Publications

INTRODUCTION: Stricturing Crohn's disease is a common phenotype and treatment aims to improve symptoms, prevent complications, assess for proximal bowel disease activity, and screen for upstream neoplasm. Management is challenging due to diagnostic limitations, stricture composition, and recurrence rate.

AREAS COVERED: Categorizing a stricture as inflammatory or fibrotic is necessary to determine appropriate management. Inflammatory strictures are treated with medical therapy, and fibrostenotic strictures require endoscopic or surgical management. While EBD is increasingly utilized, stricture recurrence rates remain high, necessitating repeat endoscopic procedures or surgery. We performed a PubMed (MEDLINE database) search for the latest research on IBD-related stricture management, including detection, diagnosis, and medical and procedural therapies. We highlight the current literature on endoscopic techniques for the treatment of intestinal strictures and future areas of research.

EXPERT OPINION: The field of intestinal stricture management is expected to evolve in the coming years and will include enhanced imaging modalities, medication optimization, and increasing use of advanced endoscopic techniques.

Therapeutic drug monitoring (TDM) for dose modification of biologics has the potential to improve patient outcomes. The US Food and Drug Administration (FDA) and the American Association of Pharmaceutical Scientists (AAPS) hosted the first US-based public workshop on TDM of biologics with contributions from a broad array of interested parties including healthcare providers, clinical pharmacologists, test developers, bioanalysis and immunogenicity scientists, health economics and outcomes research (HEOR) experts and regulators. The key insight was that despite a body of evidence to support TDM in certain therapeutic areas, there remain substantial challenges to widespread clinical implementation. There is a lack of consensus regarding the integration of TDM in clinical guidelines, and a lack of consensus on the cost-effectiveness of TDM; both factors contribute to the difficulty that healthcare providers face in obtaining reimbursement for TDM (both coverage of testing itself, and coverage of potential dosing modifications). The HEOR experts outlined alternative routes to obtaining reimbursement and suggested advocating for changes in coverage policies to promote TDM use in the clinic. Reaching alignment across policy makers, patients and advocacy groups, payers, and healthcare providers, on specific treatment settings where TDM will be clearly beneficial, was identified as an important step to advancing TDM implementation for the benefit of patients.

INTRODUCTION: Approximately one in every four patients with ulcerative colitis will develop acute severe ulcerative colitis (ASUC). Historically, this was managed with intravenous steroids and surgery when steroids failed. The use of rescue therapy.

AREAS COVERED: This review summarizes the latest research in the management of hospitalized patients with ASUC. Covering the historical data and success of rescue therapy with cyclosporine and then with infliximab changed outcomes and reduced the risk of colectomy during the hospitalization and at 1 year. More recently, more biologics and small molecules have been approved and more patients present to the hospital with ASUC already failing anti-tumor necrosis factor antagonists. More recent studies have shown some efficacy of rescue therapy with other classes of biologics (e.g. interleukins and anti-integrins). The more recently approved small molecules (i.e. tofacitinib and Upadacitinib) have shown a rapid onset in therapeutic efficacy in as little as 1 day with sustained response at 1 year in reducing the risk of colectomy following ASUC.

EXPERT OPINION: In the expert opinion, we discuss the challenges in the treatment of patients with ASUC. We summarize the data of current biologics and new small molecules and their emerging roles in the management of ASUC.

BACKGROUND: Adoptive transfer of regulatory T cells (Tregs) has been proposed as a next-generation treatment approach for the treatment of various inflammatory or autoimmune disorders(Amini et al., 2022; Bluestone et al., 2023, 2015; Dall'Era et al., 2019; Chandran et al., 2017; Laukova and Glatman Zaretsky, 2023; Voskens et al., 2023; Canavan et al., 20161-8), inclusive of inflammatory bowel diseases (IBD). Identification of the appropriate Treg populations as donor sources for effective cell therapy is of great importance. We have recently identified specialized Tregs that localize within the hematopoietic stem cell (HSC) microenvironments(Fujisaki et al., 2011; Hirata et al., 2018, 2019, 2015; Kakiuchi et al., 2021a, 2021b; Furuhashi et al., 20259-16) of bone marrow (BM), termed HSC niches. These BM niche Tregs exhibit robust anti-inflammatory and pro-regenerative effects and render HSCs immune privileged. The transfer of BM niche Tregs exhibits high therapeutic effects against BM transplantation and injury(Hirata et al., 2018; Kakiuchi et al., 2021b10, 14). Yet, the treatment effects of transferred BM niche Tregs in non-BM disease settings remain unknown.

OBJECTIVES: We investigated the therapeutic effects of transfer of BM niche Tregs for IBD using mouse models of experimental colitis. To identify the key effector molecule of niche Tregs, we further examined the roles of cell-surface ectoenzyme CD39 expressed at high levels by BM niche Tregs.

STUDY DESIGN: Mouse colitis was induced by administering dextran sulfate sodium salt. Subsequently, the mice received intravenous injections of BM niche Tregs, BM non-niche Tregs, lymph node Tregs, or vehicle alone. We compared these treatment effects on clinical scores, histopathological features and profiles of immune cells. We also tested how targeted deletion of CD39 in the adoptively transferred Tregs impacted experimental outcomes.

RESULTS: The transfer of as few as 1.5 × 104 BM niche Tregs per mouse ameliorated clinical and histopathological features of the mouse colitis far better than the transfer of other Tregs. The transfer of BM niche Tregs inhibited the generation of Th17 cells and promoted the regeneration and recovery of the colon tissue. Targeted deletion of CD39 in Tregs abrogated therapeutic effects of transferred BM niche Tregs.

CONCLUSION: We show robust therapeutic effects of the transfer of BM niche Tregs in the experimental model of colitis. Donor niche Tregs mediate anti-inflammatory and pro-regenerative effects via Treg CD39. Our work suggests the transfer of BM niche Tregs is a promising approach to treat colitic disorders and boost tissue regeneration.

BACKGROUND AND AIMS: Disordered eating is frequently reported in patients with inflammatory bowel disease (IBD). We aimed to describe the prevalence of avoidant restrictive food intake disorder (ARFID) in patients with IBD and to identify predictors of ARFID.

METHODS: Patients with IBD at 2 academic medical centers completed questionnaires including the ARFID subscale of the Pica, ARFID, and Rumination Disorder Questionnaire (PARDI-AR-Q), disease characteristics, and psychosocial variables. IBD disease activity was determined by a review of objective data within 90 days of survey completion.

RESULTS: Three hundred and twenty-five participants completed the questionnaires (56% female, average age 47.60 years, 49.5% Crohn's disease (CD), 45.5% ulcerative colitis (UC)). Using the PARDI-AR-Q, 17.8% of the total sample screened positive for ARFID. ARFID+ respondents were younger, had shorter disease duration, and worse psychosocial functioning compared to ARFID-. A higher percentage of ARFID+ patients had objective disease activity compared to ARFID- (51% vs. 40%), but this was not statistically significant. There was no statistical difference in ARFID rates between patients with CD compared to UC. In patients with inactive disease only, 16.3% screened positive for ARFID. In hierarchical logistic regression, the only significant predictor of ARFID among patients with inactive IBD was GI-specific anxiety.

CONCLUSIONS: In this multi-center study, 16.3% of patients with inactive IBD met the criteria for ARFID, and 17.8% of all patients met the criteria regardless of objective disease activity. GI-specific anxiety was the only predictor of ARFID among patients with inactive IBD, highlighting the need for multidisciplinary care in IBD.

Upadacitinib is an oral Janus kinase inhibitor approved to treat moderate-to-severe ulcerative colitis. Studies have shown that upadacitinib is highly effective, though use has been limited in certain populations due to concerns of side effects. Outside of animal studies and rare case reports, there are little data for the safety of upadacitinib use in pregnancy. We report a case of a patient with left-sided ulcerative colitis recurrently exacerbated by pregnancies who responded to upadacitinib in her fourth pregnancy. Additional data will be helpful to establish the safety for Janus kinase inhibitors for treatment of inflammatory bowel disease patients during pregnancy.

BACKGROUND & AIMS: Juvenile autoimmune liver disease (JAILD) comprises autoimmune hepatitis and autoimmune sclerosing cholangitis. JAILD-predisposing genes include HLA-DR3,DR7, DR13 and haplotype A1-B8-DR3. Mechanisms leading to liver autoimmunity remain elusive, though JAILD patients have aberrated immunoregulation. We investigated the influence of HLA genes on immune cells, focusing on T-cells and frequency and function of T regulatory cells (Tregs) in JAILD patients, their first-degree-relatives (FDRs) and healthy controls (HCs).

METHODS: HLA class I and II genotypes were defined by PCR and peripheral blood mononuclear cells were immunophenotyped by FACS in 82 patients, 72 FDRs, 50 HCs. Treg function was tested by inhibition of CD4posCD25neg T-cell proliferation. Links between HLA genes, Treg frequency/function, pro-inflammatory/immunoregulatory cytokines, soluble and membrane-bound programmed cell death-1 (PD-1) were investigated.

RESULTS: Proportion of subjects carrying HLA DR3/DR7/DR13 was 88 %, 92 %, 64 % in patients, FDRs and HCs. Circulating Treg frequency was lower in patients and FDRs than HCs. Inhibitory capacity of Tregs was lower in patients but similar in FDRs compared to HCs. FDRs possessing HLA DR3/DR7/DR13 genes had Treg frequencies lower than those without. PD-1 posCD4pos T-cells were fewer in patients than HCs; PD-1posCD8pos T-cells were fewer in patients and FDRs than HCs. Patient plasma levels of IFN-γ were higher, and ratios of IFN-γ/IL-10 and IFN-γ/IL-2 lower than in HCs. All nine FDRs with autoimmune disorders had HLA DR3/DR7/DR13 genes and lower Treg frequency than those without autoimmune disorders and HCs.

CONCLUSION: We show a link between HLA disease-predisposing genes and defective immunoregulation not only in JAILD patients, but also in their FDRs, who are prone to autoimmune disorders.

Defective CD39 levels contribute to an imbalance between Tregs and Th17 effectors in inflammatory bowel disease (IBD). CD39 initiates an ATP hydrolysis cascade that culminates with the generation of adenosine, an immune metabolite that is key to tissue homeostasis. Human CD39 is regulated by an endogenous antisense RNA (CD39-AS) that is markedly elevated in IBD Tregs and Th17 cells. In this study, we investigated how CD39-AS affects the function of Tregs and Th17 cells in healthy subjects and IBD patients. We report that CD39-AS RNA is present in two main splice variants that are specifically expressed by Tregs or Th17 cells. Blockade of CD39-AS via self-delivering oligonucleotides targeting the splice variant expressed in Tregs results in a decrease of glucose transport and glycolysis and in enhanced Treg function and stability in IBD. In Th17 cells, silencing of CD39-AS limits oxidative responses and ameliorates mitochondrial health. These metabolic effects are also noted in a model of experimental colitis in humanized mice, along with reduced disease activity. Thus, in vivo administration of oligonucleotides targeting the Treg or Th17 cell CD39-AS variant limits disease activity, decreases the expression of GLUT1 and improves mitochondrial health in gut-derived CD4 lymphocytes. Mechanistically, activation of HIF-1α and STAT3 results in the upregulation of CD39-AS in IBD cells. In conclusion, CD39-AS is an important modulator of Treg and Th17 cell metabolism. Interference with this antisense RNA, or the factors favoring its upregulation, might contain inflammation and halt disease progression in IBD by restoring immune metabolism and Treg functional stability.

Objective: Vicarious trauma (VT) is "secondhand" trauma healthcare workers experience when interacting with trauma survivors. The prospective relationship between workers' VT symptoms and physical health has not been studied.Methods: Survey data from 775 hospital workers were linked to health insurance expenditures to identify stress-related conditions known as disorders of gut-brain interaction (DGBI) occurrence within one-year follow-up. VT symptoms (modeled continuously and categorically) and conditional odds of developing DGBI were assessed with multilevel logistic regression.Results: Conditional odds of DGBI increased 4% for every one-point increase in VT symptom score (95% CI: 0.98-1.11, p = 0.17). Participants with high versus low VT symptoms had 3.40-times the conditional odds of DGBI (95% CI: 1.44-8.06, p = 0.01).Conclusion: Workers with high versus low VT symptoms had significantly higher odds of developing DGBIs, indicating that VT may adversely impact workers' physical health.