Reply to: “Use of TNFα antagonists in refractory AIH: Revealing the unforeseen”
Authors: Christina Weiler-Normann, Christoph Schramm, Ansgar W. Lohse
Journal: Journal of Hepatology (2013)

Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitisJournal of HepatologyVol. 58Issue 3PreviewAutoimmune hepatitis is a chronic inflammatory liver disease that leads to liver cirrhosis and corresponding complications, if left untreated. Current standard treatment with azathioprine and prednisolone induces remission in the vast majority of patients. However, for those patients not responding to standard treatment or not tolerating these drugs, few alternatives can be used and their effectiveness might be limited. We sought to analyze the safety and efficacy of off-label treatment with infliximab in a cohort of eleven patients with difficult-to-treat autoimmune hepatitis. Full-Text PDF Use of TNFα antagonists in refractory AIH: Revealing the unforeseenJournal of HepatologyVol. 59Issue 1PreviewWe read with considerable interest the paper by Weiler-Normann et al. in the Journal of Hepatology [1], which reported promising results regarding the use of infliximab as a therapeutic option in difficult-to-treat patients with autoimmune hepatitis (AIH). Although the exact role of tumor necrosis factor α (TNFα) in the pathogenesis of AIH has not been elucidated yet, very recently, it has been shown in a mouse model of fatal AIH that TNFα is essential in the induction of AIH through upregulation of hepatic CCL20 expression, which allows migration of dysregulated splenic T cells [2]. Full-Text PDF Open Access We would like to thank Saitis and colleagues [[1]Saitis A. Gatselis N. Zachou K. Dalekos G.N. Use of TNFa antagonists in refractory AIH: revealing the unforeseen.J Hepatol. 2013; 59: 197-198Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar] for their view on TNFα antagonist use in difficult-to-treat autoimmune hepatitis (AIH) and for the addition of pathophysiological mechanisms, which may explain the effects of this treatment in AIH [[2]Weiler-Normann C. Schramm C. Quaas A. Wiegard C. Glaubke C. Pannicke N. et al.Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis.J Hepatol. 2013; 58 (Available from: <http://www.ncbi.nlm.nih.gov/pubmed/23178709>): 529-534Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar]. There are around 40 case reports in the literature – including the most recent one presented here – that have described the development of AIH or an immune mediated hepatitis after administration of anti-TNFα agents such as infliximab [[3]Efe C. Purnak T. Ozaslan E. Wahlin S. Drug-induced autoimmune hepatitis caused by anti-tumor necrosis factor alpha agents.Hepatology. 2010; 52: 2246-2247Crossref PubMed Scopus (29) Google Scholar], adalimumab [[4]Grasland A. Sterpu R. Boussoukaya S. Mahe I. Autoimmune hepatitis induced by adalimumab with successful switch to abatacept.Eur J Clin Pharmacol. 2012; 68: 895-898Crossref PubMed Scopus (35) Google Scholar] and etanercept [[5]Fathalla B.M. Goldsmith D.P. Pascasio J.M. Baldridge A. Development of autoimmune hepatitis in a child with systemic-onset juvenile idiopathic arthritis during therapy with etanercept.J Clin Rheumatol. 2008; 14: 297-298Crossref PubMed Scopus (25) Google Scholar]. Whether the induction of AIH is limited to patients with a genetic susceptibility to AIH is unknown but seems likely. In other patients, an immune mediated hepatitis may develop under TNFα blockade, which does not necessarily evolve into the typical chronic course of AIH. The difference between the two can only be made looking at relapse after cessation of steroid treatment. In these cases, we would recommend using steroids alone for 3–6 months and then taper treatment under close monitoring [[6]Weiler-Normann C. Schramm C. Drug induced liver injury and its relationship to autoimmune hepatitis.J Hepatol. 2011; 55: 747-749Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. We would like to add another potential mechanism of action of infliximab, which is the induction of apoptosis in activated T cells, thus contributing to the treatment effects observed [[7]Van den Brande J.M. Braat H. van den Brink G.R. Versteeg H.H. Bauer C.A. Hoedemaeker I. et al.Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease.Gastroenterology. 2003; 124: 1774-1785Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar]. Infectious complications are frequent with such treatment and close monitoring of these patients seems essential. Indeed, it appears that cirrhotic AIH patients under immunosuppressive treatment are at particular risk of developing infections. The patients presented in our series all had prior treatment with other immunosuppressive agents, posing an additional risk. Yet, as it is known from the use of biologicals in rheumatic diseases, the risk is only slightly elevated for TNFα blockers [[8]Singh J.A. Wells G.A. Christensen R. Tanjong Ghogomu E. Maxwell L. Macdonald J.K. et al.Adverse effects of biologics: a network meta-analysis and Cochrane overview.Cochrane Database Syst Rev. 2011; (CD008794)Google Scholar]; in fact it seems to be lower than with the use of steroids >15 mg/diem [[9]Strangfeld A. Eveslage M. Schneider M. Bergerhausen H.J. Klopsch T. Zink A. et al.Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient?.Ann Rheum Dis. 2011; 70: 1914-1920Crossref PubMed Scopus (294) Google Scholar]. We believe that the side effect profile of infliximab on the long term is favorable as compared to calcineurin inhibitors, which have been proposed by Saitis and colleagues. Mycophenolate mofetil serves well as a drug for patients with intolerance to azathioprine, but in our hands rarely induces remission in those with inadequate response to azathioprine [[10]Hennes E.M. Oo Y.H. Schramm C. Denzer U. Buggisch P. Wiegard C. et al.Mycophenolate mofetil as second line therapy in autoimmune hepatitis?.Am J Gastroenterol. 2008; 103: 3063-3070Crossref PubMed Scopus (168) Google Scholar]. As discussed [[11]Schramm C. Lohse A.W. Role of mycophenolate mofetil in the treatment of autoimmune hepatitis.J Hepatol. 2011; 55: 510-511Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar], we do not see it as first-line treatment in patients with AIH. We therefore agree that – as also stated in our manuscript – infliximab can be considered a rescue treatment for patients with difficult-to-treat AIH. We feel that use of infliximab offers another treatment option for patients not responding to standard first- or second-line treatment. Close monitoring, not only for infectious complications but also for parameters of disease activity, is indispensable in the off-label rescue treatment of AIH with infliximab. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.