Remission maintenance by tioguanine in chronic active Crohn's disease.
ABSTRACT Tioguanine may offer an alternative for immunosuppression in chronic active Crohn's disease. Recently, we have shown that tioguanine is effective in inducing rapid remission.
To evaluate the role of tioguanine in the maintenance of remission in chronic active Crohn's disease.
A follow-up study was performed to investigate the long-term efficacy and safety of and tolerance to tioguanine in chronic active Crohn's disease. Sixteen patients who had successfully received 6-tioguanine for remission induction were enrolled. The reasons for immunosuppressive therapy were steroid dependence (n = 10), steroid refractoriness (n = 6) and intolerance (n = 6) or refractoriness (n = 1) to azathioprine. After remission induction therapy for 6 months, patients were treated for another 6 months with a daily dose of 20-40 mg tioguanine. Primary outcomes were remission (Crohn's disease activity index < 150) and complete steroid reduction in steroid-dependent patients at 12 months. Laboratory controls of white blood count and liver enzymes, as well as erythrocyte tioguanine nucleotide levels, were performed regularly.
After 12 months of treatment, 14 of 16 (88%) patients were in remission, and 12 of these were completely free of systemic steroids. Adverse events during maintenance therapy included photosensitivity (one patient), minor viral infections (one), headache (four) and mild alopecia (one). One patient developed elevated liver enzymes, splenomegaly and thrombocytopenia, indicative of nodular regenerative hyperplasia of the liver.
In responders to tioguanine, the drug appears to be very effective in maintaining remission of chronic active Crohn's disease. Unfortunately, long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction. Therefore, to date, tioguanine cannot be recommended for general use outside clinical trials.
Article: A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease.[show abstract] [hide abstract]
ABSTRACT: Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey. Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator. 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1-207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients; using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH. This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy.Wiener klinische Wochenschrift 01/2007; 119(17-18):519-26. · 0.81 Impact Factor
Article: Safety and efficacy of the immunosuppressive agent 6-tioguanine in murine model of acute and chronic colitis.[show abstract] [hide abstract]
ABSTRACT: Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD. We induced acute or chronic colitis in BALB/c mice by one or four cycles of 3% dextran sulphate sodium (DSS), respectively. Mice were treated by daily gavages of various dosages of 6-tioguanine, azathioprine, or by phosphate buffered saline (PBS) starting the first day of DSS or after two cycles of DSS, respectively. We monitored the efficacy and toxicity by measuring the weight change and serum alanine aminotransferase (ALT) activity and by disease severity and histology, at the end of the experiment. Moreover, we measured cytokine production after colon fragment cultivation by enzyme-linked immunoabsorbent assay and numbers of apoptotic cells in the spleen by flow cytometry. 6-TG is effective in the treatment of acute DSS-induced colitis in a dose-dependent manner and 40 μg of 6-TG is significantly more effective in the treatment of acute colitis than both AZA and PBS. This effect is accompanied by decrease of IL-6 and IFN-γ production in colon. We did not observe histological abnormalities in liver samples from control (PBS) or 6-TG treated mice. However, liver samples from most mice treated with AZA showed mild, yet distinct signs of hepatotoxicity. In chronic colitis, all thiopurine derivatives improved colitis, 20 μg of 6-TG per dose was superior. High doses of 6-TG led to significant weight loss at the end of the therapy, but none of the thiopurine derivatives increased levels of serum ALT. Both thiopurine derivatives reduced the proportion of apoptotic T helper cells, but a high production of both IL-6 and TGF-β was observed only in colon of AZA-treated mice. Use of 6-TG in the treatment of experimental colitis in mice appears superior to AZA administration and placebo. In contrast to 6-TG, the use of AZA resulted in histological liver abnormalities.BMC Gastroenterology 01/2011; 11:47. · 2.42 Impact Factor
Article: Thiopurines in inflammatory bowel disease: new strategies for optimization of pharmacotherapy?Current Gastroenterology Reports 05/2006; 8(2):89-92.