Introduction

Transmural response (TR) and healing (TH) assessed by intestinal ultrasound (IUS) are gaining increasing relevance as treatment targets in Crohn’s disease (CD) [1]. Even though less established in ulcerative colitis [UC], in which the inflammation mainly affects mucosa and submucosa, there is clear evidence that applying IUS in UC is beneficial to monitor short-term response to therapy [2]. However, the long-term IUS outcome, its association to clinical and lab parameters as well as the predictive value of early TR remain elusive.

Aims & Methods

The TRUST BEYOND study is an ongoing, prospective, non-interventional, multi-centre study in patients with active CD or UC who receive a biologic- or Januskinase-inhibitor (JAKi)-therapy at baseline. The study aims to assess the predictive value of TR or TH, evaluated at week 12 for the disease outcome after 52 weeks (TR: reduction of bowel wall thickness (BWT) of at least 25% and/or normalization; TH: normalization of BWT and Colour Doppler signal). For this interim analysis, we report IUS and clinical results as well as fecal calprotectin levels of 77 UC patients on the same therapy after 12 (W12) and 52 weeks (W52) and assessed the predictive value of TR at W12 for clinical remission at W52.

Results

Seventy-seven UC patients (63.6% were male, median age was 38.6 years (30.6 – 55.7) median disease duration of 5.85 years (2.49–12.77)) with clinically active disease (SCCAI 8.5 ± 2.2) with increased BWT at baseline had a documented visit after 52 weeks until February 2023. For the vast majority, the most affected bowel wall segment was the sigmoid colon with a mean BWT of 5.22 ± 1.28 mm at baseline.
At W12 after induction of therapy, the proportion of UC patients with TR and TH was 67.5% (n = 52) and 31.2% (n = 24). At W52, the rates of UC patients increased to 77.9% (n = 60) for TR and 41.6% (n = 32) for TH. Over the study course, patients with TR at W12 and W52 had a numerically lower SCCAI score and reduced fecal calprotectin levels than patients without TR.
Of note, 72.2% (n = 39) of patients with TR at W12 were in clinical remission at W52 compared to 27.8% (n = 15) of patients without early transmural response (p = 0.178).

Conclusion

In this interim analysis of the TRUST BEYOND study, UC patients demonstrated substantial rates of transmural improvements on IUS after 12 and 52 weeks. Patients with early transmural response were more likely to be in remission after one year. This suggests that in UC, IUS has to some degree a predictive value as observed for CD.

References

1. Kucharzik T, Wittig BM, Helwig U, et al. Use of Intestinal Ultrasound to Monitor Crohn's Disease Activity. Clin Gastroenterol Hepatol. 2017; 15:4, 535-42 e2.
2. Maaser C, Petersen F, Helwig U On behalf of the German IBD Study Group and the TRUST&UC study group, et alIntestinal ultrasound for monitoring therapeutic response in patients with ulcerative colitis: results from the TRUST&UC studyGut 2020;69:1629-1636.

Disclosure

T. Kucharzik, U. Helwig, F. Seibold, L. Biedermann, C. Högenauer and C. Maaser have received lecture and consulting fees from AbbVie.
I. Fischer has received consulting fees from AbbVie. L. Hammer and S. Rath are AbbVie employees and may own AbbVie stock or options.
AbbVie sponsored the study; contributed to the design; participated in the collection, analysis, and interpretation of data; in writing, reviewing, and approval of the final version. No honoraria or payments were made for authorship.

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

Hepatitis C is a major global health problem caused by the hepatitis C virus, which can result in mild to severe symptoms, including liver cirrhosis and cancer. Unsafe medical practices, lack of awareness, poverty, intravenous drug abuse and limited access to healthcare facilities contribute to the high prevalence of this disease. An estimated 58 million people are effected with hepatitis c worldwide and every year 1.5 million are adding to burden (1).Pakistan is one of the countries with the highest burden of hepatitis C, affecting around 12 million people having 4.2 % prevalence (2). While the Pakistani government and international organizations have taken steps to eliminate hepatitis C, challenges remain, such as the stigma attached to the disease, limited access to screening and treatment in remote areas, and inadequate funding for hepatitis control program (3).

Aims & Methods

To address the issue of hepatitis C elimination in rural Pakistan, a cross-sectional observational study was conducted from January 2021 to December 2022 at the MTI Gajju khan Medical College Swabi. All patients above 18 years of age who visited the gastroenterology OPD were screened for Hepatitis C. Patients who were positive for Anti HCV antibody and had detectable HCV RNA were enrolled in the study. Patients were divided into four groups: Chronic hepatitis C non cirrhotic treatment naïve and treatment experienced, Compensated Cirrhosis naïve and experienced. Sofosbuvir and Daclatasvir for 12 or 24 weeks were given, and Ribavirin was given to treatment-experienced and cirrhotic patients. Prevalence , efficacy of available free DAAs , recommendation to achieve elimination goal were discussed at end of study.

Results

Out of 10,240 patients screened for hepatitis C during their first visit to the gastroenterology OPD, 420 patients with a mean age of 36+16 having positive HCVRNA were enrolled. Almost 90% of the patients were non-affordable. After initial evaluations, the patients were separated into four groups. Chronic hepatitis C without cirrhosis was present in 287 patients, while cirrhotic were 137. Treatment-naïve patients were 307, and 113 patients were treatment-experienced. ETR was achieved in 403 (96%) patients, and SVR was achieved in 413 (91.5%) patients.

Conclusion

To achieve the hepatitis elimination goal 2030 in countries with low human development indexes, chronic hepatitis C screening, diagnosis, and management must be sponsored by national and international organizations. One-time screening should be offered for every patient above 18 years on first contact with healthcare workers. Unsafe medical practices should be strongly discouraged. The freely available drugs Sofosbuvir and Daclatasvir, with or without RBV, are highly effective treatment options for chronic HCV and the most adaptable strategy to eliminate hepatitis C. This regimen has produced excellent results in our country, influenced mainly by the presence or absence of cirrhosis and the easy and free availability of drugs.

References

1. Salari N, Kazeminia M, Hemati N, Ammari-Allahyari M, Mohammadi M, Shohaimi S. Global prevalence of hepatitis C in general population: A systematic review and meta-analysis. Travel Med Infect Dis. 2022 Jan 8;46:102255.
2. Abbas Z, Abbas M. The cost of eliminating hepatitis C in Pakistan. Lancet Glob Health. 2020 Mar;8(3):e323–4.
3. Lim AG, Walker JG, Mafirakureva N, Khalid GG, Qureshi H, Mahmood H, et al. Effects and cost of different strategies to eliminate hepatitis C virus transmission in Pakistan: a modelling analysis. Lancet Glob Health. 2020 Mar;8(3):e440–50.
4. Cox AL, El-Sayed MH, Kao JH, Lazarus JV, Lemoine M, Lok AS, et al. Progress towards elimination goals for viral hepatitis. Nat Rev Gastroenterol Hepatol. 2020;17(9):533.
5. The Lancet. Viral hepatitis elimination: a challenge, but within reach. Lancet. 2022 Jul 23;400(10348):251.
6. Waheed Y, Siddiq M, Jamil Z, Najmi MH. Hepatitis elimination by 2030: Progress and challenges. World J Gastroenterol. 2018 Nov 11;24(44):4959.

Disclosure

Authors have no conflict of interest in study.

Clinical Case Summary

A 77-year-old man underwent liver transplantation in 2008 due to alcoholic cirrhosis associated with hemochromatosis, and was taking tacrolimus and mycophenolate mofetil since that.
He was admitted in the Emergency Department in February 2023 with right upper quadrant abdominal pain and diarrhea for one week. Abdominal computed tomography(CT) showed ileal thickening. Laboratory tests revealed leukocytosis(19,000 leukocytes/mm3) and elevated C-reactive protein(16 mg/dL). Acute gastroenteritis was assumed and he was discharged on metronidazole with clinical improvement. One month later, he returned to the Emergency Department with abdominal pain for two days. CT revealed concentric wall thickening of the last ileal loop and a probable enteromesenteric fistula. He was admitted for further evaluation. Colonoscopy revealed deep mucosal ulceration of the terminal ileum. After colonoscopy, his abdominal pain worsened, so he repeated the abdominal CT, which showed a new organized collection in the right flank measuring 63 mm and small gas bubbles of pneumoperitoneum in the right upper quadrant. He underwent ileocecal resection with terminal ileostomy, and the histopathological evaluation revealed a neoplasm composed of atypical lymphoid proliferation, with positive immunohistochemistry for CD45, CD20, CD79a, BCL2, and BCL6, compatible with diffuse large B-cell lymphoma. After staging and exclusion of distant disease, the patient was proposed for chemotherapy following reduction of immunosuppression.
The clinical presentation of Inflammatory Bowel Disease can be quite heterogeneous and several pathologies can mimic its clinical, endoscopic, and/or histological findings. This case illustrates the importance of considering the diagnosis of small bowel lymphoma as a differential diagnosis of Crohn's disease, especially in elderly patients with risk factors, such as chronic immunosuppression.

Introduction

T1 colorectal cancer can be managed either by surgery or interventional endoscopy. High-risk features after endoscopic resection (G3, submucosal invasion >1000 µm, lympho-vascular invasion, tumour budding+, or R1 resection) increase the risk of lymphnode metastasis (10-15%), often requiring additional surgery. However, the benefits of surgery versus endoscopic resection alone remain unclear, particularly in elderly or frail patients.

Aims & Methods

The aim of the study is to assess recurrence rate and overall survival in patients underwent surgery, endoscopy or both. Secondary endpoints is to evaluate incidence of adverse events and length of hospital stay
All consecutive patients diagnosed with T1 colorectal cancer from 2018 to 2024 in our institution were enrolled in this retrospective study. We divided this cohort in 3 groups: endoscopic resection plus surgery (ER-S), upfront surgery (SR), or endoscopic resection alone (ER). Demographics data, mortality, cancer recurrence rate, disease free survival and AEs were recorded.

Results

One-hundred and thirty-three patients were enrolled in the study: 34 (72 years±10) in the SR group, 65 (65 years±11) in the ER-S group and 34 (77 years±11) in ER, respectively.
Lesions were similar (p-value 0.30) for dimension: 31±15 mm (ER) vs 23±12 mm (ER-S) vs 30±13 mm (ER) such as follow-up (23 vs 24 vs 21 months) for the three groups (p-value 0.428). Hospital stay after the procedure was significantly lower in the ER group (1 day median) vs SR (median 9 days;p-value 0.0001) and ER-S group (7 days median;p-value 0.003). Cumulative 30 days adverse events were higher in the SR group (62%; p-value 0.0001) and in the ER-S group (22%; p-value 0.001) compared to ER alone (12%). During the study period, no endoscopic/radiological recurrence occurred in the SR group whereas 1 patient in the ER-S group and 2 in the ER group showed recurrence non suitable for further treatments.
Five patients in SR group died after a median of 18 months (1 for early surgical complication); 2 died in the ER-S group after a median of 34 months and 3 died in the ER group after a median of 24 months (1 for rectal cancer progression) (p-value 0.365).
Overall survival was comparable among the three groups with no significant difference (p-value 0.718) with a median of 40 months (SR), 28 (ER-S) and 26 (ER) months.

Conclusion

Endoscopic resection alone appears to be a reasonable option for high-risk T1 CRC patients, especially those with increased surgical risk due to low rate of recurrence, low adverse events and a comparable overall survival in short-mid term.

References

1. Quénéhervé, L.; Pioche, M.; Jacques, J. Curative Criteria for Endoscopic Treatment of Colorectal Cancer. Best Pract. Res. Clin. Gastroenterol. 2024, 101883, doi:10.1016/j.bpg.2024.101883.
2. Chen, Y.; Jing, W.; Chen, M.; Wang, Z.; Wu, J.; Yang, J.; Yang, L.; Deng, K. Long-Term Outcomes of Local Resection versus Surgical Resection for High-Risk T1 Colorectal Cancer: A Systematic Review and Meta-Analysis. Gastrointest. Endosc. 2023, 97, 1016-1030.e14, doi:10.1016/j.gie.2023.02.027.
3. Spadaccini M, Bourke MJ, Maselli R, et al. Clinical outcome of non-curative endoscopic submucosal dissection for early colorectal cancer. Gut. Published online January 20, 2022. doi:10.1136/gutjnl-2020-323897
4. Corre, F.; Albouys, J.; Tran, V.-T.; Lepilliez, V.; Ratone, J.-P.; Coron, E.; Lambin, T.; Rahmi, G.; Karsenti, D.; Canard, J.-M.; et al. Impact of Surgery after Endoscopically Resected High-Risk T1 Colorectal Cancer: Results of an Emulated Target Trial. Gastrointest. Endosc. 2023, S0016-5107(23)02933-4, doi:10.1016/j.gie.2023.09.027.
5. UICC. TNM. Classification of malignant tumours. eighth ed. Wiley; 2016. p. 272

Disclosure

Giuseppe Grande is consultant for Olympus, Boston Scientific, ERBE, Fujifilm