Pemphigus encompasses a heterogeneous group of autoimmune blistering diseases, which affect both mucous membranes and the skin. The disease usually runs a chronic-relapsing course, with a potentially devastating impact on the patients' quality of life.
Pemphigus pathogenesis is related to
IgG autoantibodies targeting various adhesion molecules in the epidermis, including
desmoglein (Dsg) 1 and 3, major components of desmosomes. The pathogenic relevance of such
autoantibodies has been largely demonstrated experimentally.
IgG autoantibody binding to Dsg results in loss of epidermal keratinocyte adhesion, a phenomenon referred to as
acantholysis. This in turn causes intra-epidermal blistering and the clinical appearance of flaccid
blisters and erosions at involved sites. Since the advent of
glucocorticoids, the overall prognosis of
pemphigus has largely improved. However, mortality persists elevated, since long-term use of high dose
corticosteroids and adjuvant
steroid-sparing
immunosuppressants portend a high risk of serious adverse events, especially
infections. Recently,
rituximab, a chimeric anti CD20
monoclonal antibody which induces B-cell depletion, has been shown to improve patients' survival, as early
rituximab use results in higher disease remission rates, long term clinical response and faster
prednisone tapering compared to conventional immunosuppressive therapies, leading to its approval as a first line
therapy in
pemphigus. Other anti B-cell
therapies targeting B-cell receptor or downstream molecules are currently tried in clinical studies. More intriguingly, a preliminary study in a preclinical mouse model of
pemphigus has shown promise regarding future therapeutic application of Chimeric
Autoantibody Receptor T-cells engineered using Dsg domains to selectively target autoreactive B-cells. Conversely, previous studies from our group have demonstrated that B-cell depletion in
pemphigus resulted in secondary impairment of T-cell function; this may account for the observed long-term remission following B-cell recovery in
rituximab treated patients. Likewise, our data support the critical role of Dsg-specific T-cell clones in orchestrating the inflammatory response and B-cell activation in
pemphigus. Monitoring autoreactive T-cells in patients may indeed provide further information on the role of these cells, and would be the starting point for designating
therapies aimed at restoring the lost immune tolerance against Dsg. The present review focuses on current advances, unmet challenges and future perspectives of
pemphigus management.