Adalimumab for Maintenance of Clinical Response and Remission in Patients With Crohn’s Disease: The CHARM Trial

Colombel, Jean–Frédéric; Sandborn, William J.; Rutgeerts, Paul; Enns, Robert; Hanauer, Stephen B.; Panaccione, Remo; Schreiber, Stefan; Byczkowski, Dan; Li, Ju; Kent, Jeffrey D.; Pollack, Paul

doi:10.1053/j.gastro.2006.11.041

Cited by 1,951 publications

(1,481 citation statements)

References 29 publications

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“…As many patients with IBD were either refractory or intolerant to treat ment with the classic agents already discussed, there was an urgent need for the development of more specific novel therapeutic approaches. In this context, anti TNF agents, including infliximab, adalimumab, golimumab and certo lizumab pegol, were introduced into clin ical therapy for IBD 14,[23][24][25][26][27][28][29][30][31][32][33] . For instance, infliximab was shown to be effective for induction and maintenance of remission in both Crohn's disease and ulcerative colitis as well as for treatment of fistulas in Crohn's disease, highlighting the broad relevance of anti TNF therapy 14,24 .…”

Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

484

366

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: Classic Immunosuppressive Drugsmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

484

366

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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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“…Since the first double-blind, placebo-controlled trial with Infliximab (IFX) 2 numerous pivotal trials on the efficacy of IFX, Adalimumab (ADA) and Certzolizumab pegol (CTZ) in inducing and maintaining clinical response and remission and achieving mucosal healing have been published [2][3][4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

Addressing current treatment challenges in Crohn's disease in real life: A physician's survey

Vavricka

Radivojevic²,

Manser³

et al. 2014

Digestive and Liver Disease

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BACKGROUND: In recent years several trials have addressed treatment challenges in Crohn's disease. Clinical trials however, represent a very special situation. AIMS: To perform a cross-sectional survey among gastroenterologists on the current clinical real life therapeutic approach focussing on the use of biologics. METHODS: A survey including six main questions on clinical management of loss of response, diagnostic evaluation prior to major treatment changes, preference for anti-tumour necrosis factor (TNF) agent, (de-)escalation strategies as well as a basic section regarding personal information was sent by mail to all gastroenterologists in Switzerland (n=318). RESULTS: In total, 120 questionnaires were analysed (response rate 37.7%). 90% of gastroenterologists in Switzerland use a thiopurine as the first step-up strategy (anti-TNF alone 7.5%, combination 2.5%). To address loss of response, most physicians prefer shortening the interval of anti-TNF administration followed by dose increase, switching the biologic and adding a thiopurine. In case of prolonged remission on combination therapy, the thiopurine is stopped first (52.6%) after a mean treatment duration of 15.7 months (biologic first in 41.4%). CONCLUSIONS: Everyday clinical practice in Crohn's disease patients appears to be incongruent with clinical data derived from major trials. Studies investigating reasons underlying these discrepancies are of need to optimize and harmonize treatment.

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Adalimumab for Maintenance of Clinical Response and Remission in Patients With Crohn’s Disease: The CHARM Trial

Cited by 1,951 publications

References 29 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

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

Addressing current treatment challenges in Crohn's disease in real life: A physician's survey

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