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Three Part Question

In children with CD [patient], in addition to standard first-line treatment, would starting a thiopurine at diagnosis [intervention] versus using thiopurines as second-line therapy (comparison) prevent relapses [outcome]?

Clinical Scenario

A 13-year-old boy presents with an 8 month history of abdominal pain, diarrhoea and some weight loss. Investigations confirm Crohn’s disease (CD) of moderate severity. To induce remission you consider either a 6-12 week course of corticosteroids or exclusive enteral nutrition with a polymeric formula for 6 weeks. You plan to reserve the thiopurines (azathioprine [AZA] or 6-mercaptopurine [6-MP]) for second-line therapy. After an internet search, the parents are aware that relapse occurs frequently after initial treatment and that the disease often progresses. They are keen for their son to start a thiopurine straight away.

Search Strategy

Secondary sources - Cochrane Database of Systematic Reviews and BestBETS
Primary sources - Medline (1996 to November 2013) and Embase (1996 to November 2013)
The search was done via Ovid on 19th December 2013 using the search terms (Azathioprine OR 6-mercaptopurine) AND (Inflammatory Bowel Diseases OR Crohn disease) AND child and limited to English and Humans

Secondary sources yielded 8 reviews from the Cochrane Library but none were of randomised controlled trials in children. BestBETS did not yield any reviews.

Search Outcome

The primary sources yielded a total of 144 studies. There were several observational cohort studies and retrospective reviews comparing outcomes in children who had and had not been treated with a thiopurine. However, we identified only one trial where children were randomised to receive a thiopurine or placebo during the initial treatment of Crohn’s disease (summarised in Table 1).

Comment(s)

CD is a long-term, relapsing inflammatory disorder that may affect any part of the gastrointestinal tract. The chronic inflammatory state and tendency to recurrent relapses can lead to strictures and fistulas requiring surgery, osteoporosis, pubertal delay, growth failure, and severely impaired quality of life. Treatment aims to achieve and maintain long-term remission whilst preventing complications, especially protecting growth and preventing osteopaenia by limiting glucocorticosteroid exposure.2 Although initial treatment with glucocorticosteroids or exclusive enteral nutrition with a polymeric formula is usually effective in inducing remission,3 steroid dependency or relapse is common. After 30 days of treatment with systemic steroids in a cohort of 87 Danish children, 55 (63%) had complete remission, 25 (29%) partial response, 7 (8%) had no response and 32 (37%) were steroid-dependent.4 Response rates are similar with exclusive enteral nutrition but relapse occurs in 50-80% of children.2 The thiopurine AZA and its metabolite 6-MP, alone or in combination with other drugs, are effective in maintaining remission and as steroid-sparing drugs in patients with frequent flare-ups and in steroid-dependent or refractory disease.4-6 They can take up to three months to be fully effective. Current guidelines recommend adding a thiopurine to initial treatment to induce remission if the dose of glucocorticosteroids cannot be reduced or ≥2 inflammatory exacerbations occur within 12 months of starting treatment.3 A thiopurine can be continued to maintain remission in children where they have been required to induce remission, or started once remission has been achieved in children with adverse prognostic factors including early age at disease onset, perianal disease, glucocorticosteroid use at presentation and severe disease.3 Thiopurines are used frequently as second-line therapy in Crohn’s disease. Thiopurines were required in 14/29 (48.3%) Danish children within 24 months of diagnosis,7 72/88 (82%) Dutch children followed-up for at least 18 months5 and 199/247 (80%) American children within a year of diagnosis.8 However, adverse events (AEs) occur in 9–28% of patients leading to dose reduction or drug withdrawal.9 AEs are classified as dose-independent (or “allergic”) or dose-dependent. The former usually occur early (within days or weeks) and include fever, malaise, nausea, abdominal pain, diarrhoea, arthralgia and pancreatitis. The latter usually develop later (months or years) and include myelotoxicity and liver toxicity. Our literature search revealed only one randomised, placebo-controlled trial in children (Table 1).1 The primary objective of the study was to determine whether 6-MP decreased the need for corticosteroid treatment. 55 children with newly diagnosed moderate-to-severe CD recruited across 18 centres in the US were treated with corticosteroids and randomised to receive either 6-MP (1.5. mg/kg/day given within 8 weeks of presentation and continued for 18 months) or placebo. Changes in corticosteroid dose followed a strict regimen according to clinical response. Treatment with 6-MP both shortened the duration of corticosteroid use and reduced the cumulative dose over 18 months follow-up (Table 1). Amongst the secondary outcomes, the disease was assessed to be inactive in all children except for one child in the placebo group by 3 months and the cumulative rate of remission at 12 months was 89% in both groups. However, at 18 months follow-up, only 9% of children receiving 6-MP had had a relapse compared with 47% of controls (P<0.007). During the 18 month follow-up, treatment failure, defined as a high disease activity score despite 2 weeks of intravenous corticosteroid treatment or the need for additional treatment of symptoms or complications of CD, occurred in 3/27 (11%) children receiving 6-MP compared with 15/28 (54%) receiving placebo (P<0.01). Linear growth and need for surgery were similar in the two groups. We are also aware of a prospective, double-blind, placebo-controlled study of 131 adults with Crohn’s disease randomised to receive either AZA or placebo within 8 weeks of diagnosis and which gave somewhat contrasting results.10 The frequency of sustained corticosteroid-free remission after 76 weeks of treatment was similar in patients treated with AZA (44.1%) compared with placebo (36.5%; difference of 7.6%; 95% confidence interval -9.2 to 24.4%; P=0.48). Rates of relapse and corticosteroid use were also similar in the two groups. However, in keeping with the paediatric study, moderate to severe relapse was less common in the AZA than the placebo group (11.8% vs. 30.2%; P=0.01). In terms of adverse events, mild decreases in blood lymphocyte count and elevations of transaminase enzyme levels were associated with 6-MP treatment in the randomised trial in children.1 One subject discontinued 6-MP due to a low lymphocyte count and one was withdrawn following intra-abdominal abscesses secondary to enteric fistulas. The frequency of AEs was low in this study compared to thiopurines used as second-line therapy.9 The randomised trial assessed a thiopurine as adjunctive therapy with glucocorticosteroid in the first-line treatment of Crohn’s disease with follow-up for 18 months.1 We are not aware that their role in children treated with exclusive enteral nutrition, cost effectiveness, and effects on quality of life or longer-term outcomes have been evaluated. In conclusion, thiopurines used early in management might have an important role as disease modifying agents. However, despite their use widespread use for many years, further research is required to determine the most appropriate use of thiopurines in paediatric Crohn’s disease. References 1. 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. 2. Fell JME. Update of the management of inflammatory bowel disease. Arch Dis Child 2012; 97:78–83. 3. Mayberry JF, Lobo A, Ford AC, et al. NICE clinical guideline (CG152): the management of Crohn's disease in adults, children and young people. Aliment Pharmacol Ther 2013; 37:195-203. 4. Jakobsen C, Munkholm P, Paerregaard A, et al. Steroid dependency and pediatric inflammatory bowel disease in the era of immunomodulators--a population-based study. Inflamm Bowel Dis 2011; 17:1731-40. 5. Jaspers GJ, Verkade HJ, Escher JC, et al. Azathioprine maintains first remission in newly diagnosed pediatric Crohn's disease. Inflamm Bowel Dis 2006; 12:831-6. 6. Riello L, Talbotec C, Garnier-Lengliné H, et al. Tolerance and efficacy of azathioprine in pediatric Crohn's disease. Inflamm Bowel Dis 2011; 17:2138-43. 7. Jakobsen C, Bartek Jr J, Wewer V, et al. Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease – a population-based study. Aliment Pharmacol Ther 2011; 34:1217–1224 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. Kim MJ, Choe YH. Monitoring and Safety of Azathioprine Therapy in Inflammatory Bowel Disease. Pediatr Gastroenterol Hepatol Nutr 2013; 16:65-70. 10. Panés J, López-Sanromán A, Bermejo F et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn's disease. Gastroenterology 2013; 145:766-774.

Clinical Bottom Line

•Thiopurines have been used for many years as second-line treatment for Crohn’s disease in children •The benefit versus risk in the prevention of early relapse, cost-effectiveness and long term outcomes of adding a thiopurine to first-line therapy of paediatric Crohn’s disease are unclear