Abstract
Background
Patients with Crohn's disease (CD) are at risk of progressing from inflammatory to stricturing and penetrating phenotypes. The influence of the depth of remission on the risk of progression has not been adequately evaluated.
Methods
A retrospective cohort study including surgically naïve CD patients with inflammatory phenotype evaluated concomitantly by magnetic resonance enterography and colonoscopy. The degree of remission was correlated with the risk of progressing to stricturing and penetrating phenotypes.
Results
Three hundred nineteen CD patients were included: 27.0% with transmural remission, 16.0% with isolated endoscopic remission, 14.4% with isolated radiologic remission, and 42.6% without remission. Patients with transmural remission presented the lowest rates of phenotype progression (1.2%), with a significant difference compared to isolated radiologic remission (10.9%, p = 0.019), to isolated endoscopic remission (19.6%, p ≤ 0.001), and to no remission (46.3%, p ≤ 0.001). In multivariate regression analysis, transmural remission (OR 0.017 95% CI 0.002–0.135, p < 0.001), isolated radiologic remission (OR 0.139 95% CI 0.049–0.396, p < 0.001), and isolated endoscopic remission (OR 0.301 95% CI 0.123–0.736, p = 0.008) resulted in lower rates of phenotype progression compared to no remission. No patient with transmural or isolated radiologic remission progressed to penetrating phenotypes.
Conclusion
The degree of bowel remission correlates with the risk of phenotype progression. Patients with transmural remission are at the lowest risk of progressing to stricturing and penetrating phenotypes.
Keywords: Crohn, deep remission, endoscopy, IBD, inflammatory bowel disease, MRE, mucosal healing, transmural healing
Key summary.
What is already known?
Transmural remission is associated with improved clinical outcomes compared to isolated endoscopic remission, isolated radiologic remission, and no remission.
What is new here?
Endoscopic and radiological activity predicts the risk of progressing to stricturing and penetrating disease.
Transmural remission results in lower rates of phenotype progression compared to other types of remission.
Obtaining either endoscopic or radiologic remission decreases the risk of phenotype progression.
INTRODUCTION
Crohn's disease (CD) is a chronic immune‐mediated condition characterized by alternating phases of remission and active disease. Unfortunately, a significant percentage of patients will develop complications over time, such as strictures, fistulas, and abscesses, which significantly increase the risk of surgery. 1 , 2 , 3 Current treatment strategies have focused on delaying disease progression by controlling endoscopic inflammation. This is based on extensive evidence associating endoscopic remission with a lower risk of clinical relapse, steroid use, hospitalization, and surgery. 4 Unfortunately, disease progression may still occur despite endoscopic remission. In a sub‐study of the TAILORIX trial, disease progression, defined by the need of perianal or abdominal surgery, CD‐related hospitalization, or treatment change occurred similarly in patients with and without steroid‐free clinical and endoscopic remission. 5 Recent studies have highlighted the potential benefits of combined endoscopic and radiologic remission. 6 , 7 , 8 , 9 , 10 In a multicenter retrospective cohort study, transmural remission evaluated by colonoscopy and magnetic resonance enterography (MRE) was associated with lower rates of surgery, hospitalization, treatment escalation, and steroid use compared to no remission and to isolated endoscopic or radiologic remission. 7 However, it is unknown if obtaining both endoscopic and radiologic remission may delay the progression to stricturing and penetrating disease. In the present study, we aim to compare the long‐term risk of phenotype progression in patients with CD according to the degree of endoscopic and radiologic activity at baseline.
MATERIAL AND METHODS
Study design and patients
In this single center cohort study, patients with an established diagnosis of CD were included if they met the following criteria: no previous CD related surgery, ileal or ileocolonic disease location, and inflammatory phenotype at baseline confirmed by concurrent (≤3 months) colonoscopy and MRE. Patients with isolated colonic disease location, stricturing and/or penetrating complications at baseline, with inaccessible small bowel by colonoscopy, or with inadequate colonoscopy (e.g., poor bowel preparation) or MRE (eg. insufficient luminal distention) were excluded. The most proximal extent of small bowel inflammation was defined by MRE. Patients unable to reach those segments by colonoscopy (or by a complementary method such as capsule endoscopy or balloon enteroscopy) and without other signs of disease activity were also excluded. The recruitment period ranged from January 2005 to December 2022. Clinical data were retrieved from a local prospectively maintained database and included demographics, disease characteristics, disease course, past treatments, and endoscopic and radiological reports. The study selection criteria are presented in Figure S1. The study was approved by our local Ethics Committee (231/20).
Colonoscopy and MRE
Colonoscopies were performed by experienced endoscopists or by supervised residents. MREs were performed and read by experienced radiologists using a standard protocol including 4–6 h fasting, luminal distention with 1.5–2 L of a water and mannitol solution (2.5%), and intravenous hyoscine to reduce peristalsis. Sequences obtained included conventional axial and coronal T1 and T2‐weighted images, T2 fast spin echo with and without fat suppression and post‐contrast fat‐suppressed 3D T1‐weighted breath‐hold gradient eco images with acquisitions at 30, 60, and 90 s in coronal orientation and at 110 s in axial orientation. Considering the different risk of disease progression between colonic and ileal disease, only the small bowel was considered for the evaluation of endoscopic and radiologic activity. 11 Colonoscopies and MRE were classified as active or inactive. An inactive colonoscopy was defined as an absence of mucosal ulcers, excluding aphthous ulcers (<0.5 cm) or erosions, an affected segment <50%, and no evidence of a stricture, corresponding to a SES‐CD ≤3. 12 An inactive MRE was defined as a simplified Maria score (sMaria) ≤1. The sMaria score is a simplified version of the Magnetic Resonance Index of Activity (MaRIA) scoring system that includes four variables: bowel wall thickness >3 mm, bowel wall edema, bowel wall ulcers, and perienteric fat stranding. A sMaria score >1 has been shown to identify segments with active CD with 90% sensitivity and 81% specificity. 13
Progression of phenotype
Disease phenotype was classified according to the Montreal classification. 14 Inflammatory phenotype was defined as an absence of past or current history of stricturing and/or penetrating disease. Stricturing behavior was defined as the occurrence of constant luminal narrowing combined with pre‐stenotic dilatation (>25 mm) using MRE, computed tomography enterography, bowel ultrasound, or small bowel follow‐through. In addition, the stricturing phenotype also included patients with impassible luminal narrowing confirmed by colonoscopy, enteroscopy, patency capsule, capsule endoscopy, or in a surgical specimen. Penetrating disease was defined as the identification of intraabdominal fistulas, abscesses, and/or inflammatory masses using a radiological method or a surgical specimen. Patients were included at the time of the first concomitant evaluation by colonoscopy and MRE (defined as baseline) and followed until the last clinical evaluation. Any changes in phenotype reported by the previously described examinations were recorded. In patients with more than one concomitant assessment by colonoscopy and MRE, the best type of remission was selected as the baseline (eg. transmural remission > isolated radiologic/endoscopic remission > no remission). Patients were followed and managed by their attending physicians according to routine clinical practice. As previously stated, the study procedures are presented in Figure S1.
Time cohorts
As previously stated, we included patients with baseline evaluations performed between January 2005 and December 2022. Considering that the timing of inclusion may have influenced the main outcome, a categorical outcome including different time periods was created: ≤2010, 2011–2015, 2016–2020, and >2020. This variable was included in the logistic regression and cox‐regression analysis.
Study outcomes
The primary objective of this study was to compare the rates of progression from inflammatory to stricturing and penetrating phenotypes between different types of bowel remission. Four potential types of remission were considered: transmural remission, defined as the occurrence of both an inactive colonoscopy and MRE, isolated radiologic remission, including cases with inactive MRE but active colonoscopy, isolated endoscopic remission, defined as an inactive colonoscopy with active MRE, and no remission, including cases with both active endoscopy and MRE.
Statistical analysis
Continuous variables were expressed as median (range) and compared using the Mann‐Whitney U test. Categorical variables were described using frequencies and percentages and compared in pairs using the chi‐square test.
Logistic regression and Cox proportional‐hazards regression were used, respectively, to investigate factors associated with the progression and time until progression of the phenotype over the study period. Tested variables included age at evaluation, disease duration, location, presence of upper gastrointestinal disease, presence of perianal disease, sex, smoking status, immunomodulator and biological use, time cohorts, and degree of remission at baseline. Variables with a p value below 0.1 in univariate analysis were used in the multivariate analysis. Results were expressed as odds‐ratio (OR) or hazards‐ratio (HR) with 95% confidence interval (CI). Kaplan‐Meier survival curves were used to evaluate the risk of progressing to stricturing or penetrating phenotypes. The area under the receiver operating characteristics curve (AUC) was used to evaluate the prediction of progression of phenotype using radiologic and endoscopic scores. The significance level was chosen at 0.05. Statistical analysis was performed using IBM Statistical Package for the Social Sciences v26.0.
RESULTS
Baseline characteristics
A total of 319 patients were included in the study, 162 males (50.8%), with a median age of 30.0 years (20.0–43.0), and median disease duration of 1.0 years (0–6.0). Ileal disease was present in 199 (62.4%) patients. Upper gastrointestinal disease location was found in 52 (16.3%) patients, and perianal disease in 68 (21.3%) patients. Only 64 patients (20.0%) were previously exposed to biological therapies. Treatment at baseline included immunomodulators in 96 patients (30.1%) [93 thiopurines, 3 methotrexate] , and biologics in 66 patients (20.7%) [30 infliximab, 26 adalimumab, 6 ustekinumab, 4 vedolizumab]. The median follow‐up was 6.4 years (2.9–9.1). The baseline characteristics of our patients are presented in Table 1.
TABLE 1.
Baseline characteristics of our cohort.
| Total n = 319 | TR n = 86 (27.0) | IER n = 51 (16.0) | IRR n = 46 (14.4) | NR n = 136 (42.6) | |
|---|---|---|---|---|---|
| Age at baseline (years) | 30 (20–43) | 30.5 (21–42) | 35 (26–50) a | 30.5 (20–49) | 26.5 (18−41.5) a |
| Disease duration (years) | 1 (0–6) | 4 (1–9) b , c | 2 (0–9) d , e | 0 (0–3) b , e | 0 (0–3) c , d |
| Male sex (%) | 162 (50.8) | 43 (50.0) | 30 (58.8) | 26 (56.5) | 63 (46.3) |
| Active smoker (%) | 92 (28.8) | 23 (26.7) | 16 (31.4) | 11 (23.9) | 42 (30.9) |
| Disease location | |||||
| Ileal (L1) | 199 (62.4) | 49 (57.0) | 33 (64.7) | 29 (63.0) | 88 (64.7) |
| Ileo‐colonic (L3) | 120 (37.6) | 37 (43.0) | 18 (35.3) | 17 (37.0) | 48 (35.3) |
| Upper GI disease (%) | 52 (16.3) | 12 (14.0) | 6 (11.8) | 8 (17.4) | 26 (19.1) |
| Perianal disease (%) | 68 (21.3) | 17 (19.8) | 12 (23.5) | 7 (15.2) | 32 (23.5) |
| Treatment at baseline | |||||
| Biologic naïve (%) | 255 (79.9) | 51 (59.3) b , c | 37 (72.5) f , g | 44 (95.7) c , f | 123 (90.4) b , g |
| IMM at baseline (%) | 96 (30.1) | 34 (39.5) e , h | 18 (35.3) | 10 (21.7) h | 34 (25.0) e |
| Biologic at baseline (%) | 66 (20.7) | 36 (41.9) b , c | 15 (29.4) f , h | 2 (4.3) c , h | 13 (9.6) b , f |
| Number of biologics at EOF (n) | 1 (0–1) | 1 (0–1) b | 1 (0–1) i | 0 (0–1) c , i | 1 (1–1.5) b , c |
Note: Immunomodulators included azathioprine and methotrexate. Continuous variables are expressed as median (interquartile range). Comparisons with a p ≤ 0.05 are presented.
Abbreviations: EOF, end of follow‐up; GI, gastrointestinal; IER, isolated endoscopic remission; IMM, immunomodulator; IRR, isolated radiologic remission; NR, no remission; TR, transmural remission.
p = 0.004.
p ≤ 0.001.
p < 0.001.
p = 0.006.
p = 0.025.
p = 0.002.
p = 0.001.
p = 0.05.
p = 0.012.
Endoscopic and radiologic activity
The median sMaria score and SES‐CD were 2 (0–3) and 4 (0–5), respectively. This resulted in 187 (58.6%) and 182 patients (57.1%) being classified as having radiologic and endoscopic activity, respectively. According to the degree of remission, 86 patients (27.0%) presented transmural remission, 51 (16.0%) isolated endoscopic remission, 46 (14.4%) isolated radiologic remission, and 136 (42.6%) no remission. As expected, significant differences were found between cohorts with respect to age at baseline, disease duration, previous biological exposure, immunosuppressant use at baseline, and biologics performed over follow‐up. These results are presented in Table 1.
Progression of disease phenotype
Overall, progression of phenotype occurred in 79 patients (24.8%). Seventy‐seven patients (24.1%) progressed to stricturing disease, and 24 patients (7.5%) progressed to penetrating disease. By the end of follow‐up, 84 patients (98.8%) with transmural remission remained with an inflammatory phenotype. Only 1 patient (1.2%) developed stricturing disease. No patient with transmural remission progressed to penetrating disease. Similarly, most patients with isolated radiologic remission (89.1%) remained with an inflammatory phenotype, with only 5 patients (10.9%) developing stricturing disease, and no patient developing penetrating complications. Amongst patients with isolated endoscopic remission, 41 (80.4%) maintained an inflammatory phenotype, 10 (19.6%) and 3 (5.9%) patients developed stricturing and penetrating complications, respectively. Finally, in patients with no remission, 61 (44.9%) and 21 patients (15.4%) progressed to stricturing and penetrating disease, respectively. Only 73 patients (53.7%) remained with an inflammatory phenotype by the end of follow‐up. A detailed presentation of the rates of progression to stricturing and penetrating disease is presented in Figure S2.
FIGURE 2.
Progression of disease phenotype according to the degree of bowel remission at baseline.
Kaplan–Meier survival curves assessing the risk of progressing to stricturing and penetrating disease according to the type of remission at baseline are presented in Figure 1a–d. The overall risk of progression to another phenotype according to the degree of remission at baseline is presented in Figure 2.
FIGURE 1.
Kaplan–Meier estimates of remaining free of penetrating complication (upper curve) and free of stricturing and/or penetrating complication (lower curve) after the baseline assessment in patients with no remission (a), isolated endoscopic remission (b), isolated radiologic remission (c), and transmural remission (d).
Predictors of phenotype progression
The risk of phenotype progression was lowest in patients with transmural remission (1.2%), with a significant difference compared to isolated endoscopic remission (19.6%, p < 0.001), isolated radiologic remission (10.9%, p = 0.019), and no remission (46.3%, p < 0.001). Phenotype progression occurred similarly in patients with isolated radiologic and endoscopic remission (p = 0.272). These results are presented in Figure 3. In multivariate analysis, the type of remission at baseline was independently associated with the risk of phenotype progression. Using no remission as reference, transmural remission (OR 0.017 95% CI 0.002–0.135, p < 0.001), isolated radiologic remission (OR 0.139 95% CI 0.049–0.396, p < 0.001), and isolated endoscopic remission (OR 0.301 95% CI 0.123–0.736, p = 0.008) resulted in significantly lower chances of progressing to a different phenotype. A detailed presentation of the univariate and multivariate analysis 0 is available in Table 2. In cox‐regression analysis, only the degree of remission was independently associated with the time to phenotype progression. Transmural remission (HR 0.025 95% CI 0.003–0.182, p < 0.001), isolated radiologic remission (HR 0.200 95% CI 0.079–0.507, p = 0.001), and isolated endoscopic remission (HR 0.476 95% CI 0.237–0.958, p = 0.038) associated with longer survival without progression, compared to no remission. These results are shown in Table 3. Although patients from earlier time cohorts presented a higher risk of phenotype progression, this did not change the results of the multivariate analysis. The distribution of patients according to time cohorts at the baseline assessment is presented in Figure S3.
FIGURE 3.
Kaplan–Meier estimates of remaining free of progression of phenotype according to the type of remission at baseline.
TABLE 2.
Multivariate analysis for predicting progression of phenotype.
| Predictive factor | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| Odds ratio [95% CI] | p | Odds ratio [95% CI] | p | |
| Demographics and miscellaneous | ||||
| Male versus female sex | 1.234 [0.741–2.053] | 0.419 | ||
| Age at assessment, years | 0.976 [0.959−0.993] | 0.006 | 0.978 [0.957−0.998] | 0.034 |
| Non‐smoker versus active smoker | 0.937 [0.533–1.650] | 0.822 | ||
| Disease duration, years | 0.971 [0.930–1.013] | 0.177 | ||
| Time at risk of progressing, years | 1.154 [1.074−1.239] | <0.001 | 0.900 [0.789–1.026] | 0.116 |
| Time cohort (inclusion) | ||||
| ≤2010 | Reference | |||
| 2011–2015 | 0.248 [0.096–0.642] | 0.004 | 0.310 [0.095–1.005] | 0.051 |
| 2016–2020 | 0.165 [0.063–0.433] | <0.001 | 0.145 [0.034–0.609] | 0.008 |
| >2020 | 0.028 [0.008–0.107] | <0.001 | 0.017 [0.002–0.119] | <0.001 |
| Disease characteristics | ||||
| Ileal versus ileocolonic location | 1.123 [0.867–1.456] | 0.380 | ||
| Upper gastrointestinal disease | 1.286 [0.663–2.494] | 0.457 | ||
| Perianal disease | 1.016 [0.547–1.888] | 0.960 | ||
| Degree of remission | ||||
| No remission | Reference | |||
| Isolated endoscopic remission | 0.283 [0.131−0.610] | 0.001 | 0.301 [0.123−0.736] | 0.008 |
| Isolated radiologic remission | 0.141 [0.053−0.379] | <0.001 | 0.139 [0.049−0.396 | <0.001 |
| Transmural remission | 0.014 [0.002−0.101] | <0.001 | 0.017 [0.002−0.135] | <0.001 |
| Immunossupressive treatment | ||||
| Biologic naïve versus exposed | 0.648 [0.326–1.287] | 0.215 | ||
| Immunomodulator use at baseline | 0.866 [0.493–1.520] | 0.616 | ||
| Biologic use at baseline | 0.476 [0.230−0.986] | 0.046 | 1.067 [0.406–2.802] | 0.895 |
| Starting biologics before progression | 0.751 [0.446–1.262] | 0.279 | ||
| Number of biologics at EOF (n) | 1.630 [1.258−2.111] | <0.001 | 1.127 [0.829–1.531] | 0.446 |
Note: Significant predictors are highlighted in bold. Immunomodulators included azathioprine and methotrexate. Time at risk of progression is defined as the period between the baseline examination and either the development of both stricturing and penetrating complications or the last follow‐up visit.
Abbreviation: EOF, end of follow‐up.
TABLE 3.
Cox‐regression multivariate analysis for predicting the time until progression of phenotype.
| Predictive factor | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| Odds ratio [95% CI] | p | Odds ratio [95% CI] | p | |
| Demographics and miscellaneous | ||||
| Male versus female sex | 1.202 [0.773–1.871] | 0.413 | ||
| Age at assessment, years | 0.981 [0.967−0.996] | 0.014 | 0.989 [0.974–1.005] | 0.176 |
| Non‐smoker versus active smoker | 0.988 [0.604–1.617] | 0.963 | ||
| Disease duration, years | 0.976 [0.939–1.015] | 0.225 | ||
| Time at risk of progressing, years | 1.100 [1.039−1.164] | 0.001 | 0.887 [0.816−0.964] | 0.005 |
| Time cohort (inclusion) | ||||
| ≤2010 | Reference | |||
| 2011–2015 | 0.384 [0.208–0.708] | 0.002 | 0.461 [0.240–0.885] | 0.020 |
| 2016–2020 | 0.304 [0.161–0.575] | <0.001 | 0.270 [0.122–0.597] | 0.001 |
| >2020 | 0.054 [0.018–0.164] | <0.001 | 0.034 [0.009–0.127] | <0.001 |
| Disease characteristics | ||||
| Ileal versus ileocolonic location | 1.082 [0.865–1.353] | 0.488 | ||
| Upper gastrointestinal disease | 1.232 [0.702–2.163] | 0.466 | ||
| Perianal disease | 0.978 [0.572–1.673] | 0.936 | ||
| Degree of remission | ||||
| No remission | Reference | |||
| Isolated endoscopic remission | 0.387 [0.198−0.754] | 0.005 | 0.476 [0.237−0.958] | 0.038 |
| Isolated radiologic remission | 0.189 [0.076−0.469] | <0.001 | 0.200 [0.079−0.507] | 0.001 |
| Transmural remission | 0.019 [0.003−0.137] | <0.001 | 0.025 [0.003−0.182] | <0.001 |
| Immunosupressive treatment | ||||
| Biologic naïve versus exposed | 0.706 [0.382–1.305] | 0.267 | ||
| Immunomodulator use at baseline | 0.883 [0.540–1.444] | 0.620 | ||
| Biologic use at baseline | 0.528 [0.272−1.025] | 0.059 | 1.106 [0.538–2.275] | 0.783 |
| Starting biologics before progression | 0.726 [0.464–1.136] | 0.161 | ||
| Number of biologics at EOF (n) | 1.360 [1.164−1.590] | <0.001 | 1.031 [0.847–1.255] | 0.759 |
Note: Significant predictors are highlighted in bold. Immunomodulators included azathioprine and methotrexate. Time at risk of progression is defined as the period between the baseline examination and either the development of both stricturing and penetrating complications or the last follow‐up visit.
Abbreviation: EOF, end of follow‐up.
Endoscopic and radiologic activity
As expected, a higher risk of phenotype progression was found in patients with evidence of endoscopic (36.8% vs. 8.0%, p < 0.001) and radiologic activity (38.5% vs. 4.5%, p < 0.001). In multivariate analysis, radiologic activity was a stronger predictor of progression (OR 8.844 95% CI 3.477–22.497, p < 0.001) compared to endoscopic activity (OR 3.819 95% CI 1.668–8.744, p = 0.002). Each point increase in the sMaria score doubled the risk of progressing to a complicated phenotype (OR 2.0 95% CI 1.513–2.645, p < 0.001). Results were also significant for each point increase in the SES‐CD (OR 1.432 95% CI 1.190–1.724, p < 0.001). The receiver operating curve for predicting progression of phenotype using the simplified sMaria score and the SES‐CD are presented in Figure S4. Cox‐regression analysis showed a higher influence of radiologic activity (HR 7.061 95% CI 2.974–16.765, p < 0.001) compared to endoscopic activity (HR 2.488 95% CI 1.260–4.912, p = 0.009) in the time until phenotype progressed. These results are presented in Tables S1 and S2.
Benefits of obtaining any degree of remission
A total of 185 patients (58.0%) achieved at least one type of remission (radiologic and/or endoscopic). Progression of phenotype was less likely in these patients compared to patients with no remission (9.2% vs. 45.5%, p ≤ 0.001). These results are presented in Figure S5. Kaplan Meier survival curves are available as Figure S6. In multivariate analysis, obtaining any degree of remission significantly decreased the risk of progressing to another phenotype (OR 0.143 95% CI 0.072–0.282, p < 0.001). Furthermore, it also resulted in longer times until phenotype progression compared to no remission (HR 0.210 95% CI 0.119–0.373, p < 0.001). These results are presented in Tables 3 and 4.
DISCUSSION
Several studies have highlighted the progressive nature of CD. With time, most patients will eventually progress from inflammatory to stricturing and penetrating phenotypes. 1 , 2 In a systematic review, over 50% of patients developed stricturing and penetrating complications within 10 years of follow‐up. Likewise, only 12%–57.3% of patients remained with an inflammatory phenotype during the same period. 14 Unfortunately, worse clinical outcomes have been associated with phenotype progression. In the study by Louis et al, 76.7% of patients developing strictures and/or fistulas required surgery within the following 6 months. 15 In another study using cross‐sectional data from the SPARC IBD (Study of a Prospective Adult Research Cohort with IBD), patients with complicated phenotypes were more likely to present active disease, extraintestinal manifestations, require additional medication, hospitalization, and surgery, compared to patients with inflammatory phenotypes. 16 Several risk factors for disease progression have been reported, including ileal disease location, younger age at diagnosis, upper gastrointestinal involvement, perianal disease, tobacco use, and the number of annual relapses. 15 , 17 , 18 , 19 Unfortunately, only the last two factors are potentially modifiable. Current expert recommendations support early intervention and thorough control of inflammation using potent immunosuppressive medications. 20 However, the evidence that these strategies can modify the natural course of CD is still scarce. In a sub‐study of the CALM trial, deep remission at 48 weeks was associated with an 81% decrease in the risk of adverse outcomes, including new‐onset perianal or intrabdominal fistulas, abscesses, strictures, surgery or hospitalization. 21 In another study, combined endoscopic and radiologic remission were associated with a lower risk of bowel damage progression, defined as the need of surgery or the occurrence of new fistulae, strictures or worsening of pre‐existing strictures. 9 Both studies were limited by short follow‐up (3.02 and 2.43 years, respectively) and did not specifically assess phenotype progression. In the present study, we have demonstrated an association between endoscopic and radiologic activity and the risk of progression to stricturing and penetrating disease. Our study includes a large cohort of surgically naïve CD patients at an inflammatory stage of disease. We have determined that progression to stricturing and penetrating disease was an uncommon event in patients with transmural remission. Simultaneously, isolated endoscopic and radiologic remission also resulted in a substantially lower risk of phenotype progression compared to no remission. In fact, patients with transmural remission presented a 98.3% lower risk of phenotype progression compared with those with no remission. The risk was 86.1%, 69.9% and 85.7% lower for patients with isolated radiologic, isolated endoscopic and any type of remission, respectively. Of note, no patients with transmural and isolated radiologic remission developed penetrating disease. These results are very significant as they highlight that treatment strategies aiming at controlling inflammation have the potential to change the natural course of CD. Indirect evidence has long suggested that immunosuppressive drugs can decrease the risk of progressing to complicated disease. In the study by Magro et al, the use of thiopurines either in monotherapy or in combination with an anti‐TNF was associated with a decreased risk of disease progression. 2 In a large pediatric registry study, patients receiving biologics presented a lower risk of worsening phenotype. 22 On the other hand, the role of early intervention should also be emphasized, not only because immunosuppressive drugs seem to be more effective in early disease, but also because, as previously mentioned, the prevalence of non‐stricturing and non‐penetrating disease is higher at this stage. 14 , 23 , 24 Our study adds to the accumulating evidence supporting transmural remission as a treatment target in CD. To date, transmural remission has been associated with lower rates of steroid use, treatment escalation, hospitalization, surgery, and now lower phenotype progression, with consistent results over 5 years of follow‐up. 6 , 7 , 8 , 9 , 10 Of note, most studies have shown a significant benefit of transmural remission over endoscopic remission. 6 , 7 , 8 , 9 , 10 However, the currently available data is based solely on retrospective studies. Thus, prospective trials are pressingly required to determine whether transmural remission should be favored as an endpoint in routine practice.
Our study represents the first attempt at correlating different degrees of remission with progression of the disease phenotype using a large cohort of CD patients. Nevertheless, we acknowledge some limitations of our study, aside from its retrospective design. As previously stated, some baseline characteristics such as disease duration and baseline treatment differed between groups. This was expected, considering that the best available remission was selected for each patient, making it more likely that patients with any type of remission would be at a later stage of disease compared to patients with no remission. The number of biologics used was also higher in patients with no remission. Again, this was expected considering that these patients were unable to reach a better degree of remission over the follow‐up. We also noted a difference in the risk of disease progression according to the date of inclusion, with earlier patients presenting a higher risk of developing stricturing and penetrating disease. This is understandable considering the improvement in disease management in recent years. Even accounting for these variables, the degree of remission remained an independent predictor of phenotype progression. Another major point was the exclusion of patients with isolated colonic disease and previous bowel surgery. Therefore, no conclusions can be made related to these subgroups. The exclusion of patients with colonic disease was necessary as the overall number of patients was small, and follow‐up radiological examinations were seldom performed. Nevertheless, most studies have suggested that progression of phenotype is less frequent in these patients. 11 , 15 , 17 , 18 , 19 The decision to exclude patients with a previous bowel surgery considered the different nature and progression of post‐surgical CD. As an example, endoscopic recurrence following surgery may be as high as 70% within 6 months and up to 95% within 1 year. 25 , 26 Development of anastomotic strictures is also a common event in operated patients, occurring in up to 50% within 3 years of surgery. 25 In addition, not all lesions arising within the anastomotic margin are necessarily related to disease recurrence. In fact, the role of microvascular injury and ischemia in the development of anastomotic ulcerations has been previously documented. 27 Another aspect is our choice of using the sMaria score to classify radiological activity. Unlike the original Maria score, the sMaria score is less complex and does not require the use of contrast enhancement. Therefore, it may be less subject to changes in MRE image quality and acquisition over time. Nevertheless, cutoffs for radiologic remission/activity have not been adequately validated. Interestingly, the initiation of biologics did not influence the risk of phenotype progression in our study. One potential explanation is that the process of phenotype progression may have already been too advanced and beyond reversal in some patients. On the other hand, we did not account for potential no response to the biologics. The results may have been different if we had restricted our analysis to treatments with objective effectiveness (eg. Improvement or normalization of fecal calprotectin). Unfortunately, this information was not available in all patients. Finally, although we included patients with up to 2 decades of follow‐up, the median follow‐up was considerably lower (6.4 years). This may explain the low rates of phenotype progression compared to other publications. 1 , 2 Still, considering the wide difference in phenotype progression between the different types of remission, it is unlikely that a longer follow‐up would produce different results.
In conclusion, our study demonstrates a clear link between endoscopic and radiological activity and the risk of phenotype progression in CD. Transmural remission provides the best chances of remaining free of complicated disease over time. In those without transmural remission, obtaining either endoscopic or radiologic remission provides significant clinical benefits. Our study further supports the use of transmural remission as a treatment target in CD.
AUTHOR CONTRIBUTIONS
Samuel Raimundo Fernandes was responsible for designing the study, collecting, and analyzing the data, and writing the manuscript. Luís Araújo Correia, Helena Cortez‐Pinto, and Fernando Magro were responsible for designing the study and reviewing the manuscript. Sónia Bernardo, Sofia Saraiva, Ana Rita Gonçalves, Ana Valente and Paula Moura Santos reviewed the manuscript. All authors approved the final version of the article including the authorship list.
CONFLICT OF INTEREST STATEMENT
The authors have no conflicts of interest.
Supporting information
Supporting Information S1
ACKNOWLEDGMENTS
Funding to declare related to the present study.
Fernandes SR, Bernardo S, Saraiva S, Gonçalves AR, Moura Santos P, Valente A, et al. The degree of bowel remission predicts phenotype progression in Crohn's disease. United European Gastroenterol J. 2024;12(7):891–900. 10.1002/ueg2.12581
DATA AVAILABILITY STATEMENT
Data are available upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information S1
Data Availability Statement
Data are available upon reasonable request.