Introduction

Intestinal ultrasound (IUS) is increasingly used to diagnose and monitor Crohn's disease (CD). There has been considerable interest in developing and validating sonographic scores that quantify disease activity, in the hope that more systematic interpretation will improve consistency, aid comparison between consecutive examinations and facilitate treatment response assessment. A range of IUS activity scores have been proposed, including the Simple Ultrasound Score for Crohn’s disease (SUS-CD) and bowel ultrasound score (BUSS), which have both been developed recently using robust methodology, and perform well against colonoscopy.
To date, these promising indices have been derived and initially evaluated in single or dual-centre studies using few, highly specialised sonographers, so their performance characteristics in generalised practice are unknown. Whilst mucosal assessment with endoscopic or histological scoring are frequently used as a reference standard for disease activity, they neglect transmural disease, something that is captured by cross-sectional imaging, such as magnetic resonance enterography (MRE).

Aims & Methods

We compared SUS-CD and BUSS against histological and MRE reference standards in a post-hoc analysis of a prospective multicentre, multireader trial.
Participants recruited to the METRIC trial were studied, including those with available terminal ileal (TI) biopsies. Sensitivity and specificity of SUS-CD and BUSS for TI CD activity were calculated with 95% confidence intervals (CI), from the prospective observations of the original METRIC trial sonographers against the histological activity index (HAI) and the simplified magnetic resonance index of activity (sMARIA).

Results

We included 284 patients (median 31.5 years, IQR 23-46) from 8 centres, who underwent IUS and MRE. Of these, 111 patients had available terminal ileal biopsies with HAI scoring within 4 weeks of IUS. IUS was performed by one of 19 practitioners.
Against histology, sensitivity and specificity for active disease were 79% (95% CI 69-86%) and 50% (31-69%) for SUS-CD, and 66% (56-75%) and 68% (47-84%) for BUSS, respectively. Compared to sMARIA, the sensitivity and specificity for active CD were 81% (74-86%) and 75% (66-83%) for SUS-CD, and 68% (61-74%) and 85% (76-91%) for BUSS, respectively. The sensitivity of SUS-CD was significantly greater than BUSS against HAI and sMARIA (p<0.001), but its specificity was significantly lower than BUSS against the MRE reference standard (p=0.003).

Conclusion

Our study provides real-world evidence that SUS-CD and BUSS are viable IUS indices that are sensitive and specific for active TI CD, especially when compared to an MRE reference standard. More studies like ours in prospective multicentre, multireader settings will facilitate external validation of SUS-CD and BUSS, and establish their suitability for adoption into routine clinical practice.

References

Saevik F, Eriksen R, Eide GE, Gilja OH, Nylund K (2021) Development and Validation of a Simple Ultrasound Activity Score for Crohn's Disease. J Crohns Colitis 15:115-124
Allocca M, Craviotto V, Bonovas S et al (2022) Predictive Value of Bowel Ultrasound in Crohn's Disease: A 12-Month Prospective Study. Clin Gastroenterol Hepatol 20:e723-e740
Allocca M, Fiorino G, Bonifacio C et al (2018) Comparative Accuracy of Bowel Ultrasound Versus Magnetic Resonance Enterography in Combination With Colonoscopy in Assessing Crohn's Disease and Guiding Clinical Decision-making. J Crohns Colitis 12:1280-1287
Taylor SA, Mallett S, Bhatnagar G et al (2018) Diagnostic accuracy of magnetic resonance enterography and small bowel ultrasound for the extent and activity of newly diagnosed and relapsed Crohn's disease (METRIC): a multicentre trial. Lancet Gastroenterol Hepatol 3:548-558

Disclosure

SAT is a shareholder in Motilent Limited.

Introduction

The Phase 2 GALAXI 1 study evaluated the efficacy and safety of guselkumab (GUS), a human selective IL-23p19 subunit antagonist, in patients (pts) with moderate to severe Crohn’s disease (CD). Pts were randomized to GUS, ustekinumab (UST), or placebo (PBO) through Week (Wk) 48 without rerandomization after IV induction. Previously, we reported that pts who were in clinical response after IV induction had higher rates of clinical and endoscopic outcomes at Wk48 than the overall study population.¹ In this post hoc analysis, we report outcomes for pts who did not achieve Wk12 clinical response based on CD activity index (CDAI) after IV induction.

Aims & Methods

Pts were randomized 1:1:1:1:1 to induction with GUS 200, 600, or 1200mg IV, UST ~6mg/kg IV, or PBO IV. At Wk12 (Wk8 for UST), pts were transitioned to maintenance dosing: GUS 200mg IV→100mg subcutaneous (SC) q8w, GUS 600mg IV→200mg SC q4w, GUS 1200mg IV→200mg SC q4w, UST ~6mg/kg IV→90mg SC q8w, PBO nonresponders→UST ~6mg/kg IV→90mg SC q8w, and PBO responders→PBO SC q4w. Clinical response (all time points) was defined as ≥100-point reduction from baseline in CDAI or CDAI <150. Other endpoints included clinical remission (CDAI <150), pt-reported outcome (PRO)-2 remission (unweighted CDAI components of average daily abdominal pain score ≤1 and average daily stool frequency ≤3, and no worsening from baseline), and endoscopic response (≥50% improvement from baseline in simple endoscopic score [SES]-CD or SES-CD ≤2). The study was not powered to evaluate between-group efficacy differences at Wk48; UST was used for reference.

Results

Table. Efficacy Outcomes Among Patients Not in Clinical Responsea at Week 12
Outcome, %b, c	Week	Combined Guselkumab (N=63)	Ustekinumab (N=21)
Clinical responsea	16 / 20 / 24	36.5 / 47.6 / 46.0	42.9 / 52.4 / 52.4
	28 / 32 / 36	47.6 / 54.0 / 50.8	42.9 / 47.6 / 57.1
	40 / 44	54.0 / 52.4	52.4 / 47.6
	48	58.7	47.6
Clinical remissiond	48	41.3	33.3
PRO-2 remissione	48	42.9	23.8
Endoscopic responsef	48	31.7	23.8
AP=abdominal pain; CD=Crohn’s disease; CDAI=Crohn’s disease activity index; PRO-2=Patient-reported CDAI components of abdominal pain and stool frequency; SES-CD=Simple Endoscopic Score for Crohn’s Disease; SF=stool frequency. a Clinical response was defined as ≥100-point reduction from baseline in CDAI or CDAI <150. b Patients who had a prohibited change in concomitant CD medication, a CD-related surgery, or discontinued study agent due to lack of efficacy, or an adverse event of worsening CD prior to the designated analysis timepoint, were considered not to have achieved the endpoint. c Patients who had insufficient data to calculate the outcome measure at the designated analysis timepoint were considered not to have achieved the endpoint. d Clinical remission was defined as a CDAI <150. e PRO-2 remission was defined as unweighted CDAI component of average daily AP pain score ≤1 and the unweighted CDAI component of average daily SF ≤3, and no worsening of AP or SF from baseline. f Endoscopic response was defined as ≥50% improvement from baseline in SES-CD or SES-CD ≤2.

At Wk12, 63/185 (34.1%) GUS pts and 21/63 (33.3%) UST did not achieve CDAI clinical response. Among GUS Wk12 nonresponders, 46.0% were in clinical response by Wk24 (Table). Percentages of Wk12 nonresponders who went on to achieve outcomes at Wk48 in the GUS and UST groups, respectively, were as follows: clinical response, 58.7% and 47.6%; clinical remission, 41.3% and 33.3%; PRO-2 remission, 42.9% and 23.8%; and endoscopic response, 31.7% and 23.8% (Table).

Conclusion

Pts not responding to IV induction with GUS may benefit from continued SC dosing. Among pts who did not achieve clinical response at Wk12, continued treatment with GUS SC resulted in nearly half achieving clinical response at Wk24. At Wk48, a majority achieved clinical response, >40% achieved either clinical remission or PRO-2 remission, and >30% achieved endoscopic response.

References

1. Panés J, et al. UEG Journal 2022; 10 (Suppl 8).

Disclosure

RP reports consulting fees, speaker fees, or research support from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.
AA reports consulting fees from AbbVie, Takeda, Janssen, Bristol Myers Squibb/Celgene, Pfizer, Eli Lilly, Gilead, DiaSorin, and TLL Pharmaceuticals; reports speaker fees from Abbvie, Takeda, Janssen, Bristol Myers Squibb, and Pfizer; has served on advisory boards for Abbvie, Takeda, Janssen, Bristol Myers Squibb, Pfizer, Eli Lilly, and Gilead; has received research/education support from AbbVie, Janssen, Pfizer, Bristol Myers Squibb, and Takeda; and is the co-founder of IBD Horizons.
GRDH served as advisor for Abbvie, Ablynx, Amakem, Amgen, AM Pharma, Avaxia, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Ferring, DrFALK Pharma, Eli Lilly, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo-Smith Kline, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Prometheus laboratories/Nestle, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor; and has received speaker fees from Abbvie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor.
LS, NAT, AS, MEF, and ZY are employees of Janssen Research & Development, LLC and own stock/stock options.
EZ reports receiving research support and consulting fees from Janssen, AbbVie, Takeda, Neopharm, Celgene, and Pfizer.
SD reports receiving consulting fees from Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion Healthcare, Ferring, Gilead Sciences, Hospira, Inc., Janssen Research & Development, LLC, Johnson & Johnson Health Care Systems, Inc., Pfizer, Sandoz, UCB, and Vifor International Inc.
TH has performed joint research with Alfresa Pharma Co. Ltd., and EA Pharma Co. Ltd.; has received grant support from Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Daiichi-Sankyo, Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., and JIMRO Co. Ltd; has received consulting fees from EA Pharma Co. Ltd., AbbVie GK, Celgene K.K., Janssen Pharmaceutical K.K., Pfizer Inc., and Nichi-Iko Pharmaceutical Co., Ltd; and has received lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Pfizer Inc.

Introduction

The risk of postoperative recurrence (POR) within 1 year after ileocecal resection (ICR) for Crohn’s disease (CD) remains high. Currently, there is no consensus on how to optimally reduce the risk of endoscopic (e)POR, clinical (c)POR or surgical (s)POR.

Aims & Methods

The PORCSE study aims to evaluate the impact of two strategies: early medical prophylaxis (proactive strategy) versus treatment driven by findings at elective endoscopy 6-12 months after ICR (reactive strategy).
A retrospective, observational, multicentric, superiority study was performed including CD patients undergoing first ICR between 2008-2019. Patients were assigned to cohort 1 if prophylactic biological or immunomodulator therapy was administered early after ICR, or to cohort 2 if no postoperative prophylaxis was started and medical treatment was driven by endoscopic findings 6-12 months after ICR. The primary endpoint was the rate of ePOR evaluated at ileocolonoscopy 6-12 months post ICR and was defined as Rutgeerts score >i1. Secondary endpoints were colonic disease activity at first endoscopy, severe ePOR (Rutgeerts i3-i4), cPOR (symptoms leading to restart of therapy), sPOR (repeated surgery or endoscopic balloon dilatation) and differences between participating centres.
Statistical analyses were performed with SPSS v28. Propensity score matching was used for regression analyses.

Results

In total 346 patients were included from 26 centres in 9 European countries. Of these, 47.4% received prophylactic postoperative treatment before postoperative endoscopy (cohort 1) and 52.6% did not (cohort 2). Strategy selection differed significantly between countries (P=0.024). The proactive strategy was preferred in Spain and Portugal whereas the reactive strategy in Belgium, France and Ireland. Although not statistically significant (P=0.143), the same trend was noticed in postoperative metronidazole use.
Patients in cohort 1 had more refractory disease with more upper GI disease, more bio-experienced patients, more penetrating disease phenotype and longer disease duration prior to surgery. Furthermore, metronidazole was more frequently started postoperatively in the proactive cohort (31.7%vs14.3%, P<0.001).
Bivariate logistic regression analyses showed significantly higher odds for ePOR in the reactive treatment group (OR 1.809, 95%CI 1.03-3.18, P=0.039). Furthermore, univariate analyses showed higher rates of colonic disease activity in the reactive group at elective endoscopy 6-12 months after surgery. No significant difference in severe ePOR was found at first endoscopy (OR 1.285, 95%CI 0.60-2.74, P=0.517). After first endoscopy until end of follow-up, patients in the reactive group had significantly higher odds of clinical POR (OR 3.047, 95%CI 1.53-6.08, P=0.002). Surgical recurrence rates were numerically higher in the reactive group (OR 2.586, 95%CI 0.995-6.72, P=0.051) and Cox proportional hazards regression analysis showed a trend towards protective effect of the proactive approach (HR 2.497, 95%CI 0.97-6,40, P=0.057).

Table 1: Demographics and POR

Variable	Proactive N=164 (47.4%)	Reactive N=182 (52.6%)	P-value (univariate)	Total (N=346)
Smoking	67 (40.9%)	79 (43.4%)	P=0.057	146 (42.2%)
Montreal classification - +L4 - (p)B3	14 (8.5%) 69 (42.1%)	6 (3.3%) 53 (29.1%)	P=0.037 P=0.012	20 (5.8%) 122 (35.3%)
Preoperative immunomodulator	124 (75.6%)	97 (53.3%)	P<0.001	221 (63.9%)
Preoperative biologic	98 (59.8%)	78 (42.9%)	P=0.001	176 (50.9%)
Biochemical inflammation* and/or steroid use <4 weeks prior to surgery	101 (61.6%)	89 (48.9%)	P=0.018	190 (54.9%)
ePOR (Rutgeerts >i1)	68 (41.5%)	98 (53.8%)	P=0.021	166 (48.0%)
Colonic endoscopic activity	30 (18.3%)	47 (25.8%)	P=0.032	77 (33.5%)
cPOR	29 (17.7%)	65 (35.7%)	P<0.001	94 (27.2%)
sPOR	11 (6.7%)	24 (13.2%)	P=0.046	35 (10.1%)

* CRP>10mg/L or fecal calprotectin ³250mcg/g

Conclusion

The retrospective PORCSE study provides evidence to support a proactive approach over a reactive approach in terms of prevention of not only endoscopic but also clinical and surgical postoperative recurrence after first ileocecal resection for Crohn’s disease.

Disclosure

Authors have nothing to disclose related to this project