Dipeptidyl peptidase IV inhibitor-associated bullous pemphigoid: a recently recognized autoimmune blistering disease with unique clinical, immunological and genetic characteristics

Abstract Bullous pemphigoid (BP) is an organ-specific autoantibody-mediated autoimmune blistering skin disorder that tends to affect the elderly. Tense blister formation associated with itchy urticarial erythema is clinically observed in BP, and subepidermal blister formation with eosinophilic infiltration is a histopathological characteristic. BP autoantibodies target two hemidesmosomal components in basal keratinocytes: BP180 and BP230. Anti-BP180 autoantibodies play major roles in blister formation. Although the autoantibody-mediated pathomechanism of blister formation has been extensively studied, little is known about how and why immune tolerance to BP180 may be broken in certain elderly individuals. Recently, BP has been increasingly reported in diabetes mellites (DM) patients receiving dipeptidyl peptidase-IV inhibitors (DPP4is), which are widely used anti-DM drugs. Pharmacovigilance and cohort studies have revealed that DPP4is, especially vildagliptin, teneligliptin, and linagliptin, are a potential risk factor for BP onset. Interestingly, it has been revealed that Japanese DPP4i-BP tends to show a non-inflammatory phenotype, with less erythema than normal BP, and that DPP4i-BP autoantibodies target distinct epitopes on BP180. In addition, human leukocyte antigen-DQB1*03:01 was identified as the major haplotype in Japanese DPP4i-BP. This review summarizes the latest understanding of the pathogenesis of BP, with a special focus on the recently recognized DPP4i-BP