Exabis Library

IBD cannot be cured with the currently available forms of medical therapy. However, therapeutic options can be significantly improved using an artificial intelligence-based approach that takes into consideration and integrates all omics components of the disease.

•To review the available evidence on pre-clinical studies
•To propose a common terminology for the preclinical period of disease
•To discuss important research question on the field

Current endoscopic scoring indices such as the Simple Endoscopic Score for Crohn’s Disease (SES-CD) quantify the degree of mucosal inflammation in Crohn’s disease (CD) but lack prognostic potential. The Modified Multiplier of the Simple Endoscopic Score for Crohn’s Disease (MM-SES-CD) is an internally validated endoscopic scoring tool that quantifies the endoscopic burden of CD and can be accessed online (https://www.mcmasteribd.com/mm-ses-cd).¹ This analysis aims to establish thresholds of the MM-SES-CD that classify CD endoscopic burden into inactive or very mild disease, mild, moderate, and severe disease based on the probability of achieving endoscopic remission (ER) on active therapy at one-year.

This post-hoc analysis included pooled data from three CD clinical trials (n=350 patients, baseline SES-CD ≥3 with confirmed ulceration). Maximum Youden Index calculations were used to determine thresholds for severity. Chi-square tests of trend were used to compare achievement of ER between severity categories, and Kaplan-Meier survival curve analysis was used to compare time to clinical remission (CR).

Table 1 demonstrates the baseline characteristics of the 350 participants included in this analysis. MM-SES-CD severity categories were established as inactive or very mild (score <14), mild (score ≥14 to <31), moderate (≥31 to <45), and severe (score ≥45), which were predictive of one-year ER (50%, 30.3%, 21.7%, 8.8% respectively p<0.001) (Table 2). Lower MM-SES-CD scores had numerically higher rates of one-year CR, and time to CR over 52 weeks was superior to those with higher scores (p=0.0492) (Figure 1). MM-SES-CD thresholds for the achievement of ileal ER at one-year among 75 patients with isolated ileal disease were also established as mild (score <14), moderate (score ≥14 to <33), and severe (score ≥33), which were predictive of one-year ER (66.7%, 33.3%, 13.3%, respectively p=0.027) (Table 3).

We have established numerical cut-offs of the MM-SES-CD that categorize endoscopic disease severity and are prognostic for one-year ER and CR. These cut-offs could help ensure adequate balance between study arms (e.g. in prevalence of mild or moderate endoscopic disease) and identify patients with severe endoscopic disease and low probability of achieving ER.

References:

1. Predicting endoscopic remission in Crohn’s disease by the modified multiplier SES-CD (MM-SES-CD). Gut, 2021: p. gutjnl-2020-323799.

Background: CCL20-CCR6 axis is growingly recognized as playing a critical role in IBD pathogenesis by influencing the recruitment of leukocytes to inflamed tissues and the balance between effector and regulatory T cells. However, CCR6 blockade has never been tested as therapeutic approach against IBD and no small-molecule CCR6 antagonists have been investigated as potential drug candidates.

Aim: Starting from the results shown by our novel CCR6 antagonist (MR120), we aimed at:
-designing and synthesizing new small-molecule CCR6 antagonists;
-identifying the most efficacious and tolerable anti-chemotactic novel compound;
-assessing the efficacy of MR120 and of the most promising derivative in adoptive transfer colitis.

Methods:By applying the previously prepared CCR6 homology model, we generated a focused collection of new derivatives around the chemotype of the active hit MR120. The compounds preserving more than 95% cells viability in PI assay were tested for their anti-chemotactic action against CCL20-induced lymphocytes recruitment, calculated as relative migration index (RMI). Adoptive transfer colitis was induced in C.B-17 Scid mice (n=8/group) by infusion of CD4⁺CD25^- T cells or CD4⁺ T cells (sham mice, n=6) isolated from Balb/c mice. Colitic mice received daily either MR120 1mg/kg (MR120), MR452 1mg/kg (MR452), or vehicle (DMSO 1%) (C), while sham (S) group received only the vehicle b.i.d. s.c. Disease Activity Index (DAI) was registered for 8 weeks, until suppression; colonic macroscopic score (MS), length and thickness and colon and lung myeloperoxidase (MPO) activity were determined. All experiments were authorized and performed according to the guidelines for the Care and Use of Animals (DL26/2014).

Results:Among 31 newly synthesized molecules, 14 compounds, out of 20 derivatives tolerated up to 50mM, were selected and tested in the chemotaxis assay at 25mM. Except from 6 inactive derivatives, all displayed a remarkable improvement of the anti-chemotactic effect compared to MR120. Interestingly, MR452 strongly antagonized the CCL20-induced lymphocytes recruitment (RMI=0.43), and was therefore tested in vivo.Vehicle-treated C mice developed a moderate-to-severe colitis, with weight loss and diarrhea and increased colonic MS, thickening, and MPO activity compared with S. The treatment with MR120 or MR452 was mitigated the colonic MPO activity, in spite of not modifying the other inflammatory markers with respect to C. 

Conclusions:The ability of both MR120 and MR452 to attenuate the gut neutrophil recruitment suggest that the interference with the CCL20-CCR6 axis could participate in hindering the gut homing of effector leukocytes and in mitigating their inflammatory role.

Patients with inflammatory bowel disease (IBD), particularly Crohn’s disease (CD), are at increased risk for gastrointestinal and extraintestinal malignancies. Chronic inflammation is a major risk factor for the development of gastrointestinal malignancies, while some medical therapies, that diminish the mucosal inflammatory response and represent the basis of treatment, may also promote carcinogenesis in the long These excess risks have declined substantially over time term. Patients with ulcerative colitis (UC) still are at increased risk of developing colorectal cancer (CRC). However, these excess risks have declined substantially over time. Despite they are diagnosed with significantly less advanced CRC, they still are at increased risk of dying from CRC, probably because intrinsic differences in the pathogenesis of colitis-associated cancer with respect to sporadic CRC, in which inflammation drive cancer progression. Patients with CD still are at increased risk of developing CRC, are diagnosed with no significant difference in CRC stage, but are at increased risk of dying from CRC. Incidence of CRC in CD patients is lower in recent years, but remains high in those potentially eligible for surveillance: patients diagnosed before the age of 40, with colonic location or with PSC. In conclusion, we still need to do better to prevent development of CRC in IBD patients. Small bowel cancer (SBC) and associated death are more common among patients with IBD compared with the general population, but the absolute risks are low. CD is associated with a ninefold increased risk of incident SBC and a sevenfold increased risk of death due to SBC. Among patients with CD, the relative risk of incident SBC is highest for those with recently diagnosed, childhood-onset, ileal and stricturing disease. Among patients with UC, the relative risk of incident SBC is highest for those with extensive colitis and PSC. The incidence of pouch neoplasia in patients with IBD without a history of colorectal neoplasia is relatively low. Prior dysplasia or CRC, however, is associated with increased risk of developing pouch cancer. Finally, patients with anal and/or perianal CD have a high risk of anal cancer (HPV-related anal canal squamous cell carcinoma – SCC, as well as very rare cases of anal canal adenocarcinoma), including perianal fistula-related cancer, and a high risk of rectal cancer.

1. First line therapy/Monitoring
2. stratify the target
3. Anti-TNF LOR
4. TDM

Case of new diagnosis of penetrant Crohn's disease with complicated outcome