Diagnosis and Treatment of Pemphigus

Daisuke Tsuruta; Norito Ishii; Takashi Hashimoto

Disclosures

Immunotherapy. 2012;4(7):735-745. 

In This Article

Abstract and Introduction

Abstract

Pemphigus is an autoimmune bullous disease, in which autoantibodies react with the cell–cell adhesion structures, desmosomes, causing blisters and erosions on the oral mucosa and skin. Pemphigus is divided into two major subtypes: pemphigus vulgaris and pemphigus foliaceus. Oral corticosteroids are the primary treatment modality for pemphigus, while other therapeutic options, such as steroid pulse therapy, immunosuppressants, intravenous immunoglobulins, plasmapheresis and anti-CD20 monoclonal antibody therapy, are occasionally employed. Immunosuppressants used to treat pemphigus include azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil and mizoribine. In this review, we summarize the current concepts of immunotherapy for the treatment of pemphigus in the Japanese population.

Introduction

Pemphigus is an autoimmune bullous disease affecting the skin and mucous membranes.[1] On clinical examinations, patients show flaccid blisters or bullae.[1] The target antigens in pemphigus are desmogleins (Dsgs), which are the major constituents of desmosomes, one of the adhesion apparatuses in the epidermis.[2] Circulating anti-Dsg antibodies are found in pemphigus.[2] By attacking desmosomes, anti-Dsg antibodies inhibit cell–cell adhesion in keratinocytes and mucosal epithelial cells.[3] Histopathological analysis of pemphigus lesions shows acantholysis and intraepidermal bullae.[1]

Pemphigus is a chronic disease that usually lasts for several years.[1] Pemphigus is clinically divided into two major subtypes: pemphigus vulgaris and pemphigus foliaceus.[1,4] Pemphigus vulgaris usually shows mucosal lesions, while pemphigus foliaceus does not.[5] Pemphigus vulgaris is further subdivided into mucosal-dominant and mucocutaneous types.[6] Furthermore, pemphigus vegetans is a specific subtype of pemphigus vulgaris, while pemphigus erythematosus and pemphigus herpetiformis are subtypes of pemphigus foliaceus.[7,8]

Analysis of autoantigen profiles supports the relationship between pemphigus vulgaris and pemphigus vegetans, and between pemphigus foliaceus and pemphigus erythematosus.[7,9] In pemphigus herpetiformis, antibodies against desmocollins are sometimes detected; therefore, they are considered to be responsible for the herpetiform clinical presentation.[10] Paraneoplastic pemphigus is another subtype, which occurs in the setting of hematological internal malignancies.[11,12] Antibodies against plakin family proteins are detected in paraneoplastic pemphigus.[13] Finally, IgA pemphigus is a subtype that is defined by the presence of IgA-class autoantibodies.[14] The autoantigen for one type of IgA pemphigus is desmocollin-1.[14] Table 1 summarizes the classification of pemphigus and its autoantigens.

The pathogenesis of pemphigus is thought to be related to the presence of autoantibodies against Dsgs.[15–18] Anti-Dsg antibodies cause disruption to intercellular adhesion in keratinocytes.[19] There are two main mechanisms for blister formation in pemphigus. First, anti-Dsg antibody is hypothesized to cause steric hindrance of Dsg after binding, resulting in inhibition of keratinocyte–keratinocyte cell adhesions.[20,21] Second, Dsg–anti-Dsg antibody binding is thought to activate cell signal transduction, resulting in internalization of Dsg in the cytoplasm and their proteolytic cleavage.[22,23] These two hypotheses are not contradictory, but potentially corporative.

The target antigen of pemphigus vulgaris is the 130 kDa Dsg3, while that of pemphigus foliaceus is the 160 kDa Dsg1.[9] The Dsg compensation theory is accepted by many clinicians and researchers as an explanation of why pemphigus vulgaris predominately affects the mucous membrane and pemphigus foliaceus predominately affects the skin (Figure 1).[24,25] Both Dsg3 and Dsg1 are expressed in the skin, and they compensate for one another when one is disrupted by autoantibodies. In the epidermis, Dsg3 is located in the lower epidermis, while Dsg1 is located in the entire epidermal layer, with increased expression near the skin surface. In contrast to the epidermis, in the mucous membrane Dsg3 is strongly expressed in the entire mucosal epithelium, while Dsg1 is weakly expressed in the superficial epithelial layers.

Figure 1.

The desmoglein compensation theory.

In pemphigus foliaceus, anti-Dsg1 antibodies produce blister formation in the upper epidermis, because the remaining Dsg3 can maintain cell–cell adhesion in the lower epidermis; there are no blister formations on the mucous membranes, because the remaining Dsg3 can completely maintain cell–cell adhesion of the mucosal epithelium. In mucosal-dominant type of pemphigus vulgaris, epidermal damage is relatively weak because of the existence of and compensation by Dsg1, while mucosal epithelial damage is more severe owing to a lack of compensation by the weakly expressed Dsg1. In mucocutaneous pemphigus vulgaris, antibodies against both Dsg1 and Dsg3 are produced, resulting in involvement of both the skin and the mucous membranes. The mechanism of autoantibody production has yet to be elucidated.

As described in detail below, the mainstay of treatment for pemphigus is systemic steroids.[9] In addition, several immunosuppressants, intravenous immunoglobulin and plasmapheresis have been recently used.[9]

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