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Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score150). The primary end point for the maintenance trial was remission at week 44 (CDAI score150).The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).

Tumour necrosis factor (TNF)-alpha converting enzyme (TACE) releases biologically active, soluble TNF-alpha from transmembrane pro-TNF-alpha and has attracted interest as a specific therapeutic target in inflammatory bowel disease (IBD). Strong immunoreactivity for TACE protein was demonstrated recently in human colonic epithelium, but the function is unknown. We investigated if human colonic epithelial cells express functional TACE activity and how TACE expression is regulated in response to cytokine stimulation. TACE and TNF-alpha mRNA and protein expression were measured in HT-29 and DLD-1 colonic epithelial cells by reverse-transcription polymerase chain reaction, western blotting or enzyme-linked immunosorbent assay. Monocytic THP-1 cells served as positive control. Functional TACE activity was identified and quantified in detergent extracts of cell lines and freshly isolated colonocytes from 14 IBD patients and five controls by a hydrolysis assay using an oligopeptide spanning the cleavage site in pro-TNF-alpha. HT-29 and DLD-1 cells spontaneously expressed TACE mRNA and the active form of TACE protein at levels similar to those of monocytic cells. Functional TACE activity was demonstrated in all cell lines and in cells of controls or IBD patients irrespective of disease activity. TACE mRNA expression and functional activity remained unchanged in cell lines after stimulation with TNF-alpha despite clear induction of TNF-alpha mRNA expression and release of soluble TNF-alpha protein. The release of soluble TNF-alpha protein was almost completely abolished by CH4474, a synthetic TACE inhibitor. We conclude that functional TACE activity is constitutively expressed in human colonic epithelial cells and responsible for processing of the mature, soluble form of TNF-alpha in response to cytokine stimulation.

Background: Anti-tumour necrosis factor α (TNF-α) antibodies are effective in Crohn's disease and perhaps ulcerative colitis but antigenicity and the high cost have raised interest in other strategies to block TNF-α. These include the TNF-α converting enzyme (TACE) which releases soluble TNF-α from transmembrane pro-TNF-α.

Crohn's disease is a heterogeneous entity. Previous attempts of classification have been based primarily on anatomic location and behavior of disease. However, no uniform definition of patient subgroups has yet achieved broad acceptance. The aim of this international Working Party was to develop a simple classification of Crohn's disease based on objective variables. Eight outcome-related variables relevant to Crohn's disease were identified and stepwise evaluated in 413 consecutive cases, a database survey, and by clinical considerations. Allocation of variables was conducted with well-defined Crohn's disease populations from Europe and North America. Cross-table analyses were performed by chi-square testing. Three variables were finally elected: Age at Diagnosis [below 40 years (A1), equal to or above 40 years (A2)], Location [terminal ileum (L1), colon (L2), ileocolon (L3), upper gastrointestinal (L4)], and Behavior [nonstricturing nonpenetrating (B1), stricturing (B2), penetrating (B3)]. The allocation of patients to these 24 subgroups proved feasible and resulted in specific disease clusters. Cross-table analyses revealed associations between Age at Diagnosis and Location, and between Behavior and Location (all p

(1993). Cyclosporin for Inflammatory Bowel Disease: Mechanisms and Possible Actions. Scandinavian Journal of Gastroenterology: Vol. 28, No. 10, pp. 849-857.