Recent advances in intestinal fibrosis.

Despite many progresses have been made in the treatment of inflammatory bowel disease, especially due to the increasing number of effective therapies, the development of tissue fibrosis is a very common occurrence along the natural history of this condition. To a certain extent, fibrogenesis is a physiological and necessary process in all those conditions characterised by chronic inflammation. However, the excessive deposition of extracellular matrix within the bowel wall will end up in the formation of strictures, with the consequent need for surgery. A number of mechanisms have been described in this process, but some of them are not yet clear. For sure, the main trigger is the presence of a persistent inflammatory status within the mucosa, which in turn favours the occurrence of a pro-fibrogenic environment. Among the main key players, myofibroblasts, fibroblasts, immune cells, growth factors and cytokines must be mentioned. Although there are no available therapies able to target fibrosis, the only way to prevent it is by controlling inflammation. In this review, we summarize the state of art of the mechanisms involved in gut fibrogenesis, how to diagnose it, and which potential targets could be druggable to tackle fibrosis.

Role of mucosal immunity and epithelial-vascular barrier in modulating gut homeostasis.

The intestinal mucosa represents the most extensive human barrier having a defense function against microbial and food antigens. This barrier is represented externally by a mucus layer, consisting mainly of mucins, antimicrobial peptides, and secretory immunoglobulin A (sIgA), which serves as the first interaction with the intestinal microbiota. Below is placed the epithelial monolayer, comprising enterocytes and specialized cells, such as goblet cells, Paneth cells, enterochromaffin cells, and others, each with a specific protective, endocrine, or immune function. This layer interacts with both the luminal environment and the underlying lamina propria, where mucosal immunity processes primarily take place. Specifically, the interaction between the microbiota and an intact mucosal barrier results in the activation of tolerogenic processes, mainly mediated by FOXP3+ regulatory T cells, underlying intestinal homeostasis. Conversely, the impairment of the mucosal barrier function, the alteration of the normal luminal microbiota composition (dysbiosis), or the imbalance between pro- and anti-inflammatory mucosal factors may result in inflammation and disease. Another crucial component of the intestinal barrier is the gut-vascular barrier, formed by endothelial cells, pericytes, and glial cells, which regulates the passage of molecules into the bloodstream. The aim of this review is to examine the various components of the intestinal barrier, assessing their interaction with the mucosal immune system, and focus on the immunological processes underlying homeostasis or inflammation.

Antenatal thiopurine exposure in women with IBD is associated with intrahepatic cholestasis of pregnancy.

BACKGROUND: Pregnant women with inflammatory bowel disease (IBD) continue thiopurines to maintain remission. Other studies have reported intrahepatic cholestasis of pregnancy (ICP) in IBD pregnancies exposed to thiopurines. We aimed to investigate whether thiopurines are associated with an increased risk of ICP. RESEARCH DESIGN AND METHODS: Single-center retrospective cohort study comparing incidence of ICP in thiopurine-exposed versus non-exposed patients with IBD compared with age-matched pregnant controls. RESULTS: The IBD cohort consisted of 386 pregnancies in 243 patients with IBD, with 386 age-matched controls. In patients with IBD, ICP was significantly more common among thiopurine-exposed pregnancies (9.0% vs 1.8%; odds ratio [95% confidence interval] = 5.34 [1.78-16.02]; p = 0.021). IBD patients with thiopurine exposure were significantly more likely to experience ICP compared to non-IBD controls (9.0% vs 1.3%; p < 0.001). Patients with IBD not exposed to thiopurines had a comparable ICP incidence with controls (1.8% vs 1.3%; p = 0.75). Severe ICP occurred in 80% of thiopurine-exposed ICP cases versus 40% in non-exposed (p = 0.25), versus 20% in controls (p = 0.09). CONCLUSION: Thiopurine exposure was associated with a significantly increased risk of ICP among patients with IBD compared to non-exposed IBD patients and age-matched general population controls. The course of ICP was not significantly different in thiopurine-exposed cases.

Impact on direct and indirect costs of switching patients with inflammatory bowel disease from intravenous to subcutaneous infliximab (CT-P13).

BACKGROUND: We aim to compare the real-life direct and indirect costs of switching patients from intravenous to subcutaneous (SC) CT-P13, an infliximab biosimilar, in a tertiary UK Inflammatory Bowel Disease (IBD) centre. METHODS: All adult patients with IBD on standard dosing CT-P13 (5 mg/kg 8 weekly) were eligible to switch. Of 169 patients eligible to switch to SC CT-P13, 98 (58%) switched within 3 months and one moved out of area. RESULTS: Total annual intravenous cost for 168 patients was £689 507.04 (direct=£653 671.20, indirect=£35 835.84). After the switch, as-treated analysis demonstrated total annual cost for 168 patients (70 intravenous and 98 SC) was £674 922.83 (direct = £654 563, indirect = £20 359.83) resulting in £891.80 higher cost to healthcare providers. Intention to treat analysis showed a total annual cost of £665 961.01 (direct = £655 200, indirect = £10 761.01) resulting in £1528.80 higher cost to healthcare providers. However, in each scenario, the significant decrease in indirect costs resulted in lower total costs after switching to SC CT-P13. CONCLUSIONS: Our real-world analysis demonstrates switching from intravenous to SC CT-P13 is broadly cost neutral to healthcare providers. SC preparations have marginally higher direct costs, switching allows for efficient use of intravenous infusion units and reduces costs to patients.

Diagnostic delay in adult coeliac disease: An Italian multicentre study.

BACKGROUND: There are few data regarding the diagnostic delay and its predisposing factors in coeliac disease (CD). AIMS: To investigate the overall, the patient-dependant, and the physician-dependant diagnostic delays in CD. METHODS: CD adult patients were retrospectively enroled at 19 Italian CD outpatient clinics (2011-2021). Overall, patient-dependant, and physician-dependant diagnostic delays were assessed. Extreme diagnostic, i.e., lying above the third quartile of our population, was also analysed. Multivariable regression models for factors affecting the delay were fitted. RESULTS: Overall, 2362 CD patients (median age at diagnosis 38 years, IQR 27-46; M:F ratio=1:3) were included. The median overall diagnostic delay was 8 months (IQR 5-14), while patient- and physician-dependant delays were 3 (IQR 2-6) and 4 (IQR 2-6) months, respectively. Previous misdiagnosis was associated with greater physician-dependant (1.076, p = 0.005) and overall (0.659, p = 0.001) diagnostic delays. Neurological symptoms (odds ratio 2.311, p = 0.005) and a previous misdiagnosis (coefficient 9.807, p = 0.000) were associated with a greater extreme physician-dependant delay. Gastrointestinal symptoms (OR 1.880, p = 0.004), neurological symptoms (OR 2.313, p = 0.042), and previous misdiagnosis (OR 4.265, p = 0.000) were associated with increased extreme overall diagnostic delay. CONCLUSION: We identified some factors that hamper CD diagnosis. A proper screening strategy for CD should be implemented.

Ustekinumab and Vedolizumab Are Equally Safe and Effective in Elderly Crohn's Disease Patients.

BACKGROUND: Anti-tumour necrosis factor (anti-TNF) agents are associated with increased infection risk among elderly inflammatory bowel disease (IBD) patients, and thus, alternative biologics may be preferable. However, little comparative data exist on the safety and efficacy of vedolizumab and ustekinumab in elderly IBD patients. AIMS: To compare the safety and effectiveness of ustekinumab and vedolizumab in elderly Crohn's disease patients. METHODS: Patients ≥ 60 years old who commenced ustekinumab or vedolizumab for Crohn's disease (CD) were included. Primary outcome was serious infections, defined as requiring hospitalisation. Efficacy was assessed by treatment persistence and clinical response rates. We appropriately adjusted for confounders using propensity score-matched analysis weighted by the inverse predicted probability of treatment weighing and performed a logistic regression analysis to assess factors associated with serious infections and treatment persistence. RESULTS: Eighty-three patients commencing ustekinumab and 42 commencing vedolizumab therapy were included. In a propensity adjusted cohort, the rate of serious infection and treatment persistence were comparable between ustekinumab and vedolizumab. There was a significant reduction in HBI at 6 and 12 months compared to baseline in both groups. Male gender was positively associated with serious infection risk at 12 months, and penetrating disease behaviour was positively associated with 12-month treatment persistence. Baseline HBI score was negatively associated with 12-month treatment persistence. Cox regression analysis showed no overall difference in treatment discontinuation-free and serious infection-free survival by 12 months. CONCLUSIONS: We observed comparable safety and effectiveness for ustekinumab and vedolizumab in treating elderly CD patients.

Uptake of a Switching Program for Patients Receiving Intravenous Infliximab and Vedolizumab to Subcutaneous Preparations.

BACKGROUND: Recent trials support the clinical efficacy and safety of subcutaneous infliximab (IFX) or vedolizumab (VDZ) for Inflammatory Bowel Disease (IBD). We evaluated the uptake and rationale for choosing to switch from intravenous infusions to subcutaneous injections. METHODS: Retrospective analysis of all adult patients receiving standard dosing IFX or VDZ maintenance therapy to investigate uptake of subcutaneous injections and the rationale for switching to subcutaneous injections. RESULTS: Of 232 eligible patients (total = 258: IFX = 190, VDZ = 68, and no longer eligible = 26), 58% of patients on IFX and 59% of patients on VDZ chose to switch to subcutaneous treatment. Age, sex, diagnosis, drug, line of treatment, and duration of treatment were not predictors for willingness to switch. Questionnaire responses (n = 51) demonstrate that the decision to switch was not influenced by COVID-19 exposure risk, impact on wider IBD service provision, impact on patient mental health, financial savings, seeking support following a switch, or a sense of independence managing IBD. Switchers (68%) were more motivated by time savings than non-switchers (25%; p = 0.0042). CONCLUSIONS: Switch uptake rates were 58%, with 90% of patients eligible to switch. Switch decision was influenced by time savings for patients but not by other patient-related factors.