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Background Pemphigus encompasses a group of life‐threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first‐line treatment for moderate and severe pemphigus vulgaris in Europe and the United States. Objectives The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus. Results The guidelines for the management of pemphigus were updated, and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organizations.

We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first line therapy option for moderate to severe pemphigus.

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Graphical Abstract Highlights d Islet C3 expression is upregulated in human T2D and rodent models of diabetes d C3 is present within the cytosol and binds autophagy-related protein 16-1 (ATG16L1) d b cells lacking C3 have impaired autophagy d Intracellular C3 protects b cells from palmitic acid/IAPPmediated apoptosis In Brief King et al. show that the main complement protein, C3, is expressed intracellularly in pancreatic b cells. C3 binds ATG16L1, thus regulating autophagy and protecting b cells from death from various insults. These findings highlight a novel intracellular protective role of this major immunological protein. SUMMARYWe show here that human pancreatic islets highly express C3, which is both secreted and present in the cytosol. Within isolated human islets, C3 expression correlates with type 2 diabetes (T2D) donor status, HbA1c, and inflammation. Islet C3 expression is also upregulated in several rodent diabetes models. C3 interacts with ATG16L1, which is essential for autophagy. Autophagy relieves cellular stresses faced by b cells during T2D and maintains cellular homeostasis. C3 knockout in clonal b cells impaired autophagy and led to increased apoptosis after exposure of cells to palmitic acid and IAPP. In the absence of C3, autophagosomes do not undergo fusion with lysosomes. Thus, C3 may be upregulated in islets during T2D as a cytoprotective factor against b cell dysfunction caused by impaired autophagy. Therefore, we revealed a previously undescribed intracellular function for C3, connecting the complement system directly to autophagy, with a broad potential importance in other diseases and cell types.