ORCID Profile
0000-0003-1109-624X
Current Organisations
University of Leeds School of Medicine
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University of Leeds
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Publisher: Oxford University Press (OUP)
Date: 19-11-2009
DOI: 10.1093/RHEUMATOLOGY/KEP372
Abstract: To investigate the association between genotype at the soluble interleukin 6 receptor (sIL-6R) A358C single nucleotide polymorphism (SNP, rs8192284), previously reported to correlate with soluble receptor levels, and response to anti-TNF therapy in subjects with RA. In a large cohort of Caucasian RA patients treated with anti-TNF medications (total, n = 1050 etanercept, n = 455 infliximab, n = 450 and adalimumab, n = 142), the sIL-6R A358C polymorphism was genotyped using a Taqman 5'-allelic discrimination assay. Linear regression analysis adjusted for baseline 28 joint disease activity score (DAS28), baseline HAQ score, gender and use of concurrent DMARDs was used to assess the association of genotype at this polymorphism with response to anti-TNF therapy, defined by change in DAS28 after 6 months of treatment. Analyses were performed in the entire cohort, and also stratified by an anti-TNF agent. Additional analysis according to the EULAR response criteria was also performed, with the chi-squared test used to compare genotype groups. No association between genotype at sIL-6R A358C and response to anti-TNF treatment was detected either in the cohort as a whole or after stratification by anti-TNF agent, in either the linear regression analysis or with response segregated according to EULAR criteria. This study shows that genotype at the functional sIL-6R A358C SNP is not associated with response to anti-TNF treatment in patients with RA.
Publisher: Wiley
Date: 27-08-2009
DOI: 10.1002/ART.24752
Abstract: 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). Data on approximately 5,000 RA patients and approximately 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. 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). 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.
Publisher: Springer Science and Business Media LLC
Date: 08-11-2009
DOI: 10.1038/NG.479
Publisher: Oxford University Press (OUP)
Date: 22-04-2008
DOI: 10.1093/HMG/DDN128
Publisher: BMJ
Date: 31-05-2016
DOI: 10.1136/ANNRHEUMDIS-2015-208849
Abstract: To evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA) (ii) longitudinal factors associated with ADAbs and certolizumab drug levels. This prospective cohort included 115 patients with RA treated with certolizumab. Serum s les were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum s led and treatment response (ii) between ADAbs and drug levels (iii) patient-centred factors and drug levels. ADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (β=−0.037, 95% CI −0.055 to 0.018, p .0001) but not independently with 12 months EULAR response (β=0.0013 (95% CI −0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (β=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations. This is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level.
Publisher: BMJ
Date: 20-08-2009
Abstract: Genome-wide association studies in rheumatoid arthritis (RA) have failed to examine the FCGR gene cluster because of the confounding effects of segmental duplication. This study aimed to replicate previous candidate gene studies that had identified a significant association between the FCGR3A -158V allele and RA and then sought to estimate specific subgroup effects. FCGR3A -158F/V genotyping was undertaken in a UK Caucasian replication cohort comprising 2049 patients with RA and 1156 controls. Subgroup analyses assessing the magnitude of association according to gender and autoantibody (rheumatoid factor (RF) and cyclic citrullinated peptide (CCP)) status were undertaken in a pooled cohort of 2963 patients with RA and 1731 controls. Logistic regression was used to test for interaction between FCGR3A and HLA-DRB1 shared epitope (SE) alleles. In the combined RA cohort, borderline association with homozygosity was found for the FCGR3A -158V allele (OR 1.2, p=0.05), which was stronger in men (OR 1.7, p=0.01). Stratification by autoantibody status showed an increased risk in RF and CCP positive RA. Analysis of the FCGR3A-158V and HLA-DRB1 SE interaction revealed roles for both genes in susceptibility to autoantibody positive RA, with no evidence of interaction. FCGR3A is a risk factor for the development of autoantibody positive RA, particularly in men, with evidence of a multiplicative effect with HLA-DRB1 SE.
Publisher: Oxford University Press (OUP)
Date: 16-09-2016
DOI: 10.1093/RHEUMATOLOGY/KEW306
Abstract: To determine the change in established biomarkers of cardiovascular (CV) risk, namely, total cholesterol/high-density lipoprotein cholesterol ratio (TC/HDL-C), N-terminal pro-brain natriuretic peptide (NT-proBNP) and insulin resistance (IR) in patients with early RA treated with two different treat-to-target strategies. Fasting glucose, lipids, insulin and NT-proBNP were measured at baseline, weeks 26 and 78 in 79 DMARD-naïve RA patients, free of CV disease, as part of a double-blind randomized controlled trial of MTX with either infliximab (IFX) or methylprednisolone as induction therapy. Homeostasis model assessment-estimated IR (HOMA-IR) (glucose*insulin/405) was used to measure IR. Multiple imputation was employed, and linear regression analyses were adjusted for baseline values. Changes in DAS44-CRP did not differ between the treatment arms at weeks 26 and 78. Mean TC/HDL-C, HOMA-IR and NT-proBNP improved in both groups at weeks 26 and 78, although change in NT-proBNP was not statistically significant at week 78. Changes in TC/HDL-C and NT-proBNP were similar between treatment arms, but HOMA-IR values in the IFX + MTX arm were 42% lower than those treated with MTX + methylprednisolone at week 78 (P = 0.003) the difference remained significant after adjustment for baseline BMI, ACPA positivity, smoking status and intramuscular glucocorticoid use (P = 0.007). When implementing a treat-to-target approach, treatment of early RA was associated with improvement in TC/HDL-C, HOMA-IR and NT-proBNP, and a greater long-term improvement in HOMA-IR was seen in those treated with IFX. EU Clinical Trials Register, www.clinicaltrialsregister.eu, Eudract-2005-005013-37 ISRTCNregisrty, www.isrctn.com, ISRCTN48638981.
Publisher: Wiley
Date: 24-09-2013
DOI: 10.1002/ART.38064
Abstract: There is increasing evidence to indicate that genetic factors contribute significantly to radiologic joint damage in rheumatoid arthritis (RA). The aim of the present study was to determine whether genotypes of 10 recently identified RA susceptibility loci are associated with radiologic severity. A 2-stage study was performed using 3 Northern European RA populations: a British cross-sectional population (discovery cohort n=885) and the Leiden Early Arthritis Clinic (EAC) cohort (n=581) and Yorkshire Early Arthritis Register (YEAR) cohort (n=418) (validation cohorts). Radiologic damage was assessed using a modified Larsen method for scoring radiographs (in the discovery cohort) or modified Sharp/van der Heijde score (in the 2 validation cohorts). A meta-analysis was performed to bring together the evidence from the 3 studies, using data on radiologic severity of joint damage from a single time point. An allele-dose association of rs26232 was present in the discovery population (P=4×10(-4)) the median modified Larsen scores of radiologic joint damage per genotype were 31 (for those with CC), 27 (for those with CT), and 16 (for those with TT). The allele-dose association of rs26232 was replicated in both the Leiden EAC cohort during the initial 7 years of RA (P=0.04) and the YEAR cohort (P=0.039). In a fixed-effects meta-analysis of all 3 studies, the per T allele effect on the ratio of radiologic severity scores was 0.90 (95% confidence interval 0.84, 0.96 P=0.004). The variant rs26232, in the first intron of the C5orf30 locus, is associated with the severity of radiologic damage in RA and is independent of established prognostic biomarkers. The biologic activities of C5orf30 are unknown, but our genetic data suggest that it is involved in mediating joint damage in RA.
Publisher: Oxford University Press (OUP)
Date: 16-04-2019
Publisher: Public Library of Science (PLoS)
Date: 03-01-2012
Publisher: Springer Science and Business Media LLC
Date: 06-07-2015
DOI: 10.1038/NCOMMS8741
Publisher: Springer Science and Business Media LLC
Date: 13-09-2015
DOI: 10.1007/S00296-014-3128-6
Abstract: The Leeds Behçet's disease quality-of-life (BD-QoL) questionnaire is a specific and valid measure which is applied in English-speaking patients. We conducted Persian adaptation of BD-QoL questionnaire. Between June and December 2012, 220 Iranian patients fulfilling International Study Group criteria for the diagnosis of BD attending the rheumatology clinics at Tehran University of Medical Sciences were enrolled. Bilingual translators undertook the forward translation and cross-cultural adaptation of the BD-QoL questionnaire. Back-translation was conducted, and this version was sent to the designer of the questionnaire and revised accordingly. SF-36 health survey, Iranian Behçet's disease dynamic activity measure (IBDDAM), and Behçet's Disease Current Activity Form (BDCAF) were other administered measures. The Varimax rotation method with Kaiser normalization defined 5 factors with eigenvalues greater than 1.0. Studied cases were comprised of 118 males (53.6 %) and 102 females (46.4 %). Mean age of the patients was 38.3 ± 11.3 years (range 16-73). The mean BD-QoL score was 10.3 ± 8.8. Test-retest reliability was high, and two time points were significantly correlated (Spearman's correlation coefficient of 0.75-0.84). Cronbach's α coefficient of 0.949 demonstrated the excellent internal consistency. These factors cumulatively explained 58.74 % of total variance. The ratio of first to second eigenvalue was 7.08, which underlined the undimensionality. The results revealed adapted BD-QoL scores had significant correlation with IBDDAM (correlation coefficient = 0.19, P value = 0.005) and BDCAF (correlation coefficient = 0.21, P value = 0.002). Conversely, no significant correlation between BD-QoL and SF-36 results was detected (P value = 0.078). The Persian version of BD-QoL was shown to be unidimensional, highly reliable, and adequate construct validity.
Publisher: Oxford University Press (OUP)
Date: 05-05-2009
DOI: 10.1093/HMG/DDP193
Publisher: Elsevier BV
Date: 05-2016
Publisher: Public Library of Science (PLoS)
Date: 08-11-2012
Publisher: American Society of Hematology
Date: 15-12-2002
DOI: 10.1182/BLOOD-2002-03-0671
Abstract: Rheumatoid arthritis (RA) is a chronic, inflammatory disease of the synovium of uncertain pathogenesis. A number of phenotypic and functional T-cell defects have been described in RA, including abnormal clonal expansions and suppressed proliferative responses, which suggest a defect in T-cell differentiation. Here, we show that RA patients possess fewer naive CD4+ T cells than healthy controls. Furthermore, a smaller proportion of these cells contains a T-cell receptor excision circle (TREC). Patients with RA also have unusual populations of T cells. These include immature cells characterized as CD45RBbrightCD45RA+CD62L− by flow cytometry and a large population that coexpresses CD45RA and CD45RO. These cells are hyperresponsive to mitogen and TCR stimulation when compared to naive cells. Additionally, an unusual putative central memory subset expressing CD62L, but not CD45RA, appears in RA patients at the expense of more typical cells. Levels of C-reactive protein correlate inversely with the TREC content of naive T cells and positively with the sizes of naive and immature atypical T-cell subsets. These data suggest that inflammation drives proliferation of naive T cells in RA and encourages their differentiation into atypical, hyperresponsive progeny. TREC content of in idual naive and atypical T-cell subsets suggests an ontogeny consistent with this hypothesis. These studies provide further evidence of a T-cell differentiation defect in RA, which could explain some of the well-characterized immunologic features of the disease.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2007
DOI: 10.1038/NATURE05911
Publisher: Wiley
Date: 05-2015
DOI: 10.1002/ART.39169
Publisher: Springer Science and Business Media LLC
Date: 14-01-2010
Publisher: Public Library of Science (PLoS)
Date: 04-04-2013
Publisher: Wiley
Date: 09-02-2018
DOI: 10.1002/ACR.23281
Abstract: 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. 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. 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. 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.
Publisher: Oxford University Press (OUP)
Date: 30-04-2010
DOI: 10.1093/RHEUMATOLOGY/KEQ117
Abstract: 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. 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. 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. 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.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2015
DOI: 10.1038/NCOMMS7046
Abstract: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case–control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8 + memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.
Publisher: Springer Science and Business Media LLC
Date: 09-2011
DOI: 10.1038/GENE.2011.60
Abstract: Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67-74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. (70)DERAA(74), D(70) and I(67) protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1(*)0401∼(*)0404>(*)0101∼(*)1001 ((*)0404>(*)0101: P=0.0003). HLA-DRB1(*)0401/(*)0404 compound heterozygosity conferred a risk similar to (*)0401 homozygosity (P=0.70). Protective effects of D(70) and I(67) were similar. Predictions of the D(70) model fitted the data better than those of the I(67) model. The protective effect of D(70) showed a gene-dose effect (OR 0.82, 95% CI 0.73-0.92, P=5.8 × 10(-4)), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15-1.76), P=0.0012). In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D(70) specifically protected against antibody-positive RA.
Publisher: Wiley
Date: 02-02-2022
DOI: 10.1002/ART.41983
Abstract: To develop and validate classification criteria for microscopic polyangiitis (MPA). Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 5 phases: 1) identification of candidate items using consensus methodology, 2) prospective collection of candidate items present at the time of diagnosis, 3) data‐driven reduction of the number of candidate items, 4) expert panel review of cases to define the reference diagnosis, and 5) derivation of a points‐based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators. The development set for MPA consisted of 149 cases of MPA and 408 comparators. The validation set consisted of an additional 142 cases of MPA and 414 comparators. From 91 candidate items, regression analysis identified 10 items for MPA, 6 of which were retained. The final criteria and their weights were as follows: perinuclear antineutrophil cytoplasmic antibody (ANCA) or anti–myeloperoxidase‐ANCA positivity (+6), pauci‐immune glomerulonephritis (+3), lung fibrosis or interstitial lung disease (+3), sino‐nasal symptoms or signs (−3), cytoplasmic ANCA or anti–proteinase 3 ANCA positivity (−1), and eosinophil count ≥1 × 10 9 /liter (−4). After excluding mimics of vasculitis, a patient with a diagnosis of small‐ or medium‐vessel vasculitis could be classified as having MPA with a cumulative score of ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 91% (95% confidence interval [95% CI] 85–95%) and the specificity was 94% (95% CI 92–96%). The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for MPA are now validated for use in clinical research.
Publisher: Oxford University Press (OUP)
Date: 11-06-2010
DOI: 10.1093/RHEUMATOLOGY/KEQ178
Abstract: Current UK management of RA initially employs conventional DMARDs, with biological therapy reserved for DMARD-resistant RA patients with persistently high 28-joint disease activity score (DAS-28). The aim of this study was to examine the effect on patient-reported function of persistently moderate DAS-28 despite modern step-up DMARD therapy in an early arthritis cohort. Data were obtained from the Yorkshire Early Arthritis Register, a cohort of early ( 5.1 at 6- and/or 9-month visits and at the 12-month visit), persistently moderate (>3.2 and ≤ 5.1) or persistently low (≤ 3.2). We selected 194 patients for this analysis. Deteriorating HAQ scores were observed in 10.9% of patients with persistently low DAS-28 compared with 21.4% (persistently moderate DAS-28) and 46.7% (persistently high DAS-28), respectively, for MCID = 0.22 7.3, 14.3 and 20.0% for MCID = 0.31 5.5, 10.7 and 11.1% for MCID = 0.49. A high DAS-28 was generally associated with a greater degree of functional decline, but persistent moderate elevation of DAS-28 was associated with important functional deterioration in 10-21% of early RA patients (depending on choice of MCID) following a modern DMARD protocol. A proportion of patients with persistently moderate DAS-28 may therefore benefit from more aggressive therapy than that allowed by current UK recommendations.
Publisher: Public Library of Science (PLoS)
Date: 09-10-2019
Publisher: BMJ
Date: 02-08-2014
DOI: 10.1136/ANNRHEUMDIS-2013-203440
Abstract: In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis (RA), to compare the efficacy of methotrexate (MTX) and infliximab (IFX) with MTX and intravenous corticosteroid for remission induction. In a 78-week multicentre randomised controlled trial, double-blinded to week 26, 112 treatment-naive RA patients (1987 American College of Rheumatology classification criteria) with disease activity score 44 (DAS44)>2.4 were randomised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg. A treat-to-target approach was used with treatment escalation if DAS44>2.4. In the IFX group, IFX was discontinued for sustained remission (DAS44<1.6 for 6 months). The primary outcome was change in modified total Sharp-van der Heijde score (mTSS) at week 50. The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units, respectively (adjusted difference (95% CI) -1.45 (-3.35 to 0.45) p=0.132). Radiographic non-progression (mTSS<2.0) occurred in 81% vs 71% (OR 1.77 (0.56 to 5.61) p=0.328). DAS44 remission was achieved at week 50 in 49% and 36% (OR 2.13 (0.91 to 5.00) p=0.082), and at week 78 in 48% and 50% (OR 1.12 (0.47 to 2.68) p=0.792). Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group. Of the IFX group, 25% (14/55) achieved sustained remission and stopped IFX. No substantive differences in adverse events were seen. In DMARD-naive early RA patients, initial therapy with MTX+high-dose intravenous steroid resulted in good disease control with little structural damage. MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach.
Publisher: American Psychological Association (APA)
Date: 2015
DOI: 10.1037/XAN0000058
Abstract: In a 2-stimulus visual discrimination choice task with a reversal in reward contingencies midway through each session, pigeons produce a surprising number of both anticipatory errors (i.e., responding to the second-correct stimulus before the reversal) and perseverative errors (i.e., responding to the first-correct stimulus after the reversal). Here, we used a go/no-go version of the task to examine the degree to which these errors can be attributed to failure to inhibit incorrect responses near the reversal. We presented pigeons with either a green or red stimulus (randomized across trials), with pecks to 1 reinforced with food and pecks to the other stimulus leading to a 10-s time-out the reward versus time-out contingencies reversed after 40 trials. Pigeons rarely withheld responses when reward was provided for pecking, but produced many incorrect pecks near the reversal. Subsequent experiments examined these errors with longer sessions and multiple reversals, as well as on choice tasks. Our results suggest that pigeons' errors may be due to an inability to inhibit incorrect responses rather than a deliberate choice of the incorrect stimulus on simultaneous discrimination midsession reversal procedures. Results suggest that pigeons learned independent rules about the 2 stimuli, and that training with multiple reversals changed the rules that governed pigeons' responding. (PsycINFO Database Record
Publisher: Springer Science and Business Media LLC
Date: 06-06-2007
DOI: 10.1038/NG2061
Publisher: BMJ
Date: 25-05-2009
Publisher: BMJ
Date: 31-01-2012
Publisher: Oxford University Press (OUP)
Date: 23-05-2020
DOI: 10.1093/RHEUMATOLOGY/KEAA215
Abstract: ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We ided the population according to age at diagnosis: & years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). A total of 1338 patients with AAV were included: 66% had disease onset at & years of age [female 50% mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54% mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27% P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97) P = 0.03]. Within 6 months of diagnosis of AAV, patients & years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.
Publisher: Springer Science and Business Media LLC
Date: 17-07-2019
DOI: 10.1038/S41598-019-46649-Z
Abstract: Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
Publisher: Springer Science and Business Media LLC
Date: 2010
DOI: 10.1186/AR2969
Publisher: Oxford University Press (OUP)
Date: 28-02-2003
DOI: 10.1093/RHEUMATOLOGY/KEG169
Abstract: To develop a robust assay for genotyping the FcgammaRIIIA-158V/F polymorphism and to confirm the putative association between the FcgammaRIIIA-158V allele and rheumatoid arthritis (RA). This allelic association study examined the FcgammaRIIIA-158V/F polymorphism for association with RA. A novel single-stranded conformational polymorphism assay was used to genotype 828 RA patients and 581 controls from the UK. The FcgammaRIIIA-158V allele was associated with both RA (P=0.02) and nodules (P=0.04). In iduals homozygous for this higher affinity allele had a significantly increased risk of RA (OR 1.53, 95% CI 1.08-2.18) and the development of nodules (OR 2.20, 95% CI 1.20-4.01). There was no evidence of an interaction with the shared epitope. We have developed a novel assay to genotype the FcgammaRIIIA-158F/V polymorphism and confirmed that homozygosity for the FcgammaRIIIA-158V allele is associated with UK Caucasian RA, particularly in those in iduals with nodules, suggesting FcgammaRIIIA may play a role in determining disease severity or in the development of nodules per se.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2012
DOI: 10.1038/NATURE11582
Publisher: Springer Science and Business Media LLC
Date: 04-2010
DOI: 10.1038/NATURE08979
Publisher: Springer Science and Business Media LLC
Date: 14-09-2008
DOI: 10.1038/NG.218
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ann Morgan.