Patients
This retrospective study was approved by the institutional review board (IRB) of Kyung Hee University Hospital, and the requirement for informed consent was waived. We searched electronic medical records (EMRs) and picture archiving and communication system (PACS) images of patients diagnosed with CD from January 2000 to August 2020. The diagnosis of CD was determined according to clinical evaluation and a combination of biochemical, radiological, endoscopic, and histological investigations. [5, 6] Patients who were initially diagnosed with CD or treated regularly at our institution were consecutively selected as candidates for our study. Of the 256 patients identified, 85 patients were excluded as their initial records were from before 2009, and the available information was incomplete with considerable missing data. Hence, 171 patients were left; they were initially diagnosed or treated with CD since January 2009 at our institution. Among these patients, 59 patients were excluded because of the following reasons: 1) no identifiable follow-up data after treatment (n=14), 2) follow-up period less than 5 years (n=43), 3) hard to evaluate disease pattern or activity due to combined disease with tuberculous enteropathy (n=1), and 4) combined disease with ischemic enteropathy (n=1). Finally, a total of 112 CD patients were included in this study (Figure 1).
Clinical data analyses
We investigated clinical information such as age, sex, presence of bowel symptoms, Crohn’s disease activity index(CDAI), history of prior bowel or perianal operation, nonsmoker or former/current smoker, presence of family history of inflammatory bowel disease, disease duration from the initial to the last visit, and presence of extra-intestinal manifestations including arthritis, Raynaud phenomenon, sclerosing cholangitis, or ankylosing spondylitis. Information regarding treatment such as usage of systemic steroids at initial diagnosis, usage of immunosuppressants (IMS) including azathioprine, mercaptopurine, and methotrexate; usage of biologics and its type (including infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, tofacitinib, and filgotinib), time point of initial usage of biologics since diagnosis (no use, initial use, first use within 2-year follow-up, after 2-year and within 5-year follow-up, after 5-year follow-up), single or combination therapy of IMS with biologics were recorded. ‘Regimen change’ was defined as change of IMS to biologics, ‘change of biologics’ was defined as change of one type of biologics to another type of biologics, and ‘dose intensification’ was defined as a dose increase of 2-fold the usual dose. These treatment data were recorded.
Radiologic and endoscopic analyses of disease pattern
Two abdominal radiologists (with 13 years and 8 years’ experience in abdominal radiology) reviewed contrast-enhanced computed tomography (CECT) images and recorded CT activity scores. Although several CT scoring systems have been adapted in other studies [7–9], none of these have been credibly validated and grading of disease severity was only partially quantified without cut-off values of grades. Therefore, we generated a modified CT scoring system similar to the previously reported MR activity scoring system [10], with reference to CT features evaluated on other reported CT scoring systems [11]. The following CT features were recorded for each patient: wall thickness, wall enhancement with enhancement pattern, total length of the diseased segment, presence of comb sign (vascular enlargement of the vasa recta), and the presence of any complications, including abscess, fistula, or severe stenosis. Stricturing and penetrating diseases were defined according to consensus recommendations [12]. According to the sum of the total score measured with these features, one of the four categories of no activity, mild, moderate, or severe activity was determined (Table 1). In cases involving more than one lesion, the lesion with the highest activity score was selected for categorization. In each patient, the two reviewers evaluated two CECT examinations, namely initial and 2-year follow-up CT examinations. The scoring of CT activity was independently performed by each reviewer with a 2-week interval between the evaluation of disease pattern and endoscopic activity, and the interreader agreement was assessed. The disease pattern was evaluated according to the Montreal classification [13], based on CECT and endoscopic features. Disease location was classified into one of three categories L1, ileal; L2, colic; and L3, ileocolic disease. Disease behavior was classified into one of four categories B1, non-stricturing non-penetrating inflammatory; B2, stricturing; B3, penetrating; and B4, combined stricturing and penetrating disease. The presence of upper gastrointestinal tract involvement (L4 lesion) and presence of perianal lesions (P) were separately recorded. In case of no visible active or chronic lesion, disease location and behavior were recorded as ‘none’. The presence of endoscopic activity was also recorded based on the endoscopic images and reports. The evaluations of endoscopic activity and disease patterns were performed by the two reviewers, who reached a consensus.
Classification of disease course during the whole follow-up period
Disease course was classified into four categories: remission, improved and stable, chronic refractory and chronic relapsing. ‘Remission’ was defined as more than two of three categories among clinical remission, endoscopic remission, and CT activity score 0-1 at the last follow-up. ‘Clinical remission’ was defined as decrease in severity of bowel symptoms or CDAI<150. ‘Endoscopic remission’ was defined as achievement of complete mucosal normalization [14]. The individual case was classified as remission if the disease activity decreased without any residual activity after modification of medical treatment such as regimen change or dose optimization, even if there was an increase in the severity of disease activity during the follow-up. ‘Improved and stable’ was defined as an individual in clinical remission with residual endoscopic activity or residual CT activity more than 2. ‘Chronic refractory’ was defined as wax and wane, but persistent clinical symptoms, and radiologic/endoscopic activities, without remission. ‘Chronic relapsing’ was defined as more than once relapse in bowel symptoms or radiologic/endoscopic activities for each treatment regimen. ‘Relapse’ was defined as an aggravation of bowel symptoms, CT or endoscopic activities leading to the need for more intensive medical and/or surgical treatment after achieving remission. We modified these definitions from a previous report [15], adding radiological and endoscopic activities to overcome mismatched cases between clinical symptoms and radiological/endoscopic findings, especially in cases with small bowel lesions.
CT techniques
CT examinations were performed using one of the following multidetector CT scanners: 16-channel Lightspeed from GE healthcare (n= 111), 64-channel Brilliance (n=66), 128-channel Ingenuity (n=81) from Philips Healthcare, and 64-channel Aquilion Toshiba (n=62) at four time points (initial visit and 2-year, 5-year, and last follow-up). The scanning parameters were as follows: a peak voltage of 120 kVp; a tube current-time product of 150-200 mAs with automated tube current modulation; a 2.5~5-mm slice thickness with a 3-mm reconstruction interval; a field of view of 300-380 mm; a gantry rotation time of 0.5-0.6 s; detector configuration of 0.625 mm; z-axis coverage of 24, 40, and 40 mm; pitch 0.9, 0.7 and 0.8 s; table speeds of 43.2, 47.5 and 63.8 mm per second; and a single breath-hold helical acquisition time of 9-10 s for 16-,64-, and 128-channel CT exams. Among the total CT exams (n=335), two-thirds were small bowel enterography (n=241, 72%), and the remaining one-third was conventional abdomen-pelvis CT (n=92, 27%). The CT protocol for small bowel enterography was as follows: patients were asked to drink 1500 mL of 3% polyethylene glycol solution (Harprep, Pharmbio, Korea) 45 min before scanning for maximum distension of the small bowel. For contrast enhancement, 120 mL of nonionic contrast medium (Iomeprol 350, Bracco Imaging) was injected intravenously at a rate of 2 ml/s, followed by 20 ml saline flushing. The scanning delay was 60 s for the portal phase, and additional coronal reformatted images were obtained.
Statistical analyses
Comparisons of differences in categorical and continuous data were performed using Fisher’s exact probability test or Wilcoxon rank sum test, as appropriate. The association of variables with disease course was investigated using univariate and multivariate logistic regression analyses. All variables with P values <0.1, from univariate regression analysis, were included in the multivariate model. Adjustment with the firth’s method was used for multivariate regression analysis. Receiver operating characteristic (ROC) curve analyses were performed using the selected disease-related variables in the multivariate logistic regression. To perform time-to-even analyses, we used the log-rank test or Cox proportional hazards model, as appropriate. The inter-reader agreement was assessed using Cohen’s kappa value, and the interpretation of kappa values was as follows: 0.21-0.4, fair agreement; 0.41-0.6, moderate agreement; 0.61-0.8, substantial agreement; 0.81-0.99, near perfect agreement. Statistical analyses were performed using SPSS version 26 (IBM, New York, USA), SAS version 14.3 (SAS Institute Inc., NC, USA), and Medcalc version 14.8.1 (Ostend, Belgium) were used. A two-tailed test for statistical significance was performed, and the level of statistical significance was set at p <0.05.