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The association of bullous pemphigoid (BP) with the use of dipeptidylpeptidase 4 (DPP-4) inhibitors among patients with diabetes has recently emerged. The risk of developing BP during treatment with new DPP-4 inhibitor agents like linagliptin is yet to be established. The clinical features and the prognostic outcomes of patients with DPP-4 inhibitor-associated BP are yet to be established. OBJECTIVES Primarily to estimate the association between DPP-4 inhibitor exposure and the development of BP, and secondarily to characterize the clinical features and history of patients with DPP-4 inhibitor-associated BP. DESIGN, SETTING, AND PARTICIPANTS A retrospective case-control study of the intake of different DPP-4 inhibitor agents and metformin and occurrence of BP among patients with diabetes in a tertiary care referral center for autoimmune bullous diseases in northern Israel. Included were 82 consecutive patients with diabetes and immunopathologically validated BP diagnosed between January 1, 2011, and December 31, 2017, and 328 age-, sex-, and ethnicity-matched control participants with diabetes but without BP. MAIN OUTCOMES AND MEASURES Patients with diabetes and BP and exposure to DPP-4 inhibitors were followed up for a median of 2.0 years and compared with other patients with diabetes and BP who were not exposed to DPP-4 inhibitors regarding clinical and immunological features, laboratory analyses, treatments, and clinical outcomes. RESULTS Eighty-two patients with BP and 328 age-and sex-matched control participants were enrolled; mean (SD) age, 79.1 (9.1) years; and 44 patients were female (53.7%). Overall, DPP-4 inhibitor intake was associated with a 3-fold increased risk for BP (adjusted odds ratio [OR], 3.2; 95% CI, 1.9-5.4). The adjusted ORs for vildagliptin and linagliptin were 10.7 (95% CI, 5.1-22.4) and 6.7 (95% CI, 2.2-19.7), respectively. The association of DPP-4 inhibitor use with BP was independent of the use of metformin and was stronger among male (OR, 4.46; 95% CI, 2.11-9.40) than female (OR, 1.88; 95%, CI 0.92-3.86) patients and strongest in patients younger than 70 years (OR, 5.59; 95% CI, 1.73-18.01). Patients with DPP-4 inhibitorassociated BP presented with higher mucosal involvement (22.2% vs 6.5%; P = .04) and lower mean (SD) peripheral eosinophil counts (399.8 [508.0] vs 1117.6 [1847.6] cells/μL; P = .01) than those with BP who had not been exposed to DPP-4 inhibitor. Discontinuation of DPP-4 inhibitor treatment was followed by improved clinical outcomes. CONCLUSIONS AND RELEVANCE Vildagliptin and, to a lesser extent, linagliptin are associated with an increased risk of BP. This may partly explain the increasing incidence of BP in Israel. Discontinuation of DPP-4 inhibitor treatment in patients with diabetes should be considered when BP is diagnosed.
The association of bullous pemphigoid (BP) with the use of dipeptidylpeptidase 4 (DPP-4) inhibitors among patients with diabetes has recently emerged. The risk of developing BP during treatment with new DPP-4 inhibitor agents like linagliptin is yet to be established. The clinical features and the prognostic outcomes of patients with DPP-4 inhibitor-associated BP are yet to be established. OBJECTIVES Primarily to estimate the association between DPP-4 inhibitor exposure and the development of BP, and secondarily to characterize the clinical features and history of patients with DPP-4 inhibitor-associated BP. DESIGN, SETTING, AND PARTICIPANTS A retrospective case-control study of the intake of different DPP-4 inhibitor agents and metformin and occurrence of BP among patients with diabetes in a tertiary care referral center for autoimmune bullous diseases in northern Israel. Included were 82 consecutive patients with diabetes and immunopathologically validated BP diagnosed between January 1, 2011, and December 31, 2017, and 328 age-, sex-, and ethnicity-matched control participants with diabetes but without BP. MAIN OUTCOMES AND MEASURES Patients with diabetes and BP and exposure to DPP-4 inhibitors were followed up for a median of 2.0 years and compared with other patients with diabetes and BP who were not exposed to DPP-4 inhibitors regarding clinical and immunological features, laboratory analyses, treatments, and clinical outcomes. RESULTS Eighty-two patients with BP and 328 age-and sex-matched control participants were enrolled; mean (SD) age, 79.1 (9.1) years; and 44 patients were female (53.7%). Overall, DPP-4 inhibitor intake was associated with a 3-fold increased risk for BP (adjusted odds ratio [OR], 3.2; 95% CI, 1.9-5.4). The adjusted ORs for vildagliptin and linagliptin were 10.7 (95% CI, 5.1-22.4) and 6.7 (95% CI, 2.2-19.7), respectively. The association of DPP-4 inhibitor use with BP was independent of the use of metformin and was stronger among male (OR, 4.46; 95% CI, 2.11-9.40) than female (OR, 1.88; 95%, CI 0.92-3.86) patients and strongest in patients younger than 70 years (OR, 5.59; 95% CI, 1.73-18.01). Patients with DPP-4 inhibitorassociated BP presented with higher mucosal involvement (22.2% vs 6.5%; P = .04) and lower mean (SD) peripheral eosinophil counts (399.8 [508.0] vs 1117.6 [1847.6] cells/μL; P = .01) than those with BP who had not been exposed to DPP-4 inhibitor. Discontinuation of DPP-4 inhibitor treatment was followed by improved clinical outcomes. CONCLUSIONS AND RELEVANCE Vildagliptin and, to a lesser extent, linagliptin are associated with an increased risk of BP. This may partly explain the increasing incidence of BP in Israel. Discontinuation of DPP-4 inhibitor treatment in patients with diabetes should be considered when BP is diagnosed.
IMPORTANCE Recent studies suggest that dipeptidyl peptidase 4 (DPP-4) inhibitors are associated with an increased risk of developing bullous pemphigoid (BP). Population-based studies on the association between DPP-4 inhibitors and BP are limited. OBJECTIVE To characterize the potential association between the use of DPP-4 inhibitors and an increased risk of developing BP. DESIGN, SETTING, AND PARTICIPANTS This retrospective, nationwide, population-based, case-control study using Korean insurance claims data from January 1, 2012, to December 31, 2016, included patients with newly diagnosed BP and diabetes. Control patients with diabetes (and without BP) were randomly obtained after matching for age, sex, and year of diagnosis within the same period. MAIN OUTCOMES AND MEASURES The number of patients with newly diagnosed BP and diabetes per year and annual changes in the proportion of patients with diabetes among all patients with BP were measured. The association between use of DPP-4 inhibitors and risk of developing BP was analyzed using univariate and multivariate logistic regression analyses. RESULTS The study included 670 case patients (with diabetes and BP) and 670 control patients (with only diabetes) (mean [SD] age, 75.3 [10.0] years in each group; 342 [51.0%] male in each group). The number of patients with diabetes and BP more than doubled during the study period (from 77 in 2012 to 206 in 2016). The proportion of patients with diabetes among all patients with BP also increased (from 0.18 in 2012 to 0.33 in 2016). The use of DPP-4 inhibitors was associated with a significant increase in the risk of developing BP (adjusted odds ratio [aOR], 1.58; 95% CI, 1.25-2.00; P < .001); among all DPP-4 inhibitors used in Korea, the highest aOR was associated with the use of vildagliptin (aOR, 1.81; 95% CI, 1.31-2.50; P < .001). Subgroup analyses revealed a significant association in male patients (aOR, 1.91; 95% CI, 1.39-2.63; P < .001) and that vildagliptin was the most high-risk DPP-4 inhibitor (aOR, 2.70; 95% CI, 1.73-4.34; P < .001). CONCLUSIONS AND RELEVANCE The findings suggest that DPP-4 inhibitors are associated with a significantly increased risk of the development of BP in patients with diabetes. Of the DPP-4 inhibitors available in Korea, vildagliptin was associated with the highest risk, particularly in male patients. Practitioners should consider that DPP-4 inhibitors, particularly vildagliptin, may be associated with the development of BP in patients with diabetes. These nationwide, population-based results may serve as a foundation for further studies seeking to understand how DPP-4 inhibitors contribute to the development of BP.
ost patients with bullous pemphigoid (BP) classically present with tense blisters and erythema, seen predominantly in the limb flexures and the abdomen, and often in conjunction with urticarial plaques. Meanwhile, 20% present with atypical manifestations, including prurigo-like type, 1 urticaria-like type, 2 eczema-like type, 3 and dyshidrosiform type. 4 Involvement of the mucous membranes was considered an atypical physical feature by the clinical criteria of Vaillant et al, 5 which yields a positive predictive value of 95% for a clinical diagnosis of BP. Mucosal lesions in BP are typically restricted to the oral mucosa and may be observed in up to 20% of patients. [6][7][8] The involvement of other mucosal surfaces is less established and based on anecdotal case reports. [9][10][11][12][13] To our knowledge, the frequency of nonoral mucosal involvement among patients with BP was not evaluated previously in the setting of cohort or large case series studies. The knowledge about the precise mucosal structures that may be affected in BP and of the distinct features of patients with BP who have mucosal involvement is very limited.The objectives of the current study were to evaluate the prevalence of general mucosal involvement in patients with BP and to characterize the subgroup of patients with mucosal lesions, using a large cohort of patients with welldefined and immunopathologically validated BP. IMPORTANCE The prevalence of mucosal involvement in bullous pemphigoid (BP) is inconsistent. Nonoral mucosal involvement was reported anecdotally in few patients with BP.OBJECTIVE To evaluate the prevalence of mucosal involvement in patients with BP, and to characterize the subgroup of patients with mucosal lesions. DESIGN, SETTING, AND PARTICIPANTSA retrospective cohort study was performed including 328 consecutive patients diagnosed with immunopathologically validated BP at a tertiary care referral center for autoimmune bullous diseases in northern Israel between January 1, 2000, and December 31, 2017. MAIN OUTCOME AND MEASURESThe study was conducted to estimate the prevalence and distribution of mucosal involvement among patients with BP. Patients with mucosal involvement were compared with the remaining BP patients regarding clinical and immunological features, laboratory analyses, and treatments. RESULTSThe study cohort included 139 (42.4%) male and 189 (57.6%) female patients, with a mean (SD) age of 78.0 (11.8) years at presentation. Fifty-six patients (17.1%) presented with mucosal lesions. The oral mucosa was the most frequently affected mucosal surface (n = 44; 13.7%), followed by the laryngeal (n = 16; 4.9%) and the genital (n = 10; 3.0%) mucosae. Among patients with oral lesions, the most involved oral structures were the buccal mucosa (n = 25; 55.6%) and the soft palate (n = 24; 53.3%). Compared with other patients with BP, patients with mucosal involvement were younger (71.8 [14.4] years vs 79.3 [10.8] years; P < .001), presented more frequently with extensive disease (55.4% vs 39.7%; P = .002), had less p...
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