Advertisement

Pemphigus Vulgaris

  • Ilya Shoimer
  • Russell X. Wong
  • P. Régine MydlarskiEmail author
Chapter

Abstract

Pemphigus vulgaris (PV) is an autoimmune mucocutaneous blistering disorder for which early recognition and treatment are necessary to achieve a favourable prognosis. A multidisciplinary, patient-centred approach is required to optimize therapeutic outcomes. Systemic corticosteroids remain first-line treatment for PV patients, yet their optimal dosing regimen remains unknown. Further, various steroid-sparing adjuvants play an important role in the treatment of PV. As clinical trials in the field are limited by small sample sizes and a lack of standardized outcome measures, a therapeutic algorithm is presented to guide the management of PV patients.

Keywords

Pemphigus vulgaris Systemic steroids Dapsone Azathioprine Mycophenolate mofetil Cyclophosphamide Methotrexate Rituximab Tumor Necrosis Factor-α Inhibitors Intravenous Immunoglobulin 

References

  1. 1.
    Joly P, Litrowski N. Pemphigus group (vulgaris, vegetans, foliaceus, herpetiformis, brasiliensis). Clin Dermatol. 2011;29:432–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Ruocco V, Ruocco E, Lo Schiavo A, Brunetti G, Guerrera LP, Wolf R. Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies. Clin Dermatol. 2013;31:374–81.CrossRefPubMedGoogle Scholar
  3. 3.
    Zaraa I, Sellami A, Bouguerra C, et al. Pemphigus vegetans: a clinical, histological, immunopathological and prognostic study. J Eur Acad Dermatol Venereol. 2011;25:1160–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Beutner EH, Jordon RE. Demonstration of skin antibodies in sera of pemphigus vulgaris patients by indirect immunofluorescent staining. Proc Soc Exp Biol Med. 1964;117:505–10.Google Scholar
  5. 5.
    Anhalt GJ, Labib RS, Voorhees JJ, Beals TF, Diaz LA. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med. 1982;306:1189–96.CrossRefPubMedGoogle Scholar
  6. 6.
    Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. 1991;67:869–77.CrossRefPubMedGoogle Scholar
  7. 7.
    Koch PJ, Mahoney MG, Ishikawa H, et al. Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris. J Cell Biol. 1997;137:1091–102.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Yamamoto T, Ikeda K, Sasaoka S, et al. Human leukocyte antigen genotypes and antibody profiles associated with familial pemphigus in Japanese. J Dermatol. 2011;38:711–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Mohan MP, Ramesh TC. Multiple autoimmune syndrome. Indian J Dermatol Venereol Leprol. 2003;69:298–9.PubMedGoogle Scholar
  10. 10.
    Parameswaran A, Attwood K, Sato R, Seiffert-Sinha K, Sinha AA. Identification of a new disease cluster of pemphigus vulgaris with autoimmune thyroid disease, rheumatoid arthritis, and type I diabetes. Br J Dermatol. 2015;172(3):729–38.CrossRefPubMedGoogle Scholar
  11. 11.
    Ruocco E, Wolf R, Ruocco V, Brunetti G, Romano F, Lo Schiavo A. Pemphigus: associations and management guidelines: facts and controversies. Clin Dermatol. 2013;31:382–90.CrossRefPubMedGoogle Scholar
  12. 12.
    Bystryn JC, Rudolph JL. Pemphigus. Lancet. 2005;366:61–73.CrossRefPubMedGoogle Scholar
  13. 13.
    Hertl M, Jedlickova H, Karpati S, 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. 2015;29(3):405–14.CrossRefPubMedGoogle Scholar
  14. 14.
    Iraji F, Asilian A, Siadat AH. Pimecrolimus 1% cream in the treatment of cutaneous lesions of pemphigus vulgaris: a double-blind, placebo-controlled clinical trial. J Drugs Dermatol. 2010;9:684–6.PubMedGoogle Scholar
  15. 15.
    Cohen SN, Lim RP, Paul CJ, Abdullah A. Equal efficacy of topical tacrolimus and clobetasone butyrate in pemphigus foliaceus. Int J Dermatol. 2006;45:1379.CrossRefPubMedGoogle Scholar
  16. 16.
    Tabrizi MN, Chams-Davatchi C, Esmaeeli N, et al. Accelerating effects of epidermal growth factor on skin lesions of pemphigus vulgaris: a double-blind, randomized, controlled trial. J Eur Acad Dermatol Venereol. 2007;21:79–84.CrossRefPubMedGoogle Scholar
  17. 17.
    Geng Y, Savage SM, Razani-Boroujerdi S, Sopori ML. Effects of nicotine on the immune response. II. Chronic nicotine treatment induces T cell anergy. J Immunol. 1996;156:2384–90.PubMedGoogle Scholar
  18. 18.
    Nguyen VT, Arredondo J, Chernyavsky AI, Pittelkow MR, Kitajima Y, Grando SA. Pemphigus vulgaris acantholysis ameliorated by cholinergic agonists. Arch Dermatol. 2004;140:327–34.PubMedGoogle Scholar
  19. 19.
    Valikhani M, Kavusi S, Chams-Davatchi C, et al. Impact of smoking on pemphigus. Int J Dermatol. 2008;47:567–70.CrossRefPubMedGoogle Scholar
  20. 20.
    Iraji F, Yoosefi A. Healing effect of Pilocarpine gel 4% on skin lesions of pemphigus vulgaris. Int J Dermatol. 2006;45:743–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Ratnam KV, Phay KL, Tan CK. Pemphigus therapy with oral prednisolone regimens. A 5-year study. Int J Dermatol. 1990;29:363–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Mentink LF, Mackenzie MW, Toth GG, et al. Randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris: PEMPULS trial. Arch Dermatol. 2006;142:570–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol. 2011;64:903–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Frew JW, Martin LK, Murrell DF. Evidence-based treatments in pemphigus vulgaris and pemphigus foliaceus. Dermatol Clin. 2011;29:599–606.CrossRefPubMedGoogle Scholar
  25. 25.
    Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2010;62:1515–26.CrossRefGoogle Scholar
  26. 26.
    Guslandi M. Steroid ulcers: any news? World J Gastrointest Pharmacol Ther. 2013;4:39–40.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Chams-Davatchi C, Esmaili N, Daneshpazhooh M, et al. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J Am Acad Dermatol. 2007;57:622–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Chams‐Davatchi C, Mortazavizadeh A, Daneshpazhooh M, et al. Randomized double blind trial of prednisolone and azathioprine, vs. prednisolone and placebo, in the treatment of pemphigus vulgaris. J Eur Acad Dermatol Venereol. 2013;27:1285–92.PubMedGoogle Scholar
  29. 29.
    Rose E, Wever S, Zillikens D, Linse R, Haustein U, Bröcker E. Intravenous dexamethasone‐cyclophosphamide pulse therapy in comparison with oral methylprednisolone‐azathioprine therapy in patients with pemphigus: results of a multicenter prospectively randomized study. J Dtsch Dermatol Ges J Dtsc Dermatol Ges. 2005;3:200–6.CrossRefGoogle Scholar
  30. 30.
    Beissert S, Werfel T, Frieling U, et al. A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Arch Dermatol. 2006;142:1447–54.CrossRefPubMedGoogle Scholar
  31. 31.
    Dastgheib L, Sadati MS, Baghernejhad M. Assessment of the adjuvant effect of tacrolimus in the management of pemphigus vulgaris: A randomized controlled trial. J Dermatolog Treat. 2015;26(1):90–3.Google Scholar
  32. 32.
    Atzmony L, Hodak E, Gdalevich M, Rosenbaum O, Mimouni D. Treatment of pemphigus vulgaris and pemphigus foliaceus: a systematic review and meta-analysis. Am J Clin Dermatol. 2014;15:503–15.CrossRefPubMedGoogle Scholar
  33. 33.
    Meggitt S, Anstey A, Mohd Mustapa M, Reynolds N, Wakelin S. British Association of Dermatologists’ guidelines for the safe and effective prescribing of azathioprine 2011. Br J Dermatol. 2011;165:711–34.CrossRefPubMedGoogle Scholar
  34. 34.
    Badalamenti S, Kerdel F. Azathioprine. Comprehensive dermatologic drug therapy. Wolverton SE, editor. Philadelphia: WB Saunders Co; 2001. p. 165–79.Google Scholar
  35. 35.
    Chrysomallis F, Ioannides D, Teknetzis A, Panagiotidou D, Minas A. Treatment of oral pemphigus vulgaris. Int J Dermatol. 1994;33:803–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Sharma V, Khandpur S. Evaluation of cyclophosphamide pulse therapy as an adjuvant to oral corticosteroid in the management of pemphigus vulgaris. Clin Exp Dermatol. 2013;38:659–64.CrossRefPubMedGoogle Scholar
  37. 37.
    Hayag MV, Cohen JA, Kerdel FA. Immunoablative high-dose cyclophosphamide without stem cell rescue in a patient with pemphigus vulgaris. J Am Acad Dermatol. 2000;43:1065–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Ioannides D, Chrysomallis F, Bystryn J. Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus. Arch Dermatol. 2000;136:868–72.PubMedGoogle Scholar
  39. 39.
    Werth VP, Fivenson D, Pandya AG, et al. Multicenter randomized, double-blind, placebo-controlled, clinical trial of dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris. Arch Dermatol. 2008;144(1):25–32.CrossRefPubMedGoogle Scholar
  40. 40.
    Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. 2009;60:595–603.CrossRefPubMedGoogle Scholar
  41. 41.
    Mydlarski P, Mittmann N, Shear N. Intravenous immunoglobulin: use in dermatology. Skin Therapy Lett. 2004;9:1–6.PubMedGoogle Scholar
  42. 42.
    Mydlarski PR, Ho V, Shear NH. Canadian consensus statement on the use of intravenous immunoglobulin therapy in dermatology. J Cutan Med Surg. 2006;10:205–21.CrossRefPubMedGoogle Scholar
  43. 43.
    Baum S, Greenberger S, Samuelov L, et al. Methotrexate is an effective and safe adjuvant therapy for pemphigus vulgaris. Eur J Dermatol. 2012;22:83–7.PubMedGoogle Scholar
  44. 44.
    Gürcan H, Ahmed AR. Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid. Br J Dermatol. 2009;161:723–31.CrossRefPubMedGoogle Scholar
  45. 45.
    Smith TJ, Bystryn J. Methotrexate as an adjuvant treatment for pemphigus vulgaris. Arch Dermatol. 1999;135:1275–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Tran K, Wolverton J, Soter N. Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients. Br J Dermatol. 2013;169:916–21.CrossRefPubMedGoogle Scholar
  47. 47.
    Beissert S, Mimouni D, Kanwar AJ, Solomons N, Kalia V, Anhalt GJ. Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial. J Invest Dermatol. 2010;130:2041–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Ioannides D, Apalla Z, Lazaridou E, Rigopoulos D. Evaluation of mycophenolate mofetil as a steroid‐sparing agent in pemphigus: a randomized, prospective study. J Eur Acad Dermatol Venereol. 2012;26:855–60.CrossRefPubMedGoogle Scholar
  49. 49.
    Guillaume J, Roujeau J, Morel P, et al. Controlled study of plasma exchange in pemphigus. Arch Dermatol. 1988;124:1659–63.CrossRefPubMedGoogle Scholar
  50. 50.
    Kolesnik M, Becker E, Reinhold D, et al. Treatment of severe autoimmune blistering skin diseases with combination of protein A immunoadsorption and rituximab: a protocol without initial high dose or pulse steroid medication. J Eur Acad Dermatol Venereol. 2014;28:771–80.CrossRefPubMedGoogle Scholar
  51. 51.
    Mlynek A, Meurer M. Immunoadsorption in the treatment of pemphigus. Atheroscler Suppl. 2009;10:107–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Pfutze M, Eming R, Kneisel A, Kuhlmann U, Hoyer J, Hertl M. Clinical and immunological follow-up of pemphigus patients on adjuvant treatment with immunoadsorption or rituximab. Dermatology. 2009;218:237–45.CrossRefPubMedGoogle Scholar
  53. 53.
    Günther C, Laske J, Frind A, Julius U, Pfeiffer C. Successful therapy of pemphigus vulgaris with immunoadsorption using the TheraSorb™ adsorber. J Dtsch Dermatol Ges J Dtsch Dermatol Ges. 2008;6:661–3.CrossRefPubMedGoogle Scholar
  54. 54.
    Kasperkiewicz M, Shimanovich I, Meier M, 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. 2012;166:154–60.CrossRefPubMedGoogle Scholar
  55. 55.
    Behzad M, Möbs C, Kneisel A, et al. Combined treatment with immunoadsorption and rituximab leads to fast and prolonged clinical remission in difficult‐to‐treat pemphigus vulgaris. Br J Dermatol. 2012;166:844–52.CrossRefPubMedGoogle Scholar
  56. 56.
    Kaiser J, Kaatz M, Elsner P, Ziemer M. Complete remission of drug‐resistant Pemphigus vegetans treated by extracorporeal photopheresis. J Eur Acad Dermatol Venereol. 2007;21:843–4.CrossRefPubMedGoogle Scholar
  57. 57.
    Wollina U, Lange D, Looks A. Short-time extracorporeal photochemotherapy in the treatment of drug-resistant autoimmune bullous diseases. Dermatology. 1999;198:140–4.CrossRefPubMedGoogle Scholar
  58. 58.
    Gollnick HP, Owsianowski M, Taube KM, Orfanos CE. Unresponsive severe generalized pemphigus vulgaris successfully controlled by extracorporeal photopheresis. J Am Acad Dermatol. 1993;28:122–4.CrossRefPubMedGoogle Scholar
  59. 59.
    Rook AH, Jegasothy BV, Heald P, et al. Extracorporeal photochemotherapy for drug-resistant pemphigus vulgaris. Ann Intern Med. 1990;112:303–5.CrossRefPubMedGoogle Scholar
  60. 60.
    Kim J, Kim Y, Kim M, Kim S. Clinical efficacy of different doses of rituximab in the treatment of pemphigus: a retrospective study of 27 patients. Br J Dermatol. 2011;165:646–51.CrossRefPubMedGoogle Scholar
  61. 61.
    Schmidt E, Goebeler M, Zillikens D. Rituximab in severe pemphigus. Ann N Y Acad Sci. 2009;1173:683–91.CrossRefPubMedGoogle Scholar
  62. 62.
    Joly P, Mouquet H, Roujeau J, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med. 2007;357:545–52.CrossRefPubMedGoogle Scholar
  63. 63.
    Kamran B, Maryam D, Somayeh K, Mostafa M, Mahsa H, Cheyda C. Adjuvant rituximab in the treatment of pemphigus vulgaris: a phase II clinical trial. Int J Dermatol. 2013;52:862–7.CrossRefPubMedGoogle Scholar
  64. 64.
    Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med. 2006;355:1772–9.CrossRefPubMedGoogle Scholar
  65. 65.
    Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti–tumor necrosis factor therapy: results of a multicenter, randomized, double‐blind, placebo‐controlled, phase III trial evaluating primary efficacy and safety at twenty‐four weeks. Arthritis Rheum. 2006;54:2793–806.CrossRefPubMedGoogle Scholar
  66. 66.
    Heelan K, Al-Mohammedi F, Smith MJ, et al. Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 2014;150:703–8.CrossRefPubMedGoogle Scholar
  67. 67.
    Leshem YA, Hodak E, David M, Anhalt GJ, Mimouni D. Successful treatment of pemphigus with biweekly 1-g infusions of rituximab: a retrospective study of 47 patients. J Am Acad Dermatol. 2013;68:404–11.CrossRefPubMedGoogle Scholar
  68. 68.
    Lunardon L, Tsai KJ, Propert KJ, et al. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch Dermatol. 2012;148:1031–6.PubMedCentralCrossRefPubMedGoogle Scholar
  69. 69.
    Cianchini G, Lupi F, Masini C, Corona R, Puddu P, De Pità O. Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with long-term follow-up. J Am Acad Dermatol. 2012;67:617–22.CrossRefPubMedGoogle Scholar
  70. 70.
    Kanwar AJ, Vinay K, Sawatkar G, et al. Clinical and immunological outcomes of high‐and low‐dose rituximab treatments in patients with pemphigus: a randomized, comparative, observer‐blinded study. Br J Dermatol. 2014;170:1341–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Ingen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A, et al. First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency topical corticosteroids. JAMA Dermatol. 2015;151(2):200–3.CrossRefPubMedGoogle Scholar
  72. 72.
    Cho Y, Lee F, Chu C, Wang L. First-line combination therapy with rituximab and corticosteroids is effective and safe for pemphigus. Acta Derm Venereol. 2014;94:472–3.CrossRefPubMedGoogle Scholar
  73. 73.
    Ellebrecht CT, Choi EJ, Allman DM, et al. Subcutaneous veltuzumab, a humanized anti-CD20 antibody, in the treatment of refractory pemphigus vulgaris. JAMA Dermatol. 2014;150:1331–5.CrossRefPubMedGoogle Scholar
  74. 74.
    Ragab N, Abdallah M, El-Gohary E, Elewa R. Stress and serum TNF-alpha levels may predict disease outcome in patients with pemphigus: a preliminary study. Cutis. 2011;87:189–94.PubMedGoogle Scholar
  75. 75.
    Feliciani C, Toto P, Wang B, Sauder DN, Amerio P, Tulli A. Urokinase plasminogen activator mRNA is induced by IL-1alpha and TNF-alpha in in vitro acantholysis. Exp Dermatol. 2003;12:466–71.CrossRefPubMedGoogle Scholar
  76. 76.
    Fiorentino DF, Garcia MS, Rehmus W, Kimball AB. A pilot study of etanercept treatment for pemphigus vulgaris. Arch Dermatol. 2011;147:117–8.CrossRefPubMedGoogle Scholar
  77. 77.
    Hall R, Fairley J, Woodley D, et al. A multi‐centered randomized trial of the treatment of pemphigus vulgaris patients with infliximab and prednisone compared to prednisone alone. Br J Dermatol. 2015;172(3):760–8.CrossRefPubMedGoogle Scholar
  78. 78.
    El‐Darouti M, Marzouk S, Abdel Hay R, et al. The use of sulfasalazine and pentoxifylline (low‐cost antitumour necrosis factor drugs) as adjuvant therapy for the treatment of pemphigus vulgaris: a comparative study. Br J Dermatol. 2009;161:313–9.CrossRefPubMedGoogle Scholar
  79. 79.
    Strowd LC, Taylor SL, Jorizzo JL, Namazi MR. Therapeutic ladder for pemphigus vulgaris: emphasis on achieving complete remission. J Am Acad Dermatol. 2011;64:490–4.CrossRefPubMedGoogle Scholar
  80. 80.
    Daniel BS, Murrell DF. Management of pemphigus. F1000Prime Rep. 2014;6:32.PubMedCentralCrossRefPubMedGoogle Scholar
  81. 81.
    Prajapati V, et al. Advances in pemphigus therapy. Skin Therapy Lett. 2008;13:4–7.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Ilya Shoimer
    • 1
  • Russell X. Wong
    • 1
  • P. Régine Mydlarski
    • 2
    • 3
    Email author
  1. 1.Division of DermatologyUniversity of CalgaryCalgaryCanada
  2. 2.Division of Dermatology, Department of MedicineUniversity of CalgaryCalgaryCanada
  3. 3.Richmond Road Diagnostic and Treatment CentresCalgaryCanada

Personalised recommendations