Infliximab as rescue therapy in paediatric autoimmune hepatitis
Authors: Jeremy Rajanayagam, Peter J. Lewindon
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 We read with interest the report by Weiler-Normann et al. [[1]Weiler-Normann C. Schramm C. Quass A. Wiegard C. Glaubke C. Pannicke N. et al.Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis.J Hepatol. 2013; 58: 529-534Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar] regarding use of infliximab (IFX) to obtain remission in adults with difficult-to-treat autoimmune hepatitis (AIH). We report our paediatric experience with IFX for a patient with autoimmune hepatitis type 1, recalcitrant to standard medical treatment, achieving sustained biochemical response, steroid weaning, and prolonged deferral from liver transplantation. Our female patient presented at 10 years of age with hepatic failure, INR 2.5, albumin 25 g/L, bilirubin 212 μM/L (normal <20). Hepatobiliary sonography demonstrated macronodular hepatic changes and splenomegaly consistent with chronic liver disease. Anti-smooth muscle antibody T fraction and IgG levels were elevated at 1:160 and 24 mg/L, respectively. P-ANCA was negative. Liver biopsy demonstrated massive hepatic necrosis, interface hepatitis characterised by plasma cell infiltrate with no evidence of cholangitis and no excess of stainable copper or rhodanine. Extensive investigations for other causes of chronic liver disease were negative and a diagnosis of type 1 AIH was confirmed. Biochemical response to prednisolone (1 mg/kg/day), followed by azathioprine (up to 2 mg/kg/day) was slow and incomplete, leading, 7 months later, to a second biochemical relapse despite good compliance (6-TG level 440 pmol/8 × 108 RBC, 6MMP levels 1200 pmol/8 × 108 RBC) and continuing prednisolone (10 mg/day). MRCP showed no evidence of sclerosing cholangitis overlap. A diagnosis of inflammatory bowel disease was not supported by the absence of stooling abnormalities on history and stool examination although not formally excluded. Mycophenolate mofetil (40 mg/kg/day) replaced azathioprine for three months with the prednisolone dosage gradually weaned. Liver function tests failed to respond then deteriorated, prompting high dose intravenous methylprednisolone (2 mg/kg/day) with poor response. Then tacrolimus (0.2 mg/kg/day) was combined with oral prednisolone (40 mg/day) for one month with no biochemical improvement. Severe steroid related side effects developed including Cushing's syndrome and hyperglycemia requiring insulin. Tacrolimus was discontinued, azathioprine recommenced and our patient was evaluated for liver transplantation. Based on the case report of Weiler-Normann [[2]Weiler Normann C. Wiegard C. Schramm C. Lohse A.W. A case of difficult-to-treat autoimmune hepatitis successfully managed by TNF-alpha blockade.Am J Gastroenterol. 2009; 104: 2877-2878Crossref PubMed Scopus (35) Google Scholar], a single dose 5 mg/kg (200 mg) IFX was approved (drug and therapeutics ethics committee) for off-label use by our institution. Following IFX, she experienced biochemical and clinical improvement within 3 weeks, permitting successful weaning of steroids from 40 mg daily to 2.5 mg on alternate days by 8 weeks. The response was sustained for 4 months, allowing reversal of steroid related side effects and temporary delisting for liver transplantation. Subsequent biochemical relapse led to permission for 3 further doses of IFX (5 mg/kg) at 4 weekly intervals, although a re-increase in prednisolone dosage was avoided. Infusions were well tolerated, with no side effects or adverse events. A sustained biochemical response was achieved by 12 weeks, permitting further deferral of transplantation and dramatically improving quality of life. Nine months after her last dose of IFX, our patient was successfully transplanted. Histology of the explant liver showed no evidence to support a co-existing diagnosis of autoimmune sclerosing cholangitis. From her first IFX until transplant 19 months later, prednisolone was not increased above 2.5 mg daily (Fig. 1). TNF-α antagonists are used successfully in the treatment of several autoimmune conditions [3Breda L. Del Torto M. De Sanctis S. Chiarelli F. Biologics in children's autoimmune disorders: efficacy and safety.Eur J Pediatr. 2011; 170: 157-167Crossref PubMed Scopus (40) Google Scholar, 4Karampetsou M.P. Liossis S.N. Sfikakis P.P. TNF-alpha antagonists beyond approved indications: stories of success and prospects for the future.QJM. 2010; 103: 917-928Crossref PubMed Scopus (71) Google Scholar]. To our knowledge, the efficacy and safety of IFX in paediatric AIH remain unknown. Primary concerns limiting its use relate to risks of infusion-related reactions, serious infection, and autoimmune reactions including a lupus-like syndrome as well as a recently reported hepatotoxicity resembling AIH [5Weiler-Normann C. Schramm C. Drug induced liver injury and it's relationship to autoimmune hepatitis.J Hepatol. 2011; 55: 747-749Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 6Ghabril M. Bonkovsky H.L. Kum C. Davern T. Hayashi P.H. Kleiner D.E. et al.Liver injury from tumor necrosis factor-alpha antagonists: analysis of thirty-four cases.Clin Gastroenterol Hepatol. 2013; 11: 558-564Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 7Bjornsson E. Talwalkar J. Treeprasertsuk S. Kamath P.S. Takahashi N. Sanderson S. et al.Drug-induced autoimmune hepatitis: clinical characteristics and prognosis.Hepatology. 2010; 51 (Competing Interests): 2040-2048Crossref PubMed Scopus (358) Google Scholar]. We report a paediatric case of AIH, unresponsive to standard immunosuppressive therapies, with a sustained response to IFX, permitting reversal of high dose steroids, improving quality of life, and achieving a 19-month deferral from liver transplantation. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We thank the patient for permission to publish her case.