6-thioguanine treatment in inflammatory bowel disease: A critical appraisal by a European 6-TG working party

Recently, the suggestion to use 6-thioguanine (6-TG) as an alternative thiopurine in patients with inflammatory bowel disease (IBD) has been discarded due to reports about possible (hepato) toxicity. During meetings arranged in Vienna and Prague in 2004, European experts applying 6-TG further on in IBD patients presented data on safety and efficacy of 6-TG. After thorough evaluation of its risk-benefit ratio, the group consented that 6-TG may still be considered as a rescue drug in stringently defined indications in IBD, albeit restricted to a clinical research setting. As a potential indication for administering 6-TG, we delineated the requirement for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Furthermore, indications are preferred in which surgery is thought to be inappropriate. The standard 6-TG dosage should not exceed 25 mg daily. Routine laboratory controls are mandatory in short intervals. Liver biopsies should be performed after 6-12 months, three years and then three-yearly accompanied by gastroduodenoscopy, to monitor for potential hepatotoxicity, including nodular regenerative hyperplasia (NRH) and veno-occlusive disease (VOD). Treatment with 6-TG must be discontinued in case of overt or histologically proven hepatotoxicity. Copyright (c) 2006 S. Karger AG, Basel

Severe airway stenosis associated with Crohn's disease: Case report

BACKGROUND: Symptomatic respiratory tract involvement is not common in Crohn's disease. Upper-airway obstruction has been reported before in Crohn's disease and usually responds well to steroid treatment. CASE PRESENTATION: We report a case of a 32-year old patient with Crohn's disease who presented with progressively worsening dyspnea on exertion. Magnetic Resonance Imaging of the chest and bronchoscopy revealed severe tracheal stenosis and marked inflammation of tracheal mucosa. Histopathology of the lesion showed acute and chronic inflammation and extended ulceration of bronchial mucosa, without granulomas. Tracheal stenosis was attributed to Crohn's disease after exclusion of other possible causes and oral and inhaled steroids were administered. Despite steroid treatment, tracheal stenosis persisted and only mild symptomatic improvement was noted after 8 months of therapy. The patient subsequently underwent rigid bronchoscopy with successful dilatation and ablation of the stenosed areas and remission of her symptoms. CONCLUSION: Respiratory involvement in Crohn's disease might be more common than appreciated. Interventional pulmonology techniques should be considered in cases of tracheal stenosis due to Crohn's disease refractory to steroid treatment

Review article: interactions between genotype and response to therapy in inflammatory bowel diseases.

BACKGROUND: More than half of the patients with inflammatory bowel diseases are candidates for immunosuppressive therapy. However, even the most effective drugs used in inflammatory bowel disease are only successful in about two-thirds of patients. Adverse events limit their use in a further substantial proportion of patients. Recent research has focussed on the possibility of predicting a drugs' efficacy and/or toxicity by identifying polymorphic variants in the genes encoding enzymes involved in metabolic pathways. AIM: To highlight recent advances and limitations in the field of pharmacogenetics in inflammatory bowel disease. RESULTS: Recent pharmacogenetic studies have mainly focussed on immunosuppressive agents including corticosteroids, azathioprine, methotrexate and infliximab. Several polymorphic genes encoding enzymes involved in the metabolism of these drugs have been identified including the inosine triphosphate pyrophosphatase in thiopurine therapy, the methylene tetrahydrofolate reductase in methotrexate therapy and polymorphisms in apoptosis genes in infliximab therapy. However, at the present time, genotyping for the variants of the thiopurine methyltransferase gene, an enzyme important for the metabolism of the thiopurine drugs, is the only useful test in clinical practice. CONCLUSIONS: Although the field of pharmacogenetics in inflammatory bowel disease is promising most new targets have so far failed to translate into clinical practice. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner

The pharmacogenetics of methotrexate in inflammatory bowel disease.

OBJECTIVES: Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD) but its use is limited by unpredictable toxicity and efficacy. MTX metabolism is complex involving a number of enzymes. An individual's response to MTX may in part be genetically determined by functional genetic variation in genes encoding these enzymes. We report a pharmacogenetic evaluation of MTX therapy in IBD. METHODS: We studied 102 IBD patients treated with MTX, and 202 patients with Crohn's disease (CD), 205 patients with ulcerative colitis (UC) and 189 healthy volunteers served as controls to assess allele frequencies in the disease and healthy populations. All subjects were genotyped for four polymorphisms: G80A in the reduced folate carrier (RFC1) gene, G452T in the gamma-glutamyl hydrolase (GGH) gene and C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene. Three non-conservative SNPs in the RFC1 and the MTHFR gene could not be detected in our patient cohort. Genotype-phenotype associations were evaluated with respect to efficacy and toxicity of MTX therapy. RESULTS: No significant differences in the allele frequencies between CD, UC and healthy controls were detected. Overall 21% of patients experienced MTX side effects. Patients homozygous for the MTHFR 1298C allele were more likely to experience one or more side effects compared to patients with the wild-type 1298AA genotype (21.0 vs. 6.3%, P < 0.05). None of the genotyped SNPs or haplotypes, either alone or in combination, was associated with short-term efficacy or sustained response. CONCLUSIONS: Side effects of MTX in IBD are associated with a SNP in the MTHFR gene but response cannot be predicted by any of the investigated SNPs

Oral methotrexate in ulcerative colitis.

BACKGROUND: We performed an audit of methotrexate for ulcerative colitis, because efficacy is unclear. Aim : To investigate the role of methotrexate in the management of ulcerative colitis. METHODS: Patients with ulcerative colitis treated with oral methotrexate at the inflammatory bowel disease clinics of Oxford and Wycombe General Hospital, UK, were evaluated. Efficacy was defined by remission (complete steroid withdrawal for >3 months) and response (good, partial or nil, proportionate reduction of steroids). RESULTS: There were 50 patients (42 ulcerative colitis alone; eight had rheumatoid arthritis associated with ulcerative colitis and were analysed separately). Indications for methotrexate in ulcerative colitis alone were azathioprine intolerance (31 of 42) and lack of benefit from azathioprine (11 of 42). The mean dose of methotrexate in ulcerative colitis alone was 19.9 mg/week for a median of 30 weeks (range: 7-395). Remission occurred in 42%. The response was good in 54% and partial in 18%. Side-effects occurred in 23%; 10% stopped treatment because of side-effects. Of those treated with methotrexate because of treatment failure with azathioprine, three of 11 achieved remission, but four came to colectomy within 90 days of starting methotrexate. The colitis remained in remission in seven of eight of those with RA treated with methotrexate and ulcerative colitis (mean dose 15.0 mg/week). CONCLUSION: Oral methotrexate (approximately 20 mg/week) is well-tolerated and moderately effective in steroid-dependent or steroid-refractory patients with ulcerative colitis

A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease

Objective: 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. Methods: 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. Results: 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. Conclusion: 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