Pemphigus Vulgaris: An Evidence-Based Treatment Update

  • Esther Q. Wang
  • Dedee F. MurrellEmail author
Living reference work entry


Pemphigus vulgaris is a rare autoimmune blistering disease which is associated with high mortality and morbidity. The nature of this disease necessitates long-term aggressive treatment, for which systemic corticosteroid is the gold standard. However, the serious complications associated with systemic corticosteroids have led to the development of various adjuvant therapies including azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, dapsone, gold compounds, plasmapheresis, tetracyclines, and topical therapies. The evidence to support these adjuvant therapies is extremely limited and comprises of small RCTs, case series, and case studies. Newer and emerging treatments including antitumor necrosis factor agents, intravenous immunoglobulin, and rituximab appear to be promising interventions. More research should be conducted to evaluate the efficacy of these treatments.


Pemphigus Treatment Corticosteroid Azathioprine Mycophenolate mofetil Cyclophosphamide Dapsone Rituximab Intravenous immunoglobulin RCT 


  1. Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol. 2001;45(5):679–90.PubMedGoogle Scholar
  2. Ahmed AR, Gurcan HM. Use of intravenous immunoglobulin therapy during pregnancy in patients with pemphigus vulgaris. J Eur Acad Dermatol Venereol. 2011;25(9):1073–9.PubMedGoogle Scholar
  3. Akhtar SJ, Hasan MU. Treatment of pemphigus: a local experience. J Pak Med Assoc. 1998;48(10):300–4.PubMedGoogle Scholar
  4. Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus. 2005;14(Suppl 1):s2–8.PubMedGoogle Scholar
  5. Arnold DF, Burton J, Shine B, Wojnarowska F, Misbah SA. An ‘n-of-1’ placebo-controlled crossover trial of intravenous immunoglobulin as adjuvant therapy in refractory pemphigus vulgaris. Br J Dermatol. 2008;160(5):1098–102.Google Scholar
  6. Barrera MV, Mendiola MV, Bosch RJ, Herrera E. Prolonged treatment with rituximab in patients with refractory pemphigus vulgaris. J Dermatol Treat. 2007;18(5):312–4.Google Scholar
  7. Baskan EB, Yilmaz M, Tunali S, Saricaoglu H. Efficacy and safety of long-term mycophenolate sodium therapy in pemphigus vulgaris. J Eur Acad Dermatol Venereol. 2009;23(12):1432–4. Scholar
  8. Baum S, Scope A, Barzilai A, Azizi E, Trau H. The role of IVIg treatment in severe pemphigus vulgaris. J Eur Acad Dermatol Venereol. 2006;20(5):548–52. Scholar
  9. Baum S, Greenberger S, Samuelov L, Solomon M, Lyakhovitsky A, Trau H, Barzilai A. Methotrexate is an effective and safe adjuvant therapy for pemphigus vulgaris. Eur J Dermatol. 2012;22(1):83–7.PubMedGoogle Scholar
  10. 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(8):2041–8. Scholar
  11. Berookhim B, Fischer HD, Weinberg JM. Treatment of recalcitrant pemphigus vulgaris with the tumor necrosis factor alpha antagonist etanercept. Cutis. 2004;74(4):245–7.PubMedGoogle Scholar
  12. Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol. 2002;47(3):358–63.PubMedGoogle Scholar
  13. Calebotta A, Saenz AM, Gonzalez F, Carvalho M, Castillo R. Pemphigus vulgaris: benefits of tetracycline as adjuvant therapy in a series of thirteen patients. Int J Dermatol. 1999;38(3):217–21.PubMedGoogle Scholar
  14. Ch Chaidemenos G, Mourellou O, Koussidou T, Tsatsou F. An alternate-day corticosteroid regimen for pemphigus vulgaris. A 13-year prospective study. J Eur Acad Dermatol Venereol. 2007;21(10):1386–91. Scholar
  15. Chams-Davatchi C, Esmaili N, Daneshpazhooh M, Valikhani M, Balighi K, Hallaji Z, et al. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J Am Acad Dermatol. 2007;57(4):622–8.PubMedGoogle Scholar
  16. Chams-Davatchi C, Mortazavizadeh A, Daneshpazhooh M, Davatchi F, Balighi K, Esmaili N, 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(10):1285–92. Scholar
  17. Chrysomallis F, Ioannides D, Teknetzis A, Panagiotidou D, Minas A. Treatment of oral pemphigus vulgaris. Int J Dermatol. 1994;33(11):803–7.PubMedGoogle Scholar
  18. Craythorne E, du Viver A, Mufti GJ, Warnakulasuriya S. Rituximab for the treatment of corticosteroid-refractory pemphigus vulgaris with oral and skin manifestations. J Oral Pathol Med. 2011a;40(8):616–20.PubMedGoogle Scholar
  19. Craythorne EE, Mufti G, duVivier AW. Rituximab used as a first-line single agent in the treatment of pemphigus vulgaris. J Am Acad Dermatol. 2011b;65(5):1064–5. Scholar
  20. 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.PubMedGoogle Scholar
  21. Dick SE, Werth VP. Pemphigus: a treatment update. Autoimmunity. 2006;39(7):591–9. Scholar
  22. El Tal AK, Posner MR, Spigelman Z, Ahmed AR. Rituximab: a monoclonal antibody to CD20 used in the treatment of pemphigus vulgaris. J Am Acad Dermatol. 2006;55(3):449–59. Scholar
  23. el-Darouti M, Marzouk S, Abdel Hay R, el-Tawdy A, Fawzy M, Leheta T, 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(2):313–9.PubMedGoogle Scholar
  24. Feldman RJ, Ahmed AR. Relevance of rituximab therapy in pemphigus vulgaris: analysis of current data and the immunologic basis for its observed responses. Expert Rev Clin Immunol. 2011;7(4):529–41.PubMedGoogle Scholar
  25. Fellner MJ, Katz JM, McCabe JB. Successful use of cyclophosphamide and prednisone for initial treatment of pemphigus vulgaris. Arch Dermatol. 1978;114(6):889–94. Scholar
  26. Femiano F, Gombos F, Scully C. Pemphigus vulgaris with oral involvement: evaluation of two different systemic corticosteroid therapeutic protocols. J Eur Acad Dermatol Venereol. 2002;16(4):353–6.PubMedGoogle Scholar
  27. Fiorentino DF, Garcia MS, Rehmus W, Kimball AB. A pilot study of etanercept treatment for pemphigus vulgaris. Arch Dermatol. 2011;147(1):117–8.PubMedGoogle Scholar
  28. Garcia-Rabasco A, Alsina-Gibert M, Pau-Charles I, Iranzo P. Infliximab therapy failure in two patients with pemphigus vulgaris. J Am Acad Dermatol. 2012;67(5):e196–7.PubMedGoogle Scholar
  29. Gaspar ZS, Walkden V, Wojnarowska F. Minocycline is a useful adjuvant therapy for pemphigus. Australas J Dermatol. 1996;37(2):93–5.PubMedGoogle Scholar
  30. Genestier L, Paillot R, Quemeneur L, Izeradjene K, Revillard JP. Mechanisms of action of methotrexate. Immunopharmacology. 2000;47(2–3):247–57.PubMedGoogle Scholar
  31. Green MG, Bystryn JC. Effect of intravenous immunoglobulin therapy on serum levels of IgG1 and IgG4 antidesmoglein 1 and antidesmoglein 3 antibodies in pemphigus vulgaris. Arch Dermatol. 2008;144(12):1621–4.PubMedGoogle Scholar
  32. Gregoriou S, Efthymiou O, Stefanaki C, Rigopoulos D. Management of pemphigus vulgaris: challenges and solutions. Clin Cosmet Investig Dermatol. 2015;8:521–7. Scholar
  33. Guillaume J, Roujeau J, Morel P, et al. Controlled study of plasma exchange in pemphigus. Arch Dermatol. 1988;124(11):1659–63. Scholar
  34. Gürcan HM, Razzaque Ahmed A. Analysis of current data on the use of methotrexate in the treatment of pemphigus and pemphigoid. Br J Dermatol. 2009;161(4):723–31. Scholar
  35. Hall RP 3rd, Fairley J, Woodley D, Werth VP, Hannah D, Streilein RD, et al. A multicentre randomized trial of the treatment of patients with pemphigus vulgaris with infliximab and prednisone compared with prednisone alone. Br J Dermatol. 2015;172(3):760–8.PubMedPubMedCentralGoogle Scholar
  36. Hartung HP. Advances in the understanding of the mechanism of action of IVIg. J Neurol. 2008;255(Suppl 3):3–6.PubMedGoogle Scholar
  37. Hashimoto T. Treatment strategies for pemphigus vulgaris in Japan. Expert Opin Pharmacother. 2008;9(9):1519–30.PubMedGoogle Scholar
  38. Heaphy MR, Albrecht J, Werth VP. Dapsone as a glucocorticoid-sparing agent in maintenance-phase pemphigus vulgaris. Arch Dermatol. 2005;141(6):699–702.PubMedGoogle Scholar
  39. Hertl M, Jedlickova H, Karpati S, Marinovic B, Uzun S, Yayli 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. Scholar
  40. 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. Scholar
  41. 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(7):855–60.PubMedGoogle Scholar
  42. Iraji F, Faghihi G, Siadat AH. The efficacy of acyclovir in treatment of the pemphigus vulgaris. J Res Med Sci. 2013;18(11):976–8.PubMedPubMedCentralGoogle Scholar
  43. Jacobi A, Shuler G, Hertl M. Rapid control of therapy-refractory pemphigus vulgaris by treatment with the tumour necrosis factor-alpha inhibitor infliximab. Br J Dermatol. 2005;153(2):448–9.PubMedGoogle Scholar
  44. Lin MH, Hsu CK, Lee JY. Successful treatment of recalcitrant pemphigus vulgaris and pemphigus vegetans with etanercept and carbon dioxide laser. Arch Dermatol. 2005;141(6):680–2.PubMedGoogle Scholar
  45. Ljubojevic S, Lipozencic J, Brenner S, Budimcic D. Pemphigus vulgaris: a review of treatment over a 19-year period. J Eur Acad Dermatol Venereol. 2002;16(6):599–603.PubMedGoogle Scholar
  46. Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Investig. 2003;111(8):1122–4.PubMedGoogle Scholar
  47. Massari P, Duro-Garcia V, Giron F, Hernandez E, Juarez F, Castro C, et al. Safety assessment of the conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in stable renal transplant recipients. Transplant Proc. 2005;37(2):916–9.PubMedGoogle Scholar
  48. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47(2–3):119–25.PubMedGoogle Scholar
  49. Mentink LF, Mackenzie MW, Toth GG, Laseur M, Lambert FP, Veeger NJ, et al. Randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris: PEMPULS trial.[Erratum appears in Arch Dermatol. 2006 Aug;142(8):1014 note: dosage error in article text]. Arch Dermatol. 2006;142(5):570–6.PubMedGoogle Scholar
  50. Mignogna MD, Lo Muzio L, Mignogna RE, Carbone R, Ruoppo E, Bucci E. Oral pemphigus: long term behaviour and clinical response to treatment with deflazacort in sixteen cases. J Oral Pathol Med. 2000;29(4):145–52.PubMedGoogle Scholar
  51. Mignogna MD, Leuci S, Fedele S, Ruoppo E, Adamo D, Russo G, Pagliuca R. Adjuvant high-dose intravenous immunoglobulin therapy can be easily and safely introduced as an alternative treatment in patients with severe pemphigus vulgaris: a retrospective preliminary study. Am J Clin Dermatol. 2008;9(5):323–31.PubMedGoogle Scholar
  52. Mimouni D, Blank M, Payne AS, Anhalt GJ, Avivi C, Barshack I, et al. Efficacy of intravenous immunoglobulin (IVIG) affinity-purified anti-desmoglein anti-idiotypic antibodies in the treatment of an experimental model of pemphigus vulgaris. Clin Exp Immunol. 2010;162(3):543–9.PubMedPubMedCentralGoogle Scholar
  53. Mittmann N, Chan B, Knowles S, Mydlarski PR, Cosentino L, Shear N. Effect of intravenous immunoglobulin on prednisone dose in patients with pemphigus vulgaris. J Cutan Med Surg. 2006;10(5):222–7.PubMedGoogle Scholar
  54. Momeni AZ, Iraji F, Aminjavaheri M, Emami MR, Momeni A. The use of oral cyclophosphamide with dexamethasone pulse therapy in the treatment of pemphigus vulgaris. J Dermatolog Treat. 2007;18(5):275–8. Scholar
  55. Murrell DF. Blistering diseases: clinical features, pathogenesis, treatment. Heidelberg: Springer; 2015.Google Scholar
  56. Nousari CH, Brodsky R, Anhalt GJ. Evaluating the role of immunoablative high-dose cyclophosphamide therapy in pemphigus vulgaris. J Am Acad Dermatol. 2003;49(1):148–50.PubMedGoogle Scholar
  57. Pandya AG, Dyke C. Treatment of pemphigus with gold. Arch Dermatol. 1998;134(9):1104–7.PubMedGoogle Scholar
  58. Pandya AG, Sontheimer RD. Treatment of pemphigus vulgaris with pulse intravenous cyclophosphamide. Arch Dermatol. 1992;128(12):1626–30. Scholar
  59. Pardo J, Mercader P, Mahiques L, Sanchez-Carazo JL, Oliver V, Fortea JM. Infliximab in the management of severe pemphigus vulgaris. Br J Dermatol. 2005;153(1):222–3.PubMedGoogle Scholar
  60. Parmar NV, Kanwar AJ, Minz RW, Parsad D, Vinay K, Tsuruta D, et al. Assessment of the therapeutic benefit of dexamethasone cyclophosphamide pulse versus only oral cyclophosphamide in phase II of the dexamethasone cyclophosphamide pulse therapy: a preliminary prospective randomized controlled study. Indian J Dermatol Venereol Leprol. 2013;79(1):70–6. Scholar
  61. Penneys NS, Eaglstein WH, Frost P. Management of pemphigus with gold compounds: a long-term follow-up report. Arch Dermatol. 1976;112(2):185–7.PubMedGoogle Scholar
  62. Poulin Y, Perry HO, Muller SA. Pemphigus vulgaris: results of treatment with gold as a steroid-sparing agent in a series of thirteen patients. J Am Acad Dermatol. 1984;11(5 Pt 1):851–7.PubMedGoogle Scholar
  63. Quaresma MV, Bernardes Filho F, Hezel J, Peretti MC, Kac BK, Azulay-Abulafia L. Dapsone in the treatment of pemphigus vulgaris: adverse effects and its importance as a corticosteroid sparing agent. An Bras Dermatol. 2015;90(3 Suppl 1):51–4. Scholar
  64. Ratnam KV, Phay KL, Tan CK. Pemphigus therapy with oral prednisolone regimens a 5-year study. Int J Dermatol. 1990;29(5):363–7. Scholar
  65. Reeves HM, Winters JL. The mechanisms of action of plasma exchange. Br J Haematol. 2014;164(3):342–51. Scholar
  66. Rosenberg FR, Sanders S, Nelson CT. Pemphigus: a 20-year review of 107 patients treated with corticosteroids. Arch Dermatol. 1976;112(7):962–70. Scholar
  67. Roujeau JC, Andre C, Joneau Fabre M, Lauret P, Flechet ML, Kalis B, et al. Plasma exchange in pemphigus. Uncontrolled study of ten patients. Arch Dermatol. 1983;119(3):215–21.PubMedGoogle Scholar
  68. Ruocco V, Astarita C, Pisani M. Plasmapheresis as an alternative or adjunctive therapy in problem cases of pemphigus. Dermatologica. 1984;168(5):219–23.PubMedGoogle Scholar
  69. Ryan JG. Pemphigus: a 20-year survey of experience with 70 cases. Arch Dermatol. 1971;104(1):14–20. Scholar
  70. Sami N, Qureshi A, Ruocco E, Ahmed AR. Corticosteroid-sparing effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris. Arch Dermatol. 2002;138(9):1158–62.PubMedGoogle Scholar
  71. Sato N, Satake S, Fujiwara H, Ito M, Kameda K, Nagahori E, Igarashi R. Pemphigus vulgaris treated with combined oral cyclosporin and cyclophosphamide. Clin Exp Dermatol. 1998;23(2):92–4. Scholar
  72. Scully C, Paes De Almeida O, Porter SR, Gilkes JJ. Pemphigus vulgaris: the manifestations and long-term management of 55 patients with oral lesions. Br J Dermatol. 1999;140(1):84–9.PubMedGoogle Scholar
  73. Sharma VK, Khandpur S. Evaluation of cyclophosphamide pulse therapy as an adjuvant to oral corticosteroid in the management of pemphigus vulgaris. Clin Exp Dermatol. 2013;38(6):659–64. Scholar
  74. Sondergaard K, Carstens J, Zachariae H. The steroid-sparing effect of long-term plasmapheresis in pemphigus: an update. Ther Apher. 1997;1(2):155–8.PubMedGoogle Scholar
  75. Svecova D. IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects. Australas J Dermatol. 2016;57(2):141–4. Scholar
  76. Tabrizi MN, Chams-Davatchi C, Esmaeeli N, Noormohammadpoor P, Safar F, Etemadzadeh H, 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(1):79–84.PubMedGoogle Scholar
  77. Tan-Lim R, Bystryn JC. Effect of plasmapheresis therapy on circulating levels of pemphigus antibodies. J Am Acad Dermatol. 1990;22(1):35–40.PubMedGoogle Scholar
  78. Tavakolpour S. Current and future treatment options for pemphigus: is it time to move towards more effective treatments? Int Immunopharmacol. 2017;53:133–42. Scholar
  79. Tran KD, Wolverton JE, Soter NA. Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients. Br J Dermatol. 2013;169(4):916–21. Scholar
  80. Werth VP. Treatment of pemphigus vulgaris with brief, high-dose intravenous glucocorticoids. Arch Dermatol. 1996;132(12):1435–9. Scholar
  81. Werth VP, Fivenson D, Pandya AG, Chen D, Rico MJ, Albrecht J, Jacobus D. 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.PubMedGoogle Scholar
  82. Wozel G, Blasum C. Dapsone in dermatology and beyond. Arch Dermatol Res. 2014;306(2):103–24. Scholar
  83. Zhao CY, Murrell DF. Pemphigus vulgaris: an evidence-based treatment update. Drugs. 2015;75(3):271–84.PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.University of New South WalesSydneyAustralia
  2. 2.Department of Dermatology at St George HospitalUniversity of New South WalesKogarah, SydneyAustralia

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