Use of Intestinal Ultrasound to Monitor Crohn's Disease Activity

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Oct 27, 2016 - Use of Intestinal Ultrasound to Monitor Crohn's Disease Activity. Torsten Kucharzik, Bianca M. Wittig, Ulf Helwig, Norbert Börner, Alexander.
Accepted Manuscript Use of Intestinal Ultrasound to Monitor Crohn’s Disease Activity Torsten Kucharzik, Bianca M. Wittig, Ulf Helwig, Norbert Börner, Alexander Rössler, Stefan Rath, Christian Maaser

PII: DOI: Reference:

S1542-3565(16)31058-8 10.1016/j.cgh.2016.10.040 YJCGH 55001

To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 27 October 2016 Please cite this article as: Kucharzik T, Wittig BM, Helwig U, Börner N, Rössler A, Rath S, Maaser C, on behalf of the TRUST study group, Use of Intestinal Ultrasound to Monitor Crohn’s Disease Activity, Clinical Gastroenterology and Hepatology (2016), doi: 10.1016/j.cgh.2016.10.040. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Title: Use of Intestinal Ultrasound to Monitor Crohn’s Disease Activity Torsten Kucharzik1, Bianca M. Wittig2, Ulf Helwig3, Norbert Börner4, Alexander Rössler2, Stefan Rath2, and Christian Maaser5, on behalf of the TRUST study group

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Department of Internal Medicine and Gastroenterology, University Teaching Hospital

Lüneburg, Lüneburg, Germany 2

Medical Department, AbbVie Deutschland GmbH & Co. KG, Wiesbaden, Germany

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Gastroenterology Practice, Oldenburg, Germany Gastroenterology Practice, Mainz, Germany

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Ambulanzzentrum Gastroenterologie, University Teaching Hospital Lüneburg, Lüneburg,

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Germany

Short title: Ultrasonography in monitoring Crohn’s disease

Grant Support: The design, study conduct, and funding for the study was supported by

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AbbVie Deutschland GmbH & Co. KG. All authors participated in the development of the study design, interpretation of data, review, development, and approval of the publication.

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Abbreviations: BWT, bowel wall thickening; CD, Crohn’s disease; CRP, C-reactive protein; HBI, Harvey-Bradshaw index; US, transabdominal bowel ultrasonograhy

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Correspondence: Torsten Kucharzik, MD, Städtisches Klinikum Lüneburg, Klinik für Allgemeine Innere Medizin & Gastroenterologie, Bögelstr. 1, 21339 Lüneburg, Germany, Email: [email protected], Phone: +49 4131 77 2241, Fax: +49 4131 77 2245

Disclosures: Torsten Kucharzik (TK): Lecture and consulting fees: AbbVie, MSD, Ferring, Falk Foundation, Takeda, UCB, Wolff Pharma

ACCEPTED MANUSCRIPT Bianca M. Wittig (BMW): Employee of AbbVie, and may own AbbVie stock or options Ulf Helwig (UH): Lecture and consulting fees: AbbVie, MSD, Ferring, Falk Foundation, Takeda, Mundipharma, Hospira, Vifor Pharma

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Norbert Börner (NB): Lecture and consulting fees: AbbVie, MSD, Ferring, Falk Foundation, Takeda

Alexander Rössler (AR): Employee of AbbVie, and may own AbbVie stock or options

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Stefan Rath (SR): Employee of AbbVie, and may own AbbVie stock or options

Christian Maaser (CM): Lecture and consulting fees: AbbVie, MSD, Ferring, Falk Foundation,

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Takeda, Wolff Pharma Author Contributions:

TK: Study supervision, study concept and design, acquisition of data, statistical analysis,

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analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content

BMW: Study concept and design, analysis and interpretation of data, critical revision of the

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manuscript for important intellectual content, approval of the final version of the manuscript UH: Acquisition of data, statistical analysis, critical revision of the manuscript for important

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intellectual content

NB: Acquisition of data, statistical analysis, critical revision of the manuscript for important intellectual content

AR: Drafting of the manuscript, statistical analysis, analysis and interpretation of data, critical revision of the manuscript for important intellectual content SR: Study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, approval of the final version of the manuscript 2

ACCEPTED MANUSCRIPT CM: Study supervision, study concept and design, acquisition of data, statistical analysis, analysis and interpretation of data, drafting of the manuscript, critical revision of the

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manuscript for important intellectual content

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ACCEPTED MANUSCRIPT Abstract: BACKGROUND & AIMS: We performed a multicenter study to determine whether transabdominal bowel wall ultrasonography, a non-invasive procedure that does not require radiation, can be used to monitor progression of Crohn’s disease (CD).

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METHODS: We performed a 12-month prospective, non-interventional study at 47 sites in Germany, from December 2010 through September 2014. Our study included 234 adult patients with CD who experienced a flare, defined as Harvey-Bradshaw index score of ≥7. All patients received treatment intensification—most with tumor necrosis factor antagonists. Ultrasound parameters and clinical data were assessed at baseline and then after 3, 6, and 12 months. The primary endpoint was the change in ultrasound parameters within 12 months of study enrollment.

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RESULTS: All patients included had bowel wall alterations either within the terminal ileum and/or segments of the colon. After 3 and 12 months, ultrasonographic examination showed significant improvements of nearly all ultrasound parameters, including reductions in bowelwall thickening or stratification, decreased fibro-fatty proliferation, and increased signals in color Doppler ultrasound (P2 mm, colon including sigmoid colon >3 mm) was measured both in transverse and longitudinal sections. Loss of bowel wall stratification was documented, as well as other complications (prestenotic dilatations, bowel strictures, fistulae, mesenteric fibro-fatty proliferation and/or masses, abscesses, mesenteric lymphadenopathy, and ascites). The US examinations were performed by the treating gastroenterologist on different US devices, ranging from normal to high-end, using convex (3.5–5 MHz) and linear (7–12 MHz) probes from various manufacturers. Seventy-seven percent of the centers used high-end scanners (class 3, according to ultrasound systems classification DEGUM, German Ultrasound Society).12 No special patient preparations for US 6

ACCEPTED MANUSCRIPT examination, such as the use of a contrast agent or overnight fasting, were conducted. Examiners were not blinded to clinical parameters of the patient. As a semi-quantitative method for determining disease activity, the vascularity within the affected bowel wall areas was assessed by duplex US examination using the Limberg

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score.13 In addition, laboratory data (C-reactive protein [CRP], white blood cell [WBC] count, and platelets) and changes in CD-specific medication were documented at all study visits. The response to treatment was measured using the HBI. Clinical response was defined as a

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decrease in HBI score of 3 points. Patients with an HBI score of 4 or less were considered to be in remission.14 To ensure uniform investigation standards, an investigator training session

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with the study investigators was held before the study start. Furthermore, all study sites were instructed in writing and agreed to the harmonized investigation procedure. Statistical Analysis

The statistical analysis was performed using the Statistical Package for Social Sciences (SPSS 21.0, IBM, Armonk, NY, USA). For the primary endpoint, 15 parameters were

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analyzed by adaptation of the global significance level (α = 0.05), with a single-step procedure conducted after Bonferroni correction. Correlations between parameters (such as HBI and the thickened bowel wall at affected intestinal wall segments) were correlated using

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the Spearman method. Overall missing or implausible data were excluded from statistical

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analysis and extreme laboratory values were counted as missing.

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Results Patient Population Two hundred thirty-four patients were eligible for this study; data from 134 patients with

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accurate time intervals between baseline and the final visit could be analyzed (analysis population 1 [AP1]). AP2 constitutes the second analysis population, and includes 182 patients with accurate time intervals between baseline and the first follow-up visit at 3 months (for the definition of accurate time intervals, see Figure 1). The baseline characteristics of

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the different populations are shown in Table 1 and did not reveal significant differences. AP1 and AP2 are smaller than the original patient population; 68 patients missed the final visit,

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and data from 28 patients in AP1 and 48 patients in AP2 could not be used for analysis because the intervals between the visits were out of the prespecified range (Figure 1). The treatment of patients changed during the study, with an increase of therapy with TNF antagonists and a decrease of steroids (systemic or budesonide), azathioprine, and other

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CD-related medications (mainly 5-aminosalicylates) after 12 months (Figure 2).

Changes in Ultrasound Parameters

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The confirmatory analysis of the primary outcome parameter, change in US parameters

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within 12 months, was performed using data from the AP1 population (n = 134). Fifteen parameters between baseline visit and after 12 months were compared (Table 2, Figure 3). Thickening of the bowel wall statistically significant improved in all bowel segments (Figure 3 A). In the terminal ileum, at baseline, 75.4% of patients had a thickened bowel wall; after 12 months of treatment, only 35.8% had a thickened bowel wall (P < .001). In the sigmoid colon, 47% of patients at baseline had a thickened bowel wall; after 12 months of therapy, 23.1% had a thickened bowel wall (P < .001). Furthermore, other parameters indicative of intestinal inflammation improved significantly from baseline to month 12, such as bowel wall stratification (53.0% to 21.6%), mesenteric fibro-fatty proliferation (47.0% to 17.9%), and 8

ACCEPTED MANUSCRIPT lymphadenopathy (26.1% to 11.9%), as well as parameters of complications like fistulae and strictures. Details regarding patient numbers, missing data, and P values are summarized in Table 2. A slower decrease in the reduction of bowel wall thickening (BWT) was observed within the

reduction was still highly significant (Figure 3 A).

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terminal ileum compared with all other investigated sites in the colon, even though the

The observed changes at month 12 in the AP1 population (n = 134) was evident at month 3

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after treatment intensification in the larger AP2 patient population (n = 182). Relevant ultrasound parameters (e.g., BWT and improvement of bowel wall stratification) were

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significantly improved at month 3 after treatment intensification (e.g. the addition of anti-TNF therapy). Even though the parameters continued to improve in almost all cases over the 12month period, this effect was less apparent than during the first 3 months (Table 2). As clinical observation suggests that normalization of bowel structure after treatment is more the exception than the rule, we determined the percentage of patients showing a reduction in

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bowel wall thickness after 3 months. In 58.5% of patients in the AP2 population, the bowel wall normalized in the terminal ileum. Further, 10% or 25% reduction in bowel wall thickness could already be determined in 94.5% and 80.0% of patients, respectively (data not shown).

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The reduction of bowel wall thickness was concurrent with a reduction of clinical disease

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activity as determined by changes in the HBI (improvement in HBI score in 86.3% of patients and remission as defined by HBI score of 3

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ACCEPTED MANUSCRIPT mm. Even under this more stringent limit value, we observed a significant improvement after 3 months at the terminal ileum. Normalization of bowel thickness is a stringent endpoint, but it does not reflect the observation in clinical practice. Transmural inflammation, as it is observed during chronic

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intestinal inflammation in patients with CD, is often associated with structural damage that does not completely resolve after treatment.17 In clinical practice, we rarely see a complete normalization of the bowel wall via US or magnetic resonance enterographic examination. A

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discrepancy between residual transmural activity as determined by different cross-sectional imaging modalities and clinical improvement is common. Even minimal changes in BWT and

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dilation of the intestinal lumen may result in marked clinical improvement.18 Slight changes in BWT after treatment beside normalization of the intestinal wall can be determined in almost 60% of our patients at the terminal ileum. Our results also show a rapid improvement in almost all US parameters at active colonic areas or within the terminal ileum, followed by clinical improvement as determined by HBI score, as well as a drop of CRP levels within 3

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months. This improvement was significant after 3, 6, and 12 months of therapy. The improvement within the thickened bowel wall of the terminal ileum as the most prominent alteration during the US examination significantly correlated with changes in CRP levels.

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These observations are highly relevant for clinical practice and demonstrate that US can be used to monitor patients with CD.

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A number of studies have found a fair to good correlation between clinical activity and US parameter such as BWT19-20 while other studies failed to do so.8 Even though we observed a concurrent reduction in bowel wall thickness with a decrease in HBI score in our study, there was no statistical significant correlation between both parameters. This might be explained by the fact that the HBI is not a valid index to determine disease activity, as has been stated by other authors.21 Poor correlations between clinical disease activity markers such as the Crohn’s Disease Activity Index have also been determined for endoscopic activity.2 In contrast, we found a strong correlation between reduction of bowel wall thickness and CRP levels, which is a more robust and valid disease activity parameter for CD. 12

ACCEPTED MANUSCRIPT Our study results are encouraging because of the rapid improvement of almost all US parameters in the course of time and therapy. All changes observed during treatment could already be determined at the 3-month observation period. During the following 9 months of the observation period, no relevant further improvement could be determined. This

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observation leads us to question whether changes in bowel ultrasonography may occur even earlier than 3 months. Further studies should measure changes in bowel wall abnormalities at earlier time points, as these changes may even precede clinical improvement and may be used as prognostic parameters. Our study is subject to several limitations. One is the lack of

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a control group, in particular, the lack of a gold standard such as endoscopy or MRI. This limitation may be justified by the fact that the object of our study was the use of

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transabdominal US examination in routine monitoring of patients with CD and not to determine the accuracy of ultrasound compared with other diagnostic procedures. This comparison has already been the subject of several previous studies.22, 23 Further our study design excluded patients with isolated small bowel or perianal involvement

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so our results are limited to patients with Crohn´s disease affecting the colon. Another limitation may be the potential interobserver and interequipment variability that has always been raised as an issue when using US examination. However, we found no in

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diagnostic

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differences

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measurements

between

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gastroenterologists, regardless of whether they work in general practice, in university

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hospitals, or in university-affiliated teaching hospitals. Forty-seven different centers were involved in this study, the largest multicenter trial in bowel US that has been performed thus far. However, no significant differences with regard to the results of measurements were obtained at different IBD centers or with the use of different US machines. Furthermore, we found no significant differences between the disease duration at different study sites, suggesting a homologous patient distribution between the sites. Although it raises a variety of questions that hopefully will be answered in further studies, this multicenter study indicates that transabdominal US is an effective and easy-to-use tool in the 13

ACCEPTED MANUSCRIPT assessment of CD activity and in monitoring the course of the disease in daily practice. Future clinical trials with a shorter visit interval will be required to correlate US parameters and clinical or biological disease activity to gain further insights into whether and if so which US parameters might be used as prognostic indicators to guide treatment and to predict

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further disease course.

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Figure Legends Figure 1. The origin of the two analysis populations in TRUST, with primary reasons for exclusion indicated. AP1, time interval between baseline and final visit = 12 months ± 2 months. AP2, time interval between baseline and first follow-up visit = 3 months ± 4 weeks. AP, analysis population.

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Figure 2. Change in CD-related medication in AP1 (n = 134): percentage of patients with respective medication; multiple medications allowed. AP1, analysis population 1; CS, systemic corticosteroids; AZA, azathioprine; CD, Crohn’s disease; MTX, methotrexate; TNF, tumor necrosis factor. Other, mainly 5-ASA; missing, and/or not assessable data:

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Budesonide: 3 months, n = 3; 6 and 12 months, n = 5. Systemic corticosteroids: baseline, n = 3; 3 months, n = 4; 6 and 12 months, n = 6. AZA: baseline, n = 1; 3 months, n = 3; 6 months, n = 5; 12

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months, n = 4. MTX: baseline, n = 1; 3 months, n = 5; 6 months, n = 6; 12 months, n = 9. TNF antagonists: baseline, n = 1; 3 months, n = 7; 6 months, n = 12; 12 months, n = 10. Figure 3. (A) Proportion of patients with change in BWT over the study period at the investigated bowel segments (AP1, n=134); P .5. Missing data for n = 32; P >.5.

Table 2. US parameters and clinical data (laboratory data and HBI score) at baseline and at 3, 6, and 12 months for AP1 (n = 134); P values for comparison versus baseline according to chi-square test; number of patients are given in brackets. Color Doppler US signal 3+4, color Doppler ultrasonographic signal Limberg scores 3 and 4; Hb, hemoglobin; HBI, Harvey-Bradshaw Index; US, ultrasonographic; WBC, white blood cell.

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ACCEPTED MANUSCRIPT Table 3. Reduction of bowel wall thickness within the terminal ileum and improvement of CRP values from baseline to month 3. AP2, analysis population 2. CRP, C-reactive protein, *Fisher exact test,

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**Chi-square test.

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Acknowledgments The authors would like to thank the patients for their support and their active participation in the research of IBD. We would also like to thank all the members of the TRUST study group and their study nurses for the invaluable contributions to the success of this study. The

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members of the TRUST study group are listed as supplementary material in the Appendix. Finally, we would like to thank Imma Fischer, Biostatistik Tuebingen, for performing the

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statistical analyses.

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References

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ACCEPTED MANUSCRIPT 7. Parente F, Greco S, Molteni M, et al. Oral contrast enhanced bowel ultrasonography in the assessment of small intestine Crohn’s disease. A prospective comparison with conventional ultrasound, X ray studies, and ileocolonoscopy. Gut 2004;53:1652-1657. 8. Ripollés T, Martínez MJ, Barrachina MM. Crohn`s disease and color Doppler

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antibody to tumor necrosis factor (anti-TNF) alpha therapy in Crohn’s disease. Dig Dis

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12. Schuler A, Reuss J, Delorme S, et al. Costs of clinical ultrasound examinations – an economical cost calculation and analysis. Ultraschall Med 2010;31:379-386.

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ACCEPTED MANUSCRIPT 16. Rieder F, Zimmermann EM, Remzi FH, et al. Crohn's disease complicated by strictures: a systematic review Gut. 2013;62(7):1072-1084. 17. Pariente B, Cosnes J, Danese S, et al. Development of the Crohn's disease digestive

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19. Calabrese E, Petruzziello C, Onali S, et al. Severity of postoperative recurrence in Crohn’s disease: correlation between endoscopic and sonographic findings. Inflamm

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Bowel Dis 2009;15:1635-1642.

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21. Ricanek P, Brackmann S, Perminow G, et al. Evaluation of disease activity in IBD at the time of diagnosis by the use of clinical, biochemical, and fecal markers. Scand J Gastroenterol 2011;46(9):1081-1091.

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22. Maconi G, Bollani S, Bianchi Porro G. US detection of intestinal complications in

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Crohn’s disease. Dig Dis Sci 1996;41:1643-1648. 23. Gasche C, Moser G, Turetschek K, et al. Transabdominal bowel sonography for detection of intestinal complication in Crohn’s disease. Gut 1999;44:112-117.

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AP1 (n = 134) 67.1 32.8 (18.3–71.6) 3.68 (0–34.1)

AP2 (n = 182) 68.1 31.2 (18.3–71.6) 3.34 (0–34.1)

DP (n = 230) 67.0 31.4 (18.3–71.6) 3.13 (0–34.1)

73.9 36.6 32.8 37.3 47.8 9.0

70.9 40.7 33.5 36.3 44.0 8.2

70.5 40.0 32.6 33.0 43.0 8.3

Fistulae, % of patients Stenosis, % of patients HBI, median (range) CRP [mg/L], median (range) CD-related medication, % of patients Budesonide Systemic corticosteroids Azathioprine MTX TNF antagonists (IFX/ADA) Other (5-ASA)

11.9 25.4 10.0 (7–26) 29.3 (0–366)a

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23.1 35.9 28.4 3.0 18.6 (6.7/11.9) 35.9 (17.9)

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Demographic data at baseline Female, % of patients Age [years], median (range) Disease duration [years], median (range) CD location, % of patients Terminal ileum Ascending colon/cecum Transverse colon Descending colon Sigmoid colon Objective signs of inflammation within last 6 days, % of patients

10.4 26.9 10.0 (7–28) 28.3 (0–366)b

10.4 26.1 9.5 (7–28) 27.5 (0–540)c

21.4 37.4 26.9 2.2 20.8 (8.2 /12.6) 33.0 (15.4)

19.6 39.1 26.5 2.2 21.7 (8.7/13.0) 32.6 (15.2)

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Baseline

3 months

6 months

12 months

P value month 3 vs. Baseline

P value month 6 vs. Baseline

P value month 12 vs. Baseline

Terminal ileum >2 mm

75.4 (101)

56.7 (76)

44 (59)

35.8 (48)