Gastrointestinal Adverse Events Induced by Immune-Checkpoint Inhibitors

<b><i>Background:</i></b> As immune-checkpoint inhibitors (ICI) are becoming standard therapies for malignant tumors, increasing attention has been paid to their associated immune-related adverse events (irAEs). The gastrointestinal tract is the major site of irAEs, and it has recently become evident that the large bowel is the most frequently affected region. The aim of this narrative review was to clarify the endoscopic and histopathologic findings of and treatments for ICI-induced colitis. <b><i>Summary:</i></b> Endoscopic findings of ICI-induced colitis include a reddish, edematous mucosa with increased mucous exudate, loss of normal vascularity, and a granular mucosa with or without mucosal breaks. Histopathologic findings of ICI-induced colitis are expansion of the lamina propria, intraepithelial infiltration of neutrophils, crypt architectural distortion, neutrophilic crypt abscess, and prominent apoptosis. The clinical, endoscopic, and histopathologic severity of ICI-induced colitis is diverse, but colonoscopy together with biopsy is necessary for diagnosis. While a certain proportion of patients with ICI-induced colitis have an intractable clinical course, management guidelines are based on retrospective analyses. Prospective studies are needed to assess the efficacy of various medications, including immunosuppressive regimens. <b><i>Key Messages:</i></b> Colonoscopy with biopsy is the gold standard for the diagnosis of ICI-induced colitis. Endoscopists should be aware of the clinical features and pathophysiology of ICI-induced colitis for prompt diagnosis and treatment planning.

Proposed grading scheme for inflammatory bowel disease in ferrets and correlation with clinical signs

Inflammatory bowel disease (IBD) is an idiopathic, chronic, inflammatory disease of the gastrointestinal tract of companion animals, including ferrets ( Mustela putorius furo). Clinical signs of IBD are nonspecific, and intestinal biopsies are necessary for a definitive diagnosis. A grading scheme has not been established for ferrets. Additionally, the association between histologic severity and clinical signs in ferrets is unknown. We evaluated enteric samples from ferrets diagnosed with IBD, compared histologic grading schemes, and correlated the results with the severity of clinical signs. Enteric sections from 23 ferrets with IBD were analyzed using grading schemes for intestinal inflammation in cats and dogs, and a correlation with clinical signs was evaluated. After dividing the histologic samples into groups based on the severity of clinical signs, main histologic differences were identified. Age and sex were also assessed for correlation with clinical signs. No significant correlation was found between the 2 grading schemes and clinical signs (rho = 0.02, p = 0.89; rho = 0.26, p = 0.18, respectively). Degree of villus fusion, hemorrhage and/or fibrin, epithelial damage, inflammation density, and crypt abscess formation were used retrospectively to create a ferret IBD grading scheme, which was significantly correlated with the severity of clinical signs (rho = 0.48, p = 0.01). A positive correlation was observed between age ( p = 0.04) and females ( p = 0.007) with severity of clinical signs. Our ferret grading scheme may have clinical utility in providing a more objective, consistent evaluation of IBD in ferrets.

A Rare Cause of Pulmonary Nodules

Crohn’s disease is a chronic, idiopathic autoimmune disorder that primarily targets the gastrointestinal (GI) system. It is characterized by transmural inflammation of the GI tract that can occur anywhere from the mouth to the anus. Not infrequently, the disease may also have extraintestinal manifestations (EIMs) that can affect almost any organ system. It is estimated that EIMs affect up to 36% of patients with Crohn’s disease, but the incidence and prevalence of pulmonary involvement are variable in the literature and may be as low as 0.4%. There are few case reports documenting pulmonary manifestations, as they are often overlooked, especially if respiratory symptoms are present before the diagnosis of GI manifestations, as in the present case. A 44-year-old otherwise healthy woman presented with nonspecific respiratory complaints, recurrent pneumonias, and multiple computed tomography images showing diffuse, migratory, nodular, and consolidative parenchymal lung disease, with a largely unremarkable infectious and rheumatologic evaluation. Lung biopsy revealed necrotizing and nonnecrotizing granulomas, raising concern for sarcoidosis. Subsequent imaging revealed an incidental mass in the cecum. Biopsy of the cecum lesion revealed acute cryptitis, crypt abscess, and a single poorly formed granuloma, suggesting the possibility of Crohn’s disease. In this report, we present a patient whose pulmonary manifestations ultimately led to the diagnosis of Crohn’s disease.

Magnifying Endoscopic Findings Can Predict Clinical Outcome during Long-Term Follow-Up of More Than 12 Months in Patients with Ulcerative Colitis

Background and Aims. To explore the association of magnifying endoscopic (ME) findings with histopathology and relapse in ulcerative colitis (UC).Methods. Forty-six patients with UC underwent ME with narrow band imaging (NBI) and crystal violet staining and were followed for more than 12 months. ME findings with vital staining were classified into ME-A, regular arrangement of round to oval pits; ME-B, irregular arrangement with/without enlarged spaces between even pits; ME-C, irregular pits in size and shape with more irregular arrangement of pits; and ME-D, disrupted or disappeared pits. NBI-guided ME features of microvascular pattern (MVP) were divided into the MVP-regular and MVP-irregular type.Results. There were 5, 24, 10, and 7 cases of ME-A, ME-B, ME-C, and ME-D grade, respectively, while there were 21 and 25 of MVP-regular and MVP-irregular type, respectively. ME classifications were significantly associated with Matts endoscopic grade. ME classifications and MVP types were significantly associated with each pathognomonic microscopic feature of severe mucosal inflammation, crypt abscess, and goblet cell depletion. There were significant differences in the percentages of remission among ME classifications and between MVP types.Conclusion. ME findings can be predictive of relapse in UC and reliable forin vivohistopathological assessment.

Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis

Interleukin 2 (IL-2)- and IL-10-knockout mice develop spontaneous colitis under conventional but not germ-free conditions, suggesting that commensal bacteria play an important role in the pathogenesis of colitis. However, interactions between commensal bacteria and colonic epithelial cells have not been fully investigated. We therefore assessed the ability of various commensal bacteria and probiotics to adhere to and invade colonic epithelial cells. Effects of the bacteria on production of proinflammatory cytokines were also measured. Commensal bacteria, including mucosal organisms isolated from ulcerative colitis (UC) patients, such as Fusobacterium varium, reported as a possible pathogen in UC, Bacteroides vulgatus, Escherichia coli and Clostridium clostridioforme, as well as their type strains and probiotics, were assessed for their ability to adhere to and invade colonic epithelial cells using two cell lines, SW-480 and HT-29. Our experiments employed co-incubation, a combination of scanning and transmission electron microscopy and recovery of bacteria from infected-cell lysates. F. varium and several other commensal bacteria, but not probiotics, adhered to colonic epithelial cells and invaded their cytoplasm. ELISA and real-time PCR revealed that the host cells, particularly those invaded by F. varium, showed significant increases in IL-8 and TNF-α concentrations in supernatants, with elevation of IL-8, TNF-α, MCP-1 and IL-6 mRNAs. Furthermore, IL-8 and TNF-α expression and nuclear phosphorylated NF-κB p65 expression could be immunohistochemically confirmed in inflamed epithelium with cryptitis or crypt abscess in UC patients. Certain commensal bacteria can invade colonic epithelial cells, activating early intracellular signalling systems to trigger host inflammatory reactions.