scholarly journals P019 Colonic mucosal kinase activity, cytokine and chemokine profiles in inflammatory bowel disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S139-S140
Author(s):  
E Brand ◽  
B Roosenboom ◽  
B Malvar Fernandez ◽  
L Lutter ◽  
E van Koolwijk ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Kinase Activity ◽  
Cell Signalling ◽  
Explant Culture ◽  
Janus Kinase ◽  
Oncostatin M ◽  
Healthy Control ◽  
Inflammatory Bowel ◽  
The Difference

Abstract Background With the approval of tofacitinib, an oral Janus Kinase (JAK) inhibitor, modulation of kinase activity has been added to the therapeutic armamentarium of inflammatory bowel disease (IBD). Despite its established efficacy, at least a third of patients will not respond to this or other therapeutic options such as anti-tumour necrosis factor (TNF), anti-interleukin (IL)23/IL12 compounds or vedolizumab. A better understanding of the inflammatory profile could aid in tailoring drugs to individual patients. We therefore explored mucosal cytokine, chemokine and kinase activity profiles in IBD. Methods Colonic mucosal biopsies were collected from (1) patients with Crohn’s disease (CD, N = 8), (2) patients with ulcerative colitis (UC, N = 8) and (3) healthy controls (N = 4). IBD samples were collected both from inflamed and non-inflamed tissue from the same patients. All IBD patients were biological-naïve and had not used corticosteroids in the past 3 months. Biopsies were snap frozen for later kinase activity determination or directly used in a 24-h explant culture. Whole biopsy kinase activity (tyrosine, serine and threonine kinases) was assessed using the Pamgene platform. A 64-analyte panel was examined in the supernatant of the cultured biopsies employing a multiplex assay (Luminex). Results Whole-biopsy kinase activity differed between inflamed and non-inflamed mucosa of IBD patients, with more overall tyrosine kinase activity in inflamed mucosa in UC, and serine/threonine kinase activity in inflamed mucosa in CD as compared with non-inflamed mucosa (Figure 1). The kinase activity profile of non-inflamed mucosa of CD and UC patients was similarly different from mucosa of healthy control participants (Figure 2). The cytokine and chemokine profile of inflamed biopsies differed from non-inflamed IBD biopsies and healthy control biopsies, with higher levels of S100A8, TNFα, IL-6, oncostatin M (OSM) and triggering receptor expressed on myeloid cells-1 (TREM-1), amongst others (Figure 3). Conclusion In IBD, inflammation in the mucosa can be characterised both by explant-culture and kinase activity assessment. The difference in kinase activity between non-inflamed IBD mucosa and healthy control mucosa suggests the presence of sub-clinical alterations in cell signalling. The observed differences in the kinase, cytokine and chemokine profiles underscore the importance of this approach in the elucidation of the pathophysiology in IBD.

scholarly journals Premedication Does Not Influence the Incidence of Infliximab Infusion Reactions in Pediatric Patients with Inflammatory Bowel Disease—A Single Center Case–Control Study

2021 ◽  
Vol 10 (14) ◽  
pp. 3177
Author(s):  
Edyta Szymanska ◽  
Maciej Dadalski ◽  
Joanna Sieczkowska-Golub ◽  
Dorota Jarzebicka ◽  
Monika Meglicka ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Pediatric Patients ◽  
Case Control Study ◽  
Case Control ◽  
Chi Square ◽  
Infusion Reactions ◽  
Inflammatory Bowel ◽  
The Difference ◽  
Control Study

Background: Infusion reactions (IRs) are the most common adverse events (AEs) of infliximab (IFX) treatment in patients with inflammatory bowel disease (IBD). Prophylactic premedication (PM) with corticosteroids or antihistamines prior to IFX infusions has been used in clinical practice, but its efficacy is not known. The aim of this study was to assess the influence of steroid PM on IR incidence in pediatric patients with IBD receiving IFX. Methods: We performed a case–control study that included pediatric patients with IBD receiving IFX. Patients were divided into four subgroups according to the agent and PM they received: Remicade (original drug) + PM, and two biosimilars—Reshma +/− PM, and Flixabi—PM. At our site, until 2018, PM with steroids was used as a part of standard IFX infusion (PM+); however, since then, this method has no longer been administered (PM−). IRs were divided into mild/severe reactions. Differences between subgroups were assessed with the appropriate chi-square test. Multivariate logistic regression was used to assess associations between PM and IR incidence, correcting for co-medication usage. Results: There were 105 children (55 PM+, 44 male, mean age 15 years) included in the study who received 1276 infusions. There was no difference between the PM+ and PM− subgroups, either in incidence of IR (18.2% vs. 16.0% of patients, p > 0.05) or in percentage of infusions followed by IR (2.02% vs. 1.02% of infusions, p > 0.5). The OR of developing IR when using PM was 0.34, and the difference in IRs ratio in PM+ and PM− patients was not statistically significant (95% CI, 0.034–1.9). There were 11/18 (61.1%) severe IRs (anaphylactic shock) reported in all patients (both PM+ and PM−). Conclusion: At our site, the incidence of IR was low, and PM did not decrease the incidence of IR in pediatric patients with IBD receiving IFX. These results indicate that PM with steroids should not be a standard part of IFX infusion to prevent IR.

scholarly journals Tofacitinib in Patients with Ulcerative Colitis: Inflammatory Bowel Disease Questionnaire Items in Phase 3 Randomized Controlled Induction Studies

2020 ◽  
Author(s):  
Marla C Dubinsky ◽  
Marco DiBonaventura ◽  
Haiyun Fan ◽  
Andrew G Bushmakin ◽  
Joseph C Cappelleri ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Janus Kinase ◽  
Effect Sizes ◽  
Phase 3 ◽  
Inflammatory Bowel Disease Questionnaire ◽  
Bowel Symptoms ◽  
Inflammatory Bowel ◽  
Disease Questionnaire

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We examined the effect of tofacitinib induction treatment on Inflammatory Bowel Disease Questionnaire (IBDQ) items in adults with moderate to severe UC. Methods Data were pooled from the randomized, 8‑week, double-blind, phase 3 OCTAVE Induction 1 and 2 studies. The IBDQ was self-administered by patients at baseline, week 4, and week 8, with higher scores indicating better health-related quality of life (HRQoL). Change from baseline in IBDQ items was analyzed for 10 mg of tofacitinib twice daily (BID) vs placebo using a linear mixed-effects model, with no multiplicity adjustment performed. Effect sizes were calculated. Subgroup analyses by tumor necrosis factor inhibitor (TNFi) experience were performed. Results Significant improvements (nominal P < 0.05) were observed in all IBDQ items with 10 mg of tofacitinib BID vs placebo at weeks 4 and 8. For the overall population, the largest treatment differences across all items were reported for “bowel movements been loose” at weeks 4 and 8, and “problem with rectal bleeding” at week 8 (mean treatment differences all 1.1; both in bowel symptoms domain). These items also showed the largest effect sizes. Treatment benefits were generally slightly numerically higher in TNFi-experienced vs TNFi-naïve patients. Conclusions Tofacitinib induction therapy improved all IBDQ items vs placebo in patients with UC, reflecting improvements in HRQoL, with greatest benefits reported in bowel symptoms domain items (Funded by Pfizer Inc; OCTAVE Induction 1 and OCTAVE Induction 2; ClinicalTrials.gov, NCT01465763 and NCT01458951, respectively).

scholarly journals Prevalence of Joint Hypermobility and Patterns of Articular Manifestations in Patients with Inflammatory Bowel Disease

2009 ◽  
Vol 2009 ◽  
pp. 1-5 ◽  
Author(s):  
P. Vounotrypidis ◽  
E. Efremidou ◽  
P. Zezos ◽  
M. Pitiakoudis ◽  
E. Maltezos ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Study Groups ◽  
Joint Hypermobility ◽  
Fisher Exact Test ◽  
Hypermobility Syndrome ◽  
Exact Test ◽  
Significant Difference ◽  
Healthy Control ◽  
Inflammatory Bowel

Objective. The objective is the investigation of Joint Hypermobility (JH) and the Hypermobility Syndrome (HMS) in patients with inflammatory bowel disease (IBD).Methods. We examined 83 patients with IBD and 67 healthy individuals for the presence of JH. Patients were excluded if they were under 18 or over 50 years of age and if they had other conditions which affect joint mobility. Thex2and the Fisher exact test were used appropriately between study groups. Odds ratios (ORs) for the risk of JH and HMS in IBD groups were calculated.Results. A total of 150 individuals (83 IBD patients and 67 healthy controls) participated in the study. 69 IBD patients, 41 with Crohn's Disease (CD) and 28 with ulcerative colitis (UC), were finally eligible. JH was detected in 29 CD patients (70.7%), in 10 UC patients (35.7%), and in 17 healthy control subjects (25.4%). Significant difference was detected on JH in CD patients as compared to UC patients (P=.0063) and controls (P<.0001). The estimated OR for JH was 7.108 (95% CI: 2.98–16.95) in CD and 1.634 (95% CI: 0.63–4.22) in UC patients. HMS was detected in 5 (12.2%) CD and in 1 (3.57%) UC patients. The OR for HMS in CD was 3.75 (95% CI: 0.41–34.007), while 7 (17.1%) CD patients had overlapping symptoms for both HMS and early spondylarthropathy.Conclusions. JH and the HMS are common in CD patients, thus articular manifestations should be carefully interpreted. This implies an involvement of collagen varieties in the pathogenesis of IBD.

Cardiovascular Risk Assessment and Impact of Medications on Cardiovascular Disease in Inflammatory Bowel Disease

2020 ◽  
Author(s):  
Preetika Sinh ◽  
Raymond Cross
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Inflammatory Bowel Disease ◽  
Cardiovascular Risk ◽  
Lupus Erythematosus ◽  
Bowel Disease ◽  
Severe Heart Failure ◽  
Janus Kinase ◽  
Increased Risk ◽  
Inflammatory Bowel

Abstract There is increased risk of cardiovascular disease in patients with chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. Studies have shown association between cardiovascular disease (eg, myocardial infarction, heart failure, stroke) and inflammatory bowel disease. Medications such as infliximab and adalimumab (monoclonal antibodies to tumor necrosis factor α) may help decrease the inflammatory burden and cardiovascular risk; however, there have been reports of hypertriglyceridemia and worsening of moderate to severe heart failure with these medications. Janus kinase inhibitors, such as tofacitinib, have been associated with hyperlipidemia and thromboembolism. We aim to discuss clinical and imaging modalities to assess cardiovascular risk in inflammatory bowel disease patients and review the role of various medications with respect to cardiovascular disease in this population.

Anticolitic Effect of Viscum coloratum through Suppression of Mast Cell Activation

2019 ◽  
Vol 47 (01) ◽  
pp. 203-221 ◽  
Author(s):  
Jae-Myung Yoo ◽  
Kwang Il Park ◽  
Jin Yeul Ma
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mast Cell ◽  
Bowel Disease ◽  
Immunoglobulin E ◽  
Janus Kinase ◽  
Mast Cell Activation ◽  
Matrix Metalloprotease ◽  
Zonula Occludens ◽  
Inflammatory Bowel ◽  
Zonula Occludens 1

Viscum coloratum has been used as a component for traditional medicine for therapy of inflammatory diseases. Nonetheless, effect of Viscum coloratum on inflammatory bowel disease is unknown. Therefore, we investigated whether the ethanol extract of Viscum coloratum (VCE) could suppress inflammatory responses in dextran sodium sulfate (DSS)-treated mice and mast cell-derived inflammatory mediator (MDIM)-activated Caco-2 cells. VCE significantly attenuated body weight loss, shortened colon length, enteric epithelium disruption, enterorrhagia and colonic edema in DSS-treated mice. Additionally, VCE decreased the levels of immunoglobulin E, interleukin-6 and tumor necrosis factor-[Formula: see text] in serum and the activity of myeloperoxidase in colonic tissue. Moreover, VCE inhibited the infiltration of immune cells as well as the activity and expression of both matrix metalloprotease-2 and matrix metalloprotease-9. Furthermore, VCE restored zonula occludens-1 expression. Consistent with in vivo studies, VCE suppressed the activity and expression of matrix metalloprotease-2 and matrix metalloprotease-9 in MDIM-activated Caco-2 cells. In addition, VCE reinstated the expression of zonula occludens-1 through inhibiting activation of janus kinase 2/signal transducer and activator of transcription 3 in the cells. In conclusion, VCE exerts anticolitic action through inhibiting the activation of mast cells. Therefore, VCE may be useful as a phytomedicine or functional food for inflammatory bowel disease.

scholarly journals Clinical Pharmacology of Janus Kinase Inhibitors in Inflammatory Bowel Disease

2020 ◽  
Vol 14 (Supplement_2) ◽  
pp. S725-S736 ◽  
Author(s):  
Pavine L C Lefevre ◽  
Niels Vande Casteele
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Clinical Pharmacology ◽  
Gastrointestinal Tract ◽  
Bowel Disease ◽  
Kinase Inhibitors ◽  
Response To Therapy ◽  
Janus Kinase ◽  
Janus Kinase Inhibitors ◽  
Inflammatory Bowel

Abstract Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, are chronic inflammatory disorders of the gastrointestinal tract which are characterised, in part, by an imbalance in the production of several pro- and anti-inflammatory cytokines. Although various agents are effective for inducing and maintaining remission, approximately 20% of patients are treatment-refractory and require surgery. Parenterally administered monoclonal antibody-based biologics are associated with adverse effects resulting in treatment discontinuation and/or immunogenicity, leading to loss of response to therapy. Approximately 50% of patients who initially respond to treatment with tumour necrosis factor antagonists lose response to therapy within the 1st year of treatment. Incidence of immunogenicity tends to decrease over time, but once present can persist for years, even after treatment discontinuation. Nonimmunogenic oral small molecule therapies, including Janus kinase inhibitors, are currently being developed and have demonstrated efficacy in early phase clinical trials, which has already led to regulatory approval of tofacitinib for the treatment of patients with moderate-to-severe ulcerative colitis. Differentiation of T cells into T helper cells, which are mediators of the inflammatory response in inflammatory bowel disease, is mediated by the Janus kinase signal transducer and activator of the transcription signalling pathway. Absorption and distribution of Janus kinase inhibitors occurs at the site of action in the gastrointestinal tract, and newer compounds are being developed with limited systemic absorption, potentially reducing the risk of adverse effects. The current review describes the clinical pharmacology of approved Janus kinase inhibitors, as well as those in clinical development for the treatment of inflammatory bowel disease.

Advances in the Development of Janus Kinase Inhibitors in Inflammatory Bowel Disease: Future Prospects

Drugs ◽  
2017 ◽  
Vol 77 (10) ◽  
pp. 1057-1068 ◽  
Author(s):  
Mathurin Flamant ◽  
Josselin Rigaill ◽  
Stephane Paul ◽  
Xavier Roblin
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
Future Prospects ◽  
Janus Kinase Inhibitors ◽  
Inflammatory Bowel
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