Dipeptidyl Peptidase-4 Inhibitor-Related Bullous Pemphigoid: Clinical, Laboratory, and Histological Features, and Possible Pathogenesis

Abstract

Dipeptidyl peptidase-4 inhibitor (DPP4i) is a widely used antidiabetic agent. Emerging cases of DPP4i-associated bullous pemphigoid (DBP), whose pathogenesis remains unclear, have been reported. Thus, a retrospective study was conducted from January 2016 to June 2021 to determine the clinical, laboratory, and histopathological features of DBP and idiopathic bullous pemphigoid (IBP). We set up in vitro experiments using vildagliptin-treated HaCaT keratinocytes to validate what we found by analyzing published RNA sequencing data about the genes related to the dermal–epidermal junction. We also observed IL-6 expression by HaCaT cells treated with vildagliptin. We enrolled 20 patients with DBP and 40 patients with IBP. The total Bullous Pemphigoid Disease Area Index (BPDAI) score was similar in both groups. However, the BPDAI score of erosions and blisters in DBP was significantly higher than that in IBP (24.6 vs. 16.68, p = 0.0189), and the score for urticaria and erythema was lower in DBP (12 vs. 19.05, p = 0.0183). The pathological features showed that the mean infiltrating eosinophil number per high-power field was significantly lower in DBP than in IBP (16.7 vs. 27.08, p = 0.023). The expression of LAMA3, LAMB3, LAMC2, DST, and COL17A1 decreased significantly in vildagliptin-treated human keratinocytes. On the other hand, IL-6, the hallmark cytokine of bullous pemphigoid (BP) severity, was found to be upregulated in HaCaT cells by vildagliptin. These experimental findings imply less of a requirement for eosinophil infiltration to drive the inflammatory cascades in DBP blistering. Both immunologic and non-immunologic pathways could be employed for the development of DBP. Our findings may help explain the higher incidence of non-inflammatory BP that was observed in DBP.

Pemphigoid without mucous involvement showing IgG antibodies to the β3 subunit of laminin‐332

“…DPP-4i-associated bullous pemphigoid (BP) manifests a non-inflammatory phenotype, with a predominance of blisters and less erythema than idiopathic BP. 10 On histopathology, the number of infiltrating eosinophils was lower in DPP-4i-associated BP than in idiopathic BP. 10 It has been reported that the expression of LAMA3, LAMB3, LAMC2 encoding laminin-332, and COL17A1 encoding BP180 (which are related to the dermal-epidermal junction) was decreased in DPP-4i treated keratinocytes.…”

“…10 On histopathology, the number of infiltrating eosinophils was lower in DPP-4i-associated BP than in idiopathic BP. 10 It has been reported that the expression of LAMA3, LAMB3, LAMC2 encoding laminin-332, and COL17A1 encoding BP180 (which are related to the dermal-epidermal junction) was decreased in DPP-4i treated keratinocytes. 10 Therefore, DPP-4i treatment may cause fragility of the dermal-epidermal junction, leading to DPP-4i-associated BP with a non-inflammatory phenotype.…”

“…10 It has been reported that the expression of LAMA3, LAMB3, LAMC2 encoding laminin-332, and COL17A1 encoding BP180 (which are related to the dermal-epidermal junction) was decreased in DPP-4i treated keratinocytes. 10 Therefore, DPP-4i treatment may cause fragility of the dermal-epidermal junction, leading to DPP-4i-associated BP with a non-inflammatory phenotype. 9 Additionally, inflammatory cutaneous lesions predominantly involving the extremities without mucous lesions were noted in pemphigoid with autoantibodies to the α3, β3 and γ2 subunits of laminin-332 as well as BP230 in DPP-4i treatment.…”

Immunomodulatory activity of dipeptidyl peptidase‐4 inhibitors in immune‐related diseases

“…In contrast, a retrospective study on BP patients revealed that the total number of eosinophils infiltrating the skin was considerably lower in DBP patients compared to idiopathic BP patients [53]. Authors found that vildagliptin could also have immunomodulatory functions via regulating IL‐6 production in DBP pathogenesis [54]. It is speculated that suppression of DPP‐4/CD26 may be involved in the disruption of BP180, major BP autoantigen, immunotolerance, and the subsequent development of epitopes for BP autoantibodies [55].…”

From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid

“…Interestingly, Hung et al recently reported that vildagliptin can stimulate the expression of IL-6 by keratinocytes in vitro, subsequently increasing its levels through a positive feedback loop. As a result, keratinocytes treated with DPP4i may supply sufficient IL-6 in the skin of DPP4i-BP patients, even if eosinophils and other inflammatory cells are reduced [105].…”