Treating children with inflammatory bowel disease: Current and new perspectives

Table 1 Summary of the cohort studies mentioned in the review including reference, study design and population, main results, conclusions

Ref.	Study design	Population	Main results	Conclusion
Nutrition
Sigall-Boneh et al[15] Inflamm Bowel Dis 2014	Prospective cohort study	47 patients = 34 children + 13 young adults	Post treatment with 6-wk exclusion diet: access to specific foods + 50% of calories from polymeric formula	Dietary therapy involving PEN with an exclusion diet seems to lead to high remission rates in early mild-to-moderate luminal CD in children and young adults
		Mean age 16.1 ± 5.6 yr	Response in 37 (78.7%)
			Remission in 33 (70.2%)
		Active CD (PCDAI > 7.5 or Harvey-Bradshaw Index ≥ 4)	Decrease in CRP and ESR
			Normalisation of CRP in 70% of patients entering remission
Grover et al[16] J Crohns Colitis 2016	Prospective cohort study	54 children with CD	Post EEN:	Only complete MH post EEN induction predicts more favourable SR for up to 3 yr
		Age < 16	Clinical remission (PCDAI < 10) in 45/54 (83%)
		At least 6 wk EEN	Biochemical remission (PCDAI < 10, CRP < 5) in 39/54 (72%)
			Complete MH in 18/54 (33%)
			Nearly complete MH in 10/54 (19%)
			SR superior in children with MH vs active endoscopic disease:
			P 0.003 at 1 yr
			P 0.008 at 2 yr
			P 0.005 at 3 yr
Thiopurines
Stocco et al[23] World J Gastroenterol 2015	Retrospective cohort study	12 paediatric patients = 6 CD + 6 UC	NAT1 genotypes (fast enzymatic activity) were associated with reduced TGN concentration	NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drug
			The effect of NAT1 on TGN persists even 1 mo after the interruption of the aminosalicylate
			No effect of the NAT2 polymorphism was observed
Biologics and biosimilars
Sharma et al[7] Inflamm Bowel Dis 2015	IMAgINE-1 study	Paediatric CD population = 192	Strong positive association between serum ADA concentration and disease remission/response to treatment	Positive association between serum ADA concentration and remission/response in paediatric patients with moderate/severe CD
	Phase-3, randomized,		Higher body weight, baseline CRP, lower albumin, previous treatment with anti-TNF and presence of anti-IFX antibody were associated with increased ADA clearance
	Multicentre, double-blind
Nuti et al[18] J Crohns Colitis 2016	Prospective cohort study	37 biologic-naïve paediatric patients with CD	Biological therapy with IFX + AZA was effective in achieving MH (based on change in PCDAI and SES-CD)	Biologics improve mucosal lesions, more effectively if given in combination with immunomodulators.
			Combination of biologics + immunomodulators was more effective than biological monotherapy	MH predicts a better disease course
			Improvement of mucosal lesions at 2 yr follow-up was predictive of favourable outcomes
Fumery et al[33] J Pediatr Gastroenterol Nutr 2015	Retrospective population based study (EPIMAD registry)	27 paediatric patients with CD experiencing IFX failure	Effectiveness and safety of ADA:	Treatment with ADA was safe and effective in two-thirds of patients with pediatric-onset CD and IFX failure
			Clinical benefit: 19 (70%) measured by the physical global assessment score
			Significant decrease in CRP in children responding to ADA (9 vs 15 mg/L)
			Cumulative probability of failure to ADA treatment:
			38% at 6 mo, 55% at 1 yr
			Primary failure: 8 (30%)
			Secondary failure: 5 (26%)
			Adverse effects: 11 (40%)
Frymoyer et al[38] J Pediatr Gastroenterol Nutr 2016	Monte Carlo simulation analysis constructed using a published population pharmacokinetic model based on data from 112 children in the REACH trial	1000 simulated children	Trough IFX concentration > 3 mg/mL was achieved at week 14 in 21% for albumin level of 3 g/dL vs 41% for albumin of 4 g/dL	Standard IFX maintenance dosing in children with CD is predicted to frequently result in inadequate exposure, especially when albumin levels are low.
Dziechciarz et al[34] J Crohns Colitis 2016	Systematic review of 14 studies	Efficacy and safety of ADA I paediatric patients with CD	Pooled remission rates:	According to low-quality evidence based mainly on case series, approximately half of children with CD on ADA therapy achieve remission during the first year of the therapy with reasonable safety profile
			At 4 wk: 30% (n = 93/309)
			At 3 mo: 54% (n = 79/145)
			At 4 mo: 45% (n = 18/40)
			At 6 mo: 42% (n = 146/345)
			At 8 mo: 57% (n = 20/35)
			At 12 mo: 44% (n = 169/383)
			Primary non-responders: 6% (13/207)
			Severe adverse events: 12% (69/599)
Conrad et al[39] Inflamm Bowel Dis 2016	Observational, single-centre, prospective cohort study	21 paediatric patients (16 CD, 5 UC) with refractory IBD who had previously failed anti-TNFa therapy	Clinical response post treatment with vedolizumab:
			6/19 (31.6%) at week 6
			11/19 (57.9%) at week 22
			Steroid-free remission in 1/20 (5%) at week 6, 3/20 (15%) at week 14 and 4/20 (20%) at week 22.
Singh et al[44] Inflamm Bowel Dis 2016	Retrospective review on the experience with vedolizumab	52 paediatric patients with IBD, 90% of whom had failed ≥ 1 anti-TNF agent	Week 14 remission rates: 76% for UC, 42% for CD, 80% of anti-TNF naïve IBD	Clinical response to vedolizumab in children with moderate/severe CD increases from week 14 to week 22
			Week 22 remission rates:
			100% anti-TNF naïve vs 45% anti-TNF exposed
Sieczkowska et al[46] J Crohns Colitis 2016	Prospective cohort study	39 paediatric patients: 32 with CD, 7 with UC	Clinical remission:	No differences in treatment efficacy, after switching from IFX originator to its biosimilar
			88% for CD
		Children were switched from IFX originator to its biosimilar	57% for UC
		All patients had PCDAI ≥ 25 at the time of switching
Thalidomide
Lazzerini et al[49] JAMA 2013	Double-blind, placebo-controlled, randomized clinical trial	56 padiatric patients with active CD, randomised to receive either thalidomide or placebo	Clinical remission achieved by 13/28 (46.4%) of the children treated with thalidomide vs 3/26 (11.5%) of those who received placebo (P = 0.01)	Thalidomide compared with placebo resulted in improved clinical remission at 8 wk of treatment and longer-term maintenance of remission.
		Almost all had not responded to thiopurines and 35% had not responded to biologics	Responses were not different at 4 wk, but greater improvement was observed at 8 wk in the thalidomide group [75% response in 13/28 (46.4%)] vs 3/26 (11.5%)(P 0.01)
			Of the non-responders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (P = 0.01).
			Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission
			Mean duration of clinical remission in the thalidomide group was 181.1 wk vs 6.3 wk in the placebo group (P < 0.001).
Lazzerini et al[50] Inflamm Bowel Dis 2015	Multicenter, double-blind, placebo-controlled, randomized clinical trial	26 paediatric patients with active UC, randomised to receive thalidomide or placebo	Clinical remission at week in 10/12 (83.3%) of the children treated with thalidomide vs 2/11 (18.8%) of those who received placebo (P = 0.005)	Thalidomide compared with placebo resulted in improved clinical remission at 8 wk of treatment and in longer term maintenance of remission.
		All patients had had thiopurines and 35% had received prior IFX treatment	Of the non-responders to placebo who were switched to thalidomide, 8 of 11 (72.7%) subsequently reached remission at week 8 (P = 0.01)
			Clinical remission in the thalidomide group was 135 wk compared with 8 wk in the placebo group (P < 0.0001).
New treatments
Tew et al[11] Gastroenterology 2016	Retrospective analysis of two cohorts: 1. phase 2 placebo-controlled trial;	110 patients with UC (cohort 1) and 21 patients including UC and controls (cohort 2)	Increased expression of T-cell associated genes in baseline biopsies of anti-TNF naïve patients who achieved clinical remission in response to etrolizumab	Levels of GZMA and ITGAE mRNAs in colon tissues can identify patients with UC who are most likely to benefit from etrolizumab
	2. observational study at a separate site		Patients with high colonic integrin aE expression showed greater benefit	GZMA is a promising biomarker for etrolizumab response
			GZMA expression was different post-treatment
Sandborn et al[51] N Engl J Med 2016	Double-blind, placebo-controlled, phase-2 trial	197 adult patients with moderate-severe UC	Clinical remission at 8 wk:	Ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of UC than placebo
			16% of patients who received 1 mg of Ozanimod vs 14% who received 0.5 mg vs 6% of those who received placebo
			Clinical remission t 32 wk:
			21% vs 26% vs 6% respectively
			Drop in absolute lymphocyte count at week 8:
			49% from baseline in the group who received 1 mg of Ozanimod
			32% from baseline in the group who received 0.5 mg
Allez et al[52] Gut 2016	Randomised, double-blind, parallel group trial	78 adult patients with CD	No significant difference in change in CDAI from baseline to week 4, between NKG2D group and placebo group	A single s.c. dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4 vs placebo, but the difference was significant at week 12
		Age 18-75	Significant difference in change in CDAI at week 12 (delta CDAI -55, P ≤ 0.1) between NKG2D group and placebo group
		Disease duration ≥ 3 mo	Significant improvement noted in the non-failure to biologic subgroup treated with anti-NKG2D from week 1
		CDAI 220-450
		CRP ≥ 10 mg/L
		Endoscopic evidence of inflammation

ADA: Adalimumab; CD: Crohn’s disease; CDAI: Crohn’s disease activity index; CRP: C-reactive protein; EEN: Exclusive enteral nutrition; GZMA: Granzyme A; IFX: Infliximab; ITGaE: Integrin aE gene; MH: Mucosal healing; NAT: N-acetyl transferase; PCDAI: Paediatric Crohn’s disease activity index; PEN: Partial enteral nutrition; s.c.: Subcutaneous; SES-CD: Simple Endoscopic Score for Crohn's Disease; SR: Sustained remission; TGN: Thioguanine nucleotides; UC: Ulcerative colitis.

Table 2 Summary and take home messages

1. The pathogenesis of IBD is not completely understood yet, and all therapies currently available are aimed at downstream steps of the complex inflammatory process. Specific targets when treating children with IBD are achieving satisfactory growth and nutritional status.

2. Paediatric pharmacometric approaches are increasingly applied to drugs already in use but that remain unlicensed and off-label in children due to missing information on age appropriate dosing, efficacy and safety.

3. Corticosteroids can be used to induce remission in CD (when exclusive enteral nutrition is not possible) and are first-line therapy for induction of remission in UC, particularly in case of non-response to 5-ASA or with severe presentation.

4. One of the targets of current research is to customise therapy to a patient’s predictive biomarker profile in order to personalise treatments and to maximise response.

5. 5-ASA are used in induction and maintenance of remission in UC. They are not recommended in CD except from post-operative maintenance of remission.

6. Thiopurines include AZA and 6-MP and are steroid sparing agents. They are effective in maintaining disease remission in patients with CD and UC as well as post-surgical remission in CD. The use of TPMT activity and 6-TGN level measurements helps avoiding nearly a quarter of episodes of myelosuppression as well as to monitor non-compliance, under-dosing, drug-resistance or refractory state.

7. An increase in mean 6-TGN blood level has been reported in patients on 6-MP or AZA co-treated with 5-ASA, with a higher rate of myelotoxicity in respect to patients treated with the thiopurine alone.

8. MTX is effective in 50%-80% of the children who fail to respond or are intolerant to thiopurines. It is particularly suitable to patients who have coexistent inflammatory arthritis.

9. In CD, anti-TNF agents are used to treat moderate to severe disease with inadequate response, or contraindication to, or intolerance to, conventional therapy including corticosteroids and immunomodulators. They are also indicated in children with active perianal fistulising disease. Therapeutic drug monitoring of IFX has improved response rates and is increasingly used in clinical practice as a tool for the management of secondary failure to IFX.

10. ADA is a fully human IgG1k monoclonal antibody, which represents a treatment option in patients who have lost response or are intolerant to IFX. ADA achieves remission rates of 45% at 1 yr in anti-TNF naïve children and is effective in nearly 2/3 of patients with IFX failure.

11. Vedolizumab is an anti-integrin therapy which inhibits the migration of intestinal T lymphocytes. The mechanism of action of Vedolizumab is restricted to the GI tract, mitigating the risks of systemic immunosuppression such as infections and malignancies. The clinical response rate for induction with vedolizumab is 50% in UC patients. Vedolizumab is approved for treatment of CD and UC in adults and there is increasing off-label use in children.

12. Thalidomide is an immunosuppressant drug used infrequently off-label in the treatment of refractory CD and UC. Induction of remission is achieved in aroud 50% cases and clinical response in 70%.

13. Drug therapies that interfere selectively with lymphocyte trafficking (e.g., etrolizumab, ozanimod) are emerging treatment options for UC.

UC: Ulcerative colitis; IBD: Inflammatory bowel disease; ADA: Adalimumab; IFX: Infliximab; TPMT: Thiopurine methyl transferase; 5-ASA: Aminosalicylates; CD: Crohn’s disease; 6-MP: 6-mercaptopurine; AZA: Azathioprine; MTX: Methotrexate; GI: Gastrointestinal.