Janus kinase inhibitors differentially inhibit specific cytokine signals in the mesenteric lymph node cells of IBD patients.

BACKGROUND: Janus kinase (JAK) inhibitors (JAKinibs) are effective small molecule therapies for treating Crohn's Disease (CD) and Ulcerative Colitis (UC), collectively known as inflammatory bowel disease (IBD). By preventing JAKs from phosphorylating signal transducer and activator of transcription proteins, JAKinibs disrupt cytokine signaling pathways that promote inflammation. Despite considerable overlap in the JAKs they target, first and second generation JAKinibs display different clinical efficacies in CD and UC. METHODS: We conducted a comparative phosflow study of four JAKinibs (filgotinib, upadacitinib, tofacitinib, and deucravacitinib) to observe subtle mechanistic differences that may dictate their clinical behavior. Resected mesenteric lymph node (MLN) cells from 19 patients (9 CD, 10 UC) were analyzed by flow cytometry in the presence or absence of different cytokine stimuli and titrated JAKinibs. RESULTS: We found a higher potency of the JAK 1/3-preferential inhibitor, tofacitinib, for JAK 3-dependent cytokine signaling pathways in comparison to filgotinib, but a higher potency of the JAK 1-preferential inhibitors, filgotinib and upadacitinib, for JAK 3-independent cytokine signaling pathways. Deucravacitinib, a TYK2-preferential inhibitor, demonstrated a much narrower selectivity by inhibiting only IL-10 and IFN-ßpathways, albeit more potently than the other JAKinibs . Additionally, we found some differences in the sensitivity of immune cells from CD versus UC and patients with versus without a CD-associated NOD2 polymorphism to phosphorylate signal transducer and activator of transcriptions in response to specific cytokine stimulation. CONCLUSIONS: Despite their similarities, differences exist in the relative potencies of different JAKinibs against distinct cytokine families to explain their clinical efficacy.

Safe implementation of transoral incisionless fundoplication as a new technique in a tertiary care center.

BACKGROUND/AIMS: Transoral incisionless fundoplication (TIF) is an accepted anatomic treatment for gastroesophageal reflux disease in selected patients. In this report, we analyze our institution's programmatic allocation of resources during the safe implementation of TIF as a new procedure. METHODS: A retrospective analysis of all patients who underwent TIF from January 2020 to February 2021 at our institution was performed. The process of initially allocating the operating room (OR) with overnight admission and postoperative esophagram for added safety, and subsequently transitioning TIF to the endoscopy suite (ES) as an outpatient procedure was described. Patient safety and outcomes were evaluated during transition. RESULTS: Thirty patients who underwent TIF were identified. The mean age was 51.2±16.0 years. TIF was performed in an OR in nine patients (30%) and 21 (70%) in the ES. All the OR patients were admitted overnight and had routine EG. In contrast, four (19%) from the ES group required clinically-indicated admission and three (14.2%) required esophagram. The mean procedure duration was significantly lower in the ES group (65.7 min vs. 84 min, p=0.02). CONCLUSION: A stepwise, resource-efficient process was described that allowed safe initiation of TIF as a new technique and its effective transition to a fully outpatient procedure.