Introduction

In the years to follow we anticipate a rise in the prevalence of an aging population of inflammatory bowel disease (IBD) patients and a rise in cancer incidence. We are in urgent need of data to help us manage these patients.
We therefore followed a cohort of patients from a referral oncology hospital with prior and active cancer who received biologic therapy to control their IBD.

Aims & Methods

We first recorded data regarding inflammatory bowel disease characteristics: disease type, disease duration, disease severity, previous surgery or hospitalization and received therapy: type and duration of biologic therapy, prior use of immunosuppressants. We also recorded all available data regarding cancer disease: cancer site, stage, virus related cancer, family history of cancer, smoking status and received therapy (curative surgery, chemotherapy, hormone therapy, radiotherapy, immunotherapy). We monitored outcomes of IBD (steroid free clinical remission, IBD-related surgery or hospitalization) and outcomes of cancer (recurrence free survival, progression free survival, overall survival).
A blinded oncologist was asked to retrospectively evaluate all available data regarding cancer prognosis (stage, histology, response to therapy) and to categorize patients in 3 groups: low, intermediate or high risk to recur or progress.

Results

A total of 30 patients were included, 57 % female, median age 60 years, 60% Crohn's Disease, median disease duration 9.5 years, 26% prior IBD surgery, 33% prior azathioprine use, 36% smokers. They were treated with anti-TNF therapy (n=19) anti-integrin therapy (n=8) and anti-IL 12/23 therapy (n=4). The majority (20%) of patients had a history of hematologic malignancy (lymphomas, myeloproliferative disorders, leukemias), 13% with a virus related cancer and 66% with curative surgery. Patients were classified retrospectively as 63% low risk, 13% intermediate risk and 10% high risk. Four patients ) with active cancer (2 with lung cancer and 2 with myeloproliferative disorders) continue to receive biologic therapy for IBD and oncological therapy with no signs of progression from both diseases. All but 3 patients have remained in steroid free clinical remission: 3 had IBD-related surgery. Median follow up under biologic therapy was 5.5 years: only 2 patients showed cancer recurrence: 1 patient with breast cancer developed bone metastases and finally died, and 1 patient with colon cancer developed bladder cancer and died as well. Both patients were classified as high risk.
In both patients biologic therapy was interrupted and that resulted in administration of high-dose steroids and IBD-related hospitalizations and infections (pneumonia, C Difficile colitis).

Conclusion

In this cohort of cancer patients with IBD treated with biologics and followed up for more than 5 years the risk of cancer recurrence was low and not unexpected in oncology terms.
Biologic therapy was successful in the majority of patients and kept them off surgeries and steroids for their underlying IBD. We need more smart and innovative ways to study this particular clinical scenario in the future.

Introduction

Ulcerative colitis (UC) is a chronic and relapsing disease for which the number of biological therapies available are increasing over the years. Data comparing the effectiveness of a second anti-TNFɑ (aTNF) and the switch to a different mechanism of action (MoA) such as Ustekinumab (UST), Vedolizumab (VDZ), Filgotinib or Tofacibinib (JAK) is lacking.

Aims & Methods

We performed a retrospective and multicenter study (6 Andalusian sites). Patients diagnosed of UC who had failed a first biological therapy with an aTNF and started a second-line biological therapy with another aTNF or a different MoA (UST, VDZ, JAK) were included. Clinical response and remission were assessed at weeks 16 and 52. The aim of our study was to evaluate the effectiveness of a second-line biological therapy with aTNF compared to a different MoA after a first aTNF failure.

Results

185 UC patients were included. There were no differences in the demographic data except for disease duration (9 years with MoA vs 13 years in aTNF, p=0.02). As first aTNF, infliximab (IFX) was the most common in both groups (49% MoA group, 56% second aTNF), followed by adalimumab (ADA) (48% MoA group, 33% second aTNF). In the second aTNF group, immunomodulators were significatively more used (60% vs 38%, p=0.003). There were no differences in the concomitant use of steroids. 80 patients received a different MoA (37 VDZ, 24 UST, 19 JAK) and 105 a second aTNF (34 IFX, 60 ADA, 11 golimumab). At week 16, 52% of patients were in clinical response (70% with another MoA vs 54% with second aTNF, p=0.07; IFX 65%, ADA 53%, VDZ 68%, UST 71%, JAK 74%, p=0.07), being 15.6% more likely to achieve response with another MoA. Clinical remission at week 16 was obtained by 36% (39% with another MoA vs 33% with second aTNF, p=0.6; IFX 47%, ADA 30%, VDZ 35%, UST 46%, JAK 37%, p=0.1). At week 52, 48% achieved clinical response (51% with another MoA vs 45% with second aTNF, p=0.8; IFX 50%, ADA 42%, VDZ 49%, UST 54%, JAK 53%, p=0.5) and 39% were in clinical remission (40% with another MoA vs 38% with second aTNF, p=0.53; IFX 50%, ADA 32%, VDZ 35%, UST 38%, JAK 53%; p=0.06). When the effectiveness is analyzed by first aTNF used, independently of the aTNF, subsequent use of a different MoA achieves better results although not significant compared to a second aTNF. Partial Mayo and calprotectin showed a significant decrease at weeks 16 and 52 in both groups. Hemoglobin and albumin levels remained similar during follow-up in both groups.

Conclusion

Second-line biological therapy is effective regardless of biological therapy used in UC, but switching to a different MoA tend to achieve better results in terms of clinical response and remission compared to a second aTNF.

Introduction

Patients suffering from ulcerative colitis (UC) have reduced life qualities and an increased risk of developing cancer. Current treatment options are limited and have a ceiling effect with remission rates of ~35%. A possible reason is the multi-factorial aetiology, which are associated with an overactivation of the immune system and a dysbiosis of the gut microbiome. An important step towards a better understanding is the characterization of epithelial lesions. Their severity is classified by the Mayo score system based on their macroscopic appearance. While previous studies analysed cellular changes within the colon in UC patients, a detailed characterization of different UC-associated lesions are still missing, which is the aim of our study in collaboration with Sanofi Pharmaceuticals.

Aims & Methods

We recruit patients with active disease at our endoscopy unit and collect different biopsies from multiple regions within these patients to compare the reproducibility of single cell RNA sequencing (scRNAseq) results of similar appearing lesions within and between patients. For the sample preparation, we performed a cellular enrichment step for immune, epithelial and stromal cells before performing 10x scRNAseq to obtain equal numbers for each cell fraction from every sampled area. Additionally, we collected stool samples and endoscopic brushes to determine the associated microbial communities by 16S rRNA sequencing.

Results

Our cellular isolation strategy allows successful recovery of fibroblast, epithelial and immune cell fractions from each lesion. All expected epithelial cell types as previously described are detected in our dataset as well. Moreover, our experimental setup to obtain comparable numbers of fibroblasts, epithelial and immune cells enables us now to investigate cell-cell communication differences within different Mayo score lesions. For example, CXCL signals increased with the severity of macroscopic lesions and involves multiple cell types. Additionally, we are in the middle of correlating microbial diversity with the corresponding disease conditions.

Conclusion

Our results provide exciting insights into cell-cell communications at an unprecedented depth, which identifies aberrant signalling pathway that may contribute to treatment failure in the clinics.

Disclosure

We have nothing to disclose

Introduction

Inflammatory bowel disease (IBD) is a complex multi-factorial disease characterized by chronic inflammation of the gastrointestinal tract. Despite significant efforts to understand the pathogenetic mechanisms of IBD, the elucidation of its etiopathology and progression is far from fully understood. The direct analysis of the intestinal tissue from the endoscopy which lead to IBD diagnosis (before starting any treatment) would the ideal samples to elucidate IBD pathogenesis.

Aims & Methods

High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed paraffin-embedded human intestinal samples from newly diagnosed patients to elucidate the potential mechanisms responsible for gut inflammation in Crohn´s disease (CD) and ulcerative colitis (UC). For this purpose, 193 formalin-fixed paraffin-embedded samples from 40 active UC patients, 67 active CD patients and 46 normal biopsies from healthy controls (HC) were analyzed. Proteins with p-value < 0.05 were considered as significantly dysregulated. Moreover, we used Ingenuity Pathway Analysis (IPA) to analyze the pathways and functions in different locations of the gut (ileum or left colon) that could be related to IBD pathogenesis.

Results

A total of 2,903 proteins were identified, of which 1,010 were differentially expressed between left colon from CD patients and HC. 1,242 proteins were differentially expressed between left colon from UC patients and HC, and 952 differential proteins discriminated between left colon from CD and UC patients. In the comparative study of ileum biopsies from Crohn's disease patients and healthy controls, 956 proteins were differentially expressed. IPA revealed multiple canonical pathways, including EIF2 signaling, regulation of eIF4 and P7056K signaling, mitochondrial dysfunction, and oxidative phosphorylation altered in ileum biopsies from CD patients compared to HC. Regarding the proteomic study in left colon samples, the main canonical pathways enrichment in the comparison of UC and CD with HC were the following: neutrophil extracellular trap signaling pathways, fatty acid oxidation, sitruin signaling pathway, tRNA charging, and mitochondrial dysfunction.

Conclusion

The proteomic results revealed dysregulated proteins and pathways in ileum and left colon biopsies from patients with active CD and UC compared to HC that may unravel key mechanisms contributing to the pathogenesis of these diseases. The results of the study serve as a starting point for hypotheses to understand the pathogenesis and search for therapeutic targets.

Introduction

After first anti-TNFɑ (aTNF) failure in ulcerative colitis (UC), switching to a different mechanism of action (MoA) could decrease the rates of failure and discontinuation compared to a second aTNF and with a better safety profile.

Aims & Methods

We performed a retrospective and multicenter study (6 Andalusian sites). Patients diagnosed of UC who had failed a first biological therapy with an aTNF and started a second-line biological therapy with another aTNF or a different MoA such as ustekinumab (UST), vedolizumab (VDZ), tofacitinib and filgobinib (JAK) were included. The aim of our study was to evaluate the long-term durability of a different MoA compared to a second aTNF after a first-line therapy failure with aTNF.

Results

185 patients with UC were included. There were no significant differences between both groups in terms of age, sex, extension of disease, extraintestinal manifestations or IMIDs, smoking habit or HLA-DQA1*05. The only significant difference was disease duration (9 years MoA vs 12 years in second aTNF, p=0.02). 80 patients received a different MoA (37 VDZ, 24 UST, 19 JAK) and 105 a second aTNF (34 IFX, 60 ADA, 11 golimumab). Duration of first aTNF, although non-significant (p=0.06), tended to be shorter in the MoA group (7 months vs 12 months in aTNF group). The most frequent cause of suspension of first aTNF in the MoA group was primary failure (46% vs 31%, p= 0.02) and in the second aTNF group was secondary failure (51% vs 35%, p=0.02). The follow-up mean was 22.4 months in the group of a different MoA and 23.3 months in the second aTNF group. 60% of patients discontinued the second-line biological treatment, 64% with aTNF vs 35% with a different MoA. Durability of therapies in the group of different MoA was significatively longer compared with second aTNF (50% vs 31.4%, p=0.036) (figure 1). UST showed the best durability (66.7%), followed by JAK (63.2%), IFX (52.9%), VDZ (32.4%), ADA (21.7%) and golimumab (18.2%), with significant differences (p=0.03). Reasons for discontinuation were primary failure in 29.7% (63.6% second aTNF vs 36.4% different MoA), secondary failure in 25.9% (64.5% second aTNF vs 35.5% different MoA) and intolerance or adverse events in 6.4% (66.6% second aTNF vs 34.4% different MoA). Adverse events were reported in 12 patients, 8 with aTNF a 4 with other MoA (2 vs 0 infusion reactions, 1 vs 1 mild infections, 2 vs 1 respiratory adverse effects, 1 vs 1 cutaneous reactions, 1 vs 0 musculoskeletal effects, 1 vs 1 neoplasia).

Conclusion

Our study shows that after a first aTNF failure in UC, a switch to a biological therapy with a different MoA achieves longer survival compared to switching to a second aTNF, with less primary and secondary failure.

Introduction

The STRIDE II guidelines recognize endoscopic healing (EH), defined by an SES-CD score ≤2 or a CDEIS score <3, as one of the main therapeutic targets in Crohn's disease (CD). Nevertheless, complete EH could reduce the risk of long-term complications in CD. The aim of this study was to assess the risk of long-term complications in CD according to the degree of EH achieved.

Aims & Methods

We conducted a prospective multicenter study that included all patients with CD undergoing colonoscopy for EH assessment between September 2019 and September 2022 in three centers and were compared outcomes of patients with complete EH (CDEIS = 0) vs partial EH (CDEIS greater than 0 but less than 4). The primary endpoint was therapeutic failure, defined as the need for drug intensification and/or corticosteroid initiation and/or CD-related hospitalization and/or development of a luminal strictures/fistula and/or perianal CD and/or the need for intestinal resection.

Results

A total of 128 patients were included with a median disease duration of 10 (IQR, 4-18) years. Fifty-six (43%) patients had ileocolonic location and 79 (62%) an inflammatory (B1) behavior. Patients had been on treatment for a median of 12 months (8.3-24.3) prior to colonoscopy and 81 (63%) patients had complete EH. After a median follow-up of 22.5 months [IQR, 19.3-23.7], therapeutic failure was observed in 40 patients (31%). The risk of therapeutic failure was significantly higher among patients with partial EH group (25% vs. 43% p = 0.036, HR = 1.90; IC95% = [1.02 - 3.53]; p=0.043). The risk of CD-related hospitalizations (2.5% vs. 17%), p=0.005, HR= 7.09; IC95% = [1.51 – 33.4]; p=0.013) was significantly higher in patients with partial EH. The risk of intestinal resection, steroid initiation and drug intensification among patients with complete and partial EH, were 0% vs. 4.3% (p=0.13), 2.5% vs. 11% (p=0.1) and 22% vs. 36% (p=0.088), respectively.

Conclusion

This prospective multicenter study confirms that complete endoscopic healing is associated with better long-term outcomes than partial endoscopic healing in patients with CD, as well as fewer hospitalizations and an overall decreased risk of treatment failure.