Eur J Dermatol 2015; 25(2): 103-13

Review Animesh A. SINHA Melissa B. HOFFMAN Elise C. JANICKE Department of Dermatology, University of Buffalo 6078 Clinical and Translational Research Center 875 Ellicott Street, Buffalo, NY 14203

Reprints: A. A. Sinha

Article accepted on 9/11/2014



Pemphigus vulgaris: approach to treatment 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. Key words: pemphigus vulgaris, treatment, immunotherapy, immunosuppressive, rituximab

amage of the protective epidermal barrier in PV can lead to serious morbidity and even fatality through loss of body fluids or through the entry of bacteria. Before the advent of systemic corticosteroids in the 1950s, the mortality rate of PV patients within a year of diagnosis was 75% [1]. With proper treatment, the mortality rate of PV has been drastically reduced, but still stands at an unacceptable rate of approximately 5-6%, with most deaths being the result of side effects of immunosuppressive agents rather than the result of the disease itself or disease sequelae [2-4]. The only known factor that significantly reduces survival rates is a later age of onset of PV [5]. A poorer prognosis for achieving complete remission is seen when the disease is more widespread, more severe at onset, or when it responds slowly to therapy [4]. In general, a patient with lesions localized to the mucosa has a better prognosis than a patient with mucocutaneous lesions [6]. In recent years, the treatment of PV has been shifting away from the long held protocol of treating all patients with high-dose corticosteroids. A more nuanced, but still arbitrary approach that takes into account a wider variety of treatment options has emerged. Unfortunately, there is a paucity of data to support rational therapeutic decision making and presently no way to match therapy with the subset of patients likely to respond to such therapy. In 2009, an extensive Cochrane review of medications that assessed 11 separate studies concluded that there is no consensus regarding which treatments are the most effective and safe [7]. A major issue is the limited number of randomized control trials and small samples sizes in most studies. We review here the current literature on the existing treatment options for PV (table 1) and discuss emerging therapies and concepts regarding the management of disease and outlook for the future (figure 1).

EJD, vol. 25, n◦ 2, March-April 2015

Systemic corticosteroids While corticosteroids have been the mainstay of treatment of PV for over 50 years, their exact use has been undergoing major changes in the past couple of decades. While there have been studies evaluating the minimal doses of systemic steroids needed to control disease activity, the optimal dosage and regimen of systemic corticosteroids remain unclear. One randomized controlled trial reported that high-dose oral prednisolone (120-150 mg/d) is not significantly superior to low-dose oral prednisolone (45-60 mg/d) in decreasing relapse rates and increasing duration of remission [8]. An effective initial dose of corticosteroids has been suggested to be 1 mg/kg/d [9]. Others recommend an initial oral prednisolone dose of 40-60 mg/d and with severe PV, 60-100 mg/d [10]. A randomized control trial of 20 patients showed that pulsed oral dexamethasone (300 mg/d for 3 days) in addition to oral prednisolone and azathioprine does not improve time to remission, duration of remission or mortality. However, the pulsed steroid group experienced increased adverse events, with weight gain being the most commonly reported side effect [11]. Three of the patients receiving pulsed dexamethasone discontinued the study because of adverse effects including infection, high blood glucose levels, myalgia and cognitive dysfunction. The group that conducted this study concluded that conventional treatment, including prednisolone, 80 mg/day on a tapering schedule to 0 mg in 19 weeks and azathioprine sodium, 3 mg/kg continued for a year after tapering, is the most effective regimen for patients with new disease activity [11]. While systemic corticosteroids still remain the mainstay of treatment for PV, there is no consistency regarding recommended doses. With the development of increasingly effective adjuvant therapies, the doses of systemic


To cite this article: Sinha AA, Hoffman MB, Janicke EC. Pemphigus vulgaris: approach to treatment. Eur J Dermatol 2015; 25(2): 103-13 doi:10.1684/ejd.2014.2483

Table 1. Treatment strategies for pemphigus vulgaris. Treatment

Mode of Action


Systemic Corticosteroids Non-steroidal adjuvant therapy:

Reduce inflammatory response and decrease autoantibody production. All promote disease control and have the added benefit of steroid-sparing effect caused by reduction in the amount of glucocorticoid that would have previously been needed to achieve the same level of control.

8, 10, 11, 38 7, 12-15

- Mycophenolate mofetil

- Agent is cytotoxic to B and T lymphocytes that are involved in the autoantibody production of PV and has been shown to lower both antibody titers and disease activity.

- Azathioprine

- Purine synthesis inhibitor that inhibits DNA synthesis in proliferating B and T cells and has been shown to have a superior steroid-sparing effect when compared to other adjuvant therapies.

- Cyclophosphamide

- Alkylating agent that selectively inhibits lymphopoietic cells while sparing hematopoietic cells and inhibits antibody-producing B cells.

- Dapsone

- Inhibits various inflammatory mediators, but the exact mechanism of action in PV remains unknown.

- Methotrexate IVIG

B cell blockade - Rituximab

- Immunosuppressive agent that decreases autoimmune disease pathogenesis. Selectively removes the pathogenic antibodies without affecting the level of normal antibodies. IVIG also works to decrease the response to autoantibodies by interfering with the complement pathway and cytokine activation involved in disease pathogenesis. Eliminate peripheral auto-reactive B cells, decreasing the production of autoantibodies. - Antibody against CD20, a protein expressed by most developing and memory B cells.

- BAFF antagonists

- Inhibition of a cytokine BAFF, a member of the TNF superfamily that is involved in the survival and maturation of autoreactive B cells.

- APRIL antagonists

- Antagonist of this cytokine that acts as a B cell activator may lead to decreased B cell maturation and survival. Prevent blister formation by blocking TNF-␣, one of the cytokines thought to play a multifactorial role in the inflammation and acantholysis seen in PV.

Anti TNF agents - Infliximab - Etanercept Plasmapheresis/ immunoadsorption Signaling inhibitors - p38MAPK inhibitors T-cell immunotherapy

21-23, 25, 26, 30

8, 31-35

- Chimeric monoclonal antibody against TNF-␣ - Fusion protein that acts as a TNF inhibitor. Physically remove the immunoglobulins from plasma, eliminating the IgG autoantibodies present in the serum of patients with PV. Block signaling pathways that are initiated after IgG autoantibody binding to keratinocytes that may cause loss of cell-cell adhesion. - Inhibition prevents phosphorylation of HSP27, a protein involved in downstream remodeling of the actin cytoskeleton seen in acantholysis. Suppresses autoimmune pathways involved in the production of anti-Dsg 1/3 antibodies and the subsequent development of PV phenotype.

- Anti-CD154 antibody

- Inhibits the interaction between CD154, expressed on T cells and CD40 of B cells, preventing the production of autoantibodies like anti-Dsg3 involved in PV pathogenesis.

- Altered peptide ligands

- Peptide analogs that may be designed to prevent the interaction between T cells and autoantigen peptides involved in disease pathogenesis.

corticosteroids needed to achieve control of disease activity are likely to decrease or perhaps one day be supplanted entirely.

Immunosuppressive treatments There have been numerous case series and case reports regarding the use of immunosuppressive treatments as adju-



39, 45, 47 50-52, 54-56, 74

57, 65-70

vant therapy with systemic corticosteroids. There is a wide variety of immunosuppressive agents that have been used in the past to treat PV. Some of the popular agents 15 years ago included gold, dapsone and methotrexate. While all of these agents demonstrated success in controlling disease, they are all associated with a wide range of severe side effects, especially when used at the high doses that are often necessary to treat PV [12]. With the ongoing studies to find the safest and most efficacious forms of adjuvant immunosuppressive therapy, there are new agents that are EJD, vol. 25, n◦ 2, March-April 2015

Plasmapheresis Immunoadsorption IVIG

Cytokines (BAFF, APRIL, TNF-α)

T Cell

Thelper Cell

B Cell

CD154 Self Foreign Protein Antigen




T Cell Receptor

Anti CD154 agents

ClassII MHC Molecule

Anti TNF-α agents (Etanercept, Infliximab)

Altered Peptide Ligands Antigen Presenting Cell

CD40 Keratinocyte CD 20 Dsg3 Dsg1 Anti CD20 agents (Rituximab)

Figure 1. Pemphigus vulgaris pathogenesis and emerging immune targeted treatment options.

gaining momentum over the previously mentioned choices. Three particular agents, mycophenolate mofetil, azathioprine and intravenous cyclophosphamide pulse therapy are among the most popular choices for adjuvant therapy. While many reports in the literature are inconclusive or lack adequate power, one definite conclusion from the Cochrane review is that the required dose of glucocorticoids can be decreased when azathioprine or cyclophosphamide are also given [7]. Some studies claim mycophenolate mofetil is more effective in achieving disease control than azathioprine [7, 13]. Mycophenolate mofetil has been shown to have a rapid effect in lowering pemphigus antibody titers and disease activity and has fewer side effects than azathioprine, especially with regard to hepatotoxicity [7]. However, mycophenolate mofetil was inferior to azathioprine and cyclophosphamide in regards to steroid-sparing effect [7]. One randomized controlled trial allocated patients to 1 of 4 patient groups: prednisolone, prednisolone plus azathioprine, prednisolone plus mycophenolate mofetil, and prednisolone plus pulse cyclophosphamide. This study found that the group receiving prednisolone alone required a statistically significant higher mean cumulative dose of systemic steroids than did any of the other three treatment groups. The combined prednisolone and azathioprine protocol proved to be the most effective in terms of disease mortality and remission [14]. Since the publication of the Cochrane review, Beissert et al. have demonstrated in a randomized clinical trial that, in comparison to corticosteroids used as monotherapy, the addition of mycophenolate mofetil may be advantageous, since it achieved a faster and longer lasting response than corticosteroids alone [13]. A study of 18 patients attempted to determine a standard treatment regimen based on a retrospective chart review [15]. Complete disease control was achieved in 89% (16 out of 18) patients. In 14 of these patients, complete control was reached with mycophenolate mofetil at 1 gram EJD, vol. 25, n◦ 2, March-April 2015

BID and prednisone at 1 mg/kg daily. As prednisone was held steady, mycophenolate mofetil was increased by 0.5 grams every month, until a maximum dose of 3 grams daily was reached. The other 2 patients required further treatment with rituximab. For all 16 patients, prednisone was slowly tapered once there was complete control, followed by tapering of mycophenolate mofetil. As outlined above, the majority of studies on immunosuppressive agents used in the treatment of PV suggest that the benefit of immunosuppressive agents comes from their steroid sparing effects. The use of immunosuppressive adjuvant agents has even allowed some patients to taper off corticosteroids and enter a period of steroid-free remission [7, 13, 15]. The European Dermatology Forum, in collaboration with the European Academy of Dermatology and Venerology, recently submitted the “Guideline on the Diagnosis and Treatment of Autoimmune Bullous Diseases – Pemphigus” [16]. These authors agree that, based on current evidence, adjuvant immunosuppressants work via their steroid-sparing affect. The guidelines also include what the authors believe to be first line versus second line adjuvants and the recommended dosing regimen for each agent. This guideline should serve as an important reference for physicians to help guide individualized treatment plans.

Intravenous immunoglobulin Derived from pooled donor serum, IVIG is effective in fighting both infectious and autoantibody-mediated conditions [17], making it an attractive treatment for autoimmune and systemic inflammatory disorders. The mechanism of IVIG is complex, with various modes of action that are proposed to act synergistically to affect disease pathogenesis. One of the major roles of IVIG is that it selectively removes


the pathogenic antibodies without affecting the level of “normal” antibodies. IVIG also alters the expression and function of Fc receptors, affects activation, differentiation and effector functions of T cells and B cells and works to decrease the response to autoantibodies by interfering with the complement pathway and cytokine activation [17]. Another benefit of IVIG is that it has a very mild side effect profile. Because of the multiple actions of IVIG and previously reported benefits in various autoimmune and systemic inflammatory conditions, IVIG became a promising candidate for the treatment of PV. However, randomized controlled trials with IVIG in PV and in other autoimmune conditions are limited. One recent randomized controlled trial specifically studying PV was designed to assess the therapeutic effect of a single cycle of adjuvant IVIG using three dosing cohorts (400, 200 or 0 mg/kg/d). The trial showed that a single-cycle of adjuvant IVIG, given at a dose of 400 mg/kg/d for 5 consecutive days, prolongs the “time to escape from the protocol” compared to placebo (P

Pemphigus vulgaris: approach to treatment.

The therapeutic management of pemphigus vulgaris (PV) is centered around immunosuppression, which can be generalized, as in the use of corticosteroids...
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