Combined Endoscopic/Sonographic-based Risk Matrix Model for Predicting One-year Risk of Surgery: A Prospective Observational Study of a Tertiary Centre Severe/Refractory Crohn’s Disease Cohort

Combined Endoscopic/Sonographic-based Risk Matrix Model for Predicting One-year Risk of Surgery:... Abstract Background In the management of Crohn’s disease [CD] patients, having a simple score combining clinical, endoscopic, and imaging features to predict the risk of surgery could help to tailor treatment more effectively. Aims We aimed to prospectively evaluate the 1-year risk factors for surgery in refractory/severe CD and to generate a risk matrix for predicting the probability of surgery at 1 year. Methods CD patients needing a disease re-assessment at our tertiary inflammatory bowel disease [IBD] centre underwent clinical, laboratory, endoscopic, and bowel sonography [BS] examinations within 1 week. The optimal cut-off values in predicting surgery were identified using receiver operating characteristic [ROC] curves for the Simple Endoscopic Score for CD [SES-CD], bowel wall thickness [BWT] at BS, and small bowel CD extension at BS. Binary logistic regression and Cox regression were then carried out. Finally, the probabilities of surgery were calculated for selected baseline levels of covariates and results were arranged in a prediction matrix. Results Of 100 CD patients, 30 underwent surgery within 1 year. SES-CD ≥9 (odds ratio [OR] 15.3; p <0.001], BWT ≥7 mm [OR 15.8; p <0.001], small bowel CD extension at BS ≥33 cm [OR 8.23; p <0.001], and stricturing/penetrating behaviour [OR 4.3; p <0.001] were the only independent factors predictive of surgery at 1 year, based on binary logistic and Cox regressions. Our matrix model combined these risk factors, and the probability of surgery ranged from 0.48% to 87.5% [16 combinations]. Conclusions Our risk matrix combining clinical, endoscopic, and ultrasonographic findings can accurately predict the 1-year risk of surgery in patients with severe/refractory CD requiring a disease re-evaluation. This tool could be of value in clinical practice, serving as the basis for a tailored management of CD patients. Crohn’s disease, surgery, risk factors 1. Introduction Crohn’s disease [CD] is an idiopathic, chronic, and disabling inflammatory disorder which can affect any portion of the gastrointestinal tract, triggering persistent transmural inflammation with subsequent structural bowel damage and intestinal complications such as strictures, fistulas, and abscesses, which often need surgical resection.1–3 Up-to-date statistics show that within 20 years from diagnosis, up to 50% of patients with CD developed intestinal complications and approximately 60% underwent resective surgery, many requiring more than one surgical treatment.4,5 Recent data also showed that up to 50% of patients with newly diagnosed CD already presented bowel damage at the time of diagnosis.6 In 2006, Beaugerie and colleagues7 demonstrated that initial requirement for steroids, age at diagnosis below 40 years, and the presence of perianal disease at diagnosis, were predictive factors of a disabling form of CD. In recent years, several risk factors for surgery have been identified: involvement of the terminal ileum8–10; perianal disease7–9; stricturing and penetrating disease8,11,12; involvement of the upper gastrointestinal tract11; smoking12,13; and need for systemic steroids.7,9 At present, decision making in CD is based on clinical, laboratory, and endoscopic findings, as well as cross-sectional imaging [e.g. magnetic resonance enterography [MR], computed tomography [CT], and bowel sonography [BS]]. Endoscopic and cross-sectional imaging have proved to predict the risk of surgery in CD. For example, the endoscopic Rutgeerts score can accurately predict the course of CD after surgical resection14; some further data also suggest that other endoscopic scores, such as the Crohn’s Disease Endoscopic Index of Severity [CDEIS]15 and the Simple Endoscopic Score for Crohn’s Disease [SES-CD],16 may accurately predict the risk of surgery. Finally, both BS17 and MR18 have been shown to be predictive of risk of surgery in CD. It has already been demonstrated that aggressive pharmacological treatment [e.g. top-down treatment] of the disease can modify its course.19 In the context of clinical practice, it would therefore be extremely helpful to have one single simple score which, combining clinical, endoscopic, and cross-sectional imaging features, could predict the risk of surgery and allow for more accurate tailoring of treatment decisions. This study had two fundamental aims: 1] to prospectively evaluate the risk factors for surgery in patients with severe CD followed up at a tertiary IBD centre in the 12 months following assessment, on the basis of clinical, laboratory, endoscopic, and ultrasonographic findings; and 2] to generate a risk matrix that could predict the probability of resective surgery 1 year after assessment. 2. Materials and Methods 2.1. Study population and study design Between March 2015 and June 2017, we carried out an observational longitudinal prospective study enrolling CD patients needing a disease re-assessment due to CD activity, refractoriness/partial response to therapy, and/or required therapeutic decision making, in accordance with current guidelines.2021 All patients attended our tertiary care centre for inflammatory bowel disease [IBD] at Federico II University Medical School in Naples, Italy. All subjects participating in the study underwent clinical examination and laboratory, endoscopic and BS investigations within 1 week. In line with the Montreal Classification,20 CD patients were clinically classified on the basis of their age at the time of CD diagnosis, the location of the disease, disease behavior, and presence/absence of perianal disease. Other clinical variables were also considered: gender; previous surgery; smoking habits; family history; disease duration; presence of extraintestinal manifestations [EIMs]; and need of steroids at CD diagnosis. For each patient, a clinical index such as the Crohn’s Disease Activity Index [CDAI] was also calculated. Laboratory tests included C-reactive protein [CRP] [normal value <5 mg/L] and faecal calprotectin [normal value <70 μg/g] measurements, which were both performed at our centralised university laboratories. The primary outcome [surgery yes/no] was assessed after 1 year. The surgical outcome included only major laparotomic/laparoscopic abdominal interventions resulting in small bowel/colic resection or colectomy. ‘Minor’ surgical procedures [e.g. percutaneous drainage of abscess, perianal surgery, etc.] were excluded from the analysis. All patients gave their written informed consent; the study was approved by the Ethics Committee of ‘Federico II’ University. 2.2. Endoscopy A colonoscopy with retrograde ileoscopy was performed after 48 h of liquid diet and oral bowel cleansing [achieved with a 4-L solution of polyethilenglicole [PEG] 1 day before the procedure] using a conventional colonoscope [the EVIS EXERA III Video System Center CV-190, Olympus]. This endoscopic assessment was carried out by an expert operator [GDP] blinded to the other procedures. Endoscopic diagnosis of CD was made in accordance with the current European Crohn’s and Colitis Organisation [ECCO] guidelines.21 Endoscopic activity of CD was assessed using the Simple Endoscopic Score for Crohn’s Disease [SES-CD].16 In accordance with current ECCO guidelines, upper endoscopy was performed in patients with symptoms suggesting CD.21 2.3. Bowel sonography BS was performed during the morning hours [after patients’ overnight fasting], using a LOGIQ S7 ultrasound system with linear and convex probes [5–9 MHz]. Two gastroenterologists [AR, AT] with vast experience in BS and blinded to the other procedures performed the scans, systematically examining the patients’ abdominal organs without using any preparation and/or contrast and/or paralytic agents. Bowel wall thickness [BWT] was measured in both longitudinal and transverse slices and was considered normal in presence of values up to 3 mm,22 whereas positive US was defined as the occurrence of concentric and regular increased BWT >3 mm.17,23 In agreement with Maconi et al,24 the presence of strictures was indicated by the presence of thickened [>4 mm] intestinal wall, narrowed intestinal lumen, and fluid-distended or echogenic content-filled loops just above the thickened intestinal tract. Furthermore, entero-cutaneous, entero-enteric, and entero-mesenteric fistulas were identified when hypoechoic duct-like structures with fluid or air content were seen between skin and intestinal loops, between two intestinal loops, or between intestinal loop and mesentery, respectively.25 The presence of abscesses was established following the criteria recommended in the current literature.26,27 2.4. Statistical analysis Data were analysed using the Statistical Package for Social Sciences [SPSS software v.15.0, Chicago IL] for Windows and StatsDirect statistical software [v. 3.0]. The descriptive statistics used included determination of mean values and standard deviation [SD] of the continuous variables, and of percentages and proportions of the categorical variables. To appraise the discrimination ability of SES-CD at ileocolonoscopy, of BWT [mm] at bowel sonography, and of small bowel CD extension at BS [cm], in predicting the likelihood of surgery, receiver operating characteristic [ROC] curves were constructed and the areas under the curves [AUC] calculated. The optimal cut-off point for each curve was identified for sensitivity and specificity, both being of equal importance. Positive predictive value [PPV] and negative predictive value [NPV] were also reported. After best cut-off values were identified for SES-CD, BWT, and small bowel CD extension at BS [cm], a binary logistic regression was used to examine the relationship between surgery as dependent variable and the possible predictors as independent variables. The following variables were included in the analysis: male gender [yes/no], age at CD diagnosis [A1/A2 vs A3], behaviour [B2/B3 vs B1], disease location [L1/L3 vs L2], perianal disease [yes/no], previous surgery [yes/no], CRP [pathological/normal], faecal calprotectin [pathological/normal], exposure to biologics [yes/no], azathioprine exposure [yes/no], EIMs [yes/no], smoking [yes/no], family history [yes/no], steroids at CD diagnosis [yes/no], and CDAI [>150/<150]; SES-CD, BWT, and extension were dichotomised according with best cut-off previously found. The model was performed using the stepwise backward method [Wald]. The coefficients obtained from the logistic regression analysis were also expressed in terms of odds of event occurrence [odds ratio]. The probability of surgery 1 year after assessment was also calculated using the Kaplan–Meier method, and a hazard ratio [HR] with 95% confidence interval [CI] was obtained. Multivariate Cox regression was applied to examine the influence of variables on the length of time elapsed until surgery. The risk matrix was built in three steps. In Step 1, possible risk factors significantly associated with surgery after 1 year were selected for additional multivariate analyses. Risk factors that were highly associated with each other were eliminated to avoid multicollinearity. The final cut-off level was chosen based on the best separation among subgroups of patients, given their predefined features at baseline. In Step 2, several logistic regression models were built. The most suitable model was chosen based on its prediction power. The results were expressed as odds ratios [OR] with 95% CI. Finally in Step 3, the odds calculated with the selected logistic regression model were transformed into probabilities, and the results were organised into a risk matrix. A p-value of less than 0.05 was considered statistically significant. 3. Results During the study period, a total of 630 patients with CD were followed up at our IBD Unit. Of these, 105 [16%] required a disease re-assessment and were therefore eligible to participate in the study. Of these, three patients were excluded due to the fact that they presented clear indication for immediate surgery, and two dropped out during the follow-up. As a result, the study included 100 patients [males 58%, mean age 36.2 ± 11.5] with CD who attended our Unit. Their baseline features are shown in Table 1. Table 1. Demographic, clinical, laboratory, endoscopic, and ultrasonographic features of the study population [n = 100]. Gender Males/females 58/42 Age A1 10 A2 68 A3 22 Location L1 29 L2 14 L3 57 Behaviour B1 26 B2 48 B3 26 Perianal disease Yes/no 21/79 Previous surgery Yes/no 45/55 Smoking habits Yes 34 No 54 Ex 12 Familial history Yes/no 7/93 Disease duration [months] Mean ± SD 86 ± 73.34 EIMs Yes/no 17/83 Steroids at diagnosis Yes/no 37/63 SES-CD Mean ± SD 8.98 ± 5.89 SES-CD ≥ 9 [%] 41% BWT at BS [mm] Mean ± SD 5.37 ± 2.13 BWT at BS ≥ 7 [%] 30% Small bowel CD extension at BS [cm] Mean ± SD 33.52 ± 20.53 Small bowel CD extension at BS ≥ 33 [%] 34% CDAI Mean ± SD 151.59 ± 57.12 CRP [mg/L] Mean ± SD 3.62 ± 6.35 Faecal calprotectin [μg/g] Mean ± SD 150.97 ± 75.87 Treatment after enrolment No treatment 4 Antibiotics 10 Mesalamine 22 Steroids 33 Azathioprine 26 Infliximab 20 Adalimumab 18 Surgery after 1-year follow-up Yes/no 30/70 Indication for surgery Chronic bowel obstruction 13 Abscesses 7 Fistulas 5 Refractory disease 5 Months to surgery Mean ± SD 6.33 ± 3.21 Gender Males/females 58/42 Age A1 10 A2 68 A3 22 Location L1 29 L2 14 L3 57 Behaviour B1 26 B2 48 B3 26 Perianal disease Yes/no 21/79 Previous surgery Yes/no 45/55 Smoking habits Yes 34 No 54 Ex 12 Familial history Yes/no 7/93 Disease duration [months] Mean ± SD 86 ± 73.34 EIMs Yes/no 17/83 Steroids at diagnosis Yes/no 37/63 SES-CD Mean ± SD 8.98 ± 5.89 SES-CD ≥ 9 [%] 41% BWT at BS [mm] Mean ± SD 5.37 ± 2.13 BWT at BS ≥ 7 [%] 30% Small bowel CD extension at BS [cm] Mean ± SD 33.52 ± 20.53 Small bowel CD extension at BS ≥ 33 [%] 34% CDAI Mean ± SD 151.59 ± 57.12 CRP [mg/L] Mean ± SD 3.62 ± 6.35 Faecal calprotectin [μg/g] Mean ± SD 150.97 ± 75.87 Treatment after enrolment No treatment 4 Antibiotics 10 Mesalamine 22 Steroids 33 Azathioprine 26 Infliximab 20 Adalimumab 18 Surgery after 1-year follow-up Yes/no 30/70 Indication for surgery Chronic bowel obstruction 13 Abscesses 7 Fistulas 5 Refractory disease 5 Months to surgery Mean ± SD 6.33 ± 3.21 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; CRP, C-reactive protein; EIMs, extraintestinal manifestations; SD, standard deviation; CDAI, Crohn’s Disease Activity Index. View Large Table 1. Demographic, clinical, laboratory, endoscopic, and ultrasonographic features of the study population [n = 100]. Gender Males/females 58/42 Age A1 10 A2 68 A3 22 Location L1 29 L2 14 L3 57 Behaviour B1 26 B2 48 B3 26 Perianal disease Yes/no 21/79 Previous surgery Yes/no 45/55 Smoking habits Yes 34 No 54 Ex 12 Familial history Yes/no 7/93 Disease duration [months] Mean ± SD 86 ± 73.34 EIMs Yes/no 17/83 Steroids at diagnosis Yes/no 37/63 SES-CD Mean ± SD 8.98 ± 5.89 SES-CD ≥ 9 [%] 41% BWT at BS [mm] Mean ± SD 5.37 ± 2.13 BWT at BS ≥ 7 [%] 30% Small bowel CD extension at BS [cm] Mean ± SD 33.52 ± 20.53 Small bowel CD extension at BS ≥ 33 [%] 34% CDAI Mean ± SD 151.59 ± 57.12 CRP [mg/L] Mean ± SD 3.62 ± 6.35 Faecal calprotectin [μg/g] Mean ± SD 150.97 ± 75.87 Treatment after enrolment No treatment 4 Antibiotics 10 Mesalamine 22 Steroids 33 Azathioprine 26 Infliximab 20 Adalimumab 18 Surgery after 1-year follow-up Yes/no 30/70 Indication for surgery Chronic bowel obstruction 13 Abscesses 7 Fistulas 5 Refractory disease 5 Months to surgery Mean ± SD 6.33 ± 3.21 Gender Males/females 58/42 Age A1 10 A2 68 A3 22 Location L1 29 L2 14 L3 57 Behaviour B1 26 B2 48 B3 26 Perianal disease Yes/no 21/79 Previous surgery Yes/no 45/55 Smoking habits Yes 34 No 54 Ex 12 Familial history Yes/no 7/93 Disease duration [months] Mean ± SD 86 ± 73.34 EIMs Yes/no 17/83 Steroids at diagnosis Yes/no 37/63 SES-CD Mean ± SD 8.98 ± 5.89 SES-CD ≥ 9 [%] 41% BWT at BS [mm] Mean ± SD 5.37 ± 2.13 BWT at BS ≥ 7 [%] 30% Small bowel CD extension at BS [cm] Mean ± SD 33.52 ± 20.53 Small bowel CD extension at BS ≥ 33 [%] 34% CDAI Mean ± SD 151.59 ± 57.12 CRP [mg/L] Mean ± SD 3.62 ± 6.35 Faecal calprotectin [μg/g] Mean ± SD 150.97 ± 75.87 Treatment after enrolment No treatment 4 Antibiotics 10 Mesalamine 22 Steroids 33 Azathioprine 26 Infliximab 20 Adalimumab 18 Surgery after 1-year follow-up Yes/no 30/70 Indication for surgery Chronic bowel obstruction 13 Abscesses 7 Fistulas 5 Refractory disease 5 Months to surgery Mean ± SD 6.33 ± 3.21 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; CRP, C-reactive protein; EIMs, extraintestinal manifestations; SD, standard deviation; CDAI, Crohn’s Disease Activity Index. View Large After 1 year, 30 CD patients [30%] underwent surgical bowel resection [mean time to surgery was 6.33 ± 3.21 months]. The indications for surgery are reported in Table 1. Chronic bowel obstruction [43.3%] and abdominal/pelvic abscesses [23.3%] were the most frequent indications. For the SES-CD score, we found that a cut-off value of 9 presented: sensitivity 93.3% [95% CI 77.9–99.2], specificity 81.4% [95% CI 70.3–89.7], PPV 68.3% [95% CI 51.9–81.9], NPV 96.6% [95% CI 88.3–99.5], and AUC 95.4% [Figure 1A]. Figure 1. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of the Simple Endoscopic Score for Crohn’s Disease [SES-CD] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with SES-CD ≥ 9. [C] Hazard plot for SES-CD ≥ 9 [red line = surgery; blue line = no surgery]. Figure 1. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of the Simple Endoscopic Score for Crohn’s Disease [SES-CD] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with SES-CD ≥ 9. [C] Hazard plot for SES-CD ≥ 9 [red line = surgery; blue line = no surgery]. For the BWT measurement, a cut-off value of 7 mm showed: sensitivity 66.6% [95% CI 47.2–82.7], specificity 87.1% [95% CI 76.9–93.9], PPV 68.9% [95% CI 49.2–84.7], NPV 85.9% [95% CI 75.6–93], and AUC 86.5% [Figure 2A]. Figure 2. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of bowel wall thickness [BWT] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with BWT ≥ 7 mm. [C] Hazard plot for BWT ≥ 7 mm [red line = surgery; blue line = no surgery]. Figure 2. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of bowel wall thickness [BWT] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with BWT ≥ 7 mm. [C] Hazard plot for BWT ≥ 7 mm [red line = surgery; blue line = no surgery]. For small bowel CD extension measurements at BS, we found that a cut-off value of 33 cm presented: sensitivity 70.0% [95% CI 50.6–85.3], specificity 87.4% [95% CI 70.3–89.7], PPV 61.7% [95% CI 43.6–77.8], NPV 86.4% [95% CI 75.6–93.6], and AUC 73.5% [Figure 3A]. Figure 3. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of small bowel Crohn’s disease [CD] extension at bowel sonography [BS] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with disease extension ≥ 33 cm. [C] Hazard plot for disease extension ≥ 33 cm [red line = surgery; blue line = no surgery]. Figure 3. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of small bowel Crohn’s disease [CD] extension at bowel sonography [BS] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with disease extension ≥ 33 cm. [C] Hazard plot for disease extension ≥ 33 cm [red line = surgery; blue line = no surgery]. At binary logistic regression, we found that stricturing/penetrating behaviour [OR 4.3; 95% CI 1.84–6.22; p <0.001], SES-CD score ≥ 9 [OR 15.3; 95% CI 4.21–48.32; p <0.001], BWT ≥ 7 mm [OR 15.8; 95% CI 5.54–45.13; p <0.001], and small bowel CD extension at BS ≥ 33 cm [OR 8.23; 95% CI 2.98–29.12; p <0.001] were the only predictive factors for surgery [Table 2]. Table 2. Factors associated with 1-year risk of surgery in 100 subjects with Crohn’s Disease. Baseline factors Univariate analysis Binary logistic regression OR 95% CI p OR 95% CI p Male gender 1.3 0.55–3.10 0.53 Age [A1/A2 vs A3] 6.0 0.82–43.59 0.03 1.23 0.71–2.21 0.7 Behaviour [B2/B3 vs B1] 11.3 3.42–28.51 <0.001 4.3 1.84–6.22 <0.001 Location [L1/L3 vs L2] 6.21 2.89–21.31 <0.001 1.8 1.1–3.2 0.5 Perianal disease [yes/no] 4.07 1.01–16.39 0.02 1.3 0.78–3.67 0.7 Previous surgery [yes/no] 1.71 0.94–3.09 0.05 1.9 1.2–4.7 0.3 SES-CD [≥ 9 vs <9] 12.21 3.18–46.81 <0.001 15.3 4.21–48.32 <0.001 BWT at BS [≥ 7 vs <7] 13.55 4.82–38.06 <0.001 15.8 5.54–45.13 <0.001 FC [pathological vs normal] 1.7 0.72–4.16 0.3 CRP [pathological vs normal] 6.14 2.06–18.26 <0.001 1.8 1.1–3.5 0.1 Biologic use [yes/no] 1.38 0.74–2.55 0.37 Azathioprine use [yes/no] 2.35 0.88–6.25 0.08 1.4 0.89–4.54 0.1 EIMs [yes/no] 1.39 0.49–3.92 0.77 Smoking habits [yes/no] 1.19 0.63–2.23 0.65 Familial history [yes/no] 0.9 0.83–0.97 0.09 1 0.88–1.22 0.9 Steroids at diagnosis [yes/no] 1.01 0.57–1.77 0.9 Small bowel CD extension at BS [≥ 33 vs <33] 10.23 3.81–27.43 <0.001 8.23 2.98–29.12 <0.001 CDAI [≥ 150 vs <150] 1.3 0.78–2.76 0.89 Baseline factors Univariate analysis Binary logistic regression OR 95% CI p OR 95% CI p Male gender 1.3 0.55–3.10 0.53 Age [A1/A2 vs A3] 6.0 0.82–43.59 0.03 1.23 0.71–2.21 0.7 Behaviour [B2/B3 vs B1] 11.3 3.42–28.51 <0.001 4.3 1.84–6.22 <0.001 Location [L1/L3 vs L2] 6.21 2.89–21.31 <0.001 1.8 1.1–3.2 0.5 Perianal disease [yes/no] 4.07 1.01–16.39 0.02 1.3 0.78–3.67 0.7 Previous surgery [yes/no] 1.71 0.94–3.09 0.05 1.9 1.2–4.7 0.3 SES-CD [≥ 9 vs <9] 12.21 3.18–46.81 <0.001 15.3 4.21–48.32 <0.001 BWT at BS [≥ 7 vs <7] 13.55 4.82–38.06 <0.001 15.8 5.54–45.13 <0.001 FC [pathological vs normal] 1.7 0.72–4.16 0.3 CRP [pathological vs normal] 6.14 2.06–18.26 <0.001 1.8 1.1–3.5 0.1 Biologic use [yes/no] 1.38 0.74–2.55 0.37 Azathioprine use [yes/no] 2.35 0.88–6.25 0.08 1.4 0.89–4.54 0.1 EIMs [yes/no] 1.39 0.49–3.92 0.77 Smoking habits [yes/no] 1.19 0.63–2.23 0.65 Familial history [yes/no] 0.9 0.83–0.97 0.09 1 0.88–1.22 0.9 Steroids at diagnosis [yes/no] 1.01 0.57–1.77 0.9 Small bowel CD extension at BS [≥ 33 vs <33] 10.23 3.81–27.43 <0.001 8.23 2.98–29.12 <0.001 CDAI [≥ 150 vs <150] 1.3 0.78–2.76 0.89 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; FC, faecal calprotectin; CRP, C-reactive protein; EIMs, extraintestinal manifestations; CDAI, Crohn’s Disease Activity Index; OR, odds ratio; CI, confidence interval. Significant p-values have been highlighted in bold. View Large Table 2. Factors associated with 1-year risk of surgery in 100 subjects with Crohn’s Disease. Baseline factors Univariate analysis Binary logistic regression OR 95% CI p OR 95% CI p Male gender 1.3 0.55–3.10 0.53 Age [A1/A2 vs A3] 6.0 0.82–43.59 0.03 1.23 0.71–2.21 0.7 Behaviour [B2/B3 vs B1] 11.3 3.42–28.51 <0.001 4.3 1.84–6.22 <0.001 Location [L1/L3 vs L2] 6.21 2.89–21.31 <0.001 1.8 1.1–3.2 0.5 Perianal disease [yes/no] 4.07 1.01–16.39 0.02 1.3 0.78–3.67 0.7 Previous surgery [yes/no] 1.71 0.94–3.09 0.05 1.9 1.2–4.7 0.3 SES-CD [≥ 9 vs <9] 12.21 3.18–46.81 <0.001 15.3 4.21–48.32 <0.001 BWT at BS [≥ 7 vs <7] 13.55 4.82–38.06 <0.001 15.8 5.54–45.13 <0.001 FC [pathological vs normal] 1.7 0.72–4.16 0.3 CRP [pathological vs normal] 6.14 2.06–18.26 <0.001 1.8 1.1–3.5 0.1 Biologic use [yes/no] 1.38 0.74–2.55 0.37 Azathioprine use [yes/no] 2.35 0.88–6.25 0.08 1.4 0.89–4.54 0.1 EIMs [yes/no] 1.39 0.49–3.92 0.77 Smoking habits [yes/no] 1.19 0.63–2.23 0.65 Familial history [yes/no] 0.9 0.83–0.97 0.09 1 0.88–1.22 0.9 Steroids at diagnosis [yes/no] 1.01 0.57–1.77 0.9 Small bowel CD extension at BS [≥ 33 vs <33] 10.23 3.81–27.43 <0.001 8.23 2.98–29.12 <0.001 CDAI [≥ 150 vs <150] 1.3 0.78–2.76 0.89 Baseline factors Univariate analysis Binary logistic regression OR 95% CI p OR 95% CI p Male gender 1.3 0.55–3.10 0.53 Age [A1/A2 vs A3] 6.0 0.82–43.59 0.03 1.23 0.71–2.21 0.7 Behaviour [B2/B3 vs B1] 11.3 3.42–28.51 <0.001 4.3 1.84–6.22 <0.001 Location [L1/L3 vs L2] 6.21 2.89–21.31 <0.001 1.8 1.1–3.2 0.5 Perianal disease [yes/no] 4.07 1.01–16.39 0.02 1.3 0.78–3.67 0.7 Previous surgery [yes/no] 1.71 0.94–3.09 0.05 1.9 1.2–4.7 0.3 SES-CD [≥ 9 vs <9] 12.21 3.18–46.81 <0.001 15.3 4.21–48.32 <0.001 BWT at BS [≥ 7 vs <7] 13.55 4.82–38.06 <0.001 15.8 5.54–45.13 <0.001 FC [pathological vs normal] 1.7 0.72–4.16 0.3 CRP [pathological vs normal] 6.14 2.06–18.26 <0.001 1.8 1.1–3.5 0.1 Biologic use [yes/no] 1.38 0.74–2.55 0.37 Azathioprine use [yes/no] 2.35 0.88–6.25 0.08 1.4 0.89–4.54 0.1 EIMs [yes/no] 1.39 0.49–3.92 0.77 Smoking habits [yes/no] 1.19 0.63–2.23 0.65 Familial history [yes/no] 0.9 0.83–0.97 0.09 1 0.88–1.22 0.9 Steroids at diagnosis [yes/no] 1.01 0.57–1.77 0.9 Small bowel CD extension at BS [≥ 33 vs <33] 10.23 3.81–27.43 <0.001 8.23 2.98–29.12 <0.001 CDAI [≥ 150 vs <150] 1.3 0.78–2.76 0.89 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; FC, faecal calprotectin; CRP, C-reactive protein; EIMs, extraintestinal manifestations; CDAI, Crohn’s Disease Activity Index; OR, odds ratio; CI, confidence interval. Significant p-values have been highlighted in bold. View Large Interestingly, age, gender, disease location, perianal disease, previous surgery, CRP, faecal calprotectin, CDAI, therapy with anti-tumour necrosis factor [TNF] alpha drugs, azathioprine exposure, EIMs, smoking habits, familial history, and steroids at CD diagnosis were not associated with risk of surgery at 1 year. At KaplanMeier curves analysis, the HRs were 67.95 [95% CI 27.33–98.45] [Figure 1B, C], 7.94 [95% CI 3.38–18.67] [Figure 2B, C], 6.47 [95% CI 2.78–16.34] [Figure 3B, C], and 25.72 [95% CI 6.39–39.65] [Figure 4A, B] for SES-CD, BWT, small bowel CD extension at BS, and disease behaviour, respectively [p <0.001]. Figure 4. View largeDownload slide [A] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with stricturing/penetrating behaviour. [B] Hazard plot for stricturing/penetrating behaviour [red line = surgery; blue line = no surgery]. Figure 4. View largeDownload slide [A] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with stricturing/penetrating behaviour. [B] Hazard plot for stricturing/penetrating behaviour [red line = surgery; blue line = no surgery]. Multivariate survival Cox regression analysis revealed that SES-CD ≥ 9 [HR 8.3; 95% CI 1.55–44.59; p <0.001], BWT ≥ 7 mm [HR 2.0; 95% CI 1.10–3.49; p = 0.04], small bowel CD extension at BS ≥ 33 cm [HR 2.01; 95% CI 1.20–4.73; p = 0.03], and stricturing/penetrating behaviour [HR 3.4; 95% CI 1.30–27.98; p = 0.02] significantly reduced the resection-free survival [Table 3]. Table 3. Multivariate Cox regression. Factors Cox regression HR 95% CI p SES-CD [≥9 vs<9] 8.3 1.55–44.59 <0.001 Behaviour [B2/B3 vs B1] 3.4 1.30–27.98 0.02 BWT [≥7 vs <7] 2.0 1.10–3.49 0.04 Small bowel CD extension at BS [≥33 vs <33] 2.01 1.20–4.73 0.03 Factors Cox regression HR 95% CI p SES-CD [≥9 vs<9] 8.3 1.55–44.59 <0.001 Behaviour [B2/B3 vs B1] 3.4 1.30–27.98 0.02 BWT [≥7 vs <7] 2.0 1.10–3.49 0.04 Small bowel CD extension at BS [≥33 vs <33] 2.01 1.20–4.73 0.03 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; HR, hazard ratio; CI, confidence interval. Significant p-values have been highlighted in bold. View Large Table 3. Multivariate Cox regression. Factors Cox regression HR 95% CI p SES-CD [≥9 vs<9] 8.3 1.55–44.59 <0.001 Behaviour [B2/B3 vs B1] 3.4 1.30–27.98 0.02 BWT [≥7 vs <7] 2.0 1.10–3.49 0.04 Small bowel CD extension at BS [≥33 vs <33] 2.01 1.20–4.73 0.03 Factors Cox regression HR 95% CI p SES-CD [≥9 vs<9] 8.3 1.55–44.59 <0.001 Behaviour [B2/B3 vs B1] 3.4 1.30–27.98 0.02 BWT [≥7 vs <7] 2.0 1.10–3.49 0.04 Small bowel CD extension at BS [≥33 vs <33] 2.01 1.20–4.73 0.03 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; HR, hazard ratio; CI, confidence interval. Significant p-values have been highlighted in bold. View Large The following variables were associated with surgical resection and were combined in the best-fitted model: SES-CD [≥ 9 or <9], BWT [≥ 7 mm or <7 mm], small bowel CD extension at BS [≥ 33 cm or <33 cm], and disease behaviour [B2/B3]. This best-fitted model was visually presented as a risk matrix showing the risk of surgical resection for all possible combinations of these four variables [in 16 fields] [Figure 5A]. In order to make the matrix easier to use in clinical practice, we also developed a simplified version of the matrix [Figure 5B]. Figure 5. View largeDownload slide [A] Full risk matrix model and [B] simplified risk matrix model. Probabilities of risk of surgery ([95% confidence interval [CI]) of Crohn’s disease [CD] patients [n = 100] at 1 year using risk matrix model. B, behaviour; B1, non-stricturing/non-penetrating disease; B2, stricturing disease; B3, penetrating disease; BWT, bowel wall thickness [mm]; BS, bowel sonography; EXT, small bowel CD extension at BS [cm]; SES-CD, simple endoscopic score for Crohn’s Disease. Figure 5. View largeDownload slide [A] Full risk matrix model and [B] simplified risk matrix model. Probabilities of risk of surgery ([95% confidence interval [CI]) of Crohn’s disease [CD] patients [n = 100] at 1 year using risk matrix model. B, behaviour; B1, non-stricturing/non-penetrating disease; B2, stricturing disease; B3, penetrating disease; BWT, bowel wall thickness [mm]; BS, bowel sonography; EXT, small bowel CD extension at BS [cm]; SES-CD, simple endoscopic score for Crohn’s Disease. As illustrated in the matrix, the highest risk factor profile was observed in patients with SES-CD ≥ 9 at ileocolonoscopy, BWT ≥ 7 mm at BS, small bowel CD extension at BS ≥ 33 cm, and stricturing or penetrating behaviuor. In these patients, the probability of having a surgical resection was 87.5% [95% CI 78.3–94.5] at 1 year. 4. Discussion A treat-to-target strategy based on regular assessment of disease activity—as indicated by clinical and biological outcome measures—has become the new paradigm for the management of CD.28 Treatment adjustments based on clinical and biological outcome measures has been demonstrated to be effective also in reducing the risk of surgery.19,29 In order to tailor and modify the management of patients with CD effectively, it would be extremely useful in the context of clinical practice to have a simple score combining clinical, endoscopic, and imaging features, which could predict the risk of surgery. In this prospective study, including a severe/refractory CD population, we identified several predictive factors for surgery after 1 year from thorough assessment based on clinical, endoscopic, and ultrasonographic examinations. It has to be said that the study population consisted of CD patients at ‘high risk’ for surgery. The high rate of surgery within 1 year [30%], the low percentage of patients with a B1 pattern of disease [26%], and the high rates of previous surgery [45%] and current immunosuppressive/biologic therapy [64%], are all factors indicative of a ‘surgery-prone’ CD cohort. We found that SES-CD ≥ 9, BWT ≥ 7 mm, small bowel CD extension at BS ≥ 33 cm, and stricturing/penetrating behaviour were the only independent factors strongly associated with the risk of surgery. We combined these factors in a risk matrix that allows for the estimation of the probability of surgery on the basis of a specific combination of risk factors. In the presence of variables such as a B2-B3 pattern of CD, a small bowel CD extension at BS >33 cm, an endoscopic activity expressed with SES-CD ≥9, and a cross-sectional evaluation of CD with a BWT ≥7 mm at BS, we were able to identify a group of patients with very high risk [about 90%] for undergoing surgery within 1 year after assessment. We suggest that these patients should be treated more aggressively with biologics or early surgery. On the other hand, CD patients with a B1 pattern of disease, short extension of small bowel CD, low endoscopic activity [SES-CD <9], and a mild transmural inflammation at BS, would require surgery with a probability <2%. Recently, Solberg et al.30 constructed a visual risk matrix model to predict the probability of developing advanced CD 5 and 10 years after diagnosis by combining several risk factors. Their matrix, merging anti-Saccharomyces cerevisiae antibodies [ASCA] status, disease behaviour, patient age, and need for systemic steroids, was able to predict advanced disease with a probability ranging from 12.4% to 96.7%. However, they concluded that their model showed substantial differences in terms of predictive potential in the short and intermediate course of CD, and suggested that their prediction matrix was not useful in short-term management. Lakatos et al.31 built another risk matrix including the following risk factors: ASCA, disease location, and early steroids and azathioprine exposure. The authors concluded that their prediction model identified significant differences in the probability of developing advanced disease in the short and intermediate course of CD. Unlike previous studies, which included in their prediction models only clinical and serological factors, ours included in the matrix model clinical, endoscopic, and imaging factors. This choice was aimed to make our matrix more reliable with respect to the routine clinical management of CD, in line with more recent evidence.21 Ileocolonoscopy is crucial in the assessment of disease activity in CD. Although data on the Rutgeerts score have shown this to accurately predict the course of CD after surgical resection,14 little has been reported about the accuracy of SES-CD in predicting the risk of surgery. In 2002, Allez et al.32 were the first to suggest that patients exhibiting deep and extensive ulcerations at colonoscopy had a more aggressive clinical course, with an increased rate of penetrating complications and surgery. These results were not confirmed in a recent study by Jauregui-Amezaga et al.,18 who found that perianal disease, stenosis, and/or intra-abdominal fistulas at MRI independently predicted an increased risk of resection surgery in patients with CD, whereas the presence of severe endoscopic lesions, assessed with CDEIS, did not. In our study, SES-CD ≥9 [HR 8.3] was an independent predictor for surgery. We demonstrated that a value of SES-CD ≥9 presented sensitivity 93.3%, specificity 81.4%, PPV 68.3%, NPV 96.6%, and AUC 95.4% in predicting surgery [Figure 1]. Bowel sonography is a well-known imaging technique which allows for the diagnosis of CD with high accuracy.22 In 2004, Castiglione et al.17 found that a BWT >7 mm at BS was a risk factor for intestinal resection within 1 year, with sensitivity 88.4%, specificity 78.2%, PPV 63%, and NPV 94.2%. Rigazio et al.33 recently reported the same findings. In the present study, we were able to strengthen and confirm these results, showing that a BWT ≥ 7 mm at BS was an independent risk factor for surgery [OR 15.8; p <0.001]. This was confirmed by multivariate Cox regression [HR 2.0; p = 0.04]. In our experience, BS proved to be a non-invasive, inexpensive, repeatable technique to accurately establish which patients would need a closer follow-up when BWT was higher than 7 mm. Several studies have established that disease behaviour is a risk factor for surgery in CD.4,8,11,12,34,35 In this study we confirmed the role of disease behaviour in predicting the short-term risk of surgery. Interestingly, none of our patients with B1 underwent surgical resection 1 year after evaluation, whereas the risk was high in subjects with B2-B3 [OR 4.3; p <0.001]. Few studies have explored the role of disease extension as a predicting factor for surgery. Peyrin-Biroulet et al.35 found that ileocolonic disease extension [HR 3.3] and small bowel extension [HR 3.4] were associated with a higher risk of surgery. We found a specific cut-off value for small bowel CD extension at BS, which appeared predictive of surgery: an extension longer than 33 cm [OR 8.23; p <0.001] was associated with a significantly reduced surgical resection-free survival. Interestingly, age, gender, disease location, perianal disease, previous surgery, CRP, faecal calprotectin, CDAI, biologic exposure, azathioprine exposure, EIMs, smoking habits, family history, and steroids at CD diagnosis were not correlated with risk of surgery at 1 year. Confirming what we reported in an earlier study,17 our results show that smoking does not affect the risk of surgery, probably because its effect is diluted in the context of other risk factors in a highly ‘surgery-prone’ population. Also, the relevance of perianal disease as a risk factor for surgery, which was evident at univariate analysis, was lost when this factor was placed into a multivariate model. Indeed, data about patient age as predictive factor for surgery are inconclusive. Pigneur et al.36 found that patients with childhood-onset CD were more likely to have a severe disease compared with adult-onset CD, but the cumulative risk of surgical resection was not statistically different between groups. Moreover, Israeli et al.37 showed that although children were at increased risk of panenteric disease, they were not more likely to have more complicated disease or undergo surgery than adults. It is worth pointing out that we did not find any association between immunosuppressive or biologic drugs and risk of surgery. However, data on the efficacy of these drugs in reducing surgery are still contradictory.38–42 We treat this finding from our study with caution; since establishing the efficacy of biologics in reducing the risk of surgery was not one of our endpoints, our sample size would not be adequate for this type of analysis. It is already known that the CDAI correlates poorly with endoscopic activity and long-term outcome.43,44 The present study confirms the limited role of clinical activity indexes in clinical practice. Our study has some limitations, of which we are well aware. First, our patients referred to a tertiary centre, which means our results cannot be generalised and need to be corroborated by population-based inception cohort studies and/or studies in CD population at the time of first diagnosis. Second, our cohort of 100 CD patients could be too small to pick up all the potential variables associated with 1-year surgery; this may justify the magnitude of CI obtained by Cox regression. Moreover, we did not include patients with L4, although upper gastrointestinal involvement is considered a risk factor for surgery in CD.45 Finally, ours was not an inception cohort since our aim was to predict the 1-year risk of surgery in the prevalent [whole] CD population despite the duration of the disease; in our mind, this approach better reflects the everyday clinical practice in a tertiary centre. To summarise, the present study demonstrated that the following factors: SES-CD ≥ 9, BWT ≥ 7 mm at BS, small bowel CD extension at BS ≥ 33 cm, and stricturing/penetrating behaviour are independent risk factors for surgery in severe/refractory CD. The risk matrix we have constructed, combining clinical, endoscopic, and ultrasonographic findings routinely available in clinical practice, can accurately predict the risk of surgery in patients with CD at 1 year. This tool could be of relevance to clinical practice, serving as the basis for a tailored management of patients with severe/refractory CD followed up at a third-level IBD centre. Funding None. Conflict of Interest None declared. Author Contributions AR: substantial contributions to the conception and design, planning the study, drafting the article, analysis and interpretation of data, statistical analysis, revision of the manuscript, performed bowel sonography.NI: substantial contributions to the conception and design, planning the study, drafting the article, analysis and interpretation of data, statistical analysis, revision of the manuscript. AT: acquisition of data, performed bowel sonography. 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The Crohn’s disease activity index [CDAI] is similarly elevated in patients with Crohn’s disease and in patients with irritable bowel syndrome . Aliment Pharmacol Ther 2013 ; 37 : 786 – 94 . Google Scholar CrossRef Search ADS PubMed 45. Lazarev M , Huang C , Bitton A , et al. Relationship between proximal Crohn’s disease location and disease behavior and surgery: a cross-sectional study of the IBD Genetics Consortium . Am J Gastroenterol 2013 ; 108 : 106 – 12 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Combined Endoscopic/Sonographic-based Risk Matrix Model for Predicting One-year Risk of Surgery: A Prospective Observational Study of a Tertiary Centre Severe/Refractory Crohn’s Disease Cohort

Journal of Crohn's and Colitis , Volume Advance Article (7) – Mar 8, 2018

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Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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10.1093/ecco-jcc/jjy032
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Abstract

Abstract Background In the management of Crohn’s disease [CD] patients, having a simple score combining clinical, endoscopic, and imaging features to predict the risk of surgery could help to tailor treatment more effectively. Aims We aimed to prospectively evaluate the 1-year risk factors for surgery in refractory/severe CD and to generate a risk matrix for predicting the probability of surgery at 1 year. Methods CD patients needing a disease re-assessment at our tertiary inflammatory bowel disease [IBD] centre underwent clinical, laboratory, endoscopic, and bowel sonography [BS] examinations within 1 week. The optimal cut-off values in predicting surgery were identified using receiver operating characteristic [ROC] curves for the Simple Endoscopic Score for CD [SES-CD], bowel wall thickness [BWT] at BS, and small bowel CD extension at BS. Binary logistic regression and Cox regression were then carried out. Finally, the probabilities of surgery were calculated for selected baseline levels of covariates and results were arranged in a prediction matrix. Results Of 100 CD patients, 30 underwent surgery within 1 year. SES-CD ≥9 (odds ratio [OR] 15.3; p <0.001], BWT ≥7 mm [OR 15.8; p <0.001], small bowel CD extension at BS ≥33 cm [OR 8.23; p <0.001], and stricturing/penetrating behaviour [OR 4.3; p <0.001] were the only independent factors predictive of surgery at 1 year, based on binary logistic and Cox regressions. Our matrix model combined these risk factors, and the probability of surgery ranged from 0.48% to 87.5% [16 combinations]. Conclusions Our risk matrix combining clinical, endoscopic, and ultrasonographic findings can accurately predict the 1-year risk of surgery in patients with severe/refractory CD requiring a disease re-evaluation. This tool could be of value in clinical practice, serving as the basis for a tailored management of CD patients. Crohn’s disease, surgery, risk factors 1. Introduction Crohn’s disease [CD] is an idiopathic, chronic, and disabling inflammatory disorder which can affect any portion of the gastrointestinal tract, triggering persistent transmural inflammation with subsequent structural bowel damage and intestinal complications such as strictures, fistulas, and abscesses, which often need surgical resection.1–3 Up-to-date statistics show that within 20 years from diagnosis, up to 50% of patients with CD developed intestinal complications and approximately 60% underwent resective surgery, many requiring more than one surgical treatment.4,5 Recent data also showed that up to 50% of patients with newly diagnosed CD already presented bowel damage at the time of diagnosis.6 In 2006, Beaugerie and colleagues7 demonstrated that initial requirement for steroids, age at diagnosis below 40 years, and the presence of perianal disease at diagnosis, were predictive factors of a disabling form of CD. In recent years, several risk factors for surgery have been identified: involvement of the terminal ileum8–10; perianal disease7–9; stricturing and penetrating disease8,11,12; involvement of the upper gastrointestinal tract11; smoking12,13; and need for systemic steroids.7,9 At present, decision making in CD is based on clinical, laboratory, and endoscopic findings, as well as cross-sectional imaging [e.g. magnetic resonance enterography [MR], computed tomography [CT], and bowel sonography [BS]]. Endoscopic and cross-sectional imaging have proved to predict the risk of surgery in CD. For example, the endoscopic Rutgeerts score can accurately predict the course of CD after surgical resection14; some further data also suggest that other endoscopic scores, such as the Crohn’s Disease Endoscopic Index of Severity [CDEIS]15 and the Simple Endoscopic Score for Crohn’s Disease [SES-CD],16 may accurately predict the risk of surgery. Finally, both BS17 and MR18 have been shown to be predictive of risk of surgery in CD. It has already been demonstrated that aggressive pharmacological treatment [e.g. top-down treatment] of the disease can modify its course.19 In the context of clinical practice, it would therefore be extremely helpful to have one single simple score which, combining clinical, endoscopic, and cross-sectional imaging features, could predict the risk of surgery and allow for more accurate tailoring of treatment decisions. This study had two fundamental aims: 1] to prospectively evaluate the risk factors for surgery in patients with severe CD followed up at a tertiary IBD centre in the 12 months following assessment, on the basis of clinical, laboratory, endoscopic, and ultrasonographic findings; and 2] to generate a risk matrix that could predict the probability of resective surgery 1 year after assessment. 2. Materials and Methods 2.1. Study population and study design Between March 2015 and June 2017, we carried out an observational longitudinal prospective study enrolling CD patients needing a disease re-assessment due to CD activity, refractoriness/partial response to therapy, and/or required therapeutic decision making, in accordance with current guidelines.2021 All patients attended our tertiary care centre for inflammatory bowel disease [IBD] at Federico II University Medical School in Naples, Italy. All subjects participating in the study underwent clinical examination and laboratory, endoscopic and BS investigations within 1 week. In line with the Montreal Classification,20 CD patients were clinically classified on the basis of their age at the time of CD diagnosis, the location of the disease, disease behavior, and presence/absence of perianal disease. Other clinical variables were also considered: gender; previous surgery; smoking habits; family history; disease duration; presence of extraintestinal manifestations [EIMs]; and need of steroids at CD diagnosis. For each patient, a clinical index such as the Crohn’s Disease Activity Index [CDAI] was also calculated. Laboratory tests included C-reactive protein [CRP] [normal value <5 mg/L] and faecal calprotectin [normal value <70 μg/g] measurements, which were both performed at our centralised university laboratories. The primary outcome [surgery yes/no] was assessed after 1 year. The surgical outcome included only major laparotomic/laparoscopic abdominal interventions resulting in small bowel/colic resection or colectomy. ‘Minor’ surgical procedures [e.g. percutaneous drainage of abscess, perianal surgery, etc.] were excluded from the analysis. All patients gave their written informed consent; the study was approved by the Ethics Committee of ‘Federico II’ University. 2.2. Endoscopy A colonoscopy with retrograde ileoscopy was performed after 48 h of liquid diet and oral bowel cleansing [achieved with a 4-L solution of polyethilenglicole [PEG] 1 day before the procedure] using a conventional colonoscope [the EVIS EXERA III Video System Center CV-190, Olympus]. This endoscopic assessment was carried out by an expert operator [GDP] blinded to the other procedures. Endoscopic diagnosis of CD was made in accordance with the current European Crohn’s and Colitis Organisation [ECCO] guidelines.21 Endoscopic activity of CD was assessed using the Simple Endoscopic Score for Crohn’s Disease [SES-CD].16 In accordance with current ECCO guidelines, upper endoscopy was performed in patients with symptoms suggesting CD.21 2.3. Bowel sonography BS was performed during the morning hours [after patients’ overnight fasting], using a LOGIQ S7 ultrasound system with linear and convex probes [5–9 MHz]. Two gastroenterologists [AR, AT] with vast experience in BS and blinded to the other procedures performed the scans, systematically examining the patients’ abdominal organs without using any preparation and/or contrast and/or paralytic agents. Bowel wall thickness [BWT] was measured in both longitudinal and transverse slices and was considered normal in presence of values up to 3 mm,22 whereas positive US was defined as the occurrence of concentric and regular increased BWT >3 mm.17,23 In agreement with Maconi et al,24 the presence of strictures was indicated by the presence of thickened [>4 mm] intestinal wall, narrowed intestinal lumen, and fluid-distended or echogenic content-filled loops just above the thickened intestinal tract. Furthermore, entero-cutaneous, entero-enteric, and entero-mesenteric fistulas were identified when hypoechoic duct-like structures with fluid or air content were seen between skin and intestinal loops, between two intestinal loops, or between intestinal loop and mesentery, respectively.25 The presence of abscesses was established following the criteria recommended in the current literature.26,27 2.4. Statistical analysis Data were analysed using the Statistical Package for Social Sciences [SPSS software v.15.0, Chicago IL] for Windows and StatsDirect statistical software [v. 3.0]. The descriptive statistics used included determination of mean values and standard deviation [SD] of the continuous variables, and of percentages and proportions of the categorical variables. To appraise the discrimination ability of SES-CD at ileocolonoscopy, of BWT [mm] at bowel sonography, and of small bowel CD extension at BS [cm], in predicting the likelihood of surgery, receiver operating characteristic [ROC] curves were constructed and the areas under the curves [AUC] calculated. The optimal cut-off point for each curve was identified for sensitivity and specificity, both being of equal importance. Positive predictive value [PPV] and negative predictive value [NPV] were also reported. After best cut-off values were identified for SES-CD, BWT, and small bowel CD extension at BS [cm], a binary logistic regression was used to examine the relationship between surgery as dependent variable and the possible predictors as independent variables. The following variables were included in the analysis: male gender [yes/no], age at CD diagnosis [A1/A2 vs A3], behaviour [B2/B3 vs B1], disease location [L1/L3 vs L2], perianal disease [yes/no], previous surgery [yes/no], CRP [pathological/normal], faecal calprotectin [pathological/normal], exposure to biologics [yes/no], azathioprine exposure [yes/no], EIMs [yes/no], smoking [yes/no], family history [yes/no], steroids at CD diagnosis [yes/no], and CDAI [>150/<150]; SES-CD, BWT, and extension were dichotomised according with best cut-off previously found. The model was performed using the stepwise backward method [Wald]. The coefficients obtained from the logistic regression analysis were also expressed in terms of odds of event occurrence [odds ratio]. The probability of surgery 1 year after assessment was also calculated using the Kaplan–Meier method, and a hazard ratio [HR] with 95% confidence interval [CI] was obtained. Multivariate Cox regression was applied to examine the influence of variables on the length of time elapsed until surgery. The risk matrix was built in three steps. In Step 1, possible risk factors significantly associated with surgery after 1 year were selected for additional multivariate analyses. Risk factors that were highly associated with each other were eliminated to avoid multicollinearity. The final cut-off level was chosen based on the best separation among subgroups of patients, given their predefined features at baseline. In Step 2, several logistic regression models were built. The most suitable model was chosen based on its prediction power. The results were expressed as odds ratios [OR] with 95% CI. Finally in Step 3, the odds calculated with the selected logistic regression model were transformed into probabilities, and the results were organised into a risk matrix. A p-value of less than 0.05 was considered statistically significant. 3. Results During the study period, a total of 630 patients with CD were followed up at our IBD Unit. Of these, 105 [16%] required a disease re-assessment and were therefore eligible to participate in the study. Of these, three patients were excluded due to the fact that they presented clear indication for immediate surgery, and two dropped out during the follow-up. As a result, the study included 100 patients [males 58%, mean age 36.2 ± 11.5] with CD who attended our Unit. Their baseline features are shown in Table 1. Table 1. Demographic, clinical, laboratory, endoscopic, and ultrasonographic features of the study population [n = 100]. Gender Males/females 58/42 Age A1 10 A2 68 A3 22 Location L1 29 L2 14 L3 57 Behaviour B1 26 B2 48 B3 26 Perianal disease Yes/no 21/79 Previous surgery Yes/no 45/55 Smoking habits Yes 34 No 54 Ex 12 Familial history Yes/no 7/93 Disease duration [months] Mean ± SD 86 ± 73.34 EIMs Yes/no 17/83 Steroids at diagnosis Yes/no 37/63 SES-CD Mean ± SD 8.98 ± 5.89 SES-CD ≥ 9 [%] 41% BWT at BS [mm] Mean ± SD 5.37 ± 2.13 BWT at BS ≥ 7 [%] 30% Small bowel CD extension at BS [cm] Mean ± SD 33.52 ± 20.53 Small bowel CD extension at BS ≥ 33 [%] 34% CDAI Mean ± SD 151.59 ± 57.12 CRP [mg/L] Mean ± SD 3.62 ± 6.35 Faecal calprotectin [μg/g] Mean ± SD 150.97 ± 75.87 Treatment after enrolment No treatment 4 Antibiotics 10 Mesalamine 22 Steroids 33 Azathioprine 26 Infliximab 20 Adalimumab 18 Surgery after 1-year follow-up Yes/no 30/70 Indication for surgery Chronic bowel obstruction 13 Abscesses 7 Fistulas 5 Refractory disease 5 Months to surgery Mean ± SD 6.33 ± 3.21 Gender Males/females 58/42 Age A1 10 A2 68 A3 22 Location L1 29 L2 14 L3 57 Behaviour B1 26 B2 48 B3 26 Perianal disease Yes/no 21/79 Previous surgery Yes/no 45/55 Smoking habits Yes 34 No 54 Ex 12 Familial history Yes/no 7/93 Disease duration [months] Mean ± SD 86 ± 73.34 EIMs Yes/no 17/83 Steroids at diagnosis Yes/no 37/63 SES-CD Mean ± SD 8.98 ± 5.89 SES-CD ≥ 9 [%] 41% BWT at BS [mm] Mean ± SD 5.37 ± 2.13 BWT at BS ≥ 7 [%] 30% Small bowel CD extension at BS [cm] Mean ± SD 33.52 ± 20.53 Small bowel CD extension at BS ≥ 33 [%] 34% CDAI Mean ± SD 151.59 ± 57.12 CRP [mg/L] Mean ± SD 3.62 ± 6.35 Faecal calprotectin [μg/g] Mean ± SD 150.97 ± 75.87 Treatment after enrolment No treatment 4 Antibiotics 10 Mesalamine 22 Steroids 33 Azathioprine 26 Infliximab 20 Adalimumab 18 Surgery after 1-year follow-up Yes/no 30/70 Indication for surgery Chronic bowel obstruction 13 Abscesses 7 Fistulas 5 Refractory disease 5 Months to surgery Mean ± SD 6.33 ± 3.21 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; CRP, C-reactive protein; EIMs, extraintestinal manifestations; SD, standard deviation; CDAI, Crohn’s Disease Activity Index. View Large Table 1. Demographic, clinical, laboratory, endoscopic, and ultrasonographic features of the study population [n = 100]. Gender Males/females 58/42 Age A1 10 A2 68 A3 22 Location L1 29 L2 14 L3 57 Behaviour B1 26 B2 48 B3 26 Perianal disease Yes/no 21/79 Previous surgery Yes/no 45/55 Smoking habits Yes 34 No 54 Ex 12 Familial history Yes/no 7/93 Disease duration [months] Mean ± SD 86 ± 73.34 EIMs Yes/no 17/83 Steroids at diagnosis Yes/no 37/63 SES-CD Mean ± SD 8.98 ± 5.89 SES-CD ≥ 9 [%] 41% BWT at BS [mm] Mean ± SD 5.37 ± 2.13 BWT at BS ≥ 7 [%] 30% Small bowel CD extension at BS [cm] Mean ± SD 33.52 ± 20.53 Small bowel CD extension at BS ≥ 33 [%] 34% CDAI Mean ± SD 151.59 ± 57.12 CRP [mg/L] Mean ± SD 3.62 ± 6.35 Faecal calprotectin [μg/g] Mean ± SD 150.97 ± 75.87 Treatment after enrolment No treatment 4 Antibiotics 10 Mesalamine 22 Steroids 33 Azathioprine 26 Infliximab 20 Adalimumab 18 Surgery after 1-year follow-up Yes/no 30/70 Indication for surgery Chronic bowel obstruction 13 Abscesses 7 Fistulas 5 Refractory disease 5 Months to surgery Mean ± SD 6.33 ± 3.21 Gender Males/females 58/42 Age A1 10 A2 68 A3 22 Location L1 29 L2 14 L3 57 Behaviour B1 26 B2 48 B3 26 Perianal disease Yes/no 21/79 Previous surgery Yes/no 45/55 Smoking habits Yes 34 No 54 Ex 12 Familial history Yes/no 7/93 Disease duration [months] Mean ± SD 86 ± 73.34 EIMs Yes/no 17/83 Steroids at diagnosis Yes/no 37/63 SES-CD Mean ± SD 8.98 ± 5.89 SES-CD ≥ 9 [%] 41% BWT at BS [mm] Mean ± SD 5.37 ± 2.13 BWT at BS ≥ 7 [%] 30% Small bowel CD extension at BS [cm] Mean ± SD 33.52 ± 20.53 Small bowel CD extension at BS ≥ 33 [%] 34% CDAI Mean ± SD 151.59 ± 57.12 CRP [mg/L] Mean ± SD 3.62 ± 6.35 Faecal calprotectin [μg/g] Mean ± SD 150.97 ± 75.87 Treatment after enrolment No treatment 4 Antibiotics 10 Mesalamine 22 Steroids 33 Azathioprine 26 Infliximab 20 Adalimumab 18 Surgery after 1-year follow-up Yes/no 30/70 Indication for surgery Chronic bowel obstruction 13 Abscesses 7 Fistulas 5 Refractory disease 5 Months to surgery Mean ± SD 6.33 ± 3.21 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; CRP, C-reactive protein; EIMs, extraintestinal manifestations; SD, standard deviation; CDAI, Crohn’s Disease Activity Index. View Large After 1 year, 30 CD patients [30%] underwent surgical bowel resection [mean time to surgery was 6.33 ± 3.21 months]. The indications for surgery are reported in Table 1. Chronic bowel obstruction [43.3%] and abdominal/pelvic abscesses [23.3%] were the most frequent indications. For the SES-CD score, we found that a cut-off value of 9 presented: sensitivity 93.3% [95% CI 77.9–99.2], specificity 81.4% [95% CI 70.3–89.7], PPV 68.3% [95% CI 51.9–81.9], NPV 96.6% [95% CI 88.3–99.5], and AUC 95.4% [Figure 1A]. Figure 1. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of the Simple Endoscopic Score for Crohn’s Disease [SES-CD] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with SES-CD ≥ 9. [C] Hazard plot for SES-CD ≥ 9 [red line = surgery; blue line = no surgery]. Figure 1. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of the Simple Endoscopic Score for Crohn’s Disease [SES-CD] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with SES-CD ≥ 9. [C] Hazard plot for SES-CD ≥ 9 [red line = surgery; blue line = no surgery]. For the BWT measurement, a cut-off value of 7 mm showed: sensitivity 66.6% [95% CI 47.2–82.7], specificity 87.1% [95% CI 76.9–93.9], PPV 68.9% [95% CI 49.2–84.7], NPV 85.9% [95% CI 75.6–93], and AUC 86.5% [Figure 2A]. Figure 2. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of bowel wall thickness [BWT] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with BWT ≥ 7 mm. [C] Hazard plot for BWT ≥ 7 mm [red line = surgery; blue line = no surgery]. Figure 2. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of bowel wall thickness [BWT] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with BWT ≥ 7 mm. [C] Hazard plot for BWT ≥ 7 mm [red line = surgery; blue line = no surgery]. For small bowel CD extension measurements at BS, we found that a cut-off value of 33 cm presented: sensitivity 70.0% [95% CI 50.6–85.3], specificity 87.4% [95% CI 70.3–89.7], PPV 61.7% [95% CI 43.6–77.8], NPV 86.4% [95% CI 75.6–93.6], and AUC 73.5% [Figure 3A]. Figure 3. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of small bowel Crohn’s disease [CD] extension at bowel sonography [BS] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with disease extension ≥ 33 cm. [C] Hazard plot for disease extension ≥ 33 cm [red line = surgery; blue line = no surgery]. Figure 3. View largeDownload slide [A] Receiver operating characteristic [ROC] curves for the best cut-off value of small bowel Crohn’s disease [CD] extension at bowel sonography [BS] score in predicting surgery. Sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV], with their 95% confidence intervals [CI] and areas under the curve [AUC], were reported. [B] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with disease extension ≥ 33 cm. [C] Hazard plot for disease extension ≥ 33 cm [red line = surgery; blue line = no surgery]. At binary logistic regression, we found that stricturing/penetrating behaviour [OR 4.3; 95% CI 1.84–6.22; p <0.001], SES-CD score ≥ 9 [OR 15.3; 95% CI 4.21–48.32; p <0.001], BWT ≥ 7 mm [OR 15.8; 95% CI 5.54–45.13; p <0.001], and small bowel CD extension at BS ≥ 33 cm [OR 8.23; 95% CI 2.98–29.12; p <0.001] were the only predictive factors for surgery [Table 2]. Table 2. Factors associated with 1-year risk of surgery in 100 subjects with Crohn’s Disease. Baseline factors Univariate analysis Binary logistic regression OR 95% CI p OR 95% CI p Male gender 1.3 0.55–3.10 0.53 Age [A1/A2 vs A3] 6.0 0.82–43.59 0.03 1.23 0.71–2.21 0.7 Behaviour [B2/B3 vs B1] 11.3 3.42–28.51 <0.001 4.3 1.84–6.22 <0.001 Location [L1/L3 vs L2] 6.21 2.89–21.31 <0.001 1.8 1.1–3.2 0.5 Perianal disease [yes/no] 4.07 1.01–16.39 0.02 1.3 0.78–3.67 0.7 Previous surgery [yes/no] 1.71 0.94–3.09 0.05 1.9 1.2–4.7 0.3 SES-CD [≥ 9 vs <9] 12.21 3.18–46.81 <0.001 15.3 4.21–48.32 <0.001 BWT at BS [≥ 7 vs <7] 13.55 4.82–38.06 <0.001 15.8 5.54–45.13 <0.001 FC [pathological vs normal] 1.7 0.72–4.16 0.3 CRP [pathological vs normal] 6.14 2.06–18.26 <0.001 1.8 1.1–3.5 0.1 Biologic use [yes/no] 1.38 0.74–2.55 0.37 Azathioprine use [yes/no] 2.35 0.88–6.25 0.08 1.4 0.89–4.54 0.1 EIMs [yes/no] 1.39 0.49–3.92 0.77 Smoking habits [yes/no] 1.19 0.63–2.23 0.65 Familial history [yes/no] 0.9 0.83–0.97 0.09 1 0.88–1.22 0.9 Steroids at diagnosis [yes/no] 1.01 0.57–1.77 0.9 Small bowel CD extension at BS [≥ 33 vs <33] 10.23 3.81–27.43 <0.001 8.23 2.98–29.12 <0.001 CDAI [≥ 150 vs <150] 1.3 0.78–2.76 0.89 Baseline factors Univariate analysis Binary logistic regression OR 95% CI p OR 95% CI p Male gender 1.3 0.55–3.10 0.53 Age [A1/A2 vs A3] 6.0 0.82–43.59 0.03 1.23 0.71–2.21 0.7 Behaviour [B2/B3 vs B1] 11.3 3.42–28.51 <0.001 4.3 1.84–6.22 <0.001 Location [L1/L3 vs L2] 6.21 2.89–21.31 <0.001 1.8 1.1–3.2 0.5 Perianal disease [yes/no] 4.07 1.01–16.39 0.02 1.3 0.78–3.67 0.7 Previous surgery [yes/no] 1.71 0.94–3.09 0.05 1.9 1.2–4.7 0.3 SES-CD [≥ 9 vs <9] 12.21 3.18–46.81 <0.001 15.3 4.21–48.32 <0.001 BWT at BS [≥ 7 vs <7] 13.55 4.82–38.06 <0.001 15.8 5.54–45.13 <0.001 FC [pathological vs normal] 1.7 0.72–4.16 0.3 CRP [pathological vs normal] 6.14 2.06–18.26 <0.001 1.8 1.1–3.5 0.1 Biologic use [yes/no] 1.38 0.74–2.55 0.37 Azathioprine use [yes/no] 2.35 0.88–6.25 0.08 1.4 0.89–4.54 0.1 EIMs [yes/no] 1.39 0.49–3.92 0.77 Smoking habits [yes/no] 1.19 0.63–2.23 0.65 Familial history [yes/no] 0.9 0.83–0.97 0.09 1 0.88–1.22 0.9 Steroids at diagnosis [yes/no] 1.01 0.57–1.77 0.9 Small bowel CD extension at BS [≥ 33 vs <33] 10.23 3.81–27.43 <0.001 8.23 2.98–29.12 <0.001 CDAI [≥ 150 vs <150] 1.3 0.78–2.76 0.89 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; FC, faecal calprotectin; CRP, C-reactive protein; EIMs, extraintestinal manifestations; CDAI, Crohn’s Disease Activity Index; OR, odds ratio; CI, confidence interval. Significant p-values have been highlighted in bold. View Large Table 2. Factors associated with 1-year risk of surgery in 100 subjects with Crohn’s Disease. Baseline factors Univariate analysis Binary logistic regression OR 95% CI p OR 95% CI p Male gender 1.3 0.55–3.10 0.53 Age [A1/A2 vs A3] 6.0 0.82–43.59 0.03 1.23 0.71–2.21 0.7 Behaviour [B2/B3 vs B1] 11.3 3.42–28.51 <0.001 4.3 1.84–6.22 <0.001 Location [L1/L3 vs L2] 6.21 2.89–21.31 <0.001 1.8 1.1–3.2 0.5 Perianal disease [yes/no] 4.07 1.01–16.39 0.02 1.3 0.78–3.67 0.7 Previous surgery [yes/no] 1.71 0.94–3.09 0.05 1.9 1.2–4.7 0.3 SES-CD [≥ 9 vs <9] 12.21 3.18–46.81 <0.001 15.3 4.21–48.32 <0.001 BWT at BS [≥ 7 vs <7] 13.55 4.82–38.06 <0.001 15.8 5.54–45.13 <0.001 FC [pathological vs normal] 1.7 0.72–4.16 0.3 CRP [pathological vs normal] 6.14 2.06–18.26 <0.001 1.8 1.1–3.5 0.1 Biologic use [yes/no] 1.38 0.74–2.55 0.37 Azathioprine use [yes/no] 2.35 0.88–6.25 0.08 1.4 0.89–4.54 0.1 EIMs [yes/no] 1.39 0.49–3.92 0.77 Smoking habits [yes/no] 1.19 0.63–2.23 0.65 Familial history [yes/no] 0.9 0.83–0.97 0.09 1 0.88–1.22 0.9 Steroids at diagnosis [yes/no] 1.01 0.57–1.77 0.9 Small bowel CD extension at BS [≥ 33 vs <33] 10.23 3.81–27.43 <0.001 8.23 2.98–29.12 <0.001 CDAI [≥ 150 vs <150] 1.3 0.78–2.76 0.89 Baseline factors Univariate analysis Binary logistic regression OR 95% CI p OR 95% CI p Male gender 1.3 0.55–3.10 0.53 Age [A1/A2 vs A3] 6.0 0.82–43.59 0.03 1.23 0.71–2.21 0.7 Behaviour [B2/B3 vs B1] 11.3 3.42–28.51 <0.001 4.3 1.84–6.22 <0.001 Location [L1/L3 vs L2] 6.21 2.89–21.31 <0.001 1.8 1.1–3.2 0.5 Perianal disease [yes/no] 4.07 1.01–16.39 0.02 1.3 0.78–3.67 0.7 Previous surgery [yes/no] 1.71 0.94–3.09 0.05 1.9 1.2–4.7 0.3 SES-CD [≥ 9 vs <9] 12.21 3.18–46.81 <0.001 15.3 4.21–48.32 <0.001 BWT at BS [≥ 7 vs <7] 13.55 4.82–38.06 <0.001 15.8 5.54–45.13 <0.001 FC [pathological vs normal] 1.7 0.72–4.16 0.3 CRP [pathological vs normal] 6.14 2.06–18.26 <0.001 1.8 1.1–3.5 0.1 Biologic use [yes/no] 1.38 0.74–2.55 0.37 Azathioprine use [yes/no] 2.35 0.88–6.25 0.08 1.4 0.89–4.54 0.1 EIMs [yes/no] 1.39 0.49–3.92 0.77 Smoking habits [yes/no] 1.19 0.63–2.23 0.65 Familial history [yes/no] 0.9 0.83–0.97 0.09 1 0.88–1.22 0.9 Steroids at diagnosis [yes/no] 1.01 0.57–1.77 0.9 Small bowel CD extension at BS [≥ 33 vs <33] 10.23 3.81–27.43 <0.001 8.23 2.98–29.12 <0.001 CDAI [≥ 150 vs <150] 1.3 0.78–2.76 0.89 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; FC, faecal calprotectin; CRP, C-reactive protein; EIMs, extraintestinal manifestations; CDAI, Crohn’s Disease Activity Index; OR, odds ratio; CI, confidence interval. Significant p-values have been highlighted in bold. View Large Interestingly, age, gender, disease location, perianal disease, previous surgery, CRP, faecal calprotectin, CDAI, therapy with anti-tumour necrosis factor [TNF] alpha drugs, azathioprine exposure, EIMs, smoking habits, familial history, and steroids at CD diagnosis were not associated with risk of surgery at 1 year. At KaplanMeier curves analysis, the HRs were 67.95 [95% CI 27.33–98.45] [Figure 1B, C], 7.94 [95% CI 3.38–18.67] [Figure 2B, C], 6.47 [95% CI 2.78–16.34] [Figure 3B, C], and 25.72 [95% CI 6.39–39.65] [Figure 4A, B] for SES-CD, BWT, small bowel CD extension at BS, and disease behaviour, respectively [p <0.001]. Figure 4. View largeDownload slide [A] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with stricturing/penetrating behaviour. [B] Hazard plot for stricturing/penetrating behaviour [red line = surgery; blue line = no surgery]. Figure 4. View largeDownload slide [A] Survival rate free of surgical resection by Kaplan-Meier curve [red line = surgery; blue line = no surgery] in accordance with stricturing/penetrating behaviour. [B] Hazard plot for stricturing/penetrating behaviour [red line = surgery; blue line = no surgery]. Multivariate survival Cox regression analysis revealed that SES-CD ≥ 9 [HR 8.3; 95% CI 1.55–44.59; p <0.001], BWT ≥ 7 mm [HR 2.0; 95% CI 1.10–3.49; p = 0.04], small bowel CD extension at BS ≥ 33 cm [HR 2.01; 95% CI 1.20–4.73; p = 0.03], and stricturing/penetrating behaviour [HR 3.4; 95% CI 1.30–27.98; p = 0.02] significantly reduced the resection-free survival [Table 3]. Table 3. Multivariate Cox regression. Factors Cox regression HR 95% CI p SES-CD [≥9 vs<9] 8.3 1.55–44.59 <0.001 Behaviour [B2/B3 vs B1] 3.4 1.30–27.98 0.02 BWT [≥7 vs <7] 2.0 1.10–3.49 0.04 Small bowel CD extension at BS [≥33 vs <33] 2.01 1.20–4.73 0.03 Factors Cox regression HR 95% CI p SES-CD [≥9 vs<9] 8.3 1.55–44.59 <0.001 Behaviour [B2/B3 vs B1] 3.4 1.30–27.98 0.02 BWT [≥7 vs <7] 2.0 1.10–3.49 0.04 Small bowel CD extension at BS [≥33 vs <33] 2.01 1.20–4.73 0.03 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; HR, hazard ratio; CI, confidence interval. Significant p-values have been highlighted in bold. View Large Table 3. Multivariate Cox regression. Factors Cox regression HR 95% CI p SES-CD [≥9 vs<9] 8.3 1.55–44.59 <0.001 Behaviour [B2/B3 vs B1] 3.4 1.30–27.98 0.02 BWT [≥7 vs <7] 2.0 1.10–3.49 0.04 Small bowel CD extension at BS [≥33 vs <33] 2.01 1.20–4.73 0.03 Factors Cox regression HR 95% CI p SES-CD [≥9 vs<9] 8.3 1.55–44.59 <0.001 Behaviour [B2/B3 vs B1] 3.4 1.30–27.98 0.02 BWT [≥7 vs <7] 2.0 1.10–3.49 0.04 Small bowel CD extension at BS [≥33 vs <33] 2.01 1.20–4.73 0.03 SES-CD, Simple Endoscopic Score for Crohn’s Disease; BWT, bowel wall thickness; BS, bowel sonography; HR, hazard ratio; CI, confidence interval. Significant p-values have been highlighted in bold. View Large The following variables were associated with surgical resection and were combined in the best-fitted model: SES-CD [≥ 9 or <9], BWT [≥ 7 mm or <7 mm], small bowel CD extension at BS [≥ 33 cm or <33 cm], and disease behaviour [B2/B3]. This best-fitted model was visually presented as a risk matrix showing the risk of surgical resection for all possible combinations of these four variables [in 16 fields] [Figure 5A]. In order to make the matrix easier to use in clinical practice, we also developed a simplified version of the matrix [Figure 5B]. Figure 5. View largeDownload slide [A] Full risk matrix model and [B] simplified risk matrix model. Probabilities of risk of surgery ([95% confidence interval [CI]) of Crohn’s disease [CD] patients [n = 100] at 1 year using risk matrix model. B, behaviour; B1, non-stricturing/non-penetrating disease; B2, stricturing disease; B3, penetrating disease; BWT, bowel wall thickness [mm]; BS, bowel sonography; EXT, small bowel CD extension at BS [cm]; SES-CD, simple endoscopic score for Crohn’s Disease. Figure 5. View largeDownload slide [A] Full risk matrix model and [B] simplified risk matrix model. Probabilities of risk of surgery ([95% confidence interval [CI]) of Crohn’s disease [CD] patients [n = 100] at 1 year using risk matrix model. B, behaviour; B1, non-stricturing/non-penetrating disease; B2, stricturing disease; B3, penetrating disease; BWT, bowel wall thickness [mm]; BS, bowel sonography; EXT, small bowel CD extension at BS [cm]; SES-CD, simple endoscopic score for Crohn’s Disease. As illustrated in the matrix, the highest risk factor profile was observed in patients with SES-CD ≥ 9 at ileocolonoscopy, BWT ≥ 7 mm at BS, small bowel CD extension at BS ≥ 33 cm, and stricturing or penetrating behaviuor. In these patients, the probability of having a surgical resection was 87.5% [95% CI 78.3–94.5] at 1 year. 4. Discussion A treat-to-target strategy based on regular assessment of disease activity—as indicated by clinical and biological outcome measures—has become the new paradigm for the management of CD.28 Treatment adjustments based on clinical and biological outcome measures has been demonstrated to be effective also in reducing the risk of surgery.19,29 In order to tailor and modify the management of patients with CD effectively, it would be extremely useful in the context of clinical practice to have a simple score combining clinical, endoscopic, and imaging features, which could predict the risk of surgery. In this prospective study, including a severe/refractory CD population, we identified several predictive factors for surgery after 1 year from thorough assessment based on clinical, endoscopic, and ultrasonographic examinations. It has to be said that the study population consisted of CD patients at ‘high risk’ for surgery. The high rate of surgery within 1 year [30%], the low percentage of patients with a B1 pattern of disease [26%], and the high rates of previous surgery [45%] and current immunosuppressive/biologic therapy [64%], are all factors indicative of a ‘surgery-prone’ CD cohort. We found that SES-CD ≥ 9, BWT ≥ 7 mm, small bowel CD extension at BS ≥ 33 cm, and stricturing/penetrating behaviour were the only independent factors strongly associated with the risk of surgery. We combined these factors in a risk matrix that allows for the estimation of the probability of surgery on the basis of a specific combination of risk factors. In the presence of variables such as a B2-B3 pattern of CD, a small bowel CD extension at BS >33 cm, an endoscopic activity expressed with SES-CD ≥9, and a cross-sectional evaluation of CD with a BWT ≥7 mm at BS, we were able to identify a group of patients with very high risk [about 90%] for undergoing surgery within 1 year after assessment. We suggest that these patients should be treated more aggressively with biologics or early surgery. On the other hand, CD patients with a B1 pattern of disease, short extension of small bowel CD, low endoscopic activity [SES-CD <9], and a mild transmural inflammation at BS, would require surgery with a probability <2%. Recently, Solberg et al.30 constructed a visual risk matrix model to predict the probability of developing advanced CD 5 and 10 years after diagnosis by combining several risk factors. Their matrix, merging anti-Saccharomyces cerevisiae antibodies [ASCA] status, disease behaviour, patient age, and need for systemic steroids, was able to predict advanced disease with a probability ranging from 12.4% to 96.7%. However, they concluded that their model showed substantial differences in terms of predictive potential in the short and intermediate course of CD, and suggested that their prediction matrix was not useful in short-term management. Lakatos et al.31 built another risk matrix including the following risk factors: ASCA, disease location, and early steroids and azathioprine exposure. The authors concluded that their prediction model identified significant differences in the probability of developing advanced disease in the short and intermediate course of CD. Unlike previous studies, which included in their prediction models only clinical and serological factors, ours included in the matrix model clinical, endoscopic, and imaging factors. This choice was aimed to make our matrix more reliable with respect to the routine clinical management of CD, in line with more recent evidence.21 Ileocolonoscopy is crucial in the assessment of disease activity in CD. Although data on the Rutgeerts score have shown this to accurately predict the course of CD after surgical resection,14 little has been reported about the accuracy of SES-CD in predicting the risk of surgery. In 2002, Allez et al.32 were the first to suggest that patients exhibiting deep and extensive ulcerations at colonoscopy had a more aggressive clinical course, with an increased rate of penetrating complications and surgery. These results were not confirmed in a recent study by Jauregui-Amezaga et al.,18 who found that perianal disease, stenosis, and/or intra-abdominal fistulas at MRI independently predicted an increased risk of resection surgery in patients with CD, whereas the presence of severe endoscopic lesions, assessed with CDEIS, did not. In our study, SES-CD ≥9 [HR 8.3] was an independent predictor for surgery. We demonstrated that a value of SES-CD ≥9 presented sensitivity 93.3%, specificity 81.4%, PPV 68.3%, NPV 96.6%, and AUC 95.4% in predicting surgery [Figure 1]. Bowel sonography is a well-known imaging technique which allows for the diagnosis of CD with high accuracy.22 In 2004, Castiglione et al.17 found that a BWT >7 mm at BS was a risk factor for intestinal resection within 1 year, with sensitivity 88.4%, specificity 78.2%, PPV 63%, and NPV 94.2%. Rigazio et al.33 recently reported the same findings. In the present study, we were able to strengthen and confirm these results, showing that a BWT ≥ 7 mm at BS was an independent risk factor for surgery [OR 15.8; p <0.001]. This was confirmed by multivariate Cox regression [HR 2.0; p = 0.04]. In our experience, BS proved to be a non-invasive, inexpensive, repeatable technique to accurately establish which patients would need a closer follow-up when BWT was higher than 7 mm. Several studies have established that disease behaviour is a risk factor for surgery in CD.4,8,11,12,34,35 In this study we confirmed the role of disease behaviour in predicting the short-term risk of surgery. Interestingly, none of our patients with B1 underwent surgical resection 1 year after evaluation, whereas the risk was high in subjects with B2-B3 [OR 4.3; p <0.001]. Few studies have explored the role of disease extension as a predicting factor for surgery. Peyrin-Biroulet et al.35 found that ileocolonic disease extension [HR 3.3] and small bowel extension [HR 3.4] were associated with a higher risk of surgery. We found a specific cut-off value for small bowel CD extension at BS, which appeared predictive of surgery: an extension longer than 33 cm [OR 8.23; p <0.001] was associated with a significantly reduced surgical resection-free survival. Interestingly, age, gender, disease location, perianal disease, previous surgery, CRP, faecal calprotectin, CDAI, biologic exposure, azathioprine exposure, EIMs, smoking habits, family history, and steroids at CD diagnosis were not correlated with risk of surgery at 1 year. Confirming what we reported in an earlier study,17 our results show that smoking does not affect the risk of surgery, probably because its effect is diluted in the context of other risk factors in a highly ‘surgery-prone’ population. Also, the relevance of perianal disease as a risk factor for surgery, which was evident at univariate analysis, was lost when this factor was placed into a multivariate model. Indeed, data about patient age as predictive factor for surgery are inconclusive. Pigneur et al.36 found that patients with childhood-onset CD were more likely to have a severe disease compared with adult-onset CD, but the cumulative risk of surgical resection was not statistically different between groups. Moreover, Israeli et al.37 showed that although children were at increased risk of panenteric disease, they were not more likely to have more complicated disease or undergo surgery than adults. It is worth pointing out that we did not find any association between immunosuppressive or biologic drugs and risk of surgery. However, data on the efficacy of these drugs in reducing surgery are still contradictory.38–42 We treat this finding from our study with caution; since establishing the efficacy of biologics in reducing the risk of surgery was not one of our endpoints, our sample size would not be adequate for this type of analysis. It is already known that the CDAI correlates poorly with endoscopic activity and long-term outcome.43,44 The present study confirms the limited role of clinical activity indexes in clinical practice. Our study has some limitations, of which we are well aware. First, our patients referred to a tertiary centre, which means our results cannot be generalised and need to be corroborated by population-based inception cohort studies and/or studies in CD population at the time of first diagnosis. Second, our cohort of 100 CD patients could be too small to pick up all the potential variables associated with 1-year surgery; this may justify the magnitude of CI obtained by Cox regression. Moreover, we did not include patients with L4, although upper gastrointestinal involvement is considered a risk factor for surgery in CD.45 Finally, ours was not an inception cohort since our aim was to predict the 1-year risk of surgery in the prevalent [whole] CD population despite the duration of the disease; in our mind, this approach better reflects the everyday clinical practice in a tertiary centre. To summarise, the present study demonstrated that the following factors: SES-CD ≥ 9, BWT ≥ 7 mm at BS, small bowel CD extension at BS ≥ 33 cm, and stricturing/penetrating behaviour are independent risk factors for surgery in severe/refractory CD. The risk matrix we have constructed, combining clinical, endoscopic, and ultrasonographic findings routinely available in clinical practice, can accurately predict the risk of surgery in patients with CD at 1 year. This tool could be of relevance to clinical practice, serving as the basis for a tailored management of patients with severe/refractory CD followed up at a third-level IBD centre. Funding None. Conflict of Interest None declared. Author Contributions AR: substantial contributions to the conception and design, planning the study, drafting the article, analysis and interpretation of data, statistical analysis, revision of the manuscript, performed bowel sonography.NI: substantial contributions to the conception and design, planning the study, drafting the article, analysis and interpretation of data, statistical analysis, revision of the manuscript. AT: acquisition of data, performed bowel sonography. 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Journal of Crohn's and ColitisOxford University Press

Published: Mar 8, 2018

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