scholarly journals JAK inhibitors and infections risk: focus on herpes zoster

2020 ◽  
Vol 12 ◽  
pp. 1759720X2093605
Author(s):  
Flavia Sunzini ◽  
Iain McInnes ◽  
Stefan Siebert
Keyword(s):  
Herpes Zoster ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
Pathogenic Role ◽  
Immune Mediated ◽  
Post Marketing ◽  
Inflammatory Bowel

Currently, there is a growing interest in Janus kinase (JAK) intracellular signalling since targeted inhibitors against these pathways are proving effective in the treatment of a range of immune-mediated diseases, such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease and atopic dermatitis. In particular, post marketing experience and the increasing development of new pharmacological inhibitors of broad and increasingly selective JAK pathways provide new insights into the JAK pathway role in viral infections as well as their pathogenic role in immune-mediated inflammatory diseases. Herein we provide an overview of the biological role of JAK signalling and its role in immunity against viruses, with particular regard to herpes zoster reactivation. Thereafter, we will discuss the evidence currently available on the principal JAK inhibitors and their association with viral infections.

scholarly journals Selective Tyrosine Kinase 2 Inhibition for Treatment of Inflammatory Bowel Disease: New Hope on the Rise

2021 ◽  
Author(s):  
Silvio Danese ◽  
Laurent Peyrin-Biroulet
Keyword(s):  
Inflammatory Bowel Disease ◽  
Tyrosine Kinase ◽  
Bowel Disease ◽  
Inflammatory Diseases ◽  
Janus Kinase ◽  
Type I ◽  
Tyrosine Kinase 2 ◽  
Immune Mediated ◽  
Inflammatory Bowel

Abstract Conventional systemic and biologic agents are the mainstay of inflammatory bowel disease (IBD) management; however, many of these agents are associated with loss of clinical response, highlighting the need for effective, novel targeted therapies. Janus kinase (JAK) 1-3 and tyrosine kinase 2 (TYK2) mediate signal transduction events downstream of multiple cytokine receptors that regulate targeted gene transcription, including the interleukin-12, interleukin-23, and type I interferon receptors for TYK2. This review summarizes the role of TYK2 signaling in IBD pathogenesis, the differential selectivity of TYK2 inhibitors, and the potential clinical implications of TYK2 inhibition in IBD. A PubMed literature review was conducted to identify studies of JAK1-3 and TYK2 inhibitors in IBD and other immune-mediated inflammatory diseases. Key efficacy and safety information was extracted and summarized. Pan-JAK inhibitors provide inconsistent efficacy in patients with IBD and are associated with toxicities resulting from a lack of selectivity at therapeutic dosages. Selective inhibition of TYK2 signaling via an allosteric mechanism, with an agent that binds to the regulatory (pseudokinase) domain, may reduce potential toxicities typically associated with JAK1-3 inhibitors. Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD.

Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis?

2017 ◽  
Vol 77 (2) ◽  
pp. 175-187 ◽  
Author(s):  
Kenneth F Baker ◽  
John D Isaacs
Keyword(s):  
Lupus Erythematosus ◽  
First Generation ◽  
Inflammatory Diseases ◽  
Cellular Adhesion ◽  
Janus Kinase ◽  
Type I ◽  
Jak Inhibitors ◽  
T Helper 17 ◽  
Immune Mediated ◽  
Sphingosine 1 Phosphate

The past three decades have witnessed remarkable advances in our ability to target specific elements of the immune and inflammatory response, fuelled by advances in both biotechnology and disease knowledge. As well as providing superior treatments for immune-mediated inflammatory diseases (IMIDs), such therapies also offer unrivalled opportunities to study the underlying immunopathological basis of these conditions.In this review, we explore recent approaches to the treatment of IMIDs and the insights to pathobiology that they provide. We review novel biologic agents targeting the T-helper 17 axis, including therapies directed towards interleukin (IL)-17 (secukinumab, ixekizumab, bimekizumab), IL-17R (brodalumab), IL-12/23p40 (ustekinumab, briakinumab) and IL-23p19 (guselkumab, tildrakizumab, brazikumab, risankizumab, mirikizumab). We also present an overview of biologics active against type I and II interferons, including sifalumumab, rontalizumab, anifrolumab and fontolizumab. Emerging strategies to interfere with cellular adhesion processes involved in lymphocyte recruitment are discussed, including both integrin blockade (natalizumab, vedolizumab, etrolizumab) and sphingosine-1-phosphate receptor inhibition (fingolimod, ozanimod). We summarise the development and recent application of Janus kinase (JAK) inhibitors in the treatment of IMIDs, including first-generation pan-JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib) and second-generation selective JAK inhibitors (decernotinib, filgotinib, upadacitinib). New biologics targeting B-cells (including ocrelizumab, veltuzumab, tabalumab and atacicept) and the development of novel strategies for regulatory T-cell modulation (including low-dose IL-2 therapy and Tregitopes) are also discussed. Finally, we explore recent biotechnological advances such as the development of bispecific antibodies (ABT-122, COVA322), and their application to the treatment of IMIDs.

Hit the Road JAK! The Role of New Oral Treatment in Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Isabel Garrido ◽  
Susana Lopes ◽  
Guilherme Macedo
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Opportunistic Infections ◽  
Wide Spectrum ◽  
Oral Treatment ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
The Road ◽  
Inflammatory Bowel

Abstract Crohn disease (CD) and ulcerative colitis (UC) are considered chronic disorders of the gastrointestinal tract, lifelong medication often being necessary. Furthermore, they have significant implications on the quality of life. In the past few years, major advances have been achieved concerning the treatment of inflammatory bowel disease. These advances are expanding the possibilities for managing these patients. Janus kinase (JAK) inhibitors represent the most auspicious treatment to date because they consist of drugs that are orally administered, with a short half-life and low antigenicity. In addition, they seem to concurrently lessen various proinflammatory routes. In fact, tofacitinib has already been approved in patients with UC, both naïve and with prior exposure to tumor necrosis factor inhibitors. In CD, the results with tofacitinib have been less impressive. Several other JAK inhibitors are currently being investigated. However, given the wide spectrum of immunosuppressive effects, special attention has been given to the safety profile of these drugs, namely with regard to the occurrence of thromboembolic events, opportunistic infections, and malignancy. In this article, we review key evidence on the efficacy and safety of JAK inhibitors concerning both UC and CD.

scholarly journals The Role of Enterobacteriaceae in Gut Microbiota Dysbiosis in Inflammatory Bowel Diseases

2021 ◽  
Vol 9 (4) ◽  
pp. 697
Author(s):  
Valerio Baldelli ◽  
Franco Scaldaferri ◽  
Lorenza Putignani ◽  
Federica Del Chierico
Keyword(s):  
Inflammatory Bowel Diseases ◽  
Inflammatory Diseases ◽  
Species Level ◽  
Unknown Etiology ◽  
Gut Dysbiosis ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Symbiotic Microbiota ◽  
Gut Microbiota Dysbiosis

Inflammatory bowel diseases (IBDs) are a group of chronic gastrointestinal inflammatory diseases with unknown etiology. There is a combination of well documented factors in their pathogenesis, including intestinal microbiota dysbiosis. The symbiotic microbiota plays important functions in the host, and the loss of beneficial microbes could favor the expansion of microbial pathobionts. In particular, the bloom of potentially harmful Proteobacteria, especially Enterobacteriaceae, has been described as enhancing the inflammatory response, as observed in IBDs. Herein, we seek to investigate the contribution of Enterobacteriaceae to IBD pathogenesis whilst considering the continuous expansion of the literature and data. Despite the mechanism of their expansion still remaining unclear, their expansion could be correlated with the increase in nitrate and oxygen levels in the inflamed gut and with the bile acid dysmetabolism described in IBD patients. Furthermore, in several Enterobacteriaceae studies conducted at a species level, it has been suggested that some adherent-invasive Escherichia coli (AIEC) play an important role in IBD pathogenesis. Overall, this review highlights the pivotal role played by Enterobacteriaceae in gut dysbiosis associated with IBD pathogenesis and progression.

scholarly journals Role of the IL33 and IL1RL1 pathway in the pathogenesis of Immunoglobulin A vasculitis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana Prieto-Peña ◽  
Sara Remuzgo-Martínez ◽  
Fernanda Genre ◽  
Verónica Pulito-Cueto ◽  
Belén Atienza-Mateo ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Disease Onset ◽  
Immunoglobulin A ◽  
Genetic Network ◽  
Signalling Pathway ◽  
Immune Mediated ◽  
Increased Risk ◽  
Genotype And Allele Frequencies ◽  
Immunoglobulin A Vasculitis

AbstractCytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the IL33-IL1RL1 signalling pathway does not contribute to the genetic network underlying IgAV.

scholarly journals Update on the therapeutic management of patients with either psoriatic arthritis or ulcerative colitis: focus on the JAK inhibitor tofacitinib

2021 ◽  
Vol 13 ◽  
pp. 1759720X2097777
Author(s):  
Maria Sole Chimenti ◽  
Paola Conigliaro ◽  
Livia Biancone ◽  
Roberto Perricone
Keyword(s):  
Ulcerative Colitis ◽  
Psoriatic Arthritis ◽  
Janus Kinase ◽  
Phase Iii ◽  
Jak Inhibitors ◽  
Immune Mediated ◽  
Significant Burden ◽  
Phase Iii Trials ◽  
Disease Modifying Agents ◽  
Interleukin Inhibitors

Psoriatic arthritis (PsA) and ulcerative colitis (UC) are immune-mediated diseases that cause significant burden worldwide. Recent advances in their management have improved patient outcomes. However, significant unmet needs still remain as not all patients respond to current treatments, and patients may lose responsiveness over time. An improved understanding of the pathophysiology of these diseases has brought about the development of novel disease-modifying agents, including interleukin inhibitors and, more recently, Janus kinase (JAK) inhibitors. With the approval of tofacitinib for the treatment of adults with active PsA and in adult patients with moderately-to-severely active UC, JAK inhibitors have recently entered the treatment armamentarium for PsA and UC. A number of other JAK inhibitors are also undergoing clinical development and are currently in phase III trials. This review provides an overview of the current therapeutic options for PsA and UC, with a focus on the JAK inhibitors.

scholarly journals Functional heterogeneity of CD4+ T cells in liver inflammation

2021 ◽  
Author(s):  
Franziska Muscate ◽  
Anna Woestemeier ◽  
Nicola Gagliani
Keyword(s):  
T Cells ◽  
Essential Role ◽  
Inflammatory Diseases ◽  
Cell Polarization ◽  
Maturation Stage ◽  
Liver Inflammation ◽  
Functional Heterogeneity ◽  
Immune Mediated ◽  
T Cell Polarization

AbstractCD4+ T cells play an essential role in orchestrating adequate immunity, but their overactivity has been associated with the development of immune-mediated inflammatory diseases, including liver inflammatory diseases. These cells can be subclassified according to their maturation stage, cytokine profile, and pro or anti-inflammatory functions, i.e., functional heterogeneity. In this review, we summarize what has been discovered so far regarding the role of the different CD4+ T cell polarization states in the progression of two prominent and still different liver inflammatory diseases: non-alcoholic steatohepatitis (NASH) and autoimmune hepatitis (AIH). Finally, the potential of CD4+ T cells as a therapeutic target in both NASH and AIH is discussed.

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