Postoperative thiopurines in smokers with Crohn's disease
Authors: Jacques Cosnes
Journal: The Lancet. Gastroenterology & hepatology (2016)

Crohn's disease is a lifelong disease that is often not cured by resection of all macroscopic lesions and nearly always recurs clinically within a few years after so-called curative surgery. Thus, a maintenance treatment is needed in patients who undergo surgery. Thiopurines (azathioprine and mercaptopurine) are the cornerstone of maintenance treatment in Crohn's disease and decreased the risk of postoperative clinical recurrence compared with placebo in two randomised trials published at the beginning of this century.1Gordon M Taylor K Akobeng AK Thomas AG Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease.Cochrane Database Syst Rev. 2014; 8 (CD010233)Google Scholar However, the effect was modest; pooling the results from the two trials gave a risk ratio of 0·74 (95% CI 0·58–0·94).1Gordon M Taylor K Akobeng AK Thomas AG Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease.Cochrane Database Syst Rev. 2014; 8 (CD010233)Google Scholar Findings from other trials comparing thiopurines with mesalazine did not show significant differences.1Gordon M Taylor K Akobeng AK Thomas AG Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease.Cochrane Database Syst Rev. 2014; 8 (CD010233)Google Scholar Moreover, impressive results were reported from pilot studies, showing the great efficacy of anti-tumour-necrosis-factor (anti-TNF) drugs in this setting.2Regueiro M Schraut W Baidoo L et al.Infliximab prevents Crohn's disease recurrence after ileal resection.Gastroenterology. 2009; 136: 441-450Summary Full Text Full Text PDF PubMed Scopus (503) Google Scholar For these reasons, and because of problems of tolerance in up to 20% of patients, many physicians became reluctant to use thiopurines as preventive drugs, preferring to prescribe anti-TNF drugs in patients with a high risk of recurrence and to give mesalazine or no treatment at all in low-risk patients. Thus, the relevance of a new trial re-investigating the benefits of mercaptopurine after surgery could be questioned. However, the TOPPIC trial3Mowat C Arnott I Cahill A et al.for the TOPPIC Study GroupMercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.Lancet Gastroenterol Hepatol. 2016; 1: 273-282Summary Full Text Full Text PDF PubMed Scopus (68) Google Scholar of mercaptopurine to prevent recurrence of Crohn's disease after surgical resection, published in The Lancet Gastroenterology & Hepatology, is unique because of its high methodological quality, in particular its long duration of up to 3 years, the masking of participants, the dosing of the drug, and the choice of a solid and pragmatic primary endpoint of well defined clinical recurrence and need for associated medical or surgical treatment. In the trial, 128 patients with Crohn's disease received mercaptopurine and 112 placebo. 16 (13%) patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27–1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28–0·99; p=0·046). This finding of reduced clinical recurrence with mercaptopurine is not new, but this result should be put in parallel with more recent data on anti-TNF drugs: the PREVENT study4Regueiro M Feagan BG Zou B et al.Infliximab reduces endoscopic, but not clinical recurrence of Crohn's disease after ileocolonic resection.Gastroenterology. 2016; 150: 1568-1578Summary Full Text Full Text PDF PubMed Scopus (182) Google Scholar did not show a significant effect of infliximab on prevention of postoperative clinical recurrence by month 18, and, although not designed for this objective, the POCER study5De Cruz P Kamm MA Hamilton AL et al.Crohn's disease management after intestinal resection: a randomised trial.Lancet. 2015; 385: 1406-1417Summary Full Text Full Text PDF PubMed Scopus (367) Google Scholar showed that adalimumab had some efficacy, but this was not as universal as expected, with 43% of patients given adalimumab postoperatively experiencing endoscopic recurrence at 2 years. When considering long-term prescription of a drug, long-term tolerance and efficacy, constraints, and costs need to be taken into account; this would favour thiopurines over anti-TNF drugs in most patients. The key finding of the TOPPIC trial was the particular efficacy of mercaptopurine in smokers. 55 (23%) patients included in the study were active smokers. In this subgroup, mercaptopurine was effective at preventing postoperative recurrence (HR 0·13, 95% CI 0·04–0·46), with a number needed to treat to prevent one recurrence of only three. Conversely, the effect of mercaptopurine was not significant in non-smokers. Although unexplained, the efficacy of thiopurines in smokers has been known for around 20 years.6Cosnes J Carbonnel F Beaugerie L Le Quintrec Y Gendre JP Effects of cigarette smoking on the long-term course of Crohn's disease.Gastroenterology. 1996; 110: 424-431Summary Full Text PDF PubMed Scopus (384) Google Scholar Smokers have a more severe disease than do non-smokers, and they need more immunosuppressants and surgery; active smoking is recognised as the most important predictive factor of disease recurrence. Because smokers have a high risk of early postoperative recurrence, surgery must be avoided or postponed as long as possible and all efforts are needed to achieve smoking cessation before surgery. That said, results of smoking cessation programmes are disappointing in this population. When a smoker needs surgery, findings from the TOPPIC trial3Mowat C Arnott I Cahill A et al.for the TOPPIC Study GroupMercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.Lancet Gastroenterol Hepatol. 2016; 1: 273-282Summary Full Text Full Text PDF PubMed Scopus (68) Google Scholar suggest that thiopurines should be started or re-started within the 3 months after surgery, with a high probability of delaying postoperative recurrence. Postoperative recurrence, with the sequence of histological lesions, endoscopic ulcerations, clinical symptoms, then re-operation, is an amazing model to understand the natural history of Crohn's disease and to test treatments. The place of thiopurines in the management of Crohn's disease has been debated during recent years, particularly after the two negative trials testing the efficacy of azathioprine in very early Crohn's disease7Cosnes J Bourrier A Laharie D et al.Early administration of azathioprine vs conventional management of Crohn's disease: a randomized controlled trial.Gastroenterology. 2013; 145: 758-765Summary Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 8Panes J Lopez-Sanroman A Bermejo F et al.Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn's disease.Gastroenterology. 2013; 145: 766-774Summary Full Text Full Text PDF PubMed Scopus (199) Google Scholar and the evidence of an increased, albeit small, risk of malignancy.9Pasternak B Svanstrom H Schmiegelow K Jess T Hviid A Use of azathioprine and the risk of cancer in inflammatory bowel disease.Am J Epidemiol. 2013; 177: 1296-1305Crossref PubMed Scopus (153) Google Scholar In fact, the conclusion of the RAPID trial7Cosnes J Bourrier A Laharie D et al.Early administration of azathioprine vs conventional management of Crohn's disease: a randomized controlled trial.Gastroenterology. 2013; 145: 758-765Summary Full Text Full Text PDF PubMed Scopus (224) Google Scholar was not that azathioprine was useless, but that there was no need to start azathioprine very early in the disease course. Thiopurines are efficacious in 40–50% of patients with Crohn's disease. They are safe before age 65 years and in people who test positive for Epstein-Barr virus, and are safe and particularly efficacious in smokers. They should remain a major maintenance treatment for Crohn's disease, provided that their dosing is sufficient or optimised.10Moreau AC Paul S Del Tedesco E et al.Association between 6-thioguanine nucleotides levels and clinical remission in inflammatory disease: a meta-analysis.Inflamm Bowel Dis. 2014; 20: 464-471Crossref PubMed Scopus (75) Google Scholar In this regard, it is noteworthy that the hazard of clinical recurrence decreased when the concentration of thioguanine nucleotides, a marker of compliance and adequate dosing, increased in the TOPPIC trial. I have received personal fees for being an editorial board member from Vifor Pharma and have received lecture fees from AbbVie. Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trialMercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. Full-Text PDF Open Access