{'fraction_non_alphanumeric': 0.029796232218377548, 'fraction_numerical': 0.019223375624759707, 'mean_word_length': 5.157396449704142, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 1, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
In the case of nonresponse, what is the second-level treatment for induction of remission in Crohn's disease?

There are several options for second-line treatment in Crohn’s disease (CD): the most important are azathioprine/6-mercaptopurine, methotrexate, and infliximab. Immunomodulators as remission-inducing agents have been evaluated in 6 placebo-controlled trials of azathioprine and 2 with 6-mercatopurine, a metabolite of azathioprine. A recent metaanalysis of the Cochrane Collaboration1 supports the significant advantage of azathioprine/6-mercaptopurine in active disease. The pooled odds ratio (OR) for the response to these immunosuppressive drugs was 2.7, corresponding to a number needed to treat (NNT) of 5. It was also found that the response rate was dependent on treatment time, with studies lasting for 17 weeks or longer obtaining better results, with an NNT of 4. Daily dose had no impact on outcome in the meta-analysis, although an adequate dose is probably 2.5 mg/kg per day. Whether the monitoring of drug metabolite levels like 6-thioguanine or 6-methylmercaptopurine combined with dose adaptation is helpful in the induction of remission by these drugs is possible but unsettled.2 Although some CD patients may respond relatively early to azathioprine, the combination of corticosteroids plus azathioprine during the initial phase of active disease is probably wise. The benefits of these immunosuppressive agents have to be weighed against eventual toxicity. In the large experience of Present et al3 in 396 patients treated with 6-mercaptopurine based on a mean period of follow-up of 5 years, toxicity included pancreatitis (3.3%), bone marrow depression (2%), allergic reactions (2%), and drug hepatitis (0.3%). Three percent of the cohort treated developed neoplasms but only 1 (0.3%), a diffuse histiocytic lymphoma of the brain, was considered to have a probable association with the drug. However, when the lymphoma risk was calculated in a recent decision analysis, azathioprine was of benefit with respect to quality-adjusted survival.4 In another series of 591 patients, 25 malignancies were observed during or following 6-mercaptopurine treatment but none was attributed to immunosuppressive therapy. The incidence of pregnancy-related complications was significantly increased in 1 study when the fathers used 6-mercaptopurine within 3 months of conception. The patient may benefit from a switch from azathioprine to 6-mercpatopurine, especially if the intolerance is due to unspecific side effects like nausea or to hepatotoxicity. Probably it is possible to reduce the occurrence of early leukopenia by excluding patients with homozygous thiopurine methyltransferase deficiency. It may be concluded that azathioprine and 6-mercaptopurine represent a reasonable and reasonably safe medication in chronic active inflammatory bowel disease, provided that surgery is not indicated. Most important, all patients have to be carefully monitored to detect potential side effects early. Methotrexate is usually administered as weekly intramuscular injections of 25 mg during a 12-week treatment period. Upon improvement the dosing may be switched to oral medication using 15–25 mg weekly in tapered fashion to maintain remission. The controlled trial on this drug in active CD by Feagan et al5 reported a therapeutic benefit of 20%, i.e., the NNT was 5. Prolonged administration of the drug in responders maintained remission in more patients than in the control group on placebo.6 This evidence is complemented by several uncontrolled series. Methotrexate should be reserved for those not responding or intolerant to azathioprine/6-mercaptopurine. In the North American induction of remission trial, 16 of 94 patients withdrew from treatment because of adverse events5: 7 had an asymptomatic elevation of transaminases, 6 had nausea, and 1 had a skin rash, pneumonia, and optic neuritis. None of the other complaints that were not associated with termination was significantly more frequent compared to the placebo group. Thus, methotrexate in the short term is relatively well tolerated but long-term toxicity, especially hepatic fibrosis, may represent a rare problem if the cumulative dose exceeds 1.5 g. It is contraindicated during pregnancy. Currently, several anti-TNF-antibodies have been or are being tested but only 1 of these (infliximab) is available on the market. Currently, in the US particularly, extensive clinical use of infliximab for the induction of remission in CD is based on only 2 controlled trials,7,8 as well as multiple reports on uncontrolled single-center experience. In the initial controlled trial 108 patients with moderate to severe disease activity were randomized into 4 groups given a single infusion of placebo or 5 mg/kg of body weight, 10 mg/kg versus 20 mg/kg of infliximab. It was stated that the patients were resistant to treatment before starting the trial but only 28 patients had previously been on 20 mg/day of predFrom the Robert Bosch Hospital, Stuttgart, Germany. Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20654 Published online in Wiley InterScience (www.interscience.wiley.com).