More Severe Erosive Phenotype Despite Lower Circulating Autoantibody Levels in Dipeptidyl Peptidase-4 Inhibitor (DPP4i)-Associated Bullous Pemphigoid: A Retrospective Cohort Study

Abstract

Background The clinical and immunological profile of patients with dipeptidyl peptidase-4 inhibitor (DPP4i)-associated bullous pemphigoid (BP) is inconsistent in the current literature. Objectives The aims were to investigate the clinical and immunological features of patients with DPP4i-associated BP and to examine whether there are intraclass differences between different DPP4i agents. Methods A retrospective cohort study was conducted, including all consecutive patients diagnosed with BP throughout the years 2009-2019 in a tertiary referral center. Results The study encompassed 273 patients with BP (mean age at diagnosis 79.1 ± 9.9 years), of whom 24 (8.8%) were associated with DPP4i. Sitagliptin was the prescribed agent for 17 patients (70.8%), and vildagliptin was prescribed in seven patients (29.2%). Relative to other patients with BP, patients with DPP4i-associated BP had more prominent truncal involvement (95.8% vs. 73.9%; P = 0.017), greater erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) subscore (29.8 ± 17.4 vs. 20.6 ± 14.4; P = 0.018), and lower levels of anti-BP180 NC16A (279.2 ± 346.1 vs. 572.2 ± 1352.0 U/ml; P = 0.009) and anti-BP230 (25.5 ± 47.8 vs. 128.6 ± 302.9 U/ml; P = 0.009) antibodies. Relative to patients with sitagliptinassociated BP, those with vildagliptin-associated BP had a lower seropositivity rate (57.1% vs. 94.1%, P = 0.031) and lower levels (96.7 ± 139.0 vs. 354.5 ± 376.5; P = 0.023) of anti-BP180 NC16A antibodies, and tended to present with higher erosion/blister BPDAI subscore (36.3 ± 9.6 vs. 25.8 ± 19.7; P = 0.095). Conclusions DPP4i-associated BP is characterized by a more severe blistering and erosive presentation despite lower levels of typically pathogenic antibodies.

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

“…García-Díez et al [ 48 ] reported a similar case with inflammatory BP, whose initial negative ELISA results became positive months later. In our DPP4i patients, autoantibody titers were significantly lower than in nonDPP4i patients, consistent with the findings of Ständer et al [ 49 ] and Ujiie et al [ 50 ], but the small subset of the DPP4i patients limits the conclusions that may be drawn from this finding. However, some previous reports also showed comparable autoantibody titers in DPP4i-related and non-DPP4i-related BP patients [ 21 , 27 , 51 ].…”

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

“…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). In our current study, the number and proportion of eosinophils in blood samples were slightly lower in DPP4i-BP than rBP, but the difference was not statistically significant (Supplementary Table S2).…”

“…The severity of skin symptoms, classified by BP Disease Area Index (BPDAI) scores, has been reported to correlate with the level of anti-BP180 IgG autoantibodies similarly in rBP and DPP4i-BP (Chijiwa et al 2018;Patsatsi et al 2018), but also lower levels of anti-BP180 autoantibodies and higher BPDAI of DPP4i-BP patients compared to rBP patients have been found (Ständer et al 2021). Previously a positive correlation between the amount of CCL17, IL-21 and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in sera and the level of anti-BP180 NC16A auto-IgG has been described in BP patients.…”

Risk Factors for Mucosal Involvement in Bullous Pemphigoid and the Possible Mechanism: A Review

“…For these patients, withdrawal of DPP-4 inhibitors greatly benefits their recovery ( 36 ). Nevertheless, another retrospective cohort study found no significant difference in the incidence of mucosal involvement between patients treated with DPP-4 inhibitors and patients not ( 37 ). Although few studies have examined the incidence of mucosal involvement in BP patients who were and were not receiving PD-1/PD-L1 inhibitors, one review concluded that mucosal involvement occurred in 15.5% of patients who were treated with PD-1/PD-L1 inhibitors ( 38 ).…”