
==== Front
Gastro Hep Adv
Gastro Hep Adv
Gastro Hep Advances
2772-5723
Elsevier

S2772-5723(24)00057-8
10.1016/j.gastha.2024.04.007
Original Research—Clinical
Early Sonographic Improvement Predicts Clinical Remission and Mucosal Healing With Molecular-Targeted Drugs in Ulcerative Colitis
Kimura Yoko
Miyoshi Jun jmiyoshi@ks.kyorin-u.ac.jp
∗
Morikubo Hiromu
Komatsu Haruka
Moue Chihiro
Yonezawa Hiromi
Matsuura Minoru
Hisamatsu Tadakazu thisamatsu@ks.kyorin-u.ac.jp
∗∗
Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan
∗ Correspondence: Address correspondence to: Jun Miyoshi, MD, PhD, Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Shinkawa 6-20-2, Mitaka-shi, Tokyo 181-8611, Japan. jmiyoshi@ks.kyorin-u.ac.jp
∗∗ Tadakazu Hisamatsu, MD, PhD, AGAF, FACG, Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Shinkawa 6-20-2, Mitaka-shi, Tokyo 181-8611, Japan. thisamatsu@ks.kyorin-u.ac.jp
23 4 2024
2024
23 4 2024
3 6 703710
18 3 2024
15 4 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background and Aims

Predicting the efficacy of molecular-targeted drugs (MTDs) is an unmet need in the treatment of ulcerative colitis (UC). Intestinal ultrasound (IUS) can be used to safely and repeatedly assess UC activity.

Methods

Thirty-eight patients who started MTD therapy for active UC and underwent IUS at baseline and 3 months after starting therapy were analyzed. Steroid-free clinical remission (SFCR) and endoscopic improvement (EI) at 6 months were defined as a Lichtiger index of ≤3 and Mayo endoscopic subscore of ≤1 while continuing the MTD without steroid induction or surgery. Sonographically estimated EI (SE-EI) at 3 months was assessed based on a Milan Ultrasound Criterion of ≤6.2 and Kyorin Ultrasound Criterion for UC (bowel wall thickness of <3.8 mm and submucosa index of <50%).

Results

Thirty-one patients achieved SFCR at 6 months [SFCR(+) group]. The SFCR(+) group demonstrated significantly better improvement in bowel wall thickness and bowel wall vascularity at 3 months than the SFCR(−) group. The Milan Ultrasound Criterion and UC-IUS index also improved significantly more in the SFCR(+) than SFCR(−) group. The areas under the curve of these parameters for predicting SFCR were approximately 0.80. Colonoscopy was performed for 28 patients at 6 months, and 15 patients achieved EI. SE-EI at 3 months was significantly associated with achievement of EI at 6 months. The positive predictive values of SE-EI at 3 months for SFCR and EI at 6 months were 100%.

Conclusion

Sonographic improvements in 3 months predicted the clinical and endoscopic efficacy of MTD therapy at 6 months, suggesting the longitudinal significance of IUS monitoring for UC treatment.

Keywords

Intestinal Ultrasound
Ulcerative Colitis
Clinical Remission
Endoscopic Improvement
Molecular-Targeted Drug
Abbreviations used in this paper

BWF bowel wall flow

BWS bowel wall stratification

BWT bowel wall thickness

CS colonoscopy

EI endoscopic improvement

IQR interquartile range

IUS intestinal ultrasound

KUC-UC Kyorin Ultrasound Criterion for UC

LI Lichtiger index

MES Mayo endoscopic subscore

mLS modified Limberg score

MTD molecular-targeted drug

MUC Milan Ultrasound Criterion

PPV positive predictive value

SE-EI sonographically estimated endoscopic improvement

SFCR steroid-free clinical remission

SMI submucosa index

SMT submucosa thickness

UC ulcerative colitis

UII UC-IUS index
==== Body
pmcIntroduction

Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by colonic inflammation with periods of remission and relapse. The prognosis of UC has improved with advances in therapeutic options, including molecular-targeted drugs (MTDs).1 The treat-to-target strategy is now widely accepted to achieve a better prognosis in patients with UC,2 and both clinical and endoscopic improvement and remission are considered therapeutic targets in the clinical setting. Colonoscopy (CS) is the gold standard assessment technique for UC disease activity. Achieving endoscopic improvement (EI), defined as a Mayo endoscopic subscore (MES)3 of 0 or 1, at approximately 6 months after starting remission induction therapy, is considered a clinical target for a better long-term prognosis of UC.2,4, 5, 6 The ability to predict the clinical efficacy early after starting treatment, including EI at 6 months, would contribute to better clinical outcomes and reduce sociomedical costs because physicians could decide to continue or switch a medication earlier. Predicting the efficacy of an MTD is a crucial unmet need in UC treatment.

We hypothesized that intestinal ultrasound (IUS) early after beginning remission induction therapy with an MTD has the potential to predict efficacy at 6 months. IUS is considered a promising monitoring tool for UC. Whereas CS with pretreatment using laxatives can be invasive for patients, IUS is noninvasive and can be performed safely and repeatedly even for patients with active UC. IUS can be used to assess the whole colon and evaluate the disease distribution of UC.7 Additionally, various cross-sectional studies have demonstrated that several IUS findings are associated with colonic inflammation and that some sonographic findings and scoring systems can estimate EI.8, 9, 10, 11, 12, 13, 14 Bowel wall thickness (BWT), bowel wall vascularity [or bowel wall flow (BWF)], bowel wall stratification (BWS), colon haustration, and inflammatory mesenteric fat are widely used sonographic parameters for assessing UC disease activity.8 Allocca et al10,11 developed the Milan Ultrasound Criterion (MUC) using BWT and BWF and demonstrated that an MUC of ≤6.2 can estimate EI. Bots et al12 showed that their UC-IUS index (UII) using BWT, BWF, haustration, and inflammatory mesenteric fat was well correlated with the MES. We developed the submucosa index (SMI), a new parameter based on BWT and submucosa thickness (SMT), and reported that the combination of BWT and the SMI can be used as a criterion to estimate EI [Kyorin Ultrasound Criterion for UC (KUC-UC): BWT of <3.8 mm and SMI of <50%].13,14 Thus, evidence regarding the potential of IUS to estimate EI has accumulated.

In the present study, we investigated the clinical significance of IUS monitoring in MTD therapy. We found that the improvement of IUS findings at 3 months after starting induction therapy with an MTD predicts steroid-free clinical remission (SFCR) at 6 months of MTD therapy and demonstrated that achieving sonographically estimated EI (SE-EI) under IUS at 3 months leads to the achievement of EI under CS at 6 months.

Methods

Study Design and Patients

In this single-center retrospective study, we applied the following inclusion criteria to patients with UC: (1) an MTD was started as induction therapy for active UC, defined as a Lichtiger index (LI)15,16 of ≥4, at Kyorin University Hospital (Tokyo, Japan) from September 2020 to June 2023, and (2) IUS was performed at baseline and 2–4 months after starting an MTD, and the MTD was continued at least until the second IUS. The patients satisfying the inclusion criteria were consecutively enrolled in the analyses. The diagnosis of UC was based on the Inflammatory Bowel Disease Guidelines of the Japanese Society of Gastroenterology.17 The following clinical information was obtained from the hospital’s medical record system: endoscopic and IUS findings, age at the time of examination, sex, disease duration, disease type, and therapeutic drugs.

Sonographic and Endoscopic Assessment

On transabdominal IUS, we assessed BWT, BWS including SMI, haustration, and inflammatory mesenteric fat using B-mode at the most severely affected segment of the colon. BWS was categorized as maintained, unclear, or loss of stratification. The SMI was defined as the percentage of SMT within the BWT (ie, SMI = 100 × SMT/BWT).13,14 The SMI was recorded as 0 if the SMT was too thin to measure and was recorded as “undetermined” when the submucosa was unclear or could not be identified even with a BWT of >3 mm.13,14 BWF was evaluated at the site where we measured BWT using the modified Limberg score (mLS) in color Doppler mode as follows: score of 0 = BWT of <3 mm and no color Doppler signal, score of 1 = BWT of ≥3 mm and no color Doppler signal, score of 2 = point-like short color Doppler signal, score of 3 = linear-appearing Doppler signal; and score of 4 = long color Doppler signal extending through the bowel wall and mesenteric tissue.7,18 Based on the IUS findings, the MUC10,11 and UII12 were calculated as described in the original reports. An MUC cutoff value of 6.2 was employed to estimate EI.11 We also assessed the use of our KUC-UC (BWT of <3.8 mm and SMI of <50%) for estimating EI.13,14 Sonographic changes 3 months after starting MTD therapy were calculated and assessed based on the evaluation described above. A Canon Aplio i800 ultrasound system (Canon Medical Systems, Otawara, Japan) with a 6-MHz convex probe was used for all examinations. The velocity range of the color Doppler was set at 4.2 cm/s. The manufacturer’s preset parameters for bowel examinations were used. Each IUS finding was confirmed by agreement among 3 examiners (J.M., H.M., and H.Y.), one of whom (J.M.) had completed the IUS training curriculum provided by the International Bowel Ultrasound Group (https://ibus-group.org/). Multiple examiners among the 3 examiners perform IUS together for patients with UC or other diseases and discuss and determine the IUS findings during the examination at our institution. Inflammatory bowel disease specialists independently performed CS or sigmoidoscopy (when deep insertion was considered high risk with severe activity or pain during the examination) and scored the disease activity using the MES3 for the most severely affected segment. EI was defined as an MES of ≤1. Achievement of EI at 6 months was defined as an MES of ≤1 at 6 months with continuation of the MTD started for the induction therapy.

Clinical Assessment

Clinical remission was defined as an LI of ≤3. SFCR at 6 months after starting MTD therapy was defined as an LI of ≤3 without terminating the MTD (ie, switching to other medications), undergoing surgery because of insufficient control of UC disease activity, or starting steroid induction therapy before 6 months.

Statistical Analysis

Continuous and categorical variables are presented as mean ± standard error and median with interquartile range (IQR), respectively. The Mann–Whitney U test was used for comparisons between the 2 groups. Fisher’s exact test was used to analyze contingency tables. A receiver operating characteristic analysis was employed to evaluate the predictive ability of IUS findings and scoring systems for the clinical efficacy of an MTD.

Ethics

This study was approved by the Institutional Ethics Committee of Kyorin University School of Medicine (Approval Number 2264) and conducted in accordance with the Declaration of Helsinki. This study used recorded data, and the ethics committee approved a waiver for informed consent.

Results

Patient Demographics

Thirty-eight patients were analyzed (Table 1). Among these 38 patients, 28 had pancolitis and 10 had left-sided colitis. The MTD used for remission induction therapy was adalimumab, golimumab, infliximab, ustekinumab, vedolizumab, filgotinib, tofacitinib, and upadacitinib in 2, 1, 8, 13, 5, 2, 3, and 4 patients, respectively. Each patient continued the MTD without steroids or other MTDs for at least 3 months when IUS monitoring was performed. The median baseline LI of the 38 patients was 8 (IQR: 6–9). All patients showed endoscopically active colitis [MES of ≥2 (median: 2.5, IQR: 2–3)] at the baseline CS performed before starting MTD therapy (median: −2 weeks, IQR: −4 to 0 weeks). The sonographic and endoscopic findings at the baseline are shown in Table A1.Table 1 Clinical Demographics

Number of patients	38	
Sex, female/male	13/25	
Age at induction therapy, y	34.5 (22–52.5)	
UC disease duration, y	3.5 (1.2–9.8)	
UC disease type, pancolitis/left sided	28/10	
Lichtiger index at baseline	8 (6–9)	
MES at baseline	2.5 (2–3)	
MTD for induction therapy		
 Adalimumab	2	
 Golimumab	1	
 Infliximab	8	
 Ustekinumab	13	
 Vedolizumab	5	
 Filgotinib	2	
 Tofacitinib	3	
 Upadacitinib	4	
Concomitant medications		
 5-aminosalicylic acid	21	
 Predonisolone	12	
 Azathioprine	7	
Past use of MTDa		
 None (naïve)	22	
 Adalimumab	2	
 Golimumab	1	
 Infliximab	7	
 Ustekinumab	4	
 Vedolizumab	7	
 Tofacinib	2	
 Cyclosporine	2	
 Taclorimus	1	
 Carotegrast methyl	1	
Data are presented as n or median (interquartile range).

a Seven patients were treated with multiple molecular-targeted drugs before the current induction treatment.

Sonographic Improvement During Induction Period and Achievement of SFCR

Among the 38 patients, 31 (81.6%) achieved SFCR at 6 months [SFCR(+) group]. The baseline IUS was performed when starting MTD therapy (median: 0 weeks, IQR: −1 to 0 weeks). Monitoring IUS was performed at 3 months (median: 13 weeks, IQR: 12–14.7 weeks) after induction of MTD therapy. The sonographic changes at 3 months were compared between the SFCR(+) and SFCR(−) groups. The change in BWT (ΔBWT) was −1.8 ± 0.4 mm in the SFCR(+) group and 0.3 ± 0.5 mm in the SFCR(−) group (P = .0137). Given the differences in the absolute value of BWT at baseline among the patients, the change in %BWT (Δ%BWT) (the baseline value was defined as 100%) was also assessed. The SFCR(+) and SFCR(−) groups showed a Δ%BWT of −24.3% ± 5.8% and 6.5% ± 8.6%, respectively (P = .0149) (Figure 1A). The change in mLS (ΔmLS) was −1 (IQR: −2 to 0) in the SFCR(+) group and 0 (IQR: 0–0) in the SFCR(−) group (P = .0041). The Δ%mLS was −37.1% ± 7.4% and 14.3% ± 14.3% in the SFCR(+) and SFCR(−) groups, respectively (P = .0044) (Figure 1B). The changes in BWS are presented in Figure 1C. There was no clear difference in the proportion of patients showing apparent improvement of BWS (ie, change from unclear/loss of stratification to maintained stratification) between the SFCR(+) group (32.3%) and SFCR(−) group (28.6%). The change in MUC (ΔMUC) was −3.32 ± 0.66 and 0.17 ± 0.68 in the SFCR(+) and SFCR(−) groups, respectively (P = .0102). The change in %MUC (Δ%MUC) was also evaluated. The SFCR(+) and SFCR(−) groups demonstrated an Δ%MUC of −27.7% ± 5.5% and 1.9% ± 6.4%, respectively (P = .0135) (Figure 1D). The change in UII (ΔUII) was −1 (IQR: −4 to 0) and 0 (IQR: 0–0) in the SFCR(+) and SFCR(−) groups, respectively (P = .0063). The Δ%UII was −29.6% ± 6.6% and 2.4% ± 2.4% in the SFCR(+) and SFCR(−) groups, respectively (P = .0082) (Figure 1E). The changes in sonographic findings among the SFCR(+) and SFCR(−) groups are also presented in Table A2. Receiver operating characteristic analyses for SFCR demonstrated a considerable area under the curve (95% confidence interval) for ΔBWT of 0.795 (0.642–0.948), Δ%BWT of 0.793 (0.632–0.953), ΔmLS of 0.820 (0.684–0.957), Δ%mLS of 0.820 (0.684–0.957), ΔMUC of 0.807 (0.665–0.948), Δ%MUC of 0.797 (0.646–0.948), ΔUII of 0.813 (0.681–0.945), and Δ%UII of 0.809 (0.676–0.941) (Figure A1). All patients with an MUC of ≤6.2 (n = 8), KUC-UC (n = 7), and MUC of ≤6.2, and/or KUC-UC [n = 9 (6 with MUC of ≤6.2 and KUC-UC, 2 with MUC of ≤6.2, and 1 with KUC-UC)] at 3 months (ie, SE-EI at 3 months) achieved SFCR at 6 months (Table 2). However, the association between SE-EI at 3 months and SFCR at 6 months was not statistically significant.Figure 1 Changes in intestinal sonographic findings at 3 months and achievement of SFCR at 6 months after starting a molecular-targeted drug. The changes (Δ) in intestinal sonographic findings at 3 months with a molecular-targeted drug were compared between patients who did and did not achieve SFCR at 6 months. In calculating Δ%, the value at baseline was defined as 100%. (A) ΔBowel wall thickness (mm) and Δ%bowel wall thickness. (B) ΔModified Limberg score (mLS) and Δ%mLS. (C) Proportions of patients with each change pattern of bowel wall stratification. (D) ΔMilan Ultrasound Criterion and Δ%Milan Ultrasound Criterion. (E) ΔUC-IUS index and Δ%UC-IUS index. ∗P < .05 and ∗∗P < .01 with Mann–Whitney U test. IUS, intestinal ultrasound; SFCR, steroid-free clinical remission; UC, ulcerative colitis.

Table 2 SE-EI at 3 Months and Achievement of SFCR at 6 Months With a Molecular-Targeted Drug

(1) SE-EI based on MUC of ≤6.2	
	Achievement (+)/(−)	SFCR at 6 mo	
(+)	(−)	
SE-EI at 3 mo	(+)	8	0	
(−)	23	7	
(2) SE-EI based on KUC-UC	
	Achievement (+)/(−)	SFCR at 6 mo	
(+)	(−)	
SE-EI at 3 mo	(+)	7	0	
(−)	24	7	
(3) SE-EI based on MUC of ≤6.2 and/or KUC-UC	
	Achievement (+)/(−)	SFCR at 6 mo	
(+)	(−)	
SE-EI at 3 mo	(+)	9	0	
(−)	22	7	

Sonographic Improvement During Induction Period and Achievement of Endoscopic Healing

Among the 38 patients, 28 underwent CS at approximately 6 months (median: 28 weeks, IQR: 26–29.5 weeks) with continuation of the MTD started at baseline. Total CS was performed for these patients, and 15 achieved EI [EI(+) group]. Sonographic changes at 3 months were compared between patients with and without achievement of EI at 6 months [EI(+) vs EI (−) groups]. There was no significant difference in ΔBWT (−2.1 ± 0.5 vs −0.7 ± 0.5 mm) or Δ%BWT (−31.0% ± 7.7% vs −8.3% ± 6.8%) between the groups (Figure 2A). The ΔmLS was −1 (IQR: −3 to 0) in the EI(+) group and 0 (IQR: −1 to 0) in the EI(−) group (P = .0372). The Δ%mLS was −44.4% ± 12.5% and −11.54% ± 5.1% in the EI(+) and EI(−) groups, respectively (P = .0300) (Figure 2B). The changes in BWS are presented in Figure 2C. A larger proportion of patients showed apparent improvement of BWS in the EI(+) group (40.0%) than in the EI(−) group (15.3%). The ΔMUC was −3.86 ± 0.88 and −1.18 ± 0.66 in the EI(+) and EI(−) groups, respectively (P = .0476). The EI(+) and EI(−) groups demonstrated an Δ%MUC of −34.3% ± 7.9% and −8.2% ± 5.7%, respectively (P = .0325) (Figure 2D). The ΔUII was −1 (IQR: −5 to 0) and 0 (IQR: −0.5 to 0) in the EI(+) and EI(−) groups, respectively (P = .0075). The Δ%UII was −38.2% ± 10.3% and −1.0% ± 4.5% in the EI(+) and EI(−) groups, respectively (P = .0050) (Figure 2E). The changes in sonographic findings among the EI(+) and EI(−) groups are also presented in Table A3. The area under the curve (95% confidence interval) for EI at 6 months was 0.685 (0.484–0.886) for ΔBWT, 0.718 (0.525–0.911) for Δ%BWT, 0.718 (0.523–0.913) for ΔmLS, 0.726 (0.531–0.920) for Δ%mLS, 0.721 (0.527–0.914) for ΔMUC, 0.739 (0.548–0.928) for Δ%MUC, 0.780 (0.605–0.954) for ΔUII, and 0.795 (0.627–0.963) for Δ%UII (Figure A2). Among the 28 patients, 5 demonstrated an MUC of ≤6.2, 5 satisfied the KUC-UC, and 6 achieved an MUC of ≤6.2 and/or KUC-UC (4 with both MUC of ≤6.2 and KUC-UC, 1 with MUC of ≤6.2, and 1 with KUC-UC) at 3 months. There was a significant association between SE-EI at 3 months and the achievement of EI at 6 months (P = .0437 for MUC, P = .0437 for KUC-UC, and P = .0178 for MUC/KUC-UC). The positive predictive value (PPV) of SE-EI at 3 months was 100% for EI at 6 months (Table 3).Figure 2 Changes in intestinal sonographic findings in 3 months and achievement of EI at 6 months after starting a molecular-targeted drug. The changes (Δ) in intestinal sonographic findings at 3 months with a molecular-targeted drug were compared between patients who did and did not achieve EI (Mayo endoscopic subscore of ≤1) at 6 months. (A) ΔBowel wall thickness (mm) and Δ%bowel wall thickness. The bowel wall thickness at baseline was defined as 100% in calculating Δ%bowel wall thickness. (B) ΔModified Limberg score and Δ%modified Limberg score. The modified Limberg score at baseline was defined as 100% in calculating Δ%modified Limberg score. (C) Proportions of patients with each change pattern of bowel wall stratification (unclear/loss to unclear/loss, unclear/loss to maintained, and maintained to maintained). (D) ΔMilan Ultrasound Criterion and Δ%Milan Ultrasound Criterion. (E) ΔUC-IUS index and Δ%UC-IUS index. ∗P < .05 with Mann-Whitney U test. EI, endoscopic improvement; IUS, intestinal ultrasound; UC, ulcerative colitis.

Table 3 SE-EI at 3 Months and Achievement of EI at 6 Months With a Molecular-Targeted Drug

(1) SE-EI based on MUC of ≤6.2	
	Achievement (+)/(−)	EI at 6 mo	
(+)	(−)	
SE-EI at 3 mo	(+)	5	0	
(−)	10	13	
Sensitivity: 33.3% (95% CI: 15.2%–58.2%)	
Specificity: 100% (95% CI: 77.2%–100%)	
Positive predictive value: 100% (95% CI: 56.6%–100%)	
Negative predictive value: 56.5% (95% CI: 36.8%–74.3%)	
(2) SE-EI based on KUC-UC	
	Achievement (+)/(−)	EI at 6 mo	
(+)	(−)	
SE-EI at 3 mo	(+)	5	0	
(−)	10	13	
Sensitivity: 33.3% (95% CI: 15.2%–58.2%)	
Specificity: 100% (95% CI: 77.2%–100%)	
Positive predictive value: 100% (95% CI: 56.6%–100%)	
Negative predictive value: 56.5% (95% CI: 36.8%–74.3%)	
(3) SE-EI based on MUC of ≤6.2 and/or KUC-UC	
	Achievement (+)/(−)	EI at 6 mo	
(+)	(−)	
SE-EI at 3 mo	(+)	6	0	
(−)	9	13	
Sensitivity: 40.0% (95% CI: 19.8%–64.3%)	
Specificity: 100% (95% CI: 77.2%–100%)	
Positive predictive value: 100% (95% CI: 61.0%–100%)	
Negative predictive value: 59.1% (95% CI: 38.7%–76.7%)	
CI, confidence interval.

Discussion

In the present study, improvement of IUS findings in 3 months and achievement of SE-EI at 3 months predicted the clinical and endoscopic efficacy of MTD therapy at 6 months. Our results suggest that achieving “sonographic improvement,” defined using sonographic findings and scoring systems, can contribute to the clinical decision regarding whether to continue an MTD or switch to another MTD. EI is considered a more crucial target than SFCR for a preferable prognosis.2 Notably, our study showed that SE-EI at 3 months was significantly associated with EI at 6 months, with a PPV of 100%. This finding suggests that achieving SE-EI at 3 months can support the treatment plan to continue an MTD but also provide an opportunity to reconsider the timing of CS, which is commonly performed at approximately 6 months to assess the MTD efficacy for UC. That is, the burden of endoscopic examination for evaluating the inflammatory condition at 6 months could be avoided in a well-responder who achieves SE-EI at as early as 3 months. Meanwhile, it also should be noted that not achieving SE-EI at 3 months does not mean a patient will fail to achieve EI. Our results also suggest that employing multiple IUS parameters and scoring systems can improve the predictive ability of IUS for UC disease activity. Although evidence for surveillance of UC-associated neoplasia with IUS has not been established, we believe that CS to survey UC-associated neoplasia should be performed even in patients with SE-EI. The clinical purpose and significance of CS and IUS must be considered for each patient.

Our findings underscore the importance of addressing 2 new clinical challenges: developing a practical, predictive IUS scoring system for MTD efficacy for clinical decision-making and establishing the appropriate timing of CS for patients who achieve SE-EI at 3 months. Follow-up CS should not be hastily postponed for patient safety because patients who require endoscopic assessment may be overlooked. However, balancing this with the need to reduce patients’ burdens and conserve medical resources is a significant clinical challenge. Therefore, given that several sonographic parameters seemed to be promising predictors in this study and that the MUC and KUC-UC were originally developed for estimating EI but not predicting outcomes, developing a new scoring system specifically for predicting both SFCR and EI could contribute to improving the UC treatment strategy. Allocca et al19 recently reported that an MUC of ≤6.2 at 12 weeks after starting biologics could predict the endoscopic response. The average follow-up timing of CS was 9.40 months (standard deviation: 3.59) and the PPV of an MUC of ≤6.2 for an MES of ≤1 was 67% in their study.19 Given that several statements and guidelines recommend CS at 3–6 months after induction therapy,4,6 our study suggests that patients who achieve SE-EI at 3 months can postpone the follow-up CS to assess the inflammatory condition later than recommended; the abovementioned study19 seems to support this notion. Because the PPV of an MUC of ≤6.2 for an MES of ≤1 was 100% in our study but 67% in their study, we cannot exclude the possibility that some patients with SE-EI at 3 months will develop endoscopic relapse later than 6 months.

The present study has some limitations. First, this was a retrospective study that included several MTDs. Although various types of MTDs achieved SE-EI in 3 months, the appropriate timing of IUS for monitoring the drug response may vary between MTDs. A future study in which each MTD is analyzed and IUS is performed at various time points will provide insights into the best timing of IUS for each medication. It is a crucial clinical challenge to examine if IUS at an earlier time point can predict the treatment efficacy. Also, serial IUS assessments up to 6 months could contribute to understanding the late responders to each MTD in UC treatment. However, this study reflects the real-world clinical setting, and approximately 3 months after starting an MTD seems to be a reasonable time to evaluate the efficacy of induction therapy in the clinical setting. Assessing IUS findings at a common time point regardless of the drug could be practical and easy for physicians to understand. Second, we employed transabdominal IUS, and proctitis was not analyzed in this study. Because the number of patients with proctitis treated with MTDs may be smaller than that of patients with other types of UC, our results still have relevance to inflammatory bowel disease clinical practice. Given that early peritoneal IUS showed a predictive potential for the short-term clinical response in UC,20 investigating the predictive ability of the combination of transabdominal and peritoneal IUS for the middle- and long-term therapeutic efficacy of MTDs is an interesting future perspective. Finally, this was a single-center study, and the number of patients was limited. Although our study showed statistically significant findings, further prospective studies with larger cohorts will contribute to obtaining more robust insights into the longitudinal clinical significance of IUS monitoring in UC treatment. Notably, however, the single-center design provided advantages in maintaining the quality of IUS procedures and the consistency of sonographic assessments. This is a crucial scientific strength of this study. Dissemination of an IUS training system is needed for future multicenter studies with standardized IUS protocols.

Conclusion

This study demonstrated that sonographic improvements 3 months after starting an MTD could predict SFCR and endoscopic healing with that MTD at 6 months.

Supplementary Materials

Figures A1 and A2

Table A1

Table A2

Table A3

Acknowledgments:

We thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac) for English language proofreading.

Authors' Contributions:

Yoko Kimura, Jun Miyoshi, and Hiromu Morikubo conceived the study, designed the experiments, and prepared the manuscript. Yoko Kimura, Jun Miyoshi, Hiromu Morikubo, Haruka Komatsu, Chihiro Moue, and Hiromi Yonezawa collected and analyzed the data. Minoru Matsuura and Tadakazu Hisamatsu supervised the writing of the manuscript. Jun Miyoshi and Tadakazu Hisamatsu oversaw the entire project. All authors reviewed the manuscript.

Conflicts of Interest: These authors disclose the following: Jun Miyoshi has received grant support from AbbVie GK and consulting and lecture fees from EA Pharma Co Ltd, AbbVie GK, Janssen Pharmaceutical K.K., Jansen Asia Pacific Pte. Ltd, Pfizer Inc, Mitsubishi Tanabe Pharma Corporation, JIMRO Co, Miyarisan Co Ltd, and Takeda Pharmaceutical Co Ltd. Hiromu Morikubo has received grant support from Takeda Pharmaceutical. Minoru Matsuura has received consulting and lecture fees from Janssen Pharmaceutical K.K., Takeda Pharmaceutical Co Ltd, AbbVie GK, Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co Ltd, Mochida Pharmaceutical Co Ltd, JIMRO Co, Nippon Kayaku Co Ltd, Mylan EPD G.K., and Aspen Japan Co Ltd. Tadakazu Hisamatsu has performed joint research with EA Pharma Co Ltd and Kissei Pharmaceutical Co Ltd and 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, Boston Scientific Co Ltd, and Mochida Pharmaceutical Co, Ltd and consulting and lecture fees from EA Pharma Co Ltd, AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc, Nichi-Iko Pharmaceutical Co, Ltd, Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co Ltd, JIMRO Co, Mochida Pharmaceutical Co Ltd, Gilead Sciences Inc, Bristol Myers Squibb Co Ltd, and Takeda Pharmaceutical Co Ltd. The remaining authors disclose no conflicts.

Funding: This work was supported in part by the Japan Sciences Research Grant for Research on Intractable Diseases (Japanese Inflammatory Bowel Disease Research Group) affiliated with the Japan 10.13039/501100003478 Ministry of Health, Labour and Welfare .

Ethical Statement: This study was approved by the Institutional Ethics Committee of Kyorin University School of Medicine (Approval Number 2264) and conducted in accordance with the Declaration of Helsinki. This study used recorded data, and the ethics committee approved a waiver for informed consent.

Data Transparency Statement: The data will be shared upon reasonable request to the corresponding author.

Reporting Guidelines: Helsinki Declaration.

Material associated with this article can be found, in the online version, at https://doi.org/10.1016/j.gastha.2024.04.007.
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References

1 Tsai L. Ma C. Dulai P.S. Contemporary risk of surgery in patients with ulcerative colitis and Crohn's disease: a meta-analysis of population-based cohorts Clin Gastroenterol Hepatol 19 10 2021 2031 2045.e11 33127595
2 Turner D. Ricciuto A. Lewis A. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the international organization for the study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD Gastroenterology 160 5 2021 1570 1583 33359090
3 Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study N Engl J Med 317 26 1987 1625 1629 3317057
4 Peyrin-Biroulet L. Sandborn W. Sands B.E. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target Am J Gastroenterol 110 9 2015 1324 1338 26303131
5 Ungaro R. Colombel J.F. Lissoos T. A treat-to-target update in ulcerative colitis: a systematic review Am J Gastroenterol 114 6 2019 874 883 30908297
6 Maaser C. Sturm A. Vavricka S.R. ECCO-ESGAR guideline for diagnostic assessment in IBD part 1: initial diagnosis, monitoring of known IBD, detection of complications J Crohns Colitis 13 2 2019 144 164 30137275
7 Miyoshi J. Morikubo H. Yonezawa H. First aid with color atlas for the use of intestinal ultrasound for inflammatory bowel disease in daily clinical practice Intest Res 21 2 2023 177 188 37139590
8 De Voogd F. Wilkens R. Gecse K. A reliability study: strong inter-observer agreement of an expert panel for intestinal ultrasound in ulcerative colitis J Crohns Colitis 15 8 2021 1284 1290 33420784
9 Sagami S. Kobayashi T. Miyatani Y. Accuracy of ultrasound for evaluation of colorectal segments in patients with inflammatory bowel diseases: a systematic review and meta-analysis Clin Gastroenterol Hepatol 19 5 2021 908 921.e6 32777549
10 Allocca M. Fiorino G. Bonovas S. Accuracy of humanitas ultrasound criteria in assessing disease activity and severity in ulcerative colitis: a prospective study J Crohns Colitis 12 12 2018 1385 1391 30085066
11 Allocca M. Filippi E. Costantino A. Milan ultrasound criteria are accurate in assessing disease activity in ulcerative colitis: external validation United European Gastroenterol J 9 4 2021 438 442
12 Bots S. Nylund K. Lowenberg M. Intestinal ultrasound to assess disease activity in ulcerative colitis: development of a novel UC-ultrasound index J Crohns Colitis 15 8 2021 1264 1271 33411887
13 Miyoshi J. Ozaki R. Yonezawa H. Ratio of submucosal thickness to total bowel wall thickness as a new sonographic parameter to estimate endoscopic remission of ulcerative colitis J Gastroenterol 57 2 2022 82 89 35072789
14 Komatsu H. Morikubo H. Kimura Y. A combination of bowel wall thickness and submucosa index is useful for estimating endoscopic improvement in ulcerative colitis: external validation of the Kyorin Ultrasound Criterion J Gastroenterol 59 3 2024 209 215 38245879
15 Lichtiger S. Present D.H. Preliminary report: cyclosporin in treatment of severe active ulcerative colitis Lancet 336 8706 1990 16 19 1973211
16 Lichtiger S. Present D.H. Kornbluth A. Cyclosporine in severe ulcerative colitis refractory to steroid therapy N Engl J Med 330 26 1994 1841 1845 8196726
17 Nakase H. Uchino M. Shinzaki S. Evidence-based clinical practice guidelines for inflammatory bowel disease 2020 J Gastroenterol 56 6 2021 489 526 33885977
18 Limberg B. [Diagnosis of chronic inflammatory bowel disease by ultrasonography] Z Gastroenterol 37 6 1999 495 508 Diagnostik von chronisch-entzundlichen Darmerkrankungen durch Sonographie 10427656
19 Allocca M. Dell'Avalle C. Furfaro F. Early intestinal ultrasound predicts long-term endoscopic response to biologics in ulcerative colitis J Crohns Colitis 17 10 2023 1579 1586 37084137
20 Sagami S. Kobayashi T. Aihara K. Transperineal ultrasound predicts endoscopic and histological healing in ulcerative colitis Aliment Pharmacol Ther 51 12 2020 1373 1383 32383166
