgA antibodies of sera taken from this patient (Patient) at the first visit (d0) and 10 days later (d10) were examined.
Our case showed both IgG and IgA reactivity with various domains of BP180, including NC16a domain specific to BP,2 C-terminal domain specific to antiBP180-type mucous membrane pemphigoid,3 and LAD-1, truncated C-terminal domain of BP180, specific to IgA antibodies in lamina lucida-type LABD.4 Epitope spreading (ES) was reported to occur more frequently during the first 3 months in BP,
suggesting ES as an early phenomenon in BP.5 Consistent with this speculation, our case showed additional and rapidly increased reactivity of both IgG and IgA with various domains of BP180 during just 10 days. In addition, our case showed both IgG and IgA antibodies to various domains of BP180, and should be a good example to study class switching to IgG and IgA in either BP or LABD, although no
J AM ACAD DERMATOL VOLUME 70, NUMBER 6
Letters e131
significant study in this field has been reported for autoimmune bullous diseases. IgG recognition of extracellular domains of BP180 was also reported to be an early and crucial event in development of BP, followed by ES events toward intracytoplasmic domain of BP180 and BP230.5 Our case showed IgG and IgA reactivity with various extracellular domains of BP180, without reactivity with BP230. Manabu Osawa, MD,a Ikuko Ueda-Hayakawa, MD, PhD,a Taiki Isei, MD, PhD,a Ken Yoshimura, MD, PhD,b Shunpei Fukuda, MD, PhD,c Takashi Hashimoto, MD,c,d and Hiroyuki Okamoto, MD, PhDa Department of Dermatologya and Department of Pediatric,b Kansai Medical University, Hirakata; Department of Dermatology,c Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology,d Japan Funding sources: None. Conflicts of interest: None declared. Correspondence to: Manabu Osawa, MD, Department of Dermatology, Kansai Medical University, 15-10, Sonoda-Cho, Moriguchi, Osaka, Japan 570-8507 E-mail: [email protected] REFERENCES 1. Korman N. Bullous pemphigoid. J Am Acad Dermatol 1987;16: 907-24. 2. Matsumura K, Amagai M, Nishikawa T, Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of the 180-kDa bullous pemphigoid antigen. Arch Dermatol Res 1996;288:507-9. 3. Nie Z, Hashimoto T. IgA antibodies of cicatricial pemphigoid sera specifically react with C-terminus of BP180. J Invest Dermatol 1999;112:254-5. 4. Ishii N, Ohyama B, Yamaguchi Z, Hashimoto T. IgA autoantibodies against the NC16a domain of BP180 but not 120-kDa LAD-1 detected in a patient with linear IgA disease. Br J Dermatol 2008;158:1151-3. 5. Di Zenzo G, Thoma-Uszynski S, Calabresi V, Fontao L, Hofmann SC, Lacour JP, et al. Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study. J Invest Dermatol 2011;131:2271-80. http://dx.doi.org/10.1016/j.jaad.2013.06.006
Clavi syphiliticiean unusual presentation of syphilis To the Editor: The clinical manifestations of syphilis, often described as ‘‘the great imitator,’’ are varied and may be neglected or confused with other diseases.1
Fig 1. Clavi syphilitici. Palmar hyperkeratotic plaques and erythematous papules.
Furthermore, in patients with human immunodeficiency virus (HIV), infections often exhibit unusual features.2 A 24-year-old man was referred to our department for a 6-month history of warty lesions on the palms and soles, unresponsive to keratolytic treatment. He reported having sex with men, 3 sexual partners during the past year, and inconsistent condom use. Latent syphilis and HIV infection had been diagnosed 4 years earlier after screening analysis and, at that time, he was appropriately treated with penicillin. Clinical examination revealed well-demarcated hyperkeratotic plaques and some erythematous macules and papules on the palms and on the soles (Fig 1). Exudative pink papules were observed on the scrotum and violet-brown macular plaques were present in the perianal region. A biopsy specimen of a palmar lesion demonstrated hyperkeratosis and a dermal polymorphic infiltrate with histiocytes, plasma cells, and lymphocytes. Warthin-Starry stain did not demonstrate microorganisms, but polymerase chain reaction was positive for Treponema pallidum in the skin lesion sample. Histologic examination of the perianal lesions was consistent with the diagnosis of condyloma acuminata. Routine laboratory tests were normal and tests for hepatitis A, B, and C were negative. HIV viral load was 50,990 copies/mL and CD4 cell count was 308 cell/mm3 (normal range: 500-1000 cells/mm3). A positive Venereal Disease Research Laboratory test (titer 1:32) and a reactive Treponema pallidum particle agglutination assay were obtained, supporting the diagnosis of secondary syphilis. Treatment was performed with a single intramuscular dose of benzathine penicillin (2,400,000 U). Rapid regression of palmoplantar and scrotal lesions
LETTERS Immunoblot analyses of various antigen sources were performed for two sera samples obtained either at the first visit or 10 days later. Faint IgG, but not IgA, reactivity with BP180 in normal human epidermal extracts was found only at day 10 (Fig 2, A). Both IgG and IgA antibodies reacted with recombinant protein of BP180 NC16a domain, being stronger at day 10 (Fig 2, B).2 IgG, but not IgA, antibodies reacted with recombinant protein of BP180 C-terminal domain only at day 10 (Fig 2, C ).3 Both IgG and IgA antibodies reacted with the 120-kDa LAD-1 in concentrated HaCaT cell culture supernatants only at day 10, although IgA reactivity was faint (Fig 2, D).4 From the stronger reactivity of IgG antibodies, we diagnosed childhood BP, although concurrence of lamina lucida-type linear IgA bullous dermatosis (LABD) may be considered. Administration of oral prednisolone in combination with intravenous immunoglobulin, followed by diaminodiphenylsulfone, could not suppress development of skin lesions. Subsequently, three courses of intravenous pulse methylprednisolone were administered, resulting in complete remission. No relapse was observed in the following 3 years.
Fig 1. Childhood bullous pemphigoid. Clinical features on the whole body (A), dorsal foot (B), and sole (C), as well as dorsal hand at higher magnification (D). J AM ACAD DERMATOL
JUNE 2014 e129
e130 Letters
J AM ACAD DERMATOL
JUNE 2014
Fig 2. Childhood bullous pemphigoid (BP). Immunoblot analyses. A, In normal human epidermal extracts, IgG antibodies in control pemphigus vulgaris serum (PV) reacted with the 160-kDa Dsg1 and the 130-kDa Dsg3 (lane 1), IgG antibodies in control paraneoplastic pemphigus serum (PNP) reacted with the 210-kDa envoplakin and the 190-kDa periplakin (lane 2), and IgG antibodies in control BP serum reacted with the 230-kDa BP230 and the 180kDa BP180 (lane 3). B, IgG antibodies in control BP serum (lane 1), but not in normal control serum (lane 2), reacted with recombinant protein (RP) of BP180 NC16a domain. C, IgG antibodies in control anti-BP180 type MMP serum (lane 1), but neither IgG (lane 2) nor IgA (lane 3) antibodies in normal control serum, reacted with RP of BP180 C-terminal domain. D, IgA antibodies in control LABD serum (lane 1), but neither IgG (lane 2) nor IgA (lane 3) antibodies in normal control serum, reacted with the 120-kDa LAD-1 in concentrated HaCaT cell culture supernatants. In all analyses, IgG and IgA antibodies of sera taken from this patient (Patient) at the first visit (d0) and 10 days later (d10) were examined.
Our case showed both IgG and IgA reactivity with various domains of BP180, including NC16a domain specific to BP,2 C-terminal domain specific to antiBP180-type mucous membrane pemphigoid,3 and LAD-1, truncated C-terminal domain of BP180, specific to IgA antibodies in lamina lucida-type LABD.4 Epitope spreading (ES) was reported to occur more frequently during the first 3 months in BP,
suggesting ES as an early phenomenon in BP.5 Consistent with this speculation, our case showed additional and rapidly increased reactivity of both IgG and IgA with various domains of BP180 during just 10 days. In addition, our case showed both IgG and IgA antibodies to various domains of BP180, and should be a good example to study class switching to IgG and IgA in either BP or LABD, although no
J AM ACAD DERMATOL VOLUME 70, NUMBER 6
Letters e131
significant study in this field has been reported for autoimmune bullous diseases. IgG recognition of extracellular domains of BP180 was also reported to be an early and crucial event in development of BP, followed by ES events toward intracytoplasmic domain of BP180 and BP230.5 Our case showed IgG and IgA reactivity with various extracellular domains of BP180, without reactivity with BP230. Manabu Osawa, MD,a Ikuko Ueda-Hayakawa, MD, PhD,a Taiki Isei, MD, PhD,a Ken Yoshimura, MD, PhD,b Shunpei Fukuda, MD, PhD,c Takashi Hashimoto, MD,c,d and Hiroyuki Okamoto, MD, PhDa Department of Dermatologya and Department of Pediatric,b Kansai Medical University, Hirakata; Department of Dermatology,c Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology,d Japan Funding sources: None. Conflicts of interest: None declared. Correspondence to: Manabu Osawa, MD, Department of Dermatology, Kansai Medical University, 15-10, Sonoda-Cho, Moriguchi, Osaka, Japan 570-8507 E-mail: [email protected] REFERENCES 1. Korman N. Bullous pemphigoid. J Am Acad Dermatol 1987;16: 907-24. 2. Matsumura K, Amagai M, Nishikawa T, Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of the 180-kDa bullous pemphigoid antigen. Arch Dermatol Res 1996;288:507-9. 3. Nie Z, Hashimoto T. IgA antibodies of cicatricial pemphigoid sera specifically react with C-terminus of BP180. J Invest Dermatol 1999;112:254-5. 4. Ishii N, Ohyama B, Yamaguchi Z, Hashimoto T. IgA autoantibodies against the NC16a domain of BP180 but not 120-kDa LAD-1 detected in a patient with linear IgA disease. Br J Dermatol 2008;158:1151-3. 5. Di Zenzo G, Thoma-Uszynski S, Calabresi V, Fontao L, Hofmann SC, Lacour JP, et al. Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study. J Invest Dermatol 2011;131:2271-80. http://dx.doi.org/10.1016/j.jaad.2013.06.006
Clavi syphiliticiean unusual presentation of syphilis To the Editor: The clinical manifestations of syphilis, often described as ‘‘the great imitator,’’ are varied and may be neglected or confused with other diseases.1
Fig 1. Clavi syphilitici. Palmar hyperkeratotic plaques and erythematous papules.
Furthermore, in patients with human immunodeficiency virus (HIV), infections often exhibit unusual features.2 A 24-year-old man was referred to our department for a 6-month history of warty lesions on the palms and soles, unresponsive to keratolytic treatment. He reported having sex with men, 3 sexual partners during the past year, and inconsistent condom use. Latent syphilis and HIV infection had been diagnosed 4 years earlier after screening analysis and, at that time, he was appropriately treated with penicillin. Clinical examination revealed well-demarcated hyperkeratotic plaques and some erythematous macules and papules on the palms and on the soles (Fig 1). Exudative pink papules were observed on the scrotum and violet-brown macular plaques were present in the perianal region. A biopsy specimen of a palmar lesion demonstrated hyperkeratosis and a dermal polymorphic infiltrate with histiocytes, plasma cells, and lymphocytes. Warthin-Starry stain did not demonstrate microorganisms, but polymerase chain reaction was positive for Treponema pallidum in the skin lesion sample. Histologic examination of the perianal lesions was consistent with the diagnosis of condyloma acuminata. Routine laboratory tests were normal and tests for hepatitis A, B, and C were negative. HIV viral load was 50,990 copies/mL and CD4 cell count was 308 cell/mm3 (normal range: 500-1000 cells/mm3). A positive Venereal Disease Research Laboratory test (titer 1:32) and a reactive Treponema pallidum particle agglutination assay were obtained, supporting the diagnosis of secondary syphilis. Treatment was performed with a single intramuscular dose of benzathine penicillin (2,400,000 U). Rapid regression of palmoplantar and scrotal lesions
