Biomarkers for predicting immune reconstitution inflammatory syndrome in dipeptidyl peptidase‐4 inhibitor‐associated bullous pemphigoid: A retrospective observational study with a case series

Abstract

BackgroundThe prognosis of dipeptidyl peptidase‐4 inhibitor‐associated bullous pemphigoid (DPP‐4i‐BP) is variable, with some cases showing spontaneous remission after drug cessation and others showing worsening BP or developing infectious complications, termed infectious immune reconstitution inflammatory syndrome (IRIS), after DPP‐4i cessation. We recently demonstrated that the neutrophil‐to‐lymphocyte ratio measured at baseline and during treatment predicts the eventual development of infectious IRIS.ObjectivesTo identify key molecular immune parameters that correlate with, and potentially shape, subsequent immune responses after DPP‐4i cessation.MethodsThis retrospective observational study examined DPP‐4i‐BP patients who were treated at our hospital for 4 years. Patients selected for this study were those who developed BP after initiation of DPP‐4i and were followed up at least 90 days after DPP‐4i cessation, if information and the relevant parameters were available from the medical records. The patients were divided into two cohorts: a spontaneous remission group and an exacerbation group showing worsening BP or developing infectious IRIS. Serum cytokine/chemokine levels were determined using a multiplex biometric immunoassay.ResultsSerum levels of eotaxin and interferon (IFN)‐α/γ before DPP‐4i cessation were significantly higher in the remission group (161.6 [standard error 21.9] pg/mL and 14.4 [4.8]/9.2 [4.6] pg/mL, respectively) than in the exacerbation group (51.1 [standard error 9.8] pg/mL and 1.6 [1.6]/1.0 [0.5] pg/mL, respectively, p < 0.005). Importantly, regarding changes in cytokine/chemokine levels before and after cessation of DPP‐4i, increasing levels of IFN‐α/γ, interleukin‐10, and interleukin‐1RA following drug cessation were associated with the subsequent development of infectious IRIS.ConclusionsAs observed in patients with coronavirus disease 2019, if the production of IFN‐α/γ and eotaxin occurs early and intense enough before DPP‐4i cessation, virus reactivation as a manifestation of infectious IRIS can be prevented. If not, exuberant virus‐related inflammatory reactions would ensue, as observed in a cytokine storm.