34 results on '"Wisniacki N"'
Search Results
2. Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis
- Author
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Denton, C.P., Galdo, F. Del, Khanna, D., Vonk, M.C., Chung, L., Johnson, S.R., Varga, J., Furst, D.E., Temple, J., Zecchin, C., Csomor, E., Lee, A, Wisniacki, N., Flint, S.M., Reid, J., Denton, C.P., Galdo, F. Del, Khanna, D., Vonk, M.C., Chung, L., Johnson, S.R., Varga, J., Furst, D.E., Temple, J., Zecchin, C., Csomor, E., Lee, A, Wisniacki, N., Flint, S.M., and Reid, J.
- Abstract
Item does not contain fulltext, OBJECTIVES: The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process. METHODS: This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint. RESULTS: Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups. CONCLUSION: Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95.
- Published
- 2022
3. Safety and efficacy of subcutaneous belimumab and intravenous rituximab combination in patients with primary Sjogren's syndrome: A phase 2, randomised, placebo-controlled 68-week study
- Author
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Mariette, X., Baldini, C., Barone, F., Bootsma, H., Clark, K., De Vita, S., Lerang, K., Mistry, P., Morin, F., Punwaney, R., Seror, R., Van Daele, P. L., Van Maurik, A., Wisniacki, N., Roth, D., and Translational Immunology Groningen (TRIGR)
- Published
- 2021
4. OP0135 SAFETY AND EFFICACY OF SUBCUTANEOUS BELIMUMAB AND INTRAVENOUS RITUXIMAB COMBINATION IN PATIENTS WITH PRIMARY SJÖGREN’S SYNDROME: A PHASE 2, RANDOMISED, PLACEBO-CONTROLLED 68-WEEK STUDY
- Author
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Mariette, X., primary, Baldini, C., additional, Barone, F., additional, Bootsma, H., additional, Clark, K., additional, De Vita, S., additional, Lerang, K., additional, Mistry, P., additional, Morin, F., additional, Punwaney, R., additional, Seror, R., additional, Van Daele, P. L., additional, Van Maurik, A., additional, Wisniacki, N., additional, and Roth, D., additional
- Published
- 2021
- Full Text
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5. Identification and characterisation of the dose response of otelixizumab in new onset type 1 diabetes patients
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Napolitano, A., Maurik, A., Inman, D. W., Wisniacki, N., Pieter Gillard, Hilbrands, R., Gorus, F., Mathieu, C., Velde, U., Keymeulen, B., Department of Public Law, Faculty of Law and Criminology, Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, Diabetes Clinic, Vriendenkring VUB, UZB Other, and Public Health Sciences
- Published
- 2019
6. Insulin resistance and inflammatory activation in older patients with systolic and diastolic heart failure
- Author
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Wisniacki, N, Taylor, W, Lye, M, and Wilding, J P H
- Published
- 2005
7. Does diastolic function evaluated with radionuclide ventriculography predict mortality, hospitalization and the development of new onset heart failure?
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WISNIACKI, N, GOWDA, V, DAR, O, LYE, M, and VINJAMURI, S
- Published
- 2003
8. ELDERLY PATIENTS WITH CONGESTIVE HEART FAILURE WHO PARTICIPATE IN A SUPPORT PROGRAMME HAVE AN IMPROVED OUTCOME
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WISNIACKI, N., AIMSON, P., and LYE, M.
- Published
- 2001
9. P449 Selective depletion of LAG3+ cells in T-cell-driven inflammation: a randomised, double-blind, placebo-controlled, FTIH phase I/Ib clinical trial
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Ellis, J, primary, Marks, D, additional, Barrett, C, additional, Hopkins, T, additional, Richards, A, additional, Fuhr, R, additional, Albayaty, M, additional, Coenen, M, additional, Liefaard, L, additional, Leavens, K, additional, Nevin, K, additional, Tang, S, additional, Hughes, S, additional, Srinivasan, N, additional, Edwards, K, additional, Anselm, R, additional, Schmidt, T, additional, Stone, J, additional, Savage, C, additional, Wisniacki, N, additional, and Tarzi, R, additional
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- 2019
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10. THU0026 Osm is more effective than il-6 at inducing endomt of human dermal microvascular cells
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Nevin, K, primary, Stawski, L, additional, Feeney, M, additional, Wisniacki, N, additional, and Trojanowska, M, additional
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- 2017
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11. Towards the identification of multi-parametric quantitative MRI biomarkers in lupus nephritis
- Author
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Rapacchi, S, Smith, RX, Wang, Y, Yan, L, Sigalov, V, Krasileva, KE, Karpouzas, G, Plotnik, A, Sayre, J, Hernandez, E, Verma, A, Burkly, L, Wisniacki, N, Torrington, J, He, X, Hu, P, Chiao, PC, and Wang, DJJ
- Abstract
© 2015 Elsevier Inc. Purpose: To identify potential biomarkers of the renal impairment in lupus nephritis using a multi-parametric renal quantitative MRI (qMRI) protocol including diffusion weighted imaging (DWI), blood oxygen level dependent (BOLD), arterial spin labeling (ASL) and T1rho MRI between a cohort of healthy volunteers and lupus nephritis (LN) patients. Materials and methods: The renal qMRI protocol was performed twice with repositioning in between on 10 LN patients and 10 matched controls at 1.5. T. Navigator-gated and breath-hold acquisitions followed by non-rigid image registration were used to control respiratory motion. The repeatability of the 4 MRI modalities was evaluated with the intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Unpaired t-test and stepwise logistic regression were carried out to evaluate qMRI parameters between the LN and control groups. Results: The reproducibility of the 4 qMRI modalities ranged from moderate to good (ICC = 0.4-0.91, wsCV. ≤. 12%) with a few exceptions. T1rho MRI and ASL renal blood flow (RBF) demonstrated significant differences between the LN and control groups. Stepwise logistic regression yielded only one significant parameter (medullar T1rho) in differentiating LN from control groups with 95% accuracy. Conclusion: A reasonable degree of test-retest repeatability and accuracy of a multi-parametric renal qMRI protocol has been demonstrated in healthy volunteers and LN subjects. T1rho and ASL RBF are promising imaging biomarkers of LN.
- Published
- 2015
12. IS ANAEMIA A CAUSE OR A CONSEQUENCE OF HEART FAILURE IN THE ELDERLY?
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Aimson, P, Wisniacki, N, and Lye, M
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Aged -- Diseases -- Physiological aspects ,Anemia -- Physiological aspects ,Heart failure -- Causes of -- Physiological aspects ,Health - Abstract
Introduction: Moderate/severe degree of anaemia can contribute to the development or worsening of chronic heart failure (CHF). Alternatively CHF can lead to moderate anaemia. The degree of the anaemia is [...]
- Published
- 2001
13. OP0214 Identification of Gene Transcripts and Proteins That Independently PREDICT SLE Disease Activity over the Next Year
- Author
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Magder, L.S., primary, Zollars, E., additional, Bienkowska, J., additional, Stebbins, C., additional, Wager, C., additional, Burkly, L., additional, Wisniacki, N., additional, Ranger, A., additional, and Petri, M., additional
- Published
- 2014
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14. FRI0439 Urinary Collagen Fragments Are Reduced in Lupus Nephritis Subjects with Renal Dysfunction
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Wisniacki, N., primary, Wei, R., additional, Gao, B., additional, Stebbins, C., additional, Dearth, A., additional, Ranger, A., additional, Mischak, H., additional, Siwy, J., additional, Petri, M., additional, and Burkly, L., additional
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- 2014
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15. FRI0295 Urinary tweak predicts renal disease activity in patients with systemic lupus erythematosus over a 1 year period
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Wisniacki, N., primary, Stebbins, C., additional, Bienkowska, J., additional, Gawlak, S., additional, Bennett, D., additional, Xiang, Y., additional, Dearth, A., additional, Ranger, A., additional, Burkly, L., additional, and Petri, M., additional
- Published
- 2013
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16. Autonomic function in elderly patients with chronic heart failure
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Zi, M., primary, Wisniacki, N., additional, Delaney, J., additional, Donnellan, C., additional, and Lye, M., additional
- Published
- 2002
- Full Text
- View/download PDF
17. 17. Are parameters of diastolic dysfunction useful for predicting morbidity and mortality?
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Wisniacki, N., primary, Gouda, V., additional, Dar, O., additional, Lye, M., additional, and Vinjamuri, S., additional
- Published
- 2002
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18. Heart failure in the elderly: a diastolic problem?
- Author
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Lye, Michael, Wisniacki, Nicolas, Lye, M, and Wisniacki, N
- Subjects
HEART failure risk factors ,DISEASES in older people ,CARDIOVASCULAR system ,AGING ,COLLAGEN ,HEART beat ,DIASTOLE (Cardiac cycle) ,HEART failure - Abstract
The author reflects on a study regarding the problem associated with heart failure in older people. The author says that increase in age causes several changes in the structure of the cardiovascular system which includes maturation of collagen, thickness in muscles, and loss of elastic fibers, which triggers the stiffness of central and peripheral arteries. Moreover, aging causes various functional changes in the heart such as decrease in heart rate and volume.
- Published
- 2000
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19. COMPARISON OF POSTURAL CHANGE IN BLOOD PRESSURE FROM SITTING TO STANDING AND LYING TO STANDING POSITION AND 70° HEAD UP TILT TEST.
- Author
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Loharuka, S., Wisniacki, N., Turnbull, C., and Gosney, M.
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BLOOD pressure , *SITTING position , *STANDING position , *LYING down position , *POSTURE - Abstract
Presents an abstract of the study "Comparison of Postural Change in Blood Pressure From Sitting to Standing and Lying to Standing Position and 70° Head Up Tilt Test," by S. Loharuka, N. Wisniacki, C. Turnbull and M. Gosney.
- Published
- 2004
20. INSULIN RESISTANCE (IR) AND MARKERS OF SYSTEMIC INFLAMMATION (SI) IN OLDER PATIENTS WITH SYSTOLIC AND DIASTOLIC HEART FAILURE (DHF). PREDICTIVE VALUE FOR SURVIVAL.
- Author
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Wisniacki, N., Taylor, W., Lye, M., and Wilding, J. P. H.
- Subjects
- *
INSULIN resistance , *DRUG resistance , *PATIENTS , *HEART failure , *HEART diseases , *DOPPLER echocardiography , *INTERLEUKINS , *TUMOR necrosis factors - Abstract
The article focuses on a study that evaluates insulin resistance and markers of systemic inflammation in older patients with systolic and diastolic heart failure. Non-diabetic elderly patients with chronic heart failure hospitalized within 6 months due to heart failure were prospectively included, together with a control group of older healthy volunteer subjects. Based on Doppler echocardiographic criteria patients were classed as having systolic heart failure. Fasting glucose, insulin, C-reactive protein, interleukin 6 (II 6), and tumor necrosis factor α soluble receptor II were determined at least 6 weeks post discharge.
- Published
- 2004
21. Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis.
- Author
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Denton CP, Del Galdo F, Khanna D, Vonk MC, Chung L, Johnson SR, Varga J, Furst DE, Temple J, Zecchin C, Csomor E, Lee A, Wisniacki N, Flint SM, and Reid J
- Subjects
- Humans, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Inflammation drug therapy, Fibrosis, Double-Blind Method, Scleroderma, Systemic drug therapy, Scleroderma, Systemic chemically induced
- Abstract
Objectives: The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process., Methods: This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint., Results: Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups., Conclusion: Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc., Trial Registration Number: ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
- Published
- 2022
- Full Text
- View/download PDF
22. A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren's syndrome.
- Author
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Mariette X, Barone F, Baldini C, Bootsma H, Clark KL, De Vita S, Gardner DH, Henderson RB, Herdman M, Lerang K, Mistry P, Punwaney R, Seror R, Stone J, van Daele P, van Maurik A, Wisniacki N, Roth DA, and Tak PP
- Subjects
- Humans, Rituximab therapeutic use, Sjogren's Syndrome drug therapy
- Abstract
BACKGROUNDPrimary Sjögren's syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20+ B cells. Combined, these 2 mechanisms may achieve synergistic effects.METHODSThis 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab.RESULTSOverall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20+ B cells and a greater and more sustained depletion of peripheral CD19+ B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren's syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo.CONCLUSIONThe safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes.TRIAL REGISTRATIONClinicalTrials.gov NCT02631538.FUNDINGFunding was provided by GSK.
- Published
- 2022
- Full Text
- View/download PDF
23. Integrated analysis of dermal blister fluid proteomics and genome-wide skin gene expression in systemic sclerosis: an observational study.
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Clark KEN, Csomor E, Campochiaro C, Galwey N, Nevin K, Morse MA, Teo YV, Freudenberg J, Ong VH, Derrett-Smith E, Wisniacki N, Flint SM, and Denton CP
- Abstract
Background: Skin fibrosis is a hallmark feature of systemic sclerosis. Skin biopsy transcriptomics and blister fluid proteomics give insight into the local environment of the skin. We have integrated these modalities with the aim of developing a surrogate for the modified Rodnan skin score (mRSS), using candidate genes and proteins from the skin and blister fluid as anchors to identify key analytes in the plasma., Methods: In this single-centre, prospective observational study at the Royal Free Campus, University College London, London, UK, transcriptional and proteomic analyses of blood and skin were performed in a cohort of patients with systemic sclerosis (n=52) and healthy controls (n=16). Weighted gene co-expression network analysis was used to explore the association of skin transcriptomics data, clinical traits, and blister fluid proteomic results. Candidate hub analytes were identified as those present in both blister and skin gene sets (modules), and which correlated with plasma (module membership >0·7 and gene significance >0·6). Hub analytes were confirmed using RNA transcript data obtained from skin biopsy samples from patients with early diffuse cutaneous systemic sclerosis at 12 months., Findings: We identified three modules in the skin, and two in blister fluid, which correlated with a diagnosis of early diffuse cutaneous systemic sclerosis. From these modules, 11 key hub analytes were identified, present in both skin and blister fluid modules, whose transcript and protein levels correlated with plasma protein concentrations, mRSS, and showed statistically significant correlation on repeat transcriptomic samples taken at 12 months. Multivariate analysis identified four plasma analytes as correlates of mRSS (COL4A1, COMP, SPON1, and TNC), which can be used to differentiate disease subtype., Interpretation: This unbiased approach has identified potential biological candidates that might be drivers of local skin pathogenesis in systemic sclerosis. By focusing on measurable analytes in the plasma, we generated a promising composite plasma protein biomarker that could be used for assessment of skin severity, case stratification, and as a potential outcome measure for clinical trials and practice. Once fully validated, the biomarker score could replace a clinical score such as the mRSS, which carries substantial variability., Funding: GlaxoSmithKline and UK Medical Research Council., Competing Interests: CPD reports consulting fees or honoraria from Janssen, GlaxoSmithKline, Roche, Boehringer Ingelheim, Sanofi, Galapagos, Inventiva, Corbus, Acceleron, Horizon, Gesynta, and ARXX Therapeutics; and from research grants to their institution from GlaxoSmithKline, ARXX Therapeutics, Servier, and Horizon Therapeutics. NW, SMF, YVT, JF, NG, EC, KN, and MAM are employees of GlaxoSmithKline. NG, EC, JF, NW, MAM, SMF, and KN are shareholders in GlaxoSmithKline. All other authors declare no competing interests, (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)
- Published
- 2022
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24. Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis.
- Author
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Clark KEN, Campochiaro C, Csomor E, Taylor A, Nevin K, Galwey N, Morse MA, Singh J, Teo YV, Ong VH, Derrett-Smith E, Wisniacki N, Flint SM, and Denton CP
- Subjects
- Adult, Aged, Aged, 80 and over, Autoantibodies immunology, Case-Control Studies, Disease Progression, Female, Gene Expression Profiling, Humans, Hyaluronic Acid blood, Immunosuppressive Agents therapeutic use, Male, Middle Aged, Peptide Fragments blood, Procollagen blood, Prospective Studies, Proteomics, Scleroderma, Diffuse blood, Scleroderma, Diffuse drug therapy, Tissue Inhibitor of Metalloproteinase-1 blood, Transcriptome, Young Adult, Antibodies, Antinuclear immunology, DNA Topoisomerases, Type I immunology, RNA Polymerase III immunology, Scleroderma, Diffuse immunology
- Abstract
Objectives: Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodies METHODS: We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities., Results: Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis., Conclusions: Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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25. Advanced imaging for quantification of abnormalities in the salivary glands of patients with primary Sjögren's syndrome.
- Author
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Jimenez-Royo P, Bombardieri M, Ciurtin C, Kostapanos M, Tappuni AR, Jordan N, Saleem A, Fuller T, Port K, Pontarini E, Lucchesi D, Janiczek R, Galette P, Searle G, Patel N, Kershaw L, Gray C, Ratia N, van Maurik A, de Groot M, Wisniacki N, Bergstrom M, and Tarzi R
- Subjects
- Adult, Aged, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron Emission Tomography Computed Tomography, Salivary Glands diagnostic imaging, Sjogren's Syndrome diagnostic imaging
- Abstract
Objectives: To assess non-invasive imaging for detection and quantification of gland structure, inflammation and function in patients with primary Sjogren's syndrome (pSS) using PET-CT with 11C-Methionine (11C-MET; radiolabelled amino acid), and 18F-fluorodeoxyglucose (18F-FDG; glucose uptake marker), to assess protein synthesis and inflammation, respectively; multiparametric MRI evaluated salivary gland structural and physiological changes., Methods: In this imaging/clinical/histology comparative study (GSK study 203818; NCT02899377) patients with pSS and age- and sex-matched healthy volunteers underwent MRI of the salivary glands and 11C-MET PET-CT. Patients also underwent 18F-FDG PET-CT and labial salivary gland biopsies. Clinical and biomarker assessments were performed. Primary endpoints were semi-quantitative parameters of 11C-MET and 18F-FDG uptake in submandibular and parotid salivary glands and quantitative MRI measures of structure and inflammation. Clinical and minor salivary gland histological parameter correlations were explored., Results: Twelve patients with pSS and 13 healthy volunteers were included. Lower 11C-MET uptake in parotid, submandibular and lacrimal glands, lower submandibular gland volume, higher MRI fat fraction, and lower pure diffusion in parotid and submandibular glands were observed in patients vs healthy volunteer, consistent with reduced synthetic function. Disease duration correlated positively with fat fraction and negatively with 11C-MET and 18F-FDG uptake, consistent with impaired function, inflammation and fatty replacement over time. Lacrimal gland 11C-MET uptake positively correlated with tear flow in patients, and parotid gland 18F-FDG uptake positively correlated with salivary gland CD20+ B-cell infiltration., Conclusion: Molecular imaging and MRI may be useful tools to non-invasively assess loss of glandular function, increased glandular inflammation and fat accumulation in pSS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
- Published
- 2021
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26. Depletion of LAG-3 + T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781.
- Author
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Ellis J, J B Marks D, Srinivasan N, Barrett C, Hopkins TG, Richards A, Fuhr R, Albayaty M, Coenen M, Liefaard L, Leavens K, Nevin KL, Tang S, Hughes SA, Fortunato L, Edwards K, Cui Y, Anselm R, Delves CJ, Charles E, Feeney M, Webb TM, Brett SJ, Schmidt TS, Stone J, Savage COS, Wisniacki N, and Tarzi RM
- Subjects
- Adult, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacokinetics, Antigens, CD blood, CD3 Complex metabolism, Dose-Response Relationship, Immunologic, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Psoriasis genetics, Psoriasis pathology, Treatment Outcome, Lymphocyte Activation Gene 3 Protein, Antibodies, Monoclonal pharmacology, Antigens, CD immunology, Psoriasis drug therapy, T-Lymphocytes immunology
- Abstract
Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4
+ and CD8+ T cells. We describe the engineering and first-in-human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3+ cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3+ and CD3+ T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases., (© 2020 GlaxoSmithKline. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2021
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27. A randomised, single-blind, placebo-controlled, dose-finding safety and tolerability study of the anti-CD3 monoclonal antibody otelixizumab in new-onset type 1 diabetes.
- Author
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Keymeulen B, van Maurik A, Inman D, Oliveira J, McLaughlin R, Gittelman RM, Roep BO, Gillard P, Hilbrands R, Gorus F, Mathieu C, Van de Velde U, Wisniacki N, and Napolitano A
- Subjects
- Adolescent, Adult, C-Peptide metabolism, Diabetes Mellitus, Type 1 metabolism, Disease Progression, Dose-Response Relationship, Drug, Epstein-Barr Virus Infections chemically induced, Female, Humans, Latent Infection chemically induced, Male, Single-Blind Method, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, Diabetes Mellitus, Type 1 drug therapy, Insulin Secretion, Insulin-Secreting Cells metabolism
- Abstract
Aims/hypothesis: Numerous clinical studies have investigated the anti-CD3ɛ monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose-response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes., Methods: In this randomised, single-blind, placebo-controlled, 24 month study, conducted in five centres in Belgium via the Belgian Diabetes Registry, participants (16-27 years old, <32 days from diagnosis of type 1 diabetes) were scheduled to receive placebo or otelixizumab in one of four dose cohorts (cumulative i.v. dose 9, 18, 27 or 36 mg over 6 days; planned n = 40). Randomisation to treatment was by a central computer system; only participants and bedside study personnel were blinded to study treatment. The co-primary endpoints were the incidence of adverse events, the rate of Epstein-Barr virus (EBV) reactivation, and laboratory measures and vital signs. A mixed-meal tolerance test was used to assess beta cell function; exploratory biomarkers were used to measure T cell responses., Results: Thirty participants were randomised/28 were analysed (placebo, n = 6/5; otelixizumab 9 mg, n = 9/8; otelixizumab 18 mg, n = 8/8; otelixizumab 27 mg, n = 7/7; otelixizumab 36 mg, n = 0). Dosing was stopped at otelixizumab 27 mg as the predefined EBV reactivation stopping criteria were met. Adverse event frequency and severity were dose dependent; all participants on otelixizumab experienced at least one adverse event related to cytokine release syndrome during the dosing period. EBV reactivation (otelixizumab 9 mg, n = 2/9; 18 mg, n = 4/8: 27 mg, n = 5/7) and clinical manifestations (otelixizumab 9 mg, n = 0/9; 18 mg, n = 1/8; 27 mg, n = 3/7) were rapid, dose dependent and transient, and were associated with increased productive T cell clonality that diminished over time. Change from baseline mixed-meal tolerance test C-peptide weighted mean AUC
0-120 min following otelixizumab 9 mg was above baseline for up to 18 months (difference from placebo 0.39 [95% CI 0.06, 0.72]; p = 0.023); no beta cell function preservation was observed at otelixizumab 18 and 27 mg., Conclusions/interpretation: A metabolic response was observed with otelixizumab 9 mg, while doses higher than 18 mg increased the risk of unwanted clinical EBV reactivation. Although otelixizumab can temporarily compromise immunocompetence, allowing EBV to reactivate, the effect is dose dependent and transient, as evidenced by a rapid emergence of EBV-specific T cells preceding long-term control over EBV reactivation., Trial Registration: ClinicalTrials.gov NCT02000817., Funding: The study was funded by GlaxoSmithKline. Graphical abstract.- Published
- 2021
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28. Quantifying disease activity in rheumatoid arthritis with the TSPO PET ligand 18 F-GE-180 and comparison with 18 F-FDG and DCE-MRI.
- Author
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de Groot M, Patel N, Manavaki R, Janiczek RL, Bergstrom M, Östör A, Gerlag D, Roberts A, Graves MJ, Karkera Y, Fernando D, Mistry P, Walker A, Wisniacki N, Fryer TD, and Jimenez-Royo P
- Abstract
Purpose: While the aetiology of rheumatoid arthritis (RA) remains unclear, many of the inflammatory components are well characterised. For diagnosis and therapy evaluation, in vivo insight into these processes would be valuable. Various imaging probes have shown value including dynamic contrast-enhanced (DCE) MRI and PET/CT using
18 F-fluorodeoxyglucose (18 F-FDG) or tracers targeting the translocator protein (TSPO). To evaluate18 F-GE-180, a novel TSPO PET tracer, for detecting and quantifying disease activity in RA, we compared18 F-GE-180 uptake with that of18 F-FDG and DCE-MRI measures of inflammation., Methods: Eight RA patients with moderate-to-high, stable disease activity and active disease in at least one wrist were included in this study (NCT02350426). Participants underwent PET/CT examinations with18 F-GE-180 and18 F-FDG on separate visits, covering the shoulders and from the pelvis to the feet, including hands and wrists. DCE-MRI was performed on one affected hand. Uptake was compared visually between tracers as judged by an experienced radiologist and quantitatively using the maximum standardised uptake value (SUVmax ). Uptake for both tracers was correlated with DCE-MRI parameters of inflammation, including the volume transfer coefficient Ktrans using Pearson correlation (r)., Results: PET/CT imaging with18 F-GE-180 in RA patients showed marked extra-synovial uptake around the affected joints. Overall sensitivity for detecting clinically affected joints was low (14%).18 F-GE-180 uptake did not or only weakly correlate with DCE-MRI parameters in the wrist (r = 0.09-0.31).18 F-FDG showed higher sensitivity for detecting symptomatic joints (34%), as well as strong positive correlation with DCE-MRI parameters (SUVmax vs. Ktrans : r = 0.92 for wrist; r = 0.68 for metacarpophalangeal joints)., Conclusions: The correlations between DCE-MRI parameters and18 F-FDG uptake support use of this PET tracer for quantification of inflammatory burden in RA. The TSPO tracer18 F-GE-180, however, has shown limited use for the investigation of RA due to its poor sensitivity and ability to quantify disease activity in RA.- Published
- 2019
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29. In vivo affinity and target engagement in skin and blood in a first-time-in-human study of an anti-oncostatin M monoclonal antibody.
- Author
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Reid J, Zamuner S, Edwards K, Rumley SA, Nevin K, Feeney M, Zecchin C, Fernando D, and Wisniacki N
- Subjects
- Adult, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Area Under Curve, Blister drug therapy, Blister etiology, Blister immunology, Blister pathology, Double-Blind Method, Female, Healthy Volunteers, Humans, Injections, Subcutaneous, Male, Middle Aged, Models, Biological, Oncostatin M immunology, Placebos administration & dosage, Placebos adverse effects, Skin drug effects, Skin immunology, Skin pathology, Suction adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Oncostatin M antagonists & inhibitors
- Abstract
Aims: The oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, and is a potential therapeutic target for inflammatory and fibrotic diseases. The aim of this first-time-in-human experimental medicine study was to assess the safety, tolerability, pharmacokinetics and target engagement of single subcutaneous doses of GSK2330811, an anti-OSM monoclonal antibody, in healthy subjects., Methods: This was a phase I, randomized, double-blind, placebo-controlled, single-dose escalation, first-time-in-human study of subcutaneously administered GSK2330811 in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin, and the potential for antidrug antibody formation were assessed. The in vivo affinity of GSK2330811 for OSM and target engagement in serum and skin blister fluid (obtained via a skin suction blister model) were estimated using target-mediated drug disposition (TMDD) models in combination with compartmental and physiology-based pharmacokinetic (PBPK) models., Results: Thirty subjects were randomized to receive GSK2330811 and 10 to placebo in this completed study. GSK2330811 demonstrated a favourable safety profile in healthy subjects; no adverse events were serious or led to withdrawal. There were no clinically relevant trends in change from baseline in laboratory values, with the exception of a reversible dose-dependent reduction in platelet count. GSK2330811 exhibited linear pharmacokinetics over the dose range 0.1-6 mg kg
-1 . The estimated in vivo affinity (nM) of GSK2330811 for OSM was 0.568 [95% confidence interval (CI) 0.455, 0.710] in the compartmental with TMDD model and 0.629 (95% CI 0.494, 0.802) using the minimal PBPK with TMDD model., Conclusions: Single subcutaneous doses of GSK2330811 were well tolerated in healthy subjects. GSK2330811 demonstrated sufficient affinity to achieve target engagement in systemic circulation and target skin tissue, supporting the progression of GSK2330811 clinical development., (© 2018 GSK Group of Companies. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2018
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30. Alterations in urinary collagen peptides in lupus nephritis subjects correlate with renal dysfunction and renal histopathology.
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Wei R, Gao B, Shih F, Ranger A, Dearth A, Mischak H, Siwy J, Wisniacki N, Petri M, and Burkly LC
- Subjects
- Adult, Case-Control Studies, Disease Progression, Female, Humans, Kidney Diseases etiology, Kidney Diseases urine, Male, Biomarkers urine, Collagen urine, Kidney Diseases diagnosis, Lupus Erythematosus, Systemic complications, Lupus Nephritis complications, Peptide Fragments urine
- Abstract
Background: The excessive accumulation of extracellular matrix (ECM) in the renal tubulointerstitium is a key component of chronic renal damage in lupus nephritis (LN) and a critical determinant of the disease progression to renal failure. Detection of fibrosis requires renal biopsy and is therefore limited by high risks associated with an invasive procedure. This study explores whether a unique LN urinary peptidome can be identified and whether LN-specific alteration reflects the underlying fibrogenic process of altered ECM turnover., Method: Urinary peptides were analyzed for 36 LN and 35 nonrenal systemic lupus erythematosus (SLE) subjects and 58 healthy volunteers (HVs)., Results: In total, 70 collagen and 230 noncollagen peptides were significantly changed between LN and nonrenal SLE and between LN and HV and defined as 'LN peptides'; 14 proteases associated with observed LN collagen peptides were identified and activities in 9 proteases were significantly different between LN and nonrenal SLE; 28 collagen peptides were correlated with at least one parameter of clinical renal dysfunction or histolopathology., Conclusion: Urinary peptidomic alterations likely reflect pathogenic pathways involving ECM turnover in LN kidneys and potentially could be developed as biomarkers to monitor renal disease progression., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)
- Published
- 2017
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31. Population pharmacokinetic and pharmacodynamic analysis of BIIB023, an anti-TNF-like weak inducer of apoptosis (anti-TWEAK) monoclonal antibody.
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Galluppi GR, Wisniacki N, and Stebbins C
- Subjects
- Adolescent, Adult, Antibodies, Monoclonal, Humanized pharmacokinetics, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Neutralizing pharmacology, Asian People, Broadly Neutralizing Antibodies, Dose-Response Relationship, Drug, Double-Blind Method, Enzyme-Linked Immunosorbent Assay, Female, Humans, Infusions, Intravenous, Male, Nonlinear Dynamics, White People, Young Adult, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Neutralizing administration & dosage, Arthritis, Rheumatoid drug therapy, Cytokine TWEAK antagonists & inhibitors
- Abstract
Aims: Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is implicated in the pathogenesis of lupus nephritis. This study evaluated the pharmacokinetics, using the population approach, and pharmacodynamics of BIIB023, an anti-TWEAK monoclonal antibody, in healthy Chinese, Japanese and Caucasian volunteers., Methods: In this single-dose, randomized, double-blind, phase 1 study of BIIB023 in healthy volunteers, BIIB023 was administered by intravenous infusion (3 or 20 mg kg(-1) ) on Day 1; follow-up occurred through Day 71. BIIB023 serum concentration was measured using a validated enzyme-linked immunosorbent assay; BIIB023 concentration-time data were subjected to noncompartmental analysis. Population pharmacokinetic analysis was performed using data from this study and a prior phase 1 study of BIIB023 in subjects with rheumatoid arthritis. Soluble TWEAK and, Tweak: BIIB023 complex were evaluated., Results: There were no differences in BIIB023 pharmacokinetics requiring dose adjustment among the three ethnic groups or between healthy volunteers and arthritis patients. BIIB023 central compartment volume (3050 ml) and clearance (7.42 ml h(-1) ) were comparable to those observed for other monoclonal antibody drugs. BIIB023 serum exposure increased in a dose-dependent manner in all groups, but not in direct proportion to dose level; at concentrations below ~10 μg ml(-1) , nonlinear clearance was observed. Soluble TWEAK levels decreased to below the level of quantitation after BIIB023 treatment, with concomitant changes in, Tweak: BIIB023 complex levels., Conclusions: No clinically meaningful differences were observed in BIIB023 pharmacokinetic and pharmacodynamic properties in healthy Chinese, Japanese and Caucasian volunteers; pharmacodynamic measures suggested target engagement. TWEAK may be an attractive therapeutic target for lupus nephritis treatment., (© 2016 The British Pharmacological Society.)
- Published
- 2016
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32. Towards the identification of multi-parametric quantitative MRI biomarkers in lupus nephritis.
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Rapacchi S, Smith RX, Wang Y, Yan L, Sigalov V, Krasileva KE, Karpouzas G, Plotnik A, Sayre J, Hernandez E, Verma A, Burkly L, Wisniacki N, Torrington J, He X, Hu P, Chiao PC, and Wang DJJ
- Subjects
- Adult, Biomarkers, Cohort Studies, Female, Humans, Male, Reproducibility of Results, Kidney pathology, Lupus Nephritis pathology, Magnetic Resonance Imaging
- Abstract
Purpose: To identify potential biomarkers of the renal impairment in lupus nephritis using a multi-parametric renal quantitative MRI (qMRI) protocol including diffusion weighted imaging (DWI), blood oxygen level dependent (BOLD), arterial spin labeling (ASL) and T1rho MRI between a cohort of healthy volunteers and lupus nephritis (LN) patients., Materials and Methods: The renal qMRI protocol was performed twice with repositioning in between on 10 LN patients and 10 matched controls at 1.5 T. Navigator-gated and breath-hold acquisitions followed by non-rigid image registration were used to control respiratory motion. The repeatability of the 4 MRI modalities was evaluated with the intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Unpaired t-test and stepwise logistic regression were carried out to evaluate qMRI parameters between the LN and control groups., Results: The reproducibility of the 4 qMRI modalities ranged from moderate to good (ICC=0.4-0.91, wsCV≤12%) with a few exceptions. T1rho MRI and ASL renal blood flow (RBF) demonstrated significant differences between the LN and control groups. Stepwise logistic regression yielded only one significant parameter (medullar T1rho) in differentiating LN from control groups with 95% accuracy., Conclusion: A reasonable degree of test-retest repeatability and accuracy of a multi-parametric renal qMRI protocol has been demonstrated in healthy volunteers and LN subjects. T1rho and ASL RBF are promising imaging biomarkers of LN., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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33. Safety, tolerability, pharmacokinetics, and pharmacodynamics of anti-TWEAK monoclonal antibody in patients with rheumatoid arthritis.
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Wisniacki N, Amaravadi L, Galluppi GR, Zheng TS, Zhang R, Kong J, and Burkly LC
- Subjects
- Administration, Intravenous, Adolescent, Adult, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Neutralizing, Antirheumatic Agents administration & dosage, Antirheumatic Agents adverse effects, Antirheumatic Agents pharmacokinetics, Broadly Neutralizing Antibodies, Cytokine TWEAK, Double-Blind Method, Drug Administration Schedule, Drug Therapy, Combination, Female, Humans, Inflammation drug therapy, Methotrexate pharmacokinetics, Methotrexate therapeutic use, Middle Aged, Receptors, Tumor Necrosis Factor metabolism, TWEAK Receptor, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factors immunology, Tumor Necrosis Factors metabolism, Young Adult, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized pharmacokinetics, Antibodies, Monoclonal, Humanized therapeutic use, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy, Tumor Necrosis Factor Inhibitors
- Abstract
Background: Persistent upregulation of signaling by cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) through its receptor fibroblast growth factor-inducible molecule-14 (Fn14) promotes chronic inflammation and tissue destruction., Objective: The aim of this study was to explore the safety and tolerability of the TWEAK-blocking monoclonal antibody BIIB023 and determine its pharmacokinetics and effects on TWEAK pathway pharmacodynamic markers in rheumatoid arthritis (RA)., Methods: Phase I, first-in-human, 2-part, multicenter, double-blind, dose-escalation study. Patients were randomized to a single dose of BIIB023 (0.03-20 mg/kg) (n = 38) or placebo (n = 15) as an add-on to methotrexate. Three open-label cohorts of RA patients taking background disease-modifying antirheumatic drugs and stable tumor necrosis factor (TNF) inhibitor therapy (n = 12) received a single-dose of BIIB023 of 2, 10, or 20 mg/kg and were assessed over 70 days., Results: The incidence of treatment-emergent adverse events for the BIIB023 monotherapy cohorts and open-label cohorts of BIIB023 as add-on therapy to TNF inhibitors compared with placebo were 47% and 50% versus 33%, respectively. Serum exposure to BIIB023 increased in a dose-dependent manner from 0.03 to 20 mg/kg, but not in direct proportion to dose level. After administration, the time course of BIIB023 serum concentration was multiphasic and showed expedited elimination when levels decreased to < 10 µg/mL. Serum-soluble TWEAK levels were suppressed at all dose levels by 6 hours post-dose and recovered to baseline between days 7 and 28. A trend toward downward modulation of serum biomarkers of inflammatory response was suggested in monocyte chemoattractant protein 1, inducible protein 10, macrophage inflammatory protein 1β, and tissue inhibitor of metalloproteinase 1 in the BIIB023 group versus placebo., Conclusions: Single-dose BIIB023 showed a favorable safety and tolerability profile in RA. Suppression of serum-soluble TWEAK for ≤ 28 days was observed and downward trends in serum biomarkers suggested., (© 2013 Elsevier HS Journals, Inc. All rights reserved.)
- Published
- 2013
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34. Role of TWEAK in lupus nephritis: a bench-to-bedside review.
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Michaelson JS, Wisniacki N, Burkly LC, and Putterman C
- Subjects
- Animals, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Neutralizing pharmacology, Broadly Neutralizing Antibodies, Cell Proliferation drug effects, Clinical Trials, Phase II as Topic, Cytokine TWEAK, Fibrosis, Gene Expression drug effects, Humans, Kidney Glomerulus drug effects, Kidney Glomerulus pathology, Kidney Tubules drug effects, Kidney Tubules pathology, Lupus Nephritis drug therapy, Molecular Targeted Therapy, Receptors, Tumor Necrosis Factor genetics, Receptors, Tumor Necrosis Factor metabolism, Signal Transduction drug effects, TWEAK Receptor, Tumor Necrosis Factors genetics, Tumor Necrosis Factors metabolism, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Neutralizing therapeutic use, Kidney Glomerulus metabolism, Kidney Tubules metabolism, Lupus Nephritis metabolism, Lupus Nephritis pathology, Tumor Necrosis Factor Inhibitors
- Abstract
There is significant unmet need in the treatment of lupus nephritis (LN) patients. In this review, we highlight the role of the TWEAK/Fn14 pathway in mediating key pathologic processes underlying LN involving both glomerular and tubular injury, and thus the potential for renal protection via blockade of this pathway. The specific pathological mechanisms of TWEAK - namely promoting inflammation, renal cell proliferation and apoptosis, vascular activation and fibrosis - are described, with supporting data from animal models and in vitro systems. Furthermore, we detail the translational relevance of these mechanisms to clinical readouts in human LN. We present the opportunity for an anti-TWEAK therapeutic as a renal protective agent to improve efficacy relative to current standard of care treatments hopefully without increased safety risk, and highlight a phase II trial with BIIB023, an anti-TWEAK neutralizing antibody, designed to assess efficacy in LN patients. Taken together, targeting the TWEAK/Fn14 axis represents a potential new therapeutic paradigm for achieving renal protection in LN patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
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