IL-23/IL-17 INHIBITORS IN IMMUNOINFLAMMATORY RHEUMATIC DISEASES: NEW HORIZONS

2019 ◽  
Vol 57 (4) ◽  
pp. 400-406 ◽  
Author(s):  
E. L. Nasonov ◽  
T. V. Korotaeva ◽  
T. V. Dubinina ◽  
A. M. Lila
Keyword(s):  
Rheumatoid Arthritis ◽  
Psoriatic Arthritis ◽  
Small Molecules ◽  
Th17 Cells ◽  
Wide Spectrum ◽  
Interleukin 17 ◽  
New Horizons ◽  
Leading Role ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Recently, more attention has been given to Th17 cells, the pathological activation of which plays a leading role in the development of a wide spectrum of human immunoinflammatory diseases (IID), including rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel diseases, etc. This has served as an incentive to design new biological agents and small molecules, the main mechanism of action of which is based on blocking the pathological effects of interleukin-17 (IL-17), others are associated with the activation of Th17 cells cytokines or signaling pathways that regulate the effects of these cytokines. The review discusses current ideas about the mechanisms regulating the formation and functional activity of IL-17 family cytokines, as well as evidence for the importance of these cytokines in the pathogenesis of IID.

scholarly journals Paradoxical gastrointestinal effects of interleukin-17 blockers

2020 ◽  
Vol 79 (9) ◽  
pp. 1132-1138 ◽  
Author(s):  
Marine Fauny ◽  
David Moulin ◽  
Ferdinando D'Amico ◽  
Patrick Netter ◽  
Nadine Petitpain ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Monoclonal Antibody ◽  
Clinical Practice ◽  
Psoriatic Arthritis ◽  
Interleukin 17 ◽  
Disease Exacerbation ◽  
Disease Flare ◽  
Paradoxical Effects ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Secukinumab, ixekizumab and brodalumab are monoclonal antibody therapies that inhibit interleukin (IL)-17 activity and are widely used for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. The promising efficacy results in dermatology and rheumatology prompted the evaluation of these drugs in Crohn’s disease and ulcerative colitis, but the onset of paradoxical events (disease exacerbation after treatment with a theoretically curative drug) prevented their approval in patients with inflammatory bowel diseases (IBDs). To date, the pathophysiological mechanisms underlying these paradoxical effects are not well defined, and there are no clear guidelines for the management of patients with disease flare or new IBD onset after anti-IL-17 drug therapy. In this review, we summarise the literature on putative mechanisms, the clinical digestive effects after therapy with IL-17 inhibitors and provide guidance for the management of these paradoxical effects in clinical practice.

Thrombosis in IBD in the Era of JAK Inhibition

2020 ◽  
Vol 22 (1) ◽  
pp. 126-136
Author(s):  
Virginia Solitano ◽  
Gionata Fiorino ◽  
Ferdinando D’Amico ◽  
Laurent Peyrin-Biroulet ◽  
Silvio Danese
Keyword(s):  
Small Molecules ◽  
Arterial Thrombosis ◽  
Protective Role ◽  
Jak Inhibitors ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Bowel Diseases ◽  
Thrombotic Complications ◽  
Inflammatory Bowel ◽  
Inflammatory Effect

: Patients with inflammatory bowel diseases (IBD) have an increased risk of thrombosis. The interaction between inflammation and coagulation has been extensively studied. It is well-known that some drugs can influence the haemostatic system, but several concerns on the association between therapies and increased risk of thrombosis remain open. While biologics seem to have a protective role against thrombosis via their anti-inflammatory effect, some concerns about an increased risk of thrombosis with JAK inhibitors have been raised. We conducted a literature review to assess the association between biologics/small molecules and venous/arterial thrombotic complications. An increased risk of venous and arterial thrombosis was found in patients treated with corticosteroids, whereas anti-TNF were considered protective agents. No thromboembolic adverse event was reported with vedolizumab and ustekinumab. In addition, thromboembolic events rarely occurred in patients with ulcerative colitis (UC) after therapy with tofacitinib. The overall risk of both venous and arterial thrombosis was not increased based on the available evidence. Finally, in the era of JAK inhibitors, treatment should be individualized by evaluating the pre-existing potential thrombotic risk balanced with the intrinsic risk of the medication used.

Gut Mycobiota and Fungal Metabolites in Human Homeostasis

2018 ◽  
Vol 20 (2) ◽  
pp. 232-240 ◽  
Author(s):  
Izabella Mogilnicka ◽  
Marcin Ufnal
Keyword(s):  
Wide Spectrum ◽  
Biological Effects ◽  
Fungal Species ◽  
Fungal Metabolites ◽  
Human Gut ◽  
Fecal Transplantation ◽  
Bacterial Microbiota ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Background:Accumulating evidence suggests that microbiota play an important role in host’s homeostasis. Thus far, researchers have mostly focused on the role of bacterial microbiota. However, human gut is a habitat for several fungal species, which produce numerous metabolites. Furthermore, various types of food and beverages are rich in a wide spectrum of fungi and their metabolites.Methods:We searched PUBMED and Google Scholar databases to identify clinical and pre-clinical studies on fungal metabolites, composition of human mycobiota and fungal dysbiosis.Results:Fungal metabolites may serve as signaling molecules and exert significant biological effects including trophic, anti-inflammatory or antibacterial actions. Finally, research suggests an association between shifts in gut fungi composition and human health. Changes in mycobiota composition have been found in obesity, hepatitis and inflammatory bowel diseases.Conclusion:The influence of mycobiota and dietary fungi on homeostasis in mammals suggests a pharmacotherapeutic potential of modulating the mycobiota which may include treatment with probiotics and fecal transplantation. Furthermore, antibacterial action of fungi-derived molecules may be considered as a substitution for currently used antibacterial agents and preservatives in food industry.

scholarly journals BIOSIMILARS IN INFLAMMATORY BOWEL DISEASES: an important moment for Brazilian gastroenterologists

2015 ◽  
Vol 52 (1) ◽  
pp. 76-80 ◽  
Author(s):  
Fábio Vieira TEIXEIRA ◽  
Paulo Gustavo KOTZE ◽  
Aderson Omar Mourão Cintra DAMIÃO ◽  
Sender Jankiel MISZPUTEN
Keyword(s):  
Small Molecules ◽  
Inflammatory Bowel Diseases ◽  
Generic Drugs ◽  
Specific Data ◽  
Chemical Structures ◽  
Bowel Diseases ◽  
Original Product ◽  
Inflammatory Bowel ◽  
The One ◽  
Extrapolation Of Indications

ABSTRACT Biosimilars are not generic drugs. These are more complex medications than small molecules, with identical chemical structures of monoclonal antibodies that lost their patency over time. Besides identical to the original product at the end, the process of achieving its final forms differs from the one used in the reference products. These differences in the formulation process can alter final outcomes such as safety and efficacy of the drugs. Recently, a biosimilar of Infliximab was approved in some countries, even to the management of inflammatory bowel diseases. However, this decision was based on studies performed in rheumatologic conditions such as rheumatoid arthritis and ankylosing spondylitis. Extrapolation of the indications from rheumatologic conditions was done for Crohn’s disease and ulcerative colitis based on these studies. In this article, the authors explain possible different mechanisms in the pathogenesis between rheumatologic conditions and inflammatory bowel diseases, that can lead to different actions of the medications in different diseases. The authors also alert the gastroenterological community for the problem of extrapolation of indications, and explain in full details the reasons for being care with the use of biosimilars in inflammatory bowel diseases without specific data from trials performed in this scenario.

scholarly journals Modulation of PKM activity affects the differentiation of TH17 cells

2020 ◽  
Vol 13 (655) ◽  
pp. eaay9217
Author(s):  
Scott M. Seki ◽  
Kacper Posyniak ◽  
Rebecca McCloud ◽  
Dorian A. Rosen ◽  
Anthony Fernández-Castañeda ◽  
...  
Keyword(s):  
T Cell ◽  
Small Molecules ◽  
Th17 Cells ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Interleukin 17 ◽  
Gm Csf ◽  
T Cell Function ◽  
The Brain ◽  
Tgf Β1

Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell–mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17–producing TH17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of TH17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.

Can We Extrapolate Data from One Immune-Mediated Inflammatory Disease to Another One?

2019 ◽  
Vol 26 (2) ◽  
pp. 248-258 ◽  
Author(s):  
Fernando Magro ◽  
Rosa Coelho ◽  
Armando Peixoto
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Diseases ◽  
Analytical Techniques ◽  
Approval Process ◽  
Homogeneous Population ◽  
Post Translational Modifications ◽  
Innovator Product ◽  
Immune Mediated ◽  
Bowel Diseases ◽  
Inflammatory Bowel

Immune-mediated inflammatory diseases share several pathogenic pathways and this pushes sometimes to extrapolate from one disease or indication to others. A biosimilar can be defined as a biotherapeutic product which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product. We review the substrate for extrapolation, the current approval process for biosimilars and the pioneering studies on biosimilars performed in rheumatoid arthritis patients. A biosimilar has the same amino acid sequence as its innovator product. However, post-translational modifications can occur and the current analytical techniques do not allow the final structure. To test the efficacy in one indication, a homogeneous population should be chosen and immunogenicity features are essential in switching and interchangeability. CT-P13 (Remsima™; Inflectra™) is a biosimilar of reference infliximab (Remicade®). It meets most of the requirements for extrapolation. Nevertheless, in inflammatory bowel diseases (IBD) we need more studies to confirm the postulates of extrapolation from rheumatoid arthritis and ankylosing spondylitis to IBD. Furthermore, an effective pharmacovigilance schedule is mandatory to look for immunogenicity and side effects.

scholarly journals The Immunological Basis of Inflammatory Bowel Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Francesca A. R. Silva ◽  
Bruno L. Rodrigues ◽  
Maria de Lourdes S. Ayrizono ◽  
Raquel F. Leal
Keyword(s):  
Th17 Cells ◽  
Inflammatory Process ◽  
Adaptive Immune System ◽  
Treg Cells ◽  
Intestinal Wall ◽  
Adaptive Immune ◽  
Current State ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Inflammatory Profile

Inflammatory bowel diseases (IBDs) are chronic ailments, Crohn’s disease and ulcerative colitis being the most important. These diseases present an inflammatory profile and they differ according to pathophysiology, the affected area in the gastrointestinal tract, and the depth of the inflammation in the intestinal wall. The immune characteristics of IBD arise from abnormal responses of the innate and adaptive immune system. The number of Th17 cells increases in the peripheral blood of IBD patients, while Treg cells decrease, suggesting that the Th17/Treg proportion plays an important role in the development and maintenance of inflammation. The purpose of this review was to determine the current state of knowledge on the immunological basis of IBD. Many studies have shown the need for further explanation of the development and maintenance of the inflammatory process.

scholarly journals Role of Th17 Cells in the Pathogenesis of Human IBD

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Julio Gálvez
Keyword(s):  
Th17 Cells ◽  
Current Knowledge ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Inflammatory Conditions ◽  
Normal Microbiota ◽  
Bowel Diseases ◽  
Mucosal Homeostasis ◽  
Inflammatory Bowel

The gastrointestinal tract plays a central role in immune system, being able to mount efficient immune responses against pathogens, keeping the homeostasis of the human gut. However, conditions like Crohn’s disease (CD) or ulcerative colitis (UC), the main forms of inflammatory bowel diseases (IBD), are related to an excessive and uncontrolled immune response against normal microbiota, through the activation of CD4+ T helper (Th) cells. Classically, IBD was thought to be primarily mediated by Th1 cells in CD or Th2 cells in UC, but it is now known that Th17 cells and their related cytokines are crucial mediators in both conditions. Th17 cells massively infiltrate the inflamed intestine of IBD patients, where they produce interleukin- (IL-) 17A and other cytokines, triggering and amplifying the inflammatory process. However, these cells show functional plasticity, and they can be converted into either IFN-γ producing Th1 cells or regulatory T cells. This review will summarize the current knowledge regarding the regulation and functional role of Th17 cells in the gut. Deeper insights into their plasticity in inflammatory conditions will contribute to advancing our understanding of the mechanisms that regulate mucosal homeostasis and inflammation in the gut, promoting the design of novel therapeutic approaches for IBD.

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