Baseline patient characteristics (Table 1. and 2.)
The patient series consisted of 7 children (5 girls) with CD. The median age at diagnosis was 6.5 years (range: 2.9–15.1) and age at first GLM injection was 16.9 years (range: 9.2 to 19.1). Disease distribution at start was limited to the colon in one child. Three children had diffuse disease defined as gastroduodenal, ileal and colonic involvement. Two children had gastric and colonic involvement; one had gastroduodenal and colonic involvement. Perianal disease was present in one child.
Previous biological treatment (Table 1.)
All patients had been consecutively treated with IFX and ADA before start of GLM. The median age at start of IFX was 12.9 years (range: 4 to 15.5). IFX had been given for a median of one year (range: 0.5 to 1.9) with a median of 11.3 (range: 7 to 12) for the number of received infusions. The median age at start of ADA was 14.6 years (range: 5.8 to 18.8). ADA has been given for a median of 1.4 years (range: 0.3 to 3.3) with a median of 11 (range: 7 to 23) for the numbers of injections. The reason of discontinuation was loss of efficacy in 6 cases and an infusion reaction in one case. Antibodies and trough levels for IFX or ADA were not routinely measured during this study period.
GLM and dose escalation (Table 2.)
During follow up the median GLM duration was 7.2 months (range: 5.7 to 15.6 months). In 4 patients GLM doses were increased after a median of 9.7 weeks (range: 8 to 20.2 weeks) due to clinical deterioration. Dose escalation was achieved by shortening the dosing interval from four to three weeks.
Concomitant corticosteroids and immunomodulators (Table 3.)
At start of GLM, 5 of the 7 children were on corticosteroids with a median dose of 20 mg (range: 5 to 20 mg), four of these five patients were steroid-dependent defined as weaning was not possible. The initiation of GLM made a complete steroid withdrawal possible in one case after 4 weeks and steroid reduction possible in 2 out of 4 of the steroid-dependent. This steroid tapering was possible after 3 and 6 months respectively. At the last visit four children were on steroid with a daily dose range between 5 to 55 mg.
Concomitant immune modulating therapy at GLM initiation was methotrexate in 2 cases (case 1 and 7). This was throughout the study period and was stopped after 5.9 months and 10.4 months respectively. In one other patient (case 6), treatment with cyclosporine with aimed through levels around 150–200 ng/ml was started after three months.
Effect of GLM on PCDAI (Fig. 1)
PCDAI scores were available for all patients at baseline with remission in one (= patient with intolerance), mild activity in one, moderate to severe activity in 5 cases. Disease activity decreased with mean PCDAI scores falling from 32.1 ± 14.8 baseline to 25.3 ± 17.7 at 4 weeks (p = 0.13), to 28.7 ± 19.7 at 3 month (p = 0.3), to 28.9 ± 22 at 6 month (p = 0.5) to 25.3 ± 18.6 at last visit (p = 0.2). At the last visit, 2 of the 7 patients had no disease activity (PCDAI ≤ 10), 3 had mild and the remaining 2 had moderate to severe disease activity. Of the 5 patients with moderate to sever disease activity at start, one showed no response to GLM (case 1), in one patient disease activity only decreased after CSA was initiated (case 6). The remaining three patients responded to GLM therapy (case 3–5). However, the first respond only shortly and developed a duodenocolonic fistula (case 5), the second had clinical response according to PCDAI but nonetheless discontinued GLM therapy due to ineffectiveness (case 4). The remaining two (case 2 and 7) adolescent with mild and no disease activity at start, disease activity remained stable during follow-up.
Weight SDS, height SDS and BMI SDS at start and during follow up were not lower compared to reference data. There was no significant improvement in weight, height and BMI SDS post GLM (for all p = n.s).
Effect of GLM on inflammatory markers
Serum inflammatory markers were recorded at baseline and afterwards, if available. After 2 weeks there was a significant increase in mean haematocrit from 33.5 ± 3.2 to 36.2 ± 3.5 (p = 0.04), but not in the following. In week 2 to week 4 after GLM start, there was a significant increase of CRP (mean 0.9 ± 0.7 to 1.5 ± 0.7 mg/dl, p = 0.02) and from week 4 to month 3 a significant increase of ESR (78 ± 36.8 to 93 ± 37.5, p = 0.02).
Effect of GLM on mucosal healing
Comparing start of GLM to week 4 there was a statically significant improvement in faecal calprotectin (p = 0.05). For all other parameters, there were no significant changes.
In 3 children histology results were available before and under treatment with GLM. The indication for endoscopy after GLM was loss of efficacy with clinical flare-up in all children. In one case active inflammation of the mucosal biopsies was persistent with no changes under GLM treatment. In two cases there was a deterioration of inflammation.
GML and discontinuation
In two children (case 4 and 5) GLM had to be discontinued. The reason for discontinuation was loss of efficacy with persisting severe diarrhoea and abdominal pain after 7.3 months in one patient (case 4) despite improved in PCDAI. In this child GLM was used as the last treatment option before colectomy, however was switched to ustekinumab (Stelara®; Janssen Biotech, Inc., Horsham, Pa) afterwards. So further surgical procedures could be withheld due to the positive effect of GLM. The other child (case 5) developed a duodenocolonic fistula 10.2 months after GLM initiation and needed gastrointestinal surgery. Therefore, GLM was stopped preoperatively after 11.2 months. In a third child (case 1) and PCDAI non- responders GLM discontinuation might be likely in the near future, if no further clinical improvement could be seen in the next months.
Adverse events
There were no serious adverse effects, deaths or malignancies in the study cohort during the study period. There were no opportunistic infections reported. One patient underwent a surgical procedure during the time of the study with intestinal resection for active fistulising CD.