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Nearly one-third of patients with inflammatory bowel disease (IBD) do not achieve remission despite our best therapies. When this happens, it is critical to understand the reason for treatment failure. Once nonresponse is confirmed, these patients should be referred to an IBD centre for multidisciplinary care. This review will discuss the remaining treatment options, including escalation of biologics to unlicensed doses, combination biologics, nonvalidated therapies and surgical options. It will additionally provide updates in the management of acute severe ulcerative colitis (ASUC).There is an increasing interest in combination biologics to treat refractory IBD, although data supporting its safety and effectiveness are limited. The use of hyperbaric oxygen, mesenchymal stem cell therapy and dietary interventions also show early promise in this area. Studies have additionally focused on personalized therapy to identify aggressive phenotypes and predict treatment response in these challenging patients. In ASUC, infliximab and cyclosporine remain mainstays of treatment, and tofacitinib shows promise as a salvage therapy.Refractory IBD is common, yet large knowledge gaps remain. Recent and ongoing studies have focused on medical, surgical and dietary approaches with mixed success. Larger prospective studies are desperately needed to address this complex issue.

BackgroundPatients with chronic inflammatory disease (CID) treated with immunosuppressive medications have increased risk for severe COVID-19. Although mRNA-based SARS-CoV-2 vaccination provides protection in immunocompetent persons, immunogenicity in immunosuppressed patients with CID is unclear.ObjectiveTo determine the immunogenicity of mRNA-based SARS-CoV-2 vaccines in patients with CID.DesignProspective observational cohort study.SettingTwo U.S. CID referral centers.ParticipantsVolunteer sample of adults with confirmed CID eligible for early COVID-19 vaccination, including hospital employees of any age and patients older than 65 years. Immunocompetent participants were recruited separately from hospital employees. All participants received 2 doses of mRNA vaccine against SARS-CoV-2 between 10 December 2020 and 20 March 2021. Participants were assessed within 2 weeks before vaccination and 20 days after final vaccination.MeasurementsAnti-SARS-CoV-2 spike (S) IgG+ binding in all participants, and neutralizing antibody titers and circulating S-specific plasmablasts in a subset to assess humoral response after vaccination.ResultsMost of the 133 participants with CID (88.7%) and all 53 immunocompetent participants developed antibodies in response to mRNA-based SARS-CoV-2 vaccination, although some with CID developed numerically lower titers of anti-S IgG. Anti-S IgG antibody titers after vaccination were lower in participants with CID receiving glucocorticoids (n=17) than in those not receiving them; the geometric mean of anti-S IgG antibodies was 357 (95% CI, 96 to 1324) for participants receiving prednisone versus 2190 (CI, 1598 to 3002) for those not receiving it. Anti-S IgG antibody titers were also lower in those receiving B-cell depletion therapy (BCDT) (n=10). Measures of immunogenicity differed numerically between those who were and those who were not receiving antimetabolites (n=48), tumor necrosis factor inhibitors (n=39), and Janus kinase inhibitors (n=11); however, 95% CIs were wide and overlapped. Neutralization titers seemed generally consistent with anti-S IgG results. Results were not adjusted for differences in baseline clinical factors, including other immunosuppressant therapies.LimitationsSmall sample that lacked demographic diversity, and residual confounding.ConclusionCompared with nonusers, patients with CID treated with glucocorticoids and BCDT seem to have lower SARS-CoV-2 vaccine-induced antibody responses. These preliminary findings require confirmation in a larger study.Primary funding sourceThe Leona M. and Harry B. Helmsley Charitable Trust, Marcus Program in Precision Medicine Innovation, National Center for Advancing Translational Sciences, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Numerous tools have emerged over recent decades to aid in the increasingly complex management of patients with Crohn's disease (CD) beyond endoscopy, including video capsule endoscopy, magnetic resonance enterography, computed tomography enterography, a variety of biomarkers, and even wearable biosensors and smartphone applications. These tools have allowed for a more sophisticated and less invasive complementary approach to the evaluation of disease activity and treatment response in patients with CD. This article details the characteristics, practical application, and limitations of these various modalities and discusses how updated guidelines are now incorporating many of them into a treat-to-target strategy.

BackgroundIndividuals with chronic inflammatory diseases (CID) are frequently treated with immunosuppressive medications that can increase their risk of severe COVID-19. While novel mRNA-based SARS-CoV-2 vaccination platforms provide robust protection in immunocompetent individuals, the immunogenicity in CID patients on immunosuppression is not well established. Therefore, determining the effectiveness of SARS-CoV-2 vaccines in the setting of immunosuppression is essential to risk-stratify CID patients with impaired protection and provide clinical guidance regarding medication management.MethodsWe conducted a prospective assessment of mRNA-based vaccine immunogenicity in 133 adults with CIDs and 53 immunocompetent controls. Blood from participants over 18 years of age was collected before initial immunization and 1-2 weeks after the second immunization. Serum anti-SARS-CoV-2 spike (S) IgG+ binding, neutralizing antibody titers, and circulating S-specific plasmablasts were quantified to assess the magnitude and quality of the humoral response following vaccination.ResultsCompared to immunocompetent controls, a three-fold reduction in anti-S IgG titers (P=0.009) and SARS-CoV-2 neutralization (pConclusionsCID patients treated with immunosuppressive therapies exhibit impaired SARS-CoV-2 vaccine-induced immunity, with glucocorticoids and B cell depletion therapy more severely impeding optimal responses.

BACKGROUND Pseudoachalasia manifests high-resolution manometry (HRM) findings of achalasia but results from a secondary process. We analyzed clinical and HRM characteristics of pseudoachalasia, including malignant and non-malignant subtypes. METHODS High-resolution manometry was retrospectively reviewed in patients with confirmed pseudoachalasia, and corroborated with endoscopic and radiographic studies. A control cohort of idiopathic achalasia patients was identified. Clinical characteristics, Eckardt score, and HRM metrics were extracted from institutional records. Grouped data and medians (interquartile range) were compared between pseudoachalasia and idiopathic achalasia, and between malignant and non-malignant pseudoachalasia, using parametric and non-parametric statistical tests. KEY RESULTS Of 28 pseudoachalasia patients (62.2 ± 2.5 years, 60.7% female), 18 (64.3%) had malignancy, and 10 (35.7%) had non-malignant obstruction. Although Eckardt score did not differentiate pseudoachalasia from 58 achalasia patients (55.9 ± 2.5 years, 53.4% female), weight loss was greater (median 9.1 [5.0-18.5] vs 3.6 [0-9.1] kg, P

Cholangiocyte proliferation is regulated in a coordinated fashion by many neuroendocrine factors through autocrine and paracrine mechanisms. The renin-angiotensin system (RAS) is known to play a role in the activation of hepatic stellate cells and blocking the RAS attenuates hepatic fibrosis. We investigated the role of the RAS during extrahepatic cholestasis induced by bile duct ligation (BDL). In this study, we used normal and BDL rats that were treated with control, angiotensin II (ANG II), or losartan for 2 wk. In vitro studies were performed in a primary rat cholangiocyte cell line (NRIC). The expression of renin, angiotensin-converting enzyme, angiotensinogen, and angiotensin receptor type 1 was evaluated by immunohistochemistry (IHC), real-time PCR, and FACs and found to be increased in BDL compared with normal rat. The levels of ANG II were evaluated by ELISA and found to be increased in serum and conditioned media of cholangiocytes from BDL compared with normal rats. Treatment with ANG II increased biliary mass and proliferation in both normal and BDL rats. Losartan attenuated BDL-induced biliary proliferation. In vitro, ANG II stimulated NRIC proliferation via increased intracellular cAMP levels and activation of the PKA/ERK/CREB intracellular signaling pathway. ANG II stimulated a significant increase in Sirius red staining and IHC for fibronectin that was blocked by angiotensin receptor blockade. In vitro, ANG II stimulated the gene expression of collagen 1A1, fibronectin 1, and IL-6. These results indicate that cholangiocytes express a local RAS and that ANG II plays an important role in regulating biliary proliferation and fibrosis during extraheptic cholestasis.