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  • 1
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    Dose optimisation for Loss of Response to Vedolizumab— Pharmacokinetics and Immune Mechanisms
    Oxford University Press (OUP) ; 2021
    In:  Journal of Crohn's and Colitis Vol. 15, No. 10 ( 2021-10-07), p. 1707-1719
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 15, No. 10 ( 2021-10-07), p. 1707-1719
    Abstract: Real life data regarding pharmacokinetics of vedolizumab in patients needing dose optimisation are scarce. We set to examine whether pre-optimisation vedolizumab levels associate with therapy outcomes and which mechanisms explain the associations. Methods A multicentre observational study assessed the outcome of dose increase in association with pre-escalation levels in vedolizumab-treated patients. SubsequentIy, α4β7 occupancy on peripheral blood [PB] and intestinal lamina propria [LP] tissues was investigated on various cellular subsets in patients undergoing lower endoscopy on infusion day. Cellular localisation of vedolizumab-bound α4β7 and effects on M1 and M2 macrophages were also explored. Results A total of 161 inflammatory bowel disease [IBD] patients were included. Among 129/161 patients intensified during maintenance [Week 14 onward] , pre-intensification trough levels were comparable or higher among those subsequently attaining post-optimisation clinical, biomarker, and endoscopic remission, compared with non-remitting patients [p = 0.09, 0.25, 0.04, respectively]. Similar results were demonstrated for those dose-optimised during induction [Week 6, n = 32] . In the immune sub-study [n = 43], free α4β7 receptors at trough were similarly low among patients with/without mucosal healing, on PB T cells [p = 0.15] , LP T cells [p = 0.88], and on PB eosinophils [p = 0.08] . Integrin receptors on M1 and M2 macrophages were also saturated by low levels of vedolizumab and anti-inflammatory cytokine secretion was not increased. Co-localisation and dissociation experiments demonstrated membranal α4β7 receptors of two origins: non-internalised and newly generated α4β7, but re-binding was still complete at very low concentrations. Conclusions These results do not support pharmacokinetics as the mechanism responsible for loss of response to vedolizumab, nor do they support a need for higher drug concentration to enhance vedolizumab’s immune effects. Higher pre-escalation levels may indicate less clearance [less severe disease] and higher likelihood of subsequent re-gained response, regardless of therapy escalation.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjab067
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2389631-0
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  • 2
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    Host transcriptome signatures in human faecal-washes predict histological remission in patients with IBD
    BMJ ; 2022
    In:  Gut Vol. 71, No. 10 ( 2022-10), p. 1988-1997
    Details
    In: Gut, BMJ, Vol. 71, No. 10 ( 2022-10), p. 1988-1997
    Abstract: Colonoscopy is the gold standard for evaluation of inflammation in inflammatory bowel diseases (IBDs), yet entails cumbersome preparations and risks of injury. Existing non-invasive prognostic tools are limited in their diagnostic power. Moreover, transcriptomics of colonic biopsies have been inconclusive in their association with clinical features. Aims To assess the utility of host transcriptomics of faecal wash samples of patients with IBD compared with controls. Methods In this prospective cohort study, we obtained biopsies and faecal-wash samples from patients with IBD and controls undergoing lower endoscopy. We performed RNAseq of biopsies and matching faecal-washes, and associated them with endoscopic and histological inflammation status. We also performed faecal mass-spectrometry proteomics on a subset of samples. We inferred cell compositions using computational deconvolution and used classification algorithms to identify informative genes. Results We analysed biopsies and faecal washes from 39 patients (20 IBD, 19 controls). Host faecal-transcriptome carried information that was distinct from biopsy RNAseq and faecal proteomics. Transcriptomics of faecal washes, yet not of biopsies, from patients with histological inflammation were significantly correlated to one another (p=5.3×10 −12 ). Faecal-transcriptome had significantly higher statistical power in identifying histological inflammation compared with transctiptome of intestinal biopsies (150 genes with area under the curve 〉 0.9 in faecal samples vs 10 genes in biopsy RNAseq). These results were replicated in a validation cohort of 22 patients (10 IBD, 12 controls). Faecal samples were enriched in inflammatory monocytes, regulatory T cells, natural killer-cells and innate lymphoid cells. Conclusions Faecal wash host transcriptome is a statistically powerful biomarker reflecting histological inflammation. Furthermore, it opens the way to identifying important correlates and therapeutic targets that may be obscured using biopsy transcriptomics.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2021-325516
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1492637-4
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  • 3
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    Curcumin-QingDai Combination for Patients With Active Ulcerative Colitis: A Randomized, Double-Blinded, Placebo-Controlled Trial
    Elsevier BV ; 2023
    In:  Clinical Gastroenterology and Hepatology ( 2023-6)
    Details
    In: Clinical Gastroenterology and Hepatology, Elsevier BV, ( 2023-6)
    Type of Medium: Online Resource
    ISSN: 1542-3565
    URL: Article
    DOI: 10.1016/j.cgh.2023.05.023
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 4
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    Capsule Retention in Crohn’s Disease: A Meta-analysis
    Oxford University Press (OUP) ; 2020
    In:  Inflammatory Bowel Diseases Vol. 26, No. 1 ( 2020-01-01), p. 33-42
    Details
    In: Inflammatory Bowel Diseases, Oxford University Press (OUP), Vol. 26, No. 1 ( 2020-01-01), p. 33-42
    Abstract: This systematic review showed lower capsule retention rates in suspected and established Crohn’s disease than older literature. Retention rates were further reduced after patency capsule and cross-sectional imaging. Retention rates were also lower in pediatric compared with adult Crohn’s disease.
    Type of Medium: Online Resource
    ISSN: 1078-0998 , 1536-4844
    URL: Article
    DOI: 10.1093/ibd/izz083
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 5
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    Propagation of EBV-driven Lymphomatous Transformation of Peripheral Blood B Cells by Immunomodulators and Biologics Used in the Treatment of Inflammatory Bowel Disease
    Oxford University Press (OUP) ; 2020
    In:  Inflammatory Bowel Diseases Vol. 26, No. 9 ( 2020-08-20), p. 1330-1339
    Details
    In: Inflammatory Bowel Diseases, Oxford University Press (OUP), Vol. 26, No. 9 ( 2020-08-20), p. 1330-1339
    Abstract: Immunomodulators and anti tumor-necrosis-α antibodies (anti-TNFs) have been implicated in increased risk of Epstein–Barr virus (EBV)–driven B-cell lymphoproliferative disorders in inflammatory bowel disease (IBD) patients. However, the underlying mechanisms are poorly understood. Methods An in-vitro model of lymphoblastoid cell line (LCL) was established by co-incubation of EBV-infected human peripheral blood mononuclear cells (PBMC) with Cyclosporin-A (CSA). After 4 weeks, the resultant LCLs were analyzed by flow cytometry, telomerase activity assay, and next generation sequencing. Subsequently, LCLs were explored in the presence of therapeutic agents for IBD (anti-TNFs, vedolizumab, 6-Mercaptopurine [6MP], methotrexate). Epstein–Barr virus titers were quantitated by real-time polymerase chain reaction. Results In cultures of PBMC with EBV and CSA, LCLs were characterized as an expanded, long lived population of CD58+CD23hi B-cells with high telomerase activity and clonal expansion. Upon addition to the cell cultures, LCL percentages were higher with infliximab (median 19.21%, P = 0.011), adalimumab (median 19.85%, P = 0.003), and early washed-out 6MP (median 30.57%, P = 0.043) compared with PBMC with EBV alone (median 9.61%). However, vedolizumab had no such effect (median 8.97%; P = 0.435). Additionally, LCL expansion was accompanied by increase in intracellular, rather than extracellular, EBV viral copies. Compared with PBMC with EBV alone, high levels of LCL were subsequently observed after triple depletion of NK cells, CD4+ T cells, and CD8+ T cells (median 52.8% vs 16.4%; P = 0.046) but also in cultures depleted solely of CD4+ T cells (median 30.7%, P = 0.046). Conclusions These results suggest that both anti-TNFs and 6MP, but not vedolizumab, propagate EBV-driven lymphoblastoid transformation in an in vitro model of lymphoma. This model may prove useful for studying mechanisms underlying proneoplastic viral immune interactions of novel drugs in IBD therapy.
    Type of Medium: Online Resource
    ISSN: 1078-0998 , 1536-4844
    URL: Article
    DOI: 10.1093/ibd/izaa065
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 6
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    Randomized Controlled Trial of Cognitive-Behavioral and Mindfulness-Based Stress Reduction on the Quality of Life of Patients With Crohn Disease
    Oxford University Press (OUP) ; 2022
    In:  Inflammatory Bowel Diseases Vol. 28, No. 3 ( 2022-03-02), p. 393-408
    Details
    In: Inflammatory Bowel Diseases, Oxford University Press (OUP), Vol. 28, No. 3 ( 2022-03-02), p. 393-408
    Abstract: Patients with Crohn disease have debilitating psychological symptoms, mental fatigue, and poor quality of life. Psychological intervention may improve these symptoms. Methods We performed a randomized parallel-group physician-blinded trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) on quality of life and psychological symptoms in adults with mild-moderate Crohn disease. COBMINDEX was taught by social workers in one-on-one video conferences over 3 months; quotidian home practice was mandated. Results Fifty-five COBMINDEX and 61 waitlist control patients completed the study; mean age was 33 years and 65% of participants were women. At 3 months, COBMINDEX patients had significantly reduced disease activity (per Harvey-Bradshaw Index score, C-reactive protein level, and calprotectin level), increased quality of life (Short Inflammatory Bowel Disease Questionnaire [SIBDQ] score increased from baseline 41 to 50; P  & lt; 0.001), decreased psychological symptoms (Global Severity Index [GSI], 0.98-0.70; P  & lt; 0.001), reduced fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue, 26-33; P  & lt; 0.001), and increased mindfulness disposition (Freiburg Mindfulness Inventory, 33-38; P  & lt; 0.001). Waitlist patients had a significant but small change in Harvey-Bradshaw Index, SIBDQ, and GSI scores, without improvement in fatigue or mindfulness. There were significant correlations (0.02  & gt; P  & lt; 0.002) in COBMINDEX patients between baseline SIBDQ, GSI, Freiburg Mindfulness Inventory, and Functional Assessment of Chronic Illness Therapy-Fatigue scores with a relative change (baseline to 3 months) of the SIBDQ score, but none among waitlist patients. Predictors of relative change of the SIBDQ score in COBMINDEX patients included the GSI score (90% quantile; coefficient 0.52; P  & lt; 0.001), somatization (90%; 0.20; P = 0.001), depression (75%; 0.16; P = 0.03), and phobic anxiety (75%; 0.31; P = 0.008). Conclusions COBMINDEX was effective in increasing patients’ quality of life and reducing psychological symptoms and fatigue. Patients with severe baseline psychological symptoms benefited the most from COBMINDEX.
    Type of Medium: Online Resource
    ISSN: 1078-0998 , 1536-4844
    URL: Article
    DOI: 10.1093/ibd/izab083
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
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    Epidemiology of Inflammatory Bowel Diseases in Israel: A Nationwide Epi-Israeli IBD Research Nucleus Study
    Oxford University Press (OUP) ; 2021
    In:  Inflammatory Bowel Diseases Vol. 27, No. 11 ( 2021-10-20), p. 1784-1794
    Details
    In: Inflammatory Bowel Diseases, Oxford University Press (OUP), Vol. 27, No. 11 ( 2021-10-20), p. 1784-1794
    Abstract: There are currently no nationwide data on the epidemiology of inflammatory bowel diseases (IBD) in Israel. We aimed to determine the population-based epidemiological trends of IBD in the diverse Israeli population. Methods Health-administrative data were retrieved from all 4 Israeli health maintenance organizations, insuring 98% of the population, using validated identification algorithms. National trends were determined using Joinpoint regression analysis calculating annual percent change and average annual percent change (AAPC). Results By 2019, there were 46,074 patients with IBD in Israel, corresponding to a national prevalence of 519/100,000 (0.52%), of whom 54.1% had Crohn disease (CD) and 45.9% had ulcerative colitis (UC). The number of Jewish patients doubled from 18,701 in 2005 (354/100,000) to 38,950 (589/100,000) in 2018 (AAPC, +4.0%; P & lt; 0.05), and the number of Arab patients increased 3-fold from 1096 (102.1/100,000) to 3534 (240.7/100,000; AAPC, +6.8%; P & lt; 0.05) during the same years. However, the increase rate has gradually decelerated over time (annual percent change during 2005-2008, 2009-2014, and 2005-2018 was +6.7%, +4.2%, and +2.3%, respectively; P & lt; 0.05). Pediatric prevalence increased from 37.4 to 52.2/100,000, with CD predominating in both Jews and Arabs. The incidence of CD remained stable (from 15.9/100,000 to 14.9/100,000) and the incidence of UC decreased (15.4/100,000 to 10.5/100,000 (AAPC, –3.2%; P & lt; 0.001)). In contrast, pediatric incidence of CD increased from 7.3/100,000 to 8.3/100,000 (AAPC, +1.9%; P & lt; 0.05) and that of UC increased from 2.6 to 4.4/100,000 (AAPC, +5.8%; P & lt; 0.05). Conclusions The IBD prevalence rate in Israel is still increasing but gradually decelerating, probably due to the decreasing overall IBD incidence. Nonetheless, incidence rate in children is still increasing. Ongoing narrowing in the rates between Jews and Arabs over time may indicate shared environmental factors.
    Type of Medium: Online Resource
    ISSN: 1078-0998 , 1536-4844
    URL: Article
    DOI: 10.1093/ibd/izaa341
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 8
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    INCIDENTALLY DIAGNOSED ASYMPTOMATIC CROHN’S DISEASE: LONG-TERM CLINICAL OUTCOMES OF UNTREATED PATIENTS
    Oxford University Press (OUP) ; 2022
    In:  Inflammatory Bowel Diseases Vol. 28, No. Supplement_1 ( 2022-01-22), p. S74-S74
    Details
    In: Inflammatory Bowel Diseases, Oxford University Press (OUP), Vol. 28, No. Supplement_1 ( 2022-01-22), p. S74-S74
    Abstract: Crohn’s disease (CD) is occasionally diagnosed in asymptomatic patients undergoing colonoscopy for other reasons, but their clinical outcomes and optimal management remain poorly defined. METHODS A retrospective cohort study of asymptomatic patients with incidental diagnosis of CD. The primary outcome was defined as the occurrence of a clinical flare. Secondary outcomes included time to clinical flare, time to initiation of corticosteroids or immunomodulators/biologics, and rate of surgery. RESULTS Of the 2558 patients in Sheba IBD registry, 53 asymptomatic patients with incidental diagnosis of CD were identified (median age 50 (41.75-57), 52% males, 32/53 with L1, 9/53 L2, 11/53 L3,1/53 L4, 41/53 B1, 10/53 B2, 2/53 B3, 1 with perianal disease). Most patients (48/53) did not receive any treatment after diagnosis. Of these untreated patients, 43/48 (89.5%) had not experienced a flare over a median follow-up of 4.5 years (IQR 2-8, range 1-15 years). None of the patients with over 8 years follow-up (n=14) experienced a flare. When comparing the group of patients with or without immediate post-diagnosis initiation of treatment (n=5, n=48, respectively), there was no difference in survival time without flare (p=0.3). Of the 48 patients without immediate treatment, immunomodulators/biologics were initiated in 4(8.3%) during follow-up. Surgery for CD occurred in 2 patients during the follow-up. None of the parameters examined, including age, CRP, ileal versus other locations, or having a complicated phenotype (B2/B3 versus B1) was found to predict a clinical flare later on. CONCLUSION Many asymptomatic patients with an incidental diagnosis of Crohn’s disease can probably be followed-up without immediate treatment. Although the majority remain asymptomatic and without complications during follow-up, close monitoring for disease progression is prudent.
    Type of Medium: Online Resource
    ISSN: 1078-0998 , 1536-4844
    URL: Article
    DOI: 10.1093/ibd/izac015.120
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 9
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    Panenteric capsule endoscopy identifies proximal small bowel disease guiding upstaging and treatment intensification in Crohn's disease: A European multicentre observational cohort study
    Wiley ; 2021
    In:  United European Gastroenterology Journal Vol. 9, No. 2 ( 2021-03), p. 248-255
    Details
    In: United European Gastroenterology Journal, Wiley, Vol. 9, No. 2 ( 2021-03), p. 248-255
    Abstract: Summarise the established knowledge on this subject Biochemical and clinical markers poorly predict active disease and need for treatment escalation; Panenteric capsule endoscope is feasible, safe and has the potential to non‐invasively assess patients with Crohn's Disease. What are the significant and/or new findings of this study? Panenteric capsule endoscope can upstage disease in one‐third of patients with a threefold increase in the identification of proximal small bowel disease; Identification of proximal small bowel disease predicted treatment intensification.
    Type of Medium: Online Resource
    ISSN: 2050-6406 , 2050-6414
    URL: Article
    DOI: 10.1177/2050640620948664
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2728585-6
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  • 10
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    Immune function in newborns with in-utero exposure to anti-TNFα therapy
    Frontiers Media SA ; 2022
    In:  Frontiers in Pediatrics Vol. 10 ( 2022-8-31)
    Details
    In: Frontiers in Pediatrics, Frontiers Media SA, Vol. 10 ( 2022-8-31)
    Abstract: Anti-TNFα is measurable in infants exposed in utero up to 12 months of age. Data about the exposure effect on the infant’s adaptive immunity are limited. We aimed to prospectively evaluate the distribution and function of T and B cells, in infants of females with inflammatory bowel disease, in utero exposed to anti-TNFα or azathioprine. Methods A prospective multi-center study conducted 2014–2017. Anti-TNFα levels were measured in cord blood, and at 3 and 12 months. T-cell repertoire and function were analyzed at 3 and 12 months by flow-cytometry, expression of diverse T cell receptors (TCR) and T-cell receptor excision circles (TREC) quantification assay. Serum immunoglobulins and antibodies for inactivated vaccines were measured at 12 months. Baseline clinical data were retrieved, and 2-monthly telephonic interviews were performed regarding child infections and growth. Results 24 pregnant females, age 30.6 (IQR 26.5–34.5) years were recruited, 20 with anti-TNFα (infliximab 8, adalimumab 12), and 4 with azathioprine treatment. Cord blood anti-TNFα was higher than maternal blood levels [4.3 (IQR 2.3–9.2) vs. 2.5 (IQR 1.3–9.7) mcg/ml], declining at 3 and 12 months. All infants had normal number of B-cells ( n = 17), adequate levels of immunoglobulins ( n = 14), and protecting antibody levels to Tetanus, Diphtheria, Hemophilus influenza-B and hepatitis B ( n = 17). All had normal CD4+, CD8+ T-cells, and TREC numbers. TCR repertoire was polyclonal in 18/20 and slightly skewed in 2/20 infants. No serious infections requiring hospitalization were recorded. Conclusion We found that T-cell and B-cell immunity is fully mature and immune function is normal in infants exposed in utero to anti-TNFα, as in those exposed to azathioprine. Untreated controls and large-scale studies are needed to confirm these results.
    Type of Medium: Online Resource
    ISSN: 2296-2360
    URL: Article
    DOI: 10.3389/fped.2022.935034
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2711999-3
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