Pemphigus & Pemphigoid
- Pemphigus is an autoimmune bullous disorder affecting both mucous membranes and the epidermis (Kasperkiewicz et al., 2017). It is widely accepted that pemphigus is caused by autoantibodies primarily targeting desmosomal cadherins desmoglein (Dsg)1 and 3, which are crucial for intercellular cohesion of keratinocytes. The relevance of autoantibodies against other antigens detectable in pemphigus patients is unclear yet (Spindler et al., 2018). There are two main forms of pemphigus, which differ with respect to their clinical phenotype: in pemphigus vulgaris, skin blistering affects the deep epidermis when, in addition to antibodies against Dsg3, autoantibodies targeting Dsg1 are detectable (Spindler and Waschke, 2018).
- Keratinocytes bind to adjacent keratinocytes via desmosomes. Desmosomal cadherins, the transmembrane proteins of desmosomes, consist of four types of desmogleins (DSG1–4) and three types of desmocollins (DSC1–3), which form heterodimers or homodimers in the intercellular space (Delva et al., 2009). Among them, DSG1 is expressed throughout the skin epidermis, whereas DSG3 is expressed predominantly in the basal layer. In the mucosal epithelium, however, little DSG1 is expressed, whereas DSG3 is expressed throughout the epidermis (Mahoney et al., 1999).
- The incidence of pemphigus varies from 0.5 to 34 cases/million inhabitants/year, with the highest incidence rates in Brazil (Hans-Filho et al., 1996; Ishii et al., 2008; Langan et al., 2008; Meyer and Misery, 2010). Additionally, although the prognosis of pemphigus patients is considered good in the literature, recent findings reported unusually high mortality rates (Almugairen et al., 2013; Langan et al., 2008).
- Bullous pemphigoid (BP) is a potentially fatal subepidermal blistering autoimmune disease that characteristically affects elderly patients who present with large tense bullae on the entire skin and frequently on the extremities (Nousari et al., 1999; Sami et al., 2004). Subepidermal blisters with inflammation are the hallmark of BP histology. Direct immunofluorescence of perilesional skin shows linear deposits of the C3 and IgG. Two hemidesmosomal antigens have been identified, one protein of approximately 230 kDa associated with the intracellular plaque (BPAG1, also known as BP230) (Stanley et al., 1981), and the other protein of approximately 180 kDa associated with transmembrane glycoprotein (BPAG2, also known as BP180) (Diaz et al., 1990).
- Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease (Schmidt and Zillikens, 2013). BP has become more common over the past two decades (Försti et al., 2014; Joly et al., 2012; Langan et al., 2008). However, the underlying causes of the increasing incidence of BP are poorly understood. Altogether, over 50 drugs have been reported to induce BP (Stavropoulos et al., 2014). The use of dipeptidyl peptidase-4 inhibitors (DPP-4i), a class of drug used for the treatment of diabetes, has recently been scrutinized as a risk factor for BP, both in case reports (see Supplementary Table S1 online) and in national pharmacovigilance database reports (Bene et al., 2016; García et al., 2016), but large population-based studies are lacking.
- Dipeptidyl peptidase-4 inhibitor (DPP-4i) has been widely used to treat type 2 diabetes. DPP-4 inactivates incretins by catalyzing the cleavage of those proteins to inactive forms (Drucker, 2007). DPP-4i works by inhibiting the action of this enzyme and improves glycemic control (Aschner and Kipnes, 2006). DPP-4i has been known as a safe drug; however, an increased risk of bullous pemphigoid (BP) during DPP-4i exposure has been reported in diabetic patients administered DPP-4i (Béné et al., 2016).
- Chronic skin inflammation, subepidermal blistering, and severe itching are the clinical hallmarks of bullous pemphigoid (BP). The disease is caused by autoantibodies against type XVII collagen (COL17, BP180), more specifically, the extracellular fraction of the 16th noncollagenous domain of the protein (NC16A) (Schmidt and Zillikens, 2013). Two pathways are thought to drive BP pathogenesis. First, autoantibody binding to COL17 leads to activation of the complement cascade, evidenced by the detection of complement deposits along the dermal-epidermal junction in patients with BP (Jordon et al., 1967, 1975) and in mouse models of the disease (Iwata et al., 2015).
- Autoimmune bullous diseases (AIBDs) are characterized by autoantibodies against structural proteins of the epidermis (pemphigus vulgaris and foliaceus) and dermal-epidermal junction (bullous pemphigoid, mucous membrane pemphigoid, pemphigoid gestationis, linear IgA disease, and epidermolysis bullosa acquisita) (Schmidt and Groves, 2016). Clinically, blisters and erosions arise on skin and surface-close mucous membranes. Several reports have estimated the incidence of all AIBDs at between 13.3 and 66 cases per million people per year in Germany, the UK, Switzerland, France, Finland, Italy, and the US, with the highest incidences of bullous pemphigoid occurring in the population older than 80 years of age (150–300 cases/million people/year) and the lowest for epidermolysis bullous acquisita (0.2–0.5 cases/million people/year) (Bertram et al., 2009; Brick et al., 2014; Cozzani et al., 2001; Forsti et al., 2014; Joly et al., 2012; Langan et al., 2008; Marazza et al., 2009; reviewed in Schmidt et al., 2015).