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Pemphigus

Nature Reviews Disease Primers volume 3, Article number: 17026 (2017) | Download Citation

Abstract

Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell–cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20+ B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases.

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References

  1. 1.

    in Dermatology Vol. 1 Ch. 29 (eds Bolognia, J. L., Jorizzo, J. L. & Schaffer, J. V.) 461–474 (Mosby, 2012).

  2. 2.

    , & Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 67, 869–877 (1991). This study reports the cDNA cloning of a pemphigus vulgaris antigen, which turned out to be a desmosomal cadherin called desmoglein 3.

  3. 3.

    et al. Identification of desmoglein, a constitutive desmosomal glycoprotein, as a member of the cadherin family of cell adhesion molecules. Eur. J. Cell Biol. 53, 1–12 (1990).

  4. 4.

    & Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N. Engl. J. Med. 355, 1800–1810 (2006).

  5. 5.

    et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N. Engl. J. Med. 323, 1729–1735 (1990).

  6. 6.

    , & Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid. Arch. Dermatol. Res. 307, 291–298 (2015).

  7. 7.

    et al. Development of a disease registry for autoimmune bullous diseases: initial analysis of the pemphigus vulgaris subset. Acta Derm. Venereol. 95, 86–90 (2015).

  8. 8.

    & Paraneoplastic pemphigus. Australas. J. Dermatol. 54, 241–250 (2013).

  9. 9.

    Paraneoplastic pemphigus. Adv. Dermatol. 12, 77–96 (1997).

  10. 10.

    Paraneoplastic pemphigus. J. Investig. Dermatol. Symp. Proc. 9, 29–33 (2004).

  11. 11.

    & Geoepidemiologic considerations of auto-immune pemphigus. Autoimmun. Rev. 9, A379–A382 (2010).

  12. 12.

    , , & Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany. J. Dtsch. Dermatol. Ges. 7, 434–440 (2009). This study reports the lowest known incidence of patients with pemphigus.

  13. 13.

    et al. Epidemiologic survey of pemphigus vulgaris with oral manifestations in northern Greece: retrospective study of 129 patients. Int. J. Dermatol. 46, 356–361 (2007).

  14. 14.

    et al. The incidence of pemphigus in the southern region of Saudi Arabia. Int. J. Dermatol. 40, 570–572 (2001).

  15. 15.

    , , & Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surg. Oral Med. Oral Pathol. 38, 382–387 (1974).

  16. 16.

    , & Pemphigus vulgaris in Iran: epidemiology and clinical profile. Skimmed 5, 69–71 (2006).

  17. 17.

    , , & Pemphigus in Hartford County, Connecticut, from 1972 to 1977. Arch. Dermatol. 116, 1035–1037 (1980).

  18. 18.

    et al. Advances in pemphigus and its endemic pemphigus foliaceus (Fogo Selvagem) phenotype: a paradigm of human autoimmunity. J. Autoimmun. 31, 311–324 (2008).

  19. 19.

    et al. Spectrum of autoimmune blistering dermatoses in Tunisia: an 11-year study and a review of the literature. Int. J. Dermatol. 50, 939–944 (2011).

  20. 20.

    et al. Comparative epidemiology of pemphigus in Tunisia and France. Incidence of foliaceus pemphigus in young Tunisian women. Ann. Dermatol. Venereol. 123, 337–342 (in French) (1996).

  21. 21.

    et al. Cutting edge: Brazilian pemphigus foliaceus anti-desmoglein 1 autoantibodies cross-react with sand fly salivary LJM11 antigen. J. Immunol. 189, 1535–1539 (2012). This paper shows that antibodies to sand fly salivary antigens crossreact with human desmoglein 1 and, therefore, may be a trigger for endemic pemphigus foliaceus, fogo selvagem.

  22. 22.

    et al. IgE anti-LJM11 sand fly salivary antigen may herald the onset of fogo selvagem in endemic Brazilian regions. J. Invest. Dermatol. 135, 913–915 (2015).

  23. 23.

    et al. Overlapping IgG4 responses to self- and environmental antigens in endemic pemphigus foliaceus. J. Immunol. 196, 2041–2050 (2016).

  24. 24.

    The genetics of pemphigus. Dermatol. Clin. 29, 381–391 (2011).

  25. 25.

    et al. Circulating pemphigus autoantibodies in healthy relatives of pemphigus patients: coincidental phenomenon with a risk of disease development? Arch. Dermatol. Res. 299, 239–243 (2007).

  26. 26.

    , & Association between HLA-DRB1 polymorphisms and pemphigus vulgaris: a meta-analysis. Br. J. Dermatol. 167, 768–777 (2012).

  27. 27.

    et al. Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris. Hum. Immunol. 67, 125–139 (2006).

  28. 28.

    et al. HLA-E*0103X is associated with susceptibility to pemphigus vulgaris. Exp. Dermatol. 22, 108–112 (2013).

  29. 29.

    et al. Population-specific association between a polymorphic variant in ST18, encoding a pro-apoptotic molecule, and pemphigus vulgaris. J. Invest. Dermatol. 132, 1798–1805 (2012). This is the first genome-wide association study in pemphigus vulgaris, which implicates the HLA region as well as ST18 as genomic susceptibility loci.

  30. 30.

    et al. Identification of a functional risk variant for pemphigus vulgaris in the ST18 gene. PLoS Genet. 12, e1006008 (2016).

  31. 31.

    et al. Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus. Proc. Natl Acad. Sci. USA 113, 1859–1864 (2016). References 30 and 31 provide novel important insights into the complex relationship between genetics and disease development in pemphigus.

  32. 32.

    , , & Increased oxidative stress in pemphigus vulgaris is related to disease activity and HLA-association. Autoimmunity 49, 248–257 (2016).

  33. 33.

    et al. An epitope in the third hypervariable region of the DRB1 gene is involved in the susceptibility to endemic pemphigus foliaceus (fogo selvagem) in three different Brazilian populations. Tissue Antigens 49, 35–40 (1997).

  34. 34.

    et al. Paraneoplastic pemphigus is associated with the DRB1*03 allele. J. Autoimmun. 20, 91–95 (2003).

  35. 35.

    , , & Genotyping of HLA-I and HLA-II alleles in Chinese patients with paraneoplastic pemphigus. Br. J. Dermatol. 158, 587–591 (2008).

  36. 36.

    et al. Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies. Clin. Dermatol. 31, 374–381 (2013).

  37. 37.

    Desmoglein as a target in autoimmunity and infection. J. Am. Acad. Dermatol. 48, 244–252 (2003).

  38. 38.

    Autoimmunity against desmosomal cadherins in pemphigus. J. Dermatol. Sci. 20, 92–102 (1999).

  39. 39.

    et al. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J. Clin. Invest. 103, 461–468 (1999).

  40. 40.

    , , , & Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat. Med. 6, 1275–1277 (2000). This study identifies the target molecule of the exfoliative toxin produced by S. aureus as desmoglein 1, the autoantigen of pemphigus foliaceus.

  41. 41.

    et al. Autoimmunity to desmocollin 3 in pemphigus vulgaris. Am. J. Pathol. 177, 2724–2730 (2010).

  42. 42.

    et al. IgG autoantibodies against desmocollin 3 in pemphigus sera induce loss of keratinocyte adhesion. Am. J. Pathol. 178, 718–723 (2011).

  43. 43.

    , , , & Antibodies against keratinocyte antigens other than desmoglein 1 and 3 can induce pemphigus vulgaris-like lesions. J. Clin. Invest. 106, 1467–1479 (2000).

  44. 44.

    et al. Pemphigus vulgaris autoantibody profiling by proteomic technique. PLoS ONE 8, e57587 (2013).

  45. 45.

    et al. Monopathogenic versus multipathogenic explanations of pemphigus pathophysiology. Exp. Dermatol. 25, 839–846 (2016).

  46. 46.

    , , , & Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice. J. Clin. Invest. 102, 775–782 (1998).

  47. 47.

    et al. The protease inhibitor alpha-2-macroglobulin-like-1 is the p170 antigen recognized by paraneoplastic pemphigus autoantibodies in human. PLoS ONE 5, e12250 (2010).

  48. 48.

    et al. Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice. J. Clin. Invest. 121, 3677–3688 (2011). This study reports that desmoglein 3-specific CD4+ T cells not only help B cells to produce pathogenic autoantibodies but also induce interface dermatitis by cellular autoimmunity, as found in paraneoplastic pemphigus.

  49. 49.

    et al. Lichenoid paraneoplastic pemphigus in the absence of detectable antibodies. J. Am. Acad. Dermatol. 56, 153–159 (2007).

  50. 50.

    et al. Defining the role of complement in experimental pemphigus vulgaris in mice. J. Immunol. 137, 2835–2840 (1986).

  51. 51.

    Jr et al. Mechanisms of acantholysis in pemphigus vulgaris: role of IgG valence. Clin. Immunol. Immunopathol. 85, 90–96 (1997).

  52. 52.

    , & Monovalent Fab’ immunoglobulin fragments from endemic pemphigus foliaceus autoantibodies reproduce the human disease in neonatal Balb/c mice. J. Clin. Invest. 85, 296–299 (1990).

  53. 53.

    et al. The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem). N. Engl. J. Med. 320, 1463–1469 (1989).

  54. 54.

    et al. Predominant IgG4 subclass in autoantibodies of pemphigus vulgaris and foliaceus. J. Dermatol. Sci. 26, 55–61 (2001).

  55. 55.

    et al. Enrichment of total serum IgG4 in patients with pemphigus. Br. J. Dermatol. 167, 1245–1253 (2012).

  56. 56.

    & IgG4 breaking the rules. Immunology 105, 9–19 (2002).

  57. 57.

    et al. C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science 296, 1308–1313 (2002).

  58. 58.

    et al. Structural basis of adhesive binding by desmocollins and desmogleins. Proc. Natl Acad. Sci. USA 113, 7160–7165 (2016).

  59. 59.

    et al. Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3. J. Immunol. 170, 2170–2178 (2003).

  60. 60.

    et al. Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface. J. Clin. Invest. 122, 3781–3790 (2012). This paper demonstrates that human anti-desmoglein 3 antibodies binding to the cis-adhesive desmoglein 3 interface can induce acantholysis, providing support for the steric hindrance model of pemphigus pathogenesis.

  61. 61.

    , , & Pemphigus vulgaris IgG directly inhibit desmoglein 3-mediated transinteraction. J. Immunol. 181, 1825–1834 (2008).

  62. 62.

    , & Assembly pathway of desmoglein 3 to desmosomes and its perturbation by pemphigus vulgaris-IgG in cultured keratinocytes, as revealed by time-lapsed labeling immunoelectron microscopy. Lab. Invest. 80, 1583–1592 (2000).

  63. 63.

    et al. Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies. J. Biol. Chem. 281, 7623–7634 (2006).

  64. 64.

    , & Disruption of desmosome assembly by monovalent human pemphigus vulgaris monoclonal antibodies. J. Invest. Dermatol. 129, 908–918 (2009).

  65. 65.

    , , , & IgG-induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis. Br. J. Dermatol. 165, 552–562 (2011).

  66. 66.

    et al. Large-scale electron microscopy maps of patient skin and mucosa provide insight into pathogenesis of blistering diseases. J. Invest. Dermatol. 135, 1763–1770 (2015).

  67. 67.

    , , , & Pemphigus foliaceus IgG causes dissociation of desmoglein 1-containing junctions without blocking desmoglein 1 transinteraction. J. Clin. Invest. 115, 3157–3165 (2005).

  68. 68.

    et al. p38MAPK signaling and desmoglein-3 internalization are linked events in pemphigus acantholysis. J. Biol. Chem. 285, 8936–8941 (2010).

  69. 69.

    et al. Signaling dependent and independent mechanisms in pemphigus vulgaris blister formation. PLoS ONE 7, e50696 (2012). This paper provides evidence that monoclonal and polyclonal antibodies contribute to acantholysis in non-redundant and complementary ways, with polyclonal serum IgG inducing signalling-dependent desmoglein clustering not observed with monoclonal antibodies.

  70. 70.

    , , & p38 MAPK activation is downstream of the loss of intercellular adhesion in pemphigus vulgaris. J. Biol. Chem. 286, 1283–1291 (2011).

  71. 71.

    et al. MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. J. Invest. Dermatol. 134, 68–76 (2014).

  72. 72.

    , , , & A pathophysiologic role for epidermal growth factor receptor in pemphigus acantholysis. J. Biol. Chem. 288, 9447–9456 (2013).

  73. 73.

    et al. EGFR inhibitors erlotinib and lapatinib ameliorate epidermal blistering in pemphigus vulgaris in a non-linear, V-shaped relationship. Exp. Dermatol. 23, 33–38 (2014).

  74. 74.

    et al. Inhibition of Rho A activity causes pemphigus skin blistering. J. Cell Biol. 175, 721–727 (2006).

  75. 75.

    et al. Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin. EMBO J. 25, 3298–3309 (2006).

  76. 76.

    , , , & Involvement of the apoptotic mechanism in pemphigus foliaceus autoimmune injury of the skin. J. Immunol. 182, 711–717 (2009).

  77. 77.

    et al. Preclinical studies identify non-apoptotic low-level caspase-3 as therapeutic target in pemphigus vulgaris. PLoS ONE 10, e0119809 (2015).

  78. 78.

    , , , & Critical role of the neonatal Fc receptor (FcRn) in the pathogenic action of antimitochondrial autoantibodies synergizing with anti-desmoglein autoantibodies in pemphigus vulgaris. J. Biol. Chem. 290, 23826–23837 (2015).

  79. 79.

    et al. Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display. J. Clin. Invest. 115, 888–899 (2005).

  80. 80.

    et al. Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity. J. Clin. Invest. 120, 4111–4117 (2010).

  81. 81.

    et al. A higher correlation of the antibody activities against the calcium-dependent epitopes of desmoglein 3 quantified by ethylenediaminetetraacetic acid-treated enzyme-linked immunosorbent assay with clinical disease activities of pemphigus vulgaris. J. Dermatol. Sci. 70, 190–195 (2013).

  82. 82.

    et al. Synergistic pathogenic effects of combined mouse monoclonal anti-desmoglein 3 IgG antibodies on pemphigus vulgaris blister formation. J. Invest. Dermatol. 126, 2621–2630 (2006).

  83. 83.

    et al. Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nat. Commun. 5, 4167 (2014). This paper demonstrates that VH1-46 B cells require no or few somatic mutations to bind desmoglein 3 and may, therefore, be prone to desmoglein 3 autoreactivity.

  84. 84.

    et al. Pathogenic anti-desmoglein 3 mAbs cloned from a paraneoplastic pemphigus patient by phage display. J. Invest. Dermatol. 132, 1141–1148 (2012).

  85. 85.

    et al. Antibodies to the desmoglein 1 precursor proprotein but not to the mature cell surface protein cloned from individuals without pemphigus. J. Immunol. 183, 5615–5621 (2009).

  86. 86.

    et al. Antigen selection of anti-DSG1 autoantibodies during and before the onset of endemic pemphigus foliaceus. J. Invest. Dermatol. 129, 2823–2834 (2009).

  87. 87.

    et al. Immunodominance of the VH1-46 antibody gene segment in the primary repertoire of human rotavirus-specific B cells is reduced in the memory compartment through somatic mutation of nondominant clones. J. Immunol. 180, 3279–3288 (2008).

  88. 88.

    et al. Determinants of VH1-46 cross-reactivity to pemphigus vulgaris autoantigen desmoglein 3 and rotavirus antigen VP6. J. Immunol. 197, 1065–1073 (2016).

  89. 89.

    et al. Persistence of anti-desmoglein 3 IgG+ B-cell clones in pemphigus patients over years. J. Invest. Dermatol. 135, 742–749 (2015).

  90. 90.

    et al. Immune response towards the amino-terminus of desmoglein 1 prevails across different activity stages in nonendemic pemphigus foliaceus. Br. J. Dermatol. 162, 1242–1250 (2010).

  91. 91.

    et al. Epitope spreading is rarely found in pemphigus vulgaris by large-scale longitudinal study using desmoglein 2-based swapped molecules. J. Invest. Dermatol. 132, 1158–1168 (2012).

  92. 92.

    et al. Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci. Transl Med. 5, 175ra30 (2013).

  93. 93.

    et al. Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris. Proc. Natl Acad. Sci. USA 87, 7658–7662 (1990).

  94. 94.

    et al. HLA-DRB1*04 and DRB1*14 alleles are associated with susceptibility to pemphigus among Japanese. J. Invest. Dermatol. 109, 615–618 (1997).

  95. 95.

    , & Subclass distribution of human IgG autoantibodies in pemphigus. J. Clin. Immunol. 8, 43–49 (1988).

  96. 96.

    et al. Development and characterization of desmoglein-3 specific T cells from patients with pemphigus vulgaris. J. Clin. Invest. 99, 31–40 (1997).

  97. 97.

    et al. Recognition of desmoglein 3 by autoreactive T cells in pemphigus vulgaris patients and normals. J. Invest. Dermatol. 110, 62–66 (1998).

  98. 98.

    et al. Dichotomy of autoreactive Th1 and Th2 cell responses to desmoglein 3 in patients with pemphigus vulgaris (PV) and healthy carriers of PV-associated HLA class II alleles. J. Immunol. 170, 635–642 (2003).

  99. 99.

    et al. Novel system evaluating in vivo pathogenicity of desmoglein 3-reactive T cell clones using murine pemphigus vulgaris. J. Immunol. 181, 1526–1535 (2008).

  100. 100.

    , , , & Type I regulatory T cells specific for desmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris. J. Immunol. 172, 6468–6475 (2004).

  101. 101.

    et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N. Engl. J. Med. 340, 1406–1410 (1999).

  102. 102.

    , & CD8+ T lymphocytes in bronchiolitis obliterans, paraneoplastic pemphigus, and solitary Castleman's disease. N. Engl. J. Med. 349, 407–408 (2003).

  103. 103.

    et al. Ectopic expression of epidermal antigens renders the lung a target organ in paraneoplastic pemphigus. J. Immunol. 191, 83–90 (2013). This study shows that ectopic expression of epidermal antigens in the lungs as a form of squamous metaplasia could be a reason why fatal pulmonary involvement occurs in patients with paraneoplastic pemphigus.

  104. 104.

    , , , & Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N. Engl. J. Med. 306, 1189–1196 (1982).

  105. 105.

    et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353, 179–184 (2016). This paper describes a novel therapeutic strategy for antigen-specific B cell depletion in pemphigus that could avoid generalized immune suppression.

  106. 106.

    et al. Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus. J. Clin. Invest. 105, 625–631 (2000). This study describes the active disease mouse model for pemphigus vulgaris developed with a novel versatile method using adoptive transfer of lymphocytes from autoantigen-knockout mice.

  107. 107.

    , & Pemphigus mouse model as a tool to evaluate various immunosuppressive therapies. Exp. Dermatol. 18, 252–260 (2009).

  108. 108.

    et al. Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus. Br. J. Dermatol. 140, 351–357 (1999).

  109. 109.

    et al. Pathogenic IgG antibodies against desmoglein 3 in pemphigus vulgaris are regulated by HLA-DRB1*04:02-restricted T cells. J. Immunol. 193, 4391–4399 (2014).

  110. 110.

    et al. Cutaneous type pemphigus vulgaris: a rare clinical phenotype of pemphigus. J. Am. Acad. Dermatol. 52, 839–845 (2005).

  111. 111.

    et al. Antibodies to the amino-terminal domain of desmoglein 1 are retained during transition from pemphigus vulgaris to pemphigus foliaceus. Eur. J. Dermatol. 24, 174–179 (2014).

  112. 112.

    , , , & Case of pemphigus foliaceus which occurred after five years of remission from pemphigus vulgaris. Dermatology 203, 174–176 (2001).

  113. 113.

    , & Neonatal autoimmune blistering disease: a systematic review. Pediatr. Dermatol. 33, 367–374 (2016).

  114. 114.

    et al. Pregnant women with endemic pemphigus foliaceus (fogo selvagem) give birth to disease-free babies. J. Invest. Dermatol. 99, 78–82 (1992).

  115. 115.

    et al. Protection of neonates against pemphigus foliaceus by desmoglein 3. N. Engl. J. Med. 343, 31–35 (2000).

  116. 116.

    et al. Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J. Immunol. 159, 2010–2017 (1997).

  117. 117.

    et al. Novel ELISA systems for antibodies to desmoglein 1 and 3: correlation of disease activity with serum autoantibody levels in individual pemphigus patients. Exp. Dermatol. 19, 458–463 (2010).

  118. 118.

    et al. Prospective studies on the routine use of a novel multivariant enzyme-linked immunosorbent assay for the diagnosis of autoimmune bullous diseases. J. Am. Acad. Dermatol. 76, 889–894.e5 (2017).

  119. 119.

    et al. Serological diagnosis of autoimmune bullous skin diseases: prospective comparison of the BIOCHIP mosaic-based indirect immunofluorescence technique with the conventional multi-step single test strategy. Orphanet J. Rare Dis. 7, 49 (2012).

  120. 120.

    et al. Detection of autoantibodies against recombinant desmoglein 1 and 3 molecules in patients with pemphigus vulgaris: correlation with disease extent at the time of diagnosis and during follow-up. Clin. Dev. Immunol. 2009, 187864 (2009).

  121. 121.

    et al. ELISA testing of anti-desmoglein 1 and 3 antibodies in the management of pemphigus. Arch. Dermatol. 145, 529–535 (2009).

  122. 122.

    & Modern diagnosis of autoimmune blistering skin diseases. Autoimmun. Rev. 10, 84–89 (2010).

  123. 123.

    , , & Anti-desmoglein IgG autoantibodies in patients with pemphigus in remission. J. Eur. Acad. Dermatol. Venereol. 22, 1070–1075 (2008).

  124. 124.

    , & Detailed profiling of anti-desmoglein autoantibodies identifies anti-Dsg1 reactivity as a key driver of disease activity and clinical expression in pemphigus vulgaris. Autoimmunity 48, 231–241 (2015).

  125. 125.

    , & Production of low titers of anti-desmoglein 1 IgG autoantibodies in some patients with staphylococcal scalded skin syndrome. J. Invest. Dermatol. 126, 2139–2141 (2006).

  126. 126.

    et al. Prevalence of pemphigus and pemphigoid autoantibodies in the general population. Orphanet J. Rare Dis. 10, 63 (2015).

  127. 127.

    et al. Development of ELISA for the specific determination of autoantibodies against envoplakin and periplakin in paraneoplastic pemphigus. Clin. Chim. Acta 410, 13–18 (2009).

  128. 128.

    et al. Epiplakin is a paraneoplastic pemphigus autoantigen and related to bronchiolitis obliterans in Japanese patients. J. Invest. Dermatol. 136, 399–408 (2016).

  129. 129.

    et al. Consensus statement on definitions of disease endpoints and therapeutic response for pemphigus. J. Am. Acad. Dermatol. 58, 1043–1046 (2008).

  130. 130.

    et al. Japanese guidelines for the management of pemphigus. J. Dermatol. 41, 471–486 (2014). This report describes current pemphigus treatment guidelines in Japan, which are based on published evidence as well as confirmatory studies in Japanese patients.

  131. 131.

    et al. Pemphigus. S2 guideline for diagnosis and treatment — guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J. Eur. Acad. Dermatol. Venereol. 29, 405–414 (2015). This report describes evidence-based consensus on pemphigus treatment guidelines in Europe.

  132. 132.

    , , , & Treatment of pemphigus vulgaris and pemphigus foliaceus: a systematic review and meta-analysis. Am. J. Clin. Dermatol. 15, 503–515 (2014).

  133. 133.

    et al. Paraneoplastic pemphigus associated with non-Hodgkin B-cell lymphoma and good response to prednisone. Acta Derm. Venereol. 85, 233–235 (2005).

  134. 134.

    , , & Paraneoplastic pemphigus in two patients with B-cell non-Hodgkin's lymphoma: significant responses to cyclophosphamide and prednisolone. Am. J. Hematol. 63, 105–106 (2000).

  135. 135.

    , , , & Immunoablative high-dose cyclophosphamide without stem cell rescue in paraneoplastic pemphigus: report of a case and review of this new therapy for severe autoimmune disease. J. Am. Acad. Dermatol. 40, 750–754 (1999).

  136. 136.

    et al. Paraneoplastic pemphigus treated with dexamethasone/ cyclophosphamide pulse therapy. Eur. J. Dermatol. 8, 551–553 (1998).

  137. 137.

    et al. Paraneoplastic pemphigus: potential therapeutic effect of plasmapheresis. Br. J. Dermatol. 134, 987–989 (1996).

  138. 138.

    , , , & Successful treatment of a paraneoplastic pemphigus in a teenager using plasmapheresis, corticosteroids and tumour resection. Clin. Exp. Dermatol. 36, 752–754 (2011).

  139. 139.

    , , , & Successful treatment of paraneoplastic pemphigus in follicular NHL with rituximab: report of a case and review of treatment for paraneoplastic pemphigus in NHL and CLL. Am. J. Hematol. 66, 142–144 (2001).

  140. 140.

    , & Rationale and efficacy for the use of rituximab in paraneoplastic pemphigus. Expert Rev. Clin. Immunol. 4, 351–363 (2008).

  141. 141.

    , , , & Successful treatment of B cell chronic lymphocytic leukemia-associated severe paraneoplastic pemphigus with cyclosporin A. Acta Haematol. 109, 202–205 (2003).

  142. 142.

    , , & Recalcitrant paraneoplastic pemphigus associated with follicular dendritic cell sarcoma: response to prolonged rituximab and ciclosporin therapy. Intern. Med. J. 44, 1145–1146 (2014).

  143. 143.

    & Paraneoplastic pemphigus associated with chronic lymphocytic leukaemia: treatment with alemtuzumab. Leuk. Res. 36, e190–e191 (2012).

  144. 144.

    et al. Alemtuzumab is effective against severe chronic lymphocytic leukaemia-associated paraneoplastic pemphigus. Br. J. Dermatol. 169, 469–472 (2013).

  145. 145.

    Treatment of pemphigus vulgaris with brief, high-dose intravenous glucocorticoids. Arch. Dermatol. 132, 1435–1439 (1996).

  146. 146.

    et al. High-dose intravenous ‘pulse’ methylprednisone in the treatment of severe oropharyngeal pemphigus: a pilot study. J. Oral Pathol. Med. 31, 339–344 (2002).

  147. 147.

    et al. Pemphigus vulgaris IgG and methylprednisolone exhibit reciprocal effects on keratinocytes. J. Biol. Chem. 279, 2135–2146 (2004).

  148. 148.

    , , , & Prevention and management of glucocorticoid-induced side effects: a comprehensive review: a review of glucocorticoid pharmacology and bone health. J. Am. Acad. Dermatol. 76, 1–9 (2017).

  149. 149.

    & Treatment and prevention of Pneumocystis pneumonia in HIV-uninfected patients. UpToDate (2016).

  150. 150.

    Centers for Disease Control and Prevention. Targeted tuberculosis testing and interpreting tuberculin skin test results: introduction. CDC (2016).

  151. 151.

    et al. Assessment of the rate of long-term complete remission off therapy in patients with pemphigus treated with different regimens including medium- and high-dose corticosteroids. J. Am. Acad. Dermatol. 69, 583–588 (2013).

  152. 152.

    et al. A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Arch. Dermatol. 142, 1447–1454 (2006).

  153. 153.

    et al. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J. Am. Acad. Dermatol. 57, 622–628 (2007).

  154. 154.

    et al. Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial. J. Invest. Dermatol. 130, 2041–2048 (2010).

  155. 155.

    , , & Evaluation of mycophenolate mofetil as a steroid-sparing agent in pemphigus: a randomized, prospective study. J. Eur. Acad. Dermatol. Venereol. 26, 855–860 (2012).

  156. 156.

    et al. Randomized double blind trial of prednisolone and azathioprine, versus prednisolone and placebo, in the treatment of pemphigus vulgaris. J. Eur. Acad. Dermatol. Venereol. 27, 1285–1292 (2013).

  157. 157.

    et al. Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: a meta-analysis. Clin. Gastroenterol. Hepatol. 13, 847–858.e4 (2015).

  158. 158.

    , , , & Prospective registry-based observational cohort study of the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil. Am. J. Transplant. 5, 2954–2960 (2005).

  159. 159.

    et al. Pharmacokinetics of mycophenolate mofetil in patients with end-stage renal failure. Kidney Int. 57, 1164–1168 (2000).

  160. 160.

    , , , & Mycophenolic acid exposure in high- and low-weight renal transplant patients after dosing with mycophenolate mofetil in the Opticept trial. Ther. Drug Monit. 32, 224–227 (2010).

  161. 161.

    et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet (2017). This study demonstrates the remarkable efficacy of rituximab as a first-line therapy for pemphigus.

  162. 162.

    et al. A single cycle of rituximab for the treatment of severe pemphigus. N. Engl. J. Med. 357, 545–552 (2007).

  163. 163.

    , , & Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N. Engl. J. Med. 355, 1772–1779 (2006).

  164. 164.

    , & Long-term remissions in recalcitrant pemphigus vulgaris. N. Engl. J. Med. 373, 2693–2694 (2015).

  165. 165.

    & Relevance of rituximab therapy in pemphigus vulgaris: analysis of current data and the immunologic basis for its observed responses. Expert. Rev. Clin. Immunol. 7, 529–541 (2011).

  166. 166.

    , , & Efficacy of rituximab for pemphigus: a systematic review and meta-analysis of different regimens. Acta Derm. Venereol. 95, 928–932 (2015).

  167. 167.

    et al. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch. Dermatol. 148, 1031–1036 (2012).

  168. 168.

    & Inhibitory human antichimeric antibodies to rituximab in a patient with pemphigus. J. Allergy Clin. Immunol. 130, 800–803 (2012).

  169. 169.

    et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 70, 909–920 (2011).

  170. 170.

    et al. Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID). Arthritis Res. Ther. 13, R75 (2011).

  171. 171.

    et al. Efficacy and safety of rituximab in pemphigus: experience of the German Registry of Autoimmune Diseases. J. Dtsch. Dermatol. Ges. 10, 727–732 (2012).

  172. 172.

    et al. Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J. Clin. Invest. 115, 3440–3450 (2005).

  173. 173.

    , , & Inhibition of B cell-mediated antigen presentation by intravenous immunoglobulins (IVIg). Clin. Immunol. 135, 422–429 (2010).

  174. 174.

    , , & The role of FcRn in antigen presentation. Front. Immunol. 5, 408 (2014).

  175. 175.

    & The antiinflammatory activity of IgG: the intravenous IgG paradox. J. Exp. Med. 204, 11–15 (2007).

  176. 176.

    et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J. Am. Acad. Dermatol. 60, 595–603 (2009). This study reports the first placebo-controlled, randomized, multicentre clinical trial for pemphigus and demonstrates the efficacy of intravenous immunoglobulin.

  177. 177.

    , , & Long-term use of IgA-depleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies. J. Clin. Immunol. 13, 272–278 (1993).

  178. 178.

    , , & The clinical features of 16 cases of stroke associated with administration of IVIg. Neurology 60, 1822–1824 (2003).

  179. 179.

    Intravenous immunoglobulin-related thromboembolic events — an accusation that proves the opposite. Clin. Exp. Immunol. 178 (Suppl. 1), 153–155 (2014).

  180. 180.

    et al. Controlled study of plasma exchange in pemphigus. Arch. Dermatol. 124, 1659–1663 (1988).

  181. 181.

    , & The use of plasmapheresis and immuosupression in the treatment of pemphigus vulgaris. J. Am. Acad. Dermatol. 43, 1058–1064 (2000).

  182. 182.

    et al. Combined treatment with immunoadsorption and rituximab leads to fast and prolonged clinical remission in difficult-to-treat pemphigus vulgaris. Br. J. Dermatol. 166, 844–852 (2012).

  183. 183.

    et al. Treatment of severe pemphigus with a combination of immunoadsorption, rituximab, pulsed dexamethasone and azathioprine/mycophenolate mofetil: a pilot study of 23 patients. Br. J. Dermatol. 166, 154–160 (2012).

  184. 184.

    et al. Bullous pemphigoid and pemphigus vulgaris — incidence and mortality in the UK: population based cohort study. BMJ 337, a180 (2008).

  185. 185.

    , , & Incidence, mortality, and causes of death of patients with pemphigus in Taiwan: a nationwide population-based study. J. Invest. Dermatol. 132, 92–97 (2012).

  186. 186.

    , , , & Comorbidities and inpatient mortality for pemphigus in the USA. Br. J. Dermatol. 174, 1290–1298 (2016).

  187. 187.

    , , , & Autoimmune diseases in patients with pemphigus and their first-degree relatives. Int. J. Dermatol. 50, 827–831 (2011).

  188. 188.

    , , , & Identification of a new disease cluster of pemphigus vulgaris with autoimmune thyroid disease, rheumatoid arthritis and type I diabetes. Br. J. Dermatol. 172, 729–738 (2015).

  189. 189.

    et al. Prognostic factors of paraneoplastic pemphigus. Arch. Dermatol. 148, 1165–1172 (2012).

  190. 190.

    & Measuring the immeasurable: a systematic review of outcome measures in pemphigus. Australas. J. Dermatol. 47, A32–A33(2006).

  191. 191.

    & Outcome measures for autoimmune blistering diseases. J. Dermatol. 42, 31–36 (2015). This paper reviews all the standardized and validated outcome measures in pemphigus.

  192. 192.

    et al. Reliability and convergent validity of two outcome instruments for pemphigus. J. Invest. Dermatol. 129, 2404–2410 (2008). The PDAI is widely considered as the most reliable and valid pemphigus disease activity index for use in clinical trials.

  193. 193.

    , , & Introducing a novel autoimmune bullous skin disorder intensity score (ABSIS) in pemphigus. Eur. J. Dermatol. 17, 4–11 (2007). The ABSIS is a pemphigus disease activity scoring system that is commonly used in clinical and translational research studies in pemphigus.

  194. 194.

    et al. Grading criteria for disease severity by pemphigus disease area index. J. Dermatol. 41, 969–973 (2014).

  195. 195.

    et al. Calculation of cutoff values based on the ABSIS and PDAI pemphigus scoring systems for defining moderate, significant, and extensive types of pemphigus. Br. J. Dermatol. 175, 142–149 (2016).

  196. 196.

    The WHOQOL Group. The World Health Organization Quality of Life assessment (WHOQOL): position paper from the World Health Organization. Soc. Sci. Med. 41, 1403–1409 (1995).

  197. 197.

    et al. Health-related quality of life and its determinants in pemphigus: a systematic review and meta-analysis. Br. J. Dermatol. 173, 1076–1080 (2015). This paper provides an overview of studies on quality of life in pemphigus.

  198. 198.

    et al. Burden of disease during quiescent periods in patients with pemphigus. Br. J. Dermatol. 170, 1087–1091 (2014).

  199. 199.

    et al. Development of a quality-of-life instrument for autoimmune bullous disease: the Autoimmune Bullous Disease Quality of Life questionnaire. JAMA Dermatol. 149, 1186–1191 (2013). The ABQOL is the major quality-of-life index in use for patients with an autoimmune blistering disease.

  200. 200.

    et al. The development and validation of the treatment of autoimmune bullous disease quality of life questionnaire, a tool to measure the quality of life impacts of treatments used in patients with autoimmune blistering disease. Br. J. Dermatol. 169, 1000–1006 (2013).

  201. 201.

    , , , & Reliability of the autoimmune bullous disease quality of life (ABQOL) questionnaire in the USA. Qual. Life Res. 24, 2257–2260 (2015).

  202. 202.

    , & Genome-wide expression analysis suggests unique disease-promoting and disease-preventing signatures in pemphigus vulgaris. Genes Immun. 14, 487–499 (2013).

  203. 203.

    et al. Induction of T regulatory cells by the superagonistic anti-CD28 antibody D665 leads to decreased pathogenic IgG autoantibodies against desmoglein 3 in a HLA-transgenic mouse model of pemphigus vulgaris. Exp. Dermatol. 25, 293–298 (2016).

  204. 204.

    et al. Transgenic rescue of desmoglein 3 null mice with desmoglein 1 to develop a syngeneic mouse model for pemphigus vulgaris. J. Dermatol. Sci. 63, 33–39 (2011).

  205. 205.

    & AChR-specific immunosuppressive therapy of myasthenia gravis. Biochem. Pharmacol. 97, 609–619 (2015).

  206. 206.

    et al. Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis. Sci. Transl Med. 5, 188ra75 (2013).

  207. 207.

    et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J. Clin. Invest. 126, 1413–1424 (2016).

  208. 208.

    et al. Super-resolution microscopy reveals altered desmosomal protein organization in tissue from patients with pemphigus vulgaris. J. Invest. Dermatol. 136, 59–66 (2016).

  209. 209.

    et al. Subcutaneous veltuzumab, a humanized anti-CD20 antibody, for treatment of refractory pemphigus vulgaris. JAMA Dermatol. 150, 1331–1335 (2014).

  210. 210.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  211. 211.

    US National Library of Medicine. ClinicalTrials.gov (2016).

  212. 212.

    , & Future therapies for pemphigus vulgaris: rituximab and beyond. J. Am. Acad. Dermatol. 74, 746–753 (2016).

  213. 213.

    US National Library of Medicine. ClinicalTrials.gov (2016).

  214. 214.

    et al. Discovery of PRN1008, a novel, reversible covalent BTK inhibitor in clinical development for rheumatoid arthritis [abstract]. Arthritis Rheumatol. 67 (Suppl. 10), 1671 (2015).

  215. 215.

    et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J. Clin. Invest. 112, 286–297 (2003).

  216. 216.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  217. 217.

    et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype–genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 14, 407–417 (2004).

  218. 218.

    et al. Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology 149, 907–917.e7 (2015).

  219. 219.

    TPMT testing before starting azathioprine or mercaptopurine: surely just do it? Gastroenterology 149, 850–853 (2015).

  220. 220.

    et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat. Genet. 46, 1017–1020 (2014).

  221. 221.

    et al. A novel polymorphism of FcγRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J. Clin. Invest. 100, 1059–1070 (1997).

  222. 222.

    et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res. 64, 4664–4669 (2004).

  223. 223.

    et al. The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 48, 455–459 (2003).

  224. 224.

    & Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 21, 3940–3947 (2003).

  225. 225.

    et al. FcγRIIIa and FcγRIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood 103, 1472–1474 (2004).

  226. 226.

    , & Immunoglobulin G Fc receptor polymorphisms do not correlate with response to chemotherapy or clinical course in patients with follicular lymphoma. Leuk. Lymphoma 50, 1494–1500 (2009).

  227. 227.

    et al. Multicenter randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris. Arch. Dermatol. 144, 25–32 (2008).

  228. 228.

    & Glucose-6-phosphate dehydrogenase deficiency and malaria: cytochemical detection of heterozygous G6PD deficiency in women. J. Histochem. Cytochem. 57, 1003–1011 (2009).

  229. 229.

    , & Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients. Br. J. Dermatol. 169, 916–921 (2013).

  230. 230.

    et al. Treatment of nine cases of pemphigus vulgaris with cyclosporine. J. Am. Acad. Dermatol. 18, 1262–1266 (1988).

  231. 231.

    et al. The role of cyclosporine A in the treatment of pemphigus erythematosus. Int. J. Dermatol. 30, 890–892 (1991).

  232. 232.

    et al. Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris. Am. J. Clin. Dermatol. 8, 85–92 (2007).

  233. 233.

    , & Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus. Arch. Dermatol. 136, 868–872 (2000).

  234. 234.

    & Evaluation of cyclophosphamide pulse therapy as an adjuvant to oral corticosteroid in the management of pemphigus vulgaris. Clin. Exp. Dermatol. 38, 659–664 (2013).

  235. 235.

    , , , & The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J. Am. Acad. Dermatol. 40, 167–170 (1999).

  236. 236.

    et al. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc. Natl Acad. Sci. USA 103, 12855–12860 (2006).

  237. 237.

    , , , & Autoantibodies in the autoimmune disease pemphigus foliaceus induce blistering via p38 mitogen-activated protein kinase-dependent signaling in the skin. Am. J. Pathol. 173, 1628–1636 (2008).

  238. 238.

    et al. Desmoglein 3 anchors telogen hair in the follicle. J. Cell Sci. 111, 2529–2537 (1998).

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Acknowledgements

The authors thank R. Eming and M. Hertl (Philipps University of Marburg, Germany) for kindly providing the histology image in Figure 5c.

Author information

Affiliations

  1. Department of Dermatology, University of Lübeck, Lübeck, Germany.

    • Michael Kasperkiewicz
    •  & Detlef Zillikens
  2. Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Christoph T. Ellebrecht
    •  & Aimee S. Payne
  3. Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160–8582, Japan.

    • Hayato Takahashi
    • , Jun Yamagami
    •  & Masayuki Amagai

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Contributions

Introduction (M.A.); Epidemiology (M.K. and D.Z.); Mechanisms/pathophysiology (M.A., C.T.E., H.T., J.Y. and A.S.P.); Diagnosis, screening and prevention (M.K. and D.Z.); Management (C.T.E. and A.S.P.); Quality of life (M.K. and D.Z.); Outlook (C.T.E. and A.S.P.); Overview of the Primer (M.A.). M.K., C.T.E. and H.T. contributed equally to this work.

Competing interests

M.A. receives speaker honoraria and grants from Nihon Pharmaceutical, research support from Medical & Biological Laboratories, Health Sciences Research Grants for Research on Rare and Intractable Diseases from Ministry of Health, Labour, and Welfare, and grants from Japan Society for the Promotion of Science and Agency for Medical Research and Development. H.T. receives grants from Japan Society for the Promotion of Science. A.S.P. is a consultant for Syntimmune and TG Therapeutics and receives grants or research support from the US NIH (R01-AR057001, R56-AR064220 and R01-068288), the Dermatology Foundation and Sanofi. She is co-inventor on a patent related to chimeric immunoreceptor therapy of pemphigus. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US NIH. C.T.E. receives grants or research support from Deutsche Forschungsgemeinschaft (EL711/1-1) and is co-inventor on a patent related to chimeric immunoreceptor therapy of pemphigus. D.Z. is an advisory board member for Roche Pharma, and a consultant for Euroimmun, Almirall, UCB, Fresenius and arGEN-X. He received speakers honoraria and/or travel/accommodations/meeting compensation from Biotest, Fresenius, Miltenyi, Roche Pharma, Biogen Idec, AbbVie, UCB, Janssen and grants or research support from Euroimmun, Miltenyi, Fresenius, Biotest, Dompe, Almirall, Biogen and Roche. He holds the patent Euroimmun: DE 10 2006 059 574 A1. M.K. and J.Y. declare no competing interests.

Corresponding author

Correspondence to Masayuki Amagai.

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https://doi.org/10.1038/nrdp.2017.26

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