Dipeptidyl peptidase‐4 inhibitors‐associated bullous pemphigoid: A retrospective study of 168 pemphigoid and 9,304 diabetes mellitus patients

Kawaguchi, Yohei; Shimauchi, Risa; Nishibori, Nobuhiro; Kawashima, Kazuyo; Oshitani, So; Fujiya, Atsushi; Shibata, Tsutomu; Ohashi, Norimi; Izumi, Kiyotaka; Nishie, Wataru; Shimizu, Hiroshi; Arima, Hiroshi; Sano, Hiroshi

doi:10.1111/jdi.12877

Cited by 60 publications

(69 citation statements)

References 27 publications

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“… reported that there were significantly lower eosinophils infiltrating into the skin of DPP‐4 inhibitor‐related BP than non‐DPP‐4 inhibitor‐related BP. Besides, there was a lower positive rate of anti‐BP180 NC16a antibody, an autoantibody against the NC16a region of BP180, in BP patients with DPP‐4 inhibitors than without DPP‐4 inhibitors . Izumi et al.…”

Section: Discussionmentioning

confidence: 97%

“…Besides, there was a lower positive rate of anti-BP180 NC16a antibody, an autoantibody against the NC16a region of BP180, in BP patients with DPP-4 inhibitors than without DPP-4 inhibitors. 29 Izumi et al 25 identified autoantibodies in non-inflammatory BP cases targeting the mid-portion of collagen XVII, instead of the NC16a region. The associations of drug-induced reactions and human leukocyte antigen (HLA) types have been reported.…”

Section: Discussionmentioning

confidence: 99%

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Increased risk of bullous pemphigoid in dipeptidyl peptidase 4 inhibitors: A nationwide, population‐based, cohort study in Taiwan

Hung

Liu

Cheng

et al. 2019

The Journal of Dermatology

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Recent studies revealed the risk of bullous pemphigoid (BP) in patients with diabetes mellitus (DM) taking dipeptidyl peptidase 4 (DPP‐4) inhibitors. To clarify the relationship between taking DPP‐4 inhibitors and the risk of BP among patients with DM, we conducted a cohort study by using the National Health Insurance Research Database of Taiwan from 1 January 2009 to 31 December 2015. We identified 6340 patients with DM taking DPP‐4 inhibitors and 25 360 DM patients who had not taken DPP‐4 inhibitors during the 7‐year follow‐up period. Compared with the non‐DPP‐4 inhibitor group, patients taking DDP‐4 inhibitors had a higher risk of BP (adjusted hazard ratio [aHR], 2.382; 95% confidence interval (CI), 1.163–4.883; P = 0.017]. Among the DPP‐4 inhibitors available in Taiwan, vildagliptin showed the highest risk of BP (aHR, 2.849; 95% CI, 1.893–4.215; P < 0.001), followed by saxagliptin (aHR, 2.657; 95% CI, 1.770–3.934; P < 0.001). Subgroup analysis revealed that the higher risk of BP was observed in patients older than 65 years (aHR, 2.403; 95% CI, 1.590–3.627; P < 0.001). This study revealed that treatment with DPP‐4 inhibitors, especially vildagliptin, was significantly associated with an increased risk of BP among DM patients.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Increased risk of bullous pemphigoid in dipeptidyl peptidase 4 inhibitors: A nationwide, population‐based, cohort study in Taiwan

Hung

Liu

Cheng

et al. 2019

The Journal of Dermatology

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“…5 In recent years, the immunological 11,12 and clinical 13 features of BP caused by DPP4-I have been gradually elucidated. 7 In April 2016, PMDA added pemphigoid as a serious side-effect in the package inserts of sitagliptin phosphate hydrate, vildagliptin, alogliptin benzoate, linagliptin and teneligliptin hydrobromide hydrate. Metformin is a widely used anti-diabetes drug that is often combined with a DPP4-I.…”

Section: Discussionmentioning

confidence: 99%

“…1 It has been reported that the onset of BP may be associated with the use of various drugs, such as antibiotics, antihypertensive drugs, anti-inflammatory drugs, diuretics, biopharmaceuticals, antirheumatic drugs and vaccines. [3][4][5][6][7] Most recently, an inhomogeneity analysis of BP associated with the use of DPP4-I based on the Japanese Adverse Drug Event Report database (JADER) 8 was also reported. [3][4][5][6][7] Most recently, an inhomogeneity analysis of BP associated with the use of DPP4-I based on the Japanese Adverse Drug Event Report database (JADER) 8 was also reported.…”

Section: Introductionmentioning

confidence: 99%

“…2 Also, recent reports have indicated that some patients receiving dipeptidyl peptidase-4 inhibitors (DPP4-I), a class of anti-diabetes drug, develop BP. [3][4][5][6][7] Most recently, an inhomogeneity analysis of BP associated with the use of DPP4-I based on the Japanese Adverse Drug Event Report database (JADER) 8 was also reported. However, the time of BP onset, outcomes and year when reported were not analyzed.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of patients with drug‐induced pemphigoid using the Japanese Adverse Drug Event Report database

Tanaka

Ishii

2018

The Journal of Dermatology

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To clarify the incidence of drug‐induced pemphigoid in Japan, we conducted a database search and analysis using the Japanese Adverse Drug Event Report database (JADER). Among the cases recorded in JADER between April 2004 and November 2017, we targeted “pemphigoid” and analyzed the patients’ backgrounds, drug involvement, time of pemphigoid onset, outcomes and year reported. For cases where three or more drugs were reportedly involved, the signal index was calculated using the reporting odds ratio (ROR) method. The total number of reported pemphigoid cases was 769. Males accounted for 58% (446 cases) and patients over the age of 60 years accounted for 82% (630 cases). The most frequently reported causative drug was vildagliptin (288 cases), followed in order by sitagliptin phosphate hydrate (102 cases), teneligliptin hydrobromide hydrate (86 cases), linagliptin (64 cases) and furosemide (46 cases). For the 27 causative drugs, the safety signal was detected by the ROR method. The median time to onset tended to be long for these drugs. For vildagliptin with the largest reported number, the value was 508 days (range, 2–1871). Analysis of outcomes demonstrated recovery or improvement in 66.3% of cases. Analysis of the years in which reports had been published revealed that the number of pemphigoid cases has increased rapidly in recent years. Our survey was able to reveal useful data on the incidence of drug‐induced pemphigoid. We expect that these results will aid the early detection and treatment of this condition.

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

Sugiyama,

Yamamoto,

Aoyama

2023

JEADV Clinical Practice

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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.

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Dipeptidyl peptidase‐4 inhibitors‐associated bullous pemphigoid: A retrospective study of 168 pemphigoid and 9,304 diabetes mellitus patients

Cited by 60 publications

References 27 publications

Increased risk of bullous pemphigoid in dipeptidyl peptidase 4 inhibitors: A nationwide, population‐based, cohort study in Taiwan

Increased risk of bullous pemphigoid in dipeptidyl peptidase 4 inhibitors: A nationwide, population‐based, cohort study in Taiwan

Analysis of patients with drug‐induced pemphigoid using the Japanese Adverse Drug Event Report database

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

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