Abstract
The therapeutic management of pemphigus vulgaris (PV) is centered around immunosuppression, which can be generalized, as in the use of corticosteroids or steroid sparing agents, or specific, as in therapeutic blockage of autoantibody production, certain cytokines, or signaling pathways. Currently, the backbone of treatment for PV, particularly, first line therapy, remains systemic corticosteroids. Although very effective, the significant side effects of long-term corticosteroid usage are well documented. Adjunctive therapies aim to eliminate, or at least decrease, the necessary dose of corticosteroids. Specifically, azathioprine, cyclophosphamide, methotrexate, cyclosporine, mycophenolate mofetil and dapsone are now widely used in PV. Intravenous immunoglobulin (IVIG), plasmapheresis, immunoadsorption, and most recently, rituximab, are other members of the therapeutic armamentarium. However, despite the widening range of treatment options in PV, well-controlled clinical trials and consensus guidelines are lacking.
Similar content being viewed by others
References
Bystryn JC. Adjuvant therapy of pemphigus. Arch Dermatol 1984; 120: 941–51.
Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol 2001; 33: 289–94.
Bystryn JC, Steinman N. The adjuvant therapy of pemphigus- an update. Arch Dermatol 1996; 132: 203–12.
Herbst A, Bystryn J. Patterns of remission in pemphigus vulgaris. J Am Acad Dermatol 2000; 42: 422–7.
Shamsadini S, Fekri A, Farajzadeh S, et al. Determination of survival and hazard functions for pemphigus patients in Kerman, a southern province of Iran. Int J Dermatol 2006; 45: 688–771.
Mourellou O, Chaidemenos GC, Koussidou T, Kapetis E. The treatment of pemphigus vulgaris. Experience with 48 patients seen over an 11-year period. Br J Dermatol 1995; 133: 83–7.
Martin LK, Agero AL, Werth V, Villanueva E, Segall J, Murrell DF. Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev 2009. doi: 10.1002/14651858.CD006263.
Ratnam KV, L PK, K TC. Pemphigus therapy with oral prednisolone regimens. A 5-year study. Int J Dermatol 1990; 29: 363–7.
Murrell D, Amagai M, Barnadas M, et al. JAAD. Consensus statement on definitions of disease, endpoints, and therapeutic response for pemphigus. J Am Acad Dermatol 2008; 58: 1043–6.
Harman K, Albert S, Black M. British Association of Dermatologists. Guidelines for the management of pemphigus. Br J Dermatol 2003; 149(926–37).
Mentink L, Mackenzie M, Toth G, et al. Randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris: PEMPULS trial. Arch Dermatol 2006; 142: 570–6.
Yeh S, Sami N, Ahmed R. Treatment of pemphigus vulgaris: current and emerging options. Am J Clin Dermatol 2005; 6: 327–42.
Beissert S, Mimouni D, Kanwar AJ, et al. Treating pemphigus vulgaris with prednisone and mycophenolate mofetil: a multicenter, randomized, placebo-controlled trial. J Invest Dermatol 2010; 130: 2041–8.
Chams-Davatchi C, Esmaili N, Daneshpazhooh N, et al. RcoltoftrfpvJAAD-. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J Am Acad Dermatol 2007; 57: 622–8.
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.
Forum GSABDotED. Guideline on the Diagnosis and Treatment of Autoimmune Bullous Diseases–Pemphigus. 2014 [cited 2014 July 08]; Available from: http://www.euroderm.org/index.php/edf-guidelines.
Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001; 345: 747–55.
Amagai M, Ikeda S, Shimuzu H, Iizuka H, Hanada K, Aiba S. A randomized double blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol 2009; 60: 595–603.
Mimouni D, Blank M, Payne AS, 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: 543–9.
Ahmed A, V DM. Consensus Statement on the Use of Intravenous Immunoglobulin Therapy in the Treatment of Autoimmune Mucocutaneous Blistering Diseases. Arch Dermatol 2003; 139: 1051–9.
Cianchini G, Corona R, Frezzolini A, Ruffelli M, Didona B, Puddu P. Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature. Arch Dermatol 2007; 143: 1033–8.
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.
Joly P, Mouquet H, Roujeau JC, et al. A single cycle of rituximab for the treatment of severe pemphigus. N Engl J Med 2007; 357: 545–52.
Kanwar AJ, Vinay K, Sawatkar GU, 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.
Colliou N, Picard D, Caillot F, et al. Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci Transl Med 2013; 5: 175ra30.
Nagel A, Podstawa E, Eickmann M, Muller HH, Hertl M, Eming R. Rituximab mediates a strong elevation of B-cell-activating factor associated with increased pathogen-specific IgG but not autoantibodies in pemphigus vulgaris. J Invest Dermatol 2009; 129: 2202–10.
Eming R, Nagel A, Wolff-Franke S, Podstawa E, Debus D, Hertl M. Rituximab exerts a dual effect in pemphigus vulgaris. J Invest Dermatol 2008; 128: 2850–8.
Leshem YA, David M, Hodak E, et al. A prospective study on clinical response and cell-mediated immunity of pemphigus patients treated with rituximab. Arch Dermatol Res 2014; 306: 67–74.
Mouquet H, Musette P, Gougeon ML, et al. B-cell depletion immunotherapy in pemphigus: effects on cellular and humoral immune responses. J Invest Dermatol 2008; 128: 2859–69.
Asashima N, Fujimoto M, Watanabe R, et al. Serum levels of BAFF are increased in bullous pemphigoid but not in pemphigus vulgaris. Br J Dermatol 2006; 155: 330–6.
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.
Berookhim B, Fischer HD, Weinberg JM. Treatment of recalcitrant pemphigus vulgaris with the tumor necrosis factor alpha antagonist etanercept. Cutis 2004; 74: 245–7.
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: 448–9.
Shetty A, Marcum CB, Glass LF, Carter JD. Successful treatment of pemphigus vulgaris with etanercept in four patients. J Drugs Dermatol 2009; 8: 940–3.
National Institute of Allergy and Infectious Diseases. Use of Infliximab for the Treatment of Pemphigus Vulgaris. In: ClinicalTrialsgov 2000 [cited 2013 April 01]; Available from: http://clinicaltrials.gov/ct2/show/NCT00283712?term=anti+TNF+alpha+agents+and+pemphigus+vulgaris&rank=2.
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: e196–7.
Fiorentino DF, Garcia MS, Rehmus W, Kimball AB. A pilot study of etanercept treatment for pemphigus vulgaris. Arch Dermatol 2011; 147: 117–8.
Murrell DF, Dick S, Ahmed AR, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol 2008; 58: 1043–6.
Guillaume JC, Roujeau JC, Morel P, et al. Controlled study of plasma exchange in pemphigus. Arch Dermatol 1988; 124: 1659–63.
Zillikens D, Derfler K, Eming R, et al. Recommendations for the use of immunoapheresis in the treatment of autoimmune bullous diseases. Journal der Deutschen Dermatologischen Gesellschaft = J Germ Soc Dermatol (JDDG) 2007; 5: 881–7.
Behzad M, Mobs 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.
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 Euro Acad Dermatol Venereol 2014; 28: 771–80.
Nishifuji K, Amagai M, Kuwana M, Iwasaki T, Nishikawa T. Detection of antigen-specific B cells in patients with pemphigus vulgaris by enzyme-linked immunospot assay: requirement of T cell collaboration for autoantibody production. J Invest Dermatol 2000; 114: 88–94.
Veldman CM, Gebhard KL, Uter W, et al. T cell recognition of desmoglein 3 peptides in patients with pemphigus vulgaris and healthy individuals. J Immunol 2004; 172: 3883–92.
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.
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.
Schmidt E, Zillikens D. Immunoadsorption in dermatology. Arch Dermatol Res 2010; 302: 241–53.
Langenhan J, Dworschak J, Saschenbrecker S, et al. Specific immunoadsorption of pathogenic autoantibodies in pemphigus requires the entire ectodomains of desmogleins. Exp Dermatol 2014; 23: 253–9.
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.
Berkowitz P, Hu P, Liu Z, et al. Desmosome signaling. Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization. J Biol Chem 2005; 280: 23778–84.
Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA. Rubenstein DS. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Nat Ac Sci U S A 2006; 103: 12855–60.
Waschke J, Spindler V, Bruggeman P, Zillikens D, Schmidt G, Drenckhahn D. Inhibition of Rho A activity causes pemphigus skin blistering. J Cell Biol 2006; 175: 721–7.
Rubenstein D. Personal communication.
Mao X, Sano Y, Park JM, Payne AS. p38 MAPK activation is downstream of the loss of intercellular adhesion in pemphigus vulgaris. J Biol Chem 2011; 286: 1283–91.
Spindler V, Vielmuth F, Schmidt E, Rubenstein DS, Waschke J. Protective endogenous cyclic adenosine 5’-monophosphate signaling triggered by pemphigus autoantibodies. J Immunol 2010; 185: 6831–8.
Grando SA, Pittelkow MR, Schallreuter KU. Adrenergic and cholinergic control in the biology of epidermis: physiological and clinical significance. J Invest Dermatol 2006; 126: 1948–65.
Chow S, Rizzo C, Ravitskiy L, Sinha AA. The role of T cells in cutaneous autoimmune disease. Autoimmunity 2005; 38: 303–17.
Sinha AA, Brautbar C, Szafer F, et al. A newly characterized HLA DQ beta allele associated with pemphigus vulgaris. Science 1988; 239:1026–9.
Todd JA, Acha-Orbea H, Bell JI, et al. A molecular basis for MHC class IIassociated autoimmunity. Science 1988; 240: 1003–9.
Lee E, Lendas KA, Chow S, et al. Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris. Human Immunol 2006; 67: 125–39.
Hertl M, Amagai M, Sundaram H, Stanley J, Ishii K, Katz SI. Recognition of desmoglein 3 by autoreactive T cells in pemphigus vulgaris patients and normals. J Invest Dermatol 1998; 110: 62–6.
Riechers R, Grotzinger J, Hertl M. HLA class II restriction of autoreactive T cell responses in pemphigus vulgaris: review of the literature and potential applications for the development of a specific immunotherapy. Autoimmunity 1999; 30: 183–96.
Tsunoda K, Ota T, Suzuki H, et al. Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris. Euro J Immunol 2002; 32: 627–33.
Lin MS, Fu CL, Aoki V, et al. Desmoglein-1-specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem). J Clin Invest 2000; 105: 207–13.
Lee E, Sinha AA. T cell targeted immunotherapy for autoimmune disease. Autoimmunity 2005; 38: 577–96.
Aoki-Ota M, Kinoshita M, Ota T, et al. Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model. J Invest Dermatol 2006; 126: 105–13.
Takahashi H, Amagai M, Nishikawa T, Fujii Y, Kawakami Y, Kuwana M. Novel system evaluating in vivo pathogenicity of desmoglein 3-reactive T cell clones using murine pemphigus vulgaris. J Immunol 2008; 181: 1526–35.
Rizzo C, Fotino M, Zhang Y, Chow S, Spizuoco A, Sinha AA. Direct characterization of human T cells in pemphigus vulgaris reveals elevated autoantigen-specific Th2 activity in association with active disease. Clin Exp Dermatol 2005; 30: 535–40.
Angelini G, Bonamonte D, Lucchese A, et al. Preliminary data on Pemphigus vulgaris treatment by a proteomics-defined peptide: a case report. J Transl Med 2006; 4:43.
Anhalt G, Werth V, Strober B, et al. An open-label phase I clinical study to assess the safety of PI-0824 in patients with pemphigus vulgaris. J Invest Dermatol 2005; 125: 1088.
Sinha AA. The genetics of pemphigus. Dermatol Clin 2011; 29: 381–91, vii.
Sinha AA. Constructing immunoprofiles to deconstruct disease complexity in pemphigus. Autoimmunity 2012; 45: 36–43.
Dey-Rao R, Seiffert-Sinha K, Sinha AA. Genome-wide expression analysis suggests unique disease-promoting and disease-preventing signatures in Pemphigus vulgaris. Genes Immun 2013; 14: 487–99.
Werth V, Strober B, Kerdel F, et al. A Phase 2 Open-Label Uncontrolled Pilot Study of KC706 in Patients With Stable, Active Pemphigus Vulgaris. In: ClinicalTrialsgov [Internet] 2000 [cited 2013 Sep 29]; Available from: http://clinicaltrials.gov/ct2/show/NCT00606749.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Sinha, A.A., Hoffman, M.B. & Janicke, E.C. Pemphigus vulgaris: approach to treatment. Eur J Dermatol 25, 103–113 (2015). https://doi.org/10.1684/ejd.2014.2483
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1684/ejd.2014.2483