Bullous pemphigoid in diabetic patients treated by gliptins: the other side of the coin

Abstract

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease that affects primarily patients older than 60 years. The majority of BP cases are spontaneous, but BP can also be triggered by certain drugs’ exposures. Since 2011, a growing number of observations has been reporting cases of BP in Type 2 diabetic patients. These forms have been linked to the use of a new category of anti-diabetic drugs called dipeptidyl peptidase inhibitors (DPP-4i) or gliptins, but to date, the exact pathophysiological mechanisms underlying this association are not completely elucidated. Although conventional and gliptin-associated BP are thought to share similar clinical and histopathological features, our thorough review of the most recent literature, shows that these 2 forms are quite distinct: DPP-4-i-associated BP seems to appear at an earlier age than spontaneous BP, it may manifest either as a noninflammatory or inflammatory phenotype, while the conventional form presents with a typical inflammatory phenotype. Additionally, an important distinctive histological feature was recently shown in Gliptin-associated BP: these forms may present a less significant eosinophils infiltrate in the upper dermis of peri-blister lesions compared to the skin of patients with spontaneous BP, and this seems a specific feature of the clinically non-inflammatory forms. In accordance with previous literature, we found that the direct immunofluorescence (DIF) gives identical findings in both DPP-4i-associated and conventional forms of BP which is an IgG and complement C3 deposition as a linear band at the dermal–epidermal junction in perilesional skin. Indirect immunofluorescence shows the presence of IgG circulating autoantibodies in the patient's serum which titer does not differ between spontaneous and DPP-4i-associated BP, while the specificity of these autoantibodies, may be different in spontaneous, induced non-inflammatory and induced inflammatory forms, epitope spreading phenomenon seems to play a role in determining these specificities. Further research, based on integrated epidemiological, clinical, histo-immunological and pharmacogenomic approaches, may give more insight into these forms of BP. This combined approach will allow to better define BP endotypes and to unveil the mechanism of spontaneous or drug-induced breakage of the immunotolerance to skin self-antigens.

Suspected Adverse Drug Reactions of the Type 2 Antidiabetic Drug Class Dipeptidyl-Peptidase IV inhibitors (DPP4i): Can polypharmacology help explain?

“…Histological features of BP vary depending on whether it is DPP4i-induced or of classical pathogenesis. [53] DPP4 has an established role in converting plasminogen to plasmin; one suggested mechanism is that DPP4i prevents plasmin cleavage of collagen XVII,[53][59] resulting in the breakdown of immunotolerance against collagen and production of autoantibodies against distinct collagen epitopes. Furthermore, enhancement of the activity of proinflammatory chemokines, such as CCL11/exotoxin, results in blister formation,[59] as well as a possible interference with keratinocyte migration and delayed wound healing.…”

Reply to “New‐onset bullous pemphigoid after inactivated Covid‐19 vaccine: Synergistic effect of the Covid‐19 vaccine and vildagliptin”

“… 4 Rather, the putative role of DPP4‐i in ameliorating the prognosis of COVID‐19 patients may be related to their complex immunomodulatory effects. 5 …”

“…In addition, DPP‐4 is a cell‐surface plasminogen receptor capable of converting plasminogen into plasmin, a serine protease that is in turn capable of cleaving BP180 ectodomain. 5 Inhibition of plasmin could provoke an altered processing of BP180 with a possible breakdown in immune tolerance of the antigen. Also, the additive role of mechanical injury secondary to intramuscular inoculation of the vaccine cannot be disregarded.…”

“…4 Rather, the putative role of DPP4-i in ameliorating the prognosis of COVID-19 patients may be related to their complex immunomodulatory effects. 5 Several cases of anti-SARS-CoV-2-vaccine-associated BP have been observed. 6 Clinically, two of our patients recalled the noninflammatory phenotype of gliptin-associated BP originally described by Japanese authors.…”

Case Report: Bullous Pemphigoid Associated With Morphea and Lichen Sclerosus: Coincidental Diseases or Pathogenetic Association?

“…The emergence of BP is sometimes precipitated by an external or internal trigger, including drugs ( 11 , 12 ), vaccines ( 13 ), or malignancies ( 14 ). Localized forms can also arise on sites of previously damaged skin, e.g.…”