Research ArticleInfliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis
Introduction
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown cause. It is characterized by elevated transaminases, hypergammaglobulinemia, autoantibodies, and a liver biopsy compatible with autoimmune hepatitis [1]. Standard treatment comprises azathioprine and prednisolone and, in the absence of cirrhosis, leads to complete biochemical response rates in up to 77% of patients after six months of treatment [2].
However, around 5% of patients experience intolerance or toxicity while about 10% do not respond sufficiently to those standard treatment options [3]. Alternative treatments include budesonide [4], mycophenolate mofetil (MMF) [5], 6-thioguanine [6], cyclophosphamide [7], cyclosporine A (CsA) [8] or tacrolimus (FK) [9], however, these treatments have mostly been tested in small case series rather than controlled trials, and have demonstrated only variable effectiveness. Therefore, identification of efficient rescue treatment options is urgently needed for these difficult-to-treat patients. Research has shown that sufficient treatment leads to normalization of transaminases and gammaglobulins, including IgG, and also results in long-term survival comparable to the normal patient population [10]. At the same time, failure to achieve a complete biochemical remission has been shown to result in worse long-term outcomes [11]. Optimization of treatment plays, therefore, a major role in long-term prognosis and quality of life for patients with difficult-to-treat autoimmune hepatitis [3].
Infliximab is a recombinant humanized chimeric antibody currently used for the treatment of rheumatoid arthritis, psoriasis arthritis and plaque psoriasis, ankylosing spondylitis, ulcerative colitis, and colitis Crohn [12]. Autoimmune reactions during therapy, including the development of a lupus-like syndrome [13] or even cases of autoimmune-like hepatitis [14], have been described. The mechanism of action, besides the direct neutralization of soluble TNF-alpha, includes a proapoptotic effect on lymphocytes and decreased GM-CSF production by T cells [15]. GM-CSF is a proinflammatory cytokine that has been described to play a role in different autoimmune diseases. Reduction of GM-CSF production has been shown to influence T-cell pathogenicity [16]. Another possible effect may lay in the decrease of a subset of CD8+ effector memory T cells [17]. The latter may contribute to increased susceptibility to intracellular pathogens, but may also contribute to reduced disease activity in autoimmune diseases.
In 2001, our team treated the first patient off-label with infliximab. The patient responded well while developing numerous infectious side effects [18]. This article reviews the treatment history of 11 patients with difficult-to-treat AIH, who subsequently received repeated infliximab infusions. Overall, patients responded well to treatment with long lasting remissions achieved in more than 60% of the patients. Conversely, infectious side effects, some of them requiring hospitalization, were frequently seen in this group of patients. Therefore, infliximab warrants further evaluation as rescue treatment for patients with severe and difficult-to-treat AIH.
Section snippets
Patients and methods
Eleven patients (seven female and four male) with difficult-to-treat autoimmune hepatitis fulfilled the criteria for AIH according to the criteria of the International Autoimmune Hepatitis Study Group (REF 19) or the simplified criteria (REF 20). Other liver diseases, including metabolic and viral hepatitis, were excluded. Median age of the patient population was 42 years (range 28–75 years). All patients had initially received standard treatment upon diagnosis of AIH, consisting of azathioprine
Patient characteristics
Eleven patients with AIH were treated, with initial findings about patient 1 already published previously [18]. Prior to infliximab treatment, all patients had been treated with other immunosuppressive regimens with insufficient response or intolerance (Table 2). Patients received a liver biopsy prior to initiation of infliximab treatment (median mHAI was 9.2 ± 2.3 under ongoing immunosuppressive treatment). Seven patients were found to have cirrhosis at the initiation of infliximab treatment.
Discussion
This study reports on the first series of patients with difficult-to-treat autoimmune hepatitis who received rescue treatment with infliximab. Considering that patients had a very severe disease course with a history of multiple immunosuppressive drugs and advanced fibrosis/cirrhosis at the time of treatment initiation, infliximab resulted in good response rates at a tolerable side effect profile. In addition, only three infusions led to complete remission, including normalized IgG levels in 6
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Acknowledgements
The authors would like to thank Dr. Hoffmann, Schwerin, for providing additional data and Sandra Normann-Kravitz for critical reading of the manuscript.
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