Clinical, Laboratory and Histological Features of Dipeptidyl Peptidase-4 Inhibitor Related Noninflammatory Bullous Pemphigoid

Abstract

Bullous pemphigoid (BP) is an autoimmune blistering disease of elderly patients that has shown increasing incidence in the last decades. Higher prevalence of BP may be due to more frequent use of provoking agents, such as antidiabetic dipeptidyl peptidase-4 inhibitor (DPP4i) drugs. Our aim was to assess DPP4i-induced bullous pemphigoid among our BP patients and characterize the clinical, laboratory and histological features of this drug-induced disease form. In our patient cohort, out of 127 BP patients (79 females (62.2%), 48 males (37.7%)), 14 (9 females and 5 males) were treated with DPP4i at the time of BP diagnosis. The Bullous Pemphigoid Disease Area Index (BPDAI) urticaria/erythema score was significantly lower, and the BPDAI damage score was significantly higher in DPP4i-BP patients compared to the nonDPP4i group. Both the mean absolute eosinophil number and the mean periblister eosinophil number was significantly lower in DPP4i-BP patients than in nonDPP4i cases (317.7 ± 0.204 vs. 894.0 ± 1.171 cells/μL, p < 0.0001; 6.75 ± 1.72 vs. 19.09 ± 3.1, p = 0.0012, respectively). Our results provide further evidence that DPP4i-associated BP differs significantly from classical BP, and presents with less distributed skin symptoms, mild erythema, normal or slightly elevated peripheral eosinophil count, and lower titers of BP180 autoantibodies. To our knowledge, this is the first case series of DPP4i-related BP with a non-inflammatory phenotype in European patients.

Serum autoantibody reactivity in bullous pemphigoid is associated with neuropsychiatric disorders and the use of antidiabetics and antipsychotics: a large, prospective cohort study

“…This finding is in line with the association of BP with neuropsychiatric medication. 60 In contrast, lower serum anti-BP180 IgG levels were described in DPP4 inhibitorassociated BP, 45,46,61 a finding that could not be confirmed in our study. Furthermore, no association between serum anti-BP180 IgG levels and inhibitors of platelet aggregation or Lthyroxine was revealed in our study.…”

“…Insulin has not been described as a pathogenic factor for BP in a previous study. 63 While anti-DPP4 inhibitor-associated BP is a well-recognized BP subgroup, 18,61,64,65 clinical and immunopathological features that differ from those of DPP4 inhibitor-unrelated BP were contradictory in different patient populations. 46 In Japanese and Hungarian BP patients, DPP4 inhibitor use tended to reveal a noninflammatory phenotype, a low number of lesional infiltrated eosinophils, less anti-BP180 NC16A IgG reactivity and an HLA-DQB1*03:01 haplotype.…”

Dipeptidyl Peptidase 4 Inhibitor‒Associated Bullous Pemphigoid Is Characterized by an Altered Expression of Cytokines in the Skin

“…In contrast, the amount of CCL11 (eotaxin) was not increased at the protein level although its DPP4iinduced upregulation is known to enhance eosinophil infiltration in a rodent model (Forssmann et al 2008). The induction of eosinophilic cytokines especially in DPP4i-BP was unexpected since low numbers of lesional infiltrated eosinophils in the skin has been described in Japanese, Israeli, Spanish and Hungarian DPP4i-BP studies (Chijiwa et al 2018;Izumi et al 2016;Kinyó et al 2021;Kridin and Bergman 2018;Nieto-Benito et al 2021). No significant differences in the number of J o u r n a l P r e -p r o o f infiltrated eosinophils have been reported in Greek, Croatian, French and Finnish studies of DPP4i-BP patients (Bukvic-Mokos et al 2020;Lindgren et al 2019;Patsatsi et al 2018;Plaquevent et al 2019;Ständer et al 2021).…”

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

“…Blisters appear mostly over an erythematous and edematous base, and are accompanied by an intense pruritus. However, in several recent case series, patients with DPP-4i-induced BP tend to manifest a noninflammatory phenotype, distinct from conventional BP [ 83 ]. In this noninflammatory form, bullae appear mostly over a normal appearing skin, and the eruption is comprised of a few, mild erythematous lesions with limited distribution [ 68 , 69 , 74 , 82 ].…”

“…Finally, blood eosinophilia, present in around 50% of conventional BP patients [ 87 ], and reported since long as a marker of the disease severity [ 89 , 90 ], seems to be less common and less significant in patients with DPP-4i-related BP [ 15 , 83 ]. Besides that, other blood-based markers for BP, like the increased amount of soluble IL-2 receptor, macrophage migration inhibitory factor, eosinophilic cationic protein, neutrophil-derived myeloperoxidase (elevated in sera and blister fluids) and mast cell degranulation assays [ 91 ] were not studied in DPP-4i-related BP in comparison with spontaneous BP, and their use in clinical settings is very limited.…”