How has the disease course of pediatric ulcerative colitis changed throughout the biologics era? A comparison with the IBSEN study

Table 1 Demographic and clinical features of the two groups before and after infliximab approval

	Group A (n = 48)	Group B (n = 62)	P value
Age at diagnosis, yr	14.4 (12.2-17.1)	15.8 (13.1-16.5)	0.574c
Total duration of follow up with treatment, yr	4.0 (4.0-5.0)	5.5 (3.0-6.9)	0.073c
PUCAIa at diagnosis	35 (30-65)	45 (35-55)	0.969c
Hemoglobin at diagnosis, g/dL	12.3 (10.5-14.1)	12.1 (9.6-13.5)	0.245c
Albumin at diagnosis, g/dL	4.3 (4.0-4.6)	4.2 (3.9-4.6)	0.702c
ESR at diagnosis, mm/h	14.5 (7-31.3)	20 (7.5-39)	0.249c
CRP at diagnosis, mg/dL	0.04 (0.03-0.13)	0.12 (0.03-0.56)	0.791c
Disease extent of Paris classification at diagnosis			0.018d
E1 proctitis	18 (37.5)	13 (21)
E2 left colitis	8 (16.7)	8 (12.9)
E3 right colitis	6 (12.5)	7 (11.3)
E4 pancolitis	16 (33.3)	34 (54.8)
Mayo endoscopic subscore at diagnosisb			0.310d
0 normal or inactive	0	0
1 mild	12 (25.0)	7 (11.3)
2 moderate	26 (54.2)	43 (69.4)
3 severe	10 (20.8)	12 (19.4)
Corticosteroid use at baseline	21 (43.8)	30 (48.4)	0.630d
Corticosteroid-dependent	8/21 (38.1)	9/30 (30.0)	0.550d
Corticosteroid-refractory	1/21 (4.8)	1/30 (3.3)	0.360d
Cumulative number receiving medication by			0.211d
3 mo after diagnosis			0.453d
5-aminosalicylate	48 (100)	60 (96.8)
Azathioprine	42 (87.5)	51 (82.3)
Methotrexate	0 (0)	1 (1.6)
Cyclosporine	1 (2.1)	0 (0)

^aPediatric Ulcerative Colitis Activity Index (PUCAI) is a 6-item disease activity index intended for use in pediatric UC clinical trials with a score ranging from 0-85.

^bMayo endoscopy subscores were as follows: 0: Normal or inactive disease; 1: Mild disease; 2: Moderate disease; and 3: Severe disease.

^cχ² test.

^dMann-Whitney test.

Values are n (percentage) or median (interquartile range); n: Number of patients; PUCAI: Pediatric Ulcerative Colitis Activity Index.

Table 2 Comparison of composition of drugs for treatment and disease states according to colonoscopy findings 2 and 5 yr after diagnosis before (group A) and after (group B) infliximab approval

	Group A (n = 48)	Group B (n = 62)	P value
Maintenance treatment 2 year after diagnosis
None	0	5 (8.1)	0.045
5-Aminosalicylate	47 (97.9)	46 (74.2)	0.001
Azathioprine	43 (89.6)	36 (58.1)	0.001
Infliximab	0	34 (54.8)	< 0.001
Adalimumab	0	0
Vedolizumab	0	0
Ustekinumab	0	0
Tofacitinib	0	0
Disease extent of Paris classification 2 years after diagnosis			0.012b
Remission	14 (29.2)	31 (50.0)
E1 proctitis	13 (27.1)	11 (17.7)
E2 left colitis	2 (4.2)	8 (12.9)
E3 right colitis	6 (12.5)	8 (12.9)
E4 pancolitis	13 (27.1)	4 (6.5)
Mayo endoscopic subscore 2 years after diagnosisa			0.037b
0 normal or inactive	15 (24.2)	33 (53.2)
1 mild	24 (50.0)	21 (33.9)
2 moderate	8 (16.7)	8 (12.9)
3 severe	1 (2.1)	0
	Group A (n = 24)	Group B (n = 31)	P value
Maintenance treatment 5 year after diagnosis
None	2 (8.3)	5 (16.1)	0.394
5-aminosalicylate	21 (87.5)	15 (48.4)	0.003
Azathioprine	14 (58.3)	14 (45.2)	0.337
Infliximab	0	18 (58.1)	< 0.001
Adalimumab	0	2 (6.5)
Vedolizumab	0	1 (3.2)
Ustekinumab	0	0
Tofacitinib	0	0
Disease extent of Paris classification 5 years after diagnosis			0.016b
Remission	3 (12.5)	13 (41.9)
E1 proctitis	9 (37.5)	9 (29.0)
E2 left colitis	3 (12.5)	4 (12.9)
E3 right colitis	2 (8.3)	2 (6.5)
E4 pancolitis	7 (29.2)	3 (9.7)
Mayo endoscopic subscore 5 years after diagnosisa			< 0.001b
0 normal or inactive	3 (12.5)	13 (41.9)
1 mild	6 (25.0)	16 (51.6)
2 moderate	14 (58.3)	2 (6.5)
3 severe	1 (4.2)	0

^aMayo endoscopy subscores were as follows: 0: Normal or inactive disease; 1: Mild disease; 2: Moderate disease; and 3: Severe disease.

^bMann-Whitney test.

Values are n (percentage).

Table 3 Clinical outcomes during the total follow-up period before (group A) and after (group B) infliximab approval

	Group A (n = 48)	Group B (n = 62)	P value
Number of relapsed patients	23 (47.9)	16 (25.8)	0.027b
Cumulative total relapses	40	22	0.006b
Number of relapses per person	1.74	1.38
Number of relapses per person per year	0.44	0.25
First relapse interval from diagnosis, yr	1.20 (0.60-2.50)	1.95 (1.35-3.93)	0.194b
Each relapse interval, yr	1.30 (0.60-3.55)	1.70 (1.00-4.20)	0.943b
Initial disease extent of relapsed patients			0.080c
E1 proctitis	7 (30.4)	0
E2 left colitis	2 (8.7)	0
E3 right colitis	3 (13.0)	2 (12.5)
E4 pancolitis	11 (47.8)	14 (87.5)
Number of hospitalizations per person	0.13	0.18	0.964b
Median PUCAIa during treatment period	10 (5-20)	5 (3.75-15)	< 0.001b
Median PUCAIa at the time of relapse	65 (52.5-75)	45 (45-55)	< 0.001b
Median cumulative corticosteroid free period	3.0 (2.6-3.7)	4.4 (3.1-6.0)	< 0.001b
Number of cumulative colectomies1	1	0

^aPediatric Ulcerative Colitis Activity Index (PUCAI) is a 6-item disease activity index intended for use in pediatric UC clinical trials with a score ranging from 0-85.

^bχ² test.

^cMann-Whitney test.

¹Statistical analysis was not performed as there was only one patient who underwent colectomy.

Values are n (percentage) or median (interquartile range); n: Number of patients; PUCAI: Pediatric Ulcerative Colitis Activity Index.

Table 4 Univariable and multivariable analysis of the association between relapse rate and other factors

Parameter	Univariable analysisb				Multivariable analysisb
	Pr > ChiSq	HR	95%CIc of HR		Pr > ChiSq	HR		95%CIc of HR
Age at diagnosis, yr (< 10 yr)	0.063	0.434	0.642	3.714
Disease extent at diagnosis	0.317
E2	1	0.786	0.194	3.185a
E3	1	1.097	0.555	2.166a
E4	0.374	1.758	1.058	2.921a
Corticosteroid uses at baseline (Yes)	0.010	2.111	1.201	3.712	0.109	1.682	0.890		3.176
Mayo endoscopic subscore at diagnosis (> 2 Moderate)	< 0.001	2.496	1.478	4.217	0.015	2.108	1.157		3.843
PUCAId at diagnosis (> 45)	0.558	1.202	0.650	2.222

^aP value and 95%CI for hazard ratio were corrected by Bonferroni's method due to multiple testing.

^bCox’s proportional hazard regression using counting process.

^cThe robust sandwich covariance estimate was used to account for the within-subject correlation.

^dPediatric Ulcerative Colitis Activity Index (PUCAI) is a 6-item disease activity index intended for use in pediatric UC clinical trials with a score ranging from 0-85.

CI: Confidence interval; HR: Hazard ratio.