Introduction

Intestinal ultrasound (IUS) is accurate and non-invasive to detect and monitor disease activity in Crohn’s disease (CD). The Bowel Ultrasound Score [BUSS= 0.75 × bowel wall thickness (BWT) + 1.65 × presence (1) or absence (0) of color Doppler signals (CDS)] demonstrated high accuracy in detecting therapy-related changes, and good correlation with the Simple Endoscopic Score for CD (SES-CD)[1]. The most accurate cutoff value for BUSS was 3.52 for endoscopic remission (SES-CD ≤ 2) [2].

Aims & Methods

This study aimed to prospectively evaluate ultrasound remission as a relevant treatment target.
Consecutive patients with active CD (SES-CD > 2) starting biologic treatments were included. Patients underwent colonoscopy and IUS at baseline and after 1 year of treatment. Clinical, biochemical and ultrasound assessments were additionaly performed at week 12. Primary outcome was to evaluate whether ultrasound remission at week 12 could predict endoscopic remission at week 54. Endoscopic remission was defined as SES-CD ≤ 2, ultrasound remission was defined by BUSS < 3.52, clinical remission was defined by HBI (Harvey-Bradshaw Index) < 5, and biochemical remission was defined by normalization of C-reactive protein (< 5 mg/L) and fecal calprotectin (three different thresholds were assessed: < 250 µg/g, < 100 µg/g, < 50 µg/g).
The International Bowel Ultrasound Segmental Activity Score [IBUS-SAS= 4 x BWT + 15 x inflammatory mesenteric fat (i-fat) + 7 x CDS + 4 x bowel wall stratification (BWS)] [3] was calculated and the best cut-off to detect endoscopic remission was identified through ROC analysis.

Results

Ninety-three patients were included (8 under infliximab, 40 under adalimumab, 5 under vedolizumab and 40 under ustekinumab). Twenty-two patients (24%) and twenty-nine patients (31%) achieved endoscopic remission and ultrasound remission at week 54, respectively. CD patients with ultrasound remission at week 12 were more likely to achieve endoscopic remission (odds ratio [OR] 9.93 [3.10–31.80]; p < 0.001) and ultrasound remission (OR 7.27 [2.28–23.14]; p < 0.001) at week 54. Calprotectin value < 50 and < 100 µg/g at week 12 predicted endoscopic remission at univariable (OR 3.58 [1.25–10.24], p = 0.017; OR 3.77 [1.21­11.70], p = 0.021), but not at multivariable analysis. Ultrasound remission at week 12 had a NPV of 87 % for detecting endoscopic remission at week 54. A BUSS decrease of at least 1.2 points has a NPV of 94% for detecting endoscopic remission at week 54. The most accurate cutoff value for IBUS-SAS was 22.8 mm (AUC 0.906) for endoscopic remission. The comparison of the ROC curves regarding BUSS and IBUS-SAS showed no significant differences between the two scores (p = 0.46). Conversely BUSS was superior to BWT (AUC 0.918 vs 0.885, p = 0.007).

Conclusion

Early ultrasound remission predicts long-term endoscopic remission and may be an early treatment target in both clinical practice and clinical trials. Treat-to-target strategy studies with IUS are warranted.

References

1 Allocca M, Craviotto V, Bonovas S, et al. Predictive Value of Bowel Ultrasound in Crohn’s Disease: A 12-Month Prospective Study. Clin Gastroenterol Hepatol Published Online First: 2021. doi:10.1016/J.CGH.2021.04.029
2 Allocca M, Craviotto V, Dell’Avalle C, et al. Bowel ultrasound score is accurate in assessing response to therapy in patients with Crohn’s disease. Aliment Pharmacol Ther Published Online First: 15 November 2021. doi:10.1111/APT.16700
3 Novak KL, Nylund K, Maaser C, et al. Expert Consensus on Optimal Acquisition and Development of the International Bowel Ultrasound Segmental Activity Score [IBUS-SAS]: A Reliability and Inter-rater Variability Study on Intestinal Ultrasonography in Crohn’s Disease. J Crohn’s Colitis 2021;15:609–16. doi:10.1093/ecco-jcc/jjaa216

Disclosure

No conflicts of interest to disclose associated with this study

Introduction

Despite the increase in the therapeutic armamentarium of the treatment of Crohn’s disease (CD), historically less than 50% of patients achieve partial response after induction, and less than 20% achieve clinical remission. It remains unknown how response to biologic induction therapy influences disease behavior, treatment patterns, and health-care utilization in those patients who are maintained on biologic therapy for the treatment of their CD.

Aims & Methods

Aims: To determine the impact of achieving clinical remission after induction therapy for CD on post-induction outcomes.
Methods: A retrospective chart review of all persons with CD, age 18 or above, followed at Mount Sinai Hospital, Canada who were dispensed an approved biologic therapy for IBD between April 1^st, 1996, and June 30^th, 2021, and completed a complete course of induction was conducted. We stratified patients into those were in clinical remission as per the physician global assessment at completion of biologic induction (“remitters”) and those who were not (“non-remitters”). The start of follow-up was the completion date of biologic induction and patients were followed until end of last follow-up date. We extracted data on IBD symptoms, decisions on biologic therapy (such as discontinuation), healthcare utilization such as hospitalizations and emergency department (ED) visits, need for CD surgery, and endoscopic assessments. Endoscopic remission was defined based on a SES-CD score of £ 4 when available, or on the endoscopists’ impression of absence of mucosal inflammation.

Results

A total of 160 patients were eligible for data extraction; 60.0% were male, 35.6% and 25.0% had stricturing and penetrating complications respectively, 28.9% had perianal disease and 34.3% had a history of a CD surgery. The index biologic included Infliximab in 24.4% patients, adalimumab in 32.5% patients, vedolizumab in 25.0% patients, and ustekinumab in 11.9% patients. Fifty-five (34.4%) patients were remitters and 105 (65.6%) were non-remitters after completion of biologic induction. Those in clinical remission at induction were less likely to have upper gastrointestinal CD (3.6% vs. 10.5%), have penetrating complications (18.2% vs. 28.6%), and perianal disease (16.4% vs. 35.2%) at time of biologic start. Remitters were more likely to be in sustained clinical remission throughout follow-up compared to non-remitters (47.2% vs. 27.6%, p=0.01), be in clinical remission at last follow-up date (87.2% vs. 69.5%, p=0.04), and appeared to have a lower likelihood of discontinuing the index biologic (7.2% vs. 16.1%, p=0.06). Similarly, remitters were less likely to undergo a CD-related intestinal resection during follow-up (3.6% vs. 13.3%, p=0.05). There appeared to be no significant differences between remitters and non-remitters in proportion of patients being hospitalized for IBD (10.9% vs. 19.0%, p=0.14) or non-IBD (5.4% vs. 7.6%, p=0.62) reasons and visiting the emergency department (7.2% vs. 13.3% p=0.26). Of the 160 patients, 117 (73.1%) underwent a colonoscopy or sigmoidoscopy during follow-up. There were no differences in the rates of ulcer persistence (51.6% vs. 53.5%, p=0.63) or achievement of endoscopic remission (58.9% vs. 48.7%, p=0.76) between remitters and non-remitters at induction.

Conclusion

Achieving clinical remission after biologic induction is associated with sustained clinical remission in follow-up but not endoscopic remission.

Introduction

Accurate and timely endoscopic evaluation is critical for the management of postoperative Crohn’s disease (CD). Although numerous established and novel indices exist, their relative operating properties and the optimal instrument for routine use in clinical and research settings are unknown.

Aims & Methods

We characterised the reliability and responsiveness of both historical and novel endoscopic indices using centrally assessed ileocolonoscopy videos from a randomised controlled trial comparing infliximab versus placebo for preventing postoperative CD (PREVENT; NCT01190839). Three blinded central readers independently assessed 70 videos from the PREVENT trial using the Rutgeerts and modified Rutgeerts scores, POCER index, REMIND score, Simple Endoscopic Score for CD (SES-CD), and the CD Endoscopic Index of Severity (CDEIS). Indices were scored separately for the neoterminal ileum, the anastomosis (including the blind loop of a side-to-side anastomosis), and the distal colonic segment. Intra- and inter-rater reliability was quantified using the intraclass correlation coefficient (ICC) and was interpreted using the Landis and Koch benchmarks.¹ Responsiveness was quantified using the win probability (WinP), defined as the probability of a patient receiving infliximab having a better endoscopic score than a patient receiving placebo, and interpreted using Cohen’s benchmarks.²

Results

Inter-rater reliability was substantial for the Rutgeerts (ICC 0.74 [95% CI: 0.62-0.83]) and modified Rutgeerts scores (0.79 [0.68-0.86]), ileal REMIND score (0.79 [0.67-0.87]), SES‑CD (0.79 [0.70-0.86]), and CDEIS (0.80 [0.72-0.86]). Inter-rater reliability was moderate for the POCER index (ICC 0.49 [0.26-0.64]) and fair for the anastomotic REMIND score (0.30 [0.14-0.47]). Intra-rater reliability was almost perfect for all indices (ICC≥0.81) (Table 1). The Rutgeerts (WinP 0.77 [95% CI: 0.65-0.86]) and modified Rutgeerts scores (WinP 0.81 [0.69-0.89]), ileal REMIND score (WinP 0.83 [0.72-0.91]), SES-CD (WinP 0.80 [0.66-0.89]), and CDEIS (WinP 0.75 [0.61-0.86]) demonstrated a large degree of responsiveness when treatment assignment was the criterion for change. The POCER index (WinP 0.54 [0.43-0.65]) and the anastomotic REMIND score (WinP 0.53 [0.42-0.64]) had a small degree of responsiveness. The reliability and responsiveness of all indices were consistently lower when assessed at the anastomosis or distal colon compared to the neoterminal ileum.

Table 1. Reliability and responsiveness of endoscopic scores

Conclusion

Existing endoscopic indices are reliable and responsive for assessing postoperative CD activity in the neoterminal ileum but are suboptimal for assessing the anastomosis or distal colon.

References

1. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33 (1):159-174.
2. Zou G, Zou L, Qiu SF. Parametric and nonparametric methods for confidence intervals and sample size planning for win probability in parallel-group randomized trials with Likert item and Likert scale data. Pharm Stat 2023; 22 (3):418-439.

Disclosure

JH reports consulting fees from Abbvie,Alimentiv Inc,Eli Lilly,Janssen,and Takeda.
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Introduction

Tobacco smoke is an established risk factor for Crohn’s disease (CD) postoperative recurrence (POR), however, the effect of e-cigarettes and heat-not-burn tobacco (HNBT) remains unknown. We aimed to evaluate the impact of e-cigarettes and HNBT on postoperative recurrence in CD patients.

Aims & Methods

We retrospectively included consecutive CD patients who underwent ileocolic resection and endoscopic evaluation between 6 and 12 months after surgery across 9 centers in Italy, Spain, and France. Based on smoking habits between surgery and endoscopy, patients were categorized as non-smokers, cigarette smokers, HNBT users, or e-cigarette users. To avoid confounding, the use of HNBT and e-cigarettes was confirmed by phone call, and patients smoking multiple products were excluded.
The primary outcome was endoscopic recurrence (Rutgeerts score ≥2) within the first year. Secondary analyses were conducted on the population receiving prophylactic treatment, using the modified Rutgeerts score (≥i2b), the mean Rutgeerts score, transmural disease activity, fecal calprotectin, time from diagnosis to surgery, and multivariable regression analysis.

Results

In total, 1157 patients were included, of which 860 (75%) were non-smokers, 220 (19%) conventional cigarette smokers, 37 (3%) HNBT users, and 33 (3%) e-cigarette users. Groups were homogeneous for most clinical and demographic variables, including a history of intestinal surgery for CD, use of biologics in the 12 months before surgery, and prescription of POR prophylaxis, but not age. HNBT users were younger than other groups.
Recurrence rates were significantly higher in all smoking groups compared to non-smokers: 70%, 69%, and 68% for e-cigarette, HNBT, and cigarette users, respectively, vs. 39% for non-smokers; all p<0.01. The association persisted in patients receiving pharmacological prophylaxis, with 75%, 69%, 70%, and 40% recurrence for the same groups, and all comparisons remaining significant (all p<0.005).
Using the modified Rutgeerts score cutoff of i2b to define POR overall rates decreased, with 57% recurrence for e-cigarette and HNBT users, 54% for conventional cigarette smokers, and 29% for non-smokers. However, the relative proportions remained consistent, and the differences between groups did not change.
When analyzing the Rutgeerts score as a continuous variable, traditional cigarette smoking, HNBT use, and e-cigarette use remained associated with significantly greater endoscopic disease activity compared to non-smokers (2.02, 2.09, and 1.7,4 respectively, vs. 1.12; all p<0.05). Interestingly, the mean Rutgeerts score among e-cigarette users was numerically lower than that of conventional tobacco cigarettes and HNBT, although the difference was not statistically significant (1.74 vs. 2.02 and 2.09, respectively, both p>0.05). When restricting the analysis to patients receiving prophylactic biologics, differences persisted (p<0.05).
The average fecal calprotectin levels and imaging assessments confirmed the trends observed in endoscopy. The mean calprotectin levels at the time of endoscopy were 221 μ/g, 206 μ/g and 174 μ/g for tobacco, HNBT, and e-cigarettes, respectively, vs. 124 μ/g in non-smokers. Rates of transmural remission were 35%, 48%, 56%, and 61% for the same groups, respectively. Nevertheless, in calprotectin and radiologic analyses, only the differences between conventional smokers and non-smokers reached statistical significance (p<0.05), possibly due to the limited availability of these data and the wide variability of calprotectin levels.
After accounting for potential confounders such as sex, location and behavior of disease at diagnosis, disease duration, type of anastomosis, and previous intestinal resections, all smoking groups remained significantly associated with an increased risk of endoscopic recurrence compared to nonsmokers, e-cigarette (OR 3.06, 95% CI 1.08-9.57, p=0.041), and HNBT (OR 4.47, 95% CI 2.00-10.77, p<0.001), and conventional tobacco (OR 4.66, 95% CI 3.07-7.20, p<0.001).
Finally, we compared disease duration at the time of surgery. Compared to those who never smoked, patients who smoked traditional cigarettes and used HNBT had a significantly shorter disease duration at the time of intervention (7.2 and 5.2 years vs 9.0; p=0.029 and p=0.046, respectively), suggestive of a more aggressive disease course. Instead, the difference with e-cigarettes was not significant (7.5 years vs 9.0, p=0.76).

Conclusion

E-cigarettes and heat-not-burn tobacco are associated with increased endoscopic recurrence of CD compared to non-smoking.

Introduction

Therapeutic goals and clinical guidelines in Crohn’s disease (CD) have evolved to include endoscopic outcomes being a key prognostic parameter in disease management. STRIDE-II guidelines comprise of clinical and patient-reported outcome remission, along with biomarker normalization and endoscopic healing. While available publications have correlated achievement of endoscopic response with long-term outcomes, few if any have adjusted for clinical remission status. Moreover, most of the data comes from patients treated with immunomodulators and/or TNFs. The objective of this analysis was to assess the impact of endoscopic response at the end of maintenance and long-term outcomes while adjusting for clinical remission status at maintenance.

Aims & Methods

Data from two randomized clinical trials (GALAXI-1, NCT03466411 and IM-UNITI, NCT01369355) were pooled to assess the impact of endoscopic response at 1 year on long-term patient relevant outcomes including clinical response, clinical remission, quality of life as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ), and risk for hospitalizations/surgeries. This post-hoc analysis assessed endoscopic response at the end of maintenance (~48 weeks) and patient relevant outcomes in the long-term extension (LTE) duration (~96 weeks). Patients without LTE outcome data and placebo treated patients were excluded. Multivariate analyses with trial as a random effect were conducted and adjusted for treatment arm during maintenance, clinical remission status at end of maintenance (EOM), and endoscopic response at EOM.

Results

A total of 461 patients had available endoscopy and clinical remission status at EOM (IM-UNITI, N=177; GALAXI-1, N=284). The number of patients with available LTE outcomes ranged from 290 (IBDQ remission) to 383 (clinical remission/clinical response). Endoscopic response at EOM was significantly associated with higher odds of LTE clinical remission and IBDQ remission with ORs of 1.91 and 1.99 respectively, with corresponding p values below 0.05. Endoscopic response at EOM was also associated with lower odds of LTE C-reactive Protein abnormality (OR=0.46, p<0.005), a marker of inflammation and disease activity. Lastly, a greater percentage of patients without endoscopic response at EOM experienced hospitalizations/surgeries though the difference was not significant due to low event counts (16% versus 9%, p=0.1237).

Conclusion

This analysis uses clinical data from robust trials and adjusted for patients’ clinical remission status at the end of maintenance to isolate the benefit of endoscopic response in predicting long-term outcomes. Endoscopic response is significantly associated with more patients reaching clinical remission and better quality of life. Further investigation in large datasets with longer follow-up is needed to better understand whether measures of endoscopic improvement are also good surrogates for reductions in hospitalizations and surgeries.

Disclosure

Janssen Global Services provided funding for this research and I am an employee of Janssen

Introduction

Endoscopic postoperative recurrence (POR) of Crohn's disease (CD) occurs in up to 70% of patients within the first 12 months after ileocecal resection (ICR) with anastomosis if no prophylactic therapy is started. Early postoperative prophylaxis with thiopurines or anti-TNF agents may lower this number to 30-50%. However, scarce data on POR are available in the long-term.

Aims & Methods

To evaluate the long-term outcomes of patients without endoscopic POR at the first endoscopic assessment.
We performed a retrospective, observational study including consecutive CD patients undergoing ICR with anastomosis at four European referral centres since 1998. All patients underwent a first endoscopic assessment within 18 months from ICR demonstrating no endoscopic POR (Rutgeerts score i0-i1), and had a clinical follow-up ³24 months including at least one further endoscopic assessment. Main outcomes were endoscopic (Rutgeerts >i1), clinical (development of digestive symptoms together with a disease recurrence seen at endoscopic or radiological examination that prompted changes in the treatment) and surgical (new intestinal resection) POR, need for rescue therapy and “delayed POR” (any need for rescue therapy or clinical or surgical POR) during follow-up.

Results

One-hundred eighty-five patients were included (133 Rutgeerts i0, 52 Rutgeerts i1), of whom 88 (48%) started thiopurines or 17 anti-TNF (9%) early after surgery and 80 (43%) patients did not start any prophylactic therapy. No clinical risk factors for POR were present in 38%, whereas 27% met ³1 (active smoking, penetrating disease, perianal disease and/or previous ICR). By the last endoscopic assessment that was performed a median (IQR) of 58 (24-133) months after the first one, endoscopic POR was observed in 39% (17% i3-i4). Cumulative probability of remaining free of endoscopic POR in the total cohort was 97% at 1 year, 68% at 5 years and 61% at 10 years, from the index colonoscopy. During a median follow-up of 104 (IQR, 55-196) months, 30% of the patients developed clinical POR and 31% required rescue treatment (thiopurines in 14 patients, biological therapies in 43 and dose-escalation in 1). Cumulative probability of remaining free of clinical POR for the total cohort was 97.5% at one year, 81.8% at 5 years and 72.1% at 10 years. Finally, 5% of the patients had surgical POR at the end of follow-up.
In multivariate analysis, no risk factors were observed for endoscopic, severe endoscopic and surgical POR. However, early prophylactic treatment was protective for clinical POR (OR 0.54 [95%CI 0.32-0.96]; p=0.026) and need for rescue therapy (OR 0.43 [95%CI 0.23-0.79]; p=0.007), whereas a Rutgeerts score i0 at index ileocolonoscopy was the only factor that prevented from “delayed POR” (OR 2.00 [95%CI 1.18-3.31]; p=0.009).

Conclusion

Most patients without endoscopic POR after ICR will remain free of endoscopic and clinical POR in the long-term, although the risk steadily increases over time. Moreover, early postoperative prophylactic therapy seems to prevent the long-term risk of clinical POR and reduces the need for rescue therapies. Therefore, periodical non-invasive monitoring seems a suitable strategy for patients without endoscopic POR at the first postoperative endoscopic assessment, particularly if early prophylaxis was started or no endoscopic lesions (i0) were observed at index ileocolonoscopy.