Introduction

Ustekinumab has been proven to be effective for treatment of patients with Crohn's disease; however, 30–40% of patients have been reported to lose clinical response within 2 years. We aimed to evaluate the efficacy of ustekinumab and identify predictors of short- and long-term efficacy in Crohn's disease.

Aims & Methods

Patients with Crohn's disease receiving their first ustekinumab infusion in our hospital between June 2017 and September 2020 were prospectively enrolled. Concentrations of serum cytokines and chemokines were measured using a multiplex bead array assay. Trough concentration of ustekinumab in serum samples collected after 8 weeks of intravenous administration were measured by ELISA.

Results

Fifty-nine Crohn's disease patients were enrolled in this study. Among 34 clinically active patients, 38.2% achieved a clinical response at week 8. None of the assayed factors were associated with short-term clinical response. Cumulative persistence rates of ustekinumab were 77.6% at 1 year and 58.9% at 2 years. Univariate Cox regression analysis revealed that Harvey–Bradshaw Index scores at baseline, concomitant immunomodulator treatment, and concentrations of interferon gamma-induced protein-10, monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-1RA, IL-4, IL-6, and IL-8, but not other baseline parameters and trough concentrations of ustekinumab (hazard ratio (HR): 0.9846, 95% confidence interval (CI): 0.9561–1.014), were significantly associated with loss of efficacy. Multivariate Cox regression analysis found that biologic naïve status (HR: 0.1264, 95% CI: 0.02595–0.6158) and MCP-1 concentrations (HR: 1.037, 95% CI: 1.014–1.062) were significantly and associated with loss of sustained efficacy for ustekinumab treatment.

	Univariate analysis HR	Lower limit of the 95% CI	Upper limit of the 95% CI	p value	Multivariate analysis HR	Lower limit of the 95% CI	Upper limit of the 95% CI	p value
Biologic naïve, Yes	0.2367	0.05582	1.004	0.05061	0.1264	0.02595	0.6158	0.01047
Concomitant IM, Yes	2.644	1.144	6.113	0.02297
IL-4, pg/mL	1.562	1.028	2.375	0.03685
IL-6, pg/mL	1.07	1.02	1.123	0.00568
IL-8, pg/mL	1.067	1.025	1.111	0.001415
IL-1RA, pg/mL	1.003	1.001	1.005	0.00439
IP-10, pg/mL	1.001	1.001	1.001	0.02067
MCP-1, pg/mL	1.022	1.003	1.04	0.02055	1.037	1.014	1.062	0.001754
Trough level of UST at week 8	0.9846	0.9561	1.014	0.3029

Furthermore, if patients were divided into four groups according to prior biologics use and MCP-1 level which cut-off value was determined from receiver operating characteristics (ROC) at 1 year, MCP-1 low and biologics naïve group had 100% cumulative persistence rate of ustekinumab at week 140. On the other hand, MCP-1 high and biologics exposure group had below 20%.

Conclusion

Our findings suggest that pre-treatment serum MCP-1 analysis, combined with a history of biologic use could be a novel biomarker for predicting the long-term efficacy of ustekinumab in patients with Crohn's disease. However, predicting of long-term efficacy by a trough concentration of ustekinumab at week 8 might be limited.

Disclosure

The authors declare no conflicts of interest associated with this manuscript.

Clinical Case Summary

Seronegative enteropathies pose a complex diagnostic challenge, as their histology mimics celiac disease (CeD) (1). We report a 51-year-old patient with hypertension and osteoporosis, referred for abdominal pain, weight loss, and constipation. Blood tests showed no anemia; anti-transglutaminase and anti-endomysium antibodies were negative, but HLA typing was compatible with CeD. Ileocolonoscopy excluded IBD and microscopic colitis, while OEGD revealed villous atrophy (MARSH 3c). Negative anti-enterocyte antibodies, and exclusion of drugs and infections, led to a diagnosis of seronegative CeD. A gluten-free diet was started, but after 1 year, symptoms improved only partially despite good adherence. OEGD showed persistent duodenal damage with increased intraepithelial lymphocytes (IELs), CD3+ and CD8+ T-cells with monoclonal TCR expression (fig. 1), consistent with RCeD type 1, despite no overt malabsorption. The patient began prednisone 50 mg/day, then switched to open-capsule budesonide, with some clinical benefit but persistent atrophy.
A year later, his daughter was diagnosed with CVID and a heterozygous STAT3 variant (c.1252T>C, p.Cys418Arg), somatically acquired in NK-cell leukemia. A luciferase assay confirmed its gain-of-function (GOF) effect (fig. 2). Family studies revealed the same germline variant in the patient. His diagnosis was revised to STAT3 GOF-associated enteropathy. Further investigations revealed hypogammaglobulinemia, splenomegaly, bronchiectasis, and emphysema. Treatment with Ruxolitinib (a JAK1/2 inhibitor) was started, resulting in clinical and histological remission (fig. 3).
STAT3 GOF enteropathy is a very rare condition (2,3) that should be considered in the differential diagnosis of seronegative villous atrophy. Anti-JAK therapy may be effective (4).

References

References of the images:
Figure 1: Histologic aspects at diagnosis
Figure 2: Luciferase assay of STAT3
Figure 3: Histologic aspects after 1 year of therapy

1. Schiepatti A, Sanders DS, Baiardi P, Caio G, Ciacci C, Kaukinen K, et al. Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus. Gut. 2022 Jun 8;71(11):2218–25.
2. Vogel TP, Leiding JW, Cooper MA, Forbes Satter LR. STAT3 gain-of-function syndrome. Vol. 10, Frontiers in Pediatrics. Frontiers Media SA; 2023.
3. Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. 2014;46(8):812–4.
4. Kaneko S, Sakura F, Tanita K, Shimbo A, Nambu R, Yoshida M, et al. Janus kinase inhibitors ameliorate clinical symptoms in patients with STAT3 gain-of-function. Immunotherapy Advances. 2023;3(1).

Introduction

A successful colonoscopy requires ideal stool preparation, yet the percentage of insufficient bowel preparation is still very high. Frequently, the patients use website information on colonoscopy preparation. Conversely, the daily activity of the hospital staff consists of spending time with patients, communicating with them and giving answers to a high number of questions coming from patients regarding the preparation for the procedure or the exam itself. Hence, the idea to adopt a rapid and intuitive patient-oriented digital service to respond to their needs, the virtual assistant Eric.

Aims & Methods

Endo-Chat is an automated online communication platform, powered by AI (Artificial Intelligence) with the use of the Natural Language Processing and Deep Learning technologies, that answers procedure-related questions in real-time. The engine is named ERIC, stands for "Endoscopy Robot for Intelligent Chat" and is an intelligent chatbot, capable of answering autonomously to most of the doubts of a patient who is supposed to undergo an endoscopic examination.

Results

Since the introduction of the conversational artificial intelligence system at the Policlinico Gemelli starting from 24^th of January 2022 to the 16^th of March 2023, Eric has been able to autonomously manage 94% of the questions sent by patients, thus forwarding only the remaining 6% (of the requests) to specialized human operators.
We calculated that in the pre-pilot phase, a large part of the daily activity of nurses was dedicated to communicating with patients, around 40 hours per week, while in the post-pilot phase, the time spent for communication was significantly reduced to 15 hours per week. According to OECD Health Statistics 2022, the average annual salary of a European nurse is 35,300 euros, with an annual hypothetical saving of 22,062 euros, comparable to a part-time contract.
Also, the number of cancelled procedures for poor patient preparation has fallen from 22 to 7 per week, considering a volume of 200 procedures per week.
Regarding patient's experience, users can leave voluntary feedback on their virtual assistant experience directly on the ERIC website, evaluating the quality of the service. Patient service evaluations were enthusiastic till now, as 63% rated the service as excellent.

Conclusion

In our observational pilot study, the first in Europe to our knowledge, we assessed the benefits measurement for patients and Hospital staff. Starting from these preliminary interesting results, we can speculate that the introduction of Endo-Chat in high-volume endoscopy service is feasible and useful not only for patients but also for hospital staff.

Disclosure

The authors declare no conflict of interest

Introduction

Previous studies have demonstrated that the Chinese population has a more stringent interpretation of “normal” defecation. The symptom spectrum of Chinese constipated patients remains unknown.

Aims & Methods

To systematically investigate the symptom spectrum of Chinese constipated patients, and to evaluate the clinical applicability of Rome IV criteria in this distinct population.

Non-selective outpatients (aged ≥16 years) self-identified with “constipation” were enrolled and given the Rome IV questionnaire. Data on demographics, defecation frequency, stool forms, defecation symptoms, and abdominal symptoms were collected. Non-constipated controls were recruited from outpatients’ family members for demographics and defecation pattern data. Descriptive analysis was performed to contrast distribution differences between constipated and normal individuals, and to determine the abnormal defecation symptom thresholds. The consistency of Rome IV criteria with respondents’ self-assessments was evaluated, and modifications of Rome IV criteria were proposed based on these thresholds.

Results

The study enrolled 6364 constipated individuals and 1432 normal controls. In constipated individuals, the prevalent symptoms included straining (97.29%), sensation of incomplete evacuation (96.07%), hard stools (95.21%), sensation of anorectal obstruction (93.22%), reduced defecation frequency (91.67%), bloating or abdominal distension (87.13%), abdominal pain (76.71%), laxative-assisted defecation (23.98%), and manipulation-assisted defecation (21.51%).
Descriptive analysis has substantiated that constipated patients exhibit inter-individual symptom heterogeneity, validating the clinical utility of Rome IV's symptom cluster-based diagnostic paradigm. However, Rome IV criteria manifested poor consistency with self-assessment (Kappa=0.24, P<0.01), with high specificity (98.81%) but low sensitivity (47.30%). This discrepancy reflects stricter perceptions of normal defecation among the Chinese.
As for normal controls, the mean defecation frequency was 7.09±2.03/week, with the 90th percentile cutoff (4/week) stricter than Rome IV's 3/week benchmark. This quantitative analysis yielded six constipation diagnostic thresholds: defecation frequency = 4 times a week, hard stools =30%, straining =30%, sensation of incomplete evacuation =20%, sensation of anorectal obstruction or blockage =10%, and manipulation-assisted defecation =10%.
We compared five diagnostic approaches to determine the optimal symptom count for constipation diagnosis. As illustrated in the Table, the diagnostic approach with the presence of ≥2 abnormal symptoms had an excellent consistency (Kappa value =0.80, P < 0.01), high specificity (95.46%), and high sensitivity (92.94%).

Diagnostic Approach	Kappa Value	Specificity/%	Sensitivity/%
Rome IV Criteria	0.24	98.81	47.30
Two-Symptom Criteria	0.80	95.46	92.94
Three-Symptom Criteria	0.66	98.60	84.43
Four-Symptom Criteria	0.50	99.72	73.29
Five-Symptom Criteria	0.32	99.93	56.46
Six-Symptom Criteria	0.01	100.00	2.44

Conclusion

Rome IV criteria demonstrate suboptimal performance in consistency and sensitivity, mainly attributable to the stricter threshold for defecation frequency in China. After modifications, the novel dual-symptom diagnostic framework significantly improves consistency and sensitivity, offering a more tailored approach for diagnosing constipation in Chinese population. These findings underscore the necessity for region-specific adaptations of Rome IV criteria across diverse populations.

References

• 1. Chu H, Hou X. Understanding of constipation symptoms and the diagnosis and management of constipation in Chinese physicians. PLoS One. 2016 Mar 31;11(3):e0152801. https://pubmed.ncbi.nlm.nih.gov/27031865/
• 2. Mearin F, Lacy BE, Chang L, Chey WD, Lembo AJ, Simren M, Spiller R. Bowel disorders. Gastroenterology. 2016 Feb 18;150(6):1393-1407. https://pubmed.ncbi.nlm.nih.gov/27144627/
• 3. Zhu SR, Tian Y, Bai T, Hou XH. The defecation habits of people in Central China: a cross-sectional survey and a literature review. Neurogastroenterol Motil. 2020 Mar;32(S1):274. https://webofscience.clarivate.cn/wos/woscc/full-record/WOS:000521974900269