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Kinase and rheumatic disease

Yoshiya Tanaka
Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammation and joint damage that causes significant morbidity and mortality. Rapid and appropriate intervention using disease-modifying anti-rheumatic drugs(DMARDs)is prerequisite to halt joint destruction and long-term functional disabilities. Recent progress in the treatment strategy has brought about paradigm shift for the management of the disease, namely, the combined use of methotrexate, a synthetic DMARD, and a biologic DMARD targeting TNF, IL-6 and T cells has revolutionized treatment of rheumatoid arthritis...
2018: Clinical Calcium
K Krüger
Due to therapeutic advances, rheumatoid arthritis (RA) today has developed into a satisfactorily treatable disease in most cases, with remission being the target of treatment. Early diagnosis with immediate treatment initiation following treat-to-target strategy is the key to a favorable long-term outcome. A guideline-directed treatment algorithm determines the use of conventional synthetic disease-modifying anti-rheumatic drugs (DMARD; e.g., methotrexate), biological DMARD, and targeted oral DMARD (Janus kinase inhibitors)...
March 5, 2018: Der Internist
Ian C Scott, Samantha L Hider, David L Scott
Two different Janus kinase (JAK) inhibitors-baricitinib and tofacitinib-are effective and licensed in active rheumatoid arthritis (RA). There have been recent concerns about potential thromboembolic risks with these drugs. Concerns about baricitinib focus on clinical trial findings. Using all publically available data, we estimate thromboembolic risks are approximately five events per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib have been raised by analyses of the Federal Drug Administration Adverse Event Reporting System (FAERs)...
March 2, 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
Gianfranco Caselli, Albino Bonazzi, Marco Lanza, Flora Ferrari, Daniele Maggioni, Cristian Ferioli, Roberto Giambelli, Eleonora Comi, Silvia Zerbi, Marco Perrella, Ornella Letari, Elena Di Luccio, Milena Colovic, Stefano Persiani, Tiziano Zanelli, Laura Mennuni, Tiziana Piepoli, Lucio Claudio Rovati
BACKGROUND: Prostaglandin E2 (PGE2 ) acts via its EP4 receptor as a cytokine amplifier (e.g., interleukin [IL]-6) and induces the differentiation and expansion of inflammatory T-helper (Th) lymphocytes. These mechanisms play a key role in the onset and progression of rheumatoid arthritis (RA). We present the pharmacological characterisation of CR6086, a novel EP4 receptor antagonist, and provide evidence for its potential as a disease-modifying anti-rheumatic drug (DMARD). METHODS: CR6086 affinity and pharmacodynamics were studied in EP4-expressing HEK293 cells by radioligand binding and cyclic adenosine monophosphate (cAMP) production, respectively...
March 1, 2018: Arthritis Research & Therapy
Felice Rivellese, Antonio Lobasso, Letizia Barbieri, Bianca Liccardo, Amato De Paulis, Francesca Wanda Rossi
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis. Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug-free remission is nowadays a realistic goal in the treatment of RA...
February 9, 2018: Current Medicinal Chemistry
Lee A Meier, Jennifer L Auger, Brianna J Engelson, Hannah M Cowan, Elise R Breed, Mayra I Gonzalez-Torres, Joshua D Boyer, Mayank Verma, Aubyn Marath, Bryce A Binstadt
Background -Valvular heart disease (VHD) is common and affects the mitral valve (MV) most frequently. Despite the prevalence of mitral valve disease (MVD), the cellular and molecular pathways that initiate and perpetuate it are not well understood. Methods -K/B.g7 T cell receptor (TCR) transgenic mice spontaneously develop systemic autoantibody-associated autoimmunity, leading to fully-penetrant fibro-inflammatory MVD and arthritis. We used multiparameter flow cytometry, intracellular cytokine staining, and immunofluorescent staining to characterize the cells in inflamed K/B...
January 31, 2018: Circulation
Zhanguo Li, Yuan An, Houheng Su, Xiangpei Li, Jianhua Xu, Yi Zheng, Guiye Li, Kenneth Kwok, Lisy Wang, Qizhe Wu
AIM: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We assess the effect of tofacitinib + conventional synthetic disease-modifying anti rheumatic drugs (csDMARDs) on patient-reported outcomes in Chinese patients with RA and inadequate response to DMARDs. METHODS: This analysis of data from the Phase 3 study ORAL Sync included Chinese patients randomized 4 : 4 : 1 : 1 to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, placebo→tofacitinib 5 mg twice daily, or placebo→tofacitinib 10 mg twice daily, with csDMARDs...
January 4, 2018: International Journal of Rheumatic Diseases
Loukman Omarjee, Vincent Jaquinandi, Guillaume Mahe
Spondylarthritis (SpA) is an inflammatory rheumatic disease associated with increased incidence of major adverse cardiovascular events (MACEs). Recently, Paramarta et al. proposed the use of the tyrosine kinase inhibitor Nilotinib in Spondyloarthritis to target certain inflammatory pathways. However, Nilotinib, which is highly effective for the treatment of patients with chronic myeloid leukaemia (CML), is also associated with an increased risk of MACEs. The authors suggest that Nilotinib may be effective in peripheral SpA by modulating inflammation, but not in axial SpA...
December 15, 2017: Journal of Translational Medicine
Gunhyuk Park, Seung Hoon Lee, Ji-Ye Han, Dal-Seok Oh
ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum carmichaelii (AC) is a common herbal medicine used as anti-inflammatory and analgesic agent in Eastern Asia. In Korea, a commercial processed AC (Aconibal®) is traditionally used to treat the symptoms of spondylosis deformans and rheumatic pain. AIM OF STUDY: Rheumatoid arthritis (RA) is systemic and autoimmune disease characterized by chronic inflammation. Methotrexate (MTX) is often the first-line therapy for RA. If MTX monotherapy is ineffective or RA is initially severe, adding a tumor necrosis factor alpha (TNF-α) inhibitor to the treatment can be beneficial...
March 1, 2018: Journal of Ethnopharmacology
Xin Wang, Bin Shen, Dezhou Sun, Xiangyu Cui
Cerebral infarction is a cerebrovascular disease caused by local brain ischemic necrosis or softening, which is associated with diabetes, obesity, hypertension and rheumatic heart arrhythmia. Previous studies have indicated that aspirin is a potential oral anticoagulant in the treatment of cerebral ischemic stroke. However, the potential mechanism mediated by aspirin in cerebral infarction therapy is not well understood. The present study analyzed the therapeutic effects of aspirin on cerebral infarction and investigated the underlying molecular mechanism of aspirin‑ameliorated benefits for thrombolysis...
January 2018: Molecular Medicine Reports
Furong Guo, Xin Yi, Mingjiang Li, Jinrong Fu, Sha Li
The present study investigated the association between Snail1 and atrial fibrosis in patients with atrial fibrillation (AF) and rheumatic heart disease (RHD) and to determine the possible mechanism underlying this interrelation. A total of 19 patients were included in the current study and were divided into two groups: A sinus rhythm (SR) group (n=9) and an AF group (n=10). All patients underwent heart valve replacement surgery, during which ~200 mg right atrium tissue was obtained. Hematoxylin and eosin and Masson's trichrome-stained sections were used to evaluate the morphological changes of cardiomyocytes and the level of fibrosis...
November 2017: Experimental and Therapeutic Medicine
Honghai Hong, Yingmin Zeng, Wenxuan Jian, Lei Li, Liying Lin, Yousheng Mo, Meiling Liu, Shuhuan Fang, Yong Xia
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness and destruction of synovial joints, leading to severe disability. Anti-inflammatory drugs and disease-modifying anti-rheumatic drugs (DMARDs) may improve RA process. However, in most patients the treatment effect is still not satisfactory. Cyclin-dependent kinase 7 (CDK7) plays a well-established role in the regulation of the eukaryotic cell division cycle, and recent studies indicated that it exerted anti-inflammatory effect...
October 30, 2017: Journal of Cellular and Molecular Medicine
Pierre-Antoine Juge, Steven Gazal, Arnaud Constantin, Xavier Mariette, Bernard Combe, Jacques Tebib, Maxime Dougados, Jean Sibilia, Xavier Le Loet, Philippe Dieudé
BACKGROUND: The type 1 interferon (IFN) pathway has been identified to potentially affect the response to rituximab (RTX) for rheumatoid arthritis (RA), which suggests the contribution of type 1 IFN pathway genes such as IFN regulatory factor 5 and 7 (IRF5 and IRF7), tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 4 (STAT4) and osteopontin (SPP1). Our objective was to study functional variants of these IFN pathway genes as predictors of the European League Against Rheumatism (EULAR) response to RTX for RA at week 24 (W24)...
2017: RMD Open
Jisu Kim, Wonku Kang, Hyeyoung Min
Ilex cornuta, commonly known as Chinese holly, is an evergreen shrub from the family Aquifoliaceae, and it is widely distributed in Korea and China. In folk medicine, the leaves of I. cornuta are used for treatment of several disorders, including weakness of the waist and knees, arthrodynia, headache, acute conjunctivitis, toothache, urticaria, rheumatic arthralgia, and cardiovascular diseases. In this study, we investigated the anti-inflammatory effects of an I. cornuta leaf ethanol extract (ILE) and its underlying mechanisms of action...
October 2017: Journal of Medicinal Food
Philipp Rein, Ruediger B Mueller
Management and therapy of rheumatoid arthritis (RA) has been revolutionized by the development and approval of the first biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumor necrosis factor (TNF) α at the end of the last century. Today, numerous efficacious agents with different modes of action are available and achievement of clinical remission or, at least, low disease activity is the target of therapy. Early therapeutic interventions aiming at a defined goal of therapy (treat to target) are supposed to halt inflammation, improving symptoms and signs, and preserving structural integrity of the joints in RA...
December 2017: Rheumatology and Therapy
Dawei Zheng, Xiaoying Chen, Ni Li, Lebo Sun, Qingyun Zhou, Huoshun Shi, Guodong Xu, Jing Liu, Limin Xu, Shiwei Duan, Guofeng Shao
The aim of the present study was to identify differentially methylated regions (DMRs) in patients with rheumatic heart disease and secondary pulmonary arterial hypertension (RHD-PAH). A genome-wide DNA methylation assay was performed between 6 patients with RHD-PAH and 6 healthy controls using an Illumina Infinium HumanMethylation450 BeadChip kit. The Limma software package was subsequently used to identify significant DMRs. A total of 40 hypome-thylated and 64 hypermethylated CpG sites were identified between the RHD-PAH group and the control group...
August 2017: Experimental and Therapeutic Medicine
Elena V Tchetina, Natalia V Demidova, Galina A Markova, Elena A Taskina, Svetlana I Glukhova, Dmitry E Karateev
OBJECTIVE: To investigate the potential of the baseline gene expression in the whole blood of disease-modifying anti-rheumatic drug-naïve rheumatoid arthritis (RA) patients for predicting the response to methotrexate (MTX) treatment. METHODS: Twenty-six control subjects and 40 RA patients were examined. Clinical, immunological and radiographic parameters were assessed before and after 24 months of follow-up. The gene expressions in the whole blood were measured using real-time reverse transcription polymerase chain reaction...
July 25, 2017: International Journal of Rheumatic Diseases
Emma C Derrett-Smith, Viktor Martyanov, Cecilia B Chighizola, Pia Moinzadeh, Corrado Campochiaro, Korsa Khan, Tammara A Wood, Pier Luigi Meroni, David J Abraham, Voon H Ong, Robert Lafyatis, Michael L Whitfield, Christopher P Denton
BACKGROUND: Systemic sclerosis (SSc; scleroderma) is an uncommon autoimmune rheumatic disease characterised by autoimmunity, vasculopathy and fibrosis. Gene expression profiling distinguishes scleroderma from normal skin, and can detect different subsets of disease, with potential to identify prognostic biomarkers of organ involvement or response to therapy. We have performed gene expression profiling in skin samples from patients with limited cutaneous SSc (lcSSc). METHODS: Total RNA was extracted from clinically uninvolved skin biopsies of 15 patients with lcSSc and 8 healthy controls (HC)...
July 4, 2017: Arthritis Research & Therapy
Oliver Distler, Kevin K Brown, Jörg H W Distler, Shervin Assassi, Toby M Maher, Vincent Cottin, John Varga, Carl Coeck, Martina Gahlemann, Wiebke Sauter, Hendrik Schmidt, Kristin B Highland
OBJECTIVES: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF). The pathological pathways involved in fibrogenesis in IPF and interstitial lung disease associated with systemic sclerosis (SSc-ILD) show commonalities; both involve fibroblast activation, myofibroblast accumulation and deposition of extracellular matrix. The SENSCIS™ trial is a randomised, placebo-controlled Phase III trial that will evaluate the efficacy and safety of nintedanib in patients with SSc-ILD (NCT02597933)...
September 2017: Clinical and Experimental Rheumatology
Yue Sun, Ying-Xing Wu, Peng Zhang, Guang Peng, Shi-Ying Yu
The bone is one of the most common sites of metastasis in patients with cancer. Current treatments for bone metastases include bisphosphonates, denosumab, non-steroidal anti-inflammatory drugs and analgesics, but each of them has certain limitations. Cytokines and mediators released from various cells in the bone microenvironment may drive a vicious cycle of osteolytic bone metastases. Iguratimod (T-614), a novel disease-modifying anti-rheumatic drug, has demonstrated therapeutic effects by suppressing the production of inflammatory cytokines in rats and patients with rheumatoid arthritis...
June 2017: Oncology Letters
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