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

Abstract

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.

Long-Term Safety and Efficacy of Teneligliptin in Elderly Patients with Type 2 Diabetes: Subgroup Analysis of a 3-Year Post-Marketing Surveillance in Japan

“…An association between DPP4 inhibitors and pemphigoid has been reported [36,37]. As a consequence, the package inserts for DPP4 inhibitors, including teneligliptin, were revised to include a precaution regarding pemphigoid in Japan.…”

The role of Dipeptidyl Peptidase‐4 in cutaneous disease

“…Adapted from Ohnuma et al 2 and anagliptin (111.07), which are less frequently used, 43,45,56 and omarigliptin (OR, 557.20), teneligliptin (OR, 29.23-161.9), and trelagliptin (OR, 178.18), which are available in fewer countries, such as Japan, Argentina, Korea, and India. 42,45,57 Whilst individual studies found no significant risk associated with sitagliptin use, a recent meta-analysis of randomized controlled trials involving sitagliptin, saxagliptin and linagliptin identified a significant association (OR, 7.38) 12,46,47 In addition to BP, DPP4i appear to predispose towards mucous membrane pemphigoid (MMP) development. In a study examining gliptin accountability in a cohort of 313 MMP patients, 17 of 24 gliptin-treated diabetic MMP patients were considered gliptin-induced MMP due to onset within <12 weeks.…”

“…The average latency period from the exposure of DPP4i use to BP diagnosis/clinical presentation ranges from 8 months to 2.25 years with even greater interpatient variability. 44,53,56,57,59,60 Since the concomitant use of metformin or other anti-hyperglycaemic agents is noted during the latency period, it was once speculated to play a role in the development of DPP4i-induced BP 45,51,[61][62][63] ; however, subsequent studies found the risk to be limited just to DPP4 inhibition. 49,53,55,64 Pooled analyses reveal that the risk of DPP4i is higher amongst males (OR, 1.91-5.31), 44,47,49,50 and the elderly (OR, 5.31).…”

“…Vildagliptin is the leading DPP4i to confer increased risk of BP followed by linagliptin (OR, 2.70–257.4 vs. 2.67–69.42). Amongst other prominent associations include saxagliptin (OR, 18.9–46.45) and anagliptin (111.07), which are less frequently used, 43,45,56 and omarigliptin (OR, 557.20), teneligliptin (OR, 29.23–161.9), and trelagliptin (OR, 178.18), which are available in fewer countries, such as Japan, Argentina, Korea, and India 42,45,57 . Whilst individual studies found no significant risk associated with sitagliptin use, a recent meta‐analysis of randomized controlled trials involving sitagliptin, saxagliptin and linagliptin identified a significant association (OR, 7.38) 12,46,47 In addition to BP, DPP4i appear to predispose towards mucous membrane pemphigoid (MMP) development.…”

Long-Term, Real-World Safety and Efficacy of Teneligliptin: A Post-Marketing Surveillance of More Than 10,000 Patients with Type 2 Diabetes in Japan

“…The incidence of ADRs of skin and subcutaneous tissue disorders was 0.41% in this surveillance. Pemphigoid was added to the package insert for teneligliptin during the observation period [23], having emerged as a possible ADR associated with DPP4 inhibitors, including teneligliptin [39][40][41][42]. In this surveillance, pemphigoid was reported as an ADR in five patients (0.05%).…”