Thiopurines are reportedly more efficacious in children than in adults with IBD. In relation to CD, it has been proposed (7) that this is because they are used earlier in the disease course in children when inflammatory disease predominates over stricturing and penetrating disease (12). No previous studies have directly compared the responses of children and adults to thiopurines. Nor has attention been given to the influence on response to thiopurines of differing phenotypes, where, especially in CD, noninflammatory complications such as bacterial overgrowth or bile salt malabsorption may cause symptoms that would not be expected to improve with immunosuppression.
Although our numbers are relatively small and because of our retrospective design the results are potentially subject to interpretation bias, we have used clinically relevant and observer-independent outcome criteria that are likely to be applicable in day-to-day practice. Thus, having controlled for disease phenotype, we report that the rates of corticosteroid-free remission and subsequent relapse rates in children are no different from those in adults.
The rates of thiopurine-induced steroid-free remission reported here are similar to the 30% reported in the recent SONIC trial (16), and 27% to 38% at 4 to 7 months in previous studies in adults that have used CD activity index (CDAI) to define remission (17–19). Our remission rates are, however, lower than in other studies (6,20,21) that did not use complete steroid withdrawal as an outcome criterion. The marked disparity between the response rates in the only preceding randomised controlled trial of 6-mercaptopurine (6-MP) in CD in children is probably explained primarily by differences in definitions of remission: Markowitz et al (6) defined remission by CDAI and did not require discontinuation of steroids.
It is conceivable that the shorter the interval between diagnosis and the introduction of a thiopurine, the better its effect (6,7), because a higher proportion of patients treated earlier would have inflammatory rather stricturing or penetrating disease (12). In our albeit small subsample the rates of clinical remission were no different in those patients treated with a thiopurine within 6 months of diagnosis than in those treated at a later stage in the more usual “bottom-up” manner. In addition, and acknowledging the risk of making a type II error, we found no differences in response according to disease behaviour or location.
Our results for UC are consistent with those published in randomised trials in adult studies. Timmer et al, in the most recent Cochrane meta-analysis (11) of 4 trials (22–25), reports a pooled odds ratio of 0.41 (95% CI 0.24–0.70), equivalent to a 30% (range 17%–41%) chance of failing to maintain remission at 12 months or longer. No randomised controlled studies of thiopurines have been conducted exclusively in children with UC. Retrospective studies, again reporting steroid dose reduction but not withdrawal, suggest remission rates of 50% to 75% (26–28). More recent data presented in abstract form, from a large cohort of children from North America, report steroid-free survival rates of about 70% at 1 year (29), findings that resemble ours.
As reported in a previous series of different patients from our centre, the rates of intolerance and subsequent discontinuation because of adverse effects of thiopurines are higher in adults than in children (5). Drug adherence could account for the difference in tolerance, because adherence is reportedly worse in children and adolescents than in adults (30,31) and individuals not taking a drug cannot have adverse effects from it and will not therefore be recorded as being intolerant to it. Against significant nonadherence in the paediatric group here is the observation that surrogate markers of thiopurine use, including the degree to which the neutrophil count decreased and the MCV increased, were similar between groups.
In summary, it is likely that the perceived superior response rates to thiopurines in children relate not to differences in interval to treatment, and therefore disease behaviour at the time of their introduction, but to differences in definitions of remission and/or relapse employed in different studies. Corticosteroid-free remission and subsequent relapse rates are similar in children and adults when their disease phenotype is matched, although children do seem to tolerate thiopurines better than adults.
We are grateful to Dr James Lindsay, Dr Louise Langmead, Dr Sandhia Naik, and Dr Nigel Meadows for their constructive criticism whilst reviewing the work and for allowing us to include their patients. We also thank the National Association of Crohn's and Colitis and CORE/British Society of Paediatric Gastroenterology, Hepatology, and Nutrition for funding J.R.G.'s research.
1. Sawczenko A, Sandhu BK, Logan RF, et al
. Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet 2001; 357:1093–1094.
2. Armitage E, Drummond HE, Wilson DC, et al
. Increasing incidence of both juvenile-onset Crohn's disease and ulcerative colitis in Scotland. Eur J Gastroenterol Hepatol 2001; 13:1439–1447.
3. Vernier-Massouille G, Balde M, Salleron J, et al
. Natural history of pediatric Crohn's disease: a population-based cohort study. Gastroenterology 2008; 135:1106–1113.
4. Van Limbergen J, Russell RK, Drummond HE, et al
. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 2008; 135:1114–1122.
5. Goodhand J, Dawson R, Hefferon M, et al
. Inflammatory bowel disease in young people: the case for transitional clinics. Inflamm Bowel Dis 2010; 16:947–952.
6. Markowitz J, Grancher K, Kohn N, et al
. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology 2000; 119:895–902.
7. Markowitz J. Early inflammatory bowel disease: different treatment response to specific or all medications? Dig Dis 2009; 27:358–365.
8. Punati J, Markowitz J, Lerer T, et al
. Effect of early immunomodulator use in moderate to severe pediatric Crohn disease. Inflamm Bowel Dis 2008; 14:949–954.
9. Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst Rev
10. Prefontaine E, Sutherland LR, Macdonald JK, et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev
11. Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev
12. Cosnes J, Cattan S, Blain A, et al
. Long-term evolution of disease behavior of Crohn's disease. Inflamm Bowel Dis 2002; 8:244–250.
13. Silverberg MS, Satsangi J, Ahmad T, et al
. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005; 19(Suppl A):5–36.
14. Wahed M, Louis-Auguste JR, Baxter LM, et al
. Efficacy of methotrexate in Crohn's disease and ulcerative colitis patients unresponsive or intolerant to azathioprine mercaptopurine. AP&T 2009; 30:614–620.
16. Colombel JF, Sandborn WJ, Reinisch W, et al
. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010; 362:1383–1395.
17. Summers RW, Switz DM, Sessions JT, et al
. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology 1979; 77:847–869.
18. Sandborn WJ, Tremaine WJ, Wolf DC, et al
. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group. Gastroenterology 1999; 117:527–535.
19. Lemann M, Mary JY, Duclos B, et al
. Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial. Gastroenterology 2006; 130:1054–1061.
20. Candy S, Wright J, Gerber M, et al
. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut 1995; 37:674–678.
21. Present DH, Korelitz BI, Wisch N, et al
. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980; 302:981–987.
22. Sood A, Kaushal V, Midha V, et al
. The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis. J Gastroenterol 2002; 37:270–274.
23. Sood A, Midha V, Sood N, et al
. Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial. Indian J Gastroenterol 2000; 19:14–16.
24. Hawthorne AB, Logan RF, Hawkey CJ, et al
. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992; 305:20–22.
25. Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. BMJ 1974; 4:627–630.
26. Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr 1990; 117:809–814.
27. Kader HA, Mascarenhas MR, Piccoli DA, et al
. Experiences with 6-mercaptopurine and azathioprine therapy in pediatric patients with severe ulcerative colitis. J Pediatr Gastroenterol Nutr 1999; 28:54–58.
28. Tajiri H, Tomomasa T, Yoden A, et al
. Efficacy and safety of azathioprine and 6-mercaptopurine in Japanese pediatric patients with ulcerative colitis: a survey of the Japanese Society for Pediatric Inflammatory Bowel Disease. Digestion 2008; 77:150–154.
30. Ediger JP, Walker JR, Graff L, et al
. Predictors of medication adherence in inflammatory bowel disease. Am J Gastroenterol 2007; 102:1417–1426.
31. Greenley RN, Stephens M, Doughty A, et al
. Barriers to adherence among adolescents with inflammatory bowel disease. Inflamm Bowel Dis 2010; 16:36–41.