Dipeptidyl peptidase-4 inhibitors (DPP-4i), or gliptins, are a widely used glucose-lowering agents. A growing amount of evidence pointed to a possible role of DPP-4i in the induction of bullous pemphigoid (BP), which is an auto-immune skin blistering disease that mainly affects the elderly. In this article we discuss a case of DPP-4i associated BP and we provide an updated review of the current knowledge regarding this emerging entity. Use of DPP-4i, particularly vildagliptin, was found to significantly increase the risk of BP. BP180 would be in the center of the aberrant immune response. DPP-4i induced BP is thought to be associated with male gender, mucosal involvement, and milder inflammatory phenotype especially in Asian population. Generally, patients may not remit fully after DPP-4i withdrawal only and require either topical or systemic glucocorticoid courses.
Lloyd-LaveryAChiCWojnarowskaFTaghipourK.The associations between bullous pemphigoid and drug use: a UK case-control study. JAMA Dermatol. 2013;149(1):58-62. doi:10.1001/2013.jamadermatol.376
3.
AlpsoyEAkman-KarakasAUzunS.Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid. Arch Dermatol Res. 2015;307(4):291-298. doi:10.1007/s00403-014-1531-1
4.
FörstiAKJokelainenJTimonenMTasanenK.Increasing incidence of bullous pemphigoid in Northern Finland: a retrospective database study in Oulu University Hospital. Br J Dermatol. 2014;171(5):1223-1226. doi:10.1111/bjd.13189
5.
BernardPVaillantLLabeilleB, et al. Incidence and distribution of subepidermal autoimmune bullous skin diseases in three French regions. Bullous Diseases French Study Group. Arch Dermatol. 1995;131(1):48-52.
6.
JolyPBaricaultSSparsaA, et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol. 2012;132(8):1998-2004. doi:10.1038/jid.2012.35
7.
NishieW.Update on the pathogenesis of bullous pemphigoid: an autoantibody-mediated blistering disease targeting collagen XVII. J Dermatol Sci. 2014;73:179-186. doi:10.1016/j.jdermsci.2013.12.001
8.
ZillikensDMascaroJMRosePA, et al. A highly sensitive enzyme-linked immunosorbent assay for the detection of circulating anti-BP180 autoantibodies in patients with bullous pemphigoid. J Invest Dermatol. 1997;109(5):679-683. doi:10.1111/1523-1747. ep123 38088
UjiieH.IgE autoantibodies in bullous pemphigoid: supporting role, or leading player?J Dermatol Sci. 2015;78:5-10. doi:10.1016/j.jdermsci.2015.03.002
11.
LopezATKhannaTAntonovNAudrey-BayanCGeskinL.A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol. 2018;57(6):664-669. doi:10.1111/ijd.13984
12.
TasanenKVarpuluomaONishieW.Dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid. Front Immunol. 2019;10:1238. doi:10.3389/fimmu.2019.01238
13.
American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S111-S124. doi:10.2337/dc21-S009
14.
SharmaMNazarethIPetersenI.Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between 2000 and 2013 in primary care: a retrospective cohort study. BMJ Open. 2016;6(1):e010210. doi:10.1136/bmjopen-2015-010210
15.
ScheenAJ.The safety of gliptins: updated data in 2018. Expert Opin Drug Saf. 2018;17(4):387-405. doi:10.1080/14740338.2018.1444027
16.
TsengCMLiaoWCChangCY, et al. Incretin-based pharmacotherapy and risk of adverse pancreatic events in the ethnic Chinese with diabetes mellitus: a population-based study in Taiwan. Pancreatology. 2017;17(1):76-82. doi:10.1016/j.pan.2016.10.003.
17.
PasmatziEMonastirliAHabeosJGeorgiouSTsambaosD.Dipeptidyl peptidase-4 inhibitors cause bullous pemphigoid in diabetic patients: report of two cases. Diabetes Care. 2011;34(8):e133. doi:10.2337/dc11-0804
18.
PlaqueventMTétartFFardetL, et al. French Investigators for Skin Adverse Reaction to Drugs; French Study Group on Autoimmune Bullous Skin Diseases. Higher frequency of dipeptidyl peptidase-4 inhibitor intake in bullous pemphigoid patients than in the French general population. J Invest Dermatol. 2019;139(4):835-841. doi:10.1016/j.jid.2018.10.045
19.
BenzaquenMBorradoriLBerbisP, et al. Dipeptidyl peptidase IV inhibitors, a risk factor for bullous pemphigoid: retrospective multicenter case-control study from France and Switzerland. J Am Acad Dermatol. 2018;78(6):1090-1096. doi:10.1016/j.jaad.2017.12.038
20.
VarpuluomaOFörstiAKJokelainenJ, et al. Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study. J Invest Dermatol. 2018;138(7):1659-1661. doi:10.1016/j.jid.2018.01.027
21.
SilveriiGADicembriniINreuBMontereggiCMannucciEMonamiM.Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized controlled trials. Endocrine. 2020;69(3):504-507. doi:10.1007/s12020-020-02272-x
22.
PhanKCharltonOSmithSD.Dipeptidyl peptidase-4 inhibitors and bullous pemphigoid: a systematic review and adjusted meta-analysis. Aust J Dermatol. 2020;61(1):e15-e21. doi:10.1111/ajd.13100
23.
KuwataHNishiokaYNodaT, et al. Association between dipeptidyl peptidase-4 inhibitors and increased risk for bullous pemphigoid within 3 months from first use: a 5-year population-based cohort study using the Japanese National Database. J Diabetes Investig. 2022;13(3):460-467. doi:10.1111/jdi.13676
24.
LambadiariVKountouriAKousathanaF, et al. The association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors: a ten-year prospective observational study. BMC Endocr Disord. 2021;21(1):23. doi:10.1186/s12902-021-00689-7
25.
LeeSGLeeHJYoonMSKimDH.Association of dipeptidyl peptidase 4 inhibitor use with risk of bullous pemphigoid in patients with diabetes. JAMA Dermatol. 2019;155(2):172-177. doi:10.1001/jamadermatol.2018.4556
26.
HungCTLiuJSChengCY, et al. Increased risk of bullous pemphigoid in dipeptidyl peptidase 4 inhibitors: a nationwide, population-based, cohort study in Taiwan. J Dermatol. 2020;47(3):245-250. doi:10.1111/1346-8138.15195
27.
ReolidAMuñoz-AceitunoERodríguez-JiménezP, et al. Bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors. A case series and analysis of cases reported in the Spanish pharmacovigilance database. Int J Dermatol. 2020;59(2):197-206. doi:10.1111/ijd.14658
28.
GarcíaMAranburuMAPalacios-ZabalzaILertxundiUAguirreC.Dipeptidyl peptidase-IV inhibitors induced bullous pemphigoid: a case report and analysis of cases reported in the European pharmacovigilance database. J Clin Pharm Ther. 2016;41(3):368-370. doi:10.1111/jcpt.12397
29.
JhaAMisraAGuptaR, et al. Dipeptidyl peptidase 4 inhibitors linked bullous pemphigoid in patients with type 2 diabetes mellitus: a series of 13 cases. Diabetes Metab Syndr. 2020;14(3):213-216. doi:10.1016/j.dsx.2020.03.001
30.
RoyASahooJNarayananNMeruguCKamalanathanSNaikD.Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: current evidence. World J Diabetes. 2021;12(9):1426-1441. doi:10.4239/wjd.v12.i9.1426
31.
SunLWangCWuCZhouYWangC.Analysis of the clinical characteristics of dipeptidyl peptidase-4 inhibitor-induced bullous pemphigoid. Ann Pharmacother. 2022;56(2):205-212. doi:10.1177/10600280211022722
32.
KridinKBergmanR.Association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors in patients with diabetes: estimating the risk of the new agents and characterizing the patients. JAMA Dermatol. 2018;154(10):1152-1158. doi:10.1001/jamadermatol.2018.2352.
33.
BénéJMoulisGBennaniI, et al. French Association of Regional PharmacoVigilance Centres. Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case-noncase study in the French pharmacovigilance database. Br J Dermatol. 2016;175:296-301.
34.
ChouchaneK.Di ZenzoG.PitoccoD. Bullous pemphigoid in diabetic patients treated by gliptins: the other side of the coin. J Transl Med. 2021;19:520. doi:10.1186/s12967-021-03192-8
35.
IzumiKNishieWMaiY, et al. Autoantibody profile differentiates between inflammatory and noninflammatory bullous pemphigoid. J Invest Dermatol. 2016;136:2201-2210.
36.
ChijiwaCTakeokaSKamataM, et al. Decrease in eosinophils infiltrating into the skin of patients with dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid. J Dermatol. 2018;45:596-599. doi:10.1111/1346-8138.14245
37.
SawadaKSawadaTKobayashiT, et al. A case of anti-BP230 antibody-positive bullous pemphigoid receiving DPP-4 inhibitor. Immunol Med. 2021;44(1):53-55. doi:10.1080/25785826.2020.1787584
38.
UjiieHMuramatsuKMushirodaT, 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(5):1201-1204. doi:10.1016/j.jid.2017.11.023
39.
OhnumaKDangNHMorimotoC.Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function. Trends Immunol. 2008;29(6):295-301. doi:10.1016/j.it.2008.02.010
40.
ShaoSXuQYuXPanRChenY.Dipeptidyl peptidase 4 inhibitors and their potential immune modulatory functions. Pharmacol Ther. 2020;209:107503. doi:10.1016/j.pharmthera.2020.107503
41.
HofmannSCVoithUSchönauVSorokinLBruckner-TudermanLFranzkeC.Plasmin plays a role in the in vitro generation of the linear IgA dermatosis antigen LADB97. J Invest Dermatol. 2009;129:1730-1739. doi:10.1038/jid.2008.424
42.
MathiasRAWangBJiHKappEAMoritzRLZhuH.Secretome-based proteomic profiling of ras-transformed MDCK cells reveals extracellular modulators of epithelial-mesenchymal transition. J Proteome Res. 2009;8:2827-2837. doi:10.1021/pr8010974
43.
FaniaLSalemmeAProviniAPagnanelliGCollinaMCAbeniD.Detection and characterization of IgG, IgE, and IgA autoantibodies in patients with bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors. J Am Acad Dermatol. 2018;78:592-595. doi:10.1016/j.jaad.2017.09.051
