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Original Contributions: Inflammatory Bowel Disease

A Validated Prognostic Model and Nomogram to Predict Early-Onset Complications Leading to Surgery in Patients With Crohn’s Disease

Yao, Jiayin Ph.D.1,2; Jiang, Yi M.D.1,2; Ke, Jia Ph.D.2,3; Lu, Yi Ph.D.4; Hu, Jun Ph.D.5; Zhi, Min Ph.D.1,2

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Diseases of the Colon & Rectum: June 2021 - Volume 64 - Issue 6 - p 697-705
doi: 10.1097/DCR.0000000000001881
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Abstract

Crohn’s disease (CD) is a type of chronic transmural inflammatory condition affecting any segment of the GI tract.1 It has a wide range of intestinal symptoms and extraintestinal manifestations, with varying phenotypes of disease behavior, making the application of “treat to target” even more challenging.2 Most patients have experienced progression to complications, including stenosis, perforation, and severe GI bleeding, ultimately leading to surgery. According to the analysis by Thia et al3 of a population-based cohort, 19% to 36% of patients newly diagnosed with CD developed complications. This percentage increased along with the progression of inflammation. Approximately 50% of patients with CD developed complications within 5 years and nearly 70% developed complications within 10 years after diagnosis.4,5 Even during the periods when patients with aggressive CD are asymptomatic, subclinical inflammation may progress and lead to irreversible bowel damage and complications.6 Therefore, the diagnosis of aggressive CD and identification of the risk of early-onset complications are crucial because the initiation of intensive therapeutic strategies can effectively reduce the rate of complications and surgery.

The commonly used classification systems, in particular, the Montreal classification,7 identify stricturing and penetrating complications after they have manifested or become clinically apparent. Thus, such classification systems have limitations in the early evaluation of the course and behavior of CD. It is essential to evaluate patients and predict complication risks in newly diagnosed patients with nonstricturing and nonpenetrating disease to guide treatment. Thus, in this study, we aimed to develop a prognostic model to aid in predicting the risks of complications leading to surgery within 1 year after diagnosis of CD. Furthermore, we created a nomogram to facilitate clinical decision making.

MATERIALS AND METHODS

Patient Population

This retrospective study collected data from patients in the IBD center of Sun Yat-Sun University Sixth Affiliated Hospital from January 1, 2012, to December 31, 2016. Patients were included if they had an unequivocal diagnosis of CD; B1 disease behavior (nonstricturing, nonpenetrating) according to the Montreal classification; no complications at diagnosis; and at least 1 year of follow-up. The exclusion criteria were as follows: potential diagnosis other than CD, B2 (stricturing) or B3 (penetrating) disease behavior, and loss of follow-up or incomplete data. Data of consecutive patients with CD admitted to our IBD center were identified by an experienced gastroenterologist (J.Y.Y.) and were collected from the hospital’s electronic database, with discrepancies being resolved after discussion by 2 specialists (Y.J. and J.K.). Eligible patients were followed up to at least 1 year for screening complications that could lead to surgery by endoscopy and imaging. All patients with complications were fully evaluated by a professional surgeon (J.K.) for surgical indication and specific procedures. This study was approved by the Ethics Committee of Sun Yat-Sen University (2019ZSLYEC-058), permitted by the Chinese Clinical Trial Registry (ChiCTR1900025751), and, therefore, has been conducted in accordance with the ethical standards stated in the Declaration of Helsinki. The requirement for written informed consent was waived by our Institutional Review Board because it was a retrospective study that used anonymous data.

Outcomes and Definitions

The main outcome of this study was the occurrence of complications that could lead to surgery, including severe GI bleeding, stenosis, and perforations. Severe GI bleeding was defined as hemorrhage in any part of the digestive tract with a Glasgow-Blatchford score ≥68,9 confirmed by endoscopy, CT scan, and/or interventional radiology. We considered the cause for bleeding to be exclusively associated with CD. Stenosis was defined as prestenotic dilation (often defined as >3 cm10) confirmed by radiological examinations with or without obstructive symptoms.10,11 Perforation was defined as external fistulas (enterocutaneous and perianal fistulas) and/or internal fistulas (enteroenteric, enterovesical, or enterovaginal fistulas) confirmed by cross-sectional imaging10 or surgery.12,13 Crohn’s disease-related surgeries consist of bowel segment resection (ileocolic resection with primary anastomosis or end ileostomy, subtotal colectomy with ileorectal anastomosis or end ileostomy, segmental colon resection, segmental small-bowel resection, and total proctocolectomy), stricturoplasty, and fistula repair (incision and drainage of abscess, seton placement, fistulotomy, and fistulectomy). Intra-abdominal surgical procedures, including bowel segment resection and stricturoplasty, were defined as major surgeries, whereas fistula repair was defined as a minor surgery.

Selection of Predictors

Candidate predictive factors were selected from demographic and disease-related variables that were previously reported in the literature as potential factors. All factors mentioned above were identified before the diagnosis of complications leading to surgery by a professional gastroenterologist (J.Y.Y.).

We collected patients’ clinical information, including age, sex, smoking and drinking habits, previous history of surgery (perianal surgery and/or appendectomy with indication of anal fistula, perianal abscess and/or appendicitis), laboratory parameters at diagnosis (C-reactive protein, erythrocyte sedimentation rate, and albumin), duration of disease before diagnosis, extraintestinal manifestations (arthropathies and dermatological, ocular, and hepatobiliary disease),2 and therapeutic strategies. A diagnosis of CD was made according to the internationally accepted criteria14 based on a combination of radiographic, endoscopic, and histological presentations, and disease phenotype was classified according to the Montreal classification.7 In this study, L4 disease location referred specifically to isolated L4 including esophagogastroduodenal, jejunal, and proximal ileal disease. Patients were stratified according to therapeutic strategies during the initial 1 year after diagnosis into either a glucocorticoid + immunosuppression group, biologics (combine immunosuppression or not) group, or 5-aminosalicylic acid group (5-ASA).

Statistical Analyses

Continuous variables are presented as either mean and SD or median and interquartile range and were analyzed using Student t tests. Categorical variables are presented as percentages or proportions and were analyzed using the χ2 or Fisher exact test. All cases were allocated a random number ranging from 0 to 100 generated by IBM SPSS (version 22.0, IBM Corp, Armonk, NY) with random seed as 2020, to ensure that the entire statistical analyses could be easily repeated. Cases with numbers ranging from 0 to 80 were assigned to the training set, and those with numbers ranging from 80.0001 to 100 were assigned to the testing set. Thus, data were randomly stratified into a training set and a testing set at a ratio of 8:2. The actual sample size for the training and testing sets were 484 and 130. Risk factors with a p value <0.20 in the univariable analysis were included in the multivariable analyses. Logistic regression with a backward stepwise selection was used to select risk factors for the multivariable model. A significance level of 0.20 was required to allow a risk factor into the model, and a significance level of 0.20 was required for a risk factor to stay in the model. Receiver operating characteristic curves were constructed while areas under the curve (AUC) were calculated both in the training and testing sets. The optimal cutoff point was identified using the Youden J statistic.15 Our model calibration was evaluated using the Hosmer-Lemeshow goodness-of-fit test, and discrimination was assessed using AUC. The model development and validation processes were in accordance with the recommended guidelines.16,17 The application of this prognostic model could be visualized by means of a nomogram conducted using R software (R Foundation for Statistical Computing, Vienna, Austria). A 2-tailed p value <0.05 was considered statistically significant.

RESULTS

Patient Characteristics

Clinical information of 614 patients newly diagnosed with CD with B1 behavior were analyzed in our IBD unit, the biggest IBD center in China. A total of 73.78% (n = 453) of cases were men with a mean age of 26.8 (SD 10.9) years, mean disease duration of 1.3 (SD 1.6) years, and mean follow-up period of 53.5 (SD 12.8) months. Most of the patients were classified as A2 (A1, n = 79, 12.9%; A2, n = 466, 75.9%; A3, n = 69, 11.2%), and L3 (L1, n = 82, 13.4%; L2, n = 70, 11.4%; L3, n = 413, 67.3%; L4, n = 49, 8.0%). Biologics therapy was administered to 54.2% of patients (n = 333, 5-ASA, n = 132, 21.5%; glucocorticoid + immunosuppression, n = 328, 53.4%), whereas 50.2% of patients received more than 1 form of medical therapy (n = 308). A total of 83 patients (13.5%) developed complications leading to surgery within 1 year after diagnosis. The most common complications were stenosis (n = 48, 57.8%), followed by perforation (n = 26, 31.3%) and severe GI bleeding (n = 9, 10.8%). Consequently, 70 patients (84.3%) underwent a bowel segment resection, 8 patients (9.6%) underwent stricturoplasty, and 5 patients (6.0%) underwent a fistula repair. Table 1 displays the details of patient characteristics in all cases and in each subgroup divided according to the different types of complications. No data were missing for any of the investigated risk factors.

TABLE 1. - Patient baseline characteristics
Characteristic Total Complications
GI bleeding Perforation Stenosis
n 614 9 26 48
Male, n (%) 453 (73.8) 7 (77. 8) 21 (80.8) 29 (60.4)
Age at diagnosis, y, mean ± SD 26.8 ± 10.9 20.3 ± 10.2 25.12 ± 8.4 25.6 ± 11.7
Drinking, n (%) 34 (5.5) 1 (11.1) 0 (0.0) 3 (6.3)
Smoking, n (%) 72 (11.7) 1 (11.1) 2 (7.7) 7 (14.6)
Disease duration, y, mean ± SD 1.3 ± 1.6 2.8 ± 2.7 2.7 ± 2.8
BMI, kg/m2, mean ± SD 18.8 ± 2.9 17.8 ± 3.1 17.7 ± 2.4 18.6 ± 2.7
Follow-up, mo, mean ± SD 53.5 ± 12.8 54.9 ± 10.8 59.4 ± 10.1 53.2 ± 14.9
Montreal classification, n (%)
 Age at diagnosis
  A1 79 (12.9) 5 (55.6) 2 (7.7) 8 (16.7)
  A2 466 (75.9) 3 (33.3) 22 (84.6) 35 (72.9)
  A3 69 (11.2) 1 (11.1) 2 (7.7) 5 (10.4)
 Location at diagnosis
  L1 82 (13.4) 2 (22.2) 2 (7.7) 5 (10.4)
  L2 70 (11.4) 1 (11.1) 3 (11.5) 9 (18.8)
  L3 413 (67.3) 5 (55.6) 19 (73.1) 32 (66.7)
  L4 49 (8.0) 1 (11.1) 2 (7.7) 2 (4.2)
CRP at diagnosis, mg/L, mean ± SD 17.9 ± 18.1 18.5 ± 16.4 22.07 ± 20.63 16.7 ± 21.6
ESR at diagnosis, mm/h, mean ± SD 34.5 ± 28.8 34.9 ± 32.4 44.7 ± 30.8 29.3 ± 19.9
Alb at diagnosis, g/L mean ± SD 40.0 ± 32.1 40.2 ± 7.5 37.0 ± 6.6 38.5 ± 6.7
Previous surgery, n (%) 217 (35.3) 6 (66.7) 13 (50.0) 38 (79.2)
Perianal disease, n (%) 87 (14.2) 8 (88.9) 13 (50.0) 33 (68.8)
EIM, n (%) 95 (15.5) 7 (77.8) 21 (80.8) 35 (72.9)
Treatment, n (%)
 5-ASA 132 (21.5) 1 (11.1) 3 (11.5) 13 (27.1)
 Biologics (+IM) 333 (54.2) 5 (55.6) 12 (46.2) 23 (47.9)
 Corticosteroids + IM 328 (53.4) 7 (77.8) 14 (53.9) 23 (47.9)
Alb = albumin; 5-ASA = 5-aminosalicylic acid; CRP = C-reactive protein; EIM = extraintestinal manifestations; ESR = erythrocyte sedimentation rate; IM = immunosuppressant.

Prognostic Model Development and Validation

According to the univariate analysis, variables, including age at diagnosis, disease duration, previous surgery, perianal disease, and extraintestinal manifestations, were significant factors related to early-onset complications. Based on all the related variables considered in the multivariable logistic regression analysis, a prognostic model was developed as follows (Table 2):

TABLE 2. - Factors associated with surgery-relative complications in Crohn’s disease
Factor Univariate analysis (n = 484) Multivariable logistic regression (n = 484)
OR 95% CI p value OR 95% CI p value β ± SE
Sex (male vs female) 1.3 0.7–2.4 0.377
Age. ya 0.7 0.6–1.0 0.062 0.4 0.2–0.8 0.004 –0.90±0.31
Location (L1 vs L2/L3/L4)
 L2 1.2 0.4–3.3 0.738
 L3 0.8 0.4–1.8 0.647
 L4 0.8 0.2–2.9 0.756
Disease duration 1.6 1.4–1.9 <0.001 2.7 1.9–3.8 <0.001 0.98±0.18
Drinking 1.0 0.3–3.5 0.998
Smoking 1.2 0.5–2.7 0.729
BMI 0.9 0.8–1.0 0.147
Previous surgery 5.2 2.9–9.3 <0.001 3.7 1.6–8.6 0.003 1.30±0.44
Perianal disease 27.0 13.9–52.4 <0.001 16.0 4.3–59.9 <0.001 2.77±0.67
EIM 44.7 21.9–91.2 <0.001 7.6 2.3–24.9 0.001 2.03±0.60
Treatment
 5-ASA 0.9 0.4–1.8 0.734
 Corticosteroid + IM 1.0 0.6–1.8 0.945
 Biologics (+IM) 0.9 0.5–1.6 0.832
CRP at diagnosis (pathological vs normal) 1.0 0.9–1.0 0.610
ESR at diagnosis (pathological vs normal) 1.0 0.9–1.0 0.783
Alb at diagnosis (pathological vs normal) 1.0 0.9–1.0 0.703
Alb = Albumin; 5-ASA = 5-aminosalicylic acid; β = estimated regression coefficient; CRP = C-reactive protein; EIM = extraintestinal manifestations; ESR = erythrocyte sedimentation rate; IM = immunosuppressants; SE = standard error.
aAdjusted data for age as per 10-year increase in age.

where prognostic index

( = disease duration (year); = age (year, adjusted for age as per 10-year increase in age); = perianal disease (0: no, 1: yes); = previous surgery (0: no, 1: yes); = extraintestinal manifestations (0: no, 1: yes)).

This model showed an ideal receiver operating characteristic curve, and the calculated AUC was 0.97. A relatively high specificity (88.3%) and sensitivity (96.6%) confirmed the efficiency of the predictive and distinguishable ability of the model. The variance inflation factor of each risk factor in our model ranged from 1 to 3, which verified that there were no high correlations among the groups. This prognostic model was then applied to our testing cohort. Table 2 and Figure 1 showed the comparison of parameters in both the training and testing cohort. Calibration analysis showed that the predicted risks of complications of this model closely agreed with the actual risks (Fig. 2).

F1
FIGURE 1.:
Receiver operating characteristic curves in training and testing cohort. A, Predictive ability of this model was appraised with an area under the curve of 0.965, sensitivity of 96.6%, and specificity of 88.3%. B, Discrimination of the validated model was estimated with an area under the curve of 0.933, sensitivity of 92.0%, and specificity of 90.5%. NPV = negative predictive value; PPV = positive predictive value; ROC = receiver operating characteristic.
F2
FIGURE 2.:
The Hosmer-Lemeshow goodness-of-fit test (p = 1) demonstrated a good fit for the final multivariable logistic regression model.

Nomogram Establishment

Nomogram is a user-friendly prognostic device widely used as a tool to aid clinical decision making.11,18 In our study, a prognostic nomogram integrating all significant independent factors from our multivariable logistic regression analysis was created (Fig. 3). The points for each of the parameters were summed and vertically matched with the risk of complications leading to surgery within 1 year after diagnosis.

F3
FIGURE 3.:
A prognostic nomogram for risk of complications leading to surgery within 1 year after diagnosis in patients with Crohn’s disease. The nomogram consisted of 6 significant risk factors. Each factor was associated with the number of points. After summing up the points from each factor, we came up to a total point score, which corresponds to the risk of 1-year complications leading to surgery. EIM = extraintestinal manifestations.

DISCUSSION

In our research, we identified age, perianal disease at diagnosis, disease duration, previous surgery, and extraintestinal manifestations as significant independent factors associated with complications leading to surgery 1 year after a diagnosis of nonstricturing and nonpenetrating CD. A validated prognostic model can precisely predict negative outcomes and is the cornerstone in preventive and tailored therapeutics, especially for CD because of its complexity. This model was based solely on clinical and demographic variables, making it easily and broadly applicable to the real-world setting.

Stenosis and perforation are common complications of CD associated with surgical intervention. Approximately 5% of patients with CD experience GI bleeding in their lifetimes.19 More than 80% of bleeding episodes resolve spontaneously or after medical therapies, whereas a small proportion become life-threatening hemorrhages manifested by hemodynamic instability and hemorrhagic shock, and ultimately require salvage surgery.20 According to a Mayo Clinic series,21 as many as 39% of patients with GI bleeding required surgery because of the difficulties in localization and poor response to medical treatments. Severe GI bleeding is an indication for surgery and should not be ignored, despite its rarity. Therefore, we included severe GI bleeding with a Glasgow-Blatchford score of >6 as a complication leading to surgery in our study design to predict aggressive CD comprehensively.

Pediatric-onset CD shows more aggressive disease behavior than does adult-onset CD.22 Older patients with CD have significantly less perianal and penetrating diseases and a lower necessity for surgery due to its milder disease phenotype than do younger patients with CD.23 In this study, we found that age was negatively correlated with aggressive CD, consistent with the results from previous studies.22,23

Gastrointestinal inflammation continues to progress before obvious clinical manifestations emerge in CD,24 which contributes to the more severe bowel damage in disease of longer duration. According to the “treat to target” strategy,25 physicians achieve not only clinical remission, but also mucosal,26 radiological,27,28 and histological healing,29,30 to block the progression of inflammation. The landmark SONIC trial,31 stratified by disease duration, associated a shorter disease duration with higher efficacy in achieving therapeutic goals. Similar findings have been obtained with vedolizumab treatment in patients with CD.32 We found that longer disease duration was associated with a higher risk of complications leading to surgery, which can be attributed to the exacerbation of inflammation as duration prolongs.

Perianal diseases, including perianal fistulas and abscesses, are present in up to 25% of patients with CD worldwide, and are increasing in incidence and disease duration.33,34 Peyrin-Biroulet et al35 developed an IBD disability index in 2012 without taking perianal disease into account; hence, this index is limited in its applications for guiding clinical decision making. In our prognostic model, perianal disease at initial diagnosis was considered a risk factor, which predicted a worse disease course and early occurrence of complications.

Disease severity is suspected to closely correlate with the development of extraintestinal manifestations at initial diagnosis, especially in pediatric patients with CD.36 Data from the PediIBD Consortium Registry showed that the cumulative incidence of extraintestinal manifestations was 9% at 1 year, 19% at 5 years, and 29% at 15 years after diagnosis.37 With only 12.9% patients aged <16 years in our study cohort, 15.5% patients had extraintestinal manifestations at diagnosis with an average disease course of 1.28 years, illustrating that the relationship of extraintestinal manifestations with the course of CD must not be ignored. As for young age38,39 and previous surgery,40,41 the reported independent factors that predicted disabling CD were integrated in our prognostic model to improve its predictive ability.

We found that treatments exerted little influence on disease progression. Likely explanations are as follows: the treatments we observed in this study included 5-ASA, glucocorticoids, immunosuppressants, and biologics. As therapeutic strategies evolve, new agents have emerged that provide better clinical responses. Treatments administrated in our study focused on achieving symptomatic remission, which is insufficient for ameliorating underlying inflammation, preventing disease progression to complications, or lowering surgery risk. Moreover, we could not exclude potential selection bias by the gastroenterologists involved in this retrospective study. These reasons likely explain why we found no associations between treatments and disease progression, especially without the effective prediction of the aggressive phenotype of CD. The model we established can help distinguish aggressive CD at high risk of developing complications leading to surgery. We expect this to aid physicians in treatment adjustment and disease monitoring in a prophylactic fashion. More importantly, intensive therapeutic strategies for patients at a high risk of early-onset complications might enhance their quality of life, lower surgery rates, or even influence the natural course of CD. Further prospective clinical trials are warranted to verify the effects of therapeutics on early-onset complications.

Our study’s limitations included its retrospective design and relatively small participant size from a single tertiary referral center. Nevertheless, we have limited these drawbacks and strengthened our study by including a relatively long follow-up period and precise definitions of each parameter before initiating the study. The patients were followed up by regular physicians with complete data collection, and the nomogram facilitated clinical practice. To our knowledge, this was the first prognostic model to integrate several factors, including extraintestinal manifestations and disease duration, to predict complications leading to surgery in patients with CD. Undoubtedly, prospective studies with a broader population base are needed to validate our findings.

CONCLUSION

In this study, we identified age, extraintestinal manifestations, previous surgery, perianal disease, and disease duration as independent factors associated with complications leading to surgery in patients with CD. We have developed a prognostic model and a nomogram to aid in personalized clinical decision making.

ACKNOWLEDGMENTS

The authors thank Professor Xiaoming He from the Department of Nutrition Sciences, University of Alabama at Birmingham for her assistance in improving the language, and they thank Professors Jinxin Zhang and Zhuochen Lin from the Department of Medical Statistics, University of Sun Yat-Sen University for their assistance in statistical analysis.

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Keywords:

Crohn’s disease; Prognostic model; Nomogram; Complication; Retrospective study

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