Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial

Mowat, Craig; Arnott, Ian; Cahill, A; Smith, M. G.; Ahmad, Tariq; Subramanian, Sreedhar; Travis, Simon; Morris, John; Hamlin, John; Dhar, Anjan; Nwokolo, Chuka U.; Edwards, Cathryn; Creed, Tom; Bloom, Stuart; Yousif, Mohamed Omar; Thomas, Linzi; Campbell, Simon; Lewis, Stephen J.; Sebastian, Shaji; Sen, Sandip; Lal, Simon; Hawkey, C. J.; Murray, Charles; Cummings, Fraser; Goh, Jason; Lindsay, James O.; Arebi, Naila; Potts, Lindsay; McKinley, Aileen; Thomson, John; Todd, John; Collie, Mhairi; Dunlop, Malcolm G.; Mowat, Ashley G; Gaya, Daniel R.; Winter, Jack; Naismith, Graham; Ennis, Holly; Keerie, Catriona; Lewis, Steff; Prescott, R. J.; Kennedy, Nicholas A; Satsangi, Jack

doi:10.1016/s2468-1253(16)30078-4

Cited by 89 publications

(78 citation statements)

References 26 publications

(34 reference statements)

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“…There is an established strong association between smoking and CD, perhaps best demonstrated in the recent TOPPIC trial which identified smoking as the only factor which predicted post-operative recurrence in CD (35). Our study raises the hypothesis that the association of smoking and CD disease may be due to an effect of this combination on NF-B signalling dynamics.…”

Section: Discussionsupporting

confidence: 54%

Macrophage-specific NF-κB activation dynamics can segregate inflammatory bowel disease patients

Παπουτσοπουλου

Burkitt

Bergey

et al. 2019

Preprint

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The heterogeneous nature of inflammatory bowel disease (IBD) presents challenges, particularly when choosing therapy. Activation of the NF-B transcription factor is a highly-regulated, dynamic event in IBD pathogenesis. We expressed the human NF-B/p65 subunit in blood-derived macrophages, using lentivirus. Confocal imaging of p65 activation revealed that a higher proportion of macrophages from Crohn's patients responded to lipid-A compared to controls. In contrast, cells from ulcerative colitis (UC) patients exhibited a shorter duration of p65 nuclear localisation compared to healthy controls and Crohn's donors. Using a similar lentivirus approach, NF-B-regulated luciferase was expressed in patient macrophages, isolated from frozen peripheral blood mononuclear cell samples. Following activation, samples could be segregated into three clusters based on the NF-B-regulated luciferase response. The majority of UC samples appeared in hypo-responsive cluster 1, with Crohn's patients representing the majority of hyper-responsive cluster 3. A positive correlation was seen between NF-B-induced luciferase activity and cytokine levels released to medium from stimulated macrophages, but not in serum or biopsy. Analysis of macrophage cytokine responses and patient metadata revealed a strong correlation between Crohn's patients who smoked and hyperactivation of p65. These in vitro dynamic assays of NF-B activation in blood-derived macrophages segregate IBD patients into groups with different phenotypes and therefore may help determine response to therapy.

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Section: Discussionsupporting

confidence: 54%

Macrophage-specific NF-κB activation dynamics can segregate inflammatory bowel disease patients

Παπουτσοπουλου

Burkitt

Bergey

et al. 2019

Preprint

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“…Meta‐analyses confirmed that thiopurines could reduce the risk of postoperative clinical and endoscopic recurrence compared with placebo or mesalazine . Although several studies reported that postoperative thiopurines were associated with a lower rate of surgical recurrence, a large RCT failed to detect any difference between mercaptopurine and placebo . Anti‐TNF drugs are currently the most effective agents in preventing postoperative clinical and endoscopic recurrence, but their efficacy on surgical recurrence remains unknown .…”

Section: Discussionmentioning

confidence: 99%

Immediate prophylactic vs endoscopic or symptomatic‐driven azathioprine treatment to prevent surgical recurrence after intestinal resection for Crohn's disease

et al. 2018

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“…A meta‐analysis concluded that thiopurines and mercaptopurine are more effective than placebo in the prevention of clinical and endoscopic post‐operative recurrence . A recent randomised clinical trial demonstrated that mercaptopurine was effective in preventing post‐operative clinical recurrence, but only in patients who were smokers . Infliximab have a demonstrated efficacy in the prevention of post‐operative endoscopic recurrence .…”

Section: Introductionmentioning

confidence: 99%

“…16 A recent randomised clinical trial demonstrated that mercaptopurine was effective in preventing post-operative clinical recurrence, but only in patients who were smokers. 17 Infliximab have a demonstrated efficacy in the prevention of post-operative endoscopic recurrence. 15,18,19 A subanalysis performed in the POCER study suggested that adalimumab may be superior to thiopurines in preventing early endoscopic postoperative recurrence in high-risk patients.…”

Section: Introductionmentioning

confidence: 99%

Male gender, active smoking and previous intestinal resection are risk factors for post‐operative endoscopic recurrence in Crohn's disease: results from a prospective cohort study

Auzolle

Nancey

Tran‐Minh

et al. 2018

Aliment Pharmacol Ther

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Summary Background After ileocaecal resection for Crohn's disease (CD), inflammatory lesions frequently recur on the anastomosis and/or on the neo‐terminal ileum. Aim To identify predictors of early post‐operative endoscopic recurrence. Methods From September 2010 to September 2017, the REMIND group conducted a prospective nationwide study in nine French academic centres. Data were collected at the time of surgery and endoscopy, performed 6‐12 months after surgery. Endoscopic recurrence was defined as a Rutgeerts score ≥i2. Baseline factors associated with endoscopic recurrence were searched by univariate and multivariate regression analysis. Results Two hundred and eighty‐nine CD patients were included. Endoscopy within 1 year following surgery was performed in 225 (78%) patients (104M/121F). Mean age and disease duration were 35 (12.2) and 8.8 (8.9) years respectively. Seventy (32%) patients were active smokers at surgery. One hundred and forty‐two (63%) patients received at least one anti‐TNF therapy before surgery. After surgery, 40 (18%) patients received thiopurines and 66 (29%) received an anti‐TNF agent. Endoscopic recurrence occurred in 107 (47%) patients. In multivariate analysis, male gender (OR = 2.48 [IC 95% 1.40‐4.46]), active smoking at surgery (OR = 2.65 [IC 95% 1.44‐4.97]) and previous resection (OR = 3.03 [IC 95% 1.36‐7.12]) were associated with a higher risk of endoscopic recurrence. Inversely, post‐operative anti‐TNF treatment decreased the risk of endoscopic recurrence (OR = 0.50 [IC 95% 0.25‐0.96]). Conclusions Male gender, active smoking at surgery and previous intestinal resection are associated with a higher risk of endoscopic post‐operative recurrence, while post‐operative anti‐TNF treatment is associated with a lower risk.

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Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial

Abstract: Medical Research Council.

Cited by 89 publications

References 26 publications

Macrophage-specific NF-κB activation dynamics can segregate inflammatory bowel disease patients

Macrophage-specific NF-κB activation dynamics can segregate inflammatory bowel disease patients

Immediate prophylactic vs endoscopic or symptomatic‐driven azathioprine treatment to prevent surgical recurrence after intestinal resection for Crohn's disease

Male gender, active smoking and previous intestinal resection are risk factors for post‐operative endoscopic recurrence in Crohn's disease: results from a prospective cohort study

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