Comprehensive overview of novel chemical drugs for ulcerative colitis: focusing on phase 3 and beyond.

INTRODUCTION: Despite the growing number of highly efficacious biologics and chemical drugs for ulcerative colitis (UC), steroid-free disease control is still difficult to achieve in subgroups of patients due to refractoriness, adverse events, primary or secondary failure. New treatments are therefore still required in order to optimize clinical management of patients with UC. AREAS COVERED: The efficacy and safety of both currently available and newly developed small molecules have been summarized. The PubMed database and clinicaltrials.gov were considered in order to search for phase 2b and 3 trials on new chemical drugs for UC. The study drugs reviewed included Janus kinases (JAK) and sphingosine-1-phosphate receptor (S1Pr) inhibitors, α4 integrin antagonist, and micro-RNA-124 upregulators. EXPERT OPINION: Rapidity of onset, low immunogenicity, and safety are the main characteristics of small molecules currently available or under evaluation for treatment patients with UC. Among the currently available chemical drugs, the selective JAK and the S1Pr inhibitors are characterized by a good safety profile combined with the ability to induce clinical remission in UC. A relatively low frequency of endoscopic improvement and healing currently appears associated with their use, being higher in UC patients treated with S1Pr inhibitor Etrasimod. Overall, additional new safe and effective drugs are still required in order to optimize disease control in a larger majority of UC patients.

Frequency and Predictors of Dysplasia in Pseudopolyp-like Colorectal Lesions in Patients with Long-Standing Inflammatory Bowel Disease.

Current endoscopic surveillance programs do not consider inflammatory bowel disease (IBD)-associated post-inflammatory polyps (pseudopolyps) per se clinically relevant, even though their presence seems to increase the risk of colorectal cancer (CRC). However, it remains unclear whether the link between pseudopolyps and CRC is indirect or whether some subsets of pseudopolyp-like lesions might eventually undergo neoplastic transformation. This study aimed to assess the frequency and predictors of dysplasia in pseudopolyp-like lesions in a population with long-standing colonic IBD. This was a retrospective, single-center study including patients with a colonic IBD (median disease duration of 192 months) and at least a pseudopolyp-like lesion biopsied or resected in the period from April 2021 to November 2022. One hundred and five pseudopolyps were identified in 105 patients (80 with ulcerative colitis and 25 with Crohn's disease). Twenty-three out of 105 pseudopolyp samples (22%) had dysplastic foci, and half of the dysplastic lesions were hyperplastic. Multivariate analysis showed that the age of the patients (odds ratio (OR) 1.1; p = 0.0012), size (OR 1.39; p = 0.0005), and right colonic location (OR 5.32; p = 0.04) were independent predictors of dysplasia, while previous exposure to immunosuppressors/biologics and left colonic location of the lesions were inversely correlated to dysplasia (OR 0.11; p = 0.005, and OR 0.09; p = 0.0008, respectively). No differences were seen between ulcerative colitis and Crohn's disease patients. Lesions with a size greater than 5 mm had a sensitivity of 87% and a specificity of 63% to be dysplastic. These data show that one-fourth of pseudopolyp-like lesions evident during surveillance colonoscopy in patients with longstanding IBD bear dysplastic foci and suggest treating such lesions properly.

Mucinous and Signet-Ring Cell Colonic Adenocarcinoma in Inflammatory Bowel Disease: A Case-Control Study.

A higher frequency of mucinous and signet-ring cell colonic adenocarcinoma has been reported in inflammatory bowel disease (IBD). The primary aim was to investigate the frequency of mucinous and signet-ring cell colorectal adenocarcinoma in patients with IBD (Cases) versus age-matched non-IBD Controls. The secondary aims were to compare the characteristics of these two histotypes of colorectal cancer (CRC) in IBD patients vs. Controls and to search for specific risk factors in IBD. In a case-control study, all IBD patients with CRC diagnosed from 2000 to 2022 were enrolled and matched for age (1:2) with non-IBD Controls with CRC. The study population included 120 CRC patients (40 IBD, 80 Controls). In IBD, CRC included standard adenocarcinoma in 23 (57.5%) patients mucinous/signet-ring cell adenocarcinoma in 17 (42.5%) patients. The proportion of mucinous/signet-ring cell adenocarcinoma was higher in IBD than in Controls (17 [42.5%] vs. 18 [22.5%]; p = 0.03). In rectal CRC, the proportion of mucinous/signet-ring cell adenocarcinoma was higher than standard adenocarcinoma in IBD (8 [47.1%] vs. 4 [17.4%]; p = 0.04) but not in Controls (4 [22.2%] vs. 20 [32.2%]; p = 0.59). In rectal CRC, the proportion of these two histotypes was higher in Cases than in Controls (8/12 [66.6%] vs. 4/24 [16.6%]; p = 0.008), with no risk factors identified in IBD. CRC was more frequently represented by mucinous/signet-ring cell adenocarcinoma in IBD than in age-matched non-IBD Controls. In IBD, these two CRC histotypes were more frequent in the rectum.