Publications by authors named "Ian C Scott"

78 Publications

Factors associated with disability in patients with rheumatoid arthritis with persistent moderate disease activity: a retrospective cohort study.

BMC Rheumatol 2020 21;4:63. Epub 2020 Oct 21.

Department of Rheumatology, Guy's and St. Thomas' NHS Foundation Trust, Great Maze Pond, London, SE1 9RT UK.

Background: Many patients with rheumatoid arthritis (RA) do not attain remission/low disease activity, remaining in a moderate disease activity state (MDAS) with ongoing disability and impaired quality of life (QoL). If patients in persistent MDAS with poor future outcomes could be prospectively identified, they could arguably be treated more intensively. We evaluated baseline factors predicting function (Health Assessment Questionnaire-Disability Index [HAQ-DI] scores) and QoL (3-level EuroQol-5 dimensions questionnaire [EQ-5D-3L] index scores) at 12 months in patients with RA in persistent MDAS in a real-world setting.

Methods: Patients with persistent MDAS (Disease Activity Score for 28-joint count based on erythrocyte sedimentation rate [DAS28-ESR] 3.2-5.1 on at least two consecutive outpatient appointments over 12 months) were identified retrospectively from Guy's Hospital RA Centre and analysed in two groups: (1) biologic naïve at baseline or (2) receiving/ever received biologics. The baseline timepoint was the second-visit MDAS DAS28-ESR score; the endpoint was the closest visit to 12 months. Linear regression analyses evaluated relationships between baseline variables and (1) 12-month HAQ-DI scores, (2) 12-month rank-transformed EQ-5D-3L index scores, (3) 12-month changes in HAQ-DI scores, and (4) 12-month changes in EQ-5D-3L index scores.

Results: The analysis included 207 biologic-naïve and 188 biologic-experienced patients. All patients had moderate disability (mean HAQ-DI 1.21 and 1.46) and impaired QoL (mean EQ-5D-3L index scores 0.52 and 0.50). Many reported moderate/severe pain (93 and 96%) and showed little change in HAQ-DI and EQ-5D-3L index scores over 12 months. In both biologic-naïve and biologic-experienced groups, multivariate analysis revealed a significant association between baseline HAQ-DI scores and endpoint HAQ-DI scores (β = 0.67,  < 0.001 and β = 0.76,  < 0.001, respectively), 12-month changes in HAQ-DI scores (both β = - 0.21,  < 0.001), and 12-month EQ-5D-3L index scores (β = - 0.57,  < 0.001 and β = - 0.29,  = 0.004, respectively). Baseline EQ-5D-3L index scores were significantly associated with 12-month changes in EQ-5D-3L index scores in both groups (β = - 0.73,  < 0.001 and β = - 0.40,  = 0.003, respectively).

Conclusions: Patients with RA in persistent MDAS experience substantial ongoing physical disability, poor QoL, and pain. HAQ-DI is an important predictor of future disability and reduced QoL, supporting current national recommendations to measure HAQ-DI in routine care.
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http://dx.doi.org/10.1186/s41927-020-00161-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576705PMC
October 2020

Genome-Wide Analysis Identifies an Essential Human TBX3 Pacemaker Enhancer.

Circ Res 2020 Dec 12;127(12):1522-1535. Epub 2020 Oct 12.

Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam (V.W.W.v.E., F.M.B., K.v.D., R.A.M., V.W., C.d.G.-d.V., I.B.H., A.O.V., B.J.B., V.M.C.).

Rationale: The development and function of the pacemaker cardiomyocytes of the sinoatrial node (SAN), the leading pacemaker of the heart, are tightly controlled by a conserved network of transcription factors, including TBX3 (T-box transcription factor 3), ISL1 (ISL LIM homeobox 1), and SHOX2 (short stature homeobox 2). Yet, the regulatory DNA elements (REs) controlling target gene expression in the SAN pacemaker cells have remained undefined.

Objective: Identification of the regulatory landscape of human SAN-like pacemaker cells and functional assessment of SAN-specific REs potentially involved in pacemaker cell gene regulation.

Methods And Results: We performed Assay for Transposase-Accessible Chromatin using sequencing on human pluripotent stem cell-derived SAN-like pacemaker cells and ventricle-like cells and identified thousands of putative REs specific for either human cell type. We validated pacemaker cell-specific elements in the and loci. CRISPR-mediated homozygous deletion of the mouse ortholog of a noncoding region with candidate pacemaker-specific REs in the locus resulted in selective loss of expression from the developing SAN and embryonic lethality. Putative pacemaker-specific REs were identified up to 1 Mbp upstream of in a region close to harboring variants associated with heart rate recovery after exercise. The orthologous region was deleted in mice, which resulted in selective loss of expression of from the SAN and (cardiac) ganglia and in neonatal lethality. Expression of was maintained in other tissues including the atrioventricular conduction system, lungs, and liver. Heterozygous adult mice showed increased SAN recovery times after pacing. The human REs harboring the associated variants robustly drove expression in the SAN of transgenic mouse embryos.

Conclusions: We provided a genome-wide collection of candidate human pacemaker-specific REs, including the loci of , , and , and identified a link between human genetic variants influencing heart rate recovery after exercise and a variant RE with highly conserved function, driving SAN expression of .
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317054DOI Listing
December 2020

Enhancer-gene rewiring in the pathogenesis of Quebec platelet disorder.

Blood 2020 Dec;136(23):2679-2690

Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder with a unique, platelet-dependent, gain-of-function defect in fibrinolysis, without systemic fibrinolysis. The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes. This overexpression leads to a >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA); subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis. The causative mutation is a 78-kb tandem duplication of PLAU. How this duplication causes megakaryocyte-specific PLAU overexpression is unknown. To investigate the mechanism that causes QPD, we used epigenomic profiling, comparative genomics, and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes from participants with QPD and unaffected controls. QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD). Our results support a unique disease mechanism whereby the reorganization of sub-TAD genome architecture results in a dramatic, cell-type-specific blood disorder phenotype.
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http://dx.doi.org/10.1182/blood.2020005394DOI Listing
December 2020

Interleukin-33 Signaling Controls the Development of Iron-Recycling Macrophages.

Immunity 2020 05 8;52(5):782-793.e5. Epub 2020 Apr 8.

Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK; Institut National de la Santé et de la Recherche Médicale, Paris Cardiovascular Research Center, Paris, France. Electronic address:

Splenic red pulp macrophages (RPMs) contribute to erythrocyte homeostasis and are required for iron recycling. Heme induces the expression of SPIC transcription factor in monocyte-derived macrophages and promotes their differentiation into RPM precursors, pre-RPMs. However, the requirements for differentiation into mature RPMs remain unknown. Here, we have demonstrated that interleukin (IL)-33 associated with erythrocytes and co-cooperated with heme to promote the generation of mature RPMs through activation of the MyD88 adaptor protein and ERK1/2 kinases downstream of the IL-33 receptor, IL1RL1. IL-33- and IL1RL1-deficient mice showed defective iron recycling and increased splenic iron deposition. Gene expression and chromatin accessibility studies revealed a role for GATA transcription factors downstream of IL-33 signaling during the development of pre-RPMs that retained full potential to differentiate into RPMs. Thus, IL-33 instructs the development of RPMs as a response to physiological erythrocyte damage with important implications to iron recycling and iron homeostasis.
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http://dx.doi.org/10.1016/j.immuni.2020.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237885PMC
May 2020

REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects.

Nat Commun 2020 02 19;11(1):965. Epub 2020 Feb 19.

Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G1M1, Canada.

The sarco-endoplasmic reticulum (SR/ER) plays an important role in the development and progression of many heart diseases. However, many aspects of its structural organization remain largely unknown, particularly in cells with a highly differentiated SR/ER network. Here, we report a cardiac enriched, SR/ER membrane protein, REEP5 that is centrally involved in regulating SR/ER organization and cellular stress responses in cardiac myocytes. In vitro REEP5 depletion in mouse cardiac myocytes results in SR/ER membrane destabilization and luminal vacuolization along with decreased myocyte contractility and disrupted Ca cycling. Further, in vivo CRISPR/Cas9-mediated REEP5 loss-of-function zebrafish mutants show sensitized cardiac dysfunction upon short-term verapamil treatment. Additionally, in vivo adeno-associated viral (AAV9)-induced REEP5 depletion in the mouse demonstrates cardiac dysfunction. These results demonstrate the critical role of REEP5 in SR/ER organization and function as well as normal heart function and development.
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http://dx.doi.org/10.1038/s41467-019-14143-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031342PMC
February 2020

Suspected very early inflammatory rheumatic diseases in primary care.

Best Pract Res Clin Rheumatol 2019 08 24;33(4):101419. Epub 2019 Jul 24.

Primary Care Centre Versus Arthritis, Research Institute for Primary Care and Health Sciences, Primary Care Sciences, Keele University, Keele, UK; Haywood Academic Rheumatology Centre, Haywood Hospital, Midlands Partnership NHS Foundation Trust, High Lane, Burslem, Staffordshire, UK. Electronic address:

As primary care clinicians are typically the first point of contact for patients with musculoskeletal problems, they are crucial to the early diagnosis and treatment of patients with an incident inflammatory arthritis, like rheumatoid arthritis. Current UK and international guidelines recognise this, recommending the prompt referral of patients with suspected persistent synovitis to secondary care. In England and Wales, this is advised to occur within 3 working days. However, recent audit data suggests this recommendation is infrequently met, with some patients waiting many months for referral. In this review article we will discuss the various challenges to achieving the early referral of patients with a new-onset inflammatory arthritis from primary to secondary care. We will also describe how these challenges could potentially be overcome, with the ultimate goal of ensuring that the right patients are referred to the right services, and at the right time.
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http://dx.doi.org/10.1016/j.berh.2019.06.001DOI Listing
August 2019

Genetic associations with radiological damage in rheumatoid arthritis: Meta-analysis of seven genome-wide association studies of 2,775 cases.

PLoS One 2019 9;14(10):e0223246. Epub 2019 Oct 9.

Primary Care Centre Versus Arthritis, Research Institute for Primary Care and Health Sciences, Primary Care Sciences, Keele University, Keele, United Kingdom.

Background: Previous studies of radiological damage in rheumatoid arthritis (RA) have used candidate-gene approaches, or evaluated single genome-wide association studies (GWAS). We undertook the first meta-analysis of GWAS of RA radiological damage to: (1) identify novel genetic loci for this trait; and (2) test previously validated variants.

Methods: Seven GWAS (2,775 RA cases, of a range of ancestries) were combined in a meta-analysis. Radiological damage was assessed using modified Larsen scores, Sharp van Der Heijde scores, and erosive status. Single nucleotide polymophsim (SNP) associations with radiological damage were tested at a single time-point using regression models. Primary analyses included age and disease duration as covariates. Secondary analyses also included rheumatoid factor (RF). Meta-analyses were undertaken in trans-ethnic and European-only cases.

Results: In the trans-ethnic primary meta-analysis, one SNP (rs112112734) in close proximity to HLA-DRB1, and strong linkage disequilibrium with the shared-epitope, attained genome-wide significance (P = 4.2x10-8). In the secondary analysis (adjusting for RF) the association was less significant (P = 1.7x10-6). In both trans-ethnic primary and secondary meta-analyses 14 regions contained SNPs with associations reaching P<5x10-6; in the European primary and secondary analyses 13 and 10 regions contained SNPs reaching P<5x10-6, respectively. Of the previously validated SNPs for radiological progression, only rs660895 (tagging HLA-DRB1*04:01) attained significance (P = 1.6x10-5) and had a consistent direction of effect across GWAS.

Conclusions: Our meta-analysis confirms the known association between the HLA-DRB1 shared epitope and RA radiological damage. The lack of replication of previously validated non-HLA markers highlights a requirement for further research to deliver clinically-useful prognostic genetic markers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223246PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785117PMC
March 2020

The association between gravidity, parity and the risk of developing rheumatoid arthritis: A systematic review and meta-analysis.

Semin Arthritis Rheum 2020 04 11;50(2):252-260. Epub 2019 Sep 11.

Primary Care Centre Versus Arthritis, Research Institute for Primary Care and Health Sciences, Primary Care Sciences, Keele University, Staffordshire ST5 5BG, Keele, UK; Haywood Academic Rheumatology Centre, Haywood Hospital, Midlands Partnership NHS Foundation Trust, High Lane, Burslem, Staffordshire, UK. Electronic address:

Objective: To establish if gravidity and parity associate with the development of rheumatoid arthritis (RA), and to establish if this effect is influenced by the time elapsed since pregnancy/childbirth, the number of pregnancies/childbirths, and serological status, through systematically reviewing the literature and undertaking a meta-analysis.

Methods: We searched Medline/EMBASE (from 1946 to 2018) using the terms "rheumatoid arthritis.mp" or "arthritis, rheumatoid/" and "pregnancy.mp" or "pregnancy/" or "parity.mp" or "parity/" or "gravidity.mp" or "gravidity/" (observational study filter applied). Case-control/cohort studies that examined the relationship between parity/gravidity and the risk of RA in women were included. Studies reporting effect size data for RA in ever vs. never parous/gravid women as ORs/RRs with 95% confidence intervals were included in a meta-analysis. Other relationships (i.e. risk by pregnancy/childbirth numbers) were analysed descriptively.

Results: Twenty studies (from 626 articles) met our inclusion criteria, comprising 14 case-control (4799 cases; 11,941 controls) and 6 cohort studies (8575 cases; 2,368,439 individuals). No significant association was observed in the meta-analysis of studies reporting the risk of RA in ever vs. never parous women (OR 0.91; 95% CI 0.80-1.04) and ever vs. never gravid women (OR 0.86; 95% CI 0.46-1.62). No consistent evidence of a relationship between the number of pregnancies/childbirths and RA risk was seen. No significant association was observed between being pregnant, or in the immediate post-partum period, and the risk of developing RA.

Conclusion: Our systematic review does not support the concept that gravidity and parity are associated with the risk of RA development.
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http://dx.doi.org/10.1016/j.semarthrit.2019.09.003DOI Listing
April 2020

A stromal cell niche sustains ILC2-mediated type-2 conditioning in adipose tissue.

J Exp Med 2019 09 27;216(9):1999-2009. Epub 2019 Jun 27.

Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

Group-2 innate lymphoid cells (ILC2), type-2 cytokines, and eosinophils have all been implicated in sustaining adipose tissue homeostasis. However, the interplay between the stroma and adipose-resident immune cells is less well understood. We identify that white adipose tissue-resident multipotent stromal cells (WAT-MSCs) can act as a reservoir for IL-33, especially after cell stress, but also provide additional signals for sustaining ILC2. Indeed, we demonstrate that WAT-MSCs also support ICAM-1-mediated proliferation and activation of LFA-1-expressing ILC2s. Consequently, ILC2-derived IL-4 and IL-13 feed back to induce eotaxin secretion from WAT-MSCs, supporting eosinophil recruitment. Thus, MSCs provide a niche for multifaceted dialogue with ILC2 to sustain a type-2 immune environment in WAT.
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http://dx.doi.org/10.1084/jem.20190689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719433PMC
September 2019

Real world long-term impact of intensive treatment on disease activity, disability and health-related quality of life in rheumatoid arthritis.

BMC Rheumatol 2019 25;3. Epub 2019 Feb 25.

5Department of Rheumatology, Guy's and St Thomas' NHS Trust, 4th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, UK.

Background: The emphasis on treating rheumatoid arthritis (RA) intensively reduces disease activity but its impact in routine care is uncertain. We evaluated temporal changes in disease activities and outcomes in a 10-year prospective observational cohort study of patients in routine care at one unit.

Methods: The Guy's and St Thomas' RA cohort was established in 2005. It involved most RA patients managed in this hospital. Clinical diagnoses of RA were made by rheumatologists. Patients were seen regularly in routine care. Each visit included measurement of disease activity scores for 28 joints (DAS28), health assessment questionnaire scores (HAQ) and EuroQol scores. Patients received intensive treatments targeting DAS28 remission.

Results: In 1693 RA patients mean DAS28 scores fell from 2005 to 15 by 11% from 4.08 (95% CI: 3.91, 4.25) in 2005 to 3.64 (3.34, 3.78); these falls were highly significant ( < 0.001). DAS28 components: swollen joint counts fell by 32% and ESR by 24%; in contrast tender joint counts and patient global assessments showed minimal or no reductions. The reduction in DAS28 scores was predominantly between 2005 and 2010, with no falls from 2011 onwards. Associated with falls in mean DAS28s, patients achieving remission increased (18% in 2005; 27% in 2015) and the number with active disease (DAS28 > 5.1) decreased (25% in 2005; 16% in 2015). In 752 patients seen at least annually for 3 years, persisting remission (68 patients) and intermittent remission (376 patients) were associated with less disability and better health related quality of life. Over time biologic use increased, but they were used infrequently in patients in persistent remission.

Conclusions: Over 10 years an intensive management strategy in a routine practice setting increased combination DMARD and biologic use: disease activity levels declined; this association is in keeping with a causal relationship. Patients who achieved remission, even transiently, had better functional outcomes than patients never achieving remission.
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http://dx.doi.org/10.1186/s41927-019-0054-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390620PMC
February 2019

Reply.

Arthritis Rheumatol 2019 06 12;71(6):1025-1026. Epub 2019 Apr 12.

King's College London, London, UK.

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http://dx.doi.org/10.1002/art.40843DOI Listing
June 2019

Heart enhancers with deeply conserved regulatory activity are established early in zebrafish development.

Nat Commun 2018 11 26;9(1):4977. Epub 2018 Nov 26.

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.

During the phylotypic period, embryos from different genera show similar gene expression patterns, implying common regulatory mechanisms. Here we set out to identify enhancers involved in the initial events of cardiogenesis, which occurs during the phylotypic period. We isolate early cardiac progenitor cells from zebrafish embryos and characterize 3838 open chromatin regions specific to this cell population. Of these regions, 162 overlap with conserved non-coding elements (CNEs) that also map to open chromatin regions in human. Most of the zebrafish conserved open chromatin elements tested drive gene expression in the developing heart. Despite modest sequence identity, human orthologous open chromatin regions recapitulate the spatial temporal expression patterns of the zebrafish sequence, potentially providing a basis for phylotypic gene expression patterns. Genome-wide, we discover 5598 zebrafish-human conserved open chromatin regions, suggesting that a diverse repertoire of ancient enhancers is established prior to organogenesis and the phylotypic period.
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http://dx.doi.org/10.1038/s41467-018-07451-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255839PMC
November 2018

Hey2 regulates the size of the cardiac progenitor pool during vertebrate heart development.

Development 2018 11 21;145(22). Epub 2018 Nov 21.

Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada

A key event in heart development is the timely addition of cardiac progenitor cells, defects in which can lead to congenital heart defects. However, how the balance and proportion of progenitor proliferation versus addition to the heart is regulated remains poorly understood. Here, we demonstrate that Hey2 functions to regulate the dynamics of cardiac progenitor addition to the zebrafish heart. We found that the previously noted increase in myocardial cell number found in the absence of Hey2 function was due to a pronounced expansion in the size of the cardiac progenitor pool. Expression analysis and lineage tracing of -expressing cells showed that is active in cardiac progenitors. Hey2 acted to limit proliferation of cardiac progenitors, prior to heart tube formation. Use of a transplantation approach demonstrated a likely cell-autonomous (in cardiac progenitors) function for Hey2. Taken together, our data suggest a previously unappreciated role for Hey2 in controlling the proliferative capacity of cardiac progenitors, affecting the subsequent contribution of late-differentiating cardiac progenitors to the developing vertebrate heart.
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http://dx.doi.org/10.1242/dev.167510DOI Listing
November 2018

New perspectives on IL-33 and IL-1 family cytokines as innate environmental sensors.

Biochem Soc Trans 2018 10 8;46(5):1345-1353. Epub 2018 Oct 8.

Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Granta Park, Cambridge CB21 6GH, U.K.

Interleukin (IL)-1 family cytokines are important initiators of innate immunity and host defence; however, their uncontrolled activities can cause tissue-damaging inflammation. Consequently, IL-1 family cytokines have sophisticated regulatory mechanisms to control their activities including proteolytic processing for their activation and the deployment of soluble receptors and receptor antagonists to limit their activities. IL-33 is a promoter of type 2 immunity and allergic inflammation through its alarmin activity that can rapidly initiate local immune responses by stimulating innate immune cells following exposure to environmental insults, pathogens, or sterile injury. Recent publications have provided new insights into how the range and duration of IL-33 activity is regulated by direct sensing of host-derived and exogenous proteolytic activities as well as oxidative changes during tissue damage. Here, we discuss how this impacts our understanding of the roles of IL-33 in initiating immune responses and the evidence that these sensing mechanisms might regulate the activities of other IL-1 family cytokines and their biological functions. Finally, we discuss translational challenges these discoveries pose for the accurate detection of different forms of these cytokines.
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http://dx.doi.org/10.1042/BST20170567DOI Listing
October 2018

The Impact of Targeted Rheumatoid Arthritis Pharmacologic Treatment on Mental Health: A Systematic Review and Network Meta-Analysis.

Arthritis Rheumatol 2018 09 31;70(9):1377-1391. Epub 2018 Jul 31.

King's College London and King's College Hospital NHS Foundation Trust, London, UK.

Rheumatoid arthritis (RA) pharmacotherapy may impact mental health outcomes by improving pain and stiffness, potentially by targeting inflammatory processes common to RA and depression. The objectives of this review were to ascertain the frequency of mental health assessments in RA pharmacotherapy trials, quantify the efficacy of RA pharmacotherapy for mental health outcomes, and explore the clinical and demographic factors related to mental health outcomes. Effective pharmacotherapy alone is unlikely to substantially improve mental health outcomes in most patients with RA. Integrated mental health care provided within routine clinical practice is essential to optimize mental and physical health outcomes.
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http://dx.doi.org/10.1002/art.40565DOI Listing
September 2018

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.

Pharmacogenomics J 2018 07 25;18(4):528-538. Epub 2018 May 25.

Leeds Institute of Cancer and Pathology, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.
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http://dx.doi.org/10.1038/s41397-018-0025-5DOI Listing
July 2018

The DEAD-box RNA helicase Ddx39ab is essential for myocyte and lens development in zebrafish.

Development 2018 04 23;145(8). Epub 2018 Apr 23.

Model Animal Research Center, Nanjing University, Nanjing, 210031, China

RNA helicases from the DEAD-box family are found in almost all organisms and have important roles in RNA metabolism, including RNA synthesis, processing and degradation. The function and mechanism of action of most of these helicases in animal development and human disease remain largely unexplored. In a zebrafish mutagenesis screen to identify genes essential for heart development we identified a mutant that disrupts the gene encoding the RNA helicase DEAD-box 39ab (). Homozygous mutant embryos exhibit profound cardiac and trunk muscle dystrophy, along with lens abnormalities, caused by abrupt terminal differentiation of cardiomyocyte, myoblast and lens fiber cells. Loss of hindered splicing of mRNAs encoding epigenetic regulatory factors, including members of the KMT2 gene family, leading to misregulation of structural gene expression in cardiomyocyte, myoblast and lens fiber cells. Taken together, these results show that Ddx39ab plays an essential role in establishment of the proper epigenetic status during differentiation of multiple cell lineages.
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http://dx.doi.org/10.1242/dev.161018DOI Listing
April 2018

Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is the Risk?

Drug Saf 2018 07;41(7):645-653

Academic Rheumatology, King's College Hospital, London, UK.

Two different Janus kinase (JAK) inhibitors-baricitinib and tofacitinib-are effective and licensed in active rheumatoid arthritis (RA). There have been recent concerns about potential thromboembolic risks with these drugs. Concerns about baricitinib focus on clinical trial findings. Using all publically available data, we estimate thromboembolic risks are approximately five events per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib have been raised by analyses of the Federal Drug Administration Adverse Event Reporting System (FAERs). These show some evidence of increased risks of pulmonary thrombosis, though not pulmonary embolism or venous thrombosis. Observational studies suggest in the general population and non-RA controls there are one to four thromboembolic events per 1000 patient years. In RA, thromboembolic risks increase to three to seven per 1000 patient years. The impact of biologics and disease-modifying anti-rheumatic drugs (DMARDs) on disease risk appears minimal, and the number of thromboembolic events is between four and eight per 1000 patient years. In the short term, full details of thromboembolic events in trials of JAK inhibitors need to be published. As the numbers of thromboembolic events will be small and patients enrolled in trials are not representative of all RA patients who may receive JAK inhibitors, this information is unlikely to provide definitive answers. Consequently, in the longer term, large observational studies are needed to accurately quantify thromboembolic risks attributable to JAK inhibitors and other drugs used to treat RA, and differentiate these from risks attributable to RA itself and its comorbidities.
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http://dx.doi.org/10.1007/s40264-018-0651-5DOI Listing
July 2018

Interleukin-33 is activated by allergen- and necrosis-associated proteolytic activities to regulate its alarmin activity during epithelial damage.

Sci Rep 2018 02 20;8(1):3363. Epub 2018 Feb 20.

Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Granta Park, Cambridge, CB21 6GH, United Kingdom.

Interleukin (IL)-33 is an IL-1 family alarmin released from damaged epithelial and endothelial barriers to elicit immune responses and allergic inflammation via its receptor ST2. Serine proteases released from neutrophils, mast cells and cytotoxic lymphocytes have been proposed to process the N-terminus of IL-33 to enhance its activity. Here we report that processing of full length IL-33 can occur in mice deficient in these immune cell protease activities. We sought alternative mechanisms for the proteolytic activation of IL-33 and discovered that exogenous allergen proteases and endogenous calpains, from damaged airway epithelial cells, can process full length IL-33 and increase its alarmin activity up to ~60-fold. Processed forms of IL-33 of apparent molecular weights ~18, 20, 22 and 23 kDa, were detected in human lungs consistent with some, but not all, proposed processing sites. Furthermore, allergen proteases degraded processed forms of IL-33 after cysteine residue oxidation. We suggest that IL-33 can sense the proteolytic and oxidative microenvironment during tissue injury that facilitate its rapid activation and inactivation to regulate the duration of its alarmin function.
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http://dx.doi.org/10.1038/s41598-018-21589-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820248PMC
February 2018

Dynamics of Zebrafish Heart Regeneration Using an HPLC-ESI-MS/MS Approach.

J Proteome Res 2018 03 5;17(3):1300-1308. Epub 2018 Feb 5.

Model Animal Research Center, Nanjing University , Nanjing 210093, China.

Failure to properly repair damaged due to myocardial infarction is a major cause of heart failure. In contrast with adult mammals, zebrafish hearts show remarkable regenerative capabilities after substantial damage. To characterize protein dynamics during heart regeneration, we employed an HPLC-ESI-MS/MS (mass spectrometry) approach. Myocardium tissues were taken from sham-operated fish and ventricle-resected sample at three different time points (2, 7, and 14 days); dynamics of protein expression were analyzed by an ion-current-based quantitative platform. More than 2000 protein groups were quantified in all 16 experiments. Two hundred and nine heart-regeneration-related protein groups were quantified and clustered into six time-course patterns. Functional analysis indicated that multiple molecular function and metabolic pathways were involved in heart regeneration. Interestingly, Ingenuity Pathway Analysis revealed that P53 signaling was inhibited during the heart regeneration, which was further verified by real-time quantitative polymerase chain reaction (Q-PCR). In summary, we applied systematic proteomics analysis on regenerating zebrafish heart, uncovered the dynamics of regenerative genes expression and regulatory pathways, and provided invaluable insight into design regenerative-based strategies in human hearts.
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http://dx.doi.org/10.1021/acs.jproteome.7b00915DOI Listing
March 2018

How can primary care physicians enhance the early diagnosis of rheumatic diseases?

Expert Rev Clin Immunol 2018 03 25;14(3):171-173. Epub 2018 Jan 25.

a Arthritis Research UK Primary Care Centre, Institute for Primary Care and Health Sciences , Keele University , Keele , Staffordshire , UK.

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http://dx.doi.org/10.1080/1744666X.2018.1429919DOI Listing
March 2018

Primary care challenges in diagnosing and referring patients with suspected rheumatoid arthritis: a national cross-sectional GP survey.

Rheumatol Adv Pract 2018 6;2(1):rky012. Epub 2018 Apr 6.

Arthritis Research UK Primary Care Centre, Research Institute for Primary Care & Health Sciences, Primary Care Sciences, Keele University, Newcastle-under-Lyme.

Objective: National guidelines advocate referring patients with persistent synovitis to rheumatology within 3 working days of presentation to primary care. This occurs infrequently. We aimed to identify modifiable barriers to early referral of suspected RA patients among English general practitioners (GPs).

Methods: We carried out a national cross-sectional survey of 1388 English GPs (RA Questionnaire for GPs [RA-QUEST] study). Questions addressed GPs' confidence in diagnosing RA, clinical factors influencing RA diagnosis/referral, timeliness of referrals and secondary care access. Data were captured using 10-point visual analog scales, five-point Likert scales, yes/no questions or free text, and were analysed descriptively.

Results: Small joint swelling and pain were most influential in diagnosing RA (91 and 84% rated the importance of these as 4 or 5 on a five-point Likert scale, respectively); investigations including RF (61% rating 4 or 5) and anti-CCP antibody (72% rating 4 or 5) were less influential. Patient history had the greatest impact on the decision to refer (92% rating this 4 or 5 on a 5-point Likert scale), with acute phase markers (74% rating 4 or 5) and serology (76% rating 4 or 5) less impactful. Despite the importance placed on history and examination, only 26% referred suspected RA immediately without investigations; 95% of GPs organizing further tests opted to test for RF.

Conclusion: For suspected RA patients to be referred within 3 days of presentation to primary care there needs to be a paradigm shift in GPs' approaches to making referral decisions, with a focus on clinical history and examination findings, and not the use of investigations such as RF.
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http://dx.doi.org/10.1093/rap/rky012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597052PMC
April 2018

HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33.

Immunity 2017 10;47(4):739-751.e5

MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK. Electronic address:

Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy.
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http://dx.doi.org/10.1016/j.immuni.2017.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655542PMC
October 2017

hace1 Influences zebrafish cardiac development via ROS-dependent mechanisms.

Dev Dyn 2018 02 27;247(2):289-303. Epub 2017 Oct 27.

Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.

Background: In this study, we reveal a previously undescribed role of the HACE1 (HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1) tumor suppressor protein in normal vertebrate heart development using the zebrafish (Danio rerio) model. We examined the link between the cardiac phenotypes associated with hace1 loss of function to the expression of the Rho small family GTPase, rac1, which is a known target of HACE1 and promotes ROS production via its interaction with NADPH oxidase holoenzymes.

Results: We demonstrate that loss of hace1 in zebrafish via morpholino knockdown results in cardiac deformities, specifically a looping defect, where the heart is either tubular or "inverted". Whole-mount in situ hybridization of cardiac markers shows distinct abnormalities in ventricular morphology and atrioventricular valve formation in the hearts of these morphants, as well as increased expression of rac1. Importantly, this phenotype appears to be directly related to Nox enzyme-dependent ROS production, as both genetic inhibition by nox1 and nox2 morpholinos or pharmacologic rescue using ROS scavenging agents restores normal cardiac structure.

Conclusions: Our study demonstrates that HACE1 is critical in the normal development and proper function of the vertebrate heart via a ROS-dependent mechanism. Developmental Dynamics 247:289-303, 2018. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/dvdy.24600DOI Listing
February 2018

Contextual fear conditioning in zebrafish.

Learn Mem 2017 10 15;24(10):516-523. Epub 2017 Sep 15.

Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.

Zebrafish are a genetically tractable vertebrate that hold considerable promise for elucidating the molecular basis of behavior. Although numerous recent advances have been made in the ability to precisely manipulate the zebrafish genome, much less is known about many aspects of learning and memory in adult fish. Here, we describe the development of a contextual fear conditioning paradigm using an electric shock as the aversive stimulus. We find that contextual fear conditioning is modulated by shock intensity, prevented by an established amnestic agent (MK-801), lasts at least 14 d, and exhibits extinction. Furthermore, fish of various background strains (AB, Tu, and TL) are able to acquire fear conditioning, but differ in fear extinction rates. Taken together, we find that contextual fear conditioning in zebrafish shares many similarities with the widely used contextual fear conditioning paradigm in rodents. Combined with the amenability of genetic manipulation in zebrafish, we anticipate that our paradigm will prove to be a useful complementary system in which to examine the molecular basis of vertebrate learning and memory.
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http://dx.doi.org/10.1101/lm.045690.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602349PMC
October 2017

Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: the GENRA case-control study.

Rheumatology (Oxford) 2017 08;56(8):1282-1292

Department of Medical and Molecular Genetics, King's College London.

Objectives: To evaluate whether genetic and environmental factors associated with RA in European and Asian ancestry populations are also associated with RA in African ancestry individuals.

Methods: A case-control study was undertaken in 197 RA cases and 868 controls of African ancestry (Black African, Black Caribbean or Black British ethnicity) from South London. Smoking and alcohol consumption data at RA diagnosis was captured. Genotyping was undertaken (Multi-Ethnic Genotyping Array) and human leukocyte antigen (HLA) alleles imputed. The following European/Asian RA susceptibility factors were tested: 99 genome-wide loci combined into a genetic risk score; HLA region [20 haplotypes; shared epitope (SE)]; smoking; and alcohol consumption. The SE was tested for its association with radiological erosions. Logistic regression models were used, including ancestry-informative principal components, to control for admixture.

Results: European/Asian susceptibility loci were associated with RA in African ancestry individuals. The genetic risk score provided an odds ratio (OR) for RA of 1.53 (95% CI: 1.31, 1.79; P = 1.3 × 10 - 7 ). HLA haplotype ORs in European and African ancestry individuals were highly correlated ( r = 0.83, 95% CI: 0.56, 0.94; P = 1.1 × 10 - 4 ). Ever-smoking increased (OR = 2.36, 95% CI: 1.46, 3.82; P = 4.6 × 10 - 4 ) and drinking alcohol reduced (OR = 0.34, 95% CI: 0.20, 0.56; P = 2.7 × 10 - 5 ) RA risk in African ancestry individuals. The SE was associated with erosions (OR = 2.61, 95% CI: 1.36, 5.01; P = 3.9 × 10 - 3 ).

Conclusion: Gene-environment RA risk factors identified in European/Asian ancestry populations are relevant in African ancestry individuals. As modern statistical methods facilitate analysing ancestrally diverse populations, future genetic studies should incorporate African ancestry individuals to ensure their implications for precision medicine are universally applicable.
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http://dx.doi.org/10.1093/rheumatology/kex048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638023PMC
August 2017

The Relationship Between Mental Health, Disease Severity, and Genetic Risk for Depression in Early Rheumatoid Arthritis.

Psychosom Med 2017 Jul/Aug;79(6):638-645

From the SGDP Centre (Euesden, Lewis), and Department of Psychological Medicine (Matcham, Hotopf), Institute of Psychiatry, Psychology & Neuroscience, King's College London; Department of Rheumatology (Steer), Weston Education Centre, King's College Hospital; Academic Department of Rheumatology (Cope, Scott), Centre for Molecular and Cellular Biology of Inflammation, and Department of Medical and Molecular Genetics (Lewis, Scott), King's College London, London; MRC Integrative Epidemiology Unit (Euesden), School of Social and Community Medicine, University of Bristol, Bristol; and Research Institute for Primary Care & Health Sciences (Scott), Primary Care Sciences, Keele University, Staffordshire, United Kingdom.

Objective: Reduced mental health (MH) is prevalent in rheumatoid arthritis (RA). Although longitudinal studies are limited, there is evidence that depression is associated with worse disease outcomes. We evaluated reciprocal relationships between MH, RA severity, and genetic risks for depression for 2 years in a well-characterized cohort of RA patients.

Methods: We evaluated 520 early RA patients previously enrolled to two clinical trials. MH was measured using the short form-36 MH domain and mental component summary scores (MCS). MCS/MH associations over 2 years with disease activity (disease activity score on a 28-joint count), disability (health assessment questionnaire), pain visual analog scale scores, and a weighted genetic risk score for depression were tested using linear mixed-effects and regression models.

Results: Poorer MH was associated with worse RA outcomes. Lower MCS scores (indicating worse MH) were seen in patients with a greater genetic risk for depression (weighted genetic risk score: coefficient = -1.21, p = .013). Lower baseline MCS was associated with lower 2-year improvements in disease activity score on a 28-joint count (coefficient = -0.02, p < .001), pain (coefficient = -0.33, p < .001), and health assessment questionnaire (coefficient = -0.01, p = .006). Baseline MCS was associated with changes in the swollen joint count (coefficient = -0.09, p < .001) and patient global assessment (coefficient = -0.28, p < .001) but not the tender joint count (p = .983) and erythrocyte sedimentation rate (p = .973). Only baseline pain visual analog scale (coefficient = -0.07, p = .002) was associated with 2-year changes in MCS.

Conclusions: Reduced baseline MH was associated with lower improvements in disease activity, disability, and pain for 2 years, supporting current national guidelines recommending screening for depression in RA. Pain had a bidirectional relationship with MH. Depression genetic risk had a significant association with MH.
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http://dx.doi.org/10.1097/PSY.0000000000000462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638421PMC
April 2018

The Sec domain protein Scfd1 facilitates trafficking of ECM components during chondrogenesis.

Dev Biol 2017 Jan 13;421(1):8-15. Epub 2016 Nov 13.

Model Animal Research Center, Nanjing University, China. Electronic address:

Chondrogenesis in the developing skeleton requires transformation of chondrocytes from a simple mesenchymal condensation to cells with a highly enriched extracellular matrix (ECM). This transition is in part accomplished by alterations in the chondrocyte protein transport machinery to cope with both the increased amount and large size of ECM components. In a zebrafish mutagenesis screen to identify genes essential for cartilage development, we uncovered a mutant that disrupts the gene encoding Sec1 family domain containing 1 (scfd1). Homozygous scfd1 mutant embryos exhibit a profound craniofacial abnormality caused by a failure of chondrogenesis. Loss of scfd1 was found to hinder ER to Golgi transport of ECM proteins and is accompanied with activation of the unfolded protein response in chondrocytes. We further demonstrate a conserved role for Scfd1 in differentiation of mammalian chondrocytes, in which loss of either SCFD1 or STX18, a SLY1 interacting t-SNARE, severely impair transport of type II collagen. These results show that the existence of a specific export pathway, mediated by a complex containing SCFD1 and STX18 that plays an essential role in secretion of large ECM proteins during chondrogenesis.
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http://dx.doi.org/10.1016/j.ydbio.2016.11.010DOI Listing
January 2017

Mespaa can potently induce cardiac fates in zebrafish.

Dev Biol 2016 10 20;418(1):17-27. Epub 2016 Aug 20.

Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4; Department of Molecular Genetics, University of Toronto, Canada; Heart & Stroke/Richard Lewar Centres of Excellence in Cardiovascular Research, University of Toronto, Canada. Electronic address:

The Mesp family of transcription factors have been implicated in the early formation and migration of the cardiac lineage, although the precise molecular mechanisms underlying this process remain unknown. In this study we examine the function of Mesp family members in zebrafish cardiac development and find that Mespaa is remarkably efficient at promoting cardiac fates in normally non-cardiogenic cells. However, Mespaa is dispensable for normal cardiac formation. Despite no overt defects in cardiovascular specification, we find a consistent defect in cardiac laterality in mespaa null embryos. This is further exacerbated by the depletion of other mesp paralogues, highlighting a conserved role for the mesp family in left-right asymmetry, distinct from a function in cardiac specification. Despite an early requirement for mespaa to promote cardiogenesis, cells over-expressing mespaa are found to both exhibit unique cellular behaviors and activate the transcription of gata5 only after the completion of gastrulation. We propose that while mespaa remains capable of driving cardiac progenitor formation in zebrafish, it may not play an essential role in the cardiac regulatory network. Furthermore, the late activation of migration and cardiac gene transcription in mespaa over-expressing cells challenges previous studies on the timing of these events and provides intriguing questions for future study.
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http://dx.doi.org/10.1016/j.ydbio.2016.08.022DOI Listing
October 2016