While immunosuppressive agents are used widely in the management of Crohn's disease, their efficacy has not been well established in randomised controlled trials. This study was designed to examine whether azathioprine increases remission rate when used in conjunction with a diminishing dose regimen of prednisolone over a period of 12 weeks. It further examined whether azathioprine offers any therapeutic advantage over placebo in the maintenance of remission in Crohn's disease over a period of 15 months. Sixty three patients with active Crohn's disease were treated with a 12 week diminishing dose of prednisolone and at the same time entered into a randomised, double blind 15 month trial of either azathioprine (2.5 mg/kg) or placebo. Remission rates between the two groups were compared at 12 weeks and at 15 months. There was no significant difference in the proportion of patients who had achieved and maintained remission by week 12 but at 15 months there was a highly significant difference in the proportion of patients in remission (42% receiving azathioprine v 7%/o receiving placebo), p=O0OO1. Using life tables this beneficial effect was reflected as the difference in the median number of days on the trial (p=0.02). There were significandy greater decreases over the trial period in the median erythrocyte sedimentation rate, C reactive protein, and leucocyte count in the azathioprine group. There were no cases of severe bone marrow suppression or clinical pancreatitis. In conclusion, azathioprine offers a therapeutic advantage over placebo in the maintenance of remission in Crohn's disease. (Gut 1995; 37: 674-678)

BACKGROUND & AIMS: In celiac disease (CeD), gluten induces immune activation, leading to enteropathy. TAK-101, gluten protein (gliadin) encapsulated in negatively charged poly(DLlactide-co-glycolic acid) nanoparticles, is designed to induce gluten-specific tolerance. METHODS: TAK-101 was evaluated in phase 1 dose escalation safety and phase 2a double-blind, randomized, placebo-controlled studies. Primary endpoints included pharmacokinetics, safety, and tolerability of TAK-101 (phase 1) and change from baseline in circulating gliadinspecific interferon-g-producing cells at day 6 of gluten challenge, in patients with CeD (phase 2a). Secondary endpoints in the phase 2a study included changes from baseline in enteropathy (villus height to crypt depth ratio [Vh:Cd]), and frequency of intestinal intraepithelial lymphocytes and peripheral gut-homing T cells. RESULTS: In phase 2a, 33 randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-g spot-forming units vs placebo (2.01 vs 17.58, P ¼ .006). Vh:Cd deteriorated in the placebo group (À0.63, P ¼ .002), but not in the TAK-101 group (À0.18, P ¼ .110), although the intergroup change from baseline was not significant (P ¼ .08). Intraepithelial lymphocyte numbers remained equal. TAK-101 reduced changes in circulating a4b7 þ CD4 þ (0.26 vs 1.05, P ¼ .032), aEb7 þ CD8 þ (0.69 vs 3.64, P ¼ .003), and gd (0.15 vs 1.59, P ¼ .010) effector memory T cells. TAK-101 (up to 8 mg/kg) induced no clinically meaningful changes in vital signs or routine clinical laboratory evaluations. No serious adverse events occurred. CONCLUSIONS: TAK-101 was well tolerated and prevented gluten-induced immune activation in CeD. The findings from the present clinical trial suggest that antigen-specific tolerance was induced and represent a novel approach translatable to other immune-mediated diseases. ClinicalTrials.gov identifiers: NCT03486990 and NCT03738475.

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One hundred fifty-two of 399 Crohn's patients (38 percent) diagnosed over 20 years, who lived within a geographically defined area at the time of diagnosis, underwent at least one operation. One hundred seventy-one resections were performed in 160 operations during a mean follow-up of 60 months. Forty-eight percent of patients had undergone their first resection within 10 years of diagnosis, and 39 percent of these had undergone a second resection within 10 years of the first. There was no difference between smokers and nonsmokers in the timing of their surgery.

Most of the few available economic studies of CD assess testing and diagnosis costs, especially in Europe. Methods of testing generally are considered cost effective when they combine diagnostic modalities in symptomatic patients. Most costs to a payer of managing CD derive from outpatient care. Following GFD initiation, patients lose fewer days from work and school than pretreatment.