Is there an association between dipeptidyl peptidase-4 inhibitors and autoimmune disease? A population-based study
The association of dipeptidyl peptidase-4 inhibitors (DPP4is) with autoimmune diseases is controversial. While these agents were proposed as a novel therapeutic approach for several inflammatory diseases by blocking T cell proliferation and cytokine production, they were found to trigger inflammatroy bowel disease, inflammatory arthritis and bullous pemphigoid. Our objective is to examine the association between DPP4i and autoimmune diseases. This study was conducted as a cross-sectional study utilizing the database of Clalit Health Services. The prevalence of 15 autoimmune-/immune-mediated diseases was compared between patients on DPP4i treatment and age-, sex-, and ethnicity-matched controls. Univariate analysis was performed using chi-square and the Student t test and multivariate analysis was performed using a logistic regression model. The study included 283 patients treated with DPP4i agents and 5660 age-, sex-, and ethnicity-matched diabetic control subjects. The prevalence of Crohn’s disease (1.1 vs. 0.3%; odds ratios (OR), 3.56; 95% CI, 1.04–12.21, P = 0.031), psoriasis (2.5 vs. 1.2%; OR, 2.12; 95% CI, 0.99–4.66; P = 0.050), and Hashimoto’s thyroiditis (16.6 vs. 12.6%; OR, 1.38; 95% CI, 1.00–1.91; P = 0.049) was significantly higher in patients on DPP4i treatment than in controls. The prevalence of the remaining autoimmune diseases did not differ significantly between DPP4i-treated patients and their matched control subjects. In conclusion, this population-based study demonstrates an association of DPP4i intake with three autoimmune and inflammatory diseases noted to be part of a distinct autoimmune cluster that includes multiple sclerosis, psoriasis, thyroiditis, bullous pemphigoid, and inflammatory bowel disease. Experimental studies are required to define the role of DPP4i in this autoimmune cluster.
KeywordsAutoimmune diseases Dipeptidyl peptidase-4 inhibitors Psoriasis Crohn’s disease Hashimoto’s thyroiditis
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 5.Kim SC, Schneeweiss S, Glynn RJ, Doherty M, Goldfine AB, Solomon DH. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study. Ann Rheum Dis [Internet]. 2014:1–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24919467
- 6.Hatano R, Ohnuma K, Otsuka H, Komiya E, Taki I, Iwata S, et al. CD26-mediated induction of EGR2 and IL-10 as potential regulatory mechanism for CD26 costimulatory pathway. J. Immunol. [Internet]. 2015;194:960–72. Available from: http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.1402143 CrossRefGoogle Scholar
- 8.Ohnuma K, Takahashi N, Yamochi T, Hosono O, Dang NH, Morimoto C. Role of CD26/dipeptidyl peptidase IV in human T cell activation and function. Front Biosci [Internet]. 2008;13:2299–310. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17981712 CrossRefGoogle Scholar
- 9.Kamori M, Hagihara M, Nagatsu T, Iwata H, Miura T. Activities of dipeptidyl peptidase II, dipeptidyl peptidase IV, prolyl endopeptidase, and collagenase-like peptidase in synovial membrane from patients with rheumatoid arthritis and osteoarthritis. Biochem Med Metab Biol. 1991;45:154–60.CrossRefPubMedGoogle Scholar
- 11.Wong PT, Wong CK, Tam LS, Li EK, Chen DP, Lam CW. Decreased expression of T lymphocyte co-stimulatory molecule CD26 on invariant natural killer T cells in systemic lupus erythematosus. Immunol Invest [Internet]. 2009;38:350–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19811413 CrossRefGoogle Scholar
- 22.Abrahami D, Douros A, Yin H, Yu OHY, Renoux C, Bitton A, et al. Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study. BMJ 2018;360:k872. https://doi.org/10.1136/bmj.k872.
- 24.Benzaquen M, Borradori L, Berbis P, Cazzaniga S, Valero R, Richard M-A, 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. [Internet]. 2017 [cited 2018 Mar 4]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/29274348.
- 25.Varpuluoma O, Försti A-K, Jokelainen J, Turpeinen M, Timonen M, Huilaja L, et al. Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study. J. Invest. Dermatol. [Internet]. 2018 [cited 2018 Mar 4]; Available from: http://linkinghub.elsevier.com/retrieve/pii/S0022202X18301106.
- 26.García M, Aranburu MA, Palacios-Zabalza I, Lertxundi U, Aguirre C. Dipeptidyl peptidase-IV inhibitors induced bullous pemphigoid: a case report and analysis of cases reported in the European pharmacovigilance database. J Clin Pharm Ther [Internet]. 2016 [cited 2018 Mar 4];41:368–70. https://doi.org/10.1111/jcpt.12397.CrossRefGoogle Scholar
- 29.Langan SM, Groves RW, West J. The relationship between neurological disease and bullous pemphigoid: a population-based case–control study. J. Invest. Dermatol. [Internet]. 2011 [cited 2017 Apr 12];131:631–6. Available from: https://ssl.haifa.ac.il/S0022202X1535168X/,DanaInfo=.aadBhpxEjlwJn0z+1-s2.0-S0022202X1535168X-main.pdf?_tid=5741f888-1fba-11e7-9d4a-00000aacb35d&acdnat=1492027264_73a4c4a69deff5b79e40b60b1a422781.
- 31.Kridin K, Bergman R. Association between bullous pemphigoid and psoriasis: a case-control study. J Am Acad Dermatol [Internet]. 2017 [cited 2017 Sep 11];77:370–2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28711088.
- 32.Tsai T-F, Wang T-S, Hung S-T, Tsai PI-C, Schenkel B, Zhang M et al. Epidemiology and comorbidities of psoriasis patients in a national database in Taiwan. J Dermatol Sci [Internet]. Elsevier; 2011 [cited 2017 Feb 12];63:40–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21543188.
- 34.Marrie RA, Reider N, Cohen J, Stuve O, Sorensen PS, Cutter G, et al. A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis. Mult Scler [Internet]. 2015;21:282–93. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4429166&tool=pmcentrez&rendertype=abstract.CrossRefGoogle Scholar
- 36.Försti A-K, Jokelainen J, Ansakorpi H, Seppänen A, Majamaa K, Timonen M et al. Psychiatric and neurological disorders are associated with bullous pemphigoid—a nationwide Finnish Care Register study. Sci Rep [Internet]. Nature Publishing Group; 2016 [cited 2017 Apr 30];6:37125. Available from: http://www.nature.com/articles/srep37125
- 37.Kibsgaard L, Rasmussen M, Lamberg A, Deleuran M, Olesen AB, Vestergaard C. Increased frequency of multiple sclerosis among patients with bullous pemphigoid: a population-based cohort study on comorbidities anchored around the diagnosis of bullous pemphigoid. Br J Dermatol [Internet]. 2017;176:1486–91. Available from: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85017555039&doi=10.1111%2Fbjd.15405&partnerID=40&md5=f412b86e22d293226e185490c8462fc2 CrossRefGoogle Scholar
- 38.Rennert G, Peterburg Y. Prevalence of selected chronic diseases in Israel. Isr. Med. Assoc. J. [Internet]. 2001 [cited 2017 Jan 30];3:404–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11433630
- 40.Pearce N. Analysis of matched case-control studies. BMJ [Internet]. 2016;352:i969. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26916049%5Cn http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4770817 CrossRefGoogle Scholar
- 42.Höfler M. The Bradford Hill considerations on causality: a counterfactual perspective. Emerg Themes Epidemiol [Internet]. 2005;2:11. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1291382&tool=pmcentrez&rendertype=abstract CrossRefGoogle Scholar