Background. Tocilizumab, a monoclonal humanized anti-IL-6 receptor antibody, is used in treatment of refractory adult onset Still’s disease (AOSD). Mild to moderate liver enzyme elevation is a well-known side effect, but severe liver injury has only been reported in 3 cases in the literature. Case. A young female suffering from corticoid and methotrexate refractory AOSD was treated by tocilizumab. After 19 months of consecutive treatment, she developed acute severe liver injury. Liver biopsy showed extensive hepatocellular necrosis with ballooned hepatocytes, highly suggestive of drug-induced liver injury. No other relevant drug exposure beside tocilizumab was recorded. She recovered totally after treatment discontinuation and an initial 3-day course of intravenous N-acetylcysteine with normalization of liver function tests after 6 weeks. Conclusion. Acute severe hepatitis can be associated with tocilizumab as documented in this case. Careful monitoring of liver function tests is warranted during tocilizumab treatment. 1. Introduction Adult onset Still’s disease (AOSD) is a systemic inflammatory disease clinically characterized by remittent fever, polyarthritis, stain rash, and lymphadenopathy in association with deregulated proinflammatory cytokines (interleukin-1, -6 and -18, tumor necrosis factor α, and interferon γ) production [1, 2]. Of interest, a correlation of IL-6 serum levels with AOSD’s activity has been described [1, 3]. Tocilizumab is a neutralizing humanized monoclonal antibody against the human interleukin-6 (IL-6) receptor that is able to block soluble and membrane-bound receptors [4]. It is licensed over the world as second-line treatment for rheumatoid arthritis (RA) and in Japan and Europe for juvenile idiopathic arthritis [5, 6]. Disease improvement or remission has been reported following tocilizumab treatment in refractory AOSD [2, 7]. 2. Case Report An 18-year-old female from Angola was diagnosed with AOSD in September 2010 following recurrent fever, polyarthritis, abdominal lymphadenopathy, liver and spleen enlargement, and hyperferritinemia. She was initially treated with oral corticoids with early methotrexate adjunction due to incomplete control of symptoms. Despite this treatment, corticoids could not be tapered under the dose of 15？mg/day, motivating introduction of tocilizumab (8？mg/kg) in June 2011, permitting interruption of corticoids and methotrexate in December 2011. In 2012, she had no symptoms and liver function tests were normal under tocilizumab once every 3 weeks. On January 21, 2013, she complained of nausea,
References
[1]
R. Sakai, H. Nagasawa, E. Nishi et al., “Successful treatment of adult-onset Still's disease with tocilizumab monotherapy: two case reports and literature review,” Clinical Rheumatology, vol. 31, no. 3, pp. 569–574, 2012.
[2]
R. Suematsu, A. Ohta, E. Matsuura et al., “Therapeutic response of patients with adult Still's disease to biologic agents: multicenter results in Japan,” Modern Rheumatology, vol. 22, pp. 712–719, 2012.
[3]
D.-Y. Chen, J.-L. Lan, F.-J. Lin, and T.-Y. Hsieh, “Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset still's disease,” Journal of Rheumatology, vol. 31, no. 11, pp. 2189–2198, 2004.
[4]
C. Drucker, J. Gewiese, S. Malchow, J. Scheller, and S. Rose-John, “Impact of interleukin-6 classic- and trans-signaling on liver damage and regeneration,” Journal of Autoimmunity, vol. 34, no. 1, pp. 29–37, 2010.
[5]
J. S. Smolen, M. M. Schoels, N. Nishimoto, et al., “Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions,” Annals of the Rheumatic Diseases, vol. 72, pp. 482–492, 2013.
[6]
F. de Benedetti, H. I. Brunner, N. Ruperto, et al., “Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis,” The New England Journal of Medicine, vol. 367, pp. 2385–2395, 2012.
[7]
H. de Boysson, J. Fevrier, A. Nicolle, C. Auzary, and L. Geffray, “Tocilizumab in the treatment of the adult-onset Still's disease: current clinical evidence,” Clinical Rheumatology, vol. 32, pp. 141–147, 2013.
[8]
W. M. Lee, L. S. Hynan, L. Rossaro et al., “Intravenous N-acetylcysteine improves transplant-free survival in early stage non acetaminophen acute liver failure,” Gastroenterology, vol. 137, no. 3, pp. 856.e1–864.e1, 2009.
[9]
S. Singh, L. S. Hynan, and W. M. Lee, “Improvements in hepatic serological biomarkers are associated with clinical benefit of intravenous N-acetylcysteine in early stage non- acetaminophen acute liver failure,” Digestive Diseases and Sciences, vol. 58, pp. 1397–1402, 2013.
[10]
R. M. Gallagher, J. J. Kirkham, J. R. Mason et al., “Development and inter-rater reliability of the liverpool adverse drug reaction causality assessment tool,” PLoS ONE, vol. 6, no. 12, Article ID e28096, 2011.
[11]
K. Kovalovich, R. A. Deangelis, W. Li, E. E. Furth, G. Ciliberto, and R. Taub, “Increased toxin-induced liver injury and fibrosis in interleukin-6- deficient mice,” Hepatology, vol. 31, no. 1, pp. 149–159, 2000.
[12]
N. Nishimoto, K. Ito, and N. Takagi, “Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions,” Modern Rheumatology, vol. 20, no. 3, pp. 222–232, 2010.
[13]
G. Jones and C. Ding, “Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis,” Clinical Medicine Insights, vol. 3, pp. 81–89, 2010.
[14]
M. Mahamid, K. Paz, M. Reuven, and R. Safadi, “Hepatotoxicity due to tocilizumab and anakinra in rheumatoid arthritis: two case reports,” International Journal of General Medicine, vol. 4, pp. 657–660, 2011.
[15]
M. Hiura, S. Abe, A. Tabaru et al., “Case of severe liver damage after the induction of tocilizumab therapy for rheumatoid vasculitis,” Hepatology Research, vol. 41, no. 5, pp. 492–496, 2011.
[16]
M. Alfreijat, M. Habibi, P. Bhatia, and A. Bhatia, “Severe hepatitis associated with tocilizumab in a patient with rheumatoid arthritis,” Rheumatology, vol. 52, pp. 1340–1341, 2013.
[17]
M. García-Cortés, C. Stephens, M. I. Lucena, A. Fernández-Casta？er, and R. J. Andrade, “Causality assessment methods in drug induced liver injury: strengths and weaknesses,” Journal of Hepatology, vol. 55, no. 3, pp. 683–691, 2011.
[18]
K. T. Suk, D. J. Kim, C. H. Kim, et al., “A prospective nationwide study of drug-induced liver injury in Korea,” The American Journal of Gastroenterology, vol. 107, pp. 1380–1387, 2012.
[19]
X.-D. Kong, D. Xu, W. Zhang, Y. Zhao, X. Zeng, and F. Zhang, “Clinical features and prognosis in adult-onset still's disease: a study of 104 cases,” Clinical Rheumatology, vol. 29, no. 9, pp. 1015–1019, 2010.
