Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial

Hanauer, Stephen B.; Feagan, Brian G.; Lichtenstein, Gary R.; Mayer, Lloyd; Schreiber, Stefan; Colombel, Jean Fréd́eric; Rachmilewitz, Daniel; Wolf, Douglas C.; Olson, Allan; Bao, Weihang; Rutgeerts, Paul

doi:10.1016/s0140-6736(02)08512-4

Cited by 3,781 publications

(2,776 citation statements)

References 22 publications

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“…These figures compare favourably with reports of currently licenced and emerging biological therapies. [25][26][27][28] Univariate analyses highlighted baseline factors associated with achieving clinical remission off steroids for greater than 3 months. These included colonic disease, short disease duration, evidence of inflammatory rather than complex disease as well as a high endoscopic burden of disease activity.…”

Section: Discussionmentioning

confidence: 99%

Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial

Lindsay

Allez

Clark

et al. 2017

The Lancet Gastroenterology & Hepatology

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BACKGROUND The randomised controlled ASTIC trial showed no benefit of mobilisation and autologous haematopoietic stem-cell transplantation (HSCT) compared with mobilisation followed by conventional therapy using a stringent primary endpoint (steroid-free clinical remission for 3 months with no endoscopic or radiological evidence of intestinal inflammation) in patients with treatment-refractory Crohn's disease. We now assess HSCT in patients enrolled in the ASTIC trial using endpoints that are traditional for clinical trials in Crohn's disease, and identify factors that predict benefit or harm. METHODS Patients who underwent mobilisation and were randomly assigned to conventional therapy in the ASTIC trial were offered HSCT at 1 year and underwent complete assessment for a further year. We report analyses of the combined cohort of patients who underwent HSCT at any time during the ASTIC trial programme. The primary outcome for this analysis was 3-month steroid-free clinical remission at 1 year after HSCT (Crohn's Disease Activity Index [CDAI] <150). We also examined the degree of endoscopic healing at 1 year. Multivariate analysis was performed to identify factors associated with achieving the primary endpoint by using logistic regression, and factors associated with experiencing a serious adverse event using Poisson regression. Participants were not masked to treatment, but the adjudication panel that reviewed radiology and endoscopy was masked to allocation and visits. All patients who underwent HSCT and had data available at baseline and 1-year follow-up were included in the primary and safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00297193. FINDINGS Between June 28, 2007, and Sept 1, 2011, 45 patients were enrolled in the ASTIC trial from 11 European transplant units. 23 patients were randomly assigned to immediate HSCT, and 22 patients were assigned to mobilisation followed by conventional care. After completion of the ASTIC trial, 17 patients from the conventional care group received HSCT. In the combined cohort, data were available for 40 patients at baseline and 38 patients at 1 year after HSCT (one patient died, one withdrew). At 1 year after HSCT, 3-month steroid-free clinical remission was seen in 13 (38%, 95% CI 22-55) of 34 patients with available data for the whole year. Complete endoscopic healting was noted in 19 (50%, 34-66) of 38 patients. On multivariate analyses, factors associated with the primary outcome were short disease duration (odds ratio [OR] 0·64, 95% CI 0·41-0·997 per year; p=0·048) and low baseline CDAI (0·82, 0·74-0·98 per 10 units; p=0·031). 76 serious adverse events occurred in 23 of 40 patients with available data. The most common serious adverse event was infection, most of which were treatment related. Smoking and perianal disease at baseline were independent factors associated with the number of serious adverse events (OR 3·07 [95% CI 1·75-5·38; p=0·0001] for smoking and 3·97 [2·17-7·25; p<0·0001] for perianal disease) on multivariate...

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Section: Discussionmentioning

confidence: 99%

Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial

Lindsay

Allez

Clark

et al. 2017

The Lancet Gastroenterology & Hepatology

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“…19,20 Particularly in children, treatment of ocular inflammation often requires doses of infliximab higher than those usually prescribed in inflammatory arthritis and colitis in order to provide adequate drug penetration and concentration in the protected ocular compartment. The dosing flexibility of infliximab compared to etanercept may explain why infliximab appears be more efficacious than etanercept to treat noninfectious uveitis.…”

Section: Discussionmentioning

confidence: 99%

Infliximab to Treat Chronic Noninfectious Uveitis in Children: Retrospective Case Series with Long-term Follow-up

Ardoin

Kredich

Rabinovich

et al. 2007

American Journal of Ophthalmology

104

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“…As clinical experience with TNF antagonists has accumulated, functional differences among these drugs have emerged that appear to be structural in origin. The TNF antibodies infliximab and adalimumab, for example, are or appear to be effective in the treatment of granulomatous conditions such as Crohn's disease and sarcoidosis, whereas soluble type II TNF receptor (etanercept) is not (3)(4)(5)(6). In vitro, TNF antibodies inhibit the activation of T cells and the production of interferon-␥, whereas etanercept does not (7,8).…”

Section: Objective Tumor Necrosis Factor (Tnf) Blockade Increases Thmentioning

confidence: 99%

Mathematical modeling of the cause of tuberculosis during tumor necrosis factor blockade

Wallis

2008

Arthritis & Rheumatism

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Objective. Tumor necrosis factor (TNF) blockade increases the risk of tuberculosis (TB). The purpose of this study was to use Markov modeling to examine the contributions of reactivation of latent tuberculous infection (LTBI) and the progression of new infection withMycobacterium tuberculosis to active TB due to TNF blockade. These 2 pathogenic mechanisms cannot otherwise be readily distinguished.Methods. Monte Carlo simulation was used to represent the range of reported values for the incidence of TB associated with infliximab (TNF monoclonal antibody) and etanercept (soluble TNF receptor) therapy. Iterative methods were then used to identify for each pair of incidence rates the Markov model parameters that most accurately represented the distribution of time to onset of TB as reported to the Food and Drug Administration.Results. Modeling revealed an apparent median monthly rate of reactivation of LTBI by infliximab treatment of 20.8%, which was 12.1 times that with etanercept treatment (P < 0.001). In contrast, both drugs appeared to pose a high risk of progression of new M tuberculosis infection to active TB. Progression of new infection appeared to cause nearly half of the etanercept-associated cases; it became the predominant cause of infliximab-associated cases only after the first year.Conclusion. Despite sharing a common therapeutic target, infliximab and etanercept differ markedly in the rates at which they reactivate LTBI. Confirmation of these findings will require the application of molecular epidemiologic tools to studies of TB in future biologics registries. Hidden Markov modeling and Monte Carlo simulation are powerful tools for revealing otherwise hidden aspects of the pathogenesis of TB.

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Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial

Cited by 3,781 publications

References 22 publications

Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial

Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial

Infliximab to Treat Chronic Noninfectious Uveitis in Children: Retrospective Case Series with Long-term Follow-up

Mathematical modeling of the cause of tuberculosis during tumor necrosis factor blockade

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