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Kinase and rheumatic disease

Helen L Wright, Trevor Cox, Robert J Moots, Steven W Edwards
Neutrophils are implicated in the pathology of rheumatoid arthritis (RA), but the mechanisms regulating their activation are largely unknown. RA is a heterogeneous disease, and whereas many patients show clincal improvement during TNF inhibitor (TNFi) therapy, a significant proportion fails to respond. In vitro activation of neutrophils with agents, including TNF, results in rapid and selective changes in gene expression, but how neutrophils contribute to TNF signaling in RA and whether TNFi sensitivity involves differential neutrophil responses are unknown...
October 12, 2016: Journal of Leukocyte Biology
Roy Fleischmann, Michael Schiff, Désirée van der Heijde, Cesar Ramos-Remus, Alberto Spindler, Marina Stanislav, Cristiano A F Zerbini, Sirel Gurbuz, Christina Dickson, Stephanie de Bono, Douglas Schlichting, Scott Beattie, Wen-Ling Kuo, Terence Rooney, William Macias, Tsutomu Takeuchi
Objective This Phase 3 study evaluated baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and naive to biologic DMARDs. Methods Patients (N=588) were randomized 4:3:4 (MTX: baricitinib 4 mg once daily: baricitinib 4 mg + MTX) for 52 weeks. The primary endpoint assessment was noninferiority of baricitinib monotherapy to MTX based on American College of Rheumatology 20% (ACR20) response at Week 24...
October 9, 2016: Arthritis & Rheumatology
Shingo Nakayamada, Satoshi Kubo, Shigeru Iwata, Yoshiya Tanaka
Considerable advances in the treatment of rheumatoid arthritis (RA) have been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, biological DMARDs require intravenous or subcutaneous injection and some patients fail to respond to these drugs or lose their primary response. Currently, Janus kinase (JAK) inhibitors have been developed as a new class of DMARD that inhibits the non-receptor tyrosine kinase family JAK involved in intracellular signaling of various cytokines and growth factors...
October 3, 2016: Expert Opinion on Pharmacotherapy
Qiao Han, Wang Bing, Yin Di, Li Hua, Li Shi-He, Zheng Yu-Hua, Han Xiu-Guo, Wang Yu-Gang, Fan Qi-Ming, Yang Shih-Mo, Tang Ting-Ting
Gouty arthritis is a rheumatic disease that is characterized by the deposition of monosodium urate (MSU) in synovial joints cause by the increased serum hyperuricemia. This study used a three-dimensional (3D) flowing microfluidic chip to screen the effective candidate against MSU-stimulated human umbilical vein endothelial cell (HUVEC) damage, and found kinsenoside (Kin) to be the leading active component of Anoectochilus roxburghi, one of the Chinese medicinal plant widely used in the treatment of gouty arthritis clinically...
2016: Cell Death & Disease
Shingo Nakayamada, Satoshi Kubo, Shigeru Iwata, Yoshiya Tanaka
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. Considerable advance in the treatment of RA has been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, these biologics require intravenous or subcutaneous injection and some patients fail to respond to biological DMARDs or lose their primary response. Various cytokines and cell surface molecules bind to receptors on the cell surface, resulting in the activation of various cell signaling pathways, including phosphorylation of kinase proteins...
October 2016: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
Ming Li, Li Xue, Haifeng Sun, Suochun Xu
OBJECTIVES: The authors used L-carnitine as an ingredient in cardioplegic solution during valve replacement surgery to investigate the protective effect of L-carnitine on myocardial ischemia-reperfusion injury (MIRI) and its possible mechanism. DESIGN: Prospective, randomized study. SETTING: A tertiary-care hospital. PARTICIPANTS: The study comprised 90 patients undergoing valve replacement under cardiopulmonary bypass...
June 8, 2016: Journal of Cardiothoracic and Vascular Anesthesia
Sabrina Fechtner, David A Fox, Salahuddin Ahmed
Pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α are central regulators of autoinflammatory diseases. While targeting these cytokines has proven to be a successful clinical strategy, the long-term challenges such as drug resistance, lack of efficacy and poor clinical outcomes in some patients are some of the limitations faced by these therapies. This has ignited strategies to reduce inflammation by potentially targeting a variety of molecules, including cell surface receptors, signalling proteins and/or transcription factors to minimize cytokine-induced inflammation and tissue injury...
August 21, 2016: Rheumatology
Kunihiro Yamaoka
  Biologics have revolutionized the treatment of rheumatoid arthritis (RA). However certain amount of the patients cannot achieve goal of therapy. Recently, compounds targeting the intracellular kinase, Janus kinase (JAK) have demonstrated therapeutic effects resembling biologics. Tofacitinib is the only JAK inhibitor approved for RA and during the clinical trial, increased events of herpes zoster (HZ) was observed. Incidence rate was twice as much as patients treated with conventional anti-rheumatic drug and was especially increased in Japan that was four times as much...
2016: Nihon Rinshō Men'eki Gakkai Kaishi, Japanese Journal of Clinical Immunology
Yoshiya Tanaka
The combined use of synthetic disease-modifying anti-rheumatic drugs (sDMARDs) such as methotrexate and biological DMARDs (bDMARDs) has revolutionized treatment of rheumatoid arthritis (RA). Remission is now realistic targets, achieved by a large proportion of RA patients. However, bDMARDs are limited to intravenous or subcutaneous uses and orally available small but strong products have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active RA patients with sDMARD-naïve, inadequately responsive to sDMARDs or TNF-inhibitors...
June 2016: Nihon Rinsho. Japanese Journal of Clinical Medicine
Vanja Zeremski, Aleksandar Savić, Tatjana Ilić, Ivana Milosević, Marina Maksimović, Biljana Vucković
INTRODUCTION: A high platelet count, or thrombocytosis, is either a reactive process or a result of a myeloproliferative disorder. Ankylosing spondylitis is a chronic inflammatory rheumatic disease affecting the spine and sometimes peripheral joints in which reactive mild to moderate thrombocytosis is a common finding. There have been no previously reported cases of essential thrombocythemia associated with ankylosing spondylitis. CASE OUTLINE: We report a case of a 32-year-old man with human leukocyte antigen B27-positive ankylosing spondylitis and Janus kinase 2-positive essential thrombocythemia who was treated first with a combination of anagrelide and disease-modifying antirheumatic drugs and, after liver toxicity, with a combination of anagrelide and etanercept (TNF-α antagonist)...
January 2016: Srpski Arhiv za Celokupno Lekarstvo
Shigeru Iwata, Yoshiya Tanaka
INTRODUCTION: Treatment of rheumatoid arthritis (RA) has improved considerably following the advent of biologic disease-modifying anti-rheumatic drugs (DMARDs). However, these drugs require special storage and transportation. Janus kinase (JAK) inhibitors are oral synthetic DMARDs that inhibit the non-receptor tyrosine kinase family Janus kinase. Recently, many JAK inhibitors are being developed as new therapies for patients with RA. AREAS COVERED: In this article, we mainly review the efficacy and safety of JAK inhibitors currently under investigation...
October 2016: Expert Review of Clinical Immunology
Kunihiro Yamaoka
The biologics have revolutionized the treatment of rheumatoid arthritis (RA). However, there are still patients that are difficult to control and a cure is still not achievable. Tofacitinib, a Janus kinase (JAK) inhibitor is an orally available, new-in-class, disease-modifying anti-rheumatic drug with similar efficacy to biologics. JAK is activated by multiple cytokines involved in the pathology of RA, and affects non-immune and immune cells, mainly the lymphocytes. Besides its anti-rheumatic effect, the recent focus has been on adverse events...
September 2016: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
Elisa Piscianz, Vanessa Candilera, Erica Valencic, Claudia Loganes, Greta Paron, Sara De Iudicibus, Giuliana Decorti, Alberto Tommasini
Chronic inflammation associated with autoimmune activation is characteristic of rheumatic diseases from childhood to adulthood. In recent decades, significant improvements in the treatment of these types of disease have been achieved using disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) and, more recently, using biologic inhibitors. The recent introduction of kinase inhibitors (for example, tofacitinib; Tofa) further increases the available ARDs. However, there are patients that do not respond to any treatment strategies, for whom combination therapies are proposed...
July 2016: Molecular Medicine Reports
Gene V Wallenstein, Keith S Kanik, Bethanie Wilkinson, Stanley Cohen, Maurizio Cutolo, Roy Fleishmann, Mark C Genovese, Juan Gomez Reino, David Gruben, Joel Kremer, Sriram Krishnaswami, Eun Bong Lee, Virginia Pascual-Ramos, Vibeke Strand, Samuel H Zwillich
OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of tofacitinib on patient-reported outcomes (PRO) in patients with active RA. METHODS: Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate...
May 2016: Clinical and Experimental Rheumatology
Guo-Min Deng, Vasileios C Kyttaris, George C Tsokos
Spleen tyrosine kinase (Syk) is a member of the Src family of non-receptor tyrosine kinases, which associates directly with surface receptors, including B-cell receptor and Fcγ receptor, and is involved in a variety of signal transduction pathways. Rheumatoid arthritis (RA) and systemic lupus erythematosus are autoimmune diseases in which autoantibodies, immune complexes, and autoreactive T cells account for the expression of tissue inflammation and damage. Syk inhibitors efficiently suppress RA in patients albeit in the expression of unwanted side effects, including gastrointestinal effects, hypertension, and neutropenia...
2016: Frontiers in Immunology
Kunihiro Yamaoka
Treatment of autoimmune diseases, such as rheumatoid arthritis (RA), has advanced substantially over the past decade with the development of biologics targeting inflammatory cytokines. Recent progress in treating RA has been achieved with janus kinase (JAK) inhibitors (Jakinibs), an orally available disease-modifying anti-rheumatic drug targeting the intracellular kinase JAK and with similar efficacy to biologics. The first Jakinib approved for RA was tofacitinib, which exerted superiority to methotrexate and non-inferiority to tumor necrosis factor (TNF) inhibitors...
June 2016: Current Opinion in Chemical Biology
Xiangyang Qin, Xinru Jiang, Xin Jiang, Yuli Wang, Zhulei Miao, Weigang He, Guizhen Yang, Zhenhui Lv, Yizhi Yu, Yuejuan Zheng
Sepsis is the principal cause of fatality in the intensive care units worldwide. It involves uncontrolled inflammatory response resulting in multi-organ failure and even death. Micheliolide (MCL), a sesquiterpene lactone, was reported to inhibit dextran sodium sulphate (DSS)-induced inflammatory intestinal disease, colitis-associated cancer and rheumatic arthritis. Nevertheless, the role of MCL in microbial infection and sepsis is unclear. We demonstrated that MCL decreased lipopolysaccharide (LPS, the main cell wall component of Gram-negative bacteria)-mediated production of cytokines (IL-6, TNF-α, MCP-1, etc) in Raw264...
2016: Scientific Reports
Md Moniruzzaman, Shambhunath Bose, Young-Mi Kim, Young-Won Chin, Jungsook Cho
ETHNOPHARMACOLOGICAL RELEVANCE: Physalis alkekengi is an edible herb whose fruit and calyx are traditionally used to treat a wide range of diseases including inflammation, toothache, and rheumatism. However, the effects of Physalis alkekengi fruit along with its calyx (PAF) on neuroinflammation and inflammatory pain behavior have not been reported yet. AIM OF THE STUDY: This study evaluated the anti-inflammatory effect of PAF on lipopolysaccharide (LPS)-induced neuroinflammation and several in vivo model of inflammatory pain in mice...
April 2, 2016: Journal of Ethnopharmacology
Andras Perl
Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation...
March 2016: Nature Reviews. Rheumatology
Kayo Nakamura, Noriko Nakatsuka, Masatoshi Jinnin, Takamitsu Makino, Ikko Kajihara, Katsunari Makino, Noritoshi Honda, Kuniko Inoue, Satoshi Fukushima, Hironobu Ihn
Fms-like tyrosine kinase 3 (Flt-3) is a cytokine receptor expressed on the surface of bone-marrow progenitor of hematopoietic cells. Flt-3 ligands are produced by peripheral blood mononuclear cells, and found in various human body fluids. Flt-3 signal is involved in the regulation of vessel formation as well as B cell differentiation, suggesting that Flt-3 signal contributes to the pathogenesis of vascular abnormalities and immune dysregulation in rheumatic diseases. The aim of the present study is to examine serum Flt-3 ligand levels in patients with various rheumatic diseases, and to evaluate the possibility that serum Flt-3 ligand levels can be a useful disease marker...
October 2015: Bioscience Trends
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