Citations

Immune-related Adverse Events (irAEs) are the most significant toxicities associated with the use of checkpoint inhibitors, and result from disinhibition of the host’s immune homeostasis. The adverse effects experienced from immunotherapy are significantly different from those of chemotherapy and, to a lesser extent, targeted therapy. Early recognition and diagnosis of these toxicities is often challenging, but is critically important because of the potentially life-threatening nature and associated morbidity. Gastrointestinal, dermatologic, endocrine, and liver toxicities are the most commonly observed. Less commonly, the eyes, pancreas, kidneys, lungs, bone marrow, or nervous system may be affected. Although most irAEs may resolve with supportive care or discontinuation of drug, in severe cases, they may require hospitalization and immune suppressants, such as steroids, and/or may even cause death. The management of immune-related side effects requires a multidisciplinary approach.

Gut dysbiosis, host genetics, and environmental triggers are implicated as causative factors in inflammatory bowel disease (IBD), yet mechanistic insights are lacking. Longitudinal analysis of ulcerative colitis (UC) patients following total colectomy with ileal anal anastomosis (IPAA) where >50% develop pouchitis offers a unique setting to examine cause vs. effect. To recapitulate human IPAA, we employed a mouse model of surgically created blind self-filling (SFL) and self-emptying (SEL) ileal loops using wild-type (WT), IL-10 knockout (KO) (IL-10), TLR4 KO (T4), and IL-10/T4 double KO mice. After 5 wk, loop histology, host gene/protein expression, and bacterial 16s rRNA profiles were examined. SFL exhibit fecal stasis due to directional motility oriented toward the loop end, whereas SEL remain empty. In WT mice, SFL, but not SEL, develop pouchlike microbial communities without accompanying active inflammation. However, in genetically susceptible IL-10-deficient mice, SFL, but not SEL, exhibit severe inflammation and mucosal transcriptomes resembling human pouchitis. The inflammation associated with IL-10 required TLR4, as animals lacking both pathways displayed little disease. Furthermore, germ-free IL-10 mice conventionalized with SFL, but not SEL, microbiota populations develop severe colitis. These data support essential roles of stasis-induced, colon-like microbiota, TLR4-mediated colonic metaplasia, and genetic susceptibility in the development of pouchitis and possibly UC. However, these factors by themselves are not sufficient. Similarities between this model and human UC/pouchitis provide opportunities for gaining insights into the mechanistic basis of IBD and for identification of targets for novel preventative and therapeutic interventions.

SummaryBackgroundAnti‐TNFα biologics induce and maintain remission in inflammatory bowel disease (IBD). Also, they have been reported to induce or unmask idiopathic inflammatory demyelinating disease of the central nervous system (IIDD).AimTo determine if anti‐TNFα biologics increased the risk of IIDD in a large cohort of patients with IBD.MethodsWe retrospectively identified adult patients referred to the Mayo Clinic, Rochester, MN for management of IBD from a five state capture area (Minnesota, Wisconsin, North Dakota, South Dakota and Iowa) between 1996 and 2010. IIDDs were identified in both Crohn's disease (CD) and ulcerative colitis (UC) patients with and without anti‐TNFα exposure using the 2010 McDonald MRI criteria. The risk of IIDDs in patients with and without anti‐TNFα exposure was estimated for IBD; CD and UC groups separately.ResultsA total of 9095 patients with IBD were identified (4342 CD and 4753 UC). Four patients with CD with exposure to anti‐TNFα agents (4/2054) and five patients with CD without anti‐TNFα exposure (5/2288) developed a confirmed IIDD. One patient with UC with exposure to anti‐TNFα agents (1/1371) and five patients with UC without anti‐TNFα agents developed a confirmed IIDD (5/3382). The per cent of IIDDs in patients with and without anti‐TNFα exposure was; IBD: 0.15% and 0.18% (RR = 0.83, 95% CI: 0.28–2.42; P = 0.729); CD: 0.19% and 0.22% (RR = 0.89, 95% CI: 0.24–3.31; P = 0.863); UC: 0.07% and 0.15% (RR = 0.49, 95% CI: 0.06–4.22; P = 0.510).ConclusionAnti‐TNFα biologics do not appear to impact the risk of developing clinical idiopathic inflammatory demyelinating disease in patients with inflammatory bowel disease.