Biologics in the management of pediatric inflammatory bowel disease: When and what to choose

Table 1 Recommendations of pediatric guidelines regarding biologic use in inflammatory bowel disease

Characteristics	ECCO-ESPGHAN guidelines CD, 2020[13], UC, 2018[14,15]	Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition PIBD Working Group, 2022[6]	Canadian association of Gastroenterology Guidelines, 2019[16]
Indications CD	Upfront biologics for the following: (1) Extensive disease and deep colonic ulcers; (2) Perianal disease; (3) Stricturing or penetrating disease; and (4) Growth failure	Upfront biologics if severe luminal or perianal disease	Upfront biologics if severe luminal or perianal disease
	As step-up therapy: Moderate to severe active CD not responding to conventional therapy	Step-up approach: Moderate to severe active CD not responding to conventional therapy	Step-up approach: Moderate to severe active CD not responding to conventional therapy
	1st line: Infliximab, adalimumab; 2nd line: Ustekinumab	1st line: Infliximab, adalimumab, ustekinumab, and vedolizumab - no consensus	1st line: Iinfliximab, adalimumab; 2nd line: Ustekinumab; no consensus on vedolizumab
Indications UC	Chronically active moderate to severe UC, not responding to conventional therapy; tofacitinib - no consensus	Chronically active moderate to severe UC, not responding to conventional therapy	NA
	ASUC if not responding to 5 days of intravenous steroid	ASUC if not responding to 5 days of intravenous steroid
	1st line: Infliximab; 2nd line: Vedolizumab	1st line: Infliximab; vedolizumab, tofacitinib - no consensus
Co-therapy with immune-modulator	Infliximab - consider combination therapy Adalimumab - no	Infliximab and adalimumab - consider combination therapy	Infliximab - NR (male), no recommendation for or against (female)
			Adalimumab - NR (male), no recommendation for or against (female)
			If considered, methotrexate for boys and thiopurine for girls
Screening before biologic	HBV/HCV/HIV	HBV/HCV/HIV	HBV/HCV/HIV
	TB: Mantoux or IGRA (BCG-vaccinated patients), chest X-ray, sputum	TB: Mantoux and IGRA, chest X-ray, sputum	TB: Mantoux or IGRA, chest X-ray, sputum
TDM	Yes, proactive preferred	Yes, reactive	Yes, reactive
Target trough level	Infliximab: Induction (week 6) ≥ 15 μg/mL; maintenance ≥ 5 μg/mL	Infliximab: Induction > 10-15 μg/mL; maintenance ≥ 3-7 μg/mL	NA
	Adalimumab: Induction (week 4) and maintenance ≥ 7.5 μg/mL	Adalimumab: Maintenance ≥ 5-8 μg/mL

ECCO-ESPGHAN: European Crohn’s and Colitis Organization-European Society of Pediatric Gastroenterology, Hepatology and Nutrition; CD: Crohn’s disease; UC: Ulcerative colitis; ASUC: Acute severe ulcerative colitis; PIBD: Pediatric inflammatory bowel disease; TDM: Therapeutic drug monitoring; NA: Not available; NR: Not recommended; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; TB: Tuberculosis; IGRA: Interferon gold release assay; BCG: Bacille Calmette-Guerin.

Table 2 Mechanism of action, drug doses, route of administration, efficacy and side effects of biologics in children with inflammatory bowel disease

Characteristics	Infliximab	Adalimumab	Ustekinumab	Vedolizumab	Tofacitinib
Mechanism of action	Anti-TNFα antibody (chimeric)	Anti-TNFα antibody (humanized)	Anti-IL-12/23 antibody (humanized)	Anti-α4β7 integrin antibody (humanized)	JAK inhibitor
Route	IV; SCb	SC	IV (1st dose) followed by SC	IV	Oral
Dosea
Induction	5mg/kg	2.4 mg/kg, f/b 12 mg/kg	6 mg/kg if < 40 kg BW, 130 mg if > 40 kg BW	6 mg/kg < 40 kg BW, 300 mg > 40 kg BW	10 mg twice daily
Maintenance	5mg/kg	0.6 mg/kg	2 mg/kg if < 40 kg BW, 90 mg if > 40 kg BW	Same as induction dose	5 mg twice daily
Schedulea
Induction	0 week, 2 week, and 6 weeks	0 week, and 2 weeks	0 week	0 week, 2 weeks, and 6 weeks	Daily
Maintenance	8 weekly	2 weekly	8 weekly	8 weekly	Daily
Target drug level	Induction (week 6) ≥ 10-15 μg/mL; maintenance ≥ 5 μg/mL	Post-induction before 3rd dose ≥ 7.5 μg/mL	Target level not well defined	Target level not well defined	NR
	In patients at risk for accelerated drug clearance, target concentration ≥ 25 μg/mL at 2nd infusion and ≥ 15 μg/mL at 3rd infusion[13]	Maintenance ≥ 7.5 μg/mL[13]
Adverse events	Infection, reactivation of TB/ HBV; skin reaction (psoriasis)	Infection; headache, arthralgia, skin reaction	Infection; (GI most common), myalgia	Infection; (respiratory, GI); headache, myalgia	Varicella zoster infection, thrombosis, dyslipidemia, LFT, derangement
Use of concomitant immunomodulator (azathioprine/methotrexate)	Yes (initial 6-12 months)	If biological naive: No need	No	No	No
		Biological exposed: Can add

^aDose and ^aschedule: Standard dose may need to be changed to more frequent dosing or/and higher dose as per the therapeutic drug monitoring (see text); in children with weight < 30 kg, vedolizumab should be dosed by the child's body surface area (200 mg/m²) or weight (10 mg/kg)[50].

^bSC: Subcutaneous route tried in study and shown to be as effective[44,45]. Recommendations for drug level vary as per disease site and burden e.g. higher in perianal Crohn’s disease.

IV: Intravenous; SC: Subcutaneous; TNFα: Necrosis factor alpha; Anti-α4β7: Anti-alpha4beta7; IL: Interleukin; BW: Body weight; TB: Tuberculosis; HBV: Hepatitis B virus; LFT: Liver function test; GI: Gastrointestinal; NR: Not recommended.

Table 3 Summary of the pediatric studies on the efficacy and safety of infliximab and adalimumab

Ref.	CD				UC
	Number of cases	Details of cases	Efficacy	Adverse event	Number of cases	Details of cases	Efficacy	Adverse event
	Age (years), mean ± SD/median age (years); IQR				Age (years), mean ± SD/ IQR
Infliximab
Hyams et al[21], REACH trial	112	Moderate to severe	CRes and CR 89% and 59% at week 10; 63% and 56% at week 54th	94.6% (serious 19.6%)	-	-	-	-
	13.3 ± 2.5
Crandall et al[23]	22	Fistulizing perianal disease, all biologic naive	Response in 41% (9/22, partial response-4, complete response-5) at week 2nd; 73% (16/22, partial-1, complete-15) at week 54th	95.7% (serious 4.5%)	-	-	-	-
	13.3 ± 2.5
Hyams et al[26]	-	-	-	-	52	Moderate to severe, all biologic naive	CRes 27%: 6 months; CRes 38%: 12 months; CRes 21%: 24 months	None
					13.3 ± 2.6
deBruyn et al[31]	147	Moderate to severe; all biologic naive	SFCR 59% at 1 year, 59.5% at 2 years	5.4% (serious 4.7%)	-	-	-	-
	14.3; 12.1-15.1
Adalimumab
Hyams et al[30], IMAgINE trial	188	Moderate to severe, 44% infliximab exposed	CR 33.5% at week 26th	89% drug related 41% (serious 22.3%)	-	-	-	-
	13.6 ± 2.5
Croft et al[34], ENVISION I trial, high dose vs standard dose vs placebo	-	-	-	-	93	Moderate to severe, all biologic-naive	Endoscopic remission at week 8th: High dose vs placebo-60% vs 20%, P = 0.0001; standard dose vs placebo-43% vs 20%, P = 0.38	78% (serious 23%)
					4-17		At week 52th: High dose vs placebo: 45% vs 18%, P = 0.0001; standard dose vs placebo-29% vs 18%, P = 0.38)
deBruyn et al[31]	147	Moderate to severe; all biologic naive	SFCR: 63% at 1 year; 59% at 2 years	1.3% (serious-none)	-
	13.4;11.6-14.9
Rinawi et al[114]	65	Moderate to severe, all biologic-naive	CR 60% at week 24th	NA	-	-	-	-
	12.1; 10.5-13.8

Reported adverse events: (1) Infliximab: Infections, severe infections, intestinal stenosis, pneumonia, H zoster, abscess, sepsis, colitis, furunculosis, adenitis, abdominal pain, fever, vomiting, enterocolitis, infusion reaction, injection site reaction, delayed type infusion reaction; and (2) Adalimumab: Injection site reaction, hematologic-, allergic, hepatic, tooth abscess, scarlet fever, Bartholin’s/abdominal abscess, disseminated histoplasmosis, gastroenteritis, anal abscess, Influenza A, headache, anemia, nasopharyngitis.

CD: Crohn’s disease; UC: Ulcerative colitis; CRes: Clinical response; CR: Clinical remission; SFCR: Steroid free clinical remission; NA: Not available.

Table 4 Summary of the studies on the efficacy of biosimilars in pediatric inflammatory bowel disease

Ref.	Biosimilar	Patient population	Control group	Main outcomes
		Age (years), mean ± SD/median age (years); IQR	Age (years), mean ± SD/median age (years); IQR
Infliximab biosimilar
Sieczkowska-Golub et al[38], prospective	CT-P13	36 CD; 27 anti-TNF naive	No	86% CRes; 67% clinical remission at week 14
		11.8 ± 4
Chanchlani et al[39], prospective	Inflectra and remsima	82 (63 CD, 14 UC, 5 IBD-U)	175 (148 CD, 33 UC, 15 IBD-U) children on originator infliximab	Clinical remission 79% for biosimilar and 68% for the originator at week 12
		12; 10-14	12; range 10-14
Nikkonen et al[40], retrospective	CT-P13	28 (16 CD, 3 UC, 9 IBD-U)	23 (17 CD, 2 UC, 4 IBD-U) on originator infliximab	90% CRes; no difference between the two groups at week 12
		12; 4-16	12.0; 5.4-16	65% vs 61% patients on maintenance treatment at 1 year
Sieczkowska et al[41], prospective	CT-P13	39 (32 CD, 7 UC) elected to switch	No	80% and 100% clinical remission at the last follow-up assessment (median 8 months) for CD and UC patients, respectively
		CD: 11.1 ± 3.3; UC: 12.3 ± 2.3
Kang et al[42], prospective	CT-P13	38 (32 CD, 6 UC) elected to switch	36 (28 CD, 8 UC) on originator infliximab	Clinical remission rate 77.8% and 78.9% for biosimilar and originator IFX at 1 year
		17.5 ± 4.0	17.3 ± 3.4
Gianolio et al[45], retrospective	IFX-SC	7 CD	No	All (100%) remained in clinical remission at week 40
		16.5 ± 0.8
Adalimumab biosimilar
Dipasquale et al[43], retrospective	ABP501	41 (39 CD, 2 UC)	No	Clinical remission rate 70.7% at week 14 and 72% at week 52
		13.6; 11.3-15.8

IQR: Interquartile range; CD: Crohn’s disease; TNF: Tumor necrosis factor; CRes: Clinical response; UC: Ulcerative colitis; IBD-U: Inflammatory bowel disease unclassified; IFX: Infliximab; SC: Subcutaneous.

Table 5 Summary of the studies on the efficacy and safety of vedolizumab, ustekinumab and tofacitinib in children

Ref.	CD				UC
	Number of cases	Details of cases	Efficacy	Adverse event	Number of cases	Details of cases	Efficacy	Adverse event
	Age (years), mean ± SD/median age (years); IQR				Age, (years) mean ± SD/median age (years); IQR
Vedolizumab
Singh et al[47], retrospective	30	87% anti TNFα agent exposed	Clinical remission 42% at week 14	14.3%	22	95% anti TNFα agent exposed	Clinical remission 76% at week 14	Nil
	15.2; 7-17				14.3; 7-17
Hyams et al[49], HUBBLE trail	45	Refractory to steroid, immunomodulator and/or anti-TNFα agents; biologic exposed 64%	CRes 33%-63%; remission 16%-54% at week 14	90% (serious 30%)	44	Refractory to steroid, immunomodulator and/or anti-TNFα agents; biologic exposed 34%	CRes 40%-69%; remission 30%-60% at week 14	82% (serious 22%)
	2-17				2-17
Atia et al[50], VEDOKIDS	65	Refractory to steroid, immunomodulator and/or anti-TNFα agents	Clinical remission 32% at week 14	28% (none serious)	77	Refractory to steroid, immunomodulator and/or anti-TNFα agents	Clinical remission 49% at week 14	18% (none serious)
	15 ± 2.3				14.2 ± 2.9
Fang et al[51], systematic review	216	Refractory to steroid, immunomodulator and/or anti-TNFα agents	Clinical remission 18%-37% at week 14; 36%-57% at 1 year	serious 6%a	239	Refractory to steroid, immunomodulator and/or anti-TNFα agents	Clinical remission 31%-65% at week 14; 35%-54% at 1 year	Serious; 6%a
	< 21				< 21
Ustekinumab
Turner et al[53], UniStar study, Prospective	34	Moderate to severe CD, 94% anti-TNFα exposed	Clinical remission 41% at week 48	88% (serious 14.7%)	-	-	-	-
	13; 12-16
Yerushalmy-Feler et al[54], ESPGHAN Porto group, retrospective	69	98.6% anti-TNFα exposed	CRes 67% at week 12; remission 42% at week 12	8.7% (none serious)	-	-	-	-
	15.8; 13.8-16.9
Koudsi et al[55], GETAID, retrospective	48	All anti-TNFα exposed	PCDAI reduced from 28.7 to 18.7 at week 12	17%a	5	Refractory, all anti-TNFα exposed	PUCAI 47 to 25 at week 12	17%a
	15.0; 8.7-18				15.0; 8.7-18
Fang et al[56], systematic review	204	Refractory CD, 90% anti-TNFα exposed	Clinical remission 34% at week 8-16, 46% at 1 year	3.5%a	166	Refractory UC, 86% anti TNFα exposed	Clinical remission 24% at week 8-16, 46% by 1 year	3.5%a
Tofacitinib
Moore et al[57], retrospective	-	-	-	-	21	20 exposed to infliximab, 9 to adalimumab, 2 to ustekinumab, 13 to vedolizumab	CRes 43% at week 12; clinical remission 33% at week 12, 41% at week 52	71% (serious 52%, possibly non-drug related)
					18.4; 15-19.9
Ledder et al[58], retrospective	-	-	-	-	101	All at least 1 biologic exposed; 36% exposed to 3 biologics	CRes 46% at week 8; clinical remission 16% at week 8, 23% at week 24	3% (herpes zoster, dyslipidemia)
					12.8 ± 2.8

^aAdverse event rate reported for combined group of patients with Crohn’s and ulcerative colitis.

Adverse events: (1)Vedolizumab: Infection (respiratory tract infection, pneumonia, gastrointestinal tract), headache, arthralgia, muscle spasm, skin (rash, eczema), hepatic injury, hypersensitivity reaction, worsening of underlying disease; (2) Ustekinumab: Headache, arthralgia, nausea, abdominal pain, upper respiratory tract infection, and nasopharyngitis, gastroenteritis, abscess, intestinal obstruction, C. difficile; and (3) Tofacitinib: Fever, infections-viral, C. difficile, candida, pharyngitis, pneumonia, vaginitis/abdominal pain, constipation, dermatitis, headache, vomiting, ocular complaints.

CD: Crohn’s disease; UC: Ulcerative colitis; CRes: Clinical response; TNFα: Tumor necrosis factor-alpha; PCDAI: Pediatric Crohn’s disease activity index; PUCAI: Pediatric ulcerative colitis activity index; NA: Not available; IQR: Interquartile range.

Table 6 Summary of the pediatric studies on the efficacy and safety of dual-biologic therapy

Ref.	Number of cases	Details of case	Medications used	Efficacy-clinical remission	Adverse events
	Median age (years); IQR
Dolinger et al[89], retrospective	16 (CD 7, UC 9)	All failed ≥ 2 biologics	VDZ + TOFA 9, VDZ + UST 4, UST + TOFA 3	75% at 6 months	6.25% (arthritis, deep vein thrombosis)
	15.9; 13.5-16.8
Wlazło et al[90], retrospective	14 ( CD 4, UC 10)	All failed single biologic	UST + ADA 5, VDZ + ADA 5, IFX + VDZ 3, VDZ + ADA/UST + ADA-1	73% at 4 months	7% (mild infection)
	11.7; 3-17
Yerushalmy-Feler et al[91], retrospective	62 (CD 35, UC 27)	All failed 1 biologic, 76% failed ≥ 2 biologics	IFX + VDZ 18, IFX + UST 8, ADA + UST 11, ADA + VDZ 11, VDZ + UST 8, TOFA + IFX 2, TOFA + VDZ 1	35% at 3 months, 50% at 6 months, 63% at 1 year	47% (7% serious, infection, thrombosis)
	15.5; 13-16.8
Olbjørn et al[92], retrospective	13 (9 CD, 4 UC)	All failed anti-TNFα agents	IFX + VDZ 8 (4 CD, 4UC), IFX + UST 5 (all CD)	IFX + VDZ, 75% remission at 6 months in UC, 25% in CD, IFX + UST 100% remission at 2 year	IFX + VDZ 2/8 (25%), IFX + UST 1/5 (20%)
	8; 4-17.5
Goyal et al[93], retrospective	9 children with CD	All failed anti-TNFα agents	IFX + VDZ + metho 1, IFX + anakinra 1, ADA + VDZ 1, ADA + VDZ+ PEN 1, ADA + VDZ + metho 3, UST + VDZ 2	Complete response 45%, partial response 22% at 4 months	3/9 (33%), skin infection, bleeding, fracture, unrelated
	16; 8-19
Wlazlo et al[94], retrospective	14 (CD 4, UC 10)	All failed anti-TNFα agents	ADA + VDZ 5, ADA + UST 6, IFX + VDZ 3	73% CRes by 4 months	Not reported
	11.7; 3-17

IQR: Interquartile range; CD: Crohn’s disease; UC: Ulcerative colitis; VDZ: Vedolizumab; TOFA: Tofacitinib; UST: Ustekinumab; IFX: Infliximab; ADA: Aadalimumab; Metho: Methotrexate; PEN: Partial enteral nutrition; TNFα: Tumor necrosis factor-alpha.