Group of IgG-mediated autoimmune diseases of stratified squamous epithelia (such as the skin and oral mucosa), in which acantholysis (loss of cell adhesion) causes blisters and erosions.
Classification
Pathophysiology
a | The distribution and expression levels of desmoglein 1 (DSG1; blue coloured box in the first column) and DSG3 (yellow coloured box in the first column) vary in the skin and mucous membranes. The compensation theory states that the development of blisters in the skin or mucosa or both depends on the DSG type being targeted by the autoantibodies. In the mucosal-dominant type of pemphigus vulgaris, anti-DSG3 IgG antibodies induce erosions in the oral mucosa, where DSG3 is the most abundant DSG type, but fail to induce cutaneous blisters, as there is compensation from DSG1. Similarly, the anti-DSG1 IgG antibodies in pemphigus foliaceus induce superficial blisters in the skin but not in the oral mucosa. In the mucocutaneous type of pemphigus vulgaris, both anti-DSG3 and anti-DSG1 IgG antibodies are present, resulting in extensive blisters and erosions of the skin and mucous membranes. In paraneoplastic pemphigus, in addition to acantholysis (loss of cell adhesion) induced by humoral autoimmune reactions, a cellular autoimmune response to the epidermis is also observed, which results in keratinocyte apoptosis with T cell infiltration within the epidermis, obscuring of the boundary of epidermis and dermis, and a band-like dense T cell infiltration in the upper dermis indicating interface dermatitis. b | Haematoxylin and eosin staining demonstrates a suprabasilar and subcorneal blister with acantholysis in skin biopsies from patients with pemphigus vulgaris and pemphigus foliaceus, respectively, and interface dermatitis in addition to blister formation in a sample from a patient with paraneoplastic pemphigus. | Kasperkiewicz, M., Ellebrecht, C. T., Takahashi, H., Yamagami, J., Zillikens, D., Payne, A. S., & Amagai, M. (2017). Pemphigus. Nature Reviews. Disease Primers, 3, 17026. https://doi.org/10.1038/nrdp.2017.26
Clinical features
Pemphigus vulgaris can present with erosions on the buccal mucosa (a) and cutaneous flaccid blisters and haemorrhagic erosions (b). Scaly, crusted erosions in pemphigus foliaceus (c). Intractable stomatitis in paraneoplastic pemphigus, with erosions and ulcerations that characteristically extend onto the vermilion (the edge between the lip and the adjacent skin; (d). | Kasperkiewicz, M., Ellebrecht, C. T., Takahashi, H., Yamagami, J., Zillikens, D., Payne, A. S., & Amagai, M. (2017). Pemphigus. Nature Reviews. Disease Primers, 3, 17026. https://doi.org/10.1038/nrdp.2017.26
Paraneoplastic pemphigus (PNP):
Mucosal manifestations of the patients with paraneoplastic pemphigus. A, Erosions and shallow ulcers in the oral cavity and on the tongue of patient 9. B, Violet lesion with hemorrhagic crusting on the lips of patient 1. C, Erosions on the penis of patient 2. D, Lesions of the conjunctivae resembling Stevens-Johnson syndrome in the periorbital area of patient 1 | Wang, J., Zhu, X., Li, R., & al, et. (2005). Paraneoplastic pemphigus associated with castleman tumor: A commonly reported subtype of paraneoplastic pemphigus in china. Archives of Dermatology, 141(10), 1285–1293. Retrieved from http://dx.doi.org/10.1001/archderm.141.10.1285Cutaneous manifestations of patients with paraneoplastic pemphigus. A, Lichen planus–like papules on the trunk of patient 8. B, Erythema multiforme–like lesions on the hands of patient 1. C, Severe erosions and crusts on the palm and fingers of patient 7. D, Blisters, erosions, and crusts of the skin of patient 3. | Wang, J., Zhu, X., Li, R., & al, et. (2005). Paraneoplastic pemphigus associated with castleman tumor: A commonly reported subtype of paraneoplastic pemphigus in china. Archives of Dermatology, 141(10), 1285–1293. Retrieved from http://dx.doi.org/10.1001/archderm.141.10.1285
Diagnosis
Nikolsky’s sign: Lateral pressure on skin splits layers of epidermis
Skin biopsy:
Acantholysis & tombstoning
Direct immunofluorescence: Chicken wire pattern
Immunopathological characteristics of pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus: Direct immunofluorescence microscopy of skin biopsies of perilesions from patients with pemphigus vulgaris (a) and pemphigus foliaceus (b) reveals an intercellular staining of IgG antibodies. Indirect immunofluorescence microscopy of a monkey oesophagus exposed to the serum of a patient with pemphigus vulgaris shows an epithelial intercellular surface staining of IgG (c). Indirect immunofluorescence microscopy of a rat bladder exposed to the serum of a patient with paraneoplastic pemphigus presents both epithelial intercellular and cytoplasmic staining (d). | Kasperkiewicz, M., Ellebrecht, C. T., Takahashi, H., Yamagami, J., Zillikens, D., Payne, A. S., & Amagai, M. (2017). Pemphigus. Nature Reviews. Disease Primers, 3, 17026. https://doi.org/10.1038/nrdp.2017.26
Differential diagnosis
Autoimmune diseases: bullous pemphigoid, mucous membrane pemphigoid, lichen planus pemphigoides, anti-p200 pemphigoid, epidermolysis bullosa acquisita, linear IgA bullous dermatosis and bullous lupus erythematosus
Others: aphthous stomatitis, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, severe drug eruption, lichen planus, graft-versus-host disease, Grover disease (transient acantholytic dermatosis), seborrheic dermatitis and subcorneal pustular dermatosis
Management
Topical & systemic corticosteroids
Rituximab (monoclonal antibody)
Binds to B-cells → ↓ Anti-desmosomal IgG antibodies
Topical rinses (eg. viscous lidocaine)
Current and future therapeutic strategies for pemphigus are outlined based on their mechanisms of action. Whereas conventional treatments such as systemic steroid and immunosuppressive agents affect broad ranges of cells and tissues, antigen-specific treatments targeted against desmoglein-reactive cells or IgG antibodies provide more-tailored and potentially safer strategies. One of these approaches uses T cells that are engineered to express a chimeric immunoreceptor consisting of the desmoglein 3 extracellular domain fused to the T cell receptor cytoplasmic signalling and co-stimulatory domains. These desmoglein 3 chimeric autoantibody receptor T cells (CAARTs) specifically bind to and kill anti-desmoglein 3 B cells, leading to disease remission in a pemphigus mouse model. Owing to the potential for generation of long-term memory CAARTs, this technology offers the potential for long-term disease remission without the immunosuppressive effects from global B cell depletion. | Kasperkiewicz, M., Ellebrecht, C. T., Takahashi, H., Yamagami, J., Zillikens, D., Payne, A. S., & Amagai, M. (2017). Pemphigus. Nature Reviews. Disease Primers, 3, 17026. https://doi.org/10.1038/nrdp.2017.26
Pulse therapy (intermittent administration of suprapharmacologic doses of drugs)
Dexamethasone (100 mg) or methylprednisolone (20–30 mg/kg) + cyclophosphamide
