Defining the ultrasound longitudinal natural history of newly diagnosed pediatric small bowel Crohn disease treated with infliximab and infliximab-azathioprine combination therapy

Abstract

Background: Little is known about changes in the imaging appearances of the bowel and mesentery over time in either pediatric or adult patients with newly diagnosed small bowel Crohn disease treated with anti-tumor necrosis factor-alpha (anti-TNF-α) therapy.

Objective: To define how bowel ultrasound findings change over time and correlate with laboratory inflammatory markers in children who have been newly diagnosed with pediatric small bowel Crohn disease and treated with infliximab.

Materials and methods: We included 28 pediatric patients treated with infliximab for newly diagnosed ileal Crohn disease who underwent bowel sonography prior to medical therapy and at approximately 2 weeks, 1 month, 3 months and 6 months after treatment initiation; these patients also had laboratory testing at baseline, 1 month and 6 months. We used linear mixed models to compare mean results between visits and evaluate whether ultrasound measurements changed over time. We used Spearman rank correlation to assess bivariate relationships.

Results: Mean subject age was 15.3±2.2 years; 11 subjects were girls (39%). We observed decreases in mean length of disease involvement (12.0±5.4 vs. 9.1±5.3 cm, P=0.02), maximum bowel wall thickness (5.6±1.8 vs. 4.7±1.7 mm, P=0.02), bowel wall color Doppler signal (1.7±0.9 vs. 1.2±0.8, P=0.002) and mesenteric color Doppler signal (1.1±0.9 vs. 0.6±0.6, P=0.005) at approximately 2 weeks following the initiation of infliximab compared to baseline. All laboratory inflammatory markers decreased at 1 month (P-values<0.0001). There was strong correlation between bowel wall color Doppler signal and fecal calprotectin (ρ=0.710; P<0.0001). Linear mixed models confirmed that maximum bowel wall thickness (P=0.04), length of disease involvement (P=0.0002) and bowel wall color Doppler signal (P<0.0001) change over time in response to infliximab, when adjusted for age, sex, azathioprine therapy, scanning radiologist and baseline short pediatric Crohn's disease activity index score.

Conclusion: The ultrasound appearance of the bowel changes as early as 2 weeks after the initiation of infliximab therapy. There is strong correlation between bowel wall color Doppler signal and fecal calprotectin.

Keywords: Anti-tumor necrosis factor-alpha; Biologic therapy; Children; Crohn disease; Infliximab; Small bowel; Ultrasound.

Fig. 1

Tukey box plots show change in ultrasound findings over time. a Length of distal ileal involvement. b Maximum bowel wall thickness. c Bowel wall color Doppler signal. d Mesenteric color Doppler signal. Visit 1 = baseline; visit 2 = approximately 2 weeks; visit 3 = approximately 1 month; visit 4 = approximately 3 months; visit 5 = approximately 6 months. Boxes represent interquartile ranges, while horizontal lines within the boxes represent medians (some medians overlap the x-axis). Circles, triangles and diamonds represent statistical outliers. Boxes in figure parts (c) and (d) that appear to lack a horizontal line (visits 4 and 5) have a median value of zero

Fig. 1

Tukey box plots show change in ultrasound findings over time. a Length of distal ileal involvement. b Maximum bowel wall thickness. c Bowel wall color Doppler signal. d Mesenteric color Doppler signal. Visit 1 = baseline; visit 2 = approximately 2 weeks; visit 3 = approximately 1 month; visit 4 = approximately 3 months; visit 5 = approximately 6 months. Boxes represent interquartile ranges, while horizontal lines within the boxes represent medians (some medians overlap the x-axis). Circles, triangles and diamonds represent statistical outliers. Boxes in figure parts (c) and (d) that appear to lack a horizontal line (visits 4 and 5) have a median value of zero

Fig. 1

Tukey box plots show change in ultrasound findings over time. a Length of distal ileal involvement. b Maximum bowel wall thickness. c Bowel wall color Doppler signal. d Mesenteric color Doppler signal. Visit 1 = baseline; visit 2 = approximately 2 weeks; visit 3 = approximately 1 month; visit 4 = approximately 3 months; visit 5 = approximately 6 months. Boxes represent interquartile ranges, while horizontal lines within the boxes represent medians (some medians overlap the x-axis). Circles, triangles and diamonds represent statistical outliers. Boxes in figure parts (c) and (d) that appear to lack a horizontal line (visits 4 and 5) have a median value of zero

Fig. 1

Tukey box plots show change in ultrasound findings over time. a Length of distal ileal involvement. b Maximum bowel wall thickness. c Bowel wall color Doppler signal. d Mesenteric color Doppler signal. Visit 1 = baseline; visit 2 = approximately 2 weeks; visit 3 = approximately 1 month; visit 4 = approximately 3 months; visit 5 = approximately 6 months. Boxes represent interquartile ranges, while horizontal lines within the boxes represent medians (some medians overlap the x-axis). Circles, triangles and diamonds represent statistical outliers. Boxes in figure parts (c) and (d) that appear to lack a horizontal line (visits 4 and 5) have a median value of zero

Fig. 2

Baseline and follow-up US imaging in a 16-year-old boy with newly diagnosed distal ileal Crohn disease. a Baseline color Doppler image through the right lower quadrant prior to infliximab therapy shows markedly increased blood flow in the bowel wall (scored 3 by both radiologists). b Follow-up image from visit 2 shows substantially decreased color Doppler signal in the same loop of bowel following infliximab therapy (scored 1 by both radiologists). Note that imaging planes are slightly different on the images captured

Fig. 2

Baseline and follow-up US imaging in a 16-year-old boy with newly diagnosed distal ileal Crohn disease. a Baseline color Doppler image through the right lower quadrant prior to infliximab therapy shows markedly increased blood flow in the bowel wall (scored 3 by both radiologists). b Follow-up image from visit 2 shows substantially decreased color Doppler signal in the same loop of bowel following infliximab therapy (scored 1 by both radiologists). Note that imaging planes are slightly different on the images captured

Fig. 3

Tukey box plots show change in laboratory inflammatory markers and short pediatric Crohn’s disease activity index (sPCDAI) over time. a C-reactive protein. b Erythrocyte sedimentation rate. c Fecal calprotectin. d sPCDAI. Visit 1 = baseline; visit 3 = approximately 1 month; visit 5 = approximately 6 months. Boxes represent interquartile ranges, while horizontal lines within the boxes represent medians. Circles, squares and triangles represent statistical outliers

Fig. 3

Tukey box plots show change in laboratory inflammatory markers and short pediatric Crohn’s disease activity index (sPCDAI) over time. a C-reactive protein. b Erythrocyte sedimentation rate. c Fecal calprotectin. d sPCDAI. Visit 1 = baseline; visit 3 = approximately 1 month; visit 5 = approximately 6 months. Boxes represent interquartile ranges, while horizontal lines within the boxes represent medians. Circles, squares and triangles represent statistical outliers

Fig. 3

Tukey box plots show change in laboratory inflammatory markers and short pediatric Crohn’s disease activity index (sPCDAI) over time. a C-reactive protein. b Erythrocyte sedimentation rate. c Fecal calprotectin. d sPCDAI. Visit 1 = baseline; visit 3 = approximately 1 month; visit 5 = approximately 6 months. Boxes represent interquartile ranges, while horizontal lines within the boxes represent medians. Circles, squares and triangles represent statistical outliers

Fig. 3

Tukey box plots show change in laboratory inflammatory markers and short pediatric Crohn’s disease activity index (sPCDAI) over time. a C-reactive protein. b Erythrocyte sedimentation rate. c Fecal calprotectin. d sPCDAI. Visit 1 = baseline; visit 3 = approximately 1 month; visit 5 = approximately 6 months. Boxes represent interquartile ranges, while horizontal lines within the boxes represent medians. Circles, squares and triangles represent statistical outliers

Fig. 4

Scatter plot shows the relationship between bowel wall color Doppler signal (0–3) and fecal calprotectin (ρ=0.71; P<0.0001). Black line is the least squares line of best fit. Correlation between these two variables was ρ=0.54 (P=0.02) at baseline (pre-treatment), while correlation increased to ρ=0.72 (P=0.0004) at approximately 1 month into therapy