Inflammatory Bowel Disease Drugs Research Articles

Cardiovascular manifestations of inflammatory bowel diseases and the underlying pathogenic mechanisms.

Inflammatory bowel disease (IBD), consisting of ulcerative colitis and Crohn's disease, mainly affects the gastrointestinal tract but is also known to have extraintestinal manifestations because of long-standing systemic inflammation. Several national cohort studies have found that IBD is an independent risk factor for the development of cardiovascular disorders. However, the molecular mechanisms by which IBD impairs the cardiovascular system are not fully understood. Although the gut-heart axis is attracting more attention in recent years, our knowledge of the organ-to-organ communication between the gut and the heart remains limited. In patients with IBD, upregulated inflammatory factors, altered microRNAs and lipid profiles, as well as dysbiotic gut microbiota, may induce adverse cardiac remodeling. In addition, patients with IBD have a three- to four times higher risk of developing thrombosis than people without IBD, and it is believed that the increased risk of thrombosis is largely due to increased procoagulant factors, platelet count/activity, and fibrinogen concentration, in addition to decreased anticoagulant factors. The predisposing factors for atherosclerosis are present in IBD and the possible mechanisms may involve oxidative stress system, overexpression of matrix metalloproteinases, and changes in vascular smooth muscle phenotype. This review focuses mainly on 1) the prevalence of cardiovascular diseases associated with IBD, 2) the potential pathogenic mechanisms of cardiovascular diseases in patients with IBD, and 3) adverse effects of IBD drugs on the cardiovascular system. Also, we introduce here a new paradigm for the gut-heart axis that includes exosomal microRNA and the gut microbiota as a cause for cardiac remodeling and fibrosis.

Wielding the double-edged sword: Redox drug delivery systems for inflammatory bowel disease.

The etiology of inflammatory bowel disease (IBD) is extremely complex and related to an excessive immune response that results in the pathologically release of reactive oxygen species (ROS) via tissue injury and chronic inflammation. Generally, excessive ROS production is one of the essential mediators for inflammatory pathogenesis. Targeting cumulate ROS to interrupt pathological inflammatory responses has been recognized as a feasible strategy for inflammatory suppression of IBD. Correspondingly, the overexpression of ROS can also trigger the drug release of novel drug delivery systems to alleviate IBD symptoms. In this review, we summarized the pathological production of endogenous ROS in IBD, discussed the enormous potential of multiple kinds of ROS-scavenging and ROS-triggering novel delivery systems for the treatment of IBD, including enzymology, metal, polyphenols, natural pigments, nitroxide radicals-contained and sulfide-loaded drug delivery systems, and other novel ROS-responsive materials to synthesize ROS-based drug delivery systems. We also summarized the immunomodulatory effects of ROS-targeted drug delivery systems for the treatment of IBD. Besides, based on the requirements of clinical applications and industrialization development, the challenges faced in the evolution of redox drug delivery systems were also discussed. Collectively, this review provides a reliable reference to the development of ROS-scavenging and ROS-triggering drug delivery systems for the medical intervention of IBD.

The Influence of Apremilast-Induced Macrophage Polarization on Intestinal Wound Healing.

There is compelling evidence suggesting a pivotal role played by macrophages in orchestrating intestinal wound healing. Since macrophages display significant plasticity and heterogeneity, exhibiting an either classically activated (M1-like) or alternatively activated (M2-like) phenotype, they can aggravate or attenuate intestinal wound healing. Growing evidence also demonstrates a causal link between impaired mucosal healing in inflammatory bowel disease (IBD) and defects in the polarization of pro-resolving macrophages. By targeting the switch from M1 to M2 macrophages, the phosphodiesterase-4 inhibitor Apremilast has gained recent attention as a potential IBD drug. However, there is a gap in our current knowledge regarding the impact of Apremilast-induced macrophages' polarization on intestinal wound healing. The THP-1 cells were differentiated and polarized into M1 and M2 macrophages, and subsequently treated with Apremilast. Gene expression analysis was performed to characterize macrophage M1 and M2 phenotypes, and to identify possible target genes of Apremilast and the involved pathways. Next, intestinal fibroblast (CCD-18) and epithelial (CaCo-2) cell lines were scratch-wounded and exposed to a conditioned medium of Apremilast-treated macrophages. Apremilast had a clear effect on macrophage polarization, inducing an M1 to M2 phenotype switch, which was associated with NF-κB signaling. In addition, the wound-healing assays revealed an indirect influence of Apremilast on fibroblast migration. Our results support the hypothesis of Apremilast acting through the NF-κB-pathway and provide new insights into the interaction with fibroblast during intestinal wound healing.

Inflammatory bowel disease (IBD)-specific immune cell recruitment and response can be modulated with anti-TNF-α therapies in the human Colon Intestine-Chip

Abstract Objective: Inflammatory bowel disease (IBD) is a complex inflammatory disease, for which few effective therapies exist. The goal of our current work was to show: i) that such a complex, immune cell-driven pathogenesis could be captured on Emulate’s human Colon Intestine-Chips; and ii) that this could be used as a novel human-centric system to support IBD drug development including anti-TNF-α antibodies. Methods: PBMCs were perfused through the vascular (bottom) channel in untreated ‘resting’ or cytokine-‘primed’ Colon Intestine-Chips. Clinically relevant IBD drugs, including anti-TNF-α antibodies (Humira and Cimzia), as well as dexamethasone and AJM300 were administered through the vascular channel during PBMC administration. Total cell recruitment, effluent biomarker secretion (cytokines, calprotectin, C-reactive protein), and barrier function were analyzed for 72 hours. Results: α4β7 +‘gut-tropic’ PBMCs (monocytes, CD4 +, CD8 +, and NK cells) preferentially adhered and transmigrated in a cytokine priming-dependent manner. These PBMCs released clinically relevant IBD cytokines and biomarkers and induced barrier disruption, a hallmark of IBD. Anti-TNF-α antibodies and AJM300 caused reduced PBMC recruitment, inflammatory response and barrier disruption >90%. Dexamethasone had more modest effects, as expected. Conclusion: The human Colon Intestine-Chip can both model complex immune cell-driven IBD and validate effects of clinically relevant IBD drugs. This system could provide predictive validity for pre-clinical development of new IBD drugs.

Risk-Benefit of IBD Drugs: A Physicians and Patients Survey.

Treatment choices for patients with inflammatory bowel disease (IBD) are based on the balance between risks and benefits. Our AI was to compare the perspectives of patients and physicians in evaluating the risks and benefits before initiating therapy for IBD. An anonymous survey was conducted between March and August 2022. All patients with confirmed IBD and all physicians who attended an IBDscope webinar were invited to participate. In total, 367 patients and 146 physicians participated. For most patients (71.4%) and physicians (89.0%), efficacy and safety were equally important. Clinical improvement and clinical remission were the most relevant outcomes for patients (90.9 and 88.4), while clinical remission and endoscopic remission were for physicians (90.0 and 87.6). The main factors in the benefit-risk assessment were quality of life (95.1%), disease activity (87.5%), and presence of comorbidities (84.5%) for patients, and presence of comorbidities (99.3%), disease activity (97.9%), and prior failure to biologics/small molecules (96.6%) for physicians. Based on patients' and physicians' opinions, the risk of serious infections, malignancies, cardiovascular events, death, relapse, all infections, surgery, and hospitalization should be included in the benefit-risk assessment. Physicians and patients have different priorities in evaluating the benefit-risk balance of a new therapy.

Medicinal plant-based drug delivery system for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic recurrent intestinal disease. The incidence rate of IBD is increasing year by year, which seriously endangers human health worldwide. More and more studies have shown that medicinal plants or their main phytochemicals have great potential in the treatment of intestinal diseases. However, the disadvantages of low oral absorption rate, low biological distribution and low systemic bioavailability limit their clinical application to a certain extent. In recent years, the application of nanotechnology has made it possible to treat IBD. Nanoparticles (NPs) drug delivery system has attracted special attention in the treatment of IBD due to its small size, low immunogenicity, surface modification diversity, targeting and other advantages. Synthetic nanoparticles and extracellular vehicles (EVs) can deliver drug components to colon, and play a role in anti-inflammation, regulation of oxidative stress, improvement of intestinal flora, etc. In addition, some medicinal plants can secrete EVs by themselves, and carry biological molecules with therapeutic effects to act on the intestine. Some clinical trials to evaluate the safety, tolerance, toxicity and effectiveness of EVs-loaded drugs in IBD are also progressing steadily. This review introduces that synthetic nanoparticles and medicinal plants derived EVs can play an important role in the treatment of IBD by carrying the effective active phytochemicals of medicinal plants, and discuss the limitations of current research and future research needs, providing a scientific and reliable basis and perspective for further clinical application and promotion.

Systematic Review and Meta-Analysis of Observational Studies on the Effectiveness and Safety of Ustekinumab among Patients with Inflammatory Bowel Disease in Eastern and Western Countries.

Ustekinumab (UST) is an IL12/23 inhibitor utilized for altering inflammatory responses in inflammatory bowel disease (IBD). Clinical trials and case reports suggested that the effectiveness and safety of UST may differ among IBD patients in Eastern and Western countries. However, related data have not been systematically reviewed and analyzed. This systematic review and meta-analysis of the safety and effectiveness of UST in IBD included relevant literature from the Medline and Embase databases. The main outcomes were clinical response, clinical remission, endoscopic response, endoscopic remission, and adverse events in IBD. We analyzed 49 real-world studies, most of which included patients with biological failure (89.1% CD and 97.1% UC). In UC patients, clinical remission rates were 34% at 12 weeks, 40% at 24 weeks, and 37% at 1 year. In CD patients, clinical remission rates were 46% at 12 weeks, 51% at 24 weeks, and 47% at 1 year. Clinical remission rates of CD patients were 40% at 12 weeks and 44% at 24 weeks in Western countries, versus 63% and 72% in Eastern countries, respectively. UST is an effective drug for IBD with a promising safety profile. Although no RCTs have been performed in Eastern countries, the effectiveness of UST on CD patients is not inferior to that in Western countries based on the existing data.

P011 Patient-derived organoids as an epithelial model for preclinical IBD research and drug development.

Abstract Background The study of the intestinal epithelial barrier is hampered by the lack of a suitable in vitro model system. Patient-derived organoids (PDOs) recapitulate the cellular diversity and patient heterogeneity and provide a relevant platform to study the intestinal epithelium and its response to microbial or inflammatory challenges. Here, we present the characterization of an inflammatory bowel disease (IBD) organoid biobank derived from Crohn’s disease and Ulcerative Colitis patients and its application for IBD drug development efforts. Methods PDOs from different regions of the gastrointestinal tract of 14 IBD patients were established. To recapitulate the full cellular diversity, specialized medium formulations were defined that support the differentiation of distinct epithelial cell lineages as confirmed by transcriptional profiles and histology. To study the inflammation driven loss of barrier integrity observed in the mucosa of IBD patients, we employed organoid derived monolayers and mimicked the inflammatory environment by cytokine challenge (TNF, IFNγ). Results In response to differentiation media, intestinal organoids and monolayers displayed gene expression patterns consistent with maturation of epithelial cell types found in the human gut. The cytokine challenge robustly induces loss of barrier integrity across seven patient-derived monolayers. The barrier breakdown was ameliorated in all models by treatment with the IBD therapy Tofacitinib. Conclusion Intestinal PDOs were generated from IBD patients and were capable to differentiate into mature epithelial cell types. PDO-derived monolayers built trans-epithelial electrical resistance (TEER) and are a relevant model to study epithelial barrier function and inflammation mediated barrier breakdown. Proof-of-concept studies with Tofacitinib demonstrated the suitability of the assay for IBD drug development efforts.

P335 Impact of cancer therapy on the course of Inflammatory Bowel Disease (ONCOEII study of GETECCU)

Abstract Background Cancer in inflammatory bowel disease (IBD) patients is increasing mainly due to the aging of patients. There are few data regarding the effect of different types of cancer treatments in IBD disease outcome. The aim of the study was to evaluate the impact of cancer treatments on the course of IBD patients. Methods An observational, multicenter, retrospective cohort study was conducted. We identified IBD patients diagnosed for an extraintestinal malignancy and who received any of the following cancer treatment types: chemotherapy, hormonal therapy, targeted therapy or immunotherapy. Patients who simultaneously received more than one different type of cancer treatment were excluded. Primary outcome was to evaluate the risk of IBD relapse for each type of cancer treatment. IBD relapse was defined as the need for additional medication, hospitalization or surgery related to IBD. Secondary outcomes were to describe the IBD treatment modifications after cancer diagnosis and to identify predictive factors for IBD relapse. IBD relapse was defined as the need for additional medication, hospitalization or surgery related to IBD. Predictive factors for IBD relapse were identified using multivariate Cox proportional hazard analysis. Results A total of 180 patients from 26 centers were included. Median age at cancer diagnosis was 57.5 years (IQR 46.8-67), 52.2% were female and 51.1% had Crohn’s disease. 36.1% and 20.6% were receiving immunomodulators and biologic drugs at the moment of cancer diagnosis respectively. IBD was in remission in most of the patients (85%). The most frequent malignancies were breast, prostate and hematological (33.9%, 12.2% and 12.2% respectively). IBD treatment was discontinued in 40.6% of patients at cancer diagnosis (77.1% of patients receiving thiopurines and 79.2% of those receiving anti-TNF drugs). 33% of patients experienced IBD relapse after cancer treatment initiation, at a median time of 7.6 months. IBD relapse was treated more frequently with steroids, vedolizumab and anti-TNF (56%, 15.2% and 13.6% respectively). In multivariate Cox-regression analysis, older age (HR=0.98; 95% CI [0.96-0.99]) and chemotherapy (HR=0.57; 95% CI [0.34-0.96]) were associated with a lower risk of IBD relapse, and active IBD at baseline (HR=2.9; 95% CI [1.67-5.07] was associated with a higher risk. Kaplan-Meier survival curves for time to IBD relapse are shown in Figures 1 and 2. Conclusion One out of three patients experienced IBD relapse after cancer treatment initiation. IBD drugs were discontinued in almost half of the cohort, specially thiopurines and anti-TNF drugs. Older age and chemotherapy were associated with a lower risk of IBD relapse, and active IBD at baseline with a higher risk.

P385 Risk-benefit assessment of IBD drugs: a physicians and patients survey

Abstract Background Treatment choices for patients with inflammatory bowel disease (IBD) are based on the balance between risks and benefits. To date, there are no globally accepted methods for assessing the risk-benefit ratio. Our aim was to compare the perspectives of patients and physicians in evaluating the risks and benefits before initiating therapy for IBD. Methods An anonymous survey was conducted between March and August 2022. Multiple choice questions, similar for physicians and patients, were formulated. The questionnaire was developed in English and was later translated in Italian and French by native speakers. All patients with a confirmed diagnosis of IBD who were followed up at the IRCCS San Raffaele Hospital (Italy), Nancy University Hospital (France), and University Hospital CHU of Liège (Belgium) were invited to participate. All physicians who attended an IBDscope webinar were invited to participate by email. Results In total, 367 patients and 146 physicians participated in the survey from 34 countries worldwide (Tables 1 and 2). For most patients (71.4%) and physicians (89.0%), efficacy and safety were equally important in choosing a therapy. Clinical improvement and clinical remission were the most relevant outcomes for patients (90.9 and 88.4 Likert scales), while clinical remission and endoscopic remission were for physicians (90.0 and 87.6 Likert scales). The main factors in the benefit-risk assessment for patients were quality of life (95.1%), disease activity (87.5%), and presence of comorbidities (84.5%). The main factors for physicians were presence of comorbidities (99.3%), disease activity (97.9%), prior failure to biologics or small molecules (96.6%). Disease duration, family history of IBD, administration interval, therapy duration, and administration route had a limited role for both physicians and patients. Based on patients' and physicians’ opinions, the risk of serious infections (90.5% and 98.6%), malignancies (90.5% and 100.0%), cardiovascular events (88.8% and 98.6%), death (86.4% and 91.8%), relapse (86.1% and 94.5%), all infections (86.1% and 100.0%), surgery (83.1% and 93.1%), and hospitalization (76.6% and 88.4%) should be included in the benefit-risk assessment. The risk percentages considered acceptable by patients and physicians are reported in Figures 1 and 2. Infliximab was the most effective drug for physicians in inducing and maintaining disease remission in both Crohn’s disease and ulcerative colitis, while ustekinumab and vedolizumab were equally considered the safest drugs. Conclusion Physicians and patients have different priorities in evaluating the benefit-risk balance of a new therapy. Treatment decisions should be discussed and shared with patients.

OP21 COVID-19 morbidity/mortality and vaccination against SARS-CoV-2 in patients with Inflammatory Bowel Disease in Poland: Nationwide Data

Abstract Background According to the international recommendations, patients with inflammatory bowel disease (IBD) should be vaccinated against SARS-CoV-2 at the earliest opportunity to do so. The aim of this study was to assess the morbidity and mortality from COVID-19 in the adult IBD population in Poland with respect to their vaccination status. Methods We conducted a retrospective analysis of administrative health claims collected by the National Health Fund, the sole public payer in Poland. We identified adult IBD patients as of December 31th, 2021 who had at least two or more records with K50 or K51 code and two or more prescriptions for IBD drugs reimbursed or else intestinal surgery preceding the record. The vaccination status in 2021 was assessed using the database maintained by the Ministry of Health. We examined the vaccination process against SARS-CoV-2 among IBD patients along with morbidity and mortality from COVID-19. We conducted a Cox proportional hazard model analysis to determine the hazard ratio of SARS-CoV-2 infection, hospitalization and death in respect to the vaccination status during the autumn wave of the COVID-19 pandemic (October–December 2021). Results As of December 31th, 2021 there were 93 068 adult patients diagnosed with IBD. The vaccination rate in IBD patients was significantly higher than in the general population of Poland (72.1% vs 63.8%; p<0.001) and grew with age, reaching the top value among those aged 70-79 years (88.2%) [Figure 1]. 87 353 IBD patients were included into the Cox proportional hazard analysis of autumn pandemic wave, during which there were 4 042 registered COVID-19 cases in IBD population. The peak value of a weekly average of incidence rate of COVID-19 was lower for vaccinated IBD patients (7.4/10000) than for unvaccinated ones (13.0/10000). The risk of being infected was significantly lower for vaccinated IBD patients (HR 0.53; 95%CI 0.5-0.57; p<0.001). The cumulative risk of being positively tested for COVID-19 shows Figure 2. The most notable protective effect of vaccination against SARS-CoV-2 was found in patients aged 60-69 years (HR 0.47; 95%CI 0.39-0.55) and in those aged 80 years and above (HR 0.44; 95%CI 0.32-0.63). The risk of hospitalization due to COVID-19 was also significantly lower among the vaccinated IBD patients (HR 0.48; 95%CI 0.31-0.74, p<0.0001). The risk of death due to COVID-19 was more than 3 times decreased in vaccinated IBD patients in comparison to the remaining IBD population (HR 0.29, 95%CI 0.17-0.43, p<0.001) [Table 1]. Conclusion Adult patients with IBD were more likely to get vaccinated against SARS-COV-2 than adults in the general population of Poland. The vaccination significantly decreased the risk of the infection, hospitalization and death due to COVID-19.

ASSOCIATION BETWEEN ANTIBIOTIC USE AND INFLAMMATORY BOWEL DISEASE OUTCOMES

Abstract OBJECTIVE Benefit of antibiotic use in Inflammatory Bowel Disease (IBD) is unclear and has been a subject of research. This study investigated the association between antibiotic use and treatment outcomes among IBD patients using real-world data. METHODS Data from Study of a Prospective Adult Research Cohort with IBD (SPARC IBD) of Crohn’s & Colitis Foundation’s IBD Plexus program were used. Patients diagnosed with Crohn’s disease (CD) or ulcerative colitis (UC) since 2000 were included. The use of antibiotics (ciprofloxacin, metronidazole, rifaximin and vancomycin) for ≥7 days after enrollment was identified from electronic health records and case report forms. Disease activity scores were assessed at the time of enrollment (baseline) and during follow-up using 6-point Mayo score (6-pt MS) and short Clinical Disease Activity Index (sCDAI) for UC and CD, respectively. Patients’ demographic and clinical characteristics were also collected. Remission was defined as 6-pt MS of 0-1 for UC and sCDAI<150 for CD. The association between antibiotic use and outcome during follow-up was assessed in a subset of patients without remission at baseline using a multivariable Cox proportional hazards model. The model included the following covariates for adjustment: age, gender, race, family history of IBD, IBD surgery, disease activity at enrollment and other IBD drug use during follow-up. RESULTS A total of 2,959 IBD patients (UC=1,060; CD=1,899) were included. Mean age at diagnosis was 30±14 years (UC=32±15; CD=28±14). Forty-four percent of the patients were male (UC=49%; CD=41%) and 79% were White (UC=82%; CD=78%). Antibiotic use after enrollment was observed in 29% of the patients (UC=26%; CD=30%). About 60% of UC or CD patients were in remission at baseline. The antibiotic use group had significantly higher baseline disease activity (UC 6-pt MS: 1.7±1.8; CD sCDAI: 167±96) than patients without antibiotic use (UC 6-pt MS: 1.3±1.7; CD sCDAI: 137±89). In the subset of patients with mild, moderate or severe baseline IBD (6-pt MS>1 for UC; sCDAI≥150 for CD), the baseline disease activity scores were largely comparable between patients who used antibiotic and who did not (UC 6-pt MS: 3.6±1.3 vs 3.3±1.3, p-value=0.063; CD sCDAI: 248±83 vs 238±83, p-value=0.169), while patients who used antibiotics were less likely to experience remission during follow-up compared to those who did not use antibiotics (UC adjusted remission hazard ratio [aRHR] 0.39, 95% confidence interval [CI] 0.26-0.60; CD aRHR 0.60, 95% CI 0.46-0.79). CONCLUSION In this study, antibiotic use in patients with IBD was negatively associated with remission during follow-up. The effect of antibiotics on gut microbiome and optimal use of antibiotics in IBD patients need to be further explored.

Therapeutic Potential of Bioactive Components from Scutellaria baicalensis Georgi in Inflammatory Bowel Disease and Colorectal Cancer: A Review.

Scutellaria baicalensis Georgi (SBG), an herbal medicine with various biological activities, including anti-inflammatory, anticancer, antiviral, antibacterial, and antioxidant activities, is effective in treatment of colitis, hepatitis, pneumonia, respiratory infections, and allergic diseases. This herbal medicine consists of major active substances, such as baicalin, baicalein, wogonoside, and wogonin. Inflammatory bowel disease (IBD) comprises a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis being the main types. IBD can lead to serious complications, such as increased risk of colorectal cancer (CRC), one of the most common cancers worldwide. Currently, there is no cure for IBD, and its incidence has been increasing over the past few decades. This review comprehensively summarizes the efficacy of SBG in IBD and CRC and may serve as a reference for future research and development of drugs for IBD and cancer treatment.

Association between HLA DNA Variants and Long-Term Response to Anti-TNF Drugs in a Spanish Pediatric Inflammatory Bowel Disease Cohort.

The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.

Modern drug discovery for inflammatory bowel disease: The role of computational methods.

Inflammatory bowel diseases (IBDs) comprising ulcerative colitis, Crohn's disease and microscopic colitis are characterized by chronic inflammation of the gastrointestinal tract. IBD has spread around the world and is becoming more prevalent at an alarming rate in developing countries whose societies have become more westernized. Cell therapy, intestinal microecology, apheresis therapy, exosome therapy and small molecules are emerging therapeutic options for IBD. Currently, it is thought that low-molecular-mass substances with good oral bio-availability and the ability to permeate the cell membrane to regulate the action of elements of the inflammatory signaling pathway are effective therapeutic options for the treatment of IBD. Several small molecule inhibitors are being developed as a promising alternative for IBD therapy. The use of highly efficient and time-saving techniques, such as computational methods, is still a viable option for the development of these small molecule drugs. The computer-aided (in silico) discovery approach is one drug development technique that has mostly proven efficacy. Computational approaches when combined with traditional drug development methodology dramatically boost the likelihood of drug discovery in a sustainable and cost-effective manner. This review focuses on the modern drug discovery approaches for the design of novel IBD drugs with an emphasis on the role of computational methods. Some computational approaches to IBD genomic studies, target identification, and virtual screening for the discovery of new drugs and in the repurposing of existing drugs are discussed.

COVID-19 susceptibility and clinical outcomes in inflammatory bowel disease: An updated systematic review and meta-analysis.

The susceptibility, risk factors, and prognosis of COVID-19 in patients with inflammatory bowel disease (IBD) remain unknown. Thus, our study aims to assess the prevalence and clinical outcomes of COVID-19 in IBD. We searched PubMed, EMBASE, and medRxiv from 2019 to 1 June 2022 for cohort and case-control studies comparing the prevalence and clinical outcomes of COVID-19 in patients with IBD and in the general population. We also compared the outcomes of patients receiving and not receiving 5-aminosalicylates (ASA), tumour necrosis factor antagonists, biologics, systemic corticosteroids, or immunomodulators for IBD. Thirty five studies were eligible for our analysis. Pooled odds ratio of COVID-19-related hospitalisation, intensive care unit (ICU) admission, or death in IBD compared to in non-IBD were 0.58 (95% confidence interval (CI)=0.28-1.18), 1.09 (95% CI=0.27-4.47), and 0.67 (95% CI=0.32-1.42), respectively. Inflammatory bowel disease was not associated with increased hospitalisation, ICU admission, or death. Susceptibility to COVID-19 did not increase with any drugs for IBD. Hospitalisation, ICU admission, and death were more likely with 5-ASA and corticosteroid use. COVID-19-related hospitalisation (Odds Ratio (OR): 0.53; 95% CI=0.38-0.74) and death (OR: 0.13; 95% CI=0.13-0.70) were less likely with Crohn's disease than ulcerative colitis (UC). In conclusion, IBD does not increase the mortality and morbidity of COVID-19. However, physicians should be aware that additional monitoring is needed in UC patients or in patients taking 5-ASA or systemic corticosteroids.

A broad cuproptosis landscape in inflammatory bowel disease.

Cuproptosis, a genetic process of copper-dependent cell death linked to mitochondria respiration, demonstrates its correlation with inhibiting tumoral angiogenesis and motility. Recent studies have developed systematic bioinformatics frameworks to identify the association of cuproptosis with tumors but any non-neoplastic diseases. Therefore, against the background of an increased incidence of inflammatory bowel disease (IBD), the landscape of cuproptosis regulation in IBD is a critical need to be investigated. The differentially expressed cuproptosis-related genes (DECRGs) were identified with human sequencing profiles for four inflammatory digestive disorders. Another four independent IBD datasets from GEO were used as a validation cohort. And experimental mice model provides another validation method. Using single sample gene set enrichment analysis (ssGSEA), receiver operating characteristic (ROC) curve, CIBERSORT, and consensus clustering algorithms, we explored the association between immune score and cuproptosis-related genes, as well as the diagnostic value of these genes. Molecular docking screened potential interaction of IBD drugs with the structural regulator by Autodock Vina. Cuproptosis-related regulators exhibited extensive differential expression in Crohn's Disease (CD), Ulcerative Colitis (UC), Celiac Disease (CEL), and IBD-induced cancer (IBD-CA) that share common differential genes (PDHA1, DBT, DLAT, LIAS). The differential expression of DECRGs was reverified in the validated cohort and immunohistochemistry assay. Moreover, the cell signaling pathways and ontology mainly focused on the mitochondrial respiratory function, which was highly enriched in Gene set enrichment analysis (GSEA). According to ssGSEA and ROC, when considering the four regulators, which showed robust association with immune infiltration in IBD, the area under the ROC (AUC) was 0.743. In addition, two clusters of consensus clustering based on the four regulators exhibit different immune phenotypes. According to molecular docking results, methotrexate gained the highest binding affinity to the main chain of key cuproptosis-related regulators compared with the remaining ten drugs. Cuproptosis-related regulators were widely linked to risk variants, immune cells, immune function, and drug efficacy in IBD. Regulation of cuproptosis may deeply influence the occurrence and development of patients with IBD.

Inflammatory bowel disease addressed by Caco-2 and monocyte-derived macrophages: an opportunity for an in vitro drug screening assay

Inflammatory bowel disease (IBD) is a widespread disease, affecting a growing demographic. The treatment of chronic inflammation located in the GI-tract is dependent on the severity; therefore, the IBD treatment pyramid is commonly applied. Animal experimentation plays a key role for novel IBD drug development; nevertheless, it is ethically questionable and limited in its throughput. Reliable and valid in vitro assays offer the opportunity to overcome these limitations.We combined Caco-2 with monocyte-derived macrophages and exposed them to known drugs, targeting an in vitro-in vivo correlation (IVIVC) with a focus on the severity level and its related drug candidate. This co-culture assay addresses namely the intestinal barrier and the immune response in IBD. The drug efficacy was analyzed by an LPS-inflammation of the co-culture and drug exposure according to the IBD treatment pyramid. Efficacy was defined as the range between LPS control (0%) and untreated co-culture (100%) independent of the investigated read-out (TEER, Papp, cytokine release: IL-6, IL-8, IL-10, TNF-α).The release of IL-6, IL-8, and TNF-α was identified as an appropriate readout for a fast drug screening (“yes–no response”). TEER showed a remarkable IVIVC correlation to the human treatment pyramid (5-ASA, Prednisolone, 6-mercaptopurine, and infliximab) with an R2 of 0.68. Similar to the description of an adverse outcome pathway (AOP) framework, we advocate establishing an “Efficacy Outcome Pathways (EOPs)” framework for drug efficacy assays. The in vitro assay offers an easy and scalable method for IBD drug screening with a focus on human data, which requires further validation.

Risk of adverse outcomes in inflammatory bowel disease patients infected with SARS-CoV-2: a systematic review and meta-analysis.

BackgroundBetween people with and without inflammatory bowel disease (IBD), there was no statistically significant difference in the probability of contracting the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the risk of adverse outcomes in IBD patients after virus infection remains unclear.MethodsEligible studies conducted from January 1, 2020 to March 17, 2022 were obtained by searching PubMed, Embase, and Web of Science. Information was collected in tables from the included studies. Random-effects and fixed-effects models were used as measures for the pooled estimates. All data were estimated by R version 4.1.3.ResultsTwenty-four studies were included. The risk ratio (RR) of adverse outcomes in COVID-19 patients with IBD increased by 32% (RR 1.32; 95% CI 1.06–1.66) relative to COVID-19 patients without IBD. The RR of mortality was higher in COVID-19 patients with IBD from Europe (RR 1.72; 95% CI 1.11–2.67) than in those that were not from Europe (RR 1.00; 95% CI 0.79–1.26; χ2 = 4.67; P = 0.03). Patients with ulcerative colitis were at higher risk of adverse outcomes after SARS-CoV-2 infection than patients with Crohn’s disease patients (RR1.38; 95% CI 1.27–1.50). The IBD drugs treatment was associated with the risk of adverse outcomes, the pooled odds ratio (OR) of mesalazine (1.79; 95% CI 1.59–2.02), immunomodulators (1.30; 95% CI 1.10–1.53), and anti-TNF (0.47; 95% CI 0.41–0.53) were assessed.ConclusionCOVID-19 patients with IBD had an increased risk of adverse outcomes than those without IBD, whereas anti-TNF treatment might reduce the risk.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00384-022-04265-w.

Infliximab and Tofacitinib Attenuate Neutralizing Antibody Responses Against SARS-CoV-2 Ancestral and Omicron Variants in Inflammatory Bowel Disease Patients After 3 Doses of COVID-19 Vaccine

Infliximab and Tofacitinib Attenuate Neutralizing Antibody Responses Against SARS-CoV-2 Ancestral and Omicron Variants in Inflammatory Bowel Disease Patients After 3 Doses of COVID-19 Vaccine