Vascular cell adhesion molecule (VCAM)-1 has garnered significant research attention due to its potential as a disease biomarker and drug target across several inflammatory pathologies-including atherosclerosis, asthma, rheumatoid arthritis, and inflammatory bowel disease (IBD). The VCAM-1 protein has also been noted for its functional involvement in cancer metastasis and drug resistance to conventional chemotherapeutics. Although the anti-inflammatory and anti-cancer facets of VCAM-1 antagonisation have been examined separately, there is yet to be a review that explicitly addresses the functional interrelationship between these mechanisms. Furthermore, the pleiotropic mechanisms of anti-VCAM-1 therapies may present a useful paradigm for designing drug candidates with synergistic anti-inflammatory and anti-tumorigenic effects. The pathological overlap between inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CRC) serves as the quintessential disease model to observe this therapeutic duality. This review thereby details the adhesive mechanisms of VCAM-1 in colorectal disease-specifically, driving immune cell infiltration during IBD and tumour cell metastasis in CRC-and posits the potential of this receptor as a common drug target for both diseases. To explore this hypothesis, the current progress of novel VCAM-1-directed drug candidates in experimental models of IBD and CRC is also discussed.

Sphingosine-1-phospate (S1P) receptor agonists (eg, ozanimod) desensitize migrating lymphocytes by irreversibly binding to S1P receptors (S1PR) and triggering their proteasomal degradation. Desensitized lymphocytes cannot sense S1P, therefore, halting lymphocyte recirculation. The S1P lyase (SPL) irreversibly degrades S1P and its inhibition disrupts the S1P gradient. We previously found that systemic SPL inhibitors induce central immunosuppression. Here, we examined whether SPL inhibition may attenuate colitis without systemic immunotoxicity.

We first analyzed SPL expression and localization in mice using qRT-PCR and immunohistochemistry. SPL inhibitors 4-deoxypyridoxine hydrochloride (DOP) and 2-acetyl-4-(tetrahydroxybutyl) imidazole (THI) were used to inhibit SPL systemically, whereas a conditional intestinal epithelial cell (IEC)-specific SPL-deficient mouse was used to evaluate the effects of IEC-specific SPL inhibition on survival, disease activity, histological severity of dextran sulfate sodium-induced colitis, S1P levels, and intestinal permeability.

Sgpl1 mRNA transcripts and protein were ubiquitously expressed in gastrointestinal (GI) tract leukocytes and IEC. Systemic SPL inhibitors did not induce colitis by themselves but depleted CD4+ and CD8+ T cells from blood. However, contrary to its therapeutic effects on ileitis, systemic inhibition reduced survival, accelerated weight loss, worsened histopathological inflammation indices, and tissue damage. We then examined the effects of IEC-specific inhibition on peripheral cell counts and severity of colitis. We found that while it spared peripheral immunity, it similarly hastened colitis. Finally, we examined whether colitis acceleration was due to epithelial barrier compromise after disruption of the S1P gradient. We found that not only systemic but also IEC-specific SPL inhibition increased local S1P levels and led to IEC barrier compromise.

Homeostatic intestinal S1P levels are critical for the regulation of IEC barrier function. Further studies using adaptive immunity-based inflammatory bowel diseases (IBD) models are required to assess the translational value of IEC-specific SPL inhibition as a therapeutic target for human IBD.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.

Inflammatory bowel disease (IBD) is a chronic condition affecting the gastrointestinal tract, primarily manifesting as ulcerative colitis (UC) or Crohn's disease (CD). Both inflammation and disruption of the intestinal epithelial barrier are key factors in IBD pathogenesis. Substantial evidence has revealed a significant association between aberrant immune responses and impairment of the intestinal epithelial barrier in IBD pathogenesis. The components of the intestinal epithelium, particularly goblet cells and Paneth cells, are crucial to gut homeostasis, as they secrete mucin, antimicrobial peptides (AMPs), and cytokines. Furthermore, impairment of epithelial integrity, which is regulated by tight junctions, is a hallmark of IBD pathology. While common treatments for IBD, such as anti-inflammatory drugs, target various signaling pathways with varying efficacies, therapeutic approaches focused on mucosal and epithelial barrier healing have been largely neglected. Moreover, high costs, side effects, and insufficient or inconsistent therapeutic outcomes remain major drawbacks of conventional anti-IBD drugs. Recent studies on epithelial barrier regeneration and permeability reduction have introduced promising therapeutic targets, including farnesoid X receptor (FXR), urokinase-type plasminogen activator (uPA)-urokinase-type plasminogen activator receptor (uPAR) interaction, fecal microbiota transplantation (FMT), and insulin receptor (INSR). Notably, the simultaneous targeting of intestinal inflammation and promotion of epithelial barrier healing shows promise for efficient IBD treatment. Future research should explore targeted therapies and combination treatments, including natural remedies, microbiota colonization, stem cell approaches, and computer-aided drug design. It is also crucial to focus on accurate prognosis and developing a thorough understanding of IBD development mechanisms.

Tissue-resident memory T (TRM) cells are populations which settle down in non-lymphoid tissues instead of returning to secondary lymph organs after the antigen presentation. These cells can provide rapid on-site immune protection as well as long-term tissue damage. It is reported that TRM cells from small intestine and colon exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional and functional heterogeneity. In this review, we focus on the reason why they lodge in intestinal tract, their developmental plasticity of going back to to circulation, as well as their regulators associated with retention, maintenance, exhaustion and metabolism. We also elaborate their role in the inflammatory bowel disease (IBD) and discuss the potential therapeutic strategies targeting TRM cells.

Randomised placebo-controlled trials are the gold standard to assess novel drugs in ulcerative colitis and Crohn's disease. However, there might be risks associated with receiving placebo. We aimed to examine the harms associated with receiving placebo in trials of licensed biologics and small molecules for the induction of remission in ulcerative colitis and luminal Crohn's disease in a meta-analysis.

We performed a systematic review and meta-analysis. We searched MEDLINE, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials from database inception to May 30, 2024, for randomised placebo-controlled trials of licensed biologics and small molecules for induction of remission in adults (≥18 years) with moderately to severely active ulcerative colitis or luminal Crohn's disease reporting data on adverse events over a minimum treatment period of 4 weeks. There were no prespecified study exclusion criteria. We extracted summary data and pooled data using a random-effects model for any treatment-emergent adverse event, any drug-related adverse event, infection, worsening of inflammatory bowel disease (IBD) activity, withdrawal due to adverse events, serious adverse events, serious infection, serious worsening of IBD activity, or venous thromboembolic events (VTEs), reporting relative risks (RRs) with 95% CIs. The protocol for this meta-analysis was registered with PROSPERO (CRD42024527341).

The search identified 10 826 citations, of which 47 trials including 20 987 patients (14 267 [68·0%] receiving active drug and 6720 [32·0%] receiving placebo) were eligible. The risk of any treatment-emergent adverse event was no different with active drug than with placebo (7660/14 267 [53·7%] patients on active drug vs 3758/6720 [55·9%] on placebo; RR 0·97, 95% CI 0·94-1·00; I2 =36%). However, the risks of worsening of IBD activity (563/13 473 [4·2%] vs 530/6252 [8·5%]; 0·48, 0·40-0·59; I2 =54%), withdrawal due to adverse event (401/13 363 [3·0%] vs 299/6267 [4·8%]; 0·62, 0·48-0·79; I2 =46%), serious adverse event (682/14 267 [4·8%] vs 483/6720 [7·2%]; 0·69, 0·59-0·80; I2 =30%), serious infection (140/14 194 [1·0%] vs 91/6647 [1·4%]; 0·67, 0·50-0·89; I2 =0%), serious worsening of IBD activity (187/11 271 [1·7%] vs 189/5056 [3·7%]; 0·45, 0·34-0·60; I2 =27%), or VTEs (13/7542 [0·2%] vs 12/2981 [0·4%]; 0·45, 0·21-0·94; I2 =0%) were all significantly lower with active drug than placebo. Numbers needed to treat with active drug to avoid these potentially serious adverse events ranged from 23 for worsening of IBD activity to 452 for VTEs. 27 randomised controlled trials were judged as low risk of bias across all domains.

Patients with moderately to severely active IBD receiving placebo are more likely to experience significant worsening of IBD activity and some serious adverse events, which might relate to a reduction in risk of these events with active drug. Patients should be counselled about these potential harms, and alternative trial designs to mitigate these harms should be considered.

None.

The mammalian target of rapamycin (mTOR) pathway plays a key role in determining immune cells function through modulation of their metabolic status. By specific deletion of Rictor in CD11c+ myeloid cells (referred to here as CD11cRicΔ/Δ), we investigated the role of mTOR complex 2 (mTORC2) signaling in dendritic cells (DCs) function in mice. We showed that upon dextran sulfate sodium-induced colitis, the lack of mTORC2 signaling CD11c+ cells diminishes the colitis score and abrogates DC migration to the mesenteric lymph nodes, thereby diminishing the infiltration of T helper 17 cells in the lamina propria and subsequent inflammation. These findings corroborate with the abrogation of cytoskeleton organization and the decreased activation of Rac1 and Cdc42 GTPases observed in CD11c+-mTORC2-deficient cells. Meta-analysis on colonic samples from ulcerative colitis patients revealed increased gene expression of proinflammatory cytokines, which coincided with augmented expression of the mTOR pathway, a positive correlation between the DC marker ITGAX and interleukin-6, the expression of RICTOR, and CDC42. Together, this work proposes that targeting mTORC2 on DCs offers a key to hamper inflammatory responses, and this way, ameliorates the progression and severity of intestinal inflammatory diseases.

A temporal relationship between vedolizumab and new-onset spondyloarthritis (SpA) has been suggested.

We evaluated the relationship between vedolizumab initiation and development of new-onset SpA in patients with inflammatory bowel disease (IBD) through serial clinical evaluation and magnetic resonance imaging (MRI).

A single-centre prospective observational study of 24 patients with IBD. Patients were eligible if they had active ulcerative colitis or Crohn's disease (CD), were initiating vedolizumab, had no prior history of arthritis or SpA and were suitable for serial MRI. A rheumatologist performed clinical evaluation prior to the first dose and 8 and 24 weeks. Axial MRI was evaluated by a blinded central reader and performed at baseline 8 and 24 weeks.

Nine tumor necrosis factor (TNF) inhibitor-naïve patients (4 male; mean age 53.2 years; 6 UC; 3 CD) and eight TNF inhibitor-experienced patients (7 male; mean age 48 years; 3 UC; 5 CD) completed all assessments. No patients developed new features of axial arthritis or features of peripheral SpA (inflammatory oligoarthritis, enthesitis, dactylitis, or psoriasis (nail, body, or scalp)). Both groups demonstrated a good intestinal response.

Vedolizumab initiation did not induce new features of axial or peripheral SpA after 24 weeks of treatment in TNF inhibitor-experienced or TNF inhibitor-naive patients with IBD.

Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4β7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).

A microRNA miR-200c-3p is a regulator of epithelial-mesenchymal transition to control adhesion and migration of epithelial and mesenchymal cells. However, little is known about whether miR-200c-3p affects lymphocyte adhesion and migration mediated by integrins. Using TK-1 (a T lymphoblast cell) as a model of T cell, here we show that repressed expression of miR-200c-3p upregulated α4 integrin-mediated adhesion to and migration across mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Conversely, overexpression of miR-200c-3p downregulated α4 integrin-mediated adhesion and migration. Unlike in epithelial cells, miR-200c-3p did not target talin, a conformation activator of integrin, but, targeted E26-transformation-specific sequence 1 (ETS1), a transcriptional activator of α4 integrin, in T cells. Treatment of the miR-200c-3p-low-expressing TK-1 cells that possessed elevated α4 integrin with ETS1 small interfering RNA (siRNA) resulted in the reversion of the α4 integrin expression, supporting that ETS1 is a target of miR-200c-3p. A potential proinflammatory immune-modulator retinoic acid (RA) treatment of TK-1 cells elicited a significant reduction of miR-200c-3p and simultaneously a marked increase in ETS1 and α4 integrin expression. An anti-inflammatory cytokine TGF-β1 treatment elevated miR-200c-3p, thereby downregulating ETS1 and α4 integrin expression. These results suggest that miR-200c-3p is an important regulator of α4 integrin expression and functions and may be controlled by RA and TGF-β1 in an opposite way. Overexpression of miR-200c-3p could be a novel therapeutic option for treatment of gut inflammation through suppressing α4 integrin-mediated T cell migration.

The landscape of biologic agents for the treatment of inflammatory bowel disease (IBD) associated colitis is rapidly evolving, requiring surgeons to be up-to-date as part of multi-disciplinary, evidence-based care. An update on novel therapies used to induce remission in IBD-associated colitis is presented.

A systematic search through Ovid MEDLINE and CENTRAL using a combination of MeSH terms and Boolean operators was conducted.

One thousand and twenty articles from which 38 articles were selected for inclusion in this review. Novel agents were trialled as 4th or 5th line treatment following conventional treatment failure. Rates of serious adverse effects were low. Janus kinase (JAK) inhibitors (upadacitinib and tofacitinib) were efficacious in inducing remission in ulcerative colitis, and IL-23p19 inhibitors (mirikizumab, guselkumab, and risankizumab) in Crohn's colitis. Evidence was limited for other drug classes.

JAK-inhibitors and IL-23p19 inhibitors were found to be the most effective agents for inducting remission following failure of standard of care treatment. A significant proportion of patients did not respond, highlighting the inherent challenge in optimizing treatment for moderate to severe IBD-associated colitis. More robust study designs and comparator trials are required.

Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus (HIV) epidemic, people living with HIV have represented most cases for more than a decade. With the diffusion of highly active antiretroviral therapy, this group progressively decreased in favor of patients undergoing treatment with targeted therapy/immunomodulators. In this systematic review and meta-analysis, the objective was to assess which drugs are most frequently related to PML development, and report the incidence of drug-induced PML through a meta-analytic approach.

The electronic databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian Agency for Drugs and Technologies in Health Database (CADTH) were searched up to May 10, 2022. Articles that reported the risk of PML development after treatment with immunomodulatory drugs, including patients of both sexes under the age of 80 years, affected by any pathology except HIV, primary immunodeficiencies or malignancies, were included in the review. The incidence of drug-induced PML was calculated based on PML cases and total number of patients observed per 100 persons and the observation time. Random-effect metanalyses were conducted for each drug reporting pooled incidence with 95% confidence intervals (CI) and median (interquartile range [IQR]) of the observation time. Heterogeneity was measured by I2 statistics. Publication bias was examined through funnel plots and Egger's test.

A total of 103 studies were included in the systematic review. In our analysis, we found no includible study reporting cases of PML during the course of treatment with ocrelizumab, vedolizumab, abrilumab, ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, belimumab, infliximab, firategrast, disulone, azathioprine or danazole. Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a relatively safe profile, although some cases of PML have been reported. The meta-analysis showed an incidence of PML cases among patients undergoing rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI - 0.08 to 0.09; I2 = 20.4%; p = 0.25) for a median observation period of 23.5 months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 0.33 cases/100 persons (95% CI 0.29-0.37; I2 = 50%; p = 0.003) for a median observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 36.3 (standard deviation [SD] ± 20.7). When comparing data about patients treated with standard interval dosing (SID) and extended interval dosing (EID), the latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for SID.

A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents.

The recruitment of T cells to tissues and their retention there are essential processes in the pathogenesis of many autoimmune and inflammatory diseases. The mechanisms regulating these processes have become better understood over the past three decades and are now recognized to involve temporally and spatially specific interactions between cell-adhesion molecules. These include integrins, which are heterodimeric molecules that mediate in-to-out and out-to-in signalling in T cells, other leukocytes, and most other cells of the body. Integrin signalling contributes to T-cell circulation through peripheral lymph nodes, immunological synapse stability and function, extravasation at the sites of inflammation, and T-cell retention at these sites. Greater understanding of the contribution of integrin signalling to the role of T cells in autoimmune and inflammatory diseases has focused much attention on the development of therapeutics that target T-cell integrins. This literature review describes the structure, activation, and function of integrins with respect to T cells, then discusses the use of integrin-targeting therapeutics in inflammatory bowel disease, multiple sclerosis, and psoriasis. Efficacy and safety data from clinical trials and post-marketing surveillance are presented for currently approved therapeutics, therapeutics that have been withdrawn from the market, and novel therapeutics currently in clinical trials. This literature review will inform the reader of the current means of targeting T-cell integrins in autoimmune and inflammatory diseases, as well as recent developments in the field.

Inflammatory bowel disease (IBD) is a lifelong inflammatory immune mediated disorder, encompassing Crohn's disease (CD) and ulcerative colitis (UC); however, the cause and specific pathogenesis of IBD is yet incompletely understood. Multiple cytokines produced by different immune cell types results in complex functional networks that constitute a highly regulated messaging network of signaling pathways. Applying biological mechanisms underlying IBD at the single omic level, technologies and genetic engineering enable the quantification of the pattern of released cytokines and new insights into the cytokine landscape of IBD. We focus on the existing literature dealing with the biology of pro- or anti-inflammatory cytokines and interactions that facilitate cell-based modulation of the immune system for IBD inflammation. We summarize the main roles of substantial cytokines in IBD related to homeostatic tissue functions and the remodeling of cytokine networks in IBD, which may be specifically valuable for successful cytokine-targeted therapies via marketed products. Cytokines and their receptors are validated targets for multiple therapeutic areas, we review the current strategies for therapeutic intervention and developing cytokine-targeted therapies. New biologics have shown efficacy in the last few decades for the management of IBD; unfortunately, many patients are nonresponsive or develop therapy resistance over time, creating a need for novel therapeutics. Thus, the treatment options for IBD beyond the immune-modifying anti-TNF agents or combination therapies are expanding rapidly. Further studies are needed to fully understand the immune response, networks of cytokines, and the direct pathogenetic relevance regarding individually tailored, safe and efficient targeted-biotherapeutics.

Tissue-resident memory T (TRM) cells are a recently discovered subpopulation of memory T cells that reside in non-lymphoid tissues such as the intestine and skin and do not enter the bloodstream. The intestine encounters numerous pathogens daily. Intestinal mucosal immunity requires a balance between immune responses to pathogens and tolerance to food antigens and symbiotic microbiota. Therefore, intestinal TRM cells exhibit unique characteristics. In healthy intestines, TRM cells induce necessary inflammation to strengthen the intestinal barrier and inhibit bacterial translocation. During intestinal infections, TRM cells rapidly eliminate pathogens by proliferating, releasing cytokines, and recruiting other immune cells. Moreover, certain TRM cell subsets may have regulatory functions. The involvement of TRM cells in inflammatory bowel disease (IBD) is increasingly recognized as a critical factor. In IBD, the number of pro-inflammatory TRM cells increases, whereas the number of regulatory subgroups decreases. Additionally, the classic markers, CD69 and CD103, are not ideal for intestinal TRM cells. Here, we review the phenotype, development, maintenance, and function of intestinal TRM cells, as well as the latest findings in the context of IBD. Further understanding of the function of intestinal TRM cells and distinguishing their subgroups is crucial for developing therapeutic strategies to target these cells.

Background: There is limited real-world evidence on treatment patterns of patients with Crohn's disease (CD) initiating biologics with an extensive follow-up period. This study describes persistence and dose titration among CD patients with 3 years of follow-up. Methods: This retrospective observational study was conducted using the STATinMED RWD Insights all-payer medical and pharmacy data. Adult patients with at least 1 CD medical claim and at least 1 medical/pharmacy claim for a biologic (adalimumab [ADA], certolizumab pegol (CZP), infliximab [IFX] and its biosimilar products [IFX-BS], ustekinumab [UST], and vedolizumab [VDZ]) between September 2016 and October 2018 were identified. Commercially insured patients with continuous capture for at least 12 months before and at least 36 months after biologics initiation were selected. Confirmed CD patients were included in the final cohort. Baseline patient characteristics and treatment patterns over the 3-year follow-up period were evaluated. Results were summarized using means and SD or counts and percentages. Results: A total of 2309 confirmed patients with CD were identified (847 [36.7%] IFX, 534 [23.1%] ADA, 486 [21.1%] VDZ, 394 [17.1%] UST, 85 [3.7%] CZP, and 72 [3.1%] IFX-BS). CZP and IFX-BS were excluded due to small sample sizes. Approximately half of CD patients were between ages 35 and 54. Patients on UST had a higher Charlson Comorbidity Index score. Common comorbidities (>10%) included anemia, anxiety, depression, and hypertension. Persistence over 3 years' follow-up was highest for UST (61.4%) patients, followed by VDZ (58.0% ), ADA (52.1% , and IFX (48.1%). The discontinuation rate without switch or restart was highest for ADA (37.3%), followed by UST (30.7%), IFX (28.1%), and VDZ (25.3%). Over the 3 years of follow-up, the dose titration rate was highest for IFX (76.5%) and lowest for UST (50.8%). In particular, UST had the lowest dose escalation rate (35.5%) and highest dose-reduction rate (16.5%). Conclusions: Patients with CD on UST had the highest persistence and lowest dose escalation across different biologic users over the 3-year follow-up period, possibly suggesting a better clinical response of UST. Future studies with longer follow-up adjusting for confounders are needed to better understand treatment patterns among biologics users.

Phase 2 trials are fundamental to the rational and efficient design of phase 3 trials. We aimed to determine the relationship of treatment effect size estimates from phase 2 and phase 3 clinical trials on advanced therapeutics in inflammatory bowel disease.

MEDLINE, EMBASE, CENTRAL, and the Cochrane library were searched from inception to December 19, 2022, to identify paired phase 2 and 3 placebo-controlled induction studies of advanced therapeutics for Crohn's disease (CD) and ulcerative colitis (UC). Treatment effect sizes were expressed as a risk ratio (RR) between the active arm and placebo arm. For the same therapeutics, RRs from phase 2 trials were divided by the RR from phase 3 trial to quantify the relationship of effect sizes between phases.

Twenty-two studies (9 phase 2 trials, 13 phase 3 trials) were included for CD and 30 studies (12 phase 2 trials, 18 phase 3 trials) for UC. In UC (pooled RR 0.72; 95% confidence interval: 0.58-0.86; RR <1 indicates smaller treatment effect sizes in phase 2 trials), but not CD (pooled RR 1.01; 95% confidence interval: 0.84-1.18), phase 2 trials systematically underestimated treatment effect sizes for the primary endpoint compared with phase 3 trials. The underestimation was observed for clinical, but not endoscopic, endpoints in UC.

Treatment effect sizes for the primary and clinical endpoints were similar across clinical trial phases in CD, but not UC, where only endoscopic endpoints were comparable. This will help inform clinical development plans and future trial design.

The accumulation of multiple randomized controlled trials in the field of inflammatory bowel diseases provides an opportunity to compare treatment effects between phase 2 and 3 trials. We aimed to determine whether treatment effects observed in phase 3 investigating biologics and small molecule drugs differed from those in their preceding phase 2 trial.

We first performed a review of phase 2 and phase 3 trials enrolling ulcerative colitis (UC) or Crohn's disease (CD) patients. We compared the percent overall success for key endpoints between phases (several phase 3 could be matched to a single phase 2 trial). Then, we compared the percent overall success in the matched phase 2 and 3 trials (ratio 1:1), and performed sensitivity analysis.

We identified 14 phase 2 (8 CD; 6 UC) and 24 phase 3 (13 CD; 11 UC) trials. In CD, the different analyses suggest that the percentage of overall success of clinical remission and clinical response was significantly higher in phase 2 than in phase 3 trials. In UC, the analyses suggest collectively that the percent of treatment effect seemed similar for clinical remission, clinical response and histologic outcomes between phases but with a lower percentage of overall success in phase 2 than in phase 3 trials for endoscopic endpoints.

In UC, we observed a similar percentage of treatment effect for clinical and histologic outcomes between phase 2 and 3 trials but not for endoscopic outcomes. Whereas in CD, we showed a failure to reproduce similar results between phases. These results may help sponsors in the design of future drug development programs.

Graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is the main cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA2/3 scores correlate with resistance to treatment and higher NRM. We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T-cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA2/3 GVHD. Seventy-five patients who were evaluable were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events in >10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared with 150 well-matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and those treated with corticosteroids alone (60% vs 58%; P = .67% and 48% vs 48%; P = 1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival at 12 months in patients treated with natalizumab plus corticosteroids compared with controls treated with corticosteroids alone (38% vs 39%; P = .80% and 46% vs 54%; P = .48, respectively). In this multicenter biomarker-based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high-risk GVHD. This trial was registered at www.clinicaltrials.gov as # NCT02133924.

Inflammatory Bowel Diseases had their first peak in incidence in countries in North America, Europe, and Oceania and are currently experiencing a new acceleration in incidence, especially in Latin America and Asia. Despite technological advances, 90 years after the development of the first molecule for the treatment of IBD, we still do not have drugs that promote disease remission in a generalized way. We carried out a narrative review on therapeutic advances in the treatment of IBD, the mechanisms of action, and the challenges facing the therapeutic goals in the treatment of IBD. Salicylates are still used in the treatment of Ulcerative Colitis. Corticosteroids have an indication restricted to the period of therapeutic induction due to frequent adverse events, while technologies with less systemic action have been developed. Most immunomodulators showed a late onset of action, requiring a differentiated initial strategy to control the disease. New therapeutic perspectives emerged with biological therapy, initially with anti-TNF, followed by anti-integrins and anti-interleukins. Despite the different mechanisms of action, there are similarities between the general rates of effectiveness. These similar results were also evidenced in JAK inhibitors and S1p modulators, the last therapeutic classes approved for the treatment of IBD.

Along with the rising prevalence of inflammatory bowel disease (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)], biological therapies need an update/insight.

This review included randomized controlled trials (RCTs) from PubMed database (2000-October 2022) of approved biologics and small molecules with primary outcome analysis on efficacy (clinical response/remission/mucosal healing) and/or adverse events (AEs). Considered for this review under biologics classes are TNF-α inhibitors, leukocyte trafficking inhibitors, and anti IL-12/IL-23; and under small molecules are Janus-kinase inhibitors, and sphingosine-1-phosphate receptor modulators.

In CD, clinical response and remission were better with tofacitinib (61.23%) and infliximab (44.86%), respectively, in the induction phase, and these were better with ustekinumab in the maintenance phase. In UC, the maximum rate of response, remission, and mucosal healing were obtained with infliximab during the induction phase (67.49%, 35.99%, and 60.25%, respectively). During the maintenance phase, response rate was better with ustekinumab, but remission and mucosal healing were better with vedolizumab. The combined percentage of AEs was highest with infliximab (174.45%) and least with ozanimod (23.04%), and most commonly belonged to the 'infection and infestation system organ class (SOC).' These efficacy and safety analyses will help in the optimization of biologic treatment in IBD.

Fatigue is a frequent complaint in patients with inflammatory bowel disease. Biological drugs have demonstrated beneficial effects on some extraintestinal manifestations, but the effect on fatigue is not clear.

This study investigated the effects of biological and small molecule drugs approved for inflammatory bowel disease on fatigue.

We performed a systematic review and meta-analysis of randomized, placebo-controlled trials reporting Federal Drug Agency (FDA)-approved biological and small molecule drugs for use in ulcerative colitis and Crohn's disease in which measures of fatigue were recorded before and after treatment. Only induction studies were included. Maintenance studies were excluded. We searched Embase (Ovid), Medline (Ovid), PsycINFO (Ovid), Cinahl (EBSCOhost), Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov in May 2022. Risk of bias was analyzed using the Cochrane risk-of-bias tool. Standardized mean difference was used to measure the treatment effect.

A total of seven randomized controlled trials composed of 3835 patients were included in the meta-analysis. All of the studies included patients with moderately to severely active ulcerative colitis or Crohn's disease. The studies used three different generic fatigue instruments: the Functional Assessment of Chronic Illness Therapy-Fatigue and the Short Form 36 Health Survey Vitality Subscale versions 1 and 2. Overall treatment with biological or small molecule agents showed a beneficial effect compared with placebo, with a standardized mean difference of 0.25 (95% confidence interval 0.15-0.34, p < 0.001). The effect was independent of type of drug or subtype of inflammatory bowel disease.

The risk of bias was considered to be low for all domains except for missing outcome data. Even though the included studies were of high methodological quality, the review is limited by the small number of studies included and that the available studies were not designed to evaluate fatigue specifically.

Biological and small molecule drugs used in inflammatory bowel disease have a consistent, though small, beneficial effect on fatigue.

Most pharmaceutical clinical trials for inflammatory bowel disease [IBD] are placebo-controlled and require effect size estimation for a drug relative to placebo. We compared expected effect sizes in sample size calculations [SSCs] to actual effect sizes in IBD clinical trials.

MEDLINE, EMBASE, CENTRAL and the Cochrane library were searched from inception to March 26, 2021, to identify placebo-controlled induction studies for luminal Crohn's disease [CD] and ulcerative colitis [UC] that reported an SSC and a primary endpoint of clinical remission/response. Expected effects were subtracted from actual effects, and interquartile ranges [IQRs] for each corresponding median difference were calculated. Linear regression was used to assess whether placebo or drug event rate misspecifications were responsible for these differences.

Of eligible studies, 36.9% [55/149] were excluded because of incomplete SSC reporting, yielding 94 studies [46 CD, 48 UC]. Treatment effects were overestimated in CD for remission (-12.6% [IQR: -16.3 to -1.6%]), in UC for remission (-10.2% [IQR: -16.5 to -5.6%]) and in CD for response (-15.3% [IQR: -27.1 to -5.8%]). Differences observed were due to overestimated drug event rates, whereas expected and actual placebo event rates were similar. A meta-regression demonstrated associations between overestimated treatment effect sizes and several trial characteristics: isolated ileal disease, longer CD duration, extensive colitis [UC], single-centre, phase 2 and no endoscopic endpoint component [UC].

Overestimation of IBD therapy efficacy rates resulted in smaller-than-expected treatment effects. These results should be used to inform SSCs and trial design for IBD drug development.

Advanced therapies for inflammatory bowel disease [IBD] could potentially lead to a state of immunosuppression with an increased risk of opportunistic infections [OIs]. We aimed to provide an update on the incidence of OIs among adult IBD patients in randomized controlled trials [RCTs] of approved biologics and small-molecule drugs [SMDs]. Also, we aimed to describe OI definitions utilized in RCTs, to ultimately propose a standardized definition.

Electronic databases were searched from January 1, 1990, until April 16, 2022. Our primary outcome was incidence rate of overall OIs among IBD patients exposed and unexposed to biologics or SMDs. We also describe specific OIs reported in included trials, as well as definitions of OIs within studies when provided.

Ninety studies were included. The incidence rates of reported OIs were 0.42 and 0.21 per 100 person-years in patients exposed to advanced therapies and placebo, respectively. This was highest for anti-tumour necrosis factors [0.83 per 100 person-years] and Janus kinase inhibitors [0.55 per 100 person-years] and lowest for anti-integrins and ozanimod. On meta-analysis, no increased risk of OIs was observed. None of the studies provided a detailed definition of OIs, or a comprehensive list of infections considered as OIs.

Different mechanisms of action may have specific OI profiles. In the absence of a uniform definition of OIs, these estimates are less reliable. We propose a definition to be used in future studies to help provide standardized reporting. When using this definition, we saw significant differences in incidence rates of OIs across mechanisms of action.

Discrepancies in phase two and three studies can result in significant patient and financial burden, as well as the nonapproval of potentially efficacious drugs. We aimed to determine whether this discrepancy exists for clinical trials in inflammatory bowel disease (IBD). Electronic databases (MEDLINE and Embase) and clinical trial repositories were searched from 1 January 1946 to 12 March 2021, for paired phase two and three studies of advanced therapies for Crohn's disease and ulcerative colitis. The primary outcome was to compare clinical remission rates between paired phase two and three studies for Crohn's disease and ulcerative colitis. Multivariable mixed-model meta-analysis was performed to calculate odds ratios (OR) with 95% confidence intervals (CI). The Cochrane risk-of-bias tool was used to grade the risk of bias. Of 2642 studies, 29 were included. Fifteen were phase three, 11 were phase two, one was phase one/two, and two were phase two/three. There were no differences in clinical remission rates between phase two and three studies for Crohn's disease (OR, 1.07; 95% CI, 0.86-1.34; P = 0.54) and ulcerative colitis (OR, 0.81; 95% CI, 0.48-1.36; P = 0.43). Furthermore, there was a lack of any appreciable differences in study characteristics, inclusion criteria and patient demographics among paired phase two and three studies. Most studies were considered low risk of bias. Overall, paired phase two and three studies demonstrate similar clinical remission rates for advanced therapies in IBD. Whether this applies to newer outcomes, such as endoscopic and mucosal healing remains to be determined.

Immune cell trafficking is a key requirement in the pathogenesis of inflammatory bowel diseases. Consistently, therapeutic strategies to target immune cell trafficking have been established and continue to be developed for the treatment of ulcerative colitis and Crohn's disease.

In this review, we briefly summarize the most important checkpoints of intestinal immune cell trafficking and their importance during IBD. Moreover, we provide an overview of associated therapeutic targets and previous as well as current efforts on treatment strategies related to these targets.

Finally, we comment on potential future developments that might shape the field of immune cell trafficking in the context of IBD.

Emerging biologics and small-molecule drugs have changed the clinical status quo of inflammatory bowel disease (IBD). However, current treatments remain at a standstill in terms of response and remission in many cases. Accumulating evidence indicates that dual-targeted therapy (DTT) could be promising in overcoming the existing ceiling of IBD treatment. However, data on the efficacy and safety of DTT on Crohn's disease and ulcerative colitis are still limited or insufficient. Moreover, there is a lack of studies delineating the mechanisms of DTT. Given that various targeted drugs have different targets among the extensive redundant inflammatory networks, DTT could result in various outcomes. In this review, we have summarized the current data on the safety, effectiveness, and clinical development status of novel targeted drugs related to refractory IBD, and have explored the mechanism of action of therapy. We have categorized therapeutic agents into "Therapeutic Agents Targeting Cellular Signaling Pathways" and "Therapeutic Agents Targeting Leukocyte Trafficking" based on the different therapeutic targets, and also by classifying therapeutic agents targeting the cellular signaling pathways into "JAK-dependent" and "JAK-independent," and placed the existing drug combinations into 3 categories based on their mechanisms, namely, overlapping, synergistic, and complementary effects. Lastly, we have proposed the possible mechanisms of DTT to conceive a theoretical framework for clinical decision-making and further drug development and research from an IBD standpoint.

Random mutagenesis is the natural opportunity for proteins to evolve and biotechnologically it has been exploited to create diversity and identify variants with improved characteristics in the mutant pools. Rational mutagenesis based on biophysical assumptions and supported by computational power has been proposed as a faster and more predictable strategy to reach the same aim. In this work we confirm that substantial improvements in terms of both affinity and stability of nanobodies can be obtained by using combinations of algorithms, even for binders with already high affinity and elevated thermal stability. Furthermore, in silico approaches allowed the development of an optimized bispecific construct able to bind simultaneously the two clinically relevant antigens TNF-α and IL-23 and, by means of its enhanced avidity, to inhibit effectively the apoptosis of TNF-α-sensitive L929 cells. The results revealed that salt bridges, hydrogen bonds, aromatic-aromatic and cation-pi interactions had a critical role in increasing affinity. We provided a platform for the construction of high-affinity bispecific constructs based on nanobodies that can have relevant applications for the control of all those biological mechanisms in which more than a single antigen must be targeted to increase the treatment effectiveness and avoid resistance mechanisms.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system characterized by broad inter- and intraindividual heterogeneity and different prognoses. Multisystem comorbidities are frequent features in people with MS (PwMS) and can affect treatment choices, quality of life, disability and mortality. In this scenario, autoimmune comorbidities play a cardinal role for several reasons, such as the implication on MS pathogenesis, diagnostic delay, disease activity, disability progression, brain atrophy, and treatment choice. However, the impact of an autoimmune comorbid condition on MS is not fully elucidated. This review aims to summarize the currently available data on the incidence and prevalence of autoimmune diseases in PwMS, the possible effect of this association on clinical and neuroradiological MS course and its impact on treatment choice.

Inflammatory bowel diseases (IBD) cause chronic intestinal damage and extracellular matrix (ECM) remodeling. The ECM may play an active role in inflammation by modulating immune cell functions, including cell adhesion, but this hypothesis has not been tested in IBD.

Primary human intestinal myofibroblast (HIMF)-derived ECM from IBD and controls, 3D decellularized colon or ECM molecule-coated scaffolds were tested for their adhesiveness for T cells. Matrisome was analysed via proteomics. Functional integrin blockade was used to investigate the underlying mechanism. Analysis of the pediatric Crohn's disease (CD) RISK inception cohort was used to explore an altered ECM gene expression as a potential predictor for a future complicated disease course.

HIMF-derived ECM and 3D decellularized colonic ECM from IBD bound more T cells compared to control. Control HIMFs exposed to the pro-inflammatory cytokines Iinterleukin-1β (IL-1β) and tumor necrosis factor (TNF) increased, and to transforming growth factor-β1 (TGF-β1) decreased ECM adhesiveness to T cells. Matrisome analysis of the HIMF-derived ECM revealed collagen VI as a major culprit for differences in T cell adhesion. Collagen VI knockdown in HIMF reduced adhesion T cell as did the blockage of integrin αvβ1. Elevated gene expression of collagen VI in biopsies of pediatric CD patients was linked to risk for future stricturing disease.

HIMF-derived ECM in IBD binds a remarkably enhanced number of T cells, which is dependent on Collagen VI and integrin αvβ1. Collagen VI expression is a risk factor for a future complicated CD course. Blocking immune cells retention may represent a novel approach to treatment in IBD.

Spondyloarthritis (SpA) refers to a group of diseases with inflammation in joints and spines. In this family, ankylosing spondylitis (AS) is a rare but classic form that mainly involves the spine and sacroiliac joint, leading to the loss of flexibility and fusion of the spine. Compared to other diseases in SpA, AS has a very distinct hereditary disposition and pattern of involvement, and several hypotheses about its etiopathogenesis have been proposed. In spite of significant advances made in Th17 dynamics and AS treatment, the underlying mechanism remains concealed. To this end, we covered several topics, including the nature of the immune response, the microenvironment in the articulation that is behind the disease's progression, and the split between the hypotheses and the evidence on how the intestine affects arthritis. In this review, we describe the current findings of AS and SpA, with the aim of providing an integrated view of the initiation of inflammation and the development of the disease.

The incidence and prevalence of inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, have increased in Asia and developing countries. In the past two decades, anti-tumor necrosis factor (TNF) agents have revolutionized the treatment of IBD, in part by decreasing the rates of complications and surgery. Although anti-TNF agents have changed the course of IBD, there are unmet needs in terms of primary and secondary non-responses and side effects such as infections and malignancies. Novel biologics and small-molecule drugs have been developed for IBD, and the medical treatment options have improved. These drugs include sphingosine-1-phosphate receptor modulators and anti-integrins to block immune cell migration, and cytokine and Janus kinase inhibitors to block immune cell communications. In this review, we discuss the approved novel biologics and small-molecule drugs, including several of those in the late stages of development, for the treatment of IBD.

An activated, proinflammatory endothelium is a key feature in the development of complications of obesity and type 2 diabetes and can be caused by insulin resistance in endothelial cells.

We analyzed primary human endothelial cells by RNA sequencing to discover novel insulin-regulated genes and used endothelial cell culture and animal models to characterize signaling through CXCR4 (C-X-C motif chemokine receptor 4) in endothelial cells.

CXCR4 was one of the genes most potently regulated by insulin, and this was mediated by PI3K (phosphatidylinositol 3-kinase), likely through FoxO1, which bound to the CXCR4 promoter. CXCR4 mRNA in CD31+ cells was 77% higher in mice with diet-induced obesity compared with lean controls and 37% higher in db/db mice than db/+ controls, consistent with upregulation of CXCR4 in endothelial cell insulin resistance. SDF-1 (stromal cell-derived factor-1)-the ligand for CXCR4-increased leukocyte adhesion to cultured endothelial cells. This effect was lost after deletion of CXCR4 by gene editing while 80% of the increase was prevented by treatment of endothelial cells with insulin. In vivo microscopy of mesenteric venules showed an increase in leukocyte rolling after intravenous injection of SDF-1, but most of this response was prevented in transgenic mice with endothelial overexpression of IRS-1 (insulin receptor substrate-1).

Endothelial cell insulin signaling limits leukocyte/endothelial cell interaction induced by SDF-1 through downregulation of CXCR4. Improving insulin signaling in endothelial cells or inhibiting endothelial CXCR4 may reduce immune cell recruitment to the vascular wall or tissue parenchyma in insulin resistance and thereby help prevent several vascular complications.

In Crohn's disease and ulcerative colitis, the anti-α4β7 integrin antibody vedolizumab has demonstrated efficacy in phase III trials and has been successfully used under real-world conditions. Occasionally, it has also been used in other forms of inflammatory bowel disease (IBD) such as microscopic colitis (MC). However, the mechanisms of vedolizumab in MC have not been studied to date. Therefore, we aimed to investigate the expression and functional role of gut-homing integrins and in particular α4β7 integrin in a cohort study in MC.

We studied the expression of gut homing integrins on T cells from patients with MC and healthy controls by flow cytometry. To investigate the function of α4β7 integrin in MC and the potential of vedolizumab to block it, we used dynamic adhesion assays and transmigrations assays. Moreover, we describe two clinical cases of MC patients treated with vedolizumab.

A specific profile of gut homing markers can be found on T cells from patients with MC. α4β7 integrin functionally leads to firm adhesion to MAdCAM-1 and supports transmigration. Vedolizumab is able to block both processes. In two cases of MC, we observed reduced clinical symptoms and histologic improvement upon therapy with vedolizumab.

Our data suggest that α4β7 mediates gut homing of T cells also in MC and that, on single cell level, vedolizumab blocks the function of α4β7 in MC. Thus, we provide mechanistic evidence supporting vedolizumab as promising therapeutic option for MC.

Crohn’s disease (CD) leads to a poor health-related quality of life (HRQoL). This review aimed to investigate the effect of biological agents and small-molecule drugs in improving the HRQoL of patients with moderate to severe CD. We adopted a systematic protocol to search PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), which was supplemented with manual searches. Eligible studies were RCTs that matched the research objective based on population, intervention, comparison and outcomes. Studies in paediatric populations, reviews and conference abstracts were excluded. Covidence was used for screening and data extraction. We assessed all research findings using RoB2 and reported them narratively. We included 16 multicentre, multinational RCTs in this review. Of the 15 studies that compared the effect of an intervention to a placebo, 9 were induction studies and 6 investigated maintenance therapy. Of these, 13 studies showed a significant (p < 0.05) improvement in the HRQoL of patients with CD. One non-inferiority study compared the intervention with another active drug and favoured the intervention. This systematic review reported a substantial improvement in the HRQoL of patients with CD using biological agents and small-molecule drugs. These pharmaceutical substances have the potential to improve the HRQoL of patients with CD. However, further large clinical trials with long-term follow-up are essential to validate these findings.

Crohn's disease is a chronic and progressive immune-mediated disease with increasing incidence worldwide. There are no curative therapies. The primary agents used in the treatment of Crohn's disease are aminosalicylates, corticosteroids, immunomodulators, and biologics. Each agent has different roles in the induction and maintenance of remission of disease. The biologics available include anti-TNF agents, anti-integrins, and anti-interleukins. The choice of initial biologic therapy should be determined through shared decision-making between the patient and provider.