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Dipeptidyl Peptidase (DPP)-4 Inhibitor-Induced Arthritis/Arthralgia: A Review of Clinical Cases

Abstract

Dipeptidyl peptidase (DPP)-4 inhibitors are a class of oral drugs used for the treatment of type 2 diabetes mellitus (T2DM). The pharmacological inhibition of DPP-4 seems to also induce adverse events related to cytokine-induced inflammation. Recently, several clinical cases regarding the association of DPP-4 inhibitors and the onset of arthritis/arthralgia have been reported in the literature. Various mechanisms could be responsible for DPP-4 inhibitor-induced arthritis/arthralgia, and the increase of cytokines, chemokines, matrix metalloproteinases (MMPs) and genetic factors plays an important role. The US FDA published a safety announcement regarding the entire drug class, encouraging healthcare professionals and patients to pay attention to the occurrence of arthralgia during treatment with DPP-4 inhibitors; arthralgia could be assessed as a class adverse drug event for DPP-4 inhibitors. To summarize the evidence on the correlation between DPP-4 inhibitors and arthritis/arthralgia, and to explain the measures taken by the FDA with regard to arthralgia risk, we performed a literature review of recent evidence concerning this association. This review shows the necessity of other studies to better define the association between DPP-4 inhibitors and arthritis/arthralgia.

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References

  1. Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes. 1998;47:1663–70.

    CAS  Article  PubMed  Google Scholar 

  2. Deacon CF. Circulation and degradation of GIP and GLP-1. Horm Metab Res. 2004;36:761–5.

    CAS  Article  PubMed  Google Scholar 

  3. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52.

    CAS  Article  PubMed  Google Scholar 

  4. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–65.

    CAS  Article  PubMed  Google Scholar 

  5. Vilsboll T, Holst JJ. Incretins, insulin secretion and type-2 diabetes mellitus. Diabetologia. 2004;47:357–66.

    CAS  Article  PubMed  Google Scholar 

  6. Ahrén B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab. 2007;21:517–33.

    Article  PubMed  Google Scholar 

  7. Drucker DJ. Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanism of action. Diabetes Care. 2007;30:1335–43.

    CAS  Article  PubMed  Google Scholar 

  8. Busso N, Wagtmann N, Herling C, Chobaz-Péclat V, Bischof-Delaloye A, So A, et al. Circulating CD26 is negatively associated with inflammation in human and experimental arthritis. Am J Pathol. 2005;166:433–42.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord. 2010;10:7.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sasaki T, Hiki Y, Nagumo S, Ikeda R, Kimura H, Yamashiro K, et al. Acute onset of rheumatoid arthritis associated with administration of a dipeptidyl peptidase-4 (DPP4) inhibitor to patients with diabetes mellitus. Diabetol Int. 2010;1:90–2.

    Article  Google Scholar 

  11. Chaicha-Brom T, Yasmeen T. DPP-IV inhibitor-associated arthralgias. Endocr Pract. 2013;19:377.

    Article  PubMed  Google Scholar 

  12. Yokota K, Igaki N. Sitagliptin (DPP-4 inhibitor)-induced rheumatoid arthritis in type 2 diabetes mellitus: a case report. Intern Med. 2012;51:2041–4.

    CAS  Article  PubMed  Google Scholar 

  13. 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.

    Article  PubMed  Google Scholar 

  14. Yamauchi K, Sato Y, Yamahita K, Funase Y, Kaneko T, Hashimoto T, et al. RS3PE in association with dipeptidyl peptidase-4 inhibitor: report of two cases. Diabetes Care. 2012;35:e7.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Saito T, Ohnuma K, Suzuki H, Dang NH, Hatano R, Ninomiyae H, et al. Polyarthropathy in type 2 diabetes patients treated with DPP4 inhibitors. Diabetes Res Clin Pract. 2013;102:e8–12.

    CAS  Article  PubMed  Google Scholar 

  16. US Food and Drug Administration. FDA drug safety communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. 2015. http://www.fda.gov/Drugs/DrugSafety/ucm459579.htm. Accessed 31 Sep 2015.

  17. Schnyder B. Approach to the patient with drug allergy. Med Clin N Am. 2010;94:665–79.

    Article  PubMed  Google Scholar 

  18. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29:2632–7.

    CAS  Article  PubMed  Google Scholar 

  19. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP, Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205.

    CAS  Article  PubMed  Google Scholar 

  20. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49:2564–71.

    CAS  Article  PubMed  Google Scholar 

  21. Ospelt C, Mertens JC, Jungel A, Brentano F, Maciejewska-Rodriguez H, Huber LC, et al. Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage invasion by rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2010;62:1224–35.

    CAS  Article  PubMed  Google Scholar 

  22. 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.

    CAS  Article  PubMed  Google Scholar 

  23. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. 1996;184:1101–9.

    CAS  Article  PubMed  Google Scholar 

  24. Yan S, Marguet D, Dobers J, Reutter W, Fan H. Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen. Eur J Immunol. 2003;33:1519–27.

    CAS  Article  PubMed  Google Scholar 

  25. Muscat C, Bertotto A, Agea E, Bistoni O, Ercolani R, Tognellini R, et al. Expression and functional role of 1F7 (CD26) antigen on peripheral blood and synovial fluid T cells in rheumatoid arthritis patients. Clin Exp Immunol. 1994;98:252–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Cordero OJ, Salgado FJ, Mera-Varela A, Nogueira M. Serum interleukin-12, interleukin-15, soluble CD26, and adenosine deaminase in patients with rheumatoid arthritis. Rheumatol Int. 2001;21:69–74.

    CAS  Article  PubMed  Google Scholar 

  27. Cuchacovich M, Gatica H, Pizzo SV, Gonzalez-Gronow M. Characterization of human serum dipeptidyl peptidase IV (CD26) and analysis of its autoantibodies in patients with rheumatoid arthritis and other autoimmune diseases. Clin Exp Rheumatol. 2002;19:673–80.

    Google Scholar 

  28. Konig A, Krenn V, Toksoy A, Gerhard N, Gillitzer R. Mig, GRO alpha and RANTES messenger RNA expression in lining layer, infiltrates and different leucocyte populations of synovial tissue from patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Virchows Arch. 2000;436:449–58.

    CAS  Article  PubMed  Google Scholar 

  29. Loetscher P, Moser B. Homing chemokines in rheumatoid arthritis. Arthritis Res. 2002;4:233–6.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. van der Helm-van Mil AH, Huizinga TW. Advances in the genetics of rheumatoid arthritis point to subclassification into distinct disease subsets. Arthritis Res Ther. 2008;10:205.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Huizinga TW, Amos CI, van der Helm-van Mil AH, Chen W, van Gaalen FA, Jawaheer D, et al. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 2005;52:3433–8.

    CAS  Article  PubMed  Google Scholar 

  33. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga TW, Toes RE, de Vries RR. The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum. 2006;54:1117–21.

    Article  PubMed  Google Scholar 

  34. Balsa A, Cabezón A, Orozco G, Cobo T, Miranda-Carus E, López-Nevot MA, et al. Influence of HLA DRB1 alleles in the susceptibility of rheumatoid arthritis and the regulation of antibodies against citrullinated proteins and rheumatoid factor. Arthritis Res Ther. 2010;12:R62.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Irigoyen P, Lee AT, Wener MH, Li W, Kern M, Batliwalla F, et al. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLADR3 and the shared epitope alleles. Arthritis Rheum. 2005;52:3813–8.

    CAS  Article  PubMed  Google Scholar 

  36. Verpoort KN, van Gaalen FA, van der Helm-van Mil AH, Schreuder GM, Breedveld FC, Huizinga TW, et al. Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis. Arthritis Rheum. 2005;52:3058–62.

    CAS  Article  PubMed  Google Scholar 

  37. Louati K, Vidal C, Berenbaum F, Sellam J. Association between diabetes mellitus and osteoarthritis: systematic literature review and meta-analysis. RMD Open. 2015;1:e000077.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Lu MC, Yan ST, Yin WY, Koo M, Lai NS. Risk of rheumatoid arthritis in patients with type 2 diabetes: a nationwide population-based case-control study. PLoS One. 2014;9:e101528.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Aroor AR, McKarns S, Demarco VG, Jia G, Sowers JR. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metabolism. 2013;62:1543–52.

    CAS  Article  PubMed  Google Scholar 

  40. Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab. 2009;94:3171–82.

    CAS  Article  PubMed  Google Scholar 

  41. Solomon DH, Love TJ, Canning C, Schneeweiss S. Risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis and psoriasis. Ann Rheum Dis. 2010;69:2114–7.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dubreuil M, Rho YH, Man A, Zhu Y, Zhang Y, Love TJ, et al. Diabetes incidence in psoriatic arthritis, psoriasis and rheumatoid arthritis: a UK population-based cohort study. Rheumatology (Oxford). 2014;53:346–52.

    CAS  Article  Google Scholar 

  43. Hemminki K, Liu X, Försti A, Sundquist J, Sundquist K, Ji J. Subsequent type 2 diabetes in patients with autoimmune disease. Sci Rep. 2015;5:13871.

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Annamaria Mascolo.

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No sources of funding were used to assist in the preparation of this review.

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Annamaria Mascolo, Concetta Rafaniello, Liberata Sportiello, Maurizio Sessa, Daniela Cimmaruta, Francesco Rossi and Annalisa Capuano declare no conflicts of interest.

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A. Mascolo and C. Rafaniello equally contributed to the manuscript.

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Mascolo, A., Rafaniello, C., Sportiello, L. et al. Dipeptidyl Peptidase (DPP)-4 Inhibitor-Induced Arthritis/Arthralgia: A Review of Clinical Cases. Drug Saf 39, 401–407 (2016). https://doi.org/10.1007/s40264-016-0399-8

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  • DOI: https://doi.org/10.1007/s40264-016-0399-8

Keywords

  • Rheumatoid Arthritis
  • Sitagliptin
  • Vildagliptin
  • Saxagliptin
  • Nateglinide