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Drug Safety

, Volume 39, Issue 3, pp 199–208 | Cite as

Hepatotoxicity Associated with the Use of Anti-TNF-α Agents

  • Joshua B. French
  • Maurizio Bonacini
  • Marwan Ghabril
  • David Foureau
  • Herbert L. Bonkovsky
Review Article

Abstract

Medications to inhibit the actions of tumour necrosis factor alpha have revolutionized the treatment of several pro-inflammatory autoimmune conditions. Despite their many benefits, several serious side effects exist and adverse reactions do occur from these medications. While many of the medications’ potential adverse effects were anticipated and recognized in clinical trials prior to drug approval, several more rare adverse reactions were recorded in the literature as the popularity, availability and distribution of these medications grew. Of these potential adverse reactions, liver injury, although uncommon, has been observed in some patients. As case reports accrued over time and ultimately case series developed, the link became better established between this family of medicines and various patterns of liver injury. Interestingly, it appears that the majority of cases exhibit an autoimmune hepatitis profile both in serological markers of autoimmune liver disease and in classic autoimmune features seen on hepatic histopathology. Despite the growing evidence of this relationship, the pathogenesis of this reaction remains incompletely understood, but it appears to depend on characteristics of the medications and the genetic composition of the patients; it is likely more complicated than a simple medication class effect. Because of this still incomplete understanding and the infrequency of the occurrence, treatments have also been limited, although it is clear that most patients improve with cessation of the offending agent and, in certain cases, glucocorticoid use. However, more needs to be done in the future to unveil the underlying mechanisms of this adverse reaction.

Keywords

Infliximab Liver Injury Etanercept Adalimumab Primary Sclerosing Cholangitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with Ethical Standards

Funding

This work was supported by U01 cooperative agreements between the National Institutes of Health/National Institute for Diabetes and Digestive and Kidney Diseases and the University of North Carolina Chapel Hill/Wake Forest University Health Sciences (DK065201) and Indiana University (DK065211); by a U54 award from the National Institutes of Health/National Institute for Diabetes and Digestive and Kidney Diseases (DK083909) to Wake Forest [HLB, PI]; and by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute (R15 HL117199) to HLB.

Conflicts of interest

The authors (Joshua B. French, Maurizio Bonacini, Marwan Ghabril, David Foureau and Herbert L. Bonkovsky) have no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA. 1975;72(9):3666–70.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Dayer JM. The saga of the discovery of IL-1 and TNF and their specific inhibitors in the pathogenesis and treatment of rheumatoid arthritis. Joint Bone Spine. 2002;69(2):123–32.CrossRefPubMedGoogle Scholar
  3. 3.
    Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214(2):149–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2012;119(3):651–65.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med. 1997;337(15):1029–35.CrossRefPubMedGoogle Scholar
  6. 6.
  7. 7.
  8. 8.
    Ghabril M, Bonkovsky HL, Kum C, Davern T, Hayashi PH, Kleiner DE, et al. Liver injury from tumor necrosis factor-alpha antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol. 2013;11(5):558–64.e3.Google Scholar
  9. 9.
    Carroll MB, Bond MI. Use of tumor necrosis factor-alpha inhibitors in patients with chronic hepatitis B infection. Semin Arthritis Rheum. 2008;38(3):208–17.CrossRefPubMedGoogle Scholar
  10. 10.
    Nathan DM, Angus PW, Gibson PR. Hepatitis B and C virus infections and anti-tumor necrosis factor-alpha therapy: guidelines for clinical approach. J Gastroenterol Hepatol. 2006;21(9):1366–71.CrossRefPubMedGoogle Scholar
  11. 11.
    Garcia Aparicio AM, Rey JR, Sanz AH, Alvarez JS. Successful treatment with etanercept in a patient with hepatotoxicity closely related to infliximab. Clin Rheumatol. 2007;26(5):811–3.CrossRefPubMedGoogle Scholar
  12. 12.
    Thiefin G, Morelet A, Heurgue A, Diebold MD, Eschard JP. Infliximab-induced hepatitis: absence of cross-toxicity with etanercept. Joint Bone Spine. 2008;75(6):737–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Humira (adalimumab). 2015. http://www.rxabbvie.com/pdf/humira.pdf. Accessed 15 Oct 2015.
  14. 14.
    Enbrel (etanercept). 2013. http://pi.amgen.com/united_states/enbrel/derm/enbrel_pi.pdf. Accessed 15 Oct 2015.
  15. 15.
    Remicade (infliximab). 2015. http://www.remicade.com/shared/product/remicade/prescribing-information.pdf. Accessed 15 Oct 2015.
  16. 16.
    Simponi (golimumab). 2013. http://www.simponi.com/shared/product/simponi/prescribing-information.pdf. Accessed 15 Oct 2015.
  17. 17.
    Cimzia (certolizumab). 2013. http://www.cimzia.com/assets/pdf/Prescribing_Information.pdf. Accessed 15 Oct 2015.
  18. 18.
    Feuerstein JD, Cheifetz AS. Miscellaneous adverse events with biologic agents (excludes infection and malignancy). Gastroenterol Clin North Am. 2014;43(3):543–63.CrossRefPubMedGoogle Scholar
  19. 19.
    Ribeiro LB, Rego JC, Estrada BD, Bastos PR, Pineiro Maceira JM, Sodre CT. Alopecia secondary to anti-tumor necrosis factor-alpha therapy. An Bras Dermatol. 2015;90(2):232–5.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Tong Q, Cai Q, de Mooij T, Xu X, Dai S, Qu W, et al. Adverse events of anti-tumor necrosis factor alpha therapy in ankylosing spondylitis. PLoS One. 2015;10(3):e0119897.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Bonacini M, Ghabril M, Bonkovsky HL. Hepatotoxicity of anti-TNF agents. Dig Dis Sci. 2014;59(5):1070–1.CrossRefPubMedGoogle Scholar
  22. 22.
    US Food and Drug Administration [FDA] Center for Drug Evaluation and Research. FDA briefing document. Arthritis Advisory Committee. FDA. 2003. http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3930T1.htm. Accessed 15 Oct 2015
  23. 23.
    Mancini S, Amorotti E, Vecchio S, Ponz de Leon M, Roncucci L. Infliximab-related hepatitis: discussion of a case and review of the literature. Intern Emerg Med. 2010;5(3):193–200.CrossRefPubMedGoogle Scholar
  24. 24.
    Menghini VV, Arora AS. Infliximab-associated reversible cholestatic liver disease. Mayo Clin Proc. 2001;76(1):84–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Tobon GJ, Canas C, Jaller JJ, Restrepo JC, Anaya JM. Serious liver disease induced by infliximab. Clin Rheumatol. 2007;26(4):578–81.CrossRefPubMedGoogle Scholar
  26. 26.
    Parekh R, Kaur N. Liver injury secondary to anti-TNF-alpha therapy in inflammatory bowel disease: a case series and review of the literature. Case Rep Gastrointest Med. 2014;2014:956463.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Björnsson ES, Gunnarsson BI, Grondal G, Jonasson JG, Einarsdottir R, Ludviksson BR, et al. Risk of drug-induced liver injury from tumor necrosis factor antagonists. Clin Gastroenterol Hepatol. 2015;13(3):602–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Rossi RE, Parisi I, Despott EJ, Burroughs AK, O’Beirne J, Conte D, et al. Anti-tumour necrosis factor agent and liver injury: literature review, recommendations for management. World J Gastroenterol. 2014;20(46):17352–9.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Shelton E, Chaudrey K, Sauk J, Khalili H, Masia R, Nguyen DD, et al. New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2015;41(10):972–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Rochon J, Protiva P, Seeff LB, Fontana RJ, Liangpunsakul S, Watkins PB, et al. Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury. Hepatology. 2008;48(4):1175–83.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Rockey DC, Seeff LB, Rochon J, Freston J, Chalasani N, Bonacini M, et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf Causality Assessment Method. Hepatology. 2010;51(6):2117–26.PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Kim E, Bressler B, Schaeffer DF, Yoshida EM. Severe cholestasis due to adalimumab in a Crohn’s disease patient. World J Hepatol. 2013;5(10):592–5.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Germano V, Picchianti Diamanti A, Baccano G, Natale E, Onetti Muda A, Priori R, et al. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Rheum Dis. 2005;64(10):1519–20.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Ozorio G, McGarity B, Bak H, Jordan AS, Lau H, Marshall C. Autoimmune hepatitis following infliximab therapy for ankylosing spondylitis. Med J Aust. 2007;187(9):524–6.PubMedGoogle Scholar
  35. 35.
    Saleem G, Li SC, MacPherson BR, Cooper SM, et al. Hepatitis with interface inflammation and IgG, IgM, and IgA anti-double-stranded DNA antibodies following infliximab therapy: comment on the article by Charles. Arthritis Rheum. 2001;44(8):1966–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Rodrigues S, Lopes S, Magro F, Cardoso H, Horta EVAM, Marques M, et al. Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: a single center report of 8 cases. World J Gastroenterol. 2015;21(24):7584–8.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Grasland A, Sterpu R, Boussoukaya S, Mahe I. Autoimmune hepatitis induced by adalimumab with successful switch to abatacept. Eur J Clin Pharmacol. 2012;68(5):895–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Perdan-Pirkmajer K, Hocevar A, Rotar Z, Zibert J, Marolt VF, Gucev F, et al. Tumour necrosis factor-alpha inhibitor-induced hepatic injury in patients with rheumatoid arthritis: two case reports and an analysis of the laboratory data from the Slovenian National Biologicals Registry. Rheumatol Int. 2013;33(11):2885–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Titos-Arcos JC, Hallal H, Robles M, Andrade RJ. Recurrent hepatotoxicity associated with etanercept and adalimumab but not with infliximab in a patient with rheumatoid arthritis. Rev Esp Enferm Dig. 2012;104(5):282–4.CrossRefPubMedGoogle Scholar
  40. 40.
    van Casteren-Messidoro C, Prins G, van Tilburg A, Zelinkova Z, Schouten J, de Man R. Autoimmune hepatitis following treatment with infliximab for inflammatory bowel disease. J Crohns Colitis. 2012;6(5):630–1.CrossRefPubMedGoogle Scholar
  41. 41.
    Colina F, Molero A, Casis B, Martinez-Montiel P. Infliximab-related hepatitis: a case study and literature review. Dig Dis Sci. 2013;58(11):3362–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Rojas-Feria M, Castro M, Suarez E, Ampuero J, Romero-Gomez M. Hepatobiliary manifestations in inflammatory bowel disease: the gut, the drugs and the liver. World J Gastroenterol. 2013;19(42):7327–40.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Rösner S, Schad A, Kittner J, Rahman F, Worns MA, Schuchmann M, et al. Drug-induced liver injury with an autoimmune phenotype following anti-TNF therapy—presentation of cases and review of literature [in German]. Z Gastroenterol. 2014;52(1):58–63.CrossRefPubMedGoogle Scholar
  44. 44.
    Cheng FK, Bridges EE, Betteridge JD. Drug-induced liver injury from initial dose of infliximab. Mil Med. 2015;180(6):e723–4.CrossRefPubMedGoogle Scholar
  45. 45.
    Grijalva CG, Chen L, Delzell E, Baddley JW, Beukelman T, Winthrop KL, et al. Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA. 2011;306(21):2331–9.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Park KT, Sin A, Wu M, Bass D, Bhattacharya J. Utilization trends of anti-TNF agents and health outcomes in adults and children with inflammatory bowel diseases: a single-center experience. Inflamm Bowel Dis. 2014;20(7):1242–9.PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Bonafede MM, Gandra SR, Watson C, Princic N, Fox KM. Cost per treated patient for etanercept, adalimumab, and infliximab across adult indications: a claims analysis. Adv Ther. 2012;29(3):234–48.CrossRefPubMedGoogle Scholar
  48. 48.
    IMS Institute for Healthcare Informatics. Medicine use and shifting costs of healthcare: a review of the use of medicines in the United States in 2013. Danbury: IMS Health Incorporated; 2014.Google Scholar
  49. 49.
    Express Scripts®. The 2014 drug trend report. Express Scripts Holding Company. 2015. http://lab.express-scripts.com/drug-trend-report/. Accessed 15 Oct 2015
  50. 50.
    Grigoriev I, zu Castell W, Tsvetkov P, Antonov AV. AERS Spider: an online interactive tool to mine statistical associations in adverse event reporting system. Pharmacoepidemiol Drug Saf. 2014;23(8):795–801.Google Scholar
  51. 51.
    Efe C, Purnak T, Ozaslan E, Ozbalkan Z, Karaaslan Y, Altiparmak E, et al. Autoimmune liver disease in patients with systemic lupus erythematosus: a retrospective analysis of 147 cases. Scand J Gastroenterol. 2011;46(6):732–7.CrossRefPubMedGoogle Scholar
  52. 52.
    De Rycke L, Baeten D, Kruithof E, Van den Bosch F, Veys EM, De Keyser F. The effect of TNFalpha blockade on the antinuclear antibody profile in patients with chronic arthritis: biological and clinical implications. Lupus. 2005;14(12):931–7.CrossRefPubMedGoogle Scholar
  53. 53.
    Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89(1):95–106.CrossRefPubMedGoogle Scholar
  54. 54.
    Foureau DM, Walling TL, Maddukuri V, Anderson W, Culbreath K, Kleiner DE, et al. Comparative analysis of portal hepatic infiltrating leucocytes in acute drug-induced liver injury, idiopathic autoimmune and viral hepatitis. Clin Exp Immunol. 2015;180(1):40–51.CrossRefPubMedGoogle Scholar
  55. 55.
    Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants—past, present and future. Cytokine Growth Factor Rev. 2014;25(4):453–72.CrossRefPubMedGoogle Scholar
  56. 56.
    Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents. Rheumatology (Oxford, England). 2010;49(7):1215–28.Google Scholar
  57. 57.
    Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. Monoclon Antib. 2010;2(3):256–65.Google Scholar
  58. 58.
    Brenndorfer ED, Weiland M, Frelin L, Derk E, Ahlen G, Jiao J, et al. Anti-tumor necrosis factor alpha treatment promotes apoptosis and prevents liver regeneration in a transgenic mouse model of chronic hepatitis C. Hepatology. 2010;52(5):1553–63.CrossRefPubMedGoogle Scholar
  59. 59.
    Jones BE, Lo CR, Liu H, Srinivasan A, Streetz K, Valentino KL, et al. Hepatocytes sensitized to tumor necrosis factor-alpha cytotoxicity undergo apoptosis through caspase-dependent and caspase-independent pathways. J Biol Chem. 2000;275(1):705–12.CrossRefPubMedGoogle Scholar
  60. 60.
    Carvalheiro J, Mendes S, Sofia C. Infliximab induced liver injury in Crohn’s disease: a challenging diagnosis. J Crohns Colitis. 2014;8(5):436–7.CrossRefPubMedGoogle Scholar
  61. 61.
    Dang LJ, Lubel JS, Gunatheesan S, Hosking P, Su J. Drug-induced lupus and autoimmune hepatitis secondary to infliximab for psoriasis. Australas J Dermatol. 2014;55(1):75–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Kinnunen U, Farkkila M, Makisalo H. A case report: ulcerative colitis, treatment with an antibody against tumor necrosis factor (infliximab), and subsequent liver necrosis. J Crohns Colitis. 2012;6(6):724–7.CrossRefPubMedGoogle Scholar
  63. 63.
    Frider B, Bruno A, Ponte M, Amante M. Drug-induced liver injury caused by adalimumab: a case report and review of the bibliography. Case Rep Hepatol. 2013;2013:406901.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Joshua B. French
    • 1
  • Maurizio Bonacini
    • 2
  • Marwan Ghabril
    • 3
  • David Foureau
    • 4
  • Herbert L. Bonkovsky
    • 1
    • 5
    • 6
  1. 1.Section on Gastroenterology and Hepatology, Department of Internal MedicineWake Forest Health SciencesWinston-SalemUSA
  2. 2.Liver Center, Sutter HealthSan FranciscoUSA
  3. 3.Division of Gastroenterology and HepatologyIndiana University School of MedicineIndianapolisUSA
  4. 4.Department of ResearchCarolinas HealthCare SystemCharlotteUSA
  5. 5.Department of MedicineUniversity of Connecticut Health Science CenterFarmingtonUSA
  6. 6.Department of MedicineUniversity of North Carolina School of MedicineChapel HillUSA

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