Publications

BACKGROUND: Therapeutic drug monitoring is important for optimizing anti-tumor necrosis factor-α (TNF-α) therapy in inflammatory bowel disease. However, the exposure-response relationship has never been assessed in pouchitis.

AIMS: To explore associations between anti-TNF-α drug concentration and pouchitis disease activity in patients with a background of ulcerative colitis.

METHODS: A retrospective, multicenter, cross-sectional study was conducted in adult patients with pouchitis requiring anti-TNF-α treatment. Rates of clinical and endoscopic remission were calculated, and drug concentrations during maintenance therapy were compared between remission and non-remission cohorts.

RESULTS: Sixty-three patients were included: median age, 48 years (IQR 36-59) and median time since pouchitis diagnosis, 7 years (IQR 2-13). Patients received infliximab, n = 27 (43%), adalimumab, n = 29 (46%), or both n = 7 (11%). Thirty-two (51%) patients received concomitant immunomodulation. Median infliximab trough concentrations (mg/ml) were similar between patients in clinical remission (n = 21) vs non-remission (n = 11), 5.3 vs. 4.4, p = 0.73. For adalimumab, median drug concentrations did not significantly differ between remission/non-remission groups based on clinical (n = 18/18), 11.4 vs 7.6, p = 0.32, or endoscopic assessment, (n = 7/29), 9.0 vs. 7.8, p = 0.78. Four patients had positive anti-drug antibodies with undetectable drug concentration.

CONCLUSION: In a cohort of patients with pouchitis, higher anti-TNF-α drug concentrations were not associated with more clinical or endoscopic remission.

In patients with disorders of gut-brain interaction (DGBI), overlapping non-gastrointestinal conditions such as fibromyalgia, headaches, gynaecological and urological conditions, sleep disturbances and fatigue are common, as is overlap among DGBI in different regions of the gastrointestinal tract. These overlaps strongly influence patient management and outcome. Shared pathophysiology could explain this scenario, but details are not fully understood. This overlap has been shown to be of great relevance for DGBI. In addition, symptoms considered to be caused by a DGBI could have a detectable organic cause, and in patients with a diagnosed organic gastrointestinal disease, symptoms not clearly explained by the pathology defining this organic disease are common. Thus, the aims of this Rome Foundation Working Team Report were to review the literature on overlapping conditions among patients with paediatric and adult DGBI and, based on the available epidemiological and clinical evidence, make recommendations for the current diagnostic and therapeutic approach, and for future research. Specifically, we focused on other DGBI in the same or different gastrointestinal anatomical region(s), DGBI overlap with organic bowel diseases in remission, and DGBI overlap with non-gastrointestinal, non-structural conditions.

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.

Microvascular ischemia, especially in the heart and kidneys, is associated with inflammation and metabolic perturbation, resulting in cellular dysfunction and end-organ failure. Heightened production of adenosine from extracellular nucleotides released in response to inflammation results in protective effects, inclusive of adaptations to hypoxia, endothelial cell nitric oxide release with the regulation of vascular tone, and inhibition of platelet aggregation. Purinergic signaling is modulated by ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39, which is the dominant factor dictating vascular metabolism of extracellular ATP to adenosine throughout the cardiovascular tissues. Excess levels of extracellular purine metabolites, however, have been associated with metabolic and cardiovascular diseases. Physiological estrogen signaling is anti-inflammatory with vascular protective effects, but pharmacological replacement use in transgender and postmenopausal individuals is associated with thrombosis and other side effects. Crucially, the loss of this important sex hormone following menopause or with gender reassignment is associated with worsened pro-inflammatory states linked to increased oxidative stress, myocardial fibrosis, and, ultimately, diastolic dysfunction, also known as Yentl syndrome. While there is a growing body of knowledge on distinctive purinergic or estrogen signaling and endothelial health, much less is known about the relationships between the two signaling pathways. Continued studies of the interactions between these pathways will allow further insight into future therapeutic targets to improve the cardiovascular health of aging women without imparting deleterious side effects.

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 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.

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.

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.