Title: Reply to: “Comment on ‘Oral diabetes medications other than dipeptidyl peptidase-4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case control study’”
Abstract: To the Editor: We thank Dr Kridin for his interest in our recent publications.1Varpuluoma O. Försti A.K. Jokelainen J. et al.Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study.J Invest Dermatol. 2018; 138: 1659-1661Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 2Varpuluoma O. Försti A. Jokelainen J. et al.Oral diabetes medications other than dipeptidyl peptidase-4 inhibitors are not associated with bullous pemphigoid: a Finnish nationwide case control study.J Am Acad Dermatol. 2018; 79: 1034-1038.e5Abstract Full Text Full Text PDF Scopus (32) Google Scholar The limitation that we may have not been able detect the association between newer diabetes drugs and bullous pemphigoid (BP) was already acknowledged in our previous article.1Varpuluoma O. Försti A.K. Jokelainen J. et al.Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study.J Invest Dermatol. 2018; 138: 1659-1661Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar The unpublished finding of Dr Kridin's group that the use of linagliptin is associated with BP is not surprising and further confirms the significance of the use of dipeptidyl peptidase 4 inhibitors (DPP4is) (or gliptins) as a risk factor for BP. The preferred DPP4is vary between different countries, and this affects the geographic differences in DPP4i-related risk of BP. Sitagliptin is currently the most frequently used DPP4i in Finland, followed by linagliptin and vildagliptin, but linagliptin was rarely used until quite recently.1Varpuluoma O. Försti A.K. Jokelainen J. et al.Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study.J Invest Dermatol. 2018; 138: 1659-1661Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 3Fimea. Drug consumption statistics. Available from: http://www.fimea.fi/web/en/databases_and_registeries/consumption. Accessed June 7, 2018.Google Scholar The European database of suspected drug reactions shows that the number of cases of BP to date that are thought to be related to DPP4i treatment is clearly highest for vildagliptin (n = 460), but the numbers are also high for sitagliptin (n = 202) and linagliptin (n = 125). However, far fewer cases of BP are suspected to have been caused by alogliptin (n = 33) and saxagliptin (n = 13).4Eudravigilance. European database of suspected adverse drug reaction reports. Available from: http://www.adrreports.eu/. Accessed June 7, 2018.Google Scholar In case reports of gliptin-associated BP, linagliptin, sitagliptin, and vildagliptin are the most frequently named drugs, with other gliptins rarely mentioned.1Varpuluoma O. Försti A.K. Jokelainen J. et al.Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study.J Invest Dermatol. 2018; 138: 1659-1661Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 5Ujiie H. Muramatsu K. Mushiroda T. et al.HLA-DQB1* 03: 01 as a biomarker for genetic susceptibility to bullous pemphigoid induced by DPP-4 inhibitors.J Invest Dermatol. 2018; 138: 1201-1204Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 6García-Díez I. Ivars-Lleó M. López-Aventín D. et al.Bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors. Eight cases with clinical and immunological characterization.Int J Dermatol. 2018; 57: 810-8116Google Scholar, 7Mai Y. Nishie W. Izumi K. et al.Detection of anti-BP 180 NC 16A autoantibodies after the onset of dipeptidyl peptidase-IV inhibitor-associated bullous pemphigoid: a report of three cases.Br J Dermatol. 2018; 179: 790-791Crossref PubMed Scopus (24) Google Scholar We agree with Dr Kridin that on the basis of our current study population, the association between sodium glucose cotransporter 2 inhibitors (SGLT2is) cannot be analyzed. Although empagliflozin, dapagliflozin, and canagliflozin were approved by the US Food and Drug Administration 5 years ago, the higher special rate of reimbursement for empagliflozin and dapagliflozin was authorized by the Finnish authorities in early 2016, whereas canagliflozin remains unavailable in the Finnish market. Therefore, in March 2018 when our article was prepared, it was still too soon to use the data from Finnish national registries to analyze any possible association between SGLT2is and BP. However, to best of our knowledge, no case report so far has suggested an association between SGLT2is use and BP. Dr Kridin comments that estimates of the prevalence of diabetes among patients with BP are variable and that these differences may reflect the study designs used. In our opinion, the variable findings of these studies mostly reflect their small sample sizes. It is of note that in the nationwide Danish study the prevalence of type 2 diabetes in patients with BP (16%) (see Supplemental Table SI in Varpuluoma et al2Varpuluoma O. Försti A. Jokelainen J. et al.Oral diabetes medications other than dipeptidyl peptidase-4 inhibitors are not associated with bullous pemphigoid: a Finnish nationwide case control study.J Am Acad Dermatol. 2018; 79: 1034-1038.e5Abstract Full Text Full Text PDF Scopus (32) Google Scholar) resembled that found in our nationwide data (19.6%). We agree that it is important to take into account the possibility that patients with BP are prone to type 2 diabetes on account of corticosteroid treatment and that diabetes morbidity associated with the use of corticosteroids may not be detected in studies addressing comorbidities at the time of a diagnosis of BP. Our knowledge of the factors associated with the onset of BP is growing, and ever more aspects need to be considered when comprehensively treating vulnerable seniors with BP. Thus, we conclude that it is of great importance to know which diabetes drugs should be avoided in these patients to minimize the risk of aggravating their BP. Comment on “Oral diabetes medications other than dipeptidyl peptidase-4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case control study”Journal of the American Academy of DermatologyVol. 79Issue 6PreviewTo the Editor: We read with great interest the study performed by Varpuluoma et al.1 The authors conducted a nationwide case-control study aiming to estimate the prevalence of administration of oral antidiabetics among patients with bullous pemphigoid (BP) versus among matched control subjects. No association was found between exposure to any oral diabetes medications other than dipeptidyl peptidase-4 inhibitors (DPP4is) and the development of BP.1 DPP4is, particularly vildagliptin, have emerged as a risk factor for the development of BP. Full-Text PDF