Efficacy and safety of dual-targeted therapy in children with inflammatory bowel disease: Retrospective cohort study

Table 1 Inclusion and exclusion criteria of the study

Inclusion criteria	Exclusion criteria
Clinical or laboratory activity of IBD	Monogenic form of IBD requiring specific therapy (such as bone marrow transplantation, etс.)
Endoscopic activity
History of ineffectiveness or intolerance of tumor necrosis factor-alpha blockers as monotherapy or in combination with immunosuppressors, and at least one more biological drugs with a different mechanism

IBD: Inflammatory bowel disease.

Table 2 Characteristics of the study cohort

ID	Gender	Disease	Location of CD	Location of UC	Perianal disease	Extraintestinal involvement	Previous therapy	Current combination	Dose	Age of onset (years)	Age of beginning dual-targeted therapy (years)
1	M	CD	L3	-	No	No	5-ASA, GCS, AZA, INFL, UP	UP + VD	UP: 30 mg/day 12 weeks, then 15 mg/day. VD: 10 mg/kg/8 weeks	2	5
2	F	CD	L2	-	Yes	Yes	GCS, AZA, MTX, INFL, VD	VD + TOF/UP + UST	VD: 300 mg/6 weeks. TOF: 20 mg/day 8 weeks, then 10 mg/day. UP: 45 mg/day 12 weeks, then 30 mg/day. UST: 90 mg/4 weeks	11	12
3	M	UC	-	Pancolitis	-	Yes	5-ASA, GCS, AZA, MTX, INFL, ADA, VD	VD + TOF	VD: 300 mg/6 weeks. TOF: 20 mg/day 8 weeks, then 10 mg/day	7	10
4	M	UC	-	Pancolitis	-	No	5-ASA, GCS, AZA, INFL, UP	UP + VD	UP: 45 mg/day 8 weeks, then 30 mg/day. VD: 300 mg/8 weeks	11	13
5	M	CD	L3	-	Yes	No	5-ASA, GCS, AZA, MTX, INFL, ADA, TOF	TOF + VD	TOF: 20 mg/day 8 weeks, then 10 mg/day. VD: 300 mg/6 weeks	13	15
6	F	CD	L3+L4	-	No	No	Enteral nutrition, 5-ASA, GCS, TAC, SRL, INFL, ADA, VD, TOF	VD + UP	VD: 300 mg/6 weeks. UP: 45 mg/day 12 weeks, then 15 mg/day	2	12
7	M	UC	-	Left-sided	-	No	5-ASA, GCS, AZA, INFL, VD, TOF	TOF + ADA	TOF: 5 mg/day. ADA induction (40-80 mg), then 40 mg/2 weeks	2	2
8	M	CD	L2	-	Yes	Yes	GCS, AZA, TAC, INFL, ADA, UST	UST + UP	UST: 90 mg/4 weeks. UP: 45 mg/day 12 weeks, then 30 mg/day	8	15
9	F	UC	-	Pancolitis	-	Yes	5-ASA, GCS, AZA, INFL, VD	VD + UP	VD: 300 mg/6 weeks. UP: 45 mg/day 8 weeks, then 15 mg/day	6	13
10	F	UC	-	Left-sided	-	No	5-ASA, GCS, AZA, TAC, INFL, ADA	ADA + UP	ADA: 40 mg/2 weeks. UP: 30 mg/day 8 weeks, then 15 mg/day	2	6
11	M	CD	L3	-	No	No	GCS, AZA, INFL, ADA, UP	UP + UST	UP: 45 mg/day 12 weeks, then 30 mg/day. UST: 90 mg/8 weeks	14	16
12	M	CD	L2	-	No	Yes	GCS, AZA, MTX, INFL, VD, TOF	VD + UP	VD: 300 mg/4 weeks. UP: 45 mg/day 12 weeks, then 15 mg/day	13	15
13	F	CD	L3 + L4	-	No	No	5-ASA, GCS, AZA, MTX, INFL, ADA, golimumab, TAC, VD, TOF	VD + TOF/TOF + UST	VD: 10 mg/kg/6 weeks. TOF: 20 mg/day 8 weeks, then 5 mg/day. UST: 90 mg/8 weeks	2	11
14	F	CD	L3 + L4	-	No	No	5-ASA, GCS, INFL, AZA, TAC, SRL, VD	VD + TOF	VD: 10 mg/kg/6 weeks. TOF: 15 mg/day 8 weeks, then 10 mg/day	1	6
15	M	CD	L2	-	No	Yes	5-ASA, GCS, AZA, MTX, TAC, mycophenolate mofetil, INFL, ADA, UST	UST + UP	UST: 90 mg/4 weeks. UP: 45 mg/day 12 weeks, then 15 mg/day	5	17
16	M	CD	L3	-	No	No	5-ASA, GCS, AZA, MTX, TAC, INFL, ADA, VD	VD +UP	VD: 300 mg/4 weeks. UP: 45 mg/day 12 weeks, then 15 mg/day	5	12
17	F	CD	L2 + L4	-	Yes	No	GCS, AZA, MTX, INFL, ADA, UST	UST + UP	UST: 90 mg/8 weeks. UP: 45 mg/day 12 weeks, 15 mg/day	3	17
18	M	CD	L3	-	No	No	GCS, AZA, MTX, INFL, ADA, VD	VD + TOF	VD: 10 mg/kg/6 weeks. TOF: 10 mg/day	1	8

The first drug prescribed is underlined. ADA: Adalimumab; AZA: Azathioprine; CD: Crohn’s disease; F: Female; GCS: Glucocorticosteroids; INFL: Infliximab; M: Male; MTX: Methotrexate; SRL: Sirolimus; TAC: Tacrolimus; TOF: Tofacitinib; UC: Ulcerative colitis; UP: Upadacitinib; UST: Ustekinumab; VD: Vedolizumab; 5-ASA: 5-aminosalicylic acid.

Table 3 Schematic design of the study

	Baseline	At three months	At six months
Pediatric Crohn’s Disease Activity Index (in Crohn’s disease)	+	+	+
Pediatric Ulcerative Colitis Activity Index (in ulcerative colitis)	+	+	+
Endoscopy	+	-	+
Hemoglobin	+	+	+
Erythrocyte sedimentation rate	+	+	+
C-reactive protein	+	+	+
Fecal calprotectin	+	-	+

Table 4 Dynamics of laboratory parameters depending on the lesion of the upper gastrointestinal tract in patients with Crohn’s disease

Parameter	Upper gastrointestinal tract lesions		P value
	No	Yes
Нb at M3, median (IQR)	127.0 (122.0-134.0)	120.5 (117.8-121.0)	0.020a
ESR at M3, median (SD)	10.8 (6.8)	28.5 (12.6)	0.004a
CRP at M3, median (IQR)	1.0 (0.8-1.4)	0.8 (0.3-9.9)	0.905
Hb at M6, median (IQR)	129.0 (121.0-134.0)	121.0 (116.0-124.0)	0.109
ESR at M6, median (IQR)	6.0 (6.0-11.0)	19.0 (16.0-42.0)	0.019a
CRP at M6, median (IQR)	0.6 (0.20-1.0)	1.0 (0.5-11.7)	0.283
Fecal calprotectin at M6, median (IQR)	175.0 (95.0-600.0)	600.0 (155.0-800.0)	0.421
simple endoscopic index of CD at M6, median (IQR)	0.0 (0.0-2.0)	10.0 (6.0-10.0)	0.042a
Pediatric Crohn’s Disease Activity Index at M6, mean (SD)	3.6 (3.3)	11.5 (7.4)	0.016a

^aP < 0.05.

CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; Hb: Hemoglobin; IQR: Interquartile range; M3: Three months; M6: Six months.