Exclusive enteral nutrition with concomitant early thiopurine use was effective in maintaining steroid-free remission in a Southeast Asian cohort of children with Crohn’s disease

This was a retrospective study conducted at a tertiary paediatric hospital in Singapore. A prospectively maintained hospital database of children with inflammatory bowel disease was used to identify newly diagnosed children with CD from 2011 to 2014. The case records were reviewed and relevant data including demographics, details of disease location, serial weight and height measurements, and details of standard inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), haemoglobin, platelets, and albumin were extracted. The diagnosis of CD was based on standard criteria including clinical, endoscopic, histological and radiological findings [19]. Each patient had previously undergone oesophagogastroduodenoscopy, ileocolonoscopy, and a histological analysis of mucosal biopsies from multiple sites. Small bowel imaging with magnetic resonance imaging enterography is routinely performed for all newly diagnosed cases of CD as part of the standard protocol at our centre. The disease phenotype was classified according to the Paris classification for paediatric inflammatory bowel disease [20].

Disease activity was ascertained using the Paediatric Crohn’s Disease Activity Index (PCDAI) score [21]. PCDAI scores were calculated at diagnosis, at the end of the EEN therapy, and during routine visits at the specialized inflammatory bowel disease (IBD) clinics at 6 months and 12 months. Remission was defined as a PCDAI score of ≤10, while relapse was defined as a PCDAI score of > 10. All patients diagnosed with CD were routinely started on 5-aminosalicylic acid at our centre.

The inclusion criteria for the study were: (i) newly diagnosed children aged less than 18 years with active CD, (ii) completion of 8 weeks course of EEN as induction therapy, and (iii) a minimum follow-up period of one year following completion of the EEN course. Patients who had been previously treated with corticosteroids, immunosuppressive medications or biologics were excluded. This study was approved by the hospital institutional review board.

Data were collected from the patients’ medical, dietetic and laboratory records. Anthropometric records (height and weight) and PCDAI scores were collected at diagnosis, at approximately 8 weeks (post-EEN) and at 6 and 12 months post-EEN therapy. Height, weight and body mass index (BMI) measurements were converted into standard deviation z-scores using an age and sex-matched population as a reference standard [22]. Systemic markers of disease activity, namely, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), haemoglobin, platelets, and albumin were collected at diagnosis and post-EEN. Medication history including thiopurines, aminosalicylic acid, corticosteroid and other immunosuppressant use were also recorded.

All patients recruited were started on EEN using whole casein polymeric milk formula (Modulen IBD, Nestle, Nunspeet, the Netherlands) as an induction therapy to complete a course of 8 weeks. They were referred to a dietician prior to initiation of EEN. Daily volumes of formula were prescribed based on the child’s estimated energy requirement (EER). Each child’s EER was calculated using the Schofield equation, which estimates basal metabolic rate based on body weight [23]. EEN was initiated with an incremental increase in milk volume over 2 to 3 days to avoid intolerance of the formula and refeeding syndrome. Patients were reviewed regularly and, when required, energy intake was modified by adjusting formula volumes based on the adequacy of weight gain. During the period of EEN, sugar-free chewing gum, boiled sweets, and water were allowed. A normal diet was reintroduced gradually after completion of the therapy, starting with low allergen food and gradually increasing over 2 weeks, while incrementally decreasing the amount of enteral formula.

There were two groups of patients in this cohort: those who received azathioprine early (within one month of diagnosis) were classified as the Early Azathioprine (EAZ) group while those who were started on Azathioprine only following a relapse were classified as the Late Azathioprine (LAZ) group. As our centre did not have a standardized protocol regarding thiopurine therapy, initiation of azathioprine was solely determined by each clinician’s treatment decision. Azathioprine was normally prescribed at a dose of 2–2.5 mg/kg per day. The clinical characteristics, PCDAI score and laboratory parameters were further compared between the two groups of patients.

All patients were monitored over a 12-month period following the EEN therapy to determine the duration of remission. Remission on azathioprine was defined as a PCDAI score of ≤10 without requiring any steroid therapy, further courses of EEN therapy, other immunosuppressant or biologic therapy.

Forty newly diagnosed children with CD from 2011 to 2014 were started on an EEN induction therapy of which 33 patients completed the treatment course. All patients were of SEA origin. Most of the patients (70%) had ileocolonic disease (L3). Almost a quarter of the patients had mainly colonic involvement (L2). Approximately 40% of the cohort had upper gastrointestinal tract involvement. The majority of patients (85%) had non-stricturing disease (B1) while three patients had stricturing disease (B2) and two had stricturing and penetrating (B2B3) disease. The mean follow-up period was 19.4 ± 6.8 months. Seven patients were unable to tolerate the EEN course and were switched to corticosteroids for induction therapy. All children received EEN orally, and none required nutrition via a nasogastric route.

Of the 33 children (82.5%) who completed the EEN induction, 91% (30/33) achieved remission (PCDAI ≤10). There were significant improvements in growth, PCDAI and biochemical activity disease markers (CRP, ESR, albumin, platelet count and haemoglobin) post-induction with EEN (Tables 1 and 2).

For the remaining 3 patients who did not achieve remission, all had B2 disease. There were some improvements in inflammatory markers: CRP reduced from a mean of 16 ± 15.5 mg/L to 10 ± 12.1 mg/L; albumin increased from 21 ± 16.3 g/L to 34 ± 2.6 g/L; and haemoglobin increased from 10.3 ± 2.5 g/dL to 12.7 ± 1.6 g/dL. However, ESR increased from 17 ± 14.2 mm/h to 22 ± 12.6 mm/h. Two patients with B2B3 disease achieved an initial remission with EEN therapy but relapsed after 2.5 and 8 months respectively. Four children had perianal disease; three of them achieved remission with EEN. The last patient, who failed to achieve remission, had both B2 and perianal disease.

At diagnosis, 23% of the patients were thin (BMI z-score ≤ − 2 SD) with a mean body mass index (BMI) z-score of − 1.4 ± 1.5 (Table 2). Post EEN, the mean BMI z-score improved to − 0.82 ± 1.27 (p < 0.001). Similarly both the weight and height z-scores also showed significant increase post EEN. The effects on growth appeared to be sustained over 6 months post-EEN with all the three parameters showing significant improvements. Similarly at 12 months post-EEN, both weight and BMI z-scores continued to show significant improvements but not height z-score.

Oral azathioprine was started within a month of diagnosis in 16 out of 33 (49%) patients, composing the EAZ group (Fig. 1). In the LAZ group, which consisted of 17 (51%) patients, azathioprine was started only following a relapse at a mean of 5.7 (range 3–9) months post EEN. The demographic and clinical characteristics, including the PCDAI score, of EAZ and LAZ were comparable at baseline between the 2 groups (Table 3). Haemoglobin, albumin, platelet count and CRP did not show any significant difference. However, ESR was significantly higher in the EAZ group compared to the LAZ group (63.2 ± 37.5 mm/h vs 41.3 ± 16.9 mm/h, p = 0.03). Overall, none of the patients who received azathioprine experienced hepatotoxicity, marrow suppression or malignancy during the study period.

Thirty patients achieved remission; half (n = 15) were from the EAZ group. At 6 months post-EEN, 80% (n = 12) of the patients from the EAZ group were in remission versus 60% (n = 9) from the LAZ group (p = 0.018). By 12 months, 73% (n = 11) of the EAZ patients were still in continuous remission with no relapse in the intervening period compared to 40% (n = 6) from the LAZ group (p = 0.57). The overall remission rates at 6 and 12 months were 70 and 57%, respectively (Fig. 1).

We further addressed the remission rate in a Kaplan-Meier survival model (Fig. 2). Remission was maintained longer in the EAZ group compared to LAZ with a mean time to relapse of 10.1 (3.5) months vs 7.9 (4.1) months, respectively (p = 0.048). The multivariate hazard ratio determined by the Cox regression analysis was 1.9 (95% CI, 0.4–7.5, p = 0.34) after adjusting for age, sex, disease site, and baseline PCDAI score (Table 4).