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Psoriasis: HELP
Articles from Cambridgeshire
Based on 64 articles published since 2010
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These are the 64 published articles about Psoriasis that originated from Cambridgeshire during 2010-2020.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline European S3-Guideline on the systemic treatment of psoriasis vulgaris - Update Apremilast and Secukinumab - EDF in cooperation with EADV and IPC. 2017

Nast, A / Spuls, P I / van der Kraaij, G / Gisondi, P / Paul, C / Ormerod, A D / Saiag, P / Smith, C H / Dauden, E / de Jong, E M / Feist, E / Jobling, R / Maccarone, M / Mrowietz, U / Papp, K A / Reich, K / Rosumeck, S / Talme, T / Thio, H B / van de Kerkhof, P / Werner, R N / Dressler, C. ·Division of Evidence-Based Medicine, Department of Dermatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. · Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands. · Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy. · Department of Dermatology, Paul Sabatier University, Toulouse, France. · Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, UK. · Service de Dermatologie, Hôpital Ambroise Paré Université Paris V, Boulogne, France. · St Johns Institute of Dermatology, Guys and St Thomas' Hospital Foundation Trust, London, UK. · Hospital Universitario de la Princesa, Madrid, Spain. · Radboud University medical center and Radboud University, Nijmegen, The Netherlands. · Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Cambridge, UK. · Roma, Italy. · Department of Dermatology, Psoriasis-Center University Medical Center Schleswig Holstein, Kiel, Germany. · Waterloo, Canada. · Dermatologikum Hamburg, Hamburg, Germany. · Section of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden. ·J Eur Acad Dermatol Venereol · Pubmed #28895202.

ABSTRACT: -- No abstract --

2 Guideline European S3-Guidelines on the systemic treatment of psoriasis vulgaris--Update 2015--Short version--EDF in cooperation with EADV and IPC. 2015

Nast, A / Gisondi, P / Ormerod, A D / Saiag, P / Smith, C / Spuls, P I / Arenberger, P / Bachelez, H / Barker, J / Dauden, E / de Jong, E M / Feist, E / Jacobs, A / Jobling, R / Kemény, L / Maccarone, M / Mrowietz, U / Papp, K A / Paul, C / Reich, K / Rosumeck, S / Talme, T / Thio, H B / van de Kerkhof, P / Werner, R N / Yawalkar, N. ·Division of Evidence Based Medicine, Department of Dermatology, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Section of Dermatology and Venereology, Department of Medicine, University of Verona, Verona, Italy. · Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, UK. · Service de Dermatologie, Hôpital Ambroise Paré Université Paris V, Boulogne, France. · Clinical Lead for Dermatology, St Johns Institute of Dermatology, St Thomas' Hospital, London, UK. · Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands. · Third Faculty of Medicine, Department of Dermatology, Charles University, Prague, Czech Republic. · Department of Dermatology, Hôpital Saint-Louis, Paris, France. · St. Johns Institute of Dermatology, St. Thomas' Hospital, London, UK. · Hospital Universitario de la Princesa, Madrid, Spain. · University Medical Center Nijmegen St Radboud, Nijmegen, The Netherlands. · Medizinische Klinik mit Schwerpunkt Rheumatologie u. klinische Immonologie, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Cambridge, UK. · SZTE Borgyogyaszati Klinika, Szeged, Hungary. · Roma, Italy. · Department of Dermatology, Psoriasis-Center University Medical Center Schleswig Holstein, Kiel, Germany. · Waterloo, Canada. · Department of Dermatology, Paul Sabatier University, Toulouse, France. · Dermatologikum Hamburg, Hamburg, Germany. · Section of Dermatology and Venereology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden. · Department of Dermatology, Erasmus University, Rotterdam, The Netherlands. · Department of Dermatology, University Hospital Nijmegen, Nijmegen, The Netherlands. · Department of Dermatology, Inselspital, Universitätsklinik für Dermatologie, Bern, Switzerland. ·J Eur Acad Dermatol Venereol · Pubmed #26481193.

ABSTRACT: -- No abstract --

3 Editorial Residents'corner January/February 2016. Editorial: What's new this month? 2016

Villani, Axel-Patrice / Behle, Valeria / Cabete, Joana / Durack, Alana / Kuonen, François / Martin-Gorgojo, Alejandro. ·Dermatology Department, Hôpital Edouard Herriot, Lyon, France. · Department of Dermatology, Venerology and Allergology, University Hospital Wuerzburg, Joseph-Schneider-Str. 2, 97080 Wuerzburg, Germany. · Dermatology Department. Hospital de Santo António dos Capuchos - Centro Hospitalar de Lisboa Central. Alameda Santo António dos Capuchos 1169-050, Lisbon, Portugal. · Dermatology Department, Box 46, Addenbrooke's Hospital, Hills road, Cambridge, CB2 OQQ, UK. · Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne University Hospital Center, Av. de Beaumont 29, CH-1011 Lausanne, Switzerland. · Dermatology Department, General University Hospital "Gregorio Marañon", C/ Doctor Esquerdo 46, and Clinica Dermatologica Internacional and Clinica Ruber, Madrid, Spain. ·Eur J Dermatol · Pubmed #27023019.

ABSTRACT: -- No abstract --

4 Editorial Psoriasis: More Than Just Skin Deep. 2015

Tarkin, Jason M / Rudd, James H F. ·From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, UK. · From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, UK. jhfr2@cam.ac.uk. ·Arterioscler Thromb Vasc Biol · Pubmed #26607356.

ABSTRACT: -- No abstract --

5 Editorial Residents' corner June 2015. Editorial: What's new this month? 2015

Cabete, Joana / Behle, Valeria / Villani, Axel-Patrice / Durack, Alana / Kuonen, François / Martin-Gorgojo, Alejandro. ·Dermatology Department. Hospital de Santo António dos Capuchos - Centro Hospitalar de Lisboa Central. Alameda Santo António dos Capuchos 1169-050, Lisbon, Portugal. · Department of Dermatology, Venerology and Allergology, University Hospital Wuerzburg, Joseph-Schneider-Str. 2, 97080 Wuerzburg, Germany. · Dermatology Department, Hôpital Edouard Herriot, Lyon, France. · Dermatology department, Box 46, Addenbrooke's Hospital, Hills road, Cambridge, CB2 0QQ, UK. · Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne University Hospital Center, Av. de Beaumont 29, CH-1011 Lausanne, Switzerland. · Dermatology Department. General University Hospital Gregorio Marañon. C/ Doctor Esquerdo 46, 28007 Madrid, Spain. Dermatology Department. Clinica Dermatologica Internacional and Clinica Ruber. Madrid, Spain. ·Eur J Dermatol · Pubmed #26412040.

ABSTRACT: -- No abstract --

6 Review Monoclonal Antibodies: Past, Present and Future. 2019

Posner, J / Barrington, P / Brier, T / Datta-Mannan, A. ·JPC PharMed Ltd , Kent, UK. john.posner@talk21.com. · King's College London, London, UK. john.posner@talk21.com. · Transcrip Partners, Reading, UK. · Kings Health Partners, London, UK. · Guy's and St Thomas' NHS Foundation Trust, London, UK. · AstraZeneca, Cambridge, UK. · Eli-Lilly and Company, Indianapolis, IN, USA. ·Handb Exp Pharmacol · Pubmed #31820172.

ABSTRACT: Monoclonal antibodies (mAbs) are immunoglobulins designed to target a specific epitope on an antigen. Immunoglobulins of identical amino-acid sequence were originally produced by hybridomas grown in culture and, subsequently, by recombinant DNA technology using mammalian cell expression systems. The antigen-binding region of the mAb is formed by the variable domains of the heavy and light chains and contains the complementarity-determining region that imparts the high specificity for the target antigen. The pharmacokinetics of mAbs involves target-mediated and non-target-related factors that influence their disposition.Preclinical safety evaluation of mAbs differs substantially from that of small molecular (chemical) entities. Immunogenicity of mAbs has implications for their pharmacokinetics and safety. Early studies of mAbs in humans require careful consideration of the most suitable study population, route/s of administration, starting dose, study design and the potential difference in pharmacokinetics in healthy subjects compared to patients expressing the target antigen.Of the ever-increasing diversity of therapeutic indications for mAbs, we have concentrated on two that have proved dramatically successful. The contribution that mAbs have made to the treatment of inflammatory conditions, in particular arthritides and inflammatory bowel disease, has been nothing short of revolutionary. Their benefit has also been striking in the treatment of solid tumours and, most recently, as immunotherapy for a wide variety of cancers. Finally, we speculate on the future with various new approaches to the development of therapeutic antibodies.

7 Review IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases. 2016

Tauber, Marie / Bal, Elodie / Pei, Xue-Yuan / Madrange, Marine / Khelil, Amel / Sahel, Houria / Zenati, Akila / Makrelouf, Mohamed / Boubridaa, Khaled / Chiali, Amel / Smahi, Naima / Otsmane, Farida / Bouajar, Bakar / Marrakchi, Slaheddine / Turki, Hamida / Bourrat, Emmanuelle / Viguier, Manuelle / Hamel, Yamina / Bachelez, Hervé / Smahi, Asma. ·INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France. · Department of Biochemistry, University of Cambridge, Cambridge, UK. · Department of Dermatology, CHU Oran, Oran, Algeria. · Department of Dermatology, CHU Bab El Oued, Bab el Oued, Alger, Algeria. · Central laboratory of Biology, CHU Bab El Oued, Bab el Oued, Alger, Algeria. · Department of Dermatology and the Laboratory of Immunology, Hedi Chaker Hospital, Sfax University, Sfax, Tunisia. · Department of Dermatology, AP-HP, Saint-Louis Hospital, Paris, France. · Department of Dermatology, AP-HP, Saint-Louis Hospital, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France. · INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France; Department of Dermatology, AP-HP, Saint-Louis Hospital, Paris, France; University Paris-Diderot, Sorbonne Paris Cité, Paris, France. · INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France. Electronic address: asma.smahi@inserm.fr. ·J Invest Dermatol · Pubmed #27220475.

ABSTRACT: Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions including generalized pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustular eruption. We identified two unreported IL36RN homozygous mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) in patients with familial generalized pustular psoriasis. We analyzed the impact of a spectrum of IL36RN mutations on IL-36 receptor antagonist protein by using site-directed mutagenesis and expression in HEK293T cells. This enabled us to differentiate null mutations with complete absence of IL-36 receptor antagonist (the two previously unreported mutations, c.80T>C/p.Leu27Pro, c.28C>T/p.Arg10X, c.280G>T/p.Glu94X, c.368C>G/p.Thr123Arg, c.368C>T/p.Thr123Met, and c.227C>T/p.Pro76Leu) from mutations with decreased (c.95A>G/p.His32Arg, c.142C>T/p.Arg48Trp, and c.308C>T/p.Ser113Leu) or unchanged (c.304C>T/p.Arg102Trp and c.104A>G/p.Lys35Arg) protein expression. Functional assays measuring the impact of mutations on the capacity to repress IL-36-dependent activation of the NF-κB pathway showed complete functional impairment for null mutations, whereas partial or no impairment was observed for other mutations considered as hypomorphic. Finally, null mutations were associated with severe clinical phenotypes (generalized pustular psoriasis, acute generalized exanthematous pustular eruption), whereas hypomorphic mutations were identified in both localized (palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) and generalized variants. These results provide a preliminary basis for genotype-phenotype correlation in patients with deficiency of the IL-36Ra (DITRA), and suggest the involvement of other factors in the modulation of clinical expression.

8 Review A Systematic Review of Factors Associated with Non-Adherence to Treatment for Immune-Mediated Inflammatory Diseases. 2015

Vangeli, Eleni / Bakhshi, Savita / Baker, Anna / Fisher, Abigail / Bucknor, Delaney / Mrowietz, Ulrich / Östör, Andrew J K / Peyrin-Biroulet, Laurent / Lacerda, Ana P / Weinman, John. ·Department of Psychology, London South Bank University, London, UK. · Psychological Medicine, King's College London, London, UK. · Atlantis Healthcare, London, UK. · University College London, London, UK. · London Metropolitan University, London, UK. · Psoriasis-Center at the Department of Dermatology, University Medical Center of Schleswig-Holstein, Campus Kiel, Germany. · School of Clinical Medicine, University of Cambridge, Cambridge, UK. · Inserm U954 and Department of Gastroenterology, Université de Lorraine, Vandoeuvre-les-Nancy, France. · AbbVie Inc, North Chicago, IL, USA. · Institute of Pharmaceutical Science, King's College London, 5th Floor, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK. John.weinman@kcl.ac.uk. ·Adv Ther · Pubmed #26547912.

ABSTRACT: BACKGROUND: Non-adherence impacts negatively on patient health outcomes and has associated economic costs. Understanding drivers of treatment adherence in immune-mediated inflammatory diseases is key for the development of effective strategies to tackle non-adherence. OBJECTIVE: To identify factors associated with treatment non-adherence across diseases in three clinical areas: rheumatology, gastroenterology, and dermatology. DESIGN: Systematic review. DATA SOURCES: Articles published in PubMed, Science Direct, PsychINFO and the Cochrane Library from January 1, 1980 to February 14, 2014. STUDY SELECTION: Studies were eligible if they included patients with a diagnosis of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, or psoriasis and included statistics to examine associations of factors with non-adherence. DATA EXTRACTION: Data were extracted by the first reviewer using a standardized 23-item form and verified by a second/third reviewer. Quality assessment was carried out for each study using a 16-item quality checklist. RESULTS: 73 studies were identified for inclusion in the review. Demographic or clinical factors were not consistently associated with non-adherence. Limited evidence was found for an association between non-adherence and treatment factors such as dosing frequency. Consistent associations with adherence were found for psychosocial factors, with the strongest evidence for the impact of the healthcare professional-patient relationship, perceptions of treatment concerns and depression, lower treatment self-efficacy and necessity beliefs, and practical barriers to treatment. CONCLUSIONS: While examined in only a minority of studies, the strongest evidence found for non-adherence were psychosocial factors. Interventions designed to address these factors may be most effective in tackling treatment non-adherence.

9 Review Methods for observed-cluster inference when cluster size is informative: a review and clarifications. 2014

Seaman, Shaun R / Pavlou, Menelaos / Copas, Andrew J. ·MRC Biostatistics Unit, Cambridge CB2 0SR, UK. ·Biometrics · Pubmed #24479899.

ABSTRACT: Clustered data commonly arise in epidemiology. We assume each cluster member has an outcome Y and covariates X. When there are missing data in Y, the distribution of Y given X in all cluster members ("complete clusters") may be different from the distribution just in members with observed Y ("observed clusters"). Often the former is of interest, but when data are missing because in a fundamental sense Y does not exist (e.g., quality of life for a person who has died), the latter may be more meaningful (quality of life conditional on being alive). Weighted and doubly weighted generalized estimating equations and shared random-effects models have been proposed for observed-cluster inference when cluster size is informative, that is, the distribution of Y given X in observed clusters depends on observed cluster size. We show these methods can be seen as actually giving inference for complete clusters and may not also give observed-cluster inference. This is true even if observed clusters are complete in themselves rather than being the observed part of larger complete clusters: here methods may describe imaginary complete clusters rather than the observed clusters. We show under which conditions shared random-effects models proposed for observed-cluster inference do actually describe members with observed Y. A psoriatic arthritis dataset is used to illustrate the danger of misinterpreting estimates from shared random-effects models.

10 Clinical Trial Rheumatoid arthritis and psoriatic arthritis synovial fluids stimulate prolactin production by macrophages. 2017

Tang, Man Wai / Garcia, Samuel / Malvar Fernandez, Beatriz / Gerlag, Danielle M / Tak, Paul-Peter / Reedquist, Kris A. ·Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; m.w.tang@amc.uva.nl. · Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · GlaxoSmithKline, Cambridge, United Kingdom. · GlaxoSmithKline, Stevenage, United Kingdom. · Department of Rheumatology, Ghent University, Ghent, Belgium; and. · Department of Rheumatology, University of Cambridge, Cambridge, United Kingdom. ·J Leukoc Biol · Pubmed #28642278.

ABSTRACT: Prolactin (PRL) is a neuroendocrine hormone that can promote inflammation. We examined the synovial tissue and fluid levels of PRL in patients with inflammatory arthritis, PRL expression in differentiated Mϕs from patients with arthritis and from healthy donors, and the effects of different stimuli on PRL production by Mϕs. PRL levels were measured in paired synovial fluid (SF) and peripheral blood of patients with rheumatoid arthritis (RA,

11 Clinical Trial Reliability and validity of the Psoriasis Itch Visual Analog Scale in psoriasis vulgaris. 2017

Pedersen, Claus Bang / McHorney, Colleen A / Larsen, Lotte Seiding / Lophaven, Katja Wendicke / Moeller, Anders Holmen / Reaney, Matthew. ·a LEO Pharma , Ballerup , Denmark. · b ERT , Pittsburgh , PA , USA. · c ERT , Peterborough , UK. ·J Dermatolog Treat · Pubmed #27454156.

ABSTRACT: INTRODUCTION: The single-item Psoriasis Itch VAS was developed to measure itch intensity within the last 24 hours in psoriasis vulgaris to assess treatment benefit. Its psychometric properties were explored in two trials. METHODS: Data from two randomized, parallel-group phase 3 trials with subjects suffering from psoriasis vulgaris on the body (n = 426, 463) were analyzed. Cross-sectional distributional properties and construct validity of the Psoriasis Itch VAS as well as longitudinal test-retest reliability and sensitivity to change of the Psoriasis Itch VAS were investigated. All statistical tests were two-tailed. RESULTS: Across both trials, acceptable distributional properties were observed. Convergent-validity correlations between the Psoriasis Itch VAS and other patient-reported and clinician-reported outcomes provided strong endorsement for construct validity as did tests of known-groups validity. Longitudinal measurement properties, involving test-retest reliability and sensitivity to change, also offered evidence for the measurement integrity of the Psoriasis Itch VAS. DISCUSSION: Results from the assessment of validity, reliability, and sensitivity to change support the use of the Psoriasis Itch VAS to measure itch intensity in psoriasis vulgaris. Data from two trials provided evidence that the Psoriasis Itch VAS is well-defined and reliable for measuring itch in psoriasis vulgaris to assess treatment benefit (i.e. therapeutic response).

12 Clinical Trial A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis. 2015

Krueger, James G / Suárez-Fariñas, Mayte / Cueto, Inna / Khacherian, Artemis / Matheson, Robert / Parish, Lawrence C / Leonardi, Craig / Shortino, Denise / Gupta, Akanksha / Haddad, Jonathan / Vlasuk, George P / Jacobson, Eric W. ·Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, United States of America. · Center for Clinical and Translational Science, The Rockefeller University, New York, New York, United States of America. · Oregon Medical Research Center, PC, Portland, Oregon, United States of America. · Paddington Testing Co, Inc., Philadelphia, Pennsylvania, United States of America. · Central Dermatology, St. Louis, Missouri, United States of America. · Clinical Statistics, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America. · Sirtris, a GlaxoSmithKline Company, Cambridge, Massachusetts, United States of America. ·PLoS One · Pubmed #26556603.

ABSTRACT: TRIAL REGISTRATION: Clinicaltrials.gov NCT01154101.

13 Article Response to inhibition of receptor-interacting protein kinase 1 (RIPK1) in active plaque psoriasis: a randomized placebo-controlled study. 2020

Weisel, Kathleen / Berger, Scott / Papp, Kim / Maari, Catherine / Krueger, James G / Scott, Nicola / Tompson, Debra / Wang, Susanne / Simeoni, Monica / Bertin, John / Tak, Paul Peter. ·GlaxoSmithKline, Collegeville, PA, United States. · Probity Medical Research, Waterloo, Ontario, Canada. · InnovaDerm Research, Montreal, Quebec, Canada. · The Rockefeller University, New York, NY, United States. · GlaxoSmithKline, Stevenage, United Kingdom. · GlaxoSmithKline, Stockley Park, United Kingdom. · Amsterdam University Medical Center, Amsterdam, the Netherlands. · Ghent University, Ghent, Belgium; and Kintai Therapeutics, Cambridge, MA, United States. · Cambridge University, Cambridge, United Kingdom. ·Clin Pharmacol Ther · Pubmed #32301501.

ABSTRACT: Receptor-interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune-mediated inflammatory diseases (IMIDs). The objective of this phase 2a multicenter, randomized, double-blind, placebo-controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque-type psoriasis. Psoriasis patients (N=65) were randomized to 60 mg twice daily (BID) or three times daily (TID), or placebo for 84 days. .Most adverse events (AEs) were mild with no severe drug-related AEs reported. Plaque Lesion Severity Sum improved with BID treatment compared with placebo; interpretation of TID treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.

14 Article Transglutaminase 3 Reduces the Severity of Psoriasis in Imiquimod-Treated Mouse Skin. 2020

Piro, Maria Cristina / Ventura, Alessandra / Smirnov, Artem / Saggini, Andrea / Lena, Anna Maria / Mauriello, Alessandro / Bianchi, Luca / Melino, Gerry / Candi, Eleonora. ·Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", 00133 Rome, Italy. · Dermatology Unit, Department of Biotechnological and Applied Clinical Science, University of L'Aquila, IT-67100 L'Aquila, Italy. · Dermatology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy. · Medical Research Council, University of Cambridge, Cambridge CB21QP, UK. · IDI-IRCCS, Biochemistry laboratory, 00167 Rome, Italy. ·Int J Mol Sci · Pubmed #32106600.

ABSTRACT: Four transglutaminase (TG) isoforms have been detected in epidermal keratinocytes: TG1, TG2, TG3, and TG5. Except for TG1 and TG3, their contribution to keratinocyte development and structure remains undefined. In this paper, we focused on the roles of TG2 and TG3 in imiquimod-induced psoriasis in mouse skin. We evaluated the severity of psoriasis markers in the skin of imiquimod-treated TG3 null and TG2 null mice. Our results showed that compromised TG3KO mouse skin was more responsive than WT or TG2KO mouse skin to the action of the pro-inflammatory drug imiquimod.

15 Article Pharmacokinetics, pharmacodynamics and safety of the inverse retinoic acid-related orphan receptor γ agonist AZD0284. 2020

Asimus, Sara / Palmér, Robert / Albayaty, Muna / Forsman, Henrik / Lundin, Christina / Olsson, Marita / Pehrson, Rikard / Mo, John / Russell, Muir / Carlert, Sara / Close, David / Keeling, David. ·Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gaithersburg, MD, USA. · Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg, Sweden. · Early Phase Clinical Unit, Parexel, London, UK. · Clinical Development, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. · Early Biostats and Statistical Innovation, Data Science and AI, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. · Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. · Patient Safety, Respiratory, Inflammation and Autoimmunity, Chief Medical Office, R&D, AstraZeneca, Gothenburg, Sweden. · Study Delivery, Early Oncology Clinical, Oncology R&D, AstraZeneca, Cambridge, UK. · Early Product Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden. · Clinical Development, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. ·Br J Clin Pharmacol · Pubmed #32067249.

ABSTRACT: AIMS: Retinoic acid-related orphan receptor γ (RORγ), a master regulator of T-helper 17 (Th17) cell function and differentiation, is an attractive target for treatment of Th17-driven diseases. This first-in-human study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of the inverse RORγ agonist AZD0284. METHODS: We conducted a phase I, randomized, single-blind, placebo-controlled, two-part, first-in-human study with healthy subjects receiving single (4-238 mg) or multiple (12-100 mg) oral doses of AZD0284 or placebo after overnight fasting. Subjects in the one single dose cohort additionally received a single dose of AZD0284 after a high-calorie meal. AZD0284 plasma concentrations, as well as inhibition of ex vivo-stimulated interleukin (IL)-17A release in whole blood, were frequently measured after both single and multiple dosing. RESULTS: Eighty-three men participated in the study. AZD0284 was absorbed rapidly into plasma after oral dosing and exhibited a terminal half-life of 13-16 hours. Both the area under the concentration-time curve (AUC) and maximum concentration (C CONCLUSIONS: AZD0284 was well tolerated, rapidly and dose-dependently absorbed, and reduced stimulated IL-17A release after single and multiple dosing. The results of this study support further clinical development of AZD0284.

16 Article Isolation of five Enterobacteriaceae species harbouring blaNDM-1 and mcr-1 plasmids from a single paediatric patient. 2019

Martino, F / Tijet, N / Melano, R / Petroni, A / Heinz, E / De Belder, D / Faccone, D / Rapoport, M / Biondi, E / Rodrigo, V / Vazquez, M / Pasteran, F / Thomson, N R / Corso, A / Gomez, S A. ·Servicio Antimicrobianos (National Reference Laboratory on Antimicrobial Resistance), Instituto Nacional de Enfermedades Infecciosas-ANLIS "Dr. Carlos G. Malbrán", Ciudad Autónoma de Buenos Aires, Argentina. · Public Health Ontario Laboratories, Toronto, Ontario, Canada. · The Welcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. · Liverpool School of Tropical Medicine, Liverpool, United Kingdom. · Hospital de Niños "Dr. Ricardo Gutiérrez", Ciudad Autónoma de Buenos Aires, Argentina. · London School of Hygiene and Tropical Medicine, London, United Kingdom. ·PLoS One · Pubmed #31498841.

ABSTRACT: In Argentina, NDM metallo-β-lactamase was first reported in 2013. By now, it has disseminated throughout the country in diverse Gram negative bacteria. Here, we report the case of a paediatric patient that underwent a 1-year hospitalisation due to erythrodermic psoriasis in 2014 and received multiple antimicrobial treatments. During his stay, five isolates were obtained from rectal swabs (rs) or blood culture (bc) suspicious of carbapenemase production: a K. quasipneumoniae subsp. quasipneumoniae (rs), Citrobacter freundii (rs), Escherichia coli (bc), Enterobacter cloacae (rs), and a Serratia marcescens (bc). The isolates were studied with broth microdilution, biparental conjugation and plasmid and whole genome sequencing (Illumina). All isolates harboured an 138,998-bp type 1 IncC plasmid that carried blaNDM-1, bleMBL, blaCMY-6, rmtC, aac(6')-Ib, and sul1 resistance genes. Additionally, the blaNDM-plasmids contained ISKpn8 an insertion sequence previously described as associated only to blaKPC. One isolate, a colistin-resistant E. coli, also carried a mcr-1-containing an IncI2 plasmid, which did not harbour additional resistance. The whole genome of K. quasipneumoniae subsp. quasipneumoniae isolate was fully sequenced. This isolate harboured, additionally to blaNDM, three plasmid-mediated quinolone resistance genes: qnrB4, qnrB52 and aac(6')-Ib-cr1. The E. cloacae isolate also harboured qnrA1. These findings alert to the underestimated horizontal dissemination of multidrug-resistant plasmids limiting treatment options with last resort antimicrobials.

17 Article Proceedings of the 2018 GRAPPA Collaborative Research Network Meeting. 2019

Jadon, Deepak R / Chandran, Vinod / Ogdie, Alexis / Pennington, Stephen R / Stober, Carmel / Gladman, Dafna D / de Wit, Maarten / O'Sullivan, Denis / Mease, Philip / Armstrong, April W / Callis Duffin, Kristina / Magee, Conor / Helliwell, Philip / Ritchlin, Christopher T / FitzGerald, Oliver. ·From the Rheumatology Research Unit, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds; Bradford Hospitals NHS Foundation Trust, Bradford, UK; Department of Medicine, Division of Rheumatology, University of Toronto; Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Swedish Medical Center/Providence-St. Joseph Health, Seattle, Washington; University of Southern California, Los Angeles, California; University of Utah, Salt Lake City, Utah; Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA; Conway Institute for Biomolecular Research, University College Dublin; Our Lady's Hospice and Care Services; Department of Rheumatology, St. Vincent's University Hospital, Dublin, Ireland; Department of Medical Humanities, Amsterdam University Medical Center, Amsterdam, the Netherlands. dj351@medschl.cam.ac.uk. · D.R. Jadon, MBBCh, MRCP, PhD, Director of Rheumatology Research Unit, Cambridge University Hospitals NHS Foundation Trust; V. Chandran, MBBS, MD, DM, PhD, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Krembil Research Institute; A. Ogdie, MD, Assistant Professor of Medicine and Epidemiology, Perelman School of Medicine, University of Pennsylvania; S.R. Pennington, Professor of Proteomics, PhD, Conway Institute for Biomolecular Research, University College Dublin; C. Stober, PhD, MBChB, MRCP, Consultant Rheumatologist, Cambridge University Hospitals NHS Foundation Trust; D.D. Gladman, MD, FRCPC, Professor of Medicine, University of Toronto, and Senior Scientist, Krembil Research Institute, Toronto Western Hospital; M. de Wit, PhD, Patient Research Partner, Department of Medical Humanities, Amsterdam University Medical Center; D. O'Sullivan, BE, Patient Research Partner, Our Lady's Hospice and Care Services; P.J. Mease, MD, Rheumatology Research, Swedish Medical Center/Providence-St. Joseph Health; A.W. Armstrong, MD, MPH, University of Southern California; K. Callis Duffin, MD, University of Utah; C. Magee, MB, BAO, BCh, St. Vincent's University Hospital; P.S. Helliwell, DM, PhD, FRCP, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and Bradford Hospitals NHS Foundation Trust; C.T. Ritchlin, MD, MPH, Professor of Medicine, Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center; O. FitzGerald, MD, FRCPI, FRCP(UK), Newman Clinical Research Professor, Department of Rheumatology, St. Vincent's University Hospital and Conway Institute for Biomolecular Research, University College Dublin. Professor O. FitzGerald and Professor C.T. Ritchlin are joint senior authors. dj351@medschl.cam.ac.uk. · From the Rheumatology Research Unit, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds; Bradford Hospitals NHS Foundation Trust, Bradford, UK; Department of Medicine, Division of Rheumatology, University of Toronto; Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Swedish Medical Center/Providence-St. Joseph Health, Seattle, Washington; University of Southern California, Los Angeles, California; University of Utah, Salt Lake City, Utah; Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA; Conway Institute for Biomolecular Research, University College Dublin; Our Lady's Hospice and Care Services; Department of Rheumatology, St. Vincent's University Hospital, Dublin, Ireland; Department of Medical Humanities, Amsterdam University Medical Center, Amsterdam, the Netherlands. · D.R. Jadon, MBBCh, MRCP, PhD, Director of Rheumatology Research Unit, Cambridge University Hospitals NHS Foundation Trust; V. Chandran, MBBS, MD, DM, PhD, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Krembil Research Institute; A. Ogdie, MD, Assistant Professor of Medicine and Epidemiology, Perelman School of Medicine, University of Pennsylvania; S.R. Pennington, Professor of Proteomics, PhD, Conway Institute for Biomolecular Research, University College Dublin; C. Stober, PhD, MBChB, MRCP, Consultant Rheumatologist, Cambridge University Hospitals NHS Foundation Trust; D.D. Gladman, MD, FRCPC, Professor of Medicine, University of Toronto, and Senior Scientist, Krembil Research Institute, Toronto Western Hospital; M. de Wit, PhD, Patient Research Partner, Department of Medical Humanities, Amsterdam University Medical Center; D. O'Sullivan, BE, Patient Research Partner, Our Lady's Hospice and Care Services; P.J. Mease, MD, Rheumatology Research, Swedish Medical Center/Providence-St. Joseph Health; A.W. Armstrong, MD, MPH, University of Southern California; K. Callis Duffin, MD, University of Utah; C. Magee, MB, BAO, BCh, St. Vincent's University Hospital; P.S. Helliwell, DM, PhD, FRCP, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, and Bradford Hospitals NHS Foundation Trust; C.T. Ritchlin, MD, MPH, Professor of Medicine, Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center; O. FitzGerald, MD, FRCPI, FRCP(UK), Newman Clinical Research Professor, Department of Rheumatology, St. Vincent's University Hospital and Conway Institute for Biomolecular Research, University College Dublin. Professor O. FitzGerald and Professor C.T. Ritchlin are joint senior authors. ·J Rheumatol Suppl · Pubmed #31154399.

ABSTRACT: The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Collaborative Research Network (CRN) intends to launch and secure funding for 3 pilot projects related to psoriatic disease, psoriatic arthritis (PsA), and cutaneous psoriasis (PsC). The first pilot project, a PsA Biomarkers for Joint Damage (BioDAM) pilot, will seek to determine the independent predictive ability of serum biomarkers for joint damage in PsA. The second pilot project will aim to identify predictors of the development of PsA among patients with PsC. The third pilot project will aim to identify biomarkers that predict treatment response in PsA and PsC. These pilot projects will prompt the development of clinical protocols to operate across participating centers, lead to the development of standard operating procedures for the collection and transport of biosamples across international borders, and begin to establish administrative and managerial structures for the CRN. The CRN hopes that the successful completion and research outputs of these 3 pilot projects will demonstrate the CRN's value to prospective collaborators and sponsors and thereby secure sustainable longterm funding.

18 Article Trajectory of radiographic change over a decade: the effect of transition from conventional synthetic disease-modifying antirheumatic drugs to anti-tumour necrosis factor in patients with psoriatic arthritis. 2019

Allard, Andrew / Antony, Anna / Shaddick, Gavin / Jadon, Deepak R / Cavill, Charlotte / Robinson, Graham / Korendowych, Eleanor / McHugh, Neil / Tillett, William. ·Rheumatology, Royal National Hospital for Rheumatic Diseases, Bath, UK. · Mathematical Sciences, University of Exeter, Exeter, UK. · Rheumatology, Cambridge University Hospitals NHSFT, Cambridge, UK. · Radiology, Royal United Hospitals Bath, Bath, UK. · Pharmacy and Pharmacology, University of Bath, Bath, UK. ·Rheumatology (Oxford) · Pubmed #30247726.

ABSTRACT: Objectives: To describe the trajectory of radiographic progression among patients with PsA who transitioned from conventional synthetic DMARDs to anti-TNF-α inhibitors in routine care. Methods: A retrospective sample of patients with PsA (ClASsification criteria for Psoriatic ARthritis) was taken from the Bath longitudinal cohort. All patients had radiographs of the hands and feet taken: 5 years before (T0), at the time of (T1) and 5 years after (T2) commencing anti-TNF treatment. Radiographs were scored blinded using the PsA-modified Sharp-van der Heijde score (mSvdHS) and for osteoproliferation (Psoriatic Arthritis Ratingen Score) by A.Allard, A.Antony and W.T. This sample size was calculated to ensure 90% power to determine the smallest detectable difference of the mSvdHS to a 5% significance level. Cumulative probability plots were used to determine the probability of radiographic progression pre- (T0-T1) and post- (T1-T2) anti-TNF treatment. Results: Eighty-four radiographs from 28 patients were selected for inclusion. The median [interquartile range (IQR)] disease duration at baseline (T0) was 8.5 (0-19.5) years. The interval between T0-T1 and T1-T2 was 4.2 years (3.34-6.65) and 4.9 years (4.25-5.87), respectively. The median mSvdHS at baseline (T0) was 8.5 (IQR 1.75-27.5). The median (IQR) rate of change in mSvdHS per year reduced after commencing anti-TNF, from 2.1 (0.88-3.92) between T0-T1 to 1.0 (IQR 0.05-2.35) between T1-T2 (P = 0.012). Conclusion: The trajectory of damage accumulation over a 10-year period in this observational clinical cohort is low overall. The rate of radiographic damage as measured by the mSvdHS slows following commencement of anti-TNF.

19 Article A Framework for Multi-Omic Prediction of Treatment Response to Biologic Therapy for Psoriasis. 2019

Foulkes, Amy C / Watson, David S / Carr, Daniel F / Kenny, John G / Slidel, Timothy / Parslew, Richard / Pirmohamed, Munir / Anonymous7751112 / Anders, Simon / Reynolds, Nick J / Griffiths, Christopher E M / Warren, Richard B / Barnes, Michael R. ·The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: Amy.foulkes@manchester.ac.uk. · Centre for Translational Bioinformatics, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UK. · Wolfson Centre for Personalised Medicine, The University of Liverpool, Liverpool, UK. · Centre for Genomic Research, The University of Liverpool, Liverpool, UK. · MedImmune Ltd, Sir Aaron Klug Building, Granta Park Cambridge, UK. · Dermatology Department, Kent Lodge, Broadgreen Hospital, Liverpool, UK. · Centre for Molecular Biology of the University of Heidelberg (ZMBH), Heidelberg, Germany. · Institute of Cellular Medicine, Newcastle University and Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK. · The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. ·J Invest Dermatol · Pubmed #30030151.

ABSTRACT: Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (i.e., PSORT) study, we evaluated a comprehensive array of omics platforms across three time points and multiple tissues in a pilot investigation of 10 patients with severe psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA sequencing to analyze mRNA and small RNA transcriptome in blood, lesional and nonlesional skin, and the SOMAscan platform to investigate the serum proteome. Using an integrative systems biology approach, we identified signals of treatment response in genes and pathways associated with TNF signaling, psoriasis pathology, and the major histocompatibility complex region. We found association between clinical response and TNF-regulated genes in blood and skin. Using a combination of differential expression testing, upstream regulator analysis, clustering techniques, and predictive modeling, we show that baseline samples are indicative of patient response to biologic therapies, including signals in blood, which have traditionally been considered unreliable for inference in dermatology. In conclusion, our pilot study provides both an analytical framework and empirical basis to estimate power for larger studies, specifically the ongoing PSORT study, which we show as powered for biomarker discovery and patient stratification.

20 Article Proceedings of the 2017 GRAPPA Collaborative Research Network Meeting. 2018

Jadon, Deepak R / Chandran, Vinod / Stober, Carmel / Ogdie, Alexis / Armstrong, April W / Callis Duffin, Kristina / Gladman, Dafna D / Helliwell, Philip S / O'Sullivan, Denis / de Wit, Maarten / FitzGerald, Oliver / Ritchlin, Christopher T. ·From the Rheumatology Research Unit, Cambridge University Hospitals UK National Health Service (NHS) Foundation Trust, Cambridge; University of Leeds, Leeds; Bradford Hospitals NHS Foundation Trust, Bradford, UK; Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Krembil Research Institute, Toronto, Ontario, Canada; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; University of Southern California, Los Angeles, California; University of Utah, Salt Lake City, Utah; Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA; Our Lady's Hospice and Care Services; Newman Clinical Research Professor, Department of Rheumatology, St. Vincent's University Hospital and Conway Institute for Biomolecular Research, University College Dublin, Dublin, Ireland; Department of Medical Humanities, VU University Medical Centre, Amsterdam, the Netherlands. deepak.jadon@addenbrookes.nhs.uk. · D.R. Jadon, MBBCh, MRCP, PhD, Director of Rheumatology Research Unit, Cambridge University Hospitals NHS Foundation Trust; V. Chandran, MBBS, MD, DM, PhD, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Krembil Research Institute; C. Stober, PhD, MBChB, MRCP, Consultant Rheumatologist, Cambridge University Hospitals NHS Foundation Trust; A. Ogdie, MD, Assistant Professor of Medicine and Epidemiology, Perelman School of Medicine, University of Pennsylvania; A.W. Armstrong, MD, MPH, University of Southern California; K. Callis Duffin, MD, University of Utah; D.D. Gladman, MD, FRCPC, Professor of Medicine, University of Toronto, and Senior Scientist, Krembil Research Institute, Toronto Western Hospital; P.S. Helliwell, DM, PhD, FRCP, University of Leeds, and Bradford Hospitals NHS Foundation Trust; D. O'Sullivan, BE, Patient Research Partner, Our Lady's Hospice and Care Services; M. de Wit, PhD, Patient Research Partner, Department of Medical Humanities, VU University Medical Centre; O. FitzGerald, MD, FRCPI, FRCP( UK), Newman Clinical Research Professor, Department of Rheumatology, St. Vincent's University Hospital and Conway Institute for Biomolecular Research, University College Dublin; C.T. Ritchlin, MD, MPH, Professor of Medicine, Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center. deepak.jadon@addenbrookes.nhs.uk. · From the Rheumatology Research Unit, Cambridge University Hospitals UK National Health Service (NHS) Foundation Trust, Cambridge; University of Leeds, Leeds; Bradford Hospitals NHS Foundation Trust, Bradford, UK; Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Krembil Research Institute, Toronto, Ontario, Canada; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; University of Southern California, Los Angeles, California; University of Utah, Salt Lake City, Utah; Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center, Rochester, New York, USA; Our Lady's Hospice and Care Services; Newman Clinical Research Professor, Department of Rheumatology, St. Vincent's University Hospital and Conway Institute for Biomolecular Research, University College Dublin, Dublin, Ireland; Department of Medical Humanities, VU University Medical Centre, Amsterdam, the Netherlands. · D.R. Jadon, MBBCh, MRCP, PhD, Director of Rheumatology Research Unit, Cambridge University Hospitals NHS Foundation Trust; V. Chandran, MBBS, MD, DM, PhD, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Krembil Research Institute; C. Stober, PhD, MBChB, MRCP, Consultant Rheumatologist, Cambridge University Hospitals NHS Foundation Trust; A. Ogdie, MD, Assistant Professor of Medicine and Epidemiology, Perelman School of Medicine, University of Pennsylvania; A.W. Armstrong, MD, MPH, University of Southern California; K. Callis Duffin, MD, University of Utah; D.D. Gladman, MD, FRCPC, Professor of Medicine, University of Toronto, and Senior Scientist, Krembil Research Institute, Toronto Western Hospital; P.S. Helliwell, DM, PhD, FRCP, University of Leeds, and Bradford Hospitals NHS Foundation Trust; D. O'Sullivan, BE, Patient Research Partner, Our Lady's Hospice and Care Services; M. de Wit, PhD, Patient Research Partner, Department of Medical Humanities, VU University Medical Centre; O. FitzGerald, MD, FRCPI, FRCP( UK), Newman Clinical Research Professor, Department of Rheumatology, St. Vincent's University Hospital and Conway Institute for Biomolecular Research, University College Dublin; C.T. Ritchlin, MD, MPH, Professor of Medicine, Division of Allergy, Immunology, and Rheumatology, University of Rochester Medical Center. ·J Rheumatol Suppl · Pubmed #29858357.

ABSTRACT: The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Collaborative Research Network (CRN) is an endeavor that aims to address gaps in the knowledge of the etiopathogenesis and management of psoriatic disease by best using the large community of experienced investigators who are already collecting rich clinical phenotype data and biologic samples using validated techniques. Exemplar rheumatology and dermatology projects will inform strategies to implement the CRN, while input and funding from government organizations, charities, and industry will shape the CRN. The key immediate priorities to establish the CRN are discussed herein and include (1) strategies for building infrastructure to collect and store biosamples and associated clinical data, (2) best practices for sample collection and storage, (3) approaches to engage the GRAPPA community of investigators and industry to collaborate most effectively on shared priorities, and (4) agreement on a funding strategy. The following 4 CRN candidate flagship research areas were identified: (1) predictors of treatment response in psoriatic arthritis (PsA) and cutaneous psoriasis (PsC) to permit personalized and stratified medicine approaches; (2) predictors of structural damage and disease severity, linking with the existing PsA BioDAM project; (3) predictors of PsC progressing to PsA to enable earlier intervention and possibly halt progression to PsA; and (4) comorbidity prevalence and effect on clinical outcomes in psoriatic disease. The collaboration and momentum provided by a GRAPPA-CRN will offer more than the sum of its individual contributing centers. A CRN will permit high-quality research that can more effectively address questions pertinent to patients, clinicians, scientists, industry, and governments.

21 Article The Benefits and Challenges of Setting Up a Longitudinal Psoriatic Arthritis Database. 2018

Gladman, Dafna D / Coates, Laura C / Jadon, Deepak R / Tillett, William / Mease, Philip J / Vis, Marijn. ·From the University of Toronto; Krembil Research Institute; Psoriatic Arthritis Program University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada; Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford; Department of Rheumatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge; Royal National Hospital for Rheumatic Diseases; University of Bath, Bath, UK; Swedish Medical Center and University of Washington School of Medicine, Seattle, Washington, USA; Department of Rheumatology, Erasmus Medical Center, Rotterdam, the Netherlands. dafna.gladman@utoronto.ca. · D.D. Gladman, MD, FRCPC, Professor of Medicine, University of Toronto, and Senior Scientist, Krembil Research Institute, and Director, Psoriatic Arthritis Program University Health Network, Toronto Western Hospital; L.C. Coates, MBChB, PhD, Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford; D.R. Jadon, MBBCh, MRCP, PhD, Consultant Rheumatologist, Department of Rheumatology, Cambridge University Hospitals NHS Foundation Trust; W. Tillett, MBChB, PhD, Consultant Rheumatologist, Royal National Hospital for Rheumatic Diseases, and Senior Lecturer, University of Bath; P.J. Mease, MD, Rheumatology Research, Swedish Medical Center and University of Washington School of Medicine; M. Vis, MD, Department of Rheumatology, Erasmus Medical Center, Rotterdam, the Netherlands. dafna.gladman@utoronto.ca. · From the University of Toronto; Krembil Research Institute; Psoriatic Arthritis Program University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada; Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford; Department of Rheumatology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge; Royal National Hospital for Rheumatic Diseases; University of Bath, Bath, UK; Swedish Medical Center and University of Washington School of Medicine, Seattle, Washington, USA; Department of Rheumatology, Erasmus Medical Center, Rotterdam, the Netherlands. · D.D. Gladman, MD, FRCPC, Professor of Medicine, University of Toronto, and Senior Scientist, Krembil Research Institute, and Director, Psoriatic Arthritis Program University Health Network, Toronto Western Hospital; L.C. Coates, MBChB, PhD, Department of Orthopedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford; D.R. Jadon, MBBCh, MRCP, PhD, Consultant Rheumatologist, Department of Rheumatology, Cambridge University Hospitals NHS Foundation Trust; W. Tillett, MBChB, PhD, Consultant Rheumatologist, Royal National Hospital for Rheumatic Diseases, and Senior Lecturer, University of Bath; P.J. Mease, MD, Rheumatology Research, Swedish Medical Center and University of Washington School of Medicine; M. Vis, MD, Department of Rheumatology, Erasmus Medical Center, Rotterdam, the Netherlands. ·J Rheumatol Suppl · Pubmed #29858349.

ABSTRACT: The members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) have shown great interest in developing a common GRAPPA database. To address this interest, GRAPPA included a symposium at its 2017 annual meeting to examine the concepts of registries and databases. At this symposium, examples of existing databases were reviewed, and their challenges and achievements were discussed.

22 Article Patterns of peripheral joint involvement in psoriatic arthritis-Symmetric, ray and/or row? 2018

Chandran, Vinod / Stecher, Lynne / Farewell, Vern / Gladman, Dafna D. ·Departments of Medicine & Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Centre for Prognosis Studies in The Rheumatic Diseases, Krembil Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Institute of Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, 81675 Munich, Germany. · MRC Biostatistics Unit, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom. · Centre for Prognosis Studies in The Rheumatic Diseases, Krembil Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address: dafna.gladman@utoronto.ca. ·Semin Arthritis Rheum · Pubmed #29724452.

ABSTRACT: OBJECTIVE: We sought to examine whether joint involvement in psoriatic arthritis (PsA) follows a symmetric, ray, and/or row pattern using longitudinal data. METHODS: Data on activity and clinical damage of the joints of the hands and feet were obtained from a PsA cohort. For each analysis (symmetry, ray or row) for each outcome (joint damage and activity) expected values for table cells under the null hypothesis that joints progress independently to damage or activity were calculated based on a logistic regression model with patient level random effects for the probability of involvement developing between clinic visits. To determine the consistency of observed with expected values, goodness-of-fit tests were performed. RESULTS: Data from 704 patients were available. The 511 (552) patients with no hand (foot) damage at clinic entry were used for analyses of hand (foot) damage. When considering joint damage, there was strong evidence against independence of joint involvement based on evident symmetric patterns. There was little suggestion of ray patterns of joint damage. There was considerable evidence for row pattern of involvement of joints. When considering joint activity, symmetric patterns were also evident but, unlike joint damage, there was evidence of ray patterns, most notably in the hands. There was also evidence for row pattern involvement. CONCLUSION: Patterns of peripheral joint involvement seen over time in PsA patients, demonstrate consistency with expected ray patterns of disease activity, especially in the hands, but there is also considerable evidence for symmetric and row patterns for both joint damage and activity.

23 Article Prevalence and predictors of tumour necrosis factor inhibitor persistence in psoriatic arthritis. 2018

Stober, Carmel / Ye, Weiyu / Guruparan, Thushyanthan / Htut, Eiphyu / Clunie, Gavin / Jadon, Deepak. ·Department of Rheumatology, Addenbrooke's Hospital. · Department of Medicine, Cambridge University Hospitals NHS FT. · School of Clinical Medicine, University of Cambridge, Cambridge, UK. ·Rheumatology (Oxford) · Pubmed #29077973.

ABSTRACT: Objectives: To evaluate TNF-α inhibitor (TNFi) persistence when used as first- or second-line biologic therapy for the management of PsA, and to determine baseline clinical and laboratory parameters associated with TNFi persistence. Methods: A retrospective single-centre cohort study was performed on all patients with PsA initiated on TNFi therapy between 2003 and 2015. Demographic, clinical and laboratory characteristics were compared with TNFi persistence, using Kaplan-Meier survival and Cox proportional hazards models. Results: One hundred and eighty-eight patients with PsA were prescribed TNFi therapy as first-line biologic therapy over a period of 635 person-years [46% male, mean (s.d.) age 47.3 (11.4) years; median (interquartile range) disease duration 11 (7-16) years]. At 12 months of follow-up 79% of patients persisted with TNFi therapy, and 73% at 24 months. Of those discontinuing TNFi, 35% stopped due to primary inefficacy, 22% secondary inefficacy and 43% adverse events. Multivariable analysis identified female sex (hazard ratio (HR) 2.57; 95% CI: 1.26, 5.24; P = 0.01) and the presence of metabolic syndrome-related co-morbidities (HR = 2.65, 95% CI: 1.24, 5.69; P = 0.01) as predictors of lower persistence. Of 32 cases treated with a second TNFi, persistence at 12 months was 56%. TNFi persistence was 2-fold less likely in these 32 cases compared with first-line TNFi users (HR = 2.02, 95% CI: 1.20, 3.42; P = 0.01). Conclusion: Patients with PsA who are female and have metabolic syndrome-related co-morbidities have lower TNFi persistence. Although persistence was lower in patients who had switched to a second TNFi, a substantial proportion of these cases responded, advocating switching to a second TNFi as a valid therapeutic strategy.

24 Article Two-part models with stochastic processes for modelling longitudinal semicontinuous data: Computationally efficient inference and modelling the overall marginal mean. 2018

Yiu, Sean / Tom, Brian Dm. ·MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK. ·Stat Methods Med Res · Pubmed #28535715.

ABSTRACT: Several researchers have described two-part models with patient-specific stochastic processes for analysing longitudinal semicontinuous data. In theory, such models can offer greater flexibility than the standard two-part model with patient-specific random effects. However, in practice, the high dimensional integrations involved in the marginal likelihood (i.e. integrated over the stochastic processes) significantly complicates model fitting. Thus, non-standard computationally intensive procedures based on simulating the marginal likelihood have so far only been proposed. In this paper, we describe an efficient method of implementation by demonstrating how the high dimensional integrations involved in the marginal likelihood can be computed efficiently. Specifically, by using a property of the multivariate normal distribution and the standard marginal cumulative distribution function identity, we transform the marginal likelihood so that the high dimensional integrations are contained in the cumulative distribution function of a multivariate normal distribution, which can then be efficiently evaluated. Hence, maximum likelihood estimation can be used to obtain parameter estimates and asymptotic standard errors (from the observed information matrix) of model parameters. We describe our proposed efficient implementation procedure for the standard two-part model parameterisation and when it is of interest to directly model the overall marginal mean. The methodology is applied on a psoriatic arthritis data set concerning functional disability.

25 Article Crystallinity of Double-Stranded RNA-Antimicrobial Peptide Complexes Modulates Toll-Like Receptor 3-Mediated Inflammation. 2017

Lee, Ernest Y / Takahashi, Toshiya / Curk, Tine / Dobnikar, Jure / Gallo, Richard L / Wong, Gerard C L. ·Department of Bioengineering, University of California, Los Angeles , Los Angeles, California 90095, United States. · Department of Dermatology, University of California, San Diego , La Jolla, California 92093, United States. · Beijing National Laboratory for Condensed Matter Physics and CAS Key Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences , Beijing 100190, China. · Department of Chemistry, University of Cambridge , Cambridge CB2 1TN, United Kingdom. · School of Physical Sciences, University of Chinese Academy of Sciences , Beijing 100049, China. ·ACS Nano · Pubmed #29016111.

ABSTRACT: Double-stranded RNA (dsRNA) induces production of pro-inflammatory cytokines in normal human epidermal keratinocytes (NHEK) by specific binding to endosomal Toll-like receptor-3 (TLR3). Recently, it has been shown that hyperactivation of TLR3 in psoriatic keratinocytes by dsRNA can occur in the presence of human antimicrobial peptide (AMP) LL37. Here, we combine synchrotron X-ray scattering, microscopy, computer simulations, and measurements of NHEK cytokine production to elucidate a previously unanticipated form of specific molecular pattern recognition. LL37 and similar α-helical AMPs can form pro-inflammatory nanocrystalline complexes with dsRNA that are recognized by TLR3 differently than dsRNA alone. dsRNA complexes that activate IL-6 production in NHEK and those that do not are both able to enter cells and co-localize with TLR3. However, the crystallinity of these AMP-dsRNA complexes, specifically the geometric spacing between parallel dsRNA and the repeat number of ordered dsRNA, strongly influences the level of TLR3 activation. Crystalline complexes that present dsRNA at a spacing that matches with the steric size of TLR3 can recruit and engage multiple TLR3 receptors, driving receptor clustering and immune amplification, whereas crystalline complexes that exhibit poor steric matching do not. Reverse-transcription quantitative PCR of IL-6 during siRNA knockdown of TLR3 confirms that cytokine production is due to TLR3: High levels of IL-6 transcription are observed for sterically matched complexes without TLR3 knockdown, whereas such activity is abrogated with TLR3 knockdown.

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