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Iqbal I.,Mundipharma International Ltd Unit 194 | Dasgupta B.,Southend Hospital NHS Trust | Taylor P.,Kennedy Institute of Rheumatology | Heron L.,Adelphi Values | Pilling C.,Adelphi Values
Journal of Medical Economics | Year: 2012

Objective: Specific symptoms of rheumatoid arthritis (RA), including joint stiffness and functional disability, are most severe in the morning. 'Morning stiffness' has a negative impact on health-related quality-of-life (HRQoL); however, how HRQoL is correlated to morning stiffness duration is unknown. The objective of this study was to obtain population-based utility values associated with different durations of morning stiffness in RA. Design and methods: The time-trade-off (TTO) approach was used to elicit utility values for four different health states (HS), which differed in morning stiffness duration. One hundred and nine members of the UK general public rated each HS in individual face-to-face interviews with trained investigators. TTO scores were converted into utility values. Visual Analog Scale (VAS) scores were obtained to validate TTO scores. Results: On a scale of 0 (death) to 1 (full health), a mean utility value of 0.45±0.29 was elicited for ~3 h of morning stiffness (anchor HS), 0.50±0.28 for 2-3h of morning stiffness (HS1), 0.61±0.25 for 1-2h of morning stiffness (HS2) and 0.78±0.20 for <1 h of morning stiffness (HS3). The difference between each HS was statistically significant (p<0.01). Mean VAS utility scores followed the same trend. Utility incrementally increased with each HS associated with a shorter duration of morning stiffness. Limitations of this research include potential bias from the TTO method due to the discounting effect of time, scale compatibility, and loss aversion. Conclusions: The UK population-based utility values show a reduction in morning stiffness duration in RA is associated with improved HRQoL. Despite the impact of morning stiffness on HRQoL, it is rarely evaluated and little is known as to how it is affected by current treatments. The results of this study can be applied in future cost-utility analyses of healthcare interventions which target an improvement in morning stiffness duration for RA patients. © 2012 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

FOR MEDICAL AND TRADE MEDIA ONLY Anti-Interleukin-6 Monoclonal Antibody Sirukumab Efficacy and Safety Findings from SIRROUND-H and SIRROUND-T Trials Presented for the First Time at the 2016 ACR/ARHP Annual Meeting Janssen Research & Development, LLC (Janssen) announced today results from two pivotal Phase 3 studies evaluating subcutaneous (SC) sirukumab, a human anti-interleukin (IL)-6 monoclonal antibody in development for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). Data from the Janssen-sponsored head-to-head study, SIRROUND-H, showed patients receiving sirukumab monotherapy demonstrated significantly greater improvement in Disease Activity Score (DAS28), the first of two co-primary endpoints, when compared with Humira® (adalimumab) monotherapy. Investigators also reported results from a second study (SIRROUND-T), which showed that patients refractory to or intolerant to one or more anti-tumor necrosis factor (TNF) treatments receiving sirukumab demonstrated significant improvement in ACR 20 response compared with placebo.[1] Sirukumab is currently being evaluated by health authorities in Europe, the U.S. and Japan as a SC therapy for the treatment of adult patients with moderately to severely active RA. "We are focused on developing a range of therapeutic options to help meet the needs of people living with RA, including individuals who are still searching for an effective option having not experienced success with other advanced therapies," said Newman Yeilding, M.D., Head of Immunology Development, Janssen Research & Development, LLC. "We believe the sirukumab data generated to date show the potential of this IL-6-targeted therapy to benefit adults living with moderately to severely active RA in the future, and we look forward to continuing to work with global health authorities on the applications that have been submitted." SIRROUND-H: Efficacy and Safety of Monotherapy with Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, Compared with Adalimumab Monotherapy in Biologic-Naive Patients with Active Rheumatoid Arthritis[2] The Phase 3 SIRROUND-H trial is a randomised, double-blind, parallel-group study that included 559 biologic-naive patients with moderately to severely active RA who were intolerant to methotrexate (MTX), considered inappropriate for MTX treatment for safety reasons or were inadequate responders to MTX. Patients were randomised evenly to receive sirukumab 50 mg q4w or sirukumab 100 mg q2w or adalimumab 40 mg q2w as monotherapy. In addition to the co-primary endpoints evaluated, a clinically relevant proportion of patients in all three treatment groups attained the major secondary endpoints of DAS28 remission at week 24 (sirukumab 50 mg q4w, 13 percent; sirukumab 100 mg q2w, 20 percent; adalimumab 40mg q2w, 8 percent [P = 0.086 and P < 0.001, respectively]) and ACR20 response at week 24 (sirukumab 50 mg q4w, 54 percent; sirukumab 100 mg q2w, 59 percent; adalimumab 40mg q2w, 57 percent [P > 0.05]). "We saw significant improvements in disease activity among patients receiving both doses of sirukumab compared with those receiving adalimumab, and while sirukumab-treated patients demonstrated clinically relevant ACR50 improvements, the difference in ACR50 response ratesresults did not reach statistical significance," said Peter Taylor, Ph.D., Norman Collisson Professor of Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford and lead SIRROUND-H investigator. "As not all patients are appropriate candidates for TNF blocker therapy or methotrexate, and many are intolerant to methotrexate, the clinical improvements observed with sirukumab in this study provide important insights when evaluating available data for this IL-6 inhibitor in the treatment of moderately to severely active rheumatoid arthritis." The incidence of patients reporting adverse events (AEs) was 57 percent, 64 percent and 55 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and adalimumab q2w groups, respectively. The incidence of patients reporting serious AEs was 7 percent, 3 percent and 4 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and adalimumab q2w groups, respectively. The rate of reported infections was 20 percent, 24 percent and 19 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and adalimumab 40mg q2w groups, respectively, and there were few serious infections reported (sirukumab 50 mg q4w, 3 percent; sirukumab 100 mg q2w, 0 percent; adalimumab, 1 percent). The reported incidence of injection-site reactions was dose-related and greater with sirukumab 100 mg q2w (21 percent) compared with sirukumab 50 mg q4w (11 percent) and adalimumab (8 percent). No injection-site reactions were considered serious, and there were no deaths reported through week 24.[2] SIRROUND-T: Efficacy and Safety of Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, in Patients with Active Rheumatoid Arthritis Despite Anti-TNF and Other Biologic Therapy[1],[3] The Phase 3 SIRROUND-T trial is a randomised, double-blind, placebo-controlled study that included 878 patients refractory to anti-TNF therapy, approximately 40 percent of whom had prior exposure to non-TNF biologic therapies. Patients were randomised evenly to receive sirukumab 50 mg q4w or sirukumab 100 mg q2w or placebo. Patients receiving placebo with less than 20 percent improvement from baseline in both swollen and tender joint counts at weeks 18, as well as those still on placebo at week 24, were re-randomised to receive SC injections of sirukumab 50 mg q4w or 100 mg q2w through week 52. In addition to meeting the primary endpoint (ACR20 at week 16), patients receiving sirukumab also demonstrated statistically significant improvements across secondary endpoints compared with placebo. These included a change from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI), percentage of patients achieving ACR50 and percentage of patients achieving DAS28 remission at week 24 (P ≤ 0.001 for all measures). These improvements were seen as early as week four and were maintained with sirukumab therapy through week 52. Additionally, the efficacy of sirukumab was similar in patients who had previously received both anti-TNF therapy as well as other biologic therapy and in patients who had taken only TNF inhibitors. "These Phase 3 results-the first of an IL-6 cytokine inhibitor in RA-showed significant improvements in the signs and symptoms of patients with moderately to severely active RA whose disease remains active despite treatment with anti-TNF therapy, a typically difficult to treat group," said Daniel Aletaha, Consultant Physician, Division of Rheumatology, Medical University of Vienna and lead SIRROUND-T investigator. "Improvements in pain and inflammation were seen within four weeks and were maintained with sirukumab treatment through one year." The incidence of patients reporting AEs at week 24 was 62 percent, 69 percent and 62 percent in the sirukumab 50 mg q4w, sirukumab 100 mg q2w and placebo groups, respectively. Incidence of patients reporting serious AEs was 8 percent, 8 percent and 5 percent in the sirukumab 50 mg q4w, sirukumab100 mg q2w and placebo groups, respectively. Through week 52, the incidences of AEs and serious AEs were comparable between sirukumab 50 mg q4w (80 percent and 14 percent, respectively) and sirukumab 100 mg q2w (81 percent and 13 percent, respectively). No deaths were reported through week 24; there were five deaths reported through week 52 (two in the sirukumab 50 mg q4w group and three in the sirukumab 100 mg q2w group).[1] The Phase 3 clinical program in patients with active RA includes five studies investigating subcutaneously administered sirukumab 50 mg every four weeks and sirukumab 100 mg every two weeks in combination with conventional disease-modifying antirheumatic drugs (DMARDs) or as monotherapy. The comprehensive development program involves more than 3,000 patients encompassing the following five studies: Sirukumab is a human monoclonal IgG1 kappa antibody that targets the cytokine IL-6, a naturally occurring protein that is believed to play a role in autoimmune conditions like RA. It is not approved as a treatment for RA or any other indication anywhere in the world. In December 2011, Janssen and GSK entered into a licensing and co-development agreement with respect to sirukumab. Under the terms, Janssen retains exclusive rights to commercialise sirukumab in Europe, the Middle East, Africa and Asia Pacific, while GSK has commercialisation rights in North, Central and South America. The agreement gives both companies the option to investigate sirukumab for other indications beyond RA. Sirukumab is currently being evaluated by health authorities in Europe, the U.S. and Japan as a SC therapy for the treatment of adult patients with moderately to severely active RA. Rheumatoid arthritis is a chronic, systemic inflammatory condition that is characterised by pain, joint swelling, stiffness, joint destruction and disability. It is estimated that approximately 6.2 million Europeans are affected by the condition, for which there is no cure.[4] At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science. We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at Follow us at This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding new product development including ongoing clinical studies. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC and Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; competition, including technological advances, new products and patents attained by competitors; challenges to patents; manufacturing difficulties or delays; product efficacy or safety concerns resulting in product recalls or regulatory action; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 3, 2016, including in Exhibit 99 thereto, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at, or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. Humira® is a registered trademark of AbbVie Inc. 1. Aletaha, D., et al. Efficacy and Safety of Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, in Patients with Active Rheumatoid Arthritis Despite Anti-TNF Therapy: Results from a Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study. Annual Meeting of the American College of Rheumatology/Association for Rheumatology Health Professionals Meeting (ACR/ARHP 2016), Abstract 59233. 2. Taylor, P., et al. Efficacy and Safety of Monotherapy with Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, Compared with Adalimumab Monotherapy in Biologic-Naive Patients with Active Rheumatoid Arthritis: Results of a Global, Randomized, Double-Blind, Parallel-Group, Phase 3 Study. Annual Meeting of the American College of Rheumatology/Association for Rheumatology Health Professionals Meeting (ACR/ARHP 2016), Abstract 57374. 3. Tanaka, Y., et al. Efficacy of Sirukumab, an Anti-IL-6 Cytokine Monoclonal Antibody, Based upon Prior Use of Non-Anti-TNF Biologics in Patients with Active Rheumatoid Arthritis Despite Anti-TNF Therapy: Results from a Global Phase 3 Study, Annual Meeting of the American College of Rheumatology/Association for Rheumatology Health Professionals Meeting (ACR/ARHP 2016), Abstract 59315. 4. World Health Organization. "The Global Burden of Disease: 2004 Update," p. 32. Available at: . Accessed 08 November 2016.

Cuhlmann S.,National Science Foundation | Cuhlmann S.,Biological Imaging Center | Van Der Heiden K.,National Science Foundation | Saliba D.,Kennedy Institute of Rheumatology | And 12 more authors.
Circulation Research | Year: 2011

Rationale: The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain. Objective: We studied the signaling mechanisms that regulate RelA NF-κB subunit expression in endothelial cells (ECs) and their role in arterial inflammation. Methods and Results: Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-κB expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-κB may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of carotid arteries modified with a constrictive cuff, a method that was developed to study the effects of disturbed flow on vascular physiology in vivo. This approach coupled to en face staining revealed that disturbed flow elevates NF-κB expression and inflammation in murine carotid arteries via JNK1. Conclusions: We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-κB expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-κB crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis. © 2011 American Heart Association, Inc.

PubMed | Brighton and Sussex Medical School, Kennedy Institute of Rheumatology and University of Sussex
Type: Journal Article | Journal: European journal of immunology | Year: 2016

Toll-like receptors (TLRs) are innate immune receptors that respond to both exogenous and endogenous stimuli and are suggested to contribute to the perpetuation of chronic inflammation associated with rheumatoid arthritis (RA). In particular, the endosomal TLRs 3, 7, 8, and 9 have more recently been postulated to be of importance in RA pathogenesis. In this study, pan inhibition of the endosomal TLRs by a phosphorothioate-modified inhibitory oligodeoxynucleotide (ODN) is demonstrated in primary human B cells, macrophages, and RA fibroblasts. Inhibition of TLR8 was of particular interest as TLR8 has been associated with RA pathogenesis in both human and murine arthritis models. ODN1411 competitively inhibited TLR8 signaling and was observed to directly bind to a purified TLR8 ectodomain, suggesting inhibition was through a direct interaction with the receptor. Addition of ODN1411 to human RA synovial membrane cultures significantly inhibited spontaneous cytokine production from these cultures, suggesting a potential role for one or more of the endosomal TLRs in inflammatory cytokine production in RA and the potential for inhibitory ODNs as novel therapies.

Davidson R.K.,University of East Anglia | Jupp O.,University of East Anglia | De Ferrars R.,University of East Anglia | Kay C.D.,University of East Anglia | And 9 more authors.
Arthritis and Rheumatism | Year: 2013

Objective: Sulforaphane (SFN) has been reported to regulate signaling pathways relevant to chronic diseases. The aim of this study was to investigate the impact of SFN treatment on signaling pathways in chondrocytes and to determine whether sulforaphane could block cartilage destruction in osteoarthritis. Methods: Gene expression, histone acetylation, and signaling of the transcription factors NF-E2-related factor 2 (Nrf2) and NF-κB were examined in vitro. The bovine nasal cartilage explant model and the destabilization of the medial meniscus (DMM) model of osteoarthritis in the mouse were used to assess chondroprotection at the tissue and whole-animal levels. Results: SFN inhibited cytokine-induced metalloproteinase expression in primary human articular chondrocytes and in fibroblast-like synovial cells. SFN acted independently of Nrf2 and histone deacetylase activity to regulate metalloproteinase expression in human articular chondrocytes but did mediate prolonged activation of JNK and p38 MAPK. SFN attenuated NF-κB signaling at least through inhibition of DNA binding in human articular chondrocytes, with decreased expression of several NF-κB-dependent genes. Compared with cytokines alone, SFN (10 μM) abrogated cytokine-induced destruction of bovine nasal cartilage at both the proteoglycan and collagen breakdown levels. An SFN-rich diet (3 μmoles/day SFN versus control chow) decreased the arthritis score in the DMM model of osteoarthritis in the mouse, with a concurrent block of early DMM-induced gene expression changes. Conclusion: SFN inhibits the expression of key metalloproteinases implicated in osteoarthritis, independently of Nrf2, and blocks inflammation at the level of NF-κB to protect against cartilage destruction in vitro and in vivo. © 2013 The Authors.

PubMed | Northeastern University, University of Liverpool, Kennedy Institute of Rheumatology, The Royal Veterinary College and Florida Institute of Technology
Type: Journal Article | Journal: PloS one | Year: 2016

Bone development and length relies on the growth plate formation, which is dependent on degradative enzymes such as MMPs. Indeed, deletion of specific members of this enzyme family in mice results in important joint and bone abnormalities, suggesting a role in skeletal development. As such, the control of MMP activity is vital in the complex process of bone formation and growth. We generated a transgenic mouse line to overexpress TIMP3 in mouse chondrocytes using the Col2a1-chondrocyte promoter. This overexpression in cartilage resulted in a transient shortening of growth plate in homozygote mice but bone length was restored at eight weeks of age. However, tibial bone structure and mechanical properties remained compromised. Despite no transgene expression in adult osteoblasts from transgenic mice in vitro, their differentiation capacity was decreased. Neonates, however, did show transgene expression in a subset of bone cells. Our data demonstrate for the first time that transgene function persists in the chondro-osseous lineage continuum and exert influence upon bone quantity and quality.

Cribbs A.P.,Kennedy Institute of Rheumatology | Kennedy A.,Kennedy Institute of Rheumatology | Gregory B.,Kennedy Institute of Rheumatology | Brennan F.M.,Kennedy Institute of Rheumatology
BMC Biotechnology | Year: 2013

Background: Lentiviral vectors have emerged as efficient vehicles for transgene delivery in both dividing and non-dividing cells. A number of different modifications in vector design have increased biosafety and transgene expression. However, despite these advances, the transduction of primary human T cells is still challenging and methods to achieve efficient gene transfer are often expensive and time-consuming.Results: Here we present a simple optimised protocol for the generation and transduction of lentivirus in primary human CD45RA+ T cells. We show that generation of high-titre lentivirus with improved primary T cell transduction is dependent upon optimised ultracentrifuge speed during viral concentration. Moreover, we demonstrate that transduction efficiency can be increased with simple modifications to the culturing conditions. Overall, a transduction efficiency of up to 89% in primary human CD45RA+ cells is achievable when these modifications are used in conjunction.Conclusion: The optimised protocol described here is easy to implement and should facilitate the production of high-titre lentivirus with superior transduction efficiency in primary human T cells without the need for further purification methods. © 2013 Cribbs et al.; licensee BioMed Central Ltd.

Jin H.,Kennedy Institute of Rheumatology | Ralston S.H.,University of Edinburgh
Methods in Molecular Biology | Year: 2012

Transcription is the process by which the rate of RNA synthesis is regulated. Here, we describe the techniques for carrying out promoter-reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays, three commonly used methods for studying gene transcription.

Vincent T.L.,Kennedy Institute of Rheumatology | Vincent T.L.,Nuffield Orthopedic Center | Watt F.E.,Nuffield Orthopedic Center | Watt F.E.,Kennedy Institute of Rheumatology
Medicine (United Kingdom) | Year: 2014

Osteoarthritis (OA) is the most common form of joint disease, and its impact is set to grow as the prevalence of obesity rises and our elderly population increases. Many clinicians regard OA as being simply a disease of 'wear and tear', and by implication one in which disease modification is not possible. Such prejudices have led to significant academic apathy in this disease that is reflected not only in our poor understanding of disease pathogenesis, but also in the failure to classify the disease with greater precision, and to develop sensitive tools for diagnosis and prognostic assessment. The recent identification of key degradative enzymes in cartilage and the use of mouse models to study disease pathogenesis have greatly changed our outlook. The next decade is likely to see significant advances in our understanding of, and treatment for, this condition. Crown Copyright © 2014 Published by Elsevier Ltd. All rights reserved.

Strand V.,Stanford University | Wright G.C.,New York University | Bergman M.J.,Drexel University | Tambiah J.,UCB Pharma | Taylor P.C.,Kennedy Institute of Rheumatology
Journal of Rheumatology | Year: 2015

Objective. To identify how patients perceive the broad effect of active rheumatoid arthritis (RA) on their daily lives and indicate how RA disease management could benefit from the inclusion of individual goal-setting strategies. Methods. Two multinational surveys were completed by patients with RA. The "Good Days Fast" survey was conducted to explore the effect of disease on the daily lives and relationships of women with RA. The "Getting to Your Destination Faster" survey examined RA patients' treatment expectations and goal-setting practices. Results. Respondents from all countries agreed that RA had a substantial negative effect on many aspects of their lives (work productivity, daily routines, participation in social and leisure activities) and emotional well-being (loss of self-confidence, feelings of detachment, isolation). Daily pain was a paramount issue, and being pain- and fatigue-free was considered the main indicator of a "good day." Setting personal, social, and treatment goals, as well as monitoring disease progress to achieve these, was considered very beneficial by patients with RA, but discussion of treatment goals seldom appeared to be a part of medical appointments. Conclusion. Many patients with RA feel unable to communicate their disease burden and treatment goals, which are critically important to them, to their healthcare provider (HCP). Insights gained from these 2 surveys should help to guide patients and HCP to better focus upon mutually defined goals for continued improvement of management and achievement of optimal care in RA. The Journal of Rheumatology Copyright © 2015. All rights reserved.

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