Advertisement

Immunologic Research

, Volume 66, Issue 3, pp 425–430 | Cite as

Is there an association between dipeptidyl peptidase-4 inhibitors and autoimmune disease? A population-based study

  • Khalaf Kridin
  • Kyle Amber
  • Mogher Khamaisi
  • Doron Comaneshter
  • Erez Batat
  • Arnon D. Cohen
Original Article

Abstract

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.

Keywords

Autoimmune diseases Dipeptidyl peptidase-4 inhibitors Psoriasis Crohn’s disease Hashimoto’s thyroiditis 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet [Internet]. 2006;368:1696–705. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17098089 CrossRefGoogle Scholar
  2. 2.
    Ohnuma K, Hosono O, Dang NH, Morimoto C. Dipeptidyl peptidase in autoimmune pathophysiology. Adv Clin Chem. 2011;53:51–84.CrossRefPubMedGoogle Scholar
  3. 3.
    Sedo A, Duke-Cohan JS, Balaziova E, Sedova LR. Dipeptidyl peptidase IV activity and/or structure homologs: contributing factors in the pathogenesis of rheumatoid arthritis? Arthritis Res Ther. 2005;7:253–69.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yazbeck R, Howarth GS, Abbott CA. Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? Trends Pharmacol Sci. 2009;30:600–7.CrossRefPubMedGoogle Scholar
  5. 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. 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
  7. 7.
    Salgado FJ, Pérez-Díaz A, Villanueva NM, Lamas O, Arias P, Nogueira M. CD26: a negative selection marker for human Treg cells. Cytom Part A. 2012;81 A:843–55.CrossRefGoogle Scholar
  8. 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. 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
  10. 10.
    Hildebrandt M, Rose M, Rüter J, Salama A, Mönnikes H, Klapp BF. Dipeptidyl peptidase IV (DP IV, CD26) in patients with inflammatory bowel disease. Scand J Gastroenterol. 2001;36:1067–72.CrossRefPubMedGoogle Scholar
  11. 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
  12. 12.
    Liu Y, Li Y, Gong Y, Yu N, Zhang Y, You R, et al. CD26 expression is down-regulated on CD8+T cells in patients with Hashimoto’s thyroiditis. Int Immunopharmacol. 2018;54:280–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Bock O, Kreiselmeyer I, Mrowietz U. Expression of dipeptidyl-peptidase IV (CD26) on CD8+ T cells is significantly decreased in patients with psoriasis vulgaris and atopic dermatitis. Exp Dermatol. 2001;10:414–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Van Lingen RG, Van De Kerkhof PCM, Seyger MMB, De Jong EMGJ, Van Rens DWA, Poll MKP, et al. CD26/dipeptidyl-peptidase IV in psoriatic skin: upregulation and topographical changes. Br J Dermatol. 2008;158:1264–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Novelli M, Savoia P, Fierro MT, Verrone A, Quaglino P, Bernengo MG. Keratinocytes express dipeptidyl-peptidase IV (CD26) in benign and malignant skin diseases. Br J Dermatol. 1996;134(6):1052–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Steinbrecher a RD, Quigley L, Gado a TN, Izikson L, et al. Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo. J Immunol. 2001;166:2041–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Gerli R, Muscat C, Bertotto A, Bistoni O, Agea E, Tognellini R, et al. CD26 surface molecule involvement in T cell activation and lymphokine synthesis in rheumatoid and other inflammatory synovitis. Clin Immunol Immunopathol. 1996;80:31–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Khoury SJ, Guttmann CR, Orav EJ, Kikinis R, Jolesz FA, Weiner HL. Changes in activated T cells in the blood correlate with disease activity in multiple sclerosis. Arch Neurol. 2000;57:1183–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Tanaka S, Murakami T, Horikawa H, Sugiura M, Kawashima K, Sugita T. Suppression of arthritis by the inhibitors of dipeptidyl peptidase IV. Int J Immunopharmacol. 1997;19:15–24.CrossRefPubMedGoogle Scholar
  20. 20.
    Tanaka S, Murakami T, Nonaka N, Ohnuki T, Yamada M, Sugita T. Anti-arthritic effects of the novel dipeptidyl peptidase IV inhibitors TMC-2A and TSL-225. Immunopharmacology. 1998;40:21–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Williams YN, Baba H, Hayashi S, Ikai H, Sugita T, Tanaka S, et al. Dipeptidyl peptidase IV on activated T cells as a target molecule for therapy of rheumatoid arthritis. Clin Exp Immunol. 2003;131:68–74.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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.
  23. 23.
    Crickx E, Marroun I, Veyrie C, Le Beller C, Schoindre Y, Bouilloud F, et al. DPP4 inhibitor-induced polyarthritis: a report of three cases. Rheumatol Int. 2014;34:291–2.CrossRefPubMedGoogle Scholar
  24. 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. 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. 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
  27. 27.
    Béné J, Moulis G, Bennani I, Auffret M, Coupe P, Babai S, et al. Bullous pemphigoid and dipeptidyl peptidase IV inhibitors: a case–noncase study in the French pharmacovigilance database. Br J Dermatol. 2016;175:296–301.CrossRefPubMedGoogle Scholar
  28. 28.
    Amber KT, Zikry J, Hertl M. A multi-hit hypothesis of bullous pemphigoid and associated neurological disease: is HLA-DQB1*03:01 a potential link between immune privileged antigen exposure and epitope spreading? HLA. 2017;89:127–34.CrossRefPubMedGoogle Scholar
  29. 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.
  30. 30.
    Lai Y, Yew Y, Lambert W. Bullous pemphigoid and its association with neurological diseases: a systematic review and meta-analysis. J Eur Acad Dermatology Venereol [Internet]. 2016;30:2007–15.  https://doi.org/10.1111/jdv.13660.CrossRefGoogle Scholar
  31. 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. 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.
  33. 33.
    Parameswaran A, Attwood K, Sato R, Seiffert-Sinha K, Sinha AA. Identification of a new disease cluster of pemphigus vulgaris with autoimmune thyroid disease, rheumatoid arthritis and type I diabetes. Br J Dermatol. 2015;172:729–38.CrossRefPubMedGoogle Scholar
  34. 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
  35. 35.
    Barcellos LF, Kamdar BB, Ramsay PP, DeLoa C, Lincoln RR, Caillier S, et al. Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study. Lancet Neurol. 2006;5:924–31.CrossRefPubMedGoogle Scholar
  36. 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. 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. 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
  39. 39.
    Birkenfeld S, Dreiher J, Weitzman D, Cohen AD. Coeliac disease associated with psoriasis. Br J Dermatol [Internet]. 2009;161:1331–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19785615.CrossRefGoogle Scholar
  40. 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
  41. 41.
    Alter M, Kahana E, Zilber N, Miller A. Multiple sclerosis frequency in Israel’s diverse populations. Neurology. 2006;66:1061–6.CrossRefPubMedGoogle Scholar
  42. 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

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of DermatologyRambam Health Care CampusHaifaIsrael
  2. 2.Department of DermatologyUniversity of CaliforniaIrvineUSA
  3. 3.Internal Medicine D and Institute of Endocrinology, Diabetes and MetabolismRambam Health Care CampusHaifaIsrael
  4. 4.Rappaport Faculty of MedicineTechnion-Israel Institute of TechnologyHaifaIsrael
  5. 5.Department of Quality Measurements and Research, Chief Physician’s OfficeClalit Health ServicesTel AvivIsrael
  6. 6.Siaal Research Center for Family Medicine and Primary Care, Faculty of Health SciencesBen-Gurion University of the NegevBeer-ShevaIsrael

Personalised recommendations