The authors present their experience related to the diagnosis, treatment, and followup of 431 patients with bullous pemphigoid, 14 patients with juvenile bullous pemphigoid, and 273 patients with pemphigus. The detection of autoantibodies plays an outstanding role in the diagnosis and differential diagnosis. Paraneoplastic pemphigoid is suggested to be a distinct entity from the group of bullous pemphigoid in view of the linear C3 deposits along the basement membrane of the perilesional skin and the “ladder” configuration of autoantibodies demonstrated by western blot analysis. It is proposed that IgA pemphigoid should be differentiated from the linear IgA dermatoses. Immunosuppressive therapy is recommended in which the maintenance dose of corticosteroid is administered every second day, thereby reducing the side effects of the corticosteroids. Following the detection of IgA antibodies (IgA pemphigoid, linear IgA bullous dermatosis, and IgA pemphigus), diamino diphenyl sulfone (dapsone) therapy is preferred alone or in combination. The clinical relevance of autoantibodies in patients with autoimmune bullous dermatosis is stressed. 1. Introduction The most frequent autoimmune bullous skin disorders are bullous pemphigoid (BP) and pemphigus vulgaris (PV). The diagnosis of both diseases relies not only on the clinical features but also on the detection of skin- or membrane-bound and circulating autoantibodies. We first diagnosed subepidermal bullous dermatosis in 1970 [1] by means of a direct immunofluorescence technique (DIF). We have subsequently examined, diagnosed, treated, and followed up several hundred patients with bullous skin diseases, and in this paper we present our experience in comparison with the literature findings. 2. Patients and Methods Since 1970, we have diagnosed and treated 431 patients with BP (age range 38–102 years, mean 71.6 years), 14 children with juvenile BP (age range 3–14 years, mean 7.5 years), and 273 patients with pemphigus (age range 21–83 years, mean 53.9 years). All clinical investigations were conducted with the understanding and the consent of the patients. We are currently treating 47 patients with pemphigus and 45 with BP. The diagnoses were based on the clinical features and routine histological and immunohistological examinations [2]. For DIF tests, we used the intact skin adjacent to the bulla as substrate and antihuman IgG, IgA, IgM, and C3 conjugates labeled with FITC for antibody detection. For indirect immunofluorescence (IIF) examinations, we used esophagus samples from monkey and rabbit, and normal human
References
[1]
S. Husz, E. Heszler, and L. T？r？k, “Paraneoplasmic bullosis,” Dermatologica, vol. 141, no. 6, pp. 421–427, 1970.
[2]
I. L. Juki？ and B. Marinovi？, “Significance of immunofluorescence in the diagnosis of autoimmune bullous dermatoses,” Clinics in Dermatology, vol. 29, no. 4, pp. 389–397, 2011.
[3]
W. R. Gammon, R. A. Briggaman, and A. O. Inman III, “Differentiating anti-lamina lucida and anti-sublamina densa anti-BMZ antibodies by indirect immunofluorescence on 1.0？M sodium chloride-separated skin,” Journal of Investigative Dermatology, vol. 82, no. 2, pp. 139–144, 1984.
[4]
T. Hashimoto, M. M. Ogawa, A. Konohana, and T. Nishikawa, “Detection of pemphigus vulgaris and pemphigus foliaceus antigens by immunoblot analysis using different antigen sources,” Journal of Investigative Dermatology, vol. 94, no. 3, pp. 327–331, 1990.
[5]
M. Kiss, S. Husz, K. Molnár, and A. Dobozy, “Identification of different circulating autoantibodies in patients with bullous pemphigoid and pemphigus vulgaris by means of immunoblotting,” Acta Microbiologica et Immunologica Hungarica, vol. 43, no. 2-3, pp. 115–123, 1996.
[6]
S. Husz, M. Kiss, K. Molnár et al., “Development of a system for detection of circulating antibodies against hemidesmosomal proteins in patients with bullous pemphigoid,” Archives of Dermatological Research, vol. 292, no. 5, pp. 217–224, 2000.
[7]
I. Laczkó, E. Vass, G. K. Tóth, I. Marczinovits, M. Kiss, and S. Husz, “Conformational consequences of coupling bullous pemphigoid antigenic peptides to glutathione-S-Transferase and their diagnostic significance,” Journal of Peptide Science, vol. 6, no. 8, pp. 378–386, 2000.
[8]
L. Borradori and A. Sonnenberg, “Structure and function of hemidesmosomes: more than simple adhesion complexes,” Journal of Investigative Dermatology, vol. 112, no. 4, pp. 411–418, 1999.
[9]
L. Guo, L. Degenstein, J. Bowling et al., “Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration,” Cell, vol. 81, no. 2, pp. 233–243, 1995.
[10]
C. Ruhrberg and F. M. Watt, “The plakin family: versatile organizers of cytoskeletal architecture,” Current Opinion in Genetics and Development, vol. 7, no. 3, pp. 392–397, 1997.
[11]
K. Molnar, G. Van Der Steege, M. F. Jonkman et al., “Two type XVII collagen (BP180) mRNA transcripts in human keratinocytes: a long and a short form,” Clinical and Experimental Dermatology, vol. 25, no. 1, pp. 71–76, 2000.
[12]
T. Nishiyama, S. Amano, M. Tsunenaga et al., “The importance of laminin 5 in the dermal-epidermal basement membrane,” Journal of Dermatological Science, vol. 24, supplement 1, pp. S51–S59, 2000.
[13]
C. A. Egan and J. J. Zone, “Linear IgA bullous dermatosis,” International Journal of Dermatology, vol. 38, no. 11, pp. 818–827, 1999.
[14]
L. S. Chan, “Ocular and oral mucous membrane pemphigoid (cicatricial pemphigoid),” Clinics in Dermatology, vol. 30, no. 1, pp. 34–37, 2012.
[15]
N. Domloge-Hultsch, G. J. Anhalt, W. R. Gammon et al., “Antiepiligrin cicatricial pemphigoid: a subepithelial bullous disorders,” Archives of Dermatology, vol. 130, no. 12, pp. 1521–1529, 1994.
[16]
M. Kiss, A. Perenyi, I. Marczinovits et al., “Autoantibodies to human α6 integrin in patients with bullous pemphigoid,” Annals of the New York Academy of Sciences, vol. 1051, pp. 104–110, 2005.
[17]
E. Schmidt and D. Zillikens, “Modern diagnosis of autoimmune blistering skin diseases,” Autoimmunity Reviews, vol. 10, no. 2, pp. 84–89, 2010.
[18]
J. Rado？, “Autoimmune blistering diseases: histologic meaning,” Clinics in Dermatology, vol. 29, no. 4, pp. 377–388, 2011.
[19]
N. J. Korman, “Bullous pemphigoid,” Dermatologic Clinics, vol. 11, no. 3, pp. 483–498, 1993.
[20]
K. Csorba, S. Schmidt, F. Florea et al., “Development of an ELISA for sensitive and specific detection of IgA autoantibodies against BP180 in pemphigoid diseases,” Orphanet Journal of Rare Diseases, vol. 6, no. 1, article 31, 2011.
[21]
G. Di Zenzo, R. della Torre, G. Zambruno, and L. Borradori, “Bullous pemphigoid: from the clinic to the bench,” Clinics in Dermatology, vol. 30, no. 1, pp. 3–16, 2012.
[22]
I. Schneider and S. Husz, “Seborrhoic pemphigoid,” Hautarzt, vol. 37, no. 3, pp. 149–151, 1986.
[23]
T. P. Chorzelski, S. Jablonska, and E. Maciejowska, “Coexistence of malignancies with bullous pemphigoid,” Archives of Dermatology, vol. 114, no. 6, p. 964, 1978.
[24]
R. A. C. Graham-Brown, “Bullous pemphigoid with figurate erythema associated with carcinoma of the bronchus,” British Journal of Dermatology, vol. 117, no. 3, pp. 385–388, 1987.
[25]
L. Misery, F. Cambazard, R. Rimokh et al., “Bullous pemphigoid associated with chronic B-cell lymphatic ieukaemia: the anti-230-kDa autoantibody is not synthesized by leukaemic cells,” British Journal of Dermatology, vol. 141, no. 1, pp. 155–157, 1999.
[26]
T. Muramatsu, T. Iida, H. Tada et al., “Bullous pemphigoid associated with internal malignancies: identification of 180-kDa antigen by Western immunoblotting,” British Journal of Dermatology, vol. 135, no. 5, pp. 782–784, 1996.
[27]
B. Lindelof, N. Islam, G. Eklund, and L. Arfors, “Pemphigoid and cancer,” Archives of Dermatology, vol. 126, no. 1, pp. 66–68, 1990.
[28]
V. A. Venning and F. Wojnarowska, “The association of bullous pemphigoid and malignant disease: a case control study,” British Journal of Dermatology, vol. 123, no. 4, pp. 439–445, 1990.
[29]
M. Mehravaran, R. Gyulai, S. Husz, and A. Dobozy, “Drug-induced erythema multiforme-like bullous pemphigoid,” Acta Dermato-Venereologica, vol. 79, no. 3, p. 233, 1999.
[30]
E. Licarete, S. Ganz, M. J. Recknagel et al., “Prevalence of collagen VII-specific autoantibodies in patients with autoimmune and inflammatory diseases,” BMC Immunology, vol. 13, article 16, 2012.
[31]
R. M. Vodegel, M. Kiss, M. C. J. M. De Jong et al., “The use of skin substrates deficient in basement membrane molecules for the diagnosis of subepidermal autoimmune bullous disease,” European Journal of Dermatology, vol. 8, no. 2, pp. 83–85, 1998.
[32]
C. Baykal, G. Okan, and R. Sarica, “Childhood bullous pemphigoid developed after the first vaccination,” Journal of the American Academy of Dermatology, vol. 44, no. 2, supplement, pp. 348–350, 2001.
[33]
Z. Erbagci, “Childhood bullous pemphigoid following hepatitis B immunization,” Journal of Dermatology, vol. 29, no. 12, pp. 781–785, 2002.
[34]
E. Szabo, S. Husz, and L. Kovacs, “Coexistent atypical bullous pemphigoid and systemic lupus erythematosus,” British Journal of Dermatology, vol. 104, no. 1, pp. 71–75, 1981.
[35]
L. Torok, S. Husz, I. Korom, et al., “Bullous systemic lupus erythematosus with malignant papulosis atrophicans and Sch？nlein-Henoch vasculitis symptoms,” Acta Dermatovenerologica Alpina, Pannonica et Adriatica, vol. 2, no. 2, pp. 60–64, 1992.
[36]
R. Gyulai, M. Kiss, M. Mehravaran et al., “Atypical autoimmune blistering dermatosis associated with Sj？gren's syndrome,” Acta Dermato-Venereologica, vol. 82, no. 6, pp. 462–464, 2002.
[37]
L. T？r？k, S. Husz, H. ócsai, et al., “Pemphigus vegetans presenting as acrodermatitis continua suppurativa,” European Journal of Dermatology, vol. 13, no. 6, pp. 579–581, 2003.
[38]
M. Mehravaran, M. Morvay, K. Molnár et al., “Juvenile pemphigus foliaceus,” British Journal of Dermatology, vol. 139, no. 3, pp. 496–499, 1998.
[39]
M. Meurer, “Immunosuppressive therapy for autoimmune bullous diseases,” Clinics in Dermatology, vol. 30, no. 1, pp. 78–83, 2012.
[40]
G. Zambruno and L. Borradori, “Rituximab immunotherapy in pemphigus: therapeutic effects beyond B-cell depletion,” Journal of Investigative Dermatology, vol. 128, no. 12, pp. 2745–2747, 2008.
[41]
M. Kiss, S. Husz, T. Jánossy et al., “Experimental bullous pemphigoid generated in mice with an antigenic epitope of the human hemidesmosomal protein BP230,” Journal of Autoimmunity, vol. 24, no. 1, pp. 1–10, 2005.
[42]
W. F. Lever, “Pemphigus,” Medicine, vol. 32, no. 1, pp. 1–123, 1953.
[43]
E. H. Beutner and R. E. Jordon, “Demonstration of skin antibodies in sera of pemphigus vulgaris patients by indirect immunofluorescent staining,” Proceedings of the Society for Experimental Biology and Medicine, vol. 117, pp. 505–510, 1964.
[44]
R. E. Jordon, E. H. Beutner, E. Witebsky, G. Blumental, W. L. Hale, and W. F. Lever, “Basement zone antibodies in bullous pemphigoid.,” Journal of the American Medical Association, vol. 200, no. 9, pp. 751–756, 1967.
