Kellgren Center for Rheumatology

Manchester, United Kingdom

Kellgren Center for Rheumatology

Manchester, United Kingdom
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Bowes J.,University of Manchester | Budu-Aggrey A.,University of Manchester | Huffmeier U.,Friedrich - Alexander - University, Erlangen - Nuremberg | Uebe S.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 31 more authors.
Nature Communications | Year: 2015

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. © 2015 Macmillan Publishers Limited. All rights reserved.

Barta Z.,National Institute for Rehabilitation | Harrison M.J.,University of Manchester | Wangrangsimakul T.,North Manchester General Hospital | Shelmerdine J.,Kellgren Center for Rheumatology | And 7 more authors.
Lupus | Year: 2010

We tested the hypothesis that carotid atherosclerosis in systemic lupus erythematosus (SLE) is associated with poor health-related quality of life (HRQOL), which is independent of any association with traditional risk factors (TRFs), lifestyle and socioeconomic factors. Women with SLE completed the RAND Medical Outcome Study 36-Item Short-Form Health Survey version 1 (MOS SF-36). B-mode Doppler examination of the carotid arteries determined the presence of atherosclerotic plaque. The association between carotid plaque and HRQOL domains was analysed using logistic regression models with sequential adjustments for age, TRFs, education level and employment status. We studied 181 women, 47 (26%) of whom had carotid plaque. Carotid plaque was significantly associated with lower levels of physical functioning (p = 0.047), vitality (p = 0.04), role emotional (p = 0.04) and mental health subscales (p = 0.01) and lower mental component summary score (MCS) (p = 0.03). These associations were no longer significant after adjustment for age and TRFs, especially smoking. Smokers had lower physical functioning, vitality and mental health and more bodily pain. The association between carotid plaque and HRQOL was not independent of TRFs and smoking was a key mediator of the associations found. Poor HRQOL in smokers will need addressing as part of any smoking cessation strategies in SLE patients.

Bowes J.,University of Manchester | Loehr S.,Friedrich - Alexander - University, Erlangen - Nuremberg | Budu-Aggrey A.,University of Manchester | Uebe S.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 23 more authors.
Annals of the Rheumatic Diseases | Year: 2015

Objectives: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis; it has a higher estimated genetic component than psoriasis alone, however most genetic susceptibility loci identified for PsA to date are also shared with psoriasis. Here we attempt to validate novel single nucleotide polymorphisms selected from our recent PsA Immunochip study and determine specificity to PsA. Methods: A total of 15 single nucleotide polymorphisms were selected (PImmunochip <1×10-4) for validation genotyping in 1177 cases and 2155 controls using TaqMan. Meta-analysis of Immunochip and validation data sets consisted of 3139 PsA cases and 11 078 controls. Novel PsA susceptibility loci were compared with data from two large psoriasis studies (WTCCC2 and Immunochip) to determine PsA specificity. Results: We found genome-wide significant association to rs2476601, mapping to PTPN22 (p=1.49×10-9, OR=1.32), but no evidence for association in the psoriasis cohort (p=0.34) and the effect estimates were significantly different between PsA and psoriasis (p=3.2×10-4). Additionally, we found genome-wide significant association to the previously reported psoriasis risk loci; NOS2 (rs4795067, p=5.27×10-9). Conclusions: For the first time, we report genome-wide significant association of PTPN22 (rs2476601) to PsA susceptibility, but no evidence for association to psoriasis.

McElhone K.,Royal Blackburn Hospital | Castelino M.,Royal Blackburn Hospital | Abbott J.,University of Central Lancashire | Bruce I.N.,University of Manchester | And 10 more authors.
Journal of Rheumatology | Year: 2010

Objective. Having developed and validated a disease-specific health-related quality of life (HRQOL) measure for patients with systemic lupus erythematosus (SLE), the LupusQoL, we determined its relationship to demographic and clinical measurements in a group of patients with SLE. Methods. A group of 322 outpatients completed the LupusQoL. Demographic (age, sex, marital status, ethnicity) and clinical variables (disease duration, disease activity, damage) were recorded. Associations between the 8 LupusQoL domains and age, disease duration, disease activity, and damage were explored using Spearman's correlation coefficients. Differences in LupusQoL scores were examined for sex and marital status using the Mann-Whitney U test. Ethnic groups were compared using ANOVA. Results. All domains of LupusQoL were impaired, with fatigue (56.3) being the worst affected and body image (80.0) the least. The correlations between the LupusQoL domain scores and age (r = -0.01 to -0.22) and disease duration (r = 0 to 0.16) were absent or weak. Similarly, there were no significant differences in the LupusQoL scores regarding sex, marital status, or the 3 main ethnic groups (Black-Caribbean, Asian, White). Although there were statistically significant correlations between the scores of the LupusQoL domains and some scores of the British Isles Lupus Assessment Group index (r = -0.22 to 0.09) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (r = -0.29 to 0.21), these were weak. Conclusion. HRQOL was impaired in this cohort of outpatients with SLE as assessed by the validated lupus-specific LupusQoL. There were no clinically important associations between the 8 domains of the LupusQoL and clinical or demographic variables in this group of patients. Thus, the LupusQoL is a relatively independent outcome measure in patients with SLE. The Journal of Rheumatology Copyright © 2010. All rights reserved.

Bowes J.,University of Manchester | Orozco G.,University of Manchester | Flynn E.,University of Manchester | Ho P.,University of Manchester | And 17 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objectives: To investigate a shared genetic aetiology for skin involvement in psoriasis and psoriatic arthritis (PsA) by genotyping single-nucleotide polymorphisms (SNPs), reported to be associated in genome-wide association studies of psoriasis, in patients with PsA. Methods: SNPs with reported evidence for association with psoriasis were genotyped in a PsA case and control collection from the UK and Ireland. Genotype and allele frequencies were compared between PsA cases and controls using the Armitage test for trend. Results: Seven SNPs mapping to the IL1RN, TNIP1, TNFAIP3, TSC1, IL23A, SMARCA4 and RNF114 genes were successfully genotyped. The IL23A and TNIP1 genes showed convincing evidence for association (rs2066808, p = 9.1 x 10-7; rs17728338, p = 3.5 x 10-5, respectively) whilst SNPs mapping to the TNFAIP3, TSC1 and RNF114 genes showed nominal evidence for association (rs610604, p = 0.03; rs1076160, p = 0.03; rs495337, p = 0.0025). No evidence for association with IL1RN or SMARCA4 was found but the power to detect association was low. Conclusions: SNPs mapping to previously reported psoriasis loci show evidence for association to PSA, thus supporting the hypothesis that the genetic aetiology of skin involvement is the same in both PsA and psoriasis.

Bowes J.,University of Manchester | Eyre S.,University of Manchester | Flynn E.,University of Manchester | Ho P.,University of Manchester | And 23 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective There is great interest in the identification of genetic factors that differentiate psoriatic arthritis (PsA) from psoriasis vulgaris (PsV), as such discoveries could lead to the identification of distinct underlying aetiological pathways. Recent studies identified single nucleotide polymorphisms (SNPs) in the interleukin 13 ( IL-13 ) gene region as risk factors for PsV. Further investigations in one of these studies found the effect to be primarily restricted to PsA, thus suggesting the discovery of a specific genetic risk factor for PsA. Given this intriguing evidence, association to this gene was investigated in large collections of PsA and PsV patients and healthy controls. Methods Two SNPs (rs20541 and rs1800925) mapping to the IL-13 gene were genotyped in 1057 PsA and 778 type I PsV patients using the Sequenom genotyping platform. Genotype frequencies were compared to those of 5575 healthy controls. Additional analyses were performed in phenotypic subgroups of PsA (type I or II PsV and in those seronegative for rheumatoid factor). Results Both SNPs were found to be highly associated with susceptibility to PsA (rs1800925 ptrend = 6.1×10 -5 OR 1.33, rs20541 ptrend = 8.0×10 -4 OR 1.27), but neither SNP was significantly associated with susceptibility to PsV. Conclusions This study confirms that the effect of IL-13 risk locus is specific for PsA, thus highlighting a key biological pathway that differentiates PsA from PsV. The identification of markers that differentiate the two diseases raises the possibility in future of allowing screening of PsV patients to identify those at risk of developing PsA.

Bowes J.,University of Manchester | Flynn E.,University of Manchester | Ho P.,University of Manchester | Ho P.,Kellgren Center for Rheumatology | And 17 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Objective: A common deletion mapping to the psoriasis susceptibility locus 4 on chromosome 1q21, encompassing two genes of the late cornified envelope (LCE) gene cluster, has been associated with an increased risk of psoriasis vulgaris (PsV). One previous report found no association of the deletion with psoriatic arthritis (PsA), suggesting it may be a specific risk factor for PsV. Given the genetic overlap between PsA and PsV, a study was undertaken to investigate whether single nucleotide polymorphisms (SNPs) mapping to this locus are risk factors for PsA in a UK and Irish population. Methods: Three SNPs with prior evidence of association with susceptibility to PsV were genotyped in 1057 patients with PsA using Sequenom iPlex chemistry and genotype frequencies compared with data available for 5575 healthy controls. Two of the SNPs, rs4112788 and rs4085613, were reported to be highly correlated with the LCE deletion. The third SNP, rs6701216, was previously reported to be associated with PsV in a US population. Results: Alleles tagging the deletion for both rs4112788 and rs4085613 were found to be enriched in cases compared with controls (69% vs 65%) and significantly associated with increased susceptibility to PsA (ptrend = 0.001, OR 1.19 and ptrend = 0.001, OR 1.18, respectively). No association was observed with rs6701216. Conclusions: The evidence presented here supports LCE deletion as a risk factor for PsA in a UK and Irish population. It suggests that this locus is a risk factor within a shared aetiological pathway that contributes to psoriatic skin disease in both PsV and PsA.

Chiu Y.,Wirral University Teaching Hospital | Ostor A.J.K.,University of Cambridge | Hammond A.,Maidstone District General Hospital | Sokoll K.,Bradford Teaching Hospitals | And 7 more authors.
Clinical Rheumatology | Year: 2012

Patients in England and Wales with rheumatoid arthritis (RA) receive treatment from the National Health Service (NHS) with therapies approved by the European Medicines Agency (EMA), under guidance from the National Institute for Health and Clinical Excellence (NICE). This document overviews the current NICE guidelines for the treatment of RA and identifies scenarios when such guidance may not represent the optimum management strategy for individual patients. Specifically, we consider the use of tocilizumab or abatacept as the most appropriate treatments for some patients. In such scenarios, it may be possible for the clinician to secure access to the required therapy through an application procedure known as an 'individual funding request', the process of which is described in detail here. At present, it is unclear the extent to which the proposed reform of the NHS will affect the role of NICE in providing guidance and setting standards of care. Until the full impact of the proposed changes are realized, individual funding requests will remain a valuable way of securing the optimal treatment for all patients suffering from RA. © Clinical Rheumatology 2012.

Bruce I.N.,University of Manchester | Bruce I.N.,Kellgren Center for Rheumatology
Current Opinion in Rheumatology | Year: 2010

PURPOSE OF REVIEW: To consider the unmet therapeutic need in lupus and to review recent open-label data and clinical trials as well as to assess lessons to be drawn from these studies. RECENT FINDINGS: Open-label data continue to emphasize the efficacy of rituximab in refractory systemic lupus erythematosus (SLE) patients. A number of clinical trials using biologic agents, including rituximab, have not achieved their primary endpoint; however aspects of trial design such as the choice of disease activity instrument, use of concomitant medications and inadequate power to detect a realistic effect may have contributed to the endpoints not being achieved. Certain subgroups of patients within these trials also may have responded better than the whole population suggesting that SLE disease heterogeneity may be an important confounder. Recently, belimumab has been successful in two phase III trials. These trials employed a novel SLE responder index (SRI) derived from a secondary analysis of previous phase II data. SUMMARY: Biological therapy holds much promise in SLE and as we learn more about the disease and apply the lessons learned from recent trials, we will be in a strong position to further accelerate drug development in SLE. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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