High-dose azathioprine in children with inflammatory bowel disease

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1 Aliment Pharmacol Ther 2003; 17: doi: /j x High-dose azathioprine in children with inflammatory bowel disease D. FUENTES*, F. TORRENTE*, S. KEADY*, K. THIRRUPATHY*, M. A. THOMSON*, J. A. WALKER-SMITH*, S. H. MURCH* & R. B. HEUSCHKEL* *Centre for Paediatric Gastroenterology, Royal Free Hospital, London, UK; Paediatric Gastroenterology, Gaslini Institute, Genoa, Italy Accepted for publication 16 January 2003 SUMMARY Background: Azathioprine is widely used as maintenance therapy in children with moderate to severe inflammatory bowel disease (IBD). There is no data on safety at higher doses and its impact on growth and surgical morbidity in children. Methods: This retrospective cohort study included all children treated with azathioprine and diagnosed with IBD between Outcome measures included indications for azathioprine use, adverse-effects and reasons for treatment discontinuation. Height and weight at diagnosis, treatment onset and current follow-up was recorded, and Z scores for height standardised for time. Results: 107 children received azathioprine at 3 mg/kg. 61% had Crohn s disease and 83% started azathioprine within 2 years of diagnosis. Only 2/107 children had to stop azathioprine because of persistent adverse effects and 16/107 required surgery. There was a trend toward better growth in a group of children with Crohn s disease following treatment with high dose azathioprine therapy (P ¼ 0.08). Conclusions: Azathioprine is a safe and well-tolerated maintenance therapy at 3 mg/kg for children with IBD. The prevalence of surgery and growth failure in a cohort of children with moderate to severe IBD appears less than previously reported. In children with Crohn s disease, growth velocity may be maximised by an emphasis on nutritional therapy and the use of high dose azathioprine. INTRODUCTION The incidence of chronic inflammatory bowel disease in childhood continues to increase. 1 With almost 20% of cases being diagnosed in childhood, the impact of therapy on the long-term outcome and natural history of the disease has never been more important. The natural history of moderate to severe ulcerative colitis, indeterminate colitis and Crohn s disease, in both adults and children, is one of frequent disease relapse, often with a life-long need for therapies aimed at trying to maintain remission. Although much progress has been Correspondence to: Dr R. B. Heuschkel, Centre for Paediatric Gastroenterology, Royal Free Hospital, Pond Street, Hampstead, London, NW3 2QG, UK. r.heuschkel@rfc.ucl.ac.uk made at inducing remission, maintaining an effective and lasting remission continues to be difficult in some cases. Azathioprine and mercaptopurine are now widely accepted as the principal maintenance agents for moderate to severe ulcerative colitis and Crohn s disease. 2, 3 Their efficacy and safety profile have been well described; 4, 5 yet, there continue to be up to 20% of children who are intolerant to therapy, 6 and up to 40% of adults who fail to achieve remission using current regimens. 7 Despite this, the use of azathioprine at daily doses of mg/kg, or the equivalent for 6-mercaptopurine, is now standard in children with moderate to severe inflammatory bowel disease. 8 Maximum clinical efficacy was thought to take several months to occur, 9 but the drugs may have some effect Ó 2003 Blackwell Publishing Ltd 913

2 914 D. FUENTES et al. within weeks. 10 Although initial reports of intravenous loading doses suggested a more rapid onset of action, 11, 12 this has not been substantiated in randomized trials in Crohn s disease. 10 Nonetheless, there are anecdotal reports of immediate benefit with intravenous azathioprine, perhaps as a result of the poorly understood alternative breakdown pathway that has been reported for azathioprine. 13 Attention has recently focused on the measurement of active metabolites to allow a more objective method of increasing doses in non-responders. 14 However, the data remain equivocal on the association of the levels of the active metabolite, 6-thioguanine, and disease remission. 15, 16 Evidence suggests that, in over 25% of azathioprine non-responders. dose escalation may achieve clinical remission. 17 Nonetheless, clinicians still have little evidence available to inform their choice if faced with a child who is not responding to accepted doses of azathioprine or mercaptopurine. The diagnosis of inflammatory bowel disease in a young child has different implications from a diagnosis made in adult life. Particularly in Crohn s disease, the impact of ongoing active inflammation during the crucial years of growth and development cannot be under-estimated. 18 Growth velocity itself may be taken as an indicator of disease activity, and thus provides excellent information about the efficacy of long-term medical management. It is now well established that the use of immunosuppressants early in a disease process can modify the natural history of the disease. Early intervention with so-called disease-modifying drugs in rheumatoid arthritis is now a recognized management principle. 19 There has been an increasing acceptance that early intervention with azathioprine in children with inflammatory bowel disease can also lead to a more benign clinical course over the first 18 months of the disease. 20 Several studies have documented the safety and efficacy of azathioprine/mercaptopurine in children with inflammatory bowel disease. 6 However, these studies report adverse events and efficacy at daily doses lower than those reported here (mercaptopurine, mg/kg; azathioprine, mg/kg). To date, no study has documented the effect of immunosuppressants on growth in childhood inflammatory bowel disease. This study reports the use of azathioprine at a higher daily dose of 3 mg/kg, given initially by 5-day intravenous course, 11 in a cohort of children with otherwise treatment-refractory inflammatory bowel disease. The safety and tolerability of this higher dose in children are reviewed, and the impact on linear growth in a sub-group of children with Crohn s disease is assessed. METHODS This retrospective cohort study included all children (under 17 years of age) diagnosed with inflammatory bowel disease and treated with azathioprine who were seen at our institution between 1996 and From a departmental database of over 300 children with active inflammatory bowel disease, pharmacy records and the UK National Paediatric Inflammatory Bowel Disease Registry, all children who had received azathioprine at any stage of their disease course were identified. A data extraction form was designed and modified after the first 25 patients to ensure the retrieval of accurate and objective data from patient records. Two paediatric gastroenterologists oversee the clinical paediatric inflammatory bowel disease service. The paediatric inflammatory bowel disease service thus follows clear, well-established departmental guidelines and provides a relatively uniform standard of care. There is an emphasis on the treatment of newly diagnosed patients with Crohn s disease with exclusive polymeric enteral nutrition, as reported previously. 21 Following this, corticosteroid use is minimized by employing a combination of enteral nutrition, antibiotic therapy and immunosuppressants. The early use of immunosuppressants is increasingly preferred in patients with more severe colonic disease. Treatmentrefractory disease included children who were corticosteroid/enteral nutrition dependent/resistant, or who had undergone more than three relapses within 6 months. Although not every change in therapy may be recorded in the clinical case notes, data on the reasons for commencing azathioprine, reasons for reducing/ stopping treatment and all adverse effects are documented. Blood investigations for adverse effects were carried out at maximum intervals of 4 months, following weekly monitoring for 4 8 weeks and monthly monitoring for up to 6 months after starting azathioprine. Our definitions of adverse effects were similar to those previously published in the literature: 6 elevated alanine aminotransferase (more than twice the normal

3 HIGH-DOSE AZATHIOPRINE IN CHILDREN WITH IBD 915 value); elevated amylase with persistent abdominal pain; and bone marrow toxicity (leucopenia, < 4000/ mm 3 ; thrombocytopenia, < /mm 3 ; lymphopenia, < 1000/mm 3 ). Although of unclear clinical significance, a raised mean corpuscular volume (> 100 fl) has previously been reported as an indication for reducing the azathioprine dose. 6 Although this practice has now been discontinued, a few patients initially had their azathioprine reduced or discontinued as a result of this report. Details of therapies used at diagnosis are clearly recorded in the case notes and easily extracted. Data on all surgical interventions were obtained from operating theatre records over the same time interval. In order to avoid any bias in the interpretation of clinical records, disease activity was not calculated retrospectively. However, where available, values at diagnosis for haemoglobin, platelets, albumin, erythrocyte sedimentation rate and C-reactive protein were recorded. In addition, the macroscopic disease distribution of all children at diagnosis was obtained from endoscopy reports. As the long-term height is an excellent and sensitive marker of clinical disease activity, 22 we calculated the Z scores for height and weight at different time points during the disease course. The Z score is a weight/ height-for-age standard deviation score (e.g. Z ¼ actual height ) median height/standard deviation). This measure is recommended by the World Health Organization when describing groups of subjects, 23 and allows more precision than that obtained when describing anthropometric status in relation to the closest centile. Although growth velocity is usually defined as a growth rate in centimetres per year, measured over at least a 6-month time period, we used the changes in Z score to reflect growth velocity given the variable time intervals between our end-points. Accurate measurements of height and weight are documented for all patients as they attend a dedicated paediatric inflammatory bowel disease clinic on a 3 4-month basis. Trained nursing staff record the height on a wall-mounted stadiometer and the weight on electronic scales. Measurements were extracted at the time of first diagnosis of inflammatory bowel disease, at the onset of azathioprine therapy and at the most recent clinic visit. This allowed the calculation of a rate of change in Z score before and after treatment with azathioprine, growth over time (growth velocity) being the most sensitive measure of linear growth. Data were entered into Epi Info 2000 Version 1.0 for the calculation of Z scores. Growth velocity was standardized for time in all children with Crohn s disease, as this group of children, more than those with ulcerative colitis or indeterminate colitis, 22 are sensitive to growth failure secondary to active disease. The changes in Z scores between individual time points were standardized for the time in days (dz score/day). Pre-treatment was the time from diagnosis to azathioprine treatment onset; post-treatment was the time from treatment onset to the current follow-up date. The data were assessed for normality, and non-parametric tests (Fisher s exact test) were used to calculate significant differences between dz scores before and after treatment in a sub-group of children with Crohn s disease (Tables 4 and 5, see later). The following dependent variables were considered a priori as measures of growth outcome: final Z score for height, dz score/day for height post-treatment with azathioprine. Logistic regression analysis was performed to determine whether any of the following independent variables were predictive of growth outcome: age at diagnosis, disease duration prior to azathioprine therapy, laboratory parameters and disease distribution at diagnosis, and duration of azathioprine therapy. All data were entered into a database (Microsoft Access 1997) and statistical calculations were performed on SPSS version The study was granted full ethical approval by the local ethical committee. RESULTS Population characteristics One hundred and fifteen children were treated with azathioprine over 5 years. Of these, adequate records were available in 107. Their demographic characteristics are shown in Table 1. The mean follow-up was 3.1 years (s.d., 2.3 years; range, years). Of the 42 children with ulcerative colitis and indeterminate colitis, 28 (67%) had continuous inflammation of the whole colon, and 69% of the 65 children with Table 1. Demographic characteristics of children with inflammatory bowel disease (n ¼ 107) Age at diagnosis (mean; range in years) 11.1; Crohn s disease (n) 65 Ulcerative colitis (n) 30 Indeterminate colitis (n) 12 Duration of follow-up (mean; range in years) 3.18;

4 916 D. FUENTES et al. Table 2. Endoscopic disease distribution and laboratory indices (means [s.d.]) at diagnosis in children with Crohn s disease, ulcerative colitis and indeterminate colitis (n ¼ 107) Distribution n Hb (g/dl) Platelets ( 10 9 /L) ESR (mm/h) CRP (mg/l) Albumin (g/l) Crohn s disease (n ¼ 65) Ileo-colitis Colonic only 11 [1.5] [138] [29] [52] [5.5] Gastro-duodenal 3 Perianal 4 Other 2 Indeterminate colitis (n ¼ 12) Pancolitis Rectosigmoid 3 [2.0] [112] [24] [23] [6.2] Unknown 1 Ulcerative colitis (n ¼ 30) Pancolitis Left colon 4 [2.4] [145] [37] [33] [11] Rectosigmoid 5 Unknown 1 CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Hb, haemoglobin. Normal ranges: ESR, 0 20 mm/h; CRP < 5 g/l; albumin, g/l; Hb, g/dl; platelets, ( ) 10 9 /L. Crohn s disease presented with ileo-colonic disease (involvement of the terminal ileum as well as macroscopic disease in more than one segment of the colon) (Table 2). Ninety-two children (86%) received oral azathioprine at 3 mg/kg, and 84 of these (91%) were started with a 5-day intravenous loading course at the same dose. Fifteen children received maintenance doses of between 1.0 and 2.5 mg/kg of oral azathioprine, three requiring a later increase in dose for persistent disease activity. The growth outcomes of this small group were not statistically different from those on 3 mg/kg, although the study was not designed to assess this. There was no difference in laboratory parameters between the disease groups at diagnosis, except for a significantly lower serum albumin in children presenting with Crohn s disease (P ¼ 0.008). Of the 65 children with Crohn s disease, 45 received exclusive polymeric enteral nutrition as initial therapy, irrespective of their disease distribution. The efficacy and tolerability of these casein-based, whole-protein diets have been reported previously, 21, 24 and they have made the use of elemental diets in our unit obsolete. The majority of children were treated with a formula that is now available as Modulen IBD (Nestlé). As a significant number of children were referred to our unit from other hospitals, many had already received corticosteroids to induce first remission. Only five children who were commenced on exclusive enteral nutrition required the addition of corticosteroids to induce first remission, with only 8% of the 65 going on to need steroids for more than 6 months during follow-up. Almost all children with ulcerative and indeterminate colitis were treated with steroids at diagnosis (93%), with 80% of all children receiving additional aminosalicylates. Of all children, 54% were started on azathioprine within 12 months of diagnosis, with 83% being on azathioprine within 2 years. The mean duration of disease before commencing azathioprine therapy was 1.54 years (range, years), with a mean duration of follow-up on treatment of 1.7 years (range, years). Over 80% of children received azathioprine for treatment-refractory (steroid/enteral nutrition-resistant) disease and 2% received azathioprine for severe perianal Crohn s disease alone. There were 16 patients whose clinical, endoscopic and histological presentation was felt to be severe enough to warrant azathioprine therapy at diagnosis. All of these patients had severe pancolitis, with eight of the 16 having Crohn s disease with a high median paediatric Crohn s disease activity index 25 of 52.5 (range, ), four having indeterminate colitis and four having ulcerative colitis. These patients were treated more recently and are still undergoing long-term follow-up. Adverse events Seventy-two per cent of children (67/107) maintained or increased their initial 3 mg/kg daily dose throughout the period of follow-up (Figure 1). About 30% (33/107) had their azathioprine discontinued, 18 of 33 for a

5 HIGH-DOSE AZATHIOPRINE IN CHILDREN WITH IBD 917 Figure 1. Chart showing the outcomes of azathioprine (AZA) use in children with inflammatory bowel disease. Table 3. Different reasons for discontinuing azathioprine therapy in children with inflammatory bowel disease (n ¼ 33/107) Clinical indications Bone marrow toxicity 8 Azathioprine resistance 2 Surgery 5 Recurrent viral infections 3 Non-clinical indications High MCV (> 100) 5 Parental request 4 Use > 2 years 5 Unknown 1 MCV, mean corpuscular volume. clinically significant adverse event (Table 3). No child had to discontinue azathioprine for the elevation of transaminases or pancreatic enzymes. Of the 33 patients who discontinued azathioprine during the study period, 16 did not need to re-start treatment during follow-up (Figure 1). Of these 16, 11 discontinued azathioprine at the time of surgery (Crohn s disease, nine; ulcerative colitis, one; indeterminate colitis, one). The remaining 17 children needed to re-start treatment for clinical relapse. Of these 17 children, 11 had been discontinued for reasons other than adverse events (use > 2 years, parental request, high mean corpuscular volume), whilst six had suffered from previous clinically important adverse events (bone marrow toxicity, three; recurrent infections, three). As the assay for thiopurine methyltransferase was not yet available in all cases, treatment was re-started at half the dose, once laboratory indices had normalized, thereafter increasing to a daily dose of 3 mg/kg as tolerated. Of these 17 children, 15 went on to tolerate azathioprine without further adverse events. Two of the children who needed to re-start azathioprine had to discontinue treatment for a second time, both for a first episode of bone marrow toxicity. Three of the eight children who developed one episode of bone marrow toxicity required further azathioprine therapy, and all tolerated it without further evidence of toxicity (follow-up, months). Therefore, only two of 107 children who needed immunosuppression with azathioprine were persistently intolerant to it, both having thiopurine methyltransferase levels within the normal range. Of the total population, 21% (22/107) had surgery. Of the children with Crohn s disease, 26% (17/65) required surgery: nine underwent a right hemicolectomy (five for stricturing disease and four for treatment resistance), seven had a subtotal colectomy and ileostomy (for resistant colonic disease) and one had a panproctocolectomy. This compared with two of 30 and three of 12 children with treatment-resistant ulcerative colitis and indeterminate colitis, respectively, who had a subtotal colectomy and ileostomy. Fourteen children with inflammatory bowel disease went on to require other immunomodulators: nine children with Crohn s disease required infliximab, and ciclosporin was used in four children with indeterminate colitis/ulcerative colitis and in one child with Crohn s disease. Ten children received corticosteroids for more than 6 months after commencing azathioprine. Growth parameters From the available data on all children with inflammatory bowel disease, 10% had significant growth failure (Z score for height, less than ) 1.64; less than fifth centile) at diagnosis (vs. 9% in children with Crohn s disease); this percentage did not increase significantly at final follow-up, being 13% both for the group as a whole and for children with Crohn s disease. However, as growth is most commonly affected in children with Crohn s disease rather than in those with

6 918 D. FUENTES et al. Table 4. Median Z scores for height and weight at different time points in children with Crohn s disease (n ¼ 44/57) Z score for height (median) Range Z score for weight (mean) Table 5. Standardized changes in Z scores for height and weight (dhz, dwz per day) before and after the onset of azathioprine therapy in children with Crohn s disease (Fisher s exact test, two-sided) Parameter Mean Significance (P) dhz/day pre-treatment ) ) dhz/day post-treatment )4 dwz/day pre-treatment ) ) dwz/day post-treatment ) )3 Range At diagnosis ) 0.06 ) ) 0.26 ) Azathioprine onset 0.0 ) ) 0.57 ) Current follow-up ) 0.15 ) ) 0.55 ) ulcerative colitis, we analysed the sub-group of children with Crohn s disease for whom data were available at three time points: diagnosis, azathioprine treatment onset and most recent follow-up (Tables 4 and 5). Of the 65 children with Crohn s disease, eight started azathioprine at diagnosis and were thus not included in the growth analysis. Of the remaining 57, 44 had accurate height and weight data available at all three time points (some were only referred to our centre some time after diagnosis, and a few were lost to follow-up). From diagnosis to final follow-up measurement, 36% of children with Crohn s disease either maintained or increased their Z score for height. The changes in Z scores were standardized (dz/day) for pre- and posttreatment intervals. In this group, more so than in the group of children with ulcerative colitis or indeterminate colitis, there was a trend towards an increase in Z score for height, standardized for time (growth velocity), following the onset of azathioprine treatment (P ¼ 0.08, Fisher s exact test, two-sided). There was no significant difference in the standardized changes in weight following the onset of azathioprine in either the Crohn s disease or ulcerative colitis/indeterminate colitis group (P ¼ N.S., Fisher s exact test). As only four of the 65 children received corticosteroids for more than 6 months during follow-up, it was impossible to correlate this with the growth outcome. Logistic regression identified none of the selected predictors to have an effect on growth outcome measures. Although variables such as surgery and infliximab therapy confound growth outcome, the final growth data in this group are the result of clinical practices at the time, and reflect current practice in such a population. This includes the use of infliximab as rescue therapy before surgery, with four of nine going on to require a colectomy, but five of nine continuing on maintenance azathioprine therapy with a constant or increased dose. DISCUSSION AND CONCLUSIONS A daily dose of 3 mg/kg azathioprine is a safe, welltolerated and effective maintenance therapy for children with moderate to severe inflammatory bowel disease. For the first time, it has been shown that growth rates in children with the most severe Crohn s disease may not deteriorate, and indeed may improve in the first years following diagnosis using the above regimen. Compared with historical controls, the need for early surgery appears to be reduced. Only 22 of 107 children in this high-risk group had surgery during follow-up. This is almost half the value reported by Griffiths et al. in their thorough follow-up of 100 consecutively referred children with Crohn s disease. 26 Although the retrospective study design reduces the power of our conclusions, and the use of historical control data is not ideal, the findings still suggest a benefit following the use of high-dose azathioprine within 2 years of diagnosis. All these patients were selected for treatment with azathioprine on the basis of their disease severity, with the majority failing to respond to other therapies. Although no specific disease activity scores were calculated, the decision to start therapy with azathioprine was made in a standardized manner. As poor growth velocity, i.e. decreasing Z scores for height over time, is intrinsically linked to disease activity, particularly in children with Crohn s disease, treatments that improve growth velocity are of great importance in the management of paediatric inflammatory bowel disease. Our finding of a trend towards better growth velocity after treatment with high-dose azathioprine in children with Crohn s disease suggests that poor growth may be reversible with azathioprine treatment. Although the frequent use of exclusive enteral nutrition and minimal corticosteroid

7 HIGH-DOSE AZATHIOPRINE IN CHILDREN WITH IBD 919 exposure may confound the effect of azathioprine on growth, neither of these are used as maintenance therapy, and therefore would not be expected to impact on long-term growth as much as azathioprine. Azathioprine has been reported to be a well-tolerated maintenance therapy in over 80% of children with inflammatory bowel disease. 6 Despite its efficacy and good long-term safety data, 3 there are still reports of adverse effects and resistance to treatment with azathioprine and mercaptopurine. Although concerns about the long-term risks of lymphoma have delayed the more widespread use of azathioprine in children with inflammatory bowel disease, 3 the mounting evidence of its safety is leading to its use much earlier during the disease course. 20 Our study reports only two of 107 children who were persistently intolerant to the higher dose of 3 mg/kg. This is a surprisingly low result, and may suggest a better tolerability of azathioprine in children compared with that in adults. Most adverse effects (10/18) occurred within 12 months of starting treatment, although bone marrow toxicity occurred up to 2.5 years later. Although most azathioprine-related adverse events occur in children with normal thiopurine methyltransferase levels, 27 the increase in bone 28, 29 marrow toxicity found in those who are deficient makes a strong case for an early assessment of their thiopurine methyltransferase status. This should certainly be known before re-challenging a child with previous adverse events with a further trial of azathioprine. Early growth delay leading to permanent short stature still occurs in up to 20% of children despite referral and treatment. 30 Given that our 107 children with inflammatory bowel disease were selected by their requirement for azathioprine, comparison with other studies on growth in paediatric inflammatory bowel disease is complex. Despite the varying methods used to define growth failure, it is clear that inflammatory bowel disease causes growth retardation and reduced height velocity in up to 88% of children, even before treatment is started. 31 Motil et al. reported that 72% of a series of 69 children with inflammatory bowel disease presented with a negative Z score for height, with 23% less than ) Although our entire cohort went on to develop more severe disease and require azathioprine, only 57% had negative Z scores at diagnosis, with 10% below ) Although there may be some selection bias in these results, it is likely that they reflect an increasing awareness and prompt referral of paediatric inflammatory bowel disease patients by referring physicians. However, despite management within tertiary centres, others have reported that 49 65% of children with Crohn s disease in early puberty have a reduced height velocity, with growth of less than 4 cm/year during the first 1 2 years of therapy. 22, 32 Hildebrand et al. reported a mean Z score for height of ) years after diagnosis in 46 consecutive children with Crohn s disease. 22 After a mean follow-up duration of over 3 years, our study population of 65 children with Crohn s disease had a mean Z score for height of ) Although not a clinically significant difference, this also suggests a trend to better long-term growth in this group. Griffiths et al. reported that about two-thirds of consecutively diagnosed children with Crohn s disease followed to maturity maintained or increased their Z scores for height. 26 However, only about one-third of that cohort had severe disease and only 19% received immunosuppressants. In contrast, all of the children in our cohort had severe enough disease to warrant immunosuppressants, yet still over one-third maintained or increased their Z scores for height during follow-up. The outcome of many of these studies reflects management, where the mainstay of therapy was often corticosteroids, with immunosuppressants being used much later in the disease process. On-going growth failure in the first few years after diagnosis may be due to several factors. A delay in presentation to a tertiary centre has been associated with a significantly greater degree of growth impairment at diagnosis. 33 Furthermore, the frequent use of steroids during the first year after diagnosis (up to 85% of children in some studies 26, 34 ) is also likely to impact on the initial growth rates. The reduced use of steroids in our cohort (38%) at diagnosis and the reliance on early and aggressive nutritional therapy are likely to be further significant factors in determining early growth rates. Sanderson et al. established the benefit of enteral nutrition over steroid therapy on short-term growth in children with newly diagnosed Crohn s disease. 35 There also seems little doubt that ongoing inflammatory activity is a key inhibitor of growth. 36 Direct inhibitory effects of pro-inflammatory cytokines, such as tumour necrosis factor-a, on developing growth plates 37 and a down-regulation of insulin-like growth factor-1 by interleukin-6 38 may both lead to growth retardation.

8 920 D. FUENTES et al. The additional suppression of appetite by tumour necrosis factor-a, 39 a failure to down-regulate the resting energy expenditure during malnutrition in Crohn s disease 40 and the exacerbation of bowel symptoms by food intake may all contribute to growth failure. Growth data in a retrospective study such as this are clearly confounded by variables other than azathioprine alone. Surgical resections and the use of anti-tumour necrosis factor antibody (in nine children) inevitably have some impact on long-term growth. In reality, however, it is the ability of azathioprine to sustain an effective, long-term remission, together with these other remission-inducing therapies, that is likely to determine final growth. The successful achievement of a lasting disease remission with the early use of effective immunosuppressants, together with adequate nutritional support, may be the key to the maximization of growth potential. It has been clearly shown previously that the institution of mercaptopurine therapy at diagnosis can dramatically reduce disease relapse in the first 18 months. 20 Although mercaptopurine had a steroidsparing effect in this carefully designed study, the authors were unable to demonstrate any significant differences in growth between the groups, perhaps as a result of early withdrawals from their control group. Recent data have confirmed that the escalation of the mercaptopurine dose may lead to better remission induction in a significant number of patients. 17 Dubinsky et al. suggest that the early escalation of the mercaptopurine dose, together with the measurement of active metabolites, may better define which patients are likely to remain non-responders. 17 Our data indicate that an initial daily dose of 3 mg/kg azathioprine is safe and well tolerated, and may have long-term benefits in maximizing growth potential and minimizing surgery. We suggest that the practice of minimizing steroid use by the administration of exclusive enteral nutrition, followed by the use of higher dose azathioprine, may be an ideal combination therapy in children with acute Crohn s disease. It is clear that controlled, prospective studies of children at risk of growth failure are needed to better define the value of early azathioprine on growth. REFERENCES 1 Sawczenko A, Sandhu BK, Logan RF, et al. Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet 2001; 357: Pearson DC, May GR, Fick G, Sutherland LR. Azathioprine for maintaining remission of Crohn s disease. Cochrane Database Syst Rev 2000; AD: CD Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002; 50: D Haens G, Geboes K, Ponette E, Penninckx F, Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn s disease. 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