Objective
To compare disease activity and disability over 2 years in early rheumatoid arthritis (RA) before and after implementation of treat‐to‐target therapy and identify predictors of adverse ...outcome.
Methods
The Yorkshire Early Arthritis Register (YEAR) recruited 725 patients with early RA between 2002 and 2009, treated with a step‐up approach. The Inflammatory Arthritis Continuum study (IACON) recruited cases between 2010 and 2014 and treated to target. A total of 384 IACON cases met 2010 American College of Rheumatology/European League Against Rheumatism criteria. Latent growth curves of change in Disease Activity Score in 28 joints (DAS28) and the Health Assessment Questionnaire (HAQ) were compared between YEAR and IACON. Latent class growth analysis identified trajectories of change. Baseline predictors of trajectories were identified using logistic regression.
Results
The mean DAS28 over 2 years was lower in IACON than in YEAR. Latent trajectories of HAQ change in YEAR were high stable (21% of cohort), moderate reducing (35%), and low reducing (44%). Only moderate reducing (66%) and low reducing (34%) were seen in IACON. In both cohorts, female sex and fatigue predicted adverse HAQ trajectories (high stable and moderate reducing). Odds ratios (ORs) for moderate reducing compared to low reducing for women were 2.58 (95% confidence interval 95% CI 1.69, 4.49) in YEAR and 5.81 (95% CI 2.44, 14.29) in IACON. ORs per centimeter fatigue visual analog score were 1.13 (95% CI 1.07, 1.20) in YEAR and 1.16 (95% CI 1.12, 1.20) in IACON.
Conclusion
Treat‐to‐target therapy gave more favorable trajectories of change in DAS28 and HAQ, but adverse HAQ trajectory was more likely in women with greater fatigue, suggesting such patients would benefit from interventions to improve function as well as reduce inflammation.
Objectives. The 28-joint disease activity score (DAS-28) guides the use of biologics in RA. The aims of this study were to investigate agreement between the ESR- and CRP-based DAS-28 definitions, and ...to examine how this agreement may be improved. Methods. Data were obtained from registers of early (n = 520) and established RA (n = 364) patients. Agreement over disease activity levels (remission, low, moderate and high) at baseline and 6 months, and EULAR responder status at 6 months, were assessed in the early cohort. Two alternative DAS-28(CRP) definitions, obtained through linear regression analyses at baseline in the early RA patients, were validated with 6-month data from both the cohorts. Results. In early RA patients, despite a high percentage of exact agreement over DAS-28 categories (88.2%), 38 (30.4%) of 125 patients with ‘moderate’ DAS-28(CRP) at baseline had ‘high’ DAS-28(ESR). This agreement was improved by modifying the DAS-28(CRP) definition, and by incorporating age and gender: e.g. in early RA patients with moderate original DAS-28(CRP), 30.4% had ‘high’ DAS-28(ESR), whereas 3.2% had ‘low’ DAS-28(ESR); following DAS-28(CRP) transformation both proportions were 6.6%. Incorporating age and gender did not improve agreement over EULAR response states. Conclusion. The DAS-28(ESR) and DAS-28(CRP) definitions differ substantially in classifying RA patients as having moderate or high disease activity, with the ESR definition resulting in a higher proportion of high DAS-28 especially in women. Our results suggest that modifying the DAS-28(CRP) definition may improve agreement with DAS-28(ESR). There are important implications for meta-analyses and for therapy driven by DAS scores.
Recent genetic studies have led to identification of numerous loci that are associated with susceptibility to autoimmune diseases. The strategy of using information from these studies has facilitated ...the identification of novel juvenile idiopathic arthritis (JIA) susceptibility loci, specifically, PTPN22 and IL2RA. Several novel autoimmune susceptibility loci have recently been identified, and we hypothesise that single-nucleotide polymorphisms (SNPs) within these genes may also be JIA susceptibility loci. Five SNPs within the genes AFF3, IL2/IL21, IL7R, CTLA4 and CD226, previously associated with multiple autoimmune diseases were genotyped, in a large data set of Caucasian JIA patients and controls, and tested for association with JIA. We identified two susceptibility loci for JIA, AFF3 and the IL2/IL21 region and additional weak evidence supporting an association with the CTLA4 and IL7R genes, which warrant further investigation. All results require validation in independent JIA data sets. Further characterisation of the specific causal variants will be required before functional studies can be performed.
Objective
To define interactions between the HLA–DRB1 shared epitope (SE), PTPN22, and smoking in cyclic citrullinated peptide (CCP) antibody– and rheumatoid factor (RF)–positive and –negative ...rheumatoid arthritis (RA).
Methods
Data on ∼5,000 RA patients and ∼3,700 healthy controls recruited from 6 centers in the UK were analyzed; not all centers had both genotype data and smoking data available for study. The magnitude of association was assessed in autoantibody‐positive and ‐negative subgroups. The effect of smoking on antibody status among cases was assessed following adjustment for year of birth and center, using Mantel‐Haenszel analysis. Analyses of the combined effects of PTPN22, HLA–DRB1 SE, and smoking were performed using additive and multiplicative models of interaction within a logistic regression framework.
Results
The combined effects of PTPN22, HLA–DRB1 SE, and smoking were defined, with no evidence of departure from a multiplicative model. Within the case population, all 3 factors were independently associated with the generation of CCP antibodies (odds ratio OR 11.1, P < 0.0001), whereas only HLA–DRB1 SE and smoking were independently associated with RF production (OR 4.4, P < 0.0001). There was some evidence of increasing likelihood of antibody positivity with heavier smoking. Finally, we demonstrated that smoking was associated with the generation of both CCP and RF antibodies (OR 1.7, P = 0.0001).
Conclusion
PTPN22 appears to be primarily associated with anticitrulline autoimmunity, whereas HLA–DRB1 SE is independently associated with RF. This study has confirmed associations of specific gene–environment combinations with a substantially increased risk of developing RA. Further work is needed to determine how these data can be used to inform clinical practice.
Objective
IL2RA/CD25, the gene for interleukin‐2 receptor α, is emerging as a general susceptibility gene for autoimmune diseases because of its role in the development and function of regulatory T ...cells and the association of single‐nucleotide polymorphisms (SNPs) within this gene with type 1 diabetes mellitus (DM), Graves' disease, rheumatoid arthritis (RA), and multiple sclerosis (MS). The aim of this study was to determine whether SNPs within the IL2RA/CD25 gene are associated with juvenile idiopathic arthritis (JIA).
Methods
Three SNPs within the IL2RA/CD25 gene, that previously showed evidence of an association with either RA, MS, or type 1 DM, were selected for genotyping in UK JIA cases (n = 654) and controls (n = 3,849). Data for 1 SNP (rs2104286) were also available from North American JIA cases (n = 747) and controls (n = 1,161). Association analyses were performed using Plink software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.
Results
SNP rs2104286 within the IL2RA/CD25 gene was significantly associated with UK JIA cases (OR for the allele 0.76 95% CI 0.66–0.88, P for trend = 0.0002). A second SNP (rs41295061) also showed modest evidence for association with JIA (OR 0.80 95% CI 0.63–1.0, P = 0.05). Association with rs2104286 was convincingly replicated in the North American JIA cohort (OR 0.84 95% CI 0.65–0.99, P for trend = 0.05). Meta‐analysis of the 2 cohorts yielded highly significant evidence of association with JIA (OR 0.76 95% CI 0.62–0.88, P = 4.9 × 10−5).
Conclusion
These results provide strong evidence that the IL2RA/CD25 gene represents a JIA susceptibility locus. Further investigation of the gene using both genetic and functional approaches is now required.
The synthesis, characterization, and self-assembly of a range of ABC star polymers with arms of polyisoprene, poly(ferrocenylethylmethylsilane), and polystyrene is reported. A library of ...azide-functionalized polyisoprene and poly(ferrocenylethylmethylsilane) homopolymers were prepared by living anionic polymerization. Polystyrene was synthesized by living anionic polymerization and quenched with 3-triisopropylsilylethynyl-5-trimethylsilylethynylbenzaldehyde, yielding “core-functionalized” polystyrene with two different alkyne units. The azide-functionalized monomers were sequentially attached to core-functionalized polystyrene via copper(I)-catalyzed azide–alkyne cycloaddition reactions, giving polystyrene–polyisoprene–poly(ferrocenylethylmethylsilane) ABC star terpolymers with different compositions and narrow dispersities. Additionally, a chlorosilane route was employed as an alternative means of synthesis. Bulk films of each star terpolymer were prepared, and their self-assembly was analyzed by transmission electron microscopy. The formation of a diverse range of morphologies was observed, including lamellae with alternating cylinders and two different Archimedean tiling patterns.
New Findings
What is the topic of this review?
Exertional heat illness (EHI) remains a persistent problem for athletes and individuals. This threat remains despite numerous athletic position ...statements and occupational guidance policies. This review explores primary evidence that demonstrates a direct association between ‘known’ risk factors and EHI.
What advances does it highlight?
Primary evidence to support ‘known’ risk factors associated with EHI is not comprehensive. Furthermore, it is not evident that single individual factors predispose individuals to greater risk. In fact, the evidence indicates that EHI can manifest in non‐hostile compensable environments when a combination of risk factors is prevalent.
Despite the widespread knowledge of exertional heat illness (EHI) and clear guidance for its prevention, the incidence of EHI remains high. We carried out a systematic review of available literature evaluating the scientific evidence underpinning the risk factors associated with EHI. Medline, PsycINFO, SportDiscus and Embase were searched from inception to January 2019 with no date limitation, with supplementary searches also being performed. Search terms included permutations of risk and heat illness, with only studies in English included. Study selection, data extraction and quality assessment, using the QUALSYST tool, were performed by two independent reviewers. Of 8898 articles identified by the searches, 42 were included in the systematic review as primary evidence demonstrating a link between a risk factor and EHI. The quality scores ranged from 57.50 to 100%, and studies were generally considered to be of strong quality. The majority of risks attributable to EHI were categorized as those associated with lifestyle factors. The findings from the systematic review suggest complex manifestation of EHI through multiple risk factors rather than any one factor in isolation. Further research is needed to explore the accumulation of risk factors to help in development of effective preventative measures.
The directed self assembly of a 3‐miktoarm star terpolymer (polyisoprene‐arm‐polystyrene‐arm‐polyferrocenylethylmethylsilane (3μ‐ISF)) into a (4.82) square symmetry Archimedean tiling pattern is ...described. Bulk samples of 3μ‐ISF generate equilibrium columnar (4.82) tile patterns (symmetry p 4 mm) on annealing, which is preceded by a metastable c 2 mm centered rectangular structure. In contrast, in thin films of 3μ‐ISF blended with PS homopolymer, the c 2 mm phase is stable with columns oriented out of plane when the film thickness is below 50 nm. However, the 3μ‐ISF/homopolymer blend rapidly forms a p 4 mm symmetry when the film thickness is ∼80 nm, with grain sizes of several μm and excellent order. Defects in the p4mm structure are described.
3‐miktoarm star terpolymer chains consisting of polyisoprene (PI), polystyrene (PS), and polyferrocenylethylmethylsilane (PFS) self‐assemble into a (4.82) Archimedean tiling pattern with PFS (approximately square) domains occupying positions between the approximately octagonal PS and PI.
The directed self-assembly of 3-miktoarm star terpolymer chains (polyisoprene-arm-polystyrene-arm-polyferrocenylethylmethylsilane (3 μ-ISF)) into 2D Archimedean tilings is described. A morphological ...change from (4.82) to (63) tiling is reported in the 3 μ-ISF thin film blended with PS homopolymer when a greater swelling of PI is achieved during the solvent annealing process. Highly oriented (4.82) tilings were produced by templating the self-assembled three colored structures in blended thin films. The use of (4.82) and (63) tilings as nanolithographic masks to transfer square and triangular hole arrays into the substrate is also demonstrated.
Thin film knitting pattern from a miktoarm star terpolymer is demonstrated. Such structures have been predicted but not observed in bulk or thin film form. The knitting pattern exhibits well ...organized periodic structures consisting of undulating lamellae and alternating cylinders, with well‐defined defects that result in sharp 90° bends and T junctions.
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