A decade of gliptin‐induced bullous pemphigoid

We read with great interest the article by Werth et al., published in a recent issue of this journal, which reviewed the epidemiology, clinical features and burden of bullous pemphigoid (BP) and provided an overview of current treatment recommendations and the therapeutic pipeline for the disease.1 Motivated by the challenges faced in clinical practice at our University Hospital, we would like to comment on the article, specifically focusing on the distinctive features of gliptin-induced BP (GI-BP). Gliptins were initially approved for the treatment of type 2 diabetes mellitus (T2DM) in 2006 and have been prescribed as a second-line, add-on therapy to metformin. They are particularly favoured in elderly patients—the primary BP target population—due to their favourable safety profile.2 The first report suggesting the potential role of gliptins in inducing BP was published in 2011, 5 years after their initial approval.3 Since then, an increasing number of publications from multiple continents have highlighted the global emergence of GI-BP (Figure 1). A 2020 meta-analysis of randomized controlled trials (RCTs) involving 61,514 patients reported a more than fourfold increased risk of BP associated with gliptin use.4 A 4-year retrospective French multicentre study found that 6% (101/1787) of BP cases were gliptin-induced.5 Furthermore, a recently published case–control study from Crete reported that 67.2% of BP patients, compared to 31.0% of controls, were on gliptins.6 Despite regional differences, variations in sample size and methodology, and evolving antidiabetic drug prescription practices, these findings suggest a dynamic disease trajectory. GI-BP may significantly alter the overall BP epidemiology in the coming years unless risk factors predicting susceptibility are identified and preventive measures are implemented. Notably, a significant association between the HLA-DQB1*03:01 allele and GI-BP has been identified in an Italian cohort, suggesting that the occurrence of GI-BP may have a genetic component.7 GI-BP may present with distinguishing characteristics compared to idiopathic BP. It typically manifests within the first 9–13 months of gliptin use and is more frequently associated with vildagliptin, followed by linagliptin and sitagliptin, although a class effect is suspected.4, 5, 8 The necessity of discontinuing gliptins upon diagnosis remains controversial. Plaquevent et al. found no significant differences in time to disease control or in the rate and time to relapse between patients who discontinued gliptins and those who did not.5 The management of GI-BP poses a therapeutic challenge. First-line treatments, including high-potency topical steroids and oral corticosteroids, carry significant morbidity and disrupt glycemic control in an already fragile, elderly population. Werth et al. highlighted the emerging role of dupilumab in treating moderate-to-severe BP.1 Notably, the results of a phase III RCT evaluating dupilumab versus placebo (NCT04206553), announced by Regeneron in September 2024, demonstrated that dupilumab achieved the primary endpoint: the percentage of patients achieving complete remission without oral corticosteroids by week 36.9 Although the trial excluded patients with GI-BP, real-world data are encouraging, showing no significant differences in response rates between idiopathic BP and GI-BP.10 In conclusion, the purpose of our letter is to underscore an additional key aspect of BP: gliptin-induced BP. Considering the growing body of evidence in recent years, if the burden of GI-BP continues to rise, it will be imperative for dermatologists to conduct further research on predictors of gliptin sensitivity and to communicate these findings to other medical specialists, such as endocrinologists. Such efforts would substantially reduce the disease burden, particularly in regions with a high incidence of GI-BP, and advance strategies for disease prevention. The authors received no financial support for the research, authorship and/or publication of this letter. Eirini Kavvalou has no conflict of interest to declare. Maria Polina Konstantinou has received travel support and honoraria from Abbvie, Janssen, Eli Lilly, LEO Pharma and Novartis and has participated on advisory boards for UCB. S. Kruger-Krasagakis has received honoraria for lectures, presentations or educational events from Galderma and UCB; support for attending meetings and/or travel from AbbVie, Eli Lilly, Galderma, Genesis, LEO Pharma, Pfizer and UCB; and has participated on the advisory board for Galderma, UCB, Janssen and AbbVie. Konstantinos Krasagakis has received grants from Eli Lilly and Leo Pharma, travel support from AbbVie, Eli Lilly, Janssen, LEO Pharma and UCB, honoraria from UCB and Eli Lilly and has participated on advisory boards for Eli Lilly, Boehringer Ingelheim, Sanofi and UCB. Ethical approval was not required for this letter as it does not involve human or animal research. This letter adheres to ethical publishing standards and does not involve research requiring ethical approval. Data sharing does not apply to this article as no new data were created or analysed in this study.