Liver enzyme profiles after initiating biological treatment in children with inflammatory bowel diseases.

OBJECTIVES: Biological treatments (BTs) are essential in managing pediatric inflammatory bowel diseases (PIBDs). Elevated liver enzymes sometimes succeed BT, yet elucidating studies are scarce. We addressed liver biochemistry after introducing BT and searched for their determinants. METHODS: We identified PIBD patients receiving infliximab, adalimumab, vedolizumab, or ustekinumab at the Children's Hospital, University of Helsinki, Finland, in 2000-2023, and followed their alanine transaminase (ALT) and γ-glutamyl transpeptidase (GT) levels for 24 months. ALT was categorized based on the age- and sex-specific upper limit of normal. We disregarded 46 patients with underlying primary sclerosing cholangitis with/without autoimmune hepatitis (AIH), pretreatment AIH diagnosis, and elevated liver enzymes at the beginning of BT from the analyses. RESULTS: Of 618 BT episodes in 403 patients, 22.2% exhibited increased ALT or GT (ALT in 117, GT in 4, and both ALT/GT in 16 episodes). Of all ALT elevations (n = 133), 41.4% occurred within the first 3 months. ALT elevation was more common after infliximab (representing 59.5% of BTs) than other BTs (25.9% vs. 14.2%, adjusted odds ratio [OR]: 2.41, 95% confidence interval [CI]: 1.23-4.72). AIH followed 1.5% (n = 9) of BT episodes. Ninety-five percent of ALT elevations resolved within 6 months. Antibiotic exposure (particularly to metronidazole) was associated with ALT elevation in general (adjusted OR: 5.76, 95% CI: 2.40-13.9) and short disease duration before starting BT with notable ALT elevation (adjusted OR: 1.10, 95% CI: 1.01-1.22). CONCLUSIONS: Benign ALT elevation is common within 3 months after starting BT (especially infliximab) and scarcely led to cessation of the treatment. AIH is a rare finding during the first year of BT.

Temporal Trends of Inflammatory Bowel Diseases in Taiwan from 2016 to 2020: A Population-Based Study.

BACKGROUND: There are scanty population-based studies investigating the incidence and prevalence rates of inflammatory bowel disease (IBD) in Taiwan. AIMS: This study aimed to estimate the nationwide prevalence and incidence of IBD and identify its noticeable trends in Taiwan between 2016 and 2020. METHODS: A retrospective study by analyzing the data from the National Health Insurance Research Database of Taiwan. RESULTS: A total of 2595 patients with catastrophic IBD illness were registered from 2016 to 2020 in Taiwan (CD, 880; UC, 1715). The male-to-female ratio in the study sample was 1.83:1 for CD and 1.69:1 for UC. The median age of those registered with CD and UC was 37 and 47 years, respectively. The incidence rate of CD was 0.65 per 100,000 persons in 2016 and it was increased to 0.81 per 100,000 persons in 2020. The incidence rate of UC was 1.16 per 100,000 persons in 2016 and it was increased to 1.53 in 2020. Overall, the incidence of IBD was increase from 1.81 per 100,000 persons to 2.34 per 100,000 persons between 2016 and 2020. Overall, the prevalence rates of IBD was increase from 14.95 per 100,000 persons to 20.02 per 100,000 persons between 2016 and 2020. CONCLUSION: The epidemiological stages of IBD in Taiwan was considered in the acceleration in incidence stage, during which incidence rises and prevalence is relatively low. Understanding these geographical differences is important for the rising global burden of IBD.

[Two Cases of Behcet's Disease-Like Syndrome with Gene Deficiency in ELF4]. / ELF4åŸºå› ç¼ºé™·çš„ç±»ç™½å¡žç— æ ·ç»¼åˆå¾2例报告.

The patient 1, a 13-year-old boy, was admitted due to "recurrent oral ulcers for 3 years, abdominal pain for 8 months, and perianal ulcers for 10 days"; The patient 2, a 3-year-old boy, was admitted due to "recurrent abdominal pain, diarrhea, and fever for over 3 months". Genetic testing of both patients revealed "deficiency in ELF4, X-linked" (DEX), and the patients were diagnosed with Behcet's disease-like syndrome due to deficiency in ELF4, accordingly. The patient 1 was successively given intravenous methylprednisolone pulses and oral prednisone and mesalazine for symptomatic treatment. The patient 2 was successively treated with corticosteroids combined with enteral nutrition, as well as oral mercaptopurine. Subsequently, both patients showed improvements in symptoms and were discharged.

Association of diet and outdoor time with inflammatory bowel disease: a multicenter case-control study using propensity matching analysis in China.

Objective: To investigate the association between dietary and some other environmental factors and the risk of inflammatory bowel diseases (IBD) in Chinese population. Materials and methods: A multicenter case-control study was conducted involving 11 hospitals across China. A total of 1,230 subjects were enrolled consecutively, and diet and environmental factor questionnaires were collected. IBD patients were matched with healthy controls (HC) using propensity-score matching (PSM) at a 1:1 ratio with a caliper value of 0.02. Multivariate conditional logistic regression analyses were performed to evaluate the associations between diet, environmental factors, and IBD. Results: Moderate alcohol and milk consumption, as well as daily intake of fresh fruit, were protective factors for both Crohn's disease (CD) and ulcerative colitis (UC). Conversely, the consumption of eggs and chocolate increased the risk of IBD. Outdoor time for more than 25% of the day was a protective factor only for CD. In eastern regions of China, CD patients had higher egg consumption and less outdoor time, while UC patients consumed more chocolate. IBD patients from urban areas or with higher per capita monthly income consumed more fruit, eggs, and chocolate. Conclusions: This study reveals an association between specific foods, outdoor time, and the emergence of IBD in the Chinese population. The findings emphasize the importance of a balanced diet, sufficient outdoor time and activities, and tailored prevention strategies considering regional variations.

SERENE ER Analysis Part 1-SERENE CD: Exposure-Response Analysis of Higher Versus Standard Adalimumab Dosing Regimens for Patients With Moderately to Severely Active Crohn Disease.

SERENE CD (NCT02065570) evaluated whether a higher adalimumab induction dose would improve patients with Crohn disease response and suggested a flat dose-response relationship for efficacy in the induction study. We investigated exposure-response relationships in induction and maintenance studies considering patients' baseline characteristics. Adalimumab exposures were simulated using the established population pharmacokinetic model. Efficacy end points (clinical remission/endoscopic response) at Weeks 4, 12, and 56 were evaluated in exposure-response analyses using multivariable logistic regression. Analyses showed an increasing trend with heterogeneity between induction regimens, which suggested that average concentration has an impact on coprimary efficacy end points within each group, but data did not fit a single-response curve. Although higher concentrations within arms were associated with improved outcomes, increasing the concentration through a higher induction dose was not associated with increasing clinical remission/endoscopic response at Week 4/12. A model including inverse effective clearance eliminated heterogeneity and described trends across induction regimens with a single curve. In the maintenance study, the response rates at Week 56 showed no heterogeneity. In the induction study, patients with lower effective adalimumab clearance responded better, whereas in the maintenance study average concentration drove primary efficacy end points at Week 56. Research extending these findings to other indications is needed.

Proactive Therapeutic Drug Monitoring Is Associated With Increased Drug Persistence in Patients With Inflammatory Bowel Disease Treated With Intravenous Vedolizumab.

BACKGROUND: There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). This study aimed to evaluate the efficacy of proactive TDM in IBD patients treated with intravenous (iv) vedolizumab (VDZ). METHODS: This single-center retrospective cohort study included consecutive IBD patients treated with maintenance iv VDZ therapy undergoing TDM from November 2016 to March 2023. Patients were followed through June 2023 and were divided in to 2 groups: those who had at least 1 proactive TDM vs those who underwent only reactive TDM. A survival analysis was performed to evaluate drug persistence, defined as no need for drug discontinuation due to loss of response, serious adverse event, or an IBD-related surgery. RESULTS: The study population consisted of 94 patients (proactive TDM, n = 72) with IBD (ulcerative colitis, n = 53). Patients undergoing at least 1 proactive TDM compared with patients having only reactive TDM demonstrated a higher cumulative probability of drug persistence (Log-rank P < .001). In multivariable Cox proportional hazard regression analysis, at least 1 proactive TDM was the only factor associated with drug persistence (hazard ratio, 14.3; 95% confidence interval [CI], 3.8-50; P < .001). A ROC analysis identified a VDZ concentration of 12.5 µg/mL as the optimal drug concentration threshold associated with drug persistence (area under the ROC curve: 0.691; 95% CI, 0.517-0.865; P = .049). CONCLUSION: In this single-center retrospective study reflecting real-life clinical practice, proactive TDM was associated with increased drug persistence in patients with IBD treated with iv VDZ.

There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). We found that proactive TDM was associated with drug persistence in patients with IBD treated with vedolizumab. Moreover, a vedolizumab concentration of 12.5 µg/mL was identified as the optimal drug concentration threshold associated with drug persistence.

Bromodomain-containing 4 is a positive regulator of the inflammatory cytokine response in the gut.

BACKGROUND AND AIM: Bromodomain-containing protein 4 (BRD4), one of the components of the bromodomain and extraterminal domain (BET) family, is a transcriptional and epigenetic regulator of cellular proliferation and cytokine production. In this study, we assessed whether BRD4 regulates the cytokine response in inflammatory bowel diseases (IBD). MATERIALS AND METHODS: BRD4 expression was analyzed in intestinal mucosal samples of patients with ulcerative colitis (UC), patients with Crohn's disease (CD), normal controls (CTRs), and mice with chemically-induced colitis by real-time PCR, Western blotting, and confocal microscopy. Cytokine production was evaluated in lamina propria mononuclear cells (LPMCs) of IBD patients and mucosal tissues of colitic mice treated with BRD4 inhibitors. Finally, we evaluated the effect of JQ1, an inhibitor of the BRD4 signaling pathway, on the course of murine colitis. RESULTS: BRD4 RNA and protein expression was up-regulated in the inflamed mucosa of patients with UC and patients with CD as compared to the uninvolved areas of the same patients and CTRs, and in the inflamed colon of colitic mice. Knockdown of BRD4 with a specific antisense oligonucleotide in IBD LPMCs led to reduced expression of TNF-α, IL-6, IFN-γ, and IL-17A. Administration of JQ1 to colitic mice inhibited the inflammatory cytokine response and attenuated the ongoing colitis. CONCLUSIONS: This is the first study showing the up-regulation of BRD4 in IBD and suggesting the role of such a protein in the positive control of the inflammatory cytokine response in the gut.

Mechanical Stress-induced Connective Tissue Growth Factor Plays a Critical Role in Intestinal Fibrosis in Crohn's-like Colitis.

Crohn's disease (CD) is an inflammatory bowel disease characterized by transmural inflammation and intestinal fibrosis. Mechanisms of fibrosis in CD are not well understood. Transmural inflammation is associated with inflammatory cell infiltration, stenosis, and distention, which present mechanical stress (MS) to the bowel wall. We hypothesize that MS induces gene expression of pro-fibrotic mediators such as connective tissue growth factor (CTGF), which may contribute to fibrosis in CD. A rodent model of CD was induced by intracolonic instillation of TNBS to the distal colon. TNBS instillation induced a localized transmural inflammation (site I), with a distended colon segment (site P) proximal to site I. We detected significant fibrosis and collagen content not only in site I, but also in site P in CD rats by day 7. CTGF expression increased significantly in sites P and I, but not in the segment distal to the inflammation site. Increased CTGF expression was detected mainly in the smooth muscle cells (SMC). When rats were fed exclusively with clear liquid diet to prevent mechanical distention in colitis, expression of CTGF in sites P and I was blocked. Direct stretch led to robust expression of CTGF in colonic SMC. Treatment of CD rats with anti-CTGF antibody FG-3149 reduced fibrosis and collagen content in both sites P and I and exhibited consistent trends towards normalizing expression of collagen mRNAs. In conclusion, our studies suggest that mechanical stress, by up-regulating pro-fibrotic mediators i.e. CTGF, may play a critical role in fibrosis in CD.

Revolution in diet therapy for inflammatory bowel disease.

Until recently, diet as a therapeutic tool to treat inflammatory bowel disease (IBD) has not been proven effective. Nearly a century in the making we are in the grips of a revolution in diet therapies for IBD, driven by emerging data revealing diet as a key environmental factor associated with IBD susceptibility, and observational studies suggesting that dietary intake may play a role in the disease course of established IBD. This review summarizes the current evidence for diets trialed as induction and maintenance therapy for IBD. For Crohn's disease, exclusive enteral nutrition and the Crohn's disease exclusion diet with partial enteral nutrition are supported by emerging high-quality evidence as induction therapy, but are short-term approaches that are not feasible for prolonged use. Data on diet as maintenance therapy for Crohn's disease are conflicting, with some studies supporting fortification, and others suppression, of certain food components. For ulcerative colitis, data are not as robust for diet as induction and maintenance therapy; however, consistent themes are emerging, suggesting benefits for diets that are plant-based, high in fiber and low in animal protein. Further studies for both Crohn's disease and ulcerative colitis are eagerly awaited, which will allow specific recommendations to be made. Until this time, recommendations default to population based healthy eating guidelines.

Possible poor prognosis in younger-onset Crohn's disease-associated anorectal cancer: A subanalysis of the Nationwide Japanese study.

Background and aims: Crohn's disease (CD)-associated intestinal cancers are characterized by their high incidence, particularly at the anorectal site in the Japanese population. Accumulating evidence revealed that younger-onset sporadic colorectal cancer may exhibit unique biological features. To the best of our knowledge, few previous articles reported clinicopathological features in patients with CD-associated anorectal cancer (CDAAC). Therefore, we aimed to clarify the relationship between the younger onset of cancer and clinicopathological characteristics and prognosis, and the efficacy of cancer surveillance in patients with CDAAC. Methods: CD patients who had been diagnosed with intestinal cancers from 1983 to 2020 were collected from 39 Japanese institutions in this study. Of 316 patients with CD-associated intestinal cancers, we analyzed 211 patients with CDAAC. We divided the patients into two groups according to the median age at cancer diagnosis (45 years old). Results: Younger-onset CDAAC (YO-CDAAC) patients were significantly more likely to have a poor outcome than those with older-onset CDAAC (OO-CDAAC) in terms of both disease-free survival (DFS) (p = 0.0014) and overall survival (OS) (p = 0.023). Multivariate analysis showed that age under 45 years old at diagnosis of cancer was one of the independent factors for poor DFS and OS (hazard ratios: 2.15, 95% confidence interval: 1.09-4.26, p = 0.028, hazard ratios: 1.95, 95% confidence interval: 1.05-3.60, p = 0.033, respectively). Patients detected via surveillance showed significantly better DFS and OS rates than symptomatic patients in YO-CDAAC (p = 0.012 and 0.0031, respectively). Conclusions: YO-CDAAC may have a poorer prognosis compared with OO-CDAAC. Surveillance could be important to improve cancer prognosis, especially in young CD patients with anorectal disease.

Single-cell analysis of Crohn's disease: Unveiling heterogeneity and evaluating ustekinumab outcomes.

BACKGROUND: The present study aimed to dissect the cellular complexity of Crohn's disease (CD) using single-cell RNA sequencing, focusing on identifying key cell populations and their transcriptional profiles in inflamed tissue. METHODS: We applied scRNA-sequencing to compare the cellular composition of CD patients with healthy controls, utilizing Seurat for clustering and annotation. Differential gene expression analysis and protein-protein interaction networks were constructed to identify crucial genes and pathways. RESULTS: Our study identified eight distinct cell types in CD, highlighting crucial fibroblast and T cell interactions. The analysis revealed key cellular communications and identified significant genes and pathways involved in the disease's pathology. The role of fibroblasts was underscored by elevated expression in diseased samples, offering insights into disease mechanisms and potential therapeutic targets, including responses to ustekinumab treatment, thus enriching our understanding of CD at a molecular level. CONCLUSIONS: Our findings highlight the complex cellular and molecular interplay in CD, suggesting new biomarkers and therapeutic targets, offering insights into disease mechanisms and treatment implications.

Factors Associated with Delays in Initiating Biologic Therapy in Patients with Inflammatory Bowel Disease.

INTRODUCTION: Expeditious initiation of biologic therapy is important in patients with inflammatory bowel disease (IBD). However, initiation of biologics in the outpatient setting may be delayed by various clinical, social, and financial variables. AIM: To evaluate the delay in initiation of an advanced therapy in IBD and to identify factors that contributed to this delay. METHODS: This was a multi-center retrospective study. Outpatients who were initiated on a biologic therapy from 3/1/2019 to 9/30/20 were eligible for the study. Univariate and multivariate linear regression analyses were performed to identify variables associated with a delay in biologic treatment initiation. Delay was defined as the days from decision date (prescription placement) to first infusion or delivery of medication. RESULTS: In total 411 patients (Crohn's disease, n = 276; ulcerative colitis, n = 129) were included in the analysis. The median [interquartile range-(IQR)] delay for all drugs was 20 [12-37] days (infliximab, 19 [13-33] days; adalimumab, 10 [5-26] days; vedolizumab, 21 [14-42] days; and ustekinumab, 21 [14-42] days). Multivariate linear regression analysis identified that the most important variables associated with delays in biologic treatment initiation was self-identification as Black, longer distance from treatment site, and lack of initial insurance coverage approval. CONCLUSION: There may be a significant delay in biologic treatment initiation in patients with IBD. The most important variables associated with this delay included self-identification as Black, longer distance from site, and lack of initial insurance coverage approval.

After surgically induced remission, ileal and colonic mucosa-associated microbiota predicts Crohn's disease recurrence.

BACKGROUND AND AIMS: Investigating the tissue-associated microbiota after surgically induced remission may help to understand the mechanisms initiating intestinal inflammation in Crohn's disease. METHODS: Crohn's disease patients undergoing ileocolic resection were prospectively recruited in six academic centers. Biopsy samples from the neoterminal ileum, colon and rectosigmoid were obtained from colonoscopies performed after surgery. Microbial DNA was extracted for 16S rRNA gene sequencing. Microbial diversity and taxonomic differential relative abundance were analyzed. A random forest model was applied to analyze the performance of clinical and microbial features to predict recurrence. A Rutgeerts score ≥i2 was deemed as endoscopic recurrence. RESULTS: A total of 349 postoperative colonoscopies and 944 biopsy samples from 262 Crohn's disease patients were analyzed. Ileal inflammation accounted for most of the explained variance of the ileal and colonic mucosa-associated microbiota. Samples obtained from 97 patients who were in surgically induced remission at first postoperative colonoscopy who went on to develop endoscopic recurrence at second colonoscopy showed lower diversity and microbial deviations when compared to patients who remained in endoscopic remission. Depletion of genus Anaerostipes and increase of several genera from class Gammaproteobacteria at the three biopsy sites increase the risk of further recurrence. Gut microbiome was able to predict future recurrence better than clinical features. CONCLUSION: Ileal and colonic mucosa-associated microbiome deviations precede development of new onset ileal inflammation after surgically induced remission and show good predictive performance for future recurrence. These findings suggest that targeted microbial modulation is a plausible modality to prevent postoperative Crohn's disease recurrence.

The role of long non-coding RNA in Crohn's disease.

Emerging evidence has illuminated the pivotal role of long noncoding RNAs (lncRNAs) in orchestrating immunological functions and autoimmune responses. In the context of Crohn's disease (CD), an array of novel lncRNAs has been identified in the plasma and intestinal tissues of afflicted individuals, suggesting a dualistic influence on the disease progression, either exacerbating or mitigating its course. Current research has demonstrated the involvement of lncRNAs in competitive endogenous RNA, the inflammation process, epithelial barrier function, gut microbiota imbalance, and epigenetic regulation. This review aims to encapsulate the current knowledge on the lncRNA contribution to CD and underscore potential avenues for future research. LncRNAs are increasingly recognized as significant biomarkers and potential therapeutic targets, holding a key position in the pathogenesis of CD. Furthermore, the unique attributes of circulating lncRNAs, such as minimal side effects, combinational therapy potential, and personalized medicine, render them as promising therapeutic tools for individual health management in CD.

Outcomes of surgical treatment for enterovesical fistula in Crohn's disease.

Enterovesical fistula (EVF) in Crohn's disease (CD) often does not improve with medical treatment and requires surgical treatment. The surgical treatment strategy for EVF in CD is definitive resection of the intestinal tract side, and performing a leak test using dye injection into the bladder after EVF dissection to determine the appropriate surgical procedure for the bladder side. This study aimed to evaluate the outcomes of surgical treatment for EVF in CD. Twenty-one patients who underwent surgery for EVF between 2006 and 2021 were included and retrospectively evaluated for clinical background, surgical procedures, and postoperative complications. The most common origin of EVF was the ileum (17 cases; 81%), and the most common site of EVF formation was the apex (12; 57%). Surgical approaches were laparotomy in 11 (52%) cases and laparoscopy in 10 (48%). Surgical procedures on the bladder side were fistula dissection in 13 (62%) cases and sutured closure of fistula in 8 (38%). A comparison of approaches revealed no significant difference in operative time, but the amount of blood loss was significantly less in the laparoscopy (p < 0.01). There was no significant difference in the occurrence of postoperative complications between approaches. Postoperative anti-TNF-α antibody agents were used in 17 (81%) cases, and there were no cases of recurrent EVF. In conclusion, definitive resection of the intestinal tract and minimal treatment on the bladder side were sufficient to achieve satisfactory outcomes for EVF in CD.

Machine learning methods in automated detection of CT enterography findings in Crohn's disease: A feasibility study.

PURPOSE: Qualitative findings in Crohn's disease (CD) can be challenging to reliably report and quantify. We evaluated machine learning methodologies to both standardize the detection of common qualitative findings of ileal CD and determine finding spatial localization on CT enterography (CTE). MATERIALS AND METHODS: Subjects with ileal CD and a CTE from a single center retrospective study between 2016 and 2021 were included. 165 CTEs were reviewed by two fellowship-trained abdominal radiologists for the presence and spatial distribution of five qualitative CD findings: mural enhancement, mural stratification, stenosis, wall thickening, and mesenteric fat stranding. A Random Forest (RF) ensemble model using automatically extracted specialist-directed bowel features and an unbiased convolutional neural network (CNN) were developed to predict the presence of qualitative findings. Model performance was assessed using area under the curve (AUC), sensitivity, specificity, accuracy, and kappa agreement statistics. RESULTS: In 165 subjects with 29,895 individual qualitative finding assessments, agreement between radiologists for localization was good to very good (κ = 0.66 to 0.73), except for mesenteric fat stranding (κ = 0.47). RF prediction models had excellent performance, with an overall AUC, sensitivity, specificity of 0.91, 0.81 and 0.85, respectively. RF model and radiologist agreement for localization of CD findings approximated agreement between radiologists (κ = 0.67 to 0.76). Unbiased CNN models without benefit of disease knowledge had very similar performance to RF models which used specialist-defined imaging features. CONCLUSION: Machine learning techniques for CTE image analysis can identify the presence, location, and distribution of qualitative CD findings with similar performance to experienced radiologists.

Initiation of vedolizumab did not provoke new-onset spondylarthritis in patients with inflammatory bowel disease: A prospective 24-week study with imaging assessments.

BACKGROUND: A temporal relationship between vedolizumab and new-onset spondyloarthritis (SpA) has been suggested. AIMS: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The economic impact of suboptimal treatment and treatment switch among patients with Crohn's disease treated with a first-line biologic - A US retrospective claims database study.

AIMS: Suboptimal treatment indicators, including treatment switch, are common among patients with Crohn's disease (CD), but little is known about their associated healthcare resource utilization (HRU) and costs. This study assessed the impact of suboptimal treatment indicators on HRU and costs among adults with CD newly treated with a first-line biologic.METHODS: Adult patients with CD were identified in the IBM® MarketScan® Commercial Subset (10/01/2015-03/31/2020). The index date was defined as initiation of the first-line biologic, and the study period was defined as the 12 months following the index date. Patients were classified into Suboptimal Treatment and Optimal Treatment cohorts based on observed indicators of suboptimal treatment during the study period. Patients in the Suboptimal Treatment Cohort with a treatment switch were classified into the Treatment Switch Cohort and compared to patients with no treatment switch. All-cause HRU and costs were measured during the study period and assessed for patients with suboptimal vs optimal treatment and patients with vs without a treatment switch.RESULTS: The study included 4,006 patients (Suboptimal Treatment: 2,091, Optimal Treatment: 1,915). Treatment switch was a common indicator of suboptimal treatment (Treatment Switch: 640, No Treatment Switch: 3,366). HRU and costs were significantly higher among patients with suboptimal treatment than those with optimal treatment (annual costs: $92,043 vs $73,764; p < 0.01), and among those with a treatment switch than those with no treatment switch (annual costs: $95,689 vs $81,027; p < 0.01). Increases in the number of suboptimal treatment indicators were associated with increased costs.LIMITATIONS: Claims data were used to identify suboptimal treatment indicators based on observed treatment patterns; reasons for treatment decisions could not be assessed.CONCLUSION: This study demonstrates that patients with suboptimal treatment indicators, including treatment switch, incur substantially higher HRU and costs compared to patients receiving optimal treatment and those that do not switch treatments.

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis.

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly(ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, with an IBD patient cohort as well as two mouse colitis models, that is, IBD-mimicking oral dextran sulfate sodium (DSS) exposure and oral Salmonella infection. Parp14 was expressed in the human colon by cells in the lamina propria, but, in particular, by the epithelial cells with a granular staining pattern in the cytosol. The same expression pattern was evidenced in both mouse models. Parp14-deficiency caused increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss, and immune cell infiltration in DSS-exposed mice. The absence of Parp14 did not affect the mouse colon bacterial microbiota. Also, the colon leukocyte populations of Parp14-deficient mice were normal. In contrast, bulk tissue RNA-Seq demonstrated that the colon transcriptomes of Parp14-deficient mice were dominated by abnormalities in inflammation and infection responses both prior and after the DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.