scholarly journals JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines

2016 ◽  
Vol 310 (3) ◽  
pp. G155-G162 ◽  
Author(s):  
Silvio Danese ◽  
Matthew Grisham ◽  
Jennifer Hodge ◽  
Jean-Baptiste Telliez
Keyword(s):  
Inflammatory Bowel Disease ◽  
Inflammatory Cytokines ◽  
Bowel Disease ◽  
Unmet Need ◽  
Janus Kinase ◽  
Prolonged Treatment ◽  
Cytokine Signaling ◽  
Jak Inhibitor ◽  
Adaptive Immune ◽  
Inflammatory Bowel

The inflammatory diseases ulcerative colitis and Crohn's disease constitute the two main forms of inflammatory bowel disease (IBD). They are characterized by chronic, relapsing inflammation of the gastrointestinal tract, significantly impacting on patient quality of life and often requiring prolonged treatment. Existing therapies for IBD are not effective for all patients, and an unmet need exists for additional therapies to induce and maintain remission. Here we describe the mechanism of action of the Janus kinase (JAK) inhibitor, tofacitinib, for the treatment of IBD and the effect of JAK inhibition on the chronic cycle of inflammation that is characteristic of the disease. The pathogenesis of IBD involves a dysfunctional response from the innate and adaptive immune system, resulting in overexpression of multiple inflammatory cytokines, many of which signal through JAKs. Thus JAK inhibition allows multiple cytokine signaling pathways to be targeted and is expected to modulate the innate and adaptive immune response in IBD, thereby interrupting the cycle of inflammation. Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated as a targeted immunomodulator for IBD. Clinical development of tofacitinib and other JAK inhibitors is ongoing, with the aspiration of providing new treatment options for IBD that have the potential to deliver prolonged efficacy and clinically meaningful patient benefits.

scholarly journals The use of Tofacitinib in the treatment of inflammatory bowel disease

2019 ◽  
Vol 91 (2) ◽  
pp. 101-108 ◽  
Author(s):  
E L Nasonov ◽  
D I Abdulganieva ◽  
I F Fairushina
Keyword(s):  
Inflammatory Bowel Disease ◽  
Small Molecules ◽  
Bowel Disease ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Intracellular Cytokine ◽  
New Class ◽  
Inflammatory Bowel ◽  
Molecular Aspects

Major advances in pharmacology of the 21st century include the development of a new class of drugs, which are low-molecular, chemically synthesized molecules (the so-called "small molecules"), the point of application of which is Janus kinase (Janus kinase, JAK) involved in intracellular cytokine signaling. The review examines the molecular aspects of the JAK-STAT signaling pathway, justifying the use of the JAK-kinase inhibitor (tofacitinib) in the treatment of inflammatory bowel disease.

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 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 Sa1884 – Unmet Need of Inflammatory Bowel Disease in Canada: Results of a Patient Survey

2019 ◽  
Vol 156 (6) ◽  
pp. S-441
Author(s):  
James R. Gray ◽  
Gail Attara ◽  
Guy Aumais ◽  
Remo Panaccione ◽  
John K. Marshall
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Unmet Need ◽  
Patient Survey ◽  
Inflammatory Bowel

scholarly journals A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Qingdong Guan
Keyword(s):  
Inflammatory Bowel Disease ◽  
Immune Responses ◽  
Bowel Disease ◽  
Genetic Factors ◽  
Intestinal Inflammation ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Host Genetic ◽  
Inflammatory Bowel ◽  
Host Genetic Factors

Inflammatory bowel disease (IBD) is a chronic and life-threating inflammatory disease of gastroenteric tissue characterized by episodes of intestinal inflammation. The pathogenesis of IBD is complex. Recent studies have greatly improved our knowledge of the pathophysiology of IBD, leading to great advances in the treatment as well as diagnosis of IBD. In this review, we have systemically reviewed the pathogenesis of IBD and highlighted recent advances in host genetic factors, gut microbiota, and environmental factors and, especially, in abnormal innate and adaptive immune responses and their interactions, which may hold the keys to identify novel predictive or prognostic biomarkers and develop new therapies.

scholarly journals Increase in Epithelial Permeability and Cell Metabolism by High Mobility Group Box 1, Inflammatory Cytokines and TPEN in Caco-2 Cells as a Novel Model of Inflammatory Bowel Disease

2020 ◽  
Vol 21 (22) ◽  
pp. 8434
Author(s):  
Maki Miyakawa ◽  
Takumi Konno ◽  
Takayuki Kohno ◽  
Shin Kikuchi ◽  
Hiroki Tanaka ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Growth Factor ◽  
Inflammatory Cytokines ◽  
Zinc Deficiency ◽  
Bowel Disease ◽  
Kinase Inhibitor ◽  
Cell Metabolism ◽  
High Mobility ◽  
Epithelial Barrier ◽  
Inflammatory Bowel

High mobility group box 1 protein (HMGB1) is involved in the pathogenesis of inflammatory bowel disease (IBD). Patients with IBD develop zinc deficiency. However, the detailed roles of HMGB1 and zinc deficiency in the intestinal epithelial barrier and cellular metabolism of IBD remain unknown. In the present study, Caco-2 cells in 2D culture and 2.5D Matrigel culture were pretreated with transforming growth factor-β (TGF-β) type 1 receptor kinase inhibitor EW-7197, epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 and a TNFα antibody before treatment with HMGB1 and inflammatory cytokines (TNFα and IFNγ). EW-7197, AG-1478 and the TNFα antibody prevented hyperpermeability induced by HMGB1 and inflammatory cytokines in 2.5D culture. HMGB1 affected cilia formation in 2.5D culture. EW-7197, AG-1478 and the TNFα antibody prevented the increase in cell metabolism induced by HMGB1 and inflammatory cytokines in 2D culture. Furthermore, ZnSO4 prevented the hyperpermeability induced by zinc chelator TPEN in 2.5D culture. ZnSO4 and TPEN induced cellular metabolism in 2D culture. The disruption of the epithelial barrier induced by HMGB1 and inflammatory cytokines contributed to TGF-β/EGF signaling in Caco-2 cells. The TNFα antibody and ZnSO4 as well as EW-7197 and AG-1478 may have potential for use in therapy for 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 Cellular and Molecular Connections between Autophagy and Inflammation

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Pierre Lapaquette ◽  
Jean Guzzo ◽  
Lionel Bretillon ◽  
Marie-Agnès Bringer
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Unique Feature ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Mediators Of Inflammation ◽  
Wide Range ◽  
Inflammatory Bowel ◽  
Diabetes And Obesity ◽  
Autophagy Activity

Autophagy is an intracellular catabolic pathway essential for the recycling of proteins and larger substrates such as aggregates, apoptotic corpses, or long-lived and superfluous organelles whose accumulation could be toxic for cells. Because of its unique feature to engulf part of cytoplasm in double-membrane cup-shaped structures, which further fuses with lysosomes, autophagy is also involved in the elimination of host cell invaders and takes an active part of the innate and adaptive immune response. Its pivotal role in maintenance of the inflammatory balance makes dysfunctions of the autophagy process having important pathological consequences. Indeed, defects in autophagy are associated with a wide range of human diseases including metabolic disorders (diabetes and obesity), inflammatory bowel disease (IBD), and cancer. In this review, we will focus on interrelations that exist between inflammation and autophagy. We will discuss in particular how mediators of inflammation can regulate autophagy activity and, conversely, how autophagy shapes the inflammatory response. Impact of genetic polymorphisms in autophagy-related gene on inflammatory bowel disease will be also discussed.

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