Introduction

Intestinal ultrasound (IUS) is effective for monitoring treatment efficacy in Crohn's disease (CD). Bowel wall thickness (BWT) is used as a surrogate of inflammatory activity. However, the added value of other IUS parameters ((bowel wall flow (BWF), stratification (BWS), lymph node enlargement, mesenteric fat hypertrophy, and complications)) for monitoring and predicting treatment failure during anti-TNFs’ maintenance therapy is still poorly defined and was the goal of this study.

Aims & Methods

This was a retrospective cross-sectional study. The study population included patients treated on infliximab or adalimumab maintenance treatment who had undergone an index intestinal ultrasound examination. We examined the added value of various ultrasonographic activity signs, in addition to bowel wall thickness, for their association with subsequent treatment failure. Treatment failure was defined as the need for CD-related surgery, hospitalization, corticosteroid use, dose escalation, and drug discontinuation.

Results

The study included 103 CD patients treated with anti-TNF therapy (67% adalimumab and 33% infliximab) who underwent an IUS at a median of 10 months (IQR 6-18) after starting therapy. Of 103 patients, 59.2% experienced treatment failure at a median of 5 months (2-12.5) after the index IUS examination. Among the failure group, bowel thickness at preceding index IUS was significantly higher compared with patients without failure (3.9 vs 3mm, respectively, P= 0.007), BWF was higher (49.2% vs. 23.8%, P= 0.009), and mesenteric hypertrophy was more prevalent (20.4% vs 7.1%, P=0.006). Logistic regression identified increased BWT and mesenteric hypertrophy as having a significant association with therapy failure. A sensitivity analysis with the outcome of therapy discontinuation revealed that mesenteric fat hypertrophy was a significant predictive factor along with increased BWT (Table 1).

Table 1: Sonographic Characteristics Associated with Treatment Failure and Drug Discontinuation.

Conclusion

Our study highlights the significance of BWT, BWF, and mesenteric fat hypertrophy as key sonographic markers associated with anti-TNF treatment failure in Crohn's disease. Integrating these indicators into scoring systems may enhance predictive accuracy, providing a quantitative tool for evaluating disease severity and treatment response.

Introduction

Transmural healing is a promising target in Crohns’ disease (CD) that is associated with more favorable outcomes than endoscopic remission, especially lower risk of bowel damage progression. C-score has been recently developed and validated to assess transmural healing in patients with CD. However, the best time to assess transmural healing remains to be determined.

Aims & Methods

We aimed to evaluate the kinetics of transmural healing in patients with CD treated with anti-TNF therapy.
From a prospective database of patients with CD performing MRI for luminal CD, we analyzed the kinetics of transmural healing among CD patients older than 18 years-old receiving anti-TNF therapy, with objective sign of inflammation on morphological evaluation (cross-sectional imaging) before starting the treatment, who underwent at least one MRI examination to assess therapeutic efficacy within 12 months. Patients treated with anti-TNF agents for treat isolated perianal lesions were excluded.
We used a statistical model based on imputation according the last observation carry forward and clinical relevance. Transmural healing was then assessed every month during the first year. For segmental analysis, we used the same division into segments than recommended for Lemann Index calculation. Transmural healing was defined as C-score < 0.5 in each segment. C-score was calculated as previously published (0.2 x (bowel thickness in mm – 3) + 2 if ulcer + 1.5 if enlarged lymph nodes).

Results

Overall, 123 patients were included. Among them, 90 were female (73.1%), 48 (39.9%) were current smokers and 53 (43.0%) had prior intestinal resection. The median CD duration at baseline was 7.6 years [1.4-15.2]. At baseline, 41 patients (33.3%) were anti-TNF-naïve. At baseline, 67 patients (55.3%), 53 patients (43.8%) and 1 patient (0.8%) were treated with infliximab, adalimumab and golimumab, respectively with concomitant immunosuppressant in 94 patients (79.0%).
At baseline, 220 segments were considered as active (C-score > 0.5) including 100 in the terminal ileum and 120 in the colon/rectum.
According per-segment analysis (N=220), the rate of transmural healing was 6.4% at M1, 6.4% at M2, 10.0% at M3, 10.1% at M4, 14.6% at M5, 18.0% at M6, 23.2% at M7, 24.5% at M8, 26.0% at M9, 26.8% at M10, 29.1% at M11 and 30.4% at M12.
Among terminal ileum segments (n=100), the rate of transmural healing was 2.0% at M1, 2.0% at M2, 5.0% at M3, 5.0% at M4, 9.0% at M5, 12.9% at M6, 16.0% at M7, 17.0% at M8, 18.0% at M9, 19.0% at M10, 20.0% at M11 and 20.0% at M12.
Among colorectal segments (n=120), the rate of transmural healing was 6.4% at M1, 6.4% at M2, 13.8% at M3, 13.8% at M4, 15.6% at M5, 22.0% at M6, 28.4% at M7, 28.6% at M8, 28.6% at M9, 28.6% at M10, 32.8% at M11 and 34.4% at M12.
Among the 123 patients with CD, in multivariable analyses, absence of transmural healing (C-score > 0.5) within the first year was associated with increased risk of surgery (HR=3.37 [1.30-8.68]; p=0.012), drug discontinuation (HR=2.31 [1.29-4.14]; p=0.005), and bowel damage progression (p <0.001) while we observed a trend for higher risk of CD-related hospitalization (HR=1.92 [0.85-4.36]; p=0.11).

Conclusion

Transmural healing is achievable in more than 30.0% of active segments in patients with CD treated with anti-TNF therapy within the first year. The best time to assess transmural healing was between 6 and 12 months after starting anti-TNF therapy with higher rate of transmural healing for colorectal versus ileal segments. Transmural healing defined as C-score < 0.5 is associated with long-term improved outcomes in patients with CD.

Disclosure

Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda et Tillotts
Lecture fees from: Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma
Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda

Introduction

A small but significant proportion of patients with Crohn’s disease (CD) will ultimately require a permanent ileostomy. (1-3) The natural history and treatment success in these patients remain unclear and studies on endoscopic recurrence are lacking. The aim of this study was to investigate the endoscopic recurrence rate, possible risk factors, and treatment outcomes with current biological agents.

Aims & Methods

We performed a retrospective study of CD patients with a permanent ileostomy in a tertiary referral center. Inclusion criteria were CD adults (≥16 years) and the presence of an ileostomy for at least 12 months. Ileal postoperative recurrence was defined as the presence of ulcerations during ileoscopy. Traditional risk factors historically associated with postoperative recurrence (age at diagnosis ≤16 years, active smoking, penetrating phenotype, and inflammation at resection margin) were evaluated. (4,5) The probability of developing post-operative ileitis was examined by cox regression and Kaplan Meier analysis.

Results

166 patients were identified (median age 34 years (IQR 24-46), 63% female) (Table 1). Median follow-up after surgery was 5.5 years (IQR 2-14) and 37% had a loop ileostomy without resection. 115/166 (69%) underwent endoscopy during follow-up. Indications for ileoscopy were symptoms of flare (50%), planning for ostomy closure (14%) and other indications (21%). Endoscopic lesions were observed in 40% of patients, with a cumulative risk at 1-, 3- and 5-years of 13%, 27% and 36%, respectively. Controlling for traditional risk factors, patients with preoperative anti-TNF treatment were at higher risk (HR 2.18, 95% CI 1.11-4.28), with 17%, 41%, and 44% recurrence rates at 1, 3, and 5 years respectively (log rank P = 0.01). Other traditional risk factors for postoperative recurrence were not predictive of endoscopic disease recurrence in this cohort. Ileal recurrence was treated with biological therapy, including infliximab, adalimumab, vedolizumab, or ustekinumab. Patients treated with vedolizumab had the highest rate of remission (6/8 patients) and longest treatment persistence (54 months, IQR 19-102.8) (Table 1).

Conclusion

This retrospective study showed that 40% of ileostomy patients developed endoscopic recurrence. Patients with previous anti-TNF exposure were at higher risk of recurrence. Vedolizumab was the most effective treatment, although this finding needs to be confirmed in larger cohorts.

References

1. Cosnes, J., Gower-Rousseau, C., Seksik, P., & Cortot, A. (2011). Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology, 140(6), 1785–1794. https://doi.org/10.1053/j.gastro.2011.01.055
2. Ma, C., Almutairdi, A., Tanyingoh, D., Seow, C. H., Novak, K. L., Lu, C., Panaccione, R., Kaplan, G. G., & Kotze, P. G. (2019). Reduction in surgical stoma rates in Crohn's disease: a population-based time trend analysis. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland, 21(11), 1279–1287. https://doi.org/10.1111/codi.1473
3. Everhov, Å. H., Kalman, T. D., Söderling, J., Nordenvall, C., Halfvarson, J., Ekbom, A., Ludvigsson, J. F., Olén, O., & Myrelid, P. (2022). Probability of Stoma in Incident Patients With Crohn's Disease in Sweden 2003-2019: A Population-based Study. Inflammatory bowel diseases, 28(8), 1160–1168. https://doi.org/10.1093/ibd/izab245
4. Gionchetti P, Dignass A, Danese S, Magro Dias FJ, Rogler G, Lakatos PL, et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 2: Surgical Management and Special Situations. J Crohns Colitis. 2017;11(2):135-49.
5. Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68(Suppl 3):s1-s106.

Disclosure

Geert D’Haens has served as advisor and/or speaker for Abbvie, Alimentiv, Astrazeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Ferring, Eli Lilly, Galapagos, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Polpharm, Prometheus biosciences, Prometheus laboratories, Procise diagnostics, Protagonist, Sandoz, Takeda, Tillotts, Ventyx.

Introduction

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Current therapies include monoclonal antibodies, such as adalimumab (ADA) and infliximab (IFX), that target the inflammatory cytokine tumor necrosis factor alpha, collectively known as anti-TNF. While it has been shown that anti-TNF is effective at inducing and maintaining remission in patients with CD, this treatment fails in up to 40% of CD patients^​. Ineffective treatment results in disease progression and complications, emphasizing the need to understand mechanisms behind non-response and to define prognostic biomarkers. We previously identified differences in the peripheral blood DNA methylome associated with response and non-response. However, it is unclear how differential methylation can affect the transcriptome.

Aims & Methods

In this study, we assembled a cohort of 58 adult CD patients that were scheduled to start ADA or IFX treatment. Response to treatment was assessed after 6-9 months based on strict combination of endoscopic (≥50% reduction SES-CD), biochemical (CRP reduction ≥50% or CRP≤5 mg/L and FCP reduction ≥50% or FCP ≤250 µg/g) and clinical criteria (≥3 point drop in HBI or HBI ≤4 without corticosteroids). Whole peripheral blood leukocytes (PBL) were collected from patients before baseline endoscopy or at first infusion/injection, and 6-9 months later. mRNA was extracted using QIAsymphony system, converted into cDNA and sequenced in a paired-end format on the Illumina NovaSeq at the Amsterdam UMC Core Facility Genomics. Differential expression (DE) analysis was carried out within the R statistical environment (v 4.3.1) using the Bioconductor package DESeq2 (v 1.40.2).

Results

Prior to the start of treatment, we identified 504 and 750 differentially expressed genes (DEGs) distinguishing responders from non-responders in ADA and IFX cohorts, respectively. While 13 genes presented response-associated differential expression for both ADA and IFX, no overall correlation was observed between response-associated differential expression profiles. However, based on canonical pathway analysis, we found that expression differed in both ADA and IFX responders and non-responders at the level of neutrophil degranulation, B-cell receptor regulation, and cell growth and differentiation.

Conclusion

Our data suggest that response to ADA and IFX can be associated to the PBL transcriptome prior to treatment. Furthermore, while the differences between responders and non-responders to ADA and IFX display limited overlap in DEGs, we observe that response-associated pathways are shared.