The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn's disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4 + CD45RB hi T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.

BACKGROUND & AIM: Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF)a biologics, are at high risk for vaccine-preventable infections. Their ability to mount adequate vaccine responses is unclear. The aim of the study was to assess serologic responses to messenger RNA-Coronavirus Disease 2019 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared with healthy controls (HCs). METHODS: Prospective, controlled, multicenter Israeli study. Subjects enrolled received 2 BNT162b2 (Pfizer/BioNTech) doses. Anti-Gastroenterology 2021;-:1-14 CLINICAL ATspike antibody levels and functional activity, anti-TNFa levels and adverse events (AEs) were detected longitudinally. RE-SULTS: Overall, 258 subjects: 185 IBD (67 treated with anti-TNFa, 118 non-anti-TNFa), and 73 HCs. After the first vaccine dose, all HCs were seropositive, whereas w7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose, all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFa treated compared with non-anti-TNFa treated patients, and HCs (both P < .001). Neutralizing and inhibitory functions were both lower in anti-TNFa treated compared with non-anti-TNFa treated patients, and HCs (P < .03; P < .0001, respectively). Anti-TNFa drug levels and vaccine responses did not affect anti-spike levels. Infection rate (w2%) and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2. CONCLUSIONS: In this prospective study in patients with IBD stratified according to treatment, all patients mounted serologic response to 2 doses of BNT162b2; however, its magnitude was significantly lower in patients treated with anti-TNFa, regardless of administration timing and drug levels. Vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered.

Background and aims: Many inflammatory bowel disease (IBD) patients do not respond to medical therapy. Tofacitinib is a first in class, partially selective inhibitor of Janus kinase, recently approved for treating patients with ulcerative colitis (UC). We describe our experience with the use of tofacitinib for treatment of patients with moderate-to-severe IBD. Methods: This is a retrospective, observational study of the use of tofacitinib in IBD. Patients with medically resistant IBD were treated orally with 5 mg or 10 mg twice daily. Clinical response and adverse events were assessed at 8, 26, and 52 weeks. Objective response was assessed endoscopically, radiologically, and biochemically. Results: 58 patients (53 UC, 4 Crohn’s, 1 pouchitis) completed at least 8 weeks of treatment with tofacitinib. 93% of the patients previously failed treatment with anti-TNF. At 8 weeks of treatment, 21 patients (36%) achieved a clinical response, and 19 (33%) achieved clinical remission. Steroid-free remission at 8 weeks was achieved in 15 (26%) patients. Of the 48 patients followed for 26 weeks, 21% had clinical, steroid-free remission. Of the 26 patients followed for 12 months, 27% were in clinical, steroid-free remission. Twelve episodes of systemic infections were noted, mostly while on concomitant steroids. One episode of zoster infection was noted during follow up. Conclusions: In this cohort of patients with moderate-to-severe, anti-TNF resistant IBD, tofacitinib induced clinical response in 69% of patients. 27% were in clinical, steroid-free remission by one year of treatment. Tofacitinib is an effective therapeutic option for this challenging patient population.

Background Endoscopic-post-operative-recurrence (ePOR) in Crohn’s disease (CD) after ileocecal resection (ICR) is a major concern. We aimed to evaluate the effectiveness of early prophylaxis with biologics and to compare anti-TNF therapy to vedolizumab (VDZ) and ustekinumab (UST) in a real-world setting. Methods A retrospective multicenter study of CD-adults after curative ICR on early prophylaxis. ePOR was defined as a Rutgeerts score [RS]≥i2 or colonic-segmental-SES-CD≥6. Multivariable logistic regression was used to evaluate risk factors, and inverse probability treatment weighting (IPTW) was applied to compare the effectiveness between agents. Results Included 297 patients (53.9% males, age at diagnosis 24y[19-32], age at ICR-34y[26-43], 18.5% smokers, 27.6% biologic-naïve, 65.7% anti-TNF experienced, 28.6%≥2 biologics, and 17.2% previous surgery). Overall, 224, 39 and 34 patients received anti-TNF, VDZ or UST, respectively. Patients treated with VDZ and UST were more biologic experienced with higher rates of previous surgery. ePOR rates within 1-year were: 41.8%. ePOR rates by treatment groups: anti-TNF 40.2%, VDZ 33% and UST 61.8%. Risk factors for ePOR at 1-year: past-infliximab (adj.OR=1.73[95%CI:1.01-2.97]), past-adalimumab (adj.OR=2.32[95% CI:1.35-4.01) and surgical aspects. After IPTW, the risk of ePOR within 1-year of VDZ vs. anti-TNF or UST vs. anti-TNF was comparable (OR=0.55[95%CI:0.25-1.19], OR=1.86[95%CI:0.79-4.38]), respectively. Conclusion Prevention of ePOR within 1-year after surgery was successful in ~60% of patients. Patients treated with VDZ or UST consisted of a more refractory group. After controlling for confounders, no differences in ePOR risk were seen between anti-TNF prophylaxis and other groups.