UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Epidemiology and pathogenesis of bullous pemphigoid and mucous membrane pemphigoid

Author
Kristin M Leiferman, MD
Section Editor
John J Zone, MD
Deputy Editor
Abena O Ofori, MD

INTRODUCTION

Bullous pemphigoid and mucous membrane pemphigoid (MMP) are uncommon autoimmune subepithelial blistering diseases that most frequently arise in older adults and are characterized by the presence of cutaneous bullae and erosive mucosal lesions. Significant progress has been made in understanding the pathogenesis of these diseases. Multiple events, including the binding of immunoglobulins to basement membrane zone components, the subsequent activation of complement, and the migration of inflammatory cells into the subepithelial tissue, likely contribute to the clinical manifestations of bullous pemphigoid and MMP.

The epidemiology and pathogenesis of bullous pemphigoid and MMP will be reviewed here. The clinical features, diagnosis, and treatment of these disorders and greater detail on the ocular form of MMP (ocular cicatricial pemphigoid) are available separately. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Management and prognosis of bullous pemphigoid" and "Management of mucous membrane pemphigoid" and "Ocular cicatricial pemphigoid".)

CLASSIFICATION

Pemphigoid disorders, which include bullous pemphigoid, MMP, anti-laminin 332 pemphigoid (also known as anti-epiligrin cicatricial pemphigoid), pemphigoid gestationis, Brunsting-Perry pemphigoid, and anti-laminin gamma-1 (anti-p200) pemphigoid are characterized clinically by the presence of inflammatory, blistering, and/or erosive mucocutaneous lesions, and immunohistopathologically by subepithelial cleavage and IgG and/or complement deposits at the epidermal basement membrane zone (picture 1A-B). The location of blistering and immunoglobulin deposition distinguishes pemphigoid disorders from pemphigus. In pemphigus, blister formation and antibody deposition occur within the epidermis/epithelium (picture 2A-B) [1]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Pathogenesis, clinical manifestations, and diagnosis of pemphigus".)

MMP is not a single disease, rather it represents a group of heterogeneous, chronic subepithelial blistering diseases that primarily affect mucosal surfaces [2]. Historically, because of the scarring sequelae that may develop clinically, the term cicatricial pemphigoid was ascribed to diseases now categorized as MMP.

Some authors also consider mucosal-predominant forms of linear IgA bullous dermatosis and epidermolysis bullosa acquisita as forms of MMP [2]. However, our preference is to consider these diagnoses as distinct disease entities. (See "Linear IgA bullous dermatosis" and "Epidermolysis bullosa acquisita".)

                

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Tue Apr 26 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Baum S, Sakka N, Artsi O, et al. Diagnosis and classification of autoimmune blistering diseases. Autoimmun Rev 2014; 13:482.
  2. Chan LS, Ahmed AR, Anhalt GJ, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol 2002; 138:370.
  3. Marazza G, Pham HC, Schärer L, et al. Incidence of bullous pemphigoid and pemphigus in Switzerland: a 2-year prospective study. Br J Dermatol 2009; 161:861.
  4. Schmidt E, della Torre R, Borradori L. Clinical features and practical diagnosis of bullous pemphigoid. Dermatol Clin 2011; 29:427.
  5. Joly P, Baricault S, Sparsa A, et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol 2012; 132:1998.
  6. Försti AK, Jokelainen J, Timonen M, Tasanen K. Increasing incidence of bullous pemphigoid in Northern Finland: a retrospective database study in Oulu University Hospital. Br J Dermatol 2014; 171:1223.
  7. Brick KE, Weaver CH, Lohse CM, et al. Incidence of bullous pemphigoid and mortality of patients with bullous pemphigoid in Olmsted County, Minnesota, 1960 through 2009. J Am Acad Dermatol 2014; 71:92.
  8. Kulthanan K, Chularojanamontri L, Tuchinda P, et al. Prevalence and clinical features of Thai patients with bullous pemphigoid. Asian Pac J Allergy Immunol 2011; 29:66.
  9. Adam BA. Bullous diseases in Malaysia: epidemiology and natural history. Int J Dermatol 1992; 31:42.
  10. Lara-Corrales I, Pope E. Autoimmune blistering diseases in children. Semin Cutan Med Surg 2010; 29:85.
  11. Bastuji-Garin S, Joly P, Lemordant P, et al. Risk factors for bullous pemphigoid in the elderly: a prospective case-control study. J Invest Dermatol 2011; 131:637.
  12. Fisler RE, Saeb M, Liang MG, et al. Childhood bullous pemphigoid: a clinicopathologic study and review of the literature. Am J Dermatopathol 2003; 25:183.
  13. Zhao CY, Chiang YZ, Murrell DF. Neonatal Autoimmune Blistering Disease: A Systematic Review. Pediatr Dermatol 2016; 33:367.
  14. Langan SM, Smeeth L, Hubbard R, et al. Bullous pemphigoid and pemphigus vulgaris--incidence and mortality in the UK: population based cohort study. BMJ 2008; 337:a180.
  15. Bertram F, Bröcker EB, Zillikens D, Schmidt E. Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany. J Dtsch Dermatol Ges 2009; 7:434.
  16. Kharfi M, Khaled A, Anane R, et al. Early onset childhood cicatricial pemphigoid: a case report and review of the literature. Pediatr Dermatol 2010; 27:119.
  17. Knudson RM, Kalaaji AN, Bruce AJ. The management of mucous membrane pemphigoid and pemphigus. Dermatol Ther 2010; 23:268.
  18. Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol Soc 1986; 84:527.
  19. Kasperkiewicz M, Zillikens D, Schmidt E. Pemphigoid diseases: pathogenesis, diagnosis, and treatment. Autoimmunity 2012; 45:55.
  20. Sagi L, Baum S, Agmon-Levin N, et al. Autoimmune bullous diseases the spectrum of infectious agent antibodies and review of the literature. Autoimmun Rev 2011; 10:527.
  21. Nishie W. Update on the pathogenesis of bullous pemphigoid: an autoantibody-mediated blistering disease targeting collagen XVII. J Dermatol Sci 2014; 73:179.
  22. Lo Schiavo A, Ruocco E, Brancaccio G, et al. Bullous pemphigoid: etiology, pathogenesis, and inducing factors: facts and controversies. Clin Dermatol 2013; 31:391.
  23. Le Jan S, Plée J, Vallerand D, et al. Innate immune cell-produced IL-17 sustains inflammation in bullous pemphigoid. J Invest Dermatol 2014; 134:2908.
  24. Fuchs E, Raghavan S. Getting under the skin of epidermal morphogenesis. Nat Rev Genet 2002; 3:199.
  25. Mariotti F, Grosso F, Terracina M, et al. Development of a novel ELISA system for detection of anti-BP180 IgG and characterization of autoantibody profile in bullous pemphigoid patients. Br J Dermatol 2004; 151:1004.
  26. Sakuma-Oyama Y, Powell AM, Oyama N, et al. Evaluation of a BP180-NC16a enzyme-linked immunosorbent assay in the initial diagnosis of bullous pemphigoid. Br J Dermatol 2004; 151:126.
  27. Barnadas MA, Rubiales MV, González MJ, et al. Enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence testing in a bullous pemphigoid and pemphigoid gestationis. Int J Dermatol 2008; 47:1245.
  28. Zillikens D, Mascaro JM, Rose PA, et al. A highly sensitive enzyme-linked immunosorbent assay for the detection of circulating anti-BP180 autoantibodies in patients with bullous pemphigoid. J Invest Dermatol 1997; 109:679.
  29. Kobayashi M, Amagai M, Kuroda-Kinoshita K, et al. BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid. J Dermatol Sci 2002; 30:224.
  30. Ishiura N, Fujimoto M, Watanabe R, et al. Serum levels of IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid. J Dermatol Sci 2008; 49:153.
  31. Hofmann S, Thoma-Uszynski S, Hunziker T, et al. Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2- and COOH-terminal regions of the BP180 ectodomain. J Invest Dermatol 2002; 119:1065.
  32. Di Zenzo G, Grosso F, Terracina M, et al. Characterization of the anti-BP180 autoantibody reactivity profile and epitope mapping in bullous pemphigoid patients. J Invest Dermatol 2004; 122:103.
  33. Li Q, Ujiie H, Shibaki A, et al. Human IgG1 monoclonal antibody against human collagen 17 noncollagenous 16A domain induces blisters via complement activation in experimental bullous pemphigoid model. J Immunol 2010; 185:7746.
  34. Ujiie H, Shibaki A, Nishie W, et al. A novel active mouse model for bullous pemphigoid targeting humanized pathogenic antigen. J Immunol 2010; 184:2166.
  35. Heimbach L, Li N, Diaz A, Liu Z. Experimental animal models of bullous pemphigoid. G Ital Dermatol Venereol 2009; 144:423.
  36. Döpp R, Schmidt E, Chimanovitch I, et al. IgG4 and IgE are the major immunoglobulins targeting the NC16A domain of BP180 in Bullous pemphigoid: serum levels of these immunoglobulins reflect disease activity. J Am Acad Dermatol 2000; 42:577.
  37. Schmidt E, Obe K, Bröcker EB, Zillikens D. Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid. Arch Dermatol 2000; 136:174.
  38. Shirakata Y, Shiraishi S, Sayama K, Miki Y. Subclass characteristics of IgG autoantibodies in bullous pemphigoid and pemphigus. J Dermatol 1990; 17:661.
  39. Lamb PM, Patton T, Deng JS. The predominance of IgG4 in prodromal bullous pemphigoid. Int J Dermatol 2008; 47:150.
  40. Kromminga A, Scheckenbach C, Georgi M, et al. Patients with bullous pemphigoid and linear IgA disease show a dual IgA and IgG autoimmune response to BP180. J Autoimmun 2000; 15:293.
  41. Schmidt E, Zillikens D. Modern diagnosis of autoimmune blistering skin diseases. Autoimmun Rev 2010; 10:84.
  42. Woodley DT. The role of IgE anti-basement membrane zone autoantibodies in bullous pemphigoid. Arch Dermatol 2007; 143:249.
  43. Fairley JA, Burnett CT, Fu CL, et al. A pathogenic role for IgE in autoimmunity: bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice. J Invest Dermatol 2007; 127:2605.
  44. Iwata Y, Komura K, Kodera M, et al. Correlation of IgE autoantibody to BP180 with a severe form of bullous pemphigoid. Arch Dermatol 2008; 144:41.
  45. Arbesman CE, Wypych JI, Reisman RE, Beutner EH. IgE levels in sera of patients with pemphigus or bullous pemphigoid. Arch Dermatol 1974; 110:378.
  46. Di Zenzo G, Thoma-Uszynski S, Fontao L, et al. Multicenter prospective study of the humoral autoimmune response in bullous pemphigoid. Clin Immunol 2008; 128:415.
  47. Roussel A, Benichou J, Randriamanantany ZA, et al. Enzyme-linked immunosorbent assay for the combination of bullous pemphigoid antigens 1 and 2 in the diagnosis of bullous pemphigoid. Arch Dermatol 2011; 147:293.
  48. Charneux J, Lorin J, Vitry F, et al. Usefulness of BP230 and BP180-NC16a enzyme-linked immunosorbent assays in the initial diagnosis of bullous pemphigoid: a retrospective study of 138 patients. Arch Dermatol 2011; 147:286.
  49. Rashid KA, Gürcan HM, Ahmed AR. Antigen specificity in subsets of mucous membrane pemphigoid. J Invest Dermatol 2006; 126:2631.
  50. Chan LS, Majmudar AA, Tran HH, et al. Laminin-6 and laminin-5 are recognized by autoantibodies in a subset of cicatricial pemphigoid. J Invest Dermatol 1997; 108:848.
  51. Lazarova Z, Yee C, Lazar J, Yancey KB. IgG autoantibodies in patients with anti-epiligrin cicatricial pemphigoid recognize the G domain of the laminin 5 alpha-subunit. Clin Immunol 2001; 101:100.
  52. Bédane C, McMillan JR, Balding SD, et al. Bullous pemphigoid and cicatricial pemphigoid autoantibodies react with ultrastructurally separable epitopes on the BP180 ectodomain: evidence that BP180 spans the lamina lucida. J Invest Dermatol 1997; 108:901.
  53. Oyama N, Setterfield JF, Powell AM, et al. Bullous pemphigoid antigen II (BP180) and its soluble extracellular domains are major autoantigens in mucous membrane pemphigoid: the pathogenic relevance to HLA class II alleles and disease severity. Br J Dermatol 2006; 154:90.
  54. Zakka LR, Reche P, Ahmed AR. Role of MHC Class II genes in the pathogenesis of pemphigoid. Autoimmun Rev 2011; 11:40.
  55. Amber KT, Bloom R, Hertl M. A systematic review with pooled analysis of clinical presentation and immunodiagnostic testing in mucous membrane pemphigoid: association of anti-laminin-332 IgG with oropharyngeal involvement and the usefulness of ELISA. J Eur Acad Dermatol Venereol 2016; 30:72.
  56. Schmidt E, Skrobek C, Kromminga A, et al. Cicatricial pemphigoid: IgA and IgG autoantibodies target epitopes on both intra- and extracellular domains of bullous pemphigoid antigen 180. Br J Dermatol 2001; 145:778.
  57. Setterfield J, Shirlaw PJ, Bhogal BS, et al. Cicatricial pemphigoid: serial titres of circulating IgG and IgA antibasement membrane antibodies correlate with disease activity. Br J Dermatol 1999; 140:645.
  58. Aumailley M, Bruckner-Tuderman L, Carter WG, et al. A simplified laminin nomenclature. Matrix Biol 2005; 24:326.
  59. Domogatskaya A, Rodin S, Tryggvason K. Functional diversity of laminins. Annu Rev Cell Dev Biol 2012; 28:523.
  60. Dainichi T, Kurono S, Ohyama B, et al. Anti-laminin gamma-1 pemphigoid. Proc Natl Acad Sci U S A 2009; 106:2800.
  61. Groth S, Recke A, Vafia K, et al. Development of a simple enzyme-linked immunosorbent assay for the detection of autoantibodies in anti-p200 pemphigoid. Br J Dermatol 2011; 164:76.
  62. Dainichi T, Koga H, Tsuji T, et al. From anti-p200 pemphigoid to anti-laminin gamma1 pemphigoid. J Dermatol 2010; 37:231.
  63. Liu Z, Giudice GJ, Swartz SJ, et al. The role of complement in experimental bullous pemphigoid. J Clin Invest 1995; 95:1539.
  64. Yancey KB, Egan CA. Pemphigoid: clinical, histologic, immunopathologic, and therapeutic considerations. JAMA 2000; 284:350.
  65. Verraes S, Hornebeck W, Polette M, et al. Respective contribution of neutrophil elastase and matrix metalloproteinase 9 in the degradation of BP180 (type XVII collagen) in human bullous pemphigoid. J Invest Dermatol 2001; 117:1091.
  66. Ståhle-Bäckdahl M, Inoue M, Guidice GJ, Parks WC. 92-kD gelatinase is produced by eosinophils at the site of blister formation in bullous pemphigoid and cleaves the extracellular domain of recombinant 180-kD bullous pemphigoid autoantigen. J Clin Invest 1994; 93:2022.
  67. Dvorak AM, Mihm MC Jr, Osage JE, et al. Bullous pemphigoid, an ultrastructural study of the inflammatory response: eosinophil, basophil and mast cell granule changes in multiple biopsies from one patient. J Invest Dermatol 1982; 78:91.
  68. Wintroub BU, Mihm MC Jr, Goetzl EJ, et al. Morphologic and functional evidence for release of mast-cell products in bullous pemphigoid. N Engl J Med 1978; 298:417.
  69. Borrego L, Maynard B, Peterson EA, et al. Deposition of eosinophil granule proteins precedes blister formation in bullous pemphigoid. Comparison with neutrophil and mast cell granule proteins. Am J Pathol 1996; 148:897.
  70. Goldstein SM, Wasserman SI, Wintroub BU. Mast cell and eosinophil mediated damage in bullous pemphigoid. Immunol Ser 1989; 46:527.
  71. Goletz S, Hashimoto T, Zillikens D, Schmidt E. Anti-p200 pemphigoid. J Am Acad Dermatol 2014; 71:185.
  72. Wieland CN, Comfere NI, Gibson LE, et al. Anti-bullous pemphigoid 180 and 230 antibodies in a sample of unaffected subjects. Arch Dermatol 2010; 146:21.
  73. Aoyama Y, Asai K, Hioki K, et al. Herpes gestationis in a mother and newborn: immunoclinical perspectives based on a weekly follow-up of the enzyme-linked immunosorbent assay index of a bullous pemphigoid antigen noncollagenous domain. Arch Dermatol 2007; 143:1168.
  74. Feliciani C, Caldarola G, Kneisel A, et al. IgG autoantibody reactivity against bullous pemphigoid (BP) 180 and BP230 in elderly patients with pruritic dermatoses. Br J Dermatol 2009; 161:306.
  75. Liu Z, Sui W, Zhao M, et al. Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model. J Autoimmun 2008; 31:331.
  76. Zone JJ, Taylor T, Hull C, et al. IgE basement membrane zone antibodies induce eosinophil infiltration and histological blisters in engrafted human skin on SCID mice. J Invest Dermatol 2007; 127:1167.
  77. Messingham KA, Holahan HM, Fairley JA. Unraveling the significance of IgE autoantibodies in organ-specific autoimmunity: lessons learned from bullous pemphigoid. Immunol Res 2014; 59:273.
  78. Chan LS, Hammerberg C, Cooper KD. Significantly increased occurrence of HLA-DQB1*0301 allele in patients with ocular cicatricial pemphigoid. J Invest Dermatol 1997; 108:129.
  79. Delgado JC, Turbay D, Yunis EJ, et al. A common major histocompatibility complex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphigoid. Proc Natl Acad Sci U S A 1996; 93:8569.
  80. Setterfield J, Theron J, Vaughan RW, et al. Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production. Br J Dermatol 2001; 145:406.
  81. Yunis JJ, Mobini N, Yunis EJ, et al. Common major histocompatibility complex class II markers in clinical variants of cicatricial pemphigoid. Proc Natl Acad Sci U S A 1994; 91:7747.
  82. Büdinger L, Borradori L, Yee C, et al. Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls. J Clin Invest 1998; 102:2082.
  83. Okazaki A, Miyagawa S, Yamashina Y, et al. Polymorphisms of HLA-DR and -DQ genes in Japanese patients with bullous pemphigoid. J Dermatol 2000; 27:149.
  84. Gao XH, Winsey S, Li G, et al. HLA-DR and DQ polymorphisms in bullous pemphigoid from northern China. Clin Exp Dermatol 2002; 27:319.
  85. Sezin T, Egozi E, Hillou W, et al. Anti-laminin-332 mucous membrane pemphigoid developing after a diphtheria tetanus vaccination. JAMA Dermatol 2013; 149:858.
  86. de la Fuente S, Hernández-Martín Á, de Lucas R, et al. Postvaccination bullous pemphigoid in infancy: report of three new cases and literature review. Pediatr Dermatol 2013; 30:741.
  87. Stavropoulos PG, Soura E, Antoniou C. Drug-induced pemphigoid: a review of the literature. J Eur Acad Dermatol Venereol 2014; 28:1133.
  88. Di Zenzo G, Thoma-Uszynski S, Calabresi V, et al. Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study. J Invest Dermatol 2011; 131:2271.
  89. Chan LS, Soong HK, Foster CS, et al. Ocular cicatricial pemphigoid occurring as a sequela of Stevens-Johnson syndrome. JAMA 1991; 266:1543.
  90. Mignogna MD, Fortuna G, Leuci S, et al. Lichen planus pemphigoides, a possible example of epitope spreading. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109:837.
  91. Nguyen T, Kwan JM, Ahmed AR. Relationship between radiation therapy and bullous pemphigoid. Dermatology 2014; 229:88.
  92. Devaux S, Michot C, Mourad G, et al. Chronic renal graft rejection-associated bullous pemphigoid: A cross-reactive immune response? Acta Derm Venereol 2011; 91:82.
  93. Bouras C, Riederer BM, Kövari E, et al. Humoral immunity in brain aging and Alzheimer's disease. Brain Res Brain Res Rev 2005; 48:477.
  94. Laffitte E, Burkhard PR, Fontao L, et al. Bullous pemphigoid antigen 1 isoforms: potential new target autoantigens in multiple sclerosis? Br J Dermatol 2005; 152:537.
  95. Chen J, Li L, Chen J, et al. Sera of elderly bullous pemphigoid patients with associated neurological diseases recognize bullous pemphigoid antigens in the human brain. Gerontology 2011; 57:211.
  96. Li L, Chen J, Wang B, et al. Sera from patients with bullous pemphigoid (BP) associated with neurological diseases recognized BP antigen 1 in the skin and brain. Br J Dermatol 2009; 160:1343.