Target In Inflammatory Bowel Disease Research Articles

Cryo-EM structure of I domain-containing integrin αEβ7

The integrin family is a transmembrane receptor that plays critical roles in the cell-cell and cell-extracellular matrix adhesion, signal transduction such as cell cycle regulation, organization of the intracellular cytoskeleton, and immune responses. Consequently, dysfunction of integrins is associated with a wide range of human diseases, including cancer and immune diseases, which makes integrins therapeutic targets for drug discovery. Here we report the cryo-EM structure of the α-I domain-containing full-length integrin αEβ7, which is expressed in the leukocytes of the immune system and a drug target for inflammatory bowel disease (IBD). The structure reveals the half-bent conformation, an intermediate between the close and the open conformation, while the α-I domain responsible for the ligand binding covers the headpiece domain by a unique spatial arrangement. Our results provide the structural information for the drug design targeting IBD.

The atypical IκB family member Bcl3 determines differentiation and fate of intestinal RORγt+ regulatory T-cell subsets

Peripherally induced regulatory T cells (pTregs) expressing the retinoic acid receptor-related orphan-receptor gamma t (RORγt) are indispensable for intestinal immune homeostasis. NF-κB family members regulate the differentiation of thymic Tregs and promote their survival in the periphery. However, the Treg-intrinsic molecular mechanisms controling the size of the pTregs in the intestine and associated lymphoid organs remain unclear. Here, we provide direct evidence that Bcl3 limits the development of pTregs in a T cell-intrinsic manner. Moreover, the absence of Bcl3 allowed for the formation of an unusual intestinal Treg population co-expressing the transcription factors Helios and RORγt. The expanded RORγt+ Treg populations in the absence of Bcl3 displayed an activated phenotype and secreted high levels of the anti-inflammatory cytokines IL-10 and TGFβ. They were fully capable of suppressing effector T cells in a transfer colitis model despite an intrinsic bias to trans-differentiate toward Th17-like cells. Finally, we provide a Bcl3-dependent gene signature in pTregs including altered responsiveness to the cytokines IL-2, IL-6, and TNFα. Our results demonstrate that Bcl3 acts as a molecular switch to limit the expansion of different intestinal Treg subsets and may thus serve as a novel therapeutic target for inflammatory bowel disease by restoring intestinal immune tolerance.

Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y14R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y14R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y14R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y14R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y14R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y14R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y14R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.

Exploring potential biomarkers and therapeutic targets in inflammatory bowel disease: insights from a mega-analysis approach.

Understanding the molecular pathogenesis of inflammatory bowel disease (IBD) has led to the discovery of new therapeutic targets that are more specific and effective. Our aim was to explore the molecular pathways and genes involved in IBD pathogenesis and to identify new therapeutic targets and novel biomarkers that can aid in the diagnosis of the disease. To obtain the largest possible number of samples and analyze them comprehensively, we used a mega-analysis approach. This involved reprocessing raw data from multiple studies and analyzing them using bioinformatic and machine learning techniques. We analyzed a total of 697 intestinal biopsies of Ulcerative Colitis (n = 386), Crohn's disease (n = 183) and non-IBD controls (n = 128). A machine learning analysis detected 34 genes whose collective expression effectively distinguishes inflamed biopsies of IBD patients from non-IBD control samples. Most of these genes were upregulated in IBD. Notably, among these genes, three novel lncRNAs have emerged as potential contributors to IBD development: ENSG00000285744, ENSG00000287626, and MIR4435-2HG. Furthermore, by examining the expression of 29 genes, among the 34, in blood samples from IBD patients, we detected a significant upregulation of 12 genes (p-value < 0.01), underscoring their potential utility as non-invasive diagnostic biomarkers. Finally, by utilizing the CMap library, we discovered potential compounds that should be explored in future studies for their therapeutic efficacy in IBD treatment. Our findings contribute to the understanding of IBD pathogenesis, suggest novel biomarkers for IBD diagnosis and offer new prospects for therapeutic intervention.

Targeted delivery of Fc-fused PD-L1 for effective management of acute and chronic colitis

The PD-1/PD-L1 pathway in mucosal immunity is currently actively explored and considered as a target for inflammatory bowel disease (IBD) treatment. However, systemic PD-L1 administration may cause unpredictable adverse effects due to immunosuppression. Here we show that reactive oxygen species (ROS)-responsive nanoparticles enhance the efficacy and safety of PD-L1 in a mouse colitis model. The nanoparticles control the accumulation and release of PD-L1 fused to Fc (PD-L1-Fc) at inflammatory sites in the colon. The nanotherapeutics shows superiority in alleviating inflammatory symptoms over systemic PD-L1-Fc administration and mitigates the adverse effects of PD-L1-Fc administration. The nanoparticles-formulated PD-L1-Fc affects production of proinflammatory and anti-inflammatory cytokines, attenuates the infiltration of macrophages, neutrophils, and dendritic cells, increases the frequencies of Treg, Th1 and Tfh cells, reshapes the gut microbiota composition; and increases short-chain fatty acid production. In summary, PD-L1-Fc-decorated nanoparticles may provide an effective and safe strategy for the targeted treatment of IBD.

ARGINASE 2 AMELIORATES EXPERIMENTAL COLITIS THROUGH ANTIOXIDANT EFFECTS VIA SPERMIDINE PRODUCTION

Abstract BACKGROUND Spermidine which is a type of polyamine, shows elevated levels in patients with ulcerative colitis and is implicated in the pathogenesis of ulcerative colitis (UC). Arginase 2 (ARG2) plays a critical role in spermidine production. This study aimed to determine the role and mechanism of endogenous spermidine by using ARG2-deficient mice. METHODS The protective role of spermidine against oxidative stress was examined by intracellular reactive oxygen species levels and cell viability. The physiological role of spermidine was investigated using Arg2 knockdown cells with reduced spermidine. The importance of ARG2 in inflammation was examined in the dextran sulfate sodium-induced colitis model. Protein expression levels of ARG2 and accumulation of spermidine in patients with UC were evaluated by immunohistochemistry of the rectum. RESULTS ARG2 protein expression and the accumulation of spermidine were upregulated in the rectum of mice with dextran sulfate sodium colitis. Spermidine upregulated antioxidant genes in the cells. Arg2 knockdown cells showed reduced antioxidant activity. Dextran sulfate sodium colitis was more severe in Arg2-deficient mice, and organoids derived from Arg2-deficient mice showed diminished tolerance to oxidative stress. Furthermore, in the rectum of patients with UC, ARG2 and spermidine expression levels were higher in the active phase than in the remission phase. CONCLUSIONS Endogenous spermidine in the intestinal epithelium induced by ARG2 has a protective role in colitis. Spermidine may be a promising new therapeutic target for inflammatory bowel disease.

PATIENT PERCEPTIONS OF ENDOSCOPIC TESTING IN THE MANAGEMENT OF INFLAMMATORY BOWEL DISEASE

Abstract BACKGROUND Inflammatory bowel disease (IBD) is associated with significant patient and societal burden. Treatments for IBD have traditionally focused on symptom management. However, clinical guidelines (Selecting Therapeutic Targets in Inflammatory Bowel Disease [STRIDE] II) now recommend treat-to-target approaches. Mucosal healing on endoscopy is becoming a key prognostic parameter in the management of IBD. In light of new guidelines, we aimed to qualitatively assess patient understanding of, and perspectives on, endoscopic measures in the context of disease monitoring and assessing treatment impact. METHODS Twenty patients diagnosed with IBD across the United States, United Kingdom, Spain, Italy, and France participated in TeleWebs (web-enabled phone interviews; United Kingdom, Spain, Italy, France) or a 5-day online bulletin board exchange (United States) discussing their condition and experiences. Specific information regarding disease history, conversations with physicians, experiences with endoscopy, and reactions to information shared on endoscopy were captured over a 5-day period. All respondents were recruited from double opt-in volunteer consumer market research panels. RESULTS Patients generally link disease remission to the absence of symptoms. Knowledge and perceptions of endoscopic measurements are largely driven by their physician perspectives and explanation to patients. Some patients are aware of healthy mucosa as a key part of remission, while others have no concept of the term. Patients report they find it psychologically reassuring to know that they are “healthy inside”. Due to its value, most patients are willing (5.7 on a 1 to 7 Likert Scale) to undergo endoscopy annually, but would be reluctant to do so more frequently. Table 1 outlines barriers and drivers reported by patients on the adoption of endoscopy. CONCLUSION The insight from this study provides understanding of patient perceptions of endoscopy and its place in treating their IBD. This study demonstrates that despite the barriers to the use of endoscopy, patients recognize its clinical relevance for disease management and are willing to periodically undergo a procedure.

OP04 Endoscopic healing in paediatric IBD perpetuates a persistent signature characterized by pathogenic Th17 cells and tissue-associated molecular and microbial drivers of disease

Abstract Background Endoscopic healing (EH) is the major long-term treatment target for inflammatory bowel diseases (IBD) in adults and paediatric patients. However, EH may not represent disease clearance. Hence, risk of relapse remains high and treatment discontinuation after reaching EH often results in disease exacerbation. We aimed to identify persistent cellular, molecular and microbial drivers of IBD under EH and longitudinally collected endoscopic biopsies from paediatric patients for analysis of single T-cell and bulk transcriptomics as well as mucosa-associated microbiota. Methods We followed disease trajectories of paediatric IBD patients treated according to international guidelines and collected mucosal biopsies from the terminal ileum (TI) and sigmoid colon (SC) at baseline (T1) and after approximately 3-12 months (T2) to assess EH. Non-IBD controls showed no macroscopic or histologic signs of inflammation. Host RNA and bacterial DNA were simultaneously extracted from single biopsies for bulk RNA-seq, and 16S rRNA seq. A second biopsy was used for isolation of lamina propria mononuclear cells (LPMCs), followed by CD45+, CD3+ cell sorting and single T-cell analysis (10X Genomics). Data were quality controlled and integrated. Results 217 biopsies (135 simultaneous extraction of host RNA and bacterial DNA; 82 single T-cell analysis) from 32 paediatric IBD patients (mean age 13 ± 3.5 years, 21 Crohn’s disease [CD], 11 ulcerative colitis [UC]; T1 = 32, T2 = 32, T &amp;gt; 2 = 6) and 5 non-IBD controls were analysed. Time between T1 and T2 averages 40 ± 22 weeks. At baseline, 15 patients (14 CD, 1 UC) were newly diagnosed and 31/32 patients had active mucosal inflammation. Twenty-two patients (71%) achieved EH at T2 (SES-CED ≤2 and absence of ulcerations), mostly on anti-TNF therapy. One patient (EH at T1) experienced relapsing disease within 10 weeks after discontinuing medication. In the bulk RNA-seq, we identified 299 differential expressed genes (DEGs; corrected p-value &amp;lt;0.05, FC &amp;gt;2.0), such as DUOX2, SAA2-SAA4, FCGR3B and NOS2, that are associated with active IBD and remained upregulated in EH in contrast to non-IBD controls. In addition single cell analysis revealed an IBD-specific pathogenic Th17 cluster that continued to exist in EH and showed high correlation with top DEGs after data integration. 16S rRNA gene seq highlighted highly individual mucosa-associated bacterial profiles and a reduced α-diversity in active and EH compared to non-IBD controls. Conclusion A persisting IBD signature in EH reflects ongoing cellular, molecular and microbial activity in comparison to non-IBD controls despite EH and mucosal regeneration. These markers may provide targets for future or sequential therapies.

P344 Achieving Crohn's Disease treatment targets following the STRIDE-II recommendations in clinical practice

Abstract Background The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative proposes therapeutic targets for inflammatory bowel disease (IBD) to be used for a treat-to-target clinical management strategy. However, there is lack of information regarding how many patients actually achieve defined treatment targets as outlined in STRIDE-II after initiation of new therapies. The objective of this study was to investigate the treatment response of Crohn’s disease (CD) patients according to the STRIDE-II recommendations in the first year after starting a new pharmacological therapy in clinical practice. Methods CD patients included in a remote monitoring care-path using myIBDcoach, starting a new therapy between January 1st 2020 and December 31st 2021 were eligible for inclusion. The short-term (2-4 months) treatment target was defined as clinical response based on at least 50% decrease in the Monitor IBD at home (MIAH) questionnaire, a patient-reported outcome measure validated to predict endoscopic disease activity. Intermediate (5-9 months) targets were clinical remission (MIAH ≤3.6) and normalization of inflammatory parameters, i.e. faecal calprotectin (&amp;lt;150 ug/g) and C-reactive protein ([CRP] &amp;lt;10 mg/L). Long-term (10-12 months) targets were absence of disability (IBD-control questionnaire ≥13), and a combination of MIAH score ≤3.6 and calprotectin &amp;lt;150 ug/g as surrogate markers for endoscopic remission. Results 39 CD patients were included in the current analysis, of which two started treatment with thiopurines and 37 with a biological. At baseline, median MIAH score was 3.0 (IQR 3.1) and median IBD-control score was 8.5 (IQR 9.0). After three months of therapy, 26% of patients showed clinical response and 64% of patients were in clinical remission (median MIAH 2.2 [IQR 1.8]). As for intermediate targets, clinical remission was seen in 62% (median MIAH 2.0 [IQR 2.3]), and CRP and calprotectin normalization in 79% and 59% of patients, respectively. At the end of follow-up, 41% had low surrogate marker scores indicative for endoscopic remission (median MIAH 1.9 [IQR 1.6] and median calprotectin 109.0 [IQR 241.0]). Resolution of disability was achieved in 65% (median IBD-control score 14.0 [IQR 6.0]). Three patients (9%) achieved all treatment targets within a year of follow-up (Table 1). Conclusion This study used an incident user real-world cohort to evaluate the STRIDE-II recommendations. While all patients achieved at least one treatment target, only 9% achieved all treatment targets according to the STRIDE-II recommendations. Using these recommendations provides good guidance in clinical settings. However, treatment approaches need to be improved to reach the optimal outcomes in daily clinical practice.

P961 Achieving treatment targets in Ulcerative Colitis and reasons for failing to do so: Real world experience in a multi-ethnic asian population

Abstract Background In ulcerative colitis (UC), endoscopic remission (ER) is recommended as a long-term treatment target as it predicts favourable outcomes. We performed this study to identify the proportion of patients who achieved treatment targets as set out in the Selecting Therapeutic Targets in Inflammatory Bowel disease (STRIDE II) consensus. Secondly, we aim to identify the reasons for failing to meet treatment targets. Methods This is a retrospective analysis of all UC patients who were seen at Changi General Hospital, Singapore from 1 January 2000 to 31 December 2022. Patients were identified from an existing IBD registry. All patients with confirmed diagnosis of UC were included in the analysis. Those with follow up period less than 1 year or no repeat endoscopy were excluded. We collected baseline demographics, disease characteristics, medications, clinical activity scoring, biomarkers, endoscopic findings and histologic reports. We defined biomarker normalization, ER and histological remission as outlined in the STRIDE II consensus. Next, we compared factors associated with ER. We also assessed possible reasons for failure to achieve ER. SPSS version 26 was used for data analysis. Results After excluding 23 patients, a total of 139 patients were analysed with a mean follow-up time of 13.5 years. Figure 1 demonstrates the baseline demographics, disease characteristics, treatment modalities, remission targets and reasons for failure of ER. 96.4% of patients achieved clinical remission with a median time of 8 weeks (IQR: 4). Faecal calprotectin (FC) was not routinely measured at baseline but its use increase significantly after the STRIDE consensus. 53.4% of patients achieved biomarker normalization. ER was achieved in 58.3%. Of the 81 patients who achieved endoscopic remission, 49.4% also achieved histological remission. For patients who had repeat endoscopy within 1 year of diagnosis (35.3%, 49/139), 8.16% had achieved ER with a median time of 34 weeks (IQR: 4). Lower baseline C-reactive protein (CRP), follow-up FC, partial mayo score (PMS) at follow-up and biomarker normalization were associated with ER (Table 1). Interestingly more extensive disease was also associated with ER. The main reason for failing to achieve ER was non-compliance to treatment in 58% of the patients. A smaller proportion of patients refused treatment escalation due to absence of symptoms, cost concerns or repeating endoscopy after treatment escalation. Conclusion More than half of all patients with UC achieve long term target of ER in our population and baseline and follow-up biomarkers and PMS are associated with ER. Patients’ compliance is the key reason for failing to achieve ER. Thus, patient education should be reinforced to improve treatment outcomes.

P659 Prognostic markers in Treat-to-Target for Crohn’s Disease- an Asian institution’s experience

Abstract Background Endoscopic healing (EH) is a long-term treatment target in the Treat-to-Target approach for Crohn’s Disease (CD). However, not all patients with CD will achieve this treatment target due to a combination of factors. This study aims to evaluate the proportions of patients with CD who achieve EH at 24 months from diagnosis. Secondary aims include proportion of patients who achieve corticosteroid free clinical remission (CSFR), biomarker (BM) normalization and predictors of failure to achieve EH. Methods This is a retrospective study of all patients with Crohn’s disease seen at a tertiary hospital in Singapore from January 2010 to December 2021. Patients with a confirmed diagnosis of CD based on endoscopic, clinical and histological findings were identified from existing IBD registry. Those with a follow-up period of less than 12 months, no repeat endoscopy and missing data were excluded from analysis. We collected data on baseline demographics, disease characteristics and treatment received. Treatment targets were assessed in terms of CSFR, biomarkers normalization, EH and transmural healing (when available). We defined these targets as outlined in the selecting therapeutic Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) II initiative. Statistical analysis was performed in Python using statsmodels 0.14.0. Results We identified a total of 86 CD patients. After excluding 29 patients, 59 patients were included in the final analysis.Mean age at diagnosis was 33 years old, and 69.5% were males. Table 1 demonstrates the baseline demographics and disease characteristics of all patients. The median follow-up period was 101 months. Out of 59 patients, 88% (n=52) and 80% (n=47) achieved CSFR and biomarker normalization respectively at 12 months. At 24 months of follow up, EH was achieved in 54% (n =32) of all patients. Of those who achieved EH, 22 had repeat imaging and transmural healing was documented in 14 patients. On multivariate logistic regression, Montreal B3 (penetrating type) disease was predictive of failure to achieve EH (OR 9.8, p= 0.036). Use of biologics also showed a trend for failing to achieve EH though this was not statistically significant (OR 3.5, p = 0.075). Conclusion A vast majority of CD patients were able to achieve corticosteroid free clinical remission and biomarker normalization. Penetrating disease was predictive of failure to achieve EH at 24 months. This study provides additional evidence in determining treatment targets for CD patients based on their disease phenotypes. These findings could be further validated in larger cohort, prospective studies.

Treat to target in Crohn's disease: A practical guide for clinicians.

A treat-to-target (T2T) approach applies the principles of early intervention and tight disease control to optimise long-term outcomes in Crohn's disease. The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE)-II guidelines specify short, intermediate, and long-term treatment goals, documenting specific treatment targets to be achieved at each of these timepoints. Scheduled appraisal of Crohn's disease activity against pre-defined treatment targets at these timepoints remains central to determining whether current therapy should be continued or modified. Consensus treatment targets in Crohn's disease comprise combination clinical and patient-reported outcome remission, in conjunction with biomarker normalisation and endoscopic healing. Although the STRIDE-II guidelines endorse the pursuit of endoscopic healing, clinicians must consider that this may not always be appropriate, acceptable, or achievable in all patients. This underscores the need to engage patients at the outset in an effort to personalise care and individualise treatment targets. The use of non-invasive biomarkers such as faecal calprotectin in conjunction with cross-sectional imaging techniques, particularly intestinal ultrasound, holds great promise; as do emerging treatment targets such as transmural healing. Two randomised clinical trials, namely, CALM and STARDUST, have evaluated the efficacy of a T2T approach in achieving endoscopic endpoints in patients with Crohn's disease. Findings from these studies reflect that patient subgroups and Crohn's disease characteristics likely to benefit most from a T2T approach, remain to be clarified. Moreover, outside of clinical trials, data pertaining to the real-world effectiveness of a T2T approach remains scare, highlighting the need for pragmatic real-world studies. Despite the obvious promise of a T2T approach, a lack of guidance to support its integration into real-world clinical practice has the potential to limit its uptake. This highlights the need to describe strategies, processes, and models of care capable of supporting the integration and execution of a T2T approach in real-world clinical practice. Hence, this review seeks to examine the current and emerging literature to provide clinicians with practical guidance on how to incorporate the principles of T2T into routine clinical practice for the management of Crohn's disease.

Formylated Peptide Receptor-1-Mediated Gut Inflammation as a Therapeutic Target in Inflammatory Bowel Disease.

Formylated peptide receptor (FPR)-1 is a G-coupled receptor that senses foreign bacterial and host-derived mitochondrial formylated peptides (FPs), leading to innate immune system activation. We sought to investigate the role of FPR1-mediated inflammation and its potential as a therapeutic target in inflammatory bowel disease (IBD). We characterized FPR1 gene and protein expression in 8 human IBD (~1000 patients) datasets with analysis on disease subtype, mucosal inflammation, and drug response. We performed in vivo dextran-sulfate sodium (DSS) colitis in C57/BL6 FPR1 knockout mice. In ex vivo studies, we studied the role of mitochondrial FPs and pharmacological blockade of FPR1 using cyclosporin H in human peripheral blood neutrophils. Finally, we assess mitochondrial FPs as a potential mechanistic biomarker in the blood and stools of patients with IBD. Detailed in silico analysis in human intestinal biopsies showed that FPR1 is highly expressed in IBD (n = 207 IBD vs 67 non-IBD controls, P < .001), and highly correlated with gut inflammation in ulcerative colitis (UC) and Crohn's disease (CD) (both P < .001). FPR1 receptor is predominantly expressed in leukocytes, and we showed significantly higher FPR1+ve neutrophils in inflamed gut tissue section in IBD (17 CD and 24 UC; both P < .001). Further analysis in 6 independent IBD (data available under Gene Expression Omnibus accession numbers GSE59071, GSE206285, GSE73661, GSE16879, GSE92415, and GSE235970) showed an association with active gut inflammation and treatment resistance to infliximab, ustekinumab, and vedolizumab. FPR1 gene deletion is protective in murine DSS colitis with lower gut neutrophil inflammation. In the human ex vivo neutrophil system, mitochondrial FP, nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) is a potent activator of neutrophils resulting in higher CD62L shedding, CD63 expression, reactive oxygen species production, and chemotactic capacity; these effects are inhibited by cyclosporin H. We screened for mitochondrial ND6 in IBD (n = 54) using ELISA and detected ND6 in stools with median values of 2.2 gg/mL (interquartile range [IQR] 0.0-4.99; range 0-53.3) but not in blood. Stool ND6 levels, however, were not significantly correlated with paired stool calprotectin, C-reactive protein, and clinical IBD activity. Our data suggest that FPR1-mediated neutrophilic inflammation is a tractable target in IBD; however, further work is required to clarify the clinical utility of mitochondrial FPs as a potential mechanistic marker for future stratification.

Comparison of a selective STAT3 inhibitor with a dual STAT3/STAT1 inhibitor using a dextran sulfate sodium murine colitis model: new insight into the debate on selectivity.

Recent advances in the treatment of inflammatory bowel disease include antitumor necrosis factor antibodies and the Janus kinase inhibitor tofacitinib, approved for ulcerative colitis. Janus kinase recruits signal transducers and activators of transcriptions (STAT), which are promising targets in inflammatory bowel diseases. However few inhibitors have been evaluated, and their selectivity with respect to STAT1 and STAT3 remains controversial. Here, we investigated the therapeutic potential of a selective inhibitor vs. a non-selective, closely related compound, in a dextran sulfate sodium (DSS) murine colitis model. Thirty Swiss/CD-1 male mice were used in this study. They were divided into a healthy control group, a colitis-DSS control group, a compound (cpd) 23-treated group, a cpd 46-treated group and an icariin-treated group. For the coadministration experiment with rutin, the cpd 46-treated group and the icariin-treated group were replaced by the oral rutin-treated group and the coadministration rutin/cpd 23-treated group. The effect of the tested inhibitors was also assessed by quantification of proinflammatory markers. The selective inhibitor had a significantly greater effect than the dual inhibitor on the disease activity index. We also noticed in curative treatment a significant decrease in the most abundant proinflammatory biomarker present in neutrophilic granulocytes, myeloperoxidase and on proinflammatory cytokines, including tumor necrosis factor-α, interferon-γ, interleukins -6 and -23, with a mild synergy with rutin, the glycoside of quercetin. The current study shows how STAT3 selective inhibitors can exert a significant therapeutic effect in the treatment of experimental DSS-colitis.

Bringing STRIDE2 to Life in Clinical Practice

STRIDE (Selecting Therapeutic Targets in Inflammatory Bowel Disease [IBD]) is an initiative by the International Organisation for the Study of IBD that aims to delineate a core set of therapeutic targets for IBD based on literature review and expert consensus. The first iteration was published in 2015, with an update in 2021 (STRIDE2), which qualifies targets as short-, intermediate- or long-term and adds pediatric-specific targets.&#x0D; The goal of treating any disease is to allow patients to feel well and to enjoy good quality of life (QOL), while avoiding disease- and treatment-related complications. The inflammatory bowel diseases, Crohn’s disease (CD) and ulcerative colitis (UC), are no exception. Given this overarching objective, it is not surprising that the traditional target in treating IBD has been symptom resolution, while avoiding corticosteroids. The challenge is that symptom control neither guarantees the absence of intestinal inflammation in a cross-sectional fashion, nor prevents progression to “damage” (including, for example, fibrosis, strictures and fistulae). This does not imply that symptom alleviation is irrelevant; it is a necessary, but insufficient treatment target. STRIDE2 includes clinical response (immediate/short-term) and clinical remission (intermediate) as treatment targets, but the method of symptom assessment has shifted from the physician (physician-administered clinical activity indices) to the patient (patient-reported outcomes [PROs]), aligning with the FDA’s requirement for PROs as a co-primary endpoint in clinical drug trials (typically alongside an objective disease marker such as endoscopy). STRIDE2 also introduces restoration of QOL and disability avoidance as key treatment goals. This further highlights the importance of the patient experience, and acknowledges normal linear growth as a critical pediatric-specific clinical target.

APE1/Ref-1 as a Therapeutic Target for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. The prevalence of IBD is increasing with approximately 4.9 million cases reported worldwide. Current therapies are limited due to the severity of side effects and long-term toxicity, therefore, the development of novel IBD treatments is necessitated. Recent findings support apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1) as a target in many pathological conditions, including inflammatory diseases, where APE1/Ref-1 regulation of crucial transcription factors impacts significant pathways. Thus, a potential target for a novel IBD therapy is the redox activity of the multifunctional protein APE1/Ref-1. This review elaborates on the status of conventional IBD treatments, the role of an APE1/Ref-1 in intestinal inflammation, and the potential of a small molecule inhibitor of APE1/Ref-1 redox activity to modulate inflammation, oxidative stress response, and enteric neuronal damage in IBD.

Serum levels of infliximab and adalimumab are associated with deep remission in inflammatory bowel disease

ObjectiveDeep remission defined by clinical-biomarker remission and mucosal healing has emerged as a new therapeutic target in inflammatory bowel disease. The aim of this study was to define an optimal cut-off concentration for infliximab and adalimumab during maintenance therapy associated with deep remission. The secondary objective, was to evaluate the influence of variables on anti tumor necrosis factor-alpha concentrations and deep remission. MethodRetrospective study including 120 and 122 patients inflammatory bowel disease diagnosed who received maintenance therapy with infliximab and adalimumab. Biomarker remission was considered by C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g. Crohn's disease clinical remission was defined by a Harvey Bradshaw score < 5 and mucosal healing by a simple endoscopic score for Crohn's disease< 3. In ulcerative colitis, it was defined as a Mayo total score < 3 and Mayo endoscopic subscore < 2. Receiver operating characteristic test was performed to determine drug concentration thresholds associated with deep remission. Anti tumor necrosis factor-alpha concentrations were classified into quartiles. X2 and Kruskal-Wallis test were used to compare discrete and continuous variables between quartile groups. Multivariate logistic regression was performed to identify patient characteristics and serological facto C-reactive protein rs associated with deep remission. ResultsAnti tumor necrosis factor-alpha concentrations were higher in patients with deep remission, in infliximab (4.4, interquartile range: 3.3-6.5 vs 2.3, interquartile range: 1.1-4.2 µg/mL, P < 0.005) and adalimumab (6.3, interquartile range: 4.2-8.2 vs 3.9, interquartile range: 2.4-5.5 µg/mL, P < 0.005). A Receiver operating characteristic test identified a concentration threshold of 3.1 µg/mL in infliximab (area under the Receiver operating characteristic test curve, 0.72) and 6.3 µg/mL in adalimumab (area under receiver operating characteristic test curve, 0.75) associated with deep remission. Factors associated with the highest quartiles of serum infliximab concentration were: elevated body mass index, absence of previous inflammatory bowel disease-surgery, C-reactive protein < 5 mg/L, and fecal calprotectin < 100 µg/g. In adalimumab, higher quartiles were related to concomitant immunosuppressants, low body mass index, absence of previous inflammatory bowel disease-surgery, and C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g. Multivariate regression identified fecal calprotectin < 100 µg/g, C-reactive protein < 5 mg/L, infliximab > 3.1 µg/mL and adalimumab concentrations > 6.3 µg/mL as factors significantly associated with deep remission. ConclusionsTrough infliximab and adalimumab concentrations, C-reactive protein < 5 mg/L and fecal calprotectin < 100 µg/g are associated with deep remission during maintenance therapy. Cutoff point of 3.1 and 6.3 g/mL for infliximab and adalimumab respectively, were identified as deep remission predictors.

The NRF2/Keap1 pathway as a therapeutic target in inflammatory bowel disease.

Oxidative stress (OS) is an important pathophysiological mechanism in inflammatory bowel disease (IBD). However, clinical trials investigating compounds directly targeting OS in IBD yielded mixed results. The NRF2 (nuclear factor erythroid 2-related factor 2)/Keap1 (Kelch-like ECH-associated protein 1) pathway orchestrates cellular responses to OS, and dysregulation of this pathway has been implicated in IBD. Activation of the NRF2/Keap1 pathway may enhance antioxidant responses. Although this approach could help to attenuate OS and potentially improve clinical outcomes, an overview of human evidence for modulating the NRF2/Keap1 axis and more recent developments in IBD is lacking. This review explores the NRF2/Keap1 pathway as potential therapeutic target in IBD and presents compounds activating this pathway for future clinical applications.

Benefits and Challenges of Treat-to-Target in Inflammatory Bowel Disease.

There is notable disparity between symptomatology and disease activity in a significant proportion of patients with inflammatory bowel disease (IBD), and escalation of treatment based on symptoms alone can fail to significantly alter the course of disease. The STRIDE-II position statement, published in 2021 by the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organisation for the Study of IBD (IOIBD) provides the most current recommendations for a treat-to-target (T2T) approach in IBD. Despite the benefits offered by a T2T approach in IBD, there are numerous drawbacks and current limitations to its widespread implementation in real-world clinical practice. Owing to the lack of a standardised definition of MH, outcome data are heterogeneous and limit the comparability of existing data. Further, studies investigating the likelihood of achieving MH with a T2T approach are limited and largely retrospective. Evidence of the real-world feasibility of tight monitoring is currently minimal and demonstrates sub-optimal adherence among patients. Further, the few studies on the acceptability and uptake of a T2T approach in real-world practice demonstrate the need for increased acceptability on both patients' and clinicians' behalf. Real-world applicability is further limited by the need for repeated endoscopic assessments of MH as well as a lack of guidance on how to incorporate the various treatment targets into therapeutic decision-making. We aim to review the benefits and challenges of the T2T approach and to discuss potential solutions to further patient care.

Systemic immune-inflammation index as a potential biomarker to monitor ulcerative colitis

Objective The treat-to-target strategy is recommended by Selecting Therapeutic Targets in Inflammatory Bowel Disease II (STRIDE-II) for treating ulcerative colitis (UC), and monitoring remission status is crucial during this management. The systemic immune-inflammation index (SII), defined as platelet * neutrophil/lymphocyte, is a complete blood count-based index reflecting the balance of immune and inflammatory status. This study aims to investigate the feasibility of SII for diagnosing UC and monitoring UC disease activity. Methods This study retrospectively analyzed patients with UC and controls. Relationships between SII and Mayo clinical score, Mayo Endoscopic Score (MES), and Nancy Histological Index (NHI) were evaluated. Results 167 patients with UC and 106 controls were included. SII significantly increased in patients with UC and was closely correlated with the Mayo clinical score, MES, and NHI. SII diagnosed UC with a cut-off value of 619.1 × 109/L (area under the curve = 0.861, p < 0.0001, sensitivity 79.64%, specificity 77.36%), evaluated clinical remission status with a cut-off value of 1068 × 109/L (area under the curve = 0.691, p < 0.05, sensitivity 55.71%, specificity 81.48%), endoscopic improvement with a cut-off value of 981.3 × 109/L (area under the curve = 0.819, p < 0.0001, sensitivity 65.22%, specificity 89.66%), and histological healing with a cut-off value of 689.3 × 109/L (area under the curve = 0.898, p < 0.0001, sensitivity 88.89%, specificity 95.83%). Conclusion SII is a potential biomarker for diagnosing UC and monitoring UC disease severity, especially in evaluating mucosal and histological healing during the long-term management in treat-to-target strategy. However, further research is needed to confirm its usefulness and optimize its clinical application.