Pemphigus Vulgaris: Present and Future Therapeutic Strategies

Pemphigus Vulgaris: Present and Future Therapeutic Strategies


  • Dario Didona Department of Dermatology and Allergology, Philipps University, Marburg, Germany
  • Giovanni Paolino Unit of Dermatology, IRCCS San Raffaele Hospital, Milan, Italy
  • Giovanni Di Zenzo IDI-IRCCS, Rome, Italy
  • Biagio Didona IDI-IRCCS, Rome, Italy
  • Riccardo Pampena Centro Oncologico ad Alta Tecnologia Diagnostica-Dermatologica, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Italy
  • Matteo Riccardo Di Nicola Unit of Dermatology, IRCCS San Raffaele Hospital, Milan, Italy
  • Santo Raffaele Mercuri Unit of Dermatology, IRCCS San Raffaele Hospital, Milan, Italy


anti-CD20 antibodies, neonatal Fc receptor (FcRn), pemphigus, rituximab, treatment


Pemphigus vulgaris (PV) belongs to the group of autoimmune blistering diseases. PV can affect not only mucous membranes, but also the skin and it is characterized by serum IgG autoantibodies against desmoglein 1 and 3, two major components of desmosomes. The introduction of glucocorticoids improved dramatically the prognosis of patients affected by PV.  However, long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants can lead to several adverse events. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been recently approved as in-label therapy for PV, leading to an improvement of the prognosis and higher remission rate. Furthermore, other anti B-cell therapies and several anti-CD20 biosimilars have been introduced in the clinical practice. We focused on present and future therapeutic approaches in PV


Didona D, Maglie R, Eming R, Hertl M. Pemphigus: Current and Future Therapeutic Strategies. Front Immunol. 2019;10:1418. DOI: 10.3389/fimmu.2019.01418. PMID: 31293582; PMCID: PMC6603181.

Solimani F, Maglie R, Pollmann R, et al. Thymoma-Associated Paraneoplastic Autoimmune Multiorgan Syndrome-From Pemphigus to Lichenoid Dermatitis. Front Immunol. 2019;10:1413. DOI: 10.3389/fimmu.2019.01413. PMID: 31293579; PMCID: PMC6598597.

Didona D, Di Zenzo G, Joly P. Paraneoplastic autoimmune multiorgan syndrome. Ital J Dermatol Venerol. 2021;156(2):174-183. DOI: 10.23736/S0392-0488.20.06675-4. PMID: 33070576.

Didona D, Fania L, Didona B, Eming R, Hertl M, Di Zenzo G. Paraneoplastic Dermatoses: A Brief General Review and an Extensive Analysis of Paraneoplastic Pemphigus and Paraneoplastic Dermatomyositis. Int J Mol Sci. 2020;21(6):2178. DOI: 10.3390/ijms21062178. PMID: 32245283; PMCID: PMC7139382.

Solimani F, Meier K, Zimmer CL, Hashimoto T. Immune serological diagnosis of pemphigus. G Ital Dermatol Venereol. 2021;156(2):151-160. DOI: 10.23736/S2784-8671.20.06788-7.

Paolino G, Didona D, Magliulo G, et al. Paraneoplastic Pemphigus: Insight into the Autoimmune Pathogenesis, Clinical Features and Therapy. Int J Mol Sci. 2017;18(12):2532. DOI: 10.3390/ijms18122532. PMID: 29186863; PMCID: PMC5751135.

Kridin K, Zelber-Sagi S, Bergman R. Pemphigus Vulgaris and Pemphigus Foliaceus: Differences in Epidemiology and Mortality. Acta Derm Venereol. 2017;97(9):1095-1099. DOI: 10.2340/00015555-2706. PMID: 28536732.

Didona D, Di Zenzo G. Humoral Epitope Spreading in Autoimmune Bullous Diseases. Front Immunol. 2018;9:779. DOI: 10.3389/fimmu.2018.00779. PMID: 29719538; PMCID: PMC5913575.

Hanakawa Y, Amagai M, Shirakata Y, et al. Differential effects of desmoglein 1 and desmoglein 3 on desmosome formation. J Invest Dermatol. 2002;119(6):1231-1236. DOI: 10.1046/j.1523-1747.2002.19648.x. PMID: 12485422.

Kitajima Y. 150(th) anniversary series: Desmosomes and autoimmune disease, perspective of dynamic desmosome remodeling and its impairments in pemphigus. Cell Commun Adhes. 2014;21(6):269-280. DOI: 10.3109/15419061.2014.943397. PMID: 25078507.

Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. Nat Rev Dis Primers. 2017;3:17026. DOI: 10.1038/nrdp.2017.26. PMID: 28492232; PMCID: PMC5901732.

Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet. 2019;394(10201):882-894. DOI: 10.1016/S0140-6736(19)31778-7. PMID: 31498102.

Di Zenzo G, Di Lullo G, Corti D, et al. Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface. J Clin Invest. 2012;122(10):3781-3790. DOI: 10.1172/JCI64413. PMID: 22996451; PMCID: PMC3461925.

Tsunoda K, Ota T, Aoki M, et al. Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3. J Immunol. 2003;170(4):2170-2178. DOI: 10.4049/jimmunol.170.4.2170. PMID: 12574390.

Calkins CC, Setzer SV, Jennings JM, et al. Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies. J Biol Chem. 2006;281(11):7623-7634. DOI: 10.1074/jbc.M512447200. PMID: 16377623.

Mao X, Choi EJ, Payne AS. Disruption of desmosome assembly by monovalent human pemphigus vulgaris monoclonal antibodies. J Invest Dermatol. 2009;129(4):908-918. DOI: 10.1038/jid.2008.339. PMID: 19037235; PMCID: PMC2743719.

Sokol E, Kramer D, Diercks GFH, et al. Large-Scale Electron Microscopy Maps of Patient Skin and Mucosa Provide Insight into Pathogenesis of Blistering Diseases. J Invest Dermatol. 2015;135(7):1763-1770. DOI: 10.1038/jid.2015.109. PMID: 25789704.

Oktarina DA, van der Wier G, Diercks GF, Jonkman MF, Pas HH. IgG-induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis. Br J Dermatol. 2011;165(3):552-562. DOI: 10.1111/j.1365-2133.2011.10463.x. PMID: 21692763.

Di Lullo G, Calabresi V, Mariotti F, Zambruno G, Lanzavecchia A, Di Zenzo G. Identification of a Novel Non-desmoglein Autoantigen in Pemphigus Vulgaris. Front Immunol. 2019;10:1391. DOI: 10.3389/fimmu.2019.01391. PMID: 31275324; PMCID: PMC6593111.

Hoffmann K, Hertl M, Sitaru C. Molekulare Diagnostik der blasenbildenden Autoimmundermatosen [Molecular diagnosis of autoimmune dermatoses]. Hautarzt. 2016;67(1):33-39. DOI: 10.1007/s00105-015-3723-9. PMID: 26612472.

Witte M, Zillikens D, Schmidt E. Diagnosis of Autoimmune Blistering Diseases. Front Med (Lausanne). 2018;5:296. DOI: 10.3389/fmed.2018.00296. PMID: 30450358; PMCID: PMC6224342.

Musette P, Bouaziz JD. B Cell Modulation Strategies in Autoimmune Diseases: New Concepts. Front Immunol. 2018;9:622. DOI: 10.3389/fimmu.2018.00622. PMID: 29706952; PMCID: PMC5908887.

Hebert V, Joly P. Rituximab in pemphigus. Immunotherapy. 2018;10(1):27-37. DOI: 10.2217/imt-2017-0104. PMID: 29064314.

Hennerici T, Pollmann R, Schmidt T, et al. Increased Frequency of T Follicular Helper Cells and Elevated Interleukin-27 Plasma Levels in Patients with Pemphigus.

PLoS One. 2016;11(2):e0148919. DOI: 10.1371/journal.pone.0148919. PMID: 26872212; PMCID: PMC4752242.

Boross P, Jansen JH, Pastula A, van der Poel CE, Leusen JH. Both activating and inhibitory Fc gamma receptors mediate rituximab-induced trogocytosis of CD20 in mice. Immunol Lett. 2012;143(1):44-52. DOI: 10.1016/j.imlet.2012.01.004. PMID: 22285696.

Amber KT, Lamberts A, Solimani F, et al. Determining the Incidence of Pneumocystis Pneumonia in Patients With Autoimmune Blistering Diseases Not Receiving Routine Prophylaxis. JAMA Dermatol. 2017;153(11):1137-1141. DOI: 10.1001/jamadermatol.2017.2808. PMID: 28854309; PMCID: PMC5710438.

Didona D, Paolino G, Garcovich S, Caposiena Caro RD, Didona B. Successful use of etanercept in a case of toxic epidermal necrolysis induced by rituximab. J Eur Acad Dermatol Venereol. 2016;30(10):e83-e84. DOI: 10.1111/jdv.13330. PMID: 26428058.

Murrell DF, Peña S, Joly P, et al. Diagnosis and management of pemphigus: Recommendations of an international panel of experts. J Am Acad Dermatol. 2020;82(3):575-585.e1. DOI: 10.1016/j.jaad.2018.02.021. PMID: 29438767; PMCID: PMC7313440.

Joly P, Maho-Vaillant M, Prost-Squarcioni C, 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;389(10083):2031-2040. DOI: 10.1016/S0140-6736(17)30070-3. PMID: 28342637.

Cang S, Mukhi N, Wang K, Liu D. Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol. 2012;5:64. DOI: 10.1186/1756-8722-5-64. PMID: 23057966; PMCID: PMC3479003.

Rapp M, Pentland A, Richardson C. Successful Treatment of Pemphigus Vulgaris With Ofatumumab. J Drugs Dermatol. 2018;17(12):1338-1339. PMID: 30586270.

Forbat E, Ali FR, Al-Niaimi F. Intravenous immunoglobulins in dermatology. Part 2: clinical indications and outcomes. Clin Exp Dermatol. 2018;43(6):659-666. DOI: 10.1111/ced.13552. PMID: 29774587.

Dourmishev LA, Guleva DV, Miteva LG. Intravenous Immunoglobulins: Mode of Action and Indications in Autoimmune and Inflammatory Dermatoses. Int J Inflam. 2016;2016:3523057. DOI: 10.1155/2016/3523057. PMID: 26885437; PMCID: PMC4739470.

Forbat E, Ali FR, Al-Niaimi F. Intravenous immunoglobulins in dermatology. Part 1: biological mechanisms and methods of administration. Clin Exp Dermatol. 2018;43(5):513-517. DOI: 10.1111/ced.13553. PMID: 29774583.

Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. 2009;60(4):595-603. DOI: 10.1016/j.jaad.2008.09.052. PMID: 19293008.

Tufan F, Kamali S, Erer B, et al. Safety of high-dose intravenous immunoglobulin in systemic autoimmune diseases. Clin Rheumatol. 2007;26(11):1913-1915. DOI: 10.1007/s10067-007-0694-y. PMID: 17636363.

Orbach H, Katz U, Sherer Y, et al. Intravenous Immunoglobulin: Adverse Effects and Safe Administration. Clin Rev Allergy Immunol. 2005;29(3):173-184. DOI: 10.1385/CRIAI:29:3:173. PMID: 16391392.

Zhang Q, Ping J, Huang Z, et al. CAR-T Cell Therapy in Cancer: Tribulations and Road Ahead. J Immunol Res. 2020;2020:1924379. DOI: 10.1155/2020/1924379. PMID: 32411789; PMCID: PMC7201836.

Dai H, Wang Y, Lu X, Han W. Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy. J Natl Cancer Inst. 2016;108(7):djv439. DOI: 10.1093/jnci/djv439. PMID: 26819347; PMCID: PMC4948566.

Ellebrecht CT, Bhoj VG, Nace A, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;353(6295):179-184. DOI: 10.1126/science.aaf6756. PMID: 27365313; PMCID: PMC5343513.

Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A. 1996;93(11):5512-5516. DOI: 10.1073/pnas.93.11.5512. PMID: 8643606; PMCID: PMC39277.

Goebl NA, Babbey CM, Datta-Mannan A, Witcher DR, Wroblewski VJ, Dunn KW. Neonatal Fc receptor mediates internalization of Fc in transfected human endothelial cells. Mol Biol Cell. 2008;19(12):5490-5505. DOI: 10.1091/mbc.e07-02-0101. PMID: 18843053; PMCID: PMC2592658.

Ward ES, Ober RJ. Targeting FcRn to Generate Antibody-Based Therapeutics. Trends Pharmacol Sci. 2018;39(10):892-904. DOI: 10.1016/ PMID: 30143244; PMCID: PMC6169532.

Li N, Zhao M, Hilario-Vargas J, et al. Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J Clin Invest. 2005;115(12):3440-3450. DOI: 10.1172/JCI24394. PMID: 16284651; PMCID: PMC1280965.

Chen Y, Chernyavsky A, Webber RJ, Grando SA, Wang PH. 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. 2015;290(39):23826-23837. DOI: 10.1074/jbc.M115.668061. PMID: 26260795; PMCID: PMC4583029.

Ulrichts P, Guglietta A, Dreier T, et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest. 2018;128(10):4372-4386. DOI: 10.1172/JCI97911. PMID: 30040076; PMCID: PMC6159959.







How to Cite

Pemphigus Vulgaris: Present and Future Therapeutic Strategies. Dermatol Pract Concept [Internet]. 2022 Feb. 2 [cited 2024 Apr. 23];12(1):e2022037. Available from: