Rheumatoid Arthritis: Silman A

Combe B, Landewe R, Lukas C, Bolosiu HD, Breedveld F, Dougados M, Emery P, Ferraccioli G, Hazes JM, Klareskog L, Machold K, Martin-Mola E, Nielsen H, Silman A, Smolen J, Yazici H. · Immuno-Rhumatologie, Lapeyronie Hosp, Montpellier, France. · Ann Rheum Dis. · Pubmed #16396980 No free full text.

Abstract: OBJECTIVE: To formulate EULAR recommendations for the management of early arthritis. METHODS: In accordance with EULAR's "standardised operating procedures", the task force pursued an evidence based approach and an approach based on expert opinion. A steering group comprised of 14 rheumatologists representing 10 European countries. The group defined the focus of the process, the target population, and formulated an operational definition of "management". Each participant was invited to propose issues of interest regarding the management of early arthritis or early rheumatoid arthritis. Fifteen issues for further research were selected by use of a modified Delphi technique. A systematic literature search was carried out. Evidence was categorised according to usual guidelines. A set of draft recommendations was proposed on the basis of the research questions and the results of the literature search.. The strength of the recommendations was based on the category of evidence and expert opinion. RESULTS: 15 research questions, covering the entire spectrum of "management of early arthritis", were formulated for further research; and 284 studies were identified and evaluated. Twelve recommendations for the management of early arthritis were selected and presented with short sentences. The selected statements included recognition of arthritis, referral, diagnosis, prognosis, classification, and treatment of early arthritis (information, education, non-pharmacological interventions, pharmacological treatments, and monitoring of the disease process). On the basis of expert opinion, 11 items were identified as being important for future research. CONCLUSIONS: 12 key recommendations for the management of early arthritis or early rheumatoid arthritis were developed, based on evidence in the literature and expert consensus.

Griffiths I, Silman A, Symmons D, Scott DG. · No affiliation provided · Rheumatology (Oxford). · Pubmed #15328420 links to  free full text

This publication has no abstract.

Franklin J, Lunt M, Bunn D, Symmons D, Silman A. · ARC Epidemiology Research Unit, Manchester University Medical School, Oxford Road, Manchester M13 9PT, UK. · Ann Rheum Dis. · Pubmed #16249224 links to  free full text

Abstract: OBJECTIVE: To determine the risk of lymphoma in a primary care derived cohort of new onset cases of inflammatory polyarthritis and assess the contribution of disease severity and standard immunosuppressive treatment. DESIGN: Prospective cohort study. METHODS: 2105 subjects with new onset inflammatory polyarthritis were recruited to the Norfolk Arthritis Register (NOAR) and followed annually for (median) 8.4 years. Occurrence of lymphoma was determined by annual morbidity review and linkage to the central hospital database serving the NOAR area. Cases of lymphoma were verified by record review. Standardised incidence ratios (SIRs) for lymphoma were calculated compared with the local, age, sex, and calendar year expected rates. Stratified analyses were undertaken for various markers of disease severity and treatment history. RESULTS: There were 11 cases of lymphoma during 15,548 person years of follow up, the majority of which were of large B cell type. Compared with the local population the SIR was 2.4 (95% confidence interval, 1.2 to 4.2). The risks in cases classified as rheumatoid arthritis, ever rheumatoid factor positive, or ever treated with DMARDs were all higher, the highest risk group being those treated with methotrexate: SIR = 4.9 (1.8 to 10.6). CONCLUSIONS: There was a doubling in risk of lymphoma in new onset cases of inflammatory polyarthritis. Patients with the most severe disease were twice as likely as other patients to develop lymphoma. These results need to be taken into account when considering reported increased risks of lymphoma compared to background population risk in users of new biological agents.

Watson K, Symmons D, Griffiths I, Silman A. · Epidemiology Research Unit, Manchester University Medical School, Manchester, UK. · Ann Rheum Dis. · Pubmed #16239385 links to  free full text

Abstract: The British Society for Rheumatology (BSR) established a nationwide register for patients with rheumatological disorders treated with biologic agents. The register is designed as a national prospective study whose primary purpose is to assess long term toxicity from the use of these agents in routine practice. In addition, the data will be capable of addressing the benefits from their use in relation to their toxicity. One specific feature of the BSR register is the recruitment and collection of data from a parallel comparison group, comprising patients with active rheumatoid arthritis treated with conventional disease modifying agents. Both class specific and drug specific analyses of the group treated with biologicals are planned.

Adib N, Silman A, Thomson W. · Arthritis Research Campaign Epidemiology Unit, School of Epidemiology and Health Sciences, University of Manchester Medical School, Manchester M13 9PT, UK. · Rheumatology (Oxford). · Pubmed #15827045 links to  free full text

Abstract: OBJECTIVE: To determine the outcome, following the onset of juvenile idiopathic inflammatory arthritis, in terms of remission of disease activity, loss of function and structural damage based on a review of the available published data. METHODS: Electronic databases were searched for major studies publishing outcome data in the past 10 yr in juvenile idiopathic arthritis, juvenile rheumatoid arthritis and juvenile chronic arthritis, and 21 studies were selected. The proportions of children in the different categories of the outcomes of interest are described. Data were stratified where possible by disease subtype. RESULTS: There were major differences between the studies reviewed in terms of study design, case selection and the results obtained. In general, children with systemic- or polyarticular-onset disease were much less likely to go into remission than those with oligoarticular onset, although the remission rates in the latter group ranged from 36 to 84%. Several different approaches were used to assess functional outcome but the pattern of results between the different subgroups was the same as with remission. Similarly, children with polyarticular disease in all the cohorts reviewed were substantially more likely to have erosive radiological damage on follow-up. The rates of individual outcomes, even within a subgroup, varied considerably between studies and this does not appear to be explained solely by differences in methodology. CONCLUSIONS: There remains a considerable lack of clarity in the prognosis following onset of juvenile idiopathic arthritis for the major outcomes considered, although those with oligoarthritis at presentation have the best outcome. The ability to offer accurate prognosis is particularly important to both reassure parents and guide treatment at disease onset. To achieve this, large definitive prospective studies will be required.

Adib N, Silman A, Thomson W. · Arthritis Research Campaign Epidemiology Unit, School of Epidemiology and Health Sciences, University of Manchester Medical School, Manchester M13 9PT, UK. · Rheumatology (Oxford). · Pubmed #15827044 links to  free full text

Abstract: OBJECTIVE: To assess the relative contributions of demographic, clinical and laboratory variables in predicting outcome in juvenile idiopathic inflammatory arthritis (JIA), based on a review of the existing literature. METHODS: Electronic reference database searches for the previous 10 yr were conducted and studies examining the role of major potential predictors of main outcomes were identified. Where possible, subjects were grouped by JIA disease subtype. In addition to demographic variables, the following disease-related predictors were assessed: nature of joint involvement, acute-phase response, and presence of autoantibodies. These were then analysed for three main outcomes of interest: remission as assessed by disease activity; functional impairment; and structural damage as assessed by radiological joint erosions. RESULTS: In general, female gender, polyarticular and symmetrical joint involvement, elevated inflammatory markers and rheumatoid factor positivity were the most consistent predictors of a poor outcome, although the studies were frequently inconsistent in both the direction and the magnitude of the effects. CONCLUSIONS: These data are too variable to accurately identify those predictors associated with poor outcome following the onset of JIA. Although some of this variation may be the result of true differences between study populations, the vast majority of inconsistencies are explainable by the absence of standardized classification systems, outcome definitions, therapeutic approach and research tools. More comprehensive prospective evaluation is required before robust prediction models can be generated.

Bukhari M, Thomson W, Naseem H, Bunn D, Silman A, Symmons D, Barton A. · University of Manchester, Manchester, UK. · Arthritis Rheum. · Pubmed #17763407 links to  free full text

Abstract: OBJECTIVE: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are a stronger predictor of the severity of rheumatoid arthritis than is rheumatoid factor (RF). Their role in predicting outcome in unselected patients with new-onset inflammatory polyarthritis (IP) has not been examined. The aims of this study were to examine the role of baseline RF and anti-CCP antibodies in determining the likelihood of patients having erosions at presentation or in predicting future radiologic damage, and to determine whether anti-CCP antibodies or RF is sufficiently robust to be clinically useful in guiding treatment decisions in early IP. METHODS: Patients were recruited from the Norfolk Arthritis Register. Logistic regression models were fitted to test the ability of anti-CCP antibodies and RF to predict erosions. Further models were investigated to examine the role of anti-CCP antibodies in patients stratified by RF status. RESULTS: The presence of anti-CCP antibodies at baseline was strongly associated with both prevalent erosions (odds ratio [OR] 2.53 [95% confidence interval (95% CI) 1.48-4.30]) and developing erosions at 5 years (OR 10.2 [95% CI 6.2-16.9]). These ORs were higher than those for RF (OR 1.63 [95% CI 0.94-2.82] and OR 3.4 [95% CI 2.2-5.2], respectively). The likelihood ratio (LR) for the prediction of prevalent erosions and erosions at 5 years was highest in the RF-subgroup (LR 2.2 and 5.8, respectively). However, 27% of anti-CCP-patients had developed erosions by 5 years. CONCLUSION: Despite their strong association with the presence, development, and extent of erosions, anti-CCP antibodies alone are not a sufficiently accurate measure upon which to base clinical treatment decisions. Knowledge of anti-CCP antibody status is most informative in RF-negative patients.

Naseem H, Thomson W, Silman A, Worthington J, Symmons D, Barton A. · ARC Epidemiology Unit, University of Manchester, Oxford Road, Manchester, M13 9PT, UK. · Ann Rheum Dis. · Pubmed #17666450 links to  free full text

Abstract: BACKGROUND: The PTPN22 gene has been widely confirmed as a susceptibility gene for rheumatoid arthritis (RA) in populations of Northern European descent. The aim of the current study was to explore the role of variants spanning the PTPN22 gene in determining susceptibility to and outcome of inflammatory polyarthritis (IP). PATIENTS AND METHODS: Single nucleotide polymorphism (SNP) variants spanning the gene were genotyped using the Sequenom MassArray platform and tested, firstly for their association with susceptibility to IP. Genotype frequencies were compared between new onset IP cases (n = 843) and population controls (n = 471). Secondly, a within-cohort analysis was performed testing each variant for association with a number of clinical outcome measures reflecting disease severity including radiological erosions, physical function, measured using the Health Assessment Questionnaire (HAQ) score, and disease activity at defined time-points following disease presentation. RESULTS: A significant association between carriage of the PTPN22*1858T allele and IP (odds ratio (OR) = 1.4 (95% CI 1.1-1.9), p = 0.02) was observed. The strength of the effect was similar in the RA subgroup (OR = 1.4 (95% CI 1.0-1.9), p = 0.05). No association between IP susceptibility and any of the other SNPs was detected. No association was detected for any of the SNPs tested, including the PTPN22*C1858T polymorphism, for either erosive status, Larsen score by 5 years or other markers of clinical outcome. CONCLUSION: The PTPN22*C1858T polymorphism is associated with susceptibility to IP, but we have found no evidence for association of this or other variants spanning the gene with clinical outcome measures.

Franklin J, Lunt M, Bunn D, Symmons D, Silman A. · University of Manchester, Manchester, UK. · Arthritis Rheum. · Pubmed #17328051 links to  free full text

Abstract: OBJECTIVE: To investigate whether the incidence of cancer is increased and whether the rate of cancer survival is reduced in patients following the onset of inflammatory polyarthritis. METHODS: Between 1990 and 1999, we recruited 2,105 patients to a large primary care-based register of new-onset inflammatory polyarthritis. Subsequent cancers were ascertained by linkage to hospital and death records and were confirmed by the regional cancer register. Cancer incidence, both all-site and site-specific, was compared with regional rates, adjusting for age, sex, and calendar year. Overall cancer survival, adjusted for site, was compared with regional data using Kaplan-Meier curves and Cox regression. RESULTS: There were 123 incident cases of cancer in the cohort of patients with inflammatory polyarthritis. The overall incidence of cancer among this cohort of patients with inflammatory polyarthritis was not increased compared with that in the regional population. Among cancers of all major organ systems, only the incidence of hematopoietic cancers (including lymphoma) was increased. Five-year cancer survival was reduced in patients with inflammatory polyarthritis compared with patients without inflammatory polyarthritis. After adjusting for diagnosis, age, sex, and tumor type, mortality in patients with inflammatory polyarthritis and cancer was significantly increased (hazard ratio 1.4, 95% confidence interval 1.1-1.7). CONCLUSION: This is the first investigation of overall cancer survival in patients with inflammatory polyarthritis. Compared with an increased incidence of cancer, reduced cancer survival might be a greater contributor to the increased cancer mortality observed in some rheumatoid arthritis populations.

Franklin J, Lunt M, Bunn D, Symmons D, Silman A. · Epidemiology Research Unit, Manchester University Medical School, Manchester M13 9PT, UK. · Ann Rheum Dis. · Pubmed #16984941 No free full text.

Abstract: BACKGROUND: The increased mortality observed in patients with rheumatoid arthritis is partly due to an increased occurrence of serious infections. A retrospective study from the Mayo Clinic found that infection risk is increased in rheumatoid arthritis. In particular, serious infection was associated with severe disease and use of corticosteroids. Robust estimates are required from prospective studies of incident cases. OBJECTIVE: To examine the risk of infection leading to hospitalisation and potential factors associated with this risk in an unselected population of patients with inflammatory polyarthritis. DESIGN: A prospective cohort study comparing infection incidence in new-onset patients with inflammatory polyarthritis with local population experience. PATIENTS AND METHODS: 2108 patients with inflammatory polyarthritis from a community-based register were studied and followed up annually (median 9.2 years). The rate of hospitalisations for serious infection was compared with the rate of hospitalisations in the regional population. The contribution of potential predictors was assessed by undertaking a within-cohort analysis. RESULTS: Overall, the incidence of infection was more than two and a half times that of the general population (varying by site). History of smoking, corticosteroid use and rheumatoid factor were found to be significantly independent predictors of infection-related hospitalisation. Patients with inflammatory polyarthritis with all three factors were more than seven times as likely to be hospitalised compared with the rest of the cohort. DISCUSSION: These findings provide background data on the risk of infection associated with rheumatoid arthritis, and are of particular interest given the current awareness of the risk of infection associated with anti-tumour necrosis factoralpha treatments.

Bukhari M, Lunt M, Barton A, Bunn D, Silman A, Symmons D. · ARC Epidemiology Unit, University of Manchester, Oxford Road, Manchester M13 9PT, UK. · Ann Rheum Dis. · Pubmed #16950810 No free full text.

Abstract: BACKGROUND: Increasing age at onset has been associated with worse outcome in rheumatoid arthritis, although there are few data from unselected inception cohorts. HYPOTHESIS: Increasing age is associated with a higher risk of erosions at presentation, and this increase is not explained by age-related disease confounders. SUBJECTS AND METHODS: 222 subjects (median onset age 59 years) were studied from a primary-care-based register of new-onset inflammatory polyarthritis. Patients had hand and feet radiographs taken within 12 months from symptom onset. Films were scored by two readers using the Larsen score. The risk of erosions in those aged 50-69 and >or=70 years at onset was compared with the risk in those aged <50 years both before and after adjustment for possible age-related disease confounders. RESULT: The prevalences of erosions were 22%, 52% and 71% in those aged <50, 50-69 and >or=70 years at onset equivalent to odds ratios (ORs) (95% confidence intervals (CIs)) of 3.5 (2.2 to 5.7) and 7.4 (4.5 to 12.1), respectively, in the two older age groups. Excluding those with proximal interphalangeal (PIP) erosions alone (due to possible osteoarthritis) did not alter these findings. Adjustments for disease characteristics using logistic regression did not attenuate these findings: adjusted ORs (95% CIs) 3.6 (2.1 to 6.1) and 6.9 (3.8 to 12.2) for age groups 50-69 and >or=70 years, respectively. The influence of age was stronger than most of the disease-related variables in predicting erosions in this cohort. CONCLUSION: Increasing age at symptom onset is strongly associated with higher occurrence of erosions within the first year unexplained by greater disease severity.

Dixon W, Silman A. · Epidemiology Unit, University of Manchester Medical School, Manchester, UK. · Arthritis Res Ther. · Pubmed #16911768 links to  free full text

Abstract: A recent meta-analysis of randomized clinical trials reported by Bongartz and coworkers raised concerns about an increased rate of malignancy and serious infection in rheumatoid arthritis patients treated with anti-tumour necrosis factor monoclonal antibodies. This commentary discusses some of the methodological issues in their analysis and urges caution in interpreting the results.

Deighton C, Criswell LA, Lum RF, Silman A. · Department of Rheumatology, Derbyshire Royal Infirmary, Derby, DE1 2QY, UK. · Rheumatology (Oxford). · Pubmed #16754627 links to  free full text

Abstract: OBJECTIVES: Previous work has suggested that features of genetic anticipation might be present in familial rheumatoid arthritis (RA), but bias is difficult to exclude when looking at disease in two consecutive generations. We used data from the North American Rheumatoid Arthritis Consortium (NARAC) and the Arthritis Research Campaign National repository for RA multicase pedigrees to determine whether differences in age of onset within multicase sibships were supportive of genetic anticipation. METHOD: RA sibling pairs were identified from both data sets. The period of observation was defined as the time between the first sibling developing RA and the time that the sibship was ascertained for the study. A paired t-test for the difference in ages of RA onset within the pairs was calculated. Ages of conception of the parent were correlated with the age of RA onset. RESULTS: Information was available for 743 sibships in the NARAC data set and 396 sibships in the Arthritis Research Campaign (ARC) data set. In both data sets, the older siblings had an older age of onset than their younger siblings (39.3 vs 36.9 in the NARAC, and 43.8 vs 40.1 in the ARC data set, both P < 0.001). The two data sets were then stratified into tertiles by a period of observation. In both data sets, there was a progressive decline in the sibling age of onset differences. For the first tertile (shortest observation period), the older sibling had a significantly older age of onset than the younger. This difference decreased in the second tertile, and was not significant in the third tertile (longest observation period). There was no significant correlation between the age of RA onset and the maternal or paternal ages of conception in either data set. CONCLUSION: Features compatible with genetic anticipation in RA multicase sibships are subject to observational bias. This does not support a role for genetic anticipation in familial RA.

John S, Amos C, Shephard N, Chen W, Butterworth A, Etzel C, Jawaheer D, Seldin M, Silman A, Gregersen P, Worthington J. · ARC Epidemiology Unit, University of Manchester, Manchester, UK. · Arthritis Rheum. · Pubmed #16646029 links to  free full text

Abstract: OBJECTIVE: HLA is the most strongly associated locus in rheumatoid arthritis (RA), accounting for up to one-third of the genetic contribution. Conditioning on the effect of true disease loci such as HLA can lead to increased power to detect effects at other loci and, in addition, allows investigation of the underlying disease models, including interactions. The aim of this study was to detect susceptibility loci for RA by conditioning on HLA in a large sample of affected sibling pairs (ASPs) and to test for evidence of interaction between novel loci and HLA. METHODS: Genotype data from 3 whole-genome linkage scans for RA in a US population and a UK population were pooled, resulting in a combined data set of 886 ASPs. This pooling of data increased the power to detect loci showing low levels of heterogeneity. Nonparametric linkage analysis was performed to identify regions of interest. Joint 2-locus analysis was then performed for HLA and each of the loci that demonstrated evidence of linkage in the 886 ASPs. RESULTS: Evidence for linkage was most significant at HLA (P = 4 x 10(-16)), with 7 non-HLA loci showing some evidence for linkage (P = 0.05-0.003). Joint modeling of these loci with HLA provided evidence for linkage at a genome-wide significance level for loci on 6q (P = 2.7 x 10(-6)) and 16p (P = 2 x 10(-4)). CONCLUSION: These data provide the most convincing evidence to date that 6q and 16p harbor susceptibility genes. In addition, these loci may interact with HLA, facilitating the search for candidate genes within this region.

Hyrich K, Symmons D, Watson K, Silman A, Anonymous00004, Anonymous00005. · ARC Unit, University of Manchester, Manchester, UK. · Ann Rheum Dis. · Pubmed #16339291 links to  free full text

Abstract: OBJECTIVE: To describe the occurrence of baseline comorbidity in subjects with active rheumatoid arthritis starting treatment with biological agents. Such data are necessary to interpret the reported occurrence of adverse events following treatment. METHODS: Baseline comorbidity was recorded in a large national cohort of patients with rheumatoid arthritis newly starting biological agents. The distribution of the number and types of comorbidities is presented. RESULTS: In all, 7818 patients treated with biological agents (infliximab 3332, etanercept 3302, adalimumab 1059, anakinra 132) were included in the analysis. Comorbidity was common, with 58% of patients having at least one comorbid condition and 25% having more than one. The most frequent comorbid conditions were hypertension, depression, peptic ulcer disease, and respiratory disease. CONCLUSIONS: In routine use, patients treated with biological agents have high levels of baseline comorbidity, which should influence the interpretation of reported adverse events.

Ho P, Bruce IN, Silman A, Symmons D, Newman B, Young H, Griffiths CE, John S, Worthington J, Barton A. · University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. · Arthritis Rheum. · Pubmed #16255050 links to  free full text

Abstract: OBJECTIVE: Clinical, pharmacologic, and epidemiologic evidence supports the hypothesis that common genetic pathways may underlie inflammatory diseases. In a previous study, a Crohn's disease gene, CARD15, was demonstrated to be associated with psoriatic arthritis (PsA). Recently, a functional haplotype of 2 single-nucleotide polymorphisms (SNPs) mapping to the organic cation transporter (OCTN) genes, SLC22A4 and SLC22A5, was identified as a second Crohn's disease susceptibility locus. The SLC22A4 gene has also been associated with rheumatoid arthritis. This study was undertaken to further elucidate associations of PsA with Crohn's disease susceptibility genes. METHODS: Association with CARD15 and OCTN was investigated in UK Caucasian patients with PsA (n = 472) and population controls (n = 594), using 5' allelic discrimination assays (TaqMan). Two SNPs in OCTN, forming a haplotype previously associated with Crohn's disease, were also tested in patients with psoriasis (n = 218) and patients with early undifferentiated inflammatory arthritis (n = 386). Allele and estimated haplotype frequencies were compared between patients and controls. RESULTS: No association of PsA with CARD15 was detected. In contrast, a functional SNP mapping to the promoter region of SLC22A5 (rs2631367) was associated with PsA (for CC versus GG, odds ratio 1.65, 95% confidence interval 1.13-2.41, uncorrected P = 0.005). In addition, the haplotype associated with Crohn's disease was also associated with PsA (P = 0.001). No association was detected in the cohort with psoriasis alone or in the cohort with undifferentiated inflammatory arthritis. CONCLUSION: The OCTN haplotype previously associated with Crohn's disease is also associated with PsA, suggesting that these 2 diseases may share some common genetic control in pathways of inflammation.

Hinks A, Barton A, John S, Bruce I, Hawkins C, Griffiths CE, Donn R, Thomson W, Silman A, Worthington J. · University of Manchester, Manchester, UK. · Arthritis Rheum. · Pubmed #15934099 links to  free full text

Abstract: OBJECTIVE: The protein tyrosine phosphatase N22 (PTPN22) gene exhibits regulatory activities for both T cells and B cells. A missense single-nucleotide polymorphism (SNP) within this gene (rs2476601) has recently been associated with 4 autoimmune diseases: rheumatoid arthritis (RA), systemic lupus erythematosus, autoimmune thyroid disease, and type 1 diabetes mellitus, all of which are T cell-mediated and associated with the elaboration of autoantibody. The aim of this study was to investigate associations of the missense SNP of PTPN22 in a number of autoimmune diseases in the UK population, including RA, juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis (PsA), and multiple sclerosis (MS), some of which have not been examined previously. METHODS: The PTPN22 missense SNP was genotyped in 886 RA, 661 JIA, 279 psoriasis, 455 PsA, and 379 MS patients and in 595 healthy controls. Association with the PTPN22 SNP was analyzed by chi-square test as implemented in Stata software. RESULTS: There was a significant association between the PTPN22 SNP and RA (P = 1.8 x 10(-8)) and JIA (P = 0.0005). In contrast, no association with psoriasis, PsA, or MS was detected. CONCLUSION: We replicated the findings of a previous association with RA and identified a novel association with JIA. Together with previous data showing associations with other autoimmune diseases, our findings provide further evidence that the PTPN22 gene plays a role in the pathogenesis of a subgroup of autoimmune diseases.

Barton A, Bowes J, Eyre S, Symmons D, Worthington J, Silman A. · ARC-EU, Stopford Building, University of Manchester, Manchester M13 9PT, UK. · Ann Rheum Dis. · Pubmed #15731287 links to  free full text

Abstract: BACKGROUND: A functional haplotype of the peptidylarginine deiminase 4 (PADI4) gene has recently been identified as a rheumatoid arthritis susceptibility gene in a Japanese but not in a UK population. One possible explanation for this disparity is that the gene determines severity of rather than susceptibility to inflammatory polyarthritis (IP) and that the UK and Japanese cohorts differed in terms of outcome.Aim: To examine the association between individual PADI4 single nucleotide polymorphisms (SNPs) and haplotypes, with the development and severity of erosions by five years in patients with IP. METHODS: 438 patients from the NOAR inception cohort of patients with IP were x rayed five years after presentation with early IP. Association with four exonic SNPs (padi4_89*G/A, padi4_90*T/C, padi4_92*G/C, and padi4_104*T/C), mapping to the PADI4 gene and defining a haplotype previously reported to be associated with rheumatoid arthritis, was investigated. Patients were compared for the presence, extent, and progression of erosions by five years and the presence of antibodies to citrullinated peptide (anti-CCP antibodies). RESULTS: There was no association between individual PADI4 SNPs or haplotypes and the development or extent of erosions by five years. Restricting analysis to patients who satisfied ACR criteria for rheumatoid arthritis by five years did not alter the conclusions. No association with presence of anti-CCP antibodies was detected. CONCLUSIONS: No evidence was found for association of the PADI4 gene with severity as assessed by erosive outcome at five years or with presence of anti-CCP antibodies in patients with IP.

John S, Shephard N, Liu G, Zeggini E, Cao M, Chen W, Vasavda N, Mills T, Barton A, Hinks A, Eyre S, Jones KW, Ollier W, Silman A, Gibson N, Worthington J, Kennedy GC. · University of Manchester, Manchester, United Kingdom. · Am J Hum Genet. · Pubmed #15154113 links to  free full text

Abstract: Despite the theoretical evidence of the utility of single-nucleotide polymorphisms (SNPs) for linkage analysis, no whole-genome scans of a complex disease have yet been published to directly compare SNPs with microsatellites. Here, we describe a whole-genome screen of 157 families with multiple cases of rheumatoid arthritis (RA), performed using 11,245 genomewide SNPs. The results were compared with those from a 10-cM microsatellite scan in the same cohort. The SNP analysis detected HLA*DRB1, the major RA susceptibility locus (P=.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the microsatellite scan. In addition, four loci were detected at a nominal significance level (P<.05) in the SNP linkage analysis; these were not observed in the microsatellite scan. We demonstrate that variation in information content was the main factor contributing to observed differences in the two scans, with the SNPs providing significantly higher information content than the microsatellites. Reducing the number of SNPs in the marker set to 3,300 (1-cM spacing) caused several loci to drop below nominal significance levels, suggesting that decreases in information content can have significant effects on linkage results. In contrast, differences in maps employed in the analysis, the low detectable rate of genotyping error, and the presence of moderate linkage disequilibrium between markers did not significantly affect the results. We have demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allows loci to be defined more precisely and provides a partial scaffold for association studies, substantially reducing the resource requirement for gene-mapping studies.

Eyre S, Barton A, Shephard N, Hinks A, Brintnell W, MacKay K, Silman A, Ollier W, Wordsworth P, John S, Worthington J. · Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, UK. · Arthritis Rheum. · Pubmed #15022312 links to  free full text

Abstract: OBJECTIVE: A previous whole-genome scan (WGS) of 182 UK rheumatoid arthritis (RA) affected sibling pair (ASP) families suggested linkage to HLA and 11 other chromosome regions. Replication of such findings in an independent cohort can help to distinguish true linkages from false-positive linkages. Since RA is a heterogeneous disease, some loci may be linked only in subsets of patients. Thus, the aim of this study was to investigate in an additional set of RA ASP families linkage to regions showing deviation in expected allele-sharing ratios in the UK WGS and to perform subset analysis on the combined cohort. METHODS: Twenty loci were investigated for linkage in 217 Caucasian UK RA ASPs. Stratification analysis was performed on the combined cohort of 377 RA ASP families to account for sex, RA severity, and the shared epitope (SE). RESULTS: None of the regions of linkage identified in the initial WGS achieved statistical significance in the second cohort. In contrast, after stratification analysis, 14 regions showed nominal evidence of linkage (logarithm of odds score >0.8) in one or more subgroups. In particular, the strength of evidence for linkage to chromosome 16p was increased in subsets of ASPs with younger age at disease onset (LOD score 2.38) and for linkage to chromosome 6q in female-female ASPs (LOD score 2.31) and in ASPs in which both siblings had 2 copies of the SE (LOD score 3.03). CONCLUSION: These results support the evidence for heterogeneity of RA. This information will inform the future design of association-based investigations as the search for disease genes in the linked regions begins.

Barton A, Platt H, Salway F, Symmons D, Lunt M, Worthington J, Silman A. · Arthritis and Rheumatism Campaign Epidemiology Unit, University of Manchester, Manchester, UK. ABarton@fs 1.ser.man.ac.uk · J Rheumatol. · Pubmed #14994386 No free full text.

Abstract: OBJECTIVE: To investigate the association between the mannose binding lectin gene (MBL) promoter and structural single nucleotide polymorphisms (SNP) with development of erosions in a primary care inception cohort of patients with inflammatory polyarthritis (IP). METHODS: DNA was available from 438 patients with IP and radiographic data were available for all patients at 5 years. Four SNP [MBL-550*C/G (H/L), MBL-221*G/C (Y/X), MBL codon 52*C/T, and MBL codon 54*G/A] mapping to the MBL gene were genotyped using primer extension techniques. Allele frequencies were compared between IP cases with erosions by 5 years and those without. RESULTS: None of the SNP were associated with erosive outcomes by 5 years. Furthermore there was no association with Larsen score by 1 or 5 years or with the change in Larsen score between 1 and 5 years. Similarly, the genotype combinations known to encode for low MBL protein production were not associated with erosive outcome in the IP cohort as a whole or in those with rheumatoid arthritis (RA) by 5 years. CONCLUSION: Polymorphism within the MBL gene is not associated with presence or extent of erosions by 5 years in patients with RA or IP.

Barton A, Platt H, Salway F, Symmons D, Barrett E, Bukhari M, Lunt M, Zeggini E, Eyre S, Hinks A, Tellam D, Brintnell B, Ollier W, Worthington J, Silman A. · University of Manchester, UK. · Ann Rheum Dis. · Pubmed #14962963 links to  free full text

Abstract: BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a powerful inflammatory mediator in rheumatoid and other types of inflammatory arthritis. Polymorphisms within the TNFalpha gene have previously been investigated to determine their role in the aetiopathogenesis of rheumatoid arthritis (RA), but it is unclear whether reported associations are with susceptibility to, or severity of, disease. OBJECTIVE: To examine the association between both individual TNFalpha single nucleotide polymorphisms (SNPs) and haplotypes with the development and severity of erosions by 5 years in patients with inflammatory polyarthritis (IP). METHODS: 438 patients from the Norfolk Arthritis Register observational inception cohort of patients with IP were x rayed 5 years after disease onset. They were genotyped for nine SNPs mapping to the TNFalpha gene, using a SNaPshot primer extension assay. Haplotypes were constructed in patients with IP, who were compared for the presence and extent of erosions at 5 years. RESULTS: No association between individual TNFalpha SNPs or haplotypes in the patients who developed erosions at 5 years compared with those who remained non-erosive was found. Restricting analysis to patients who satisfied ACR criteria for RA by 5 years did not affect the conclusions. CONCLUSION: The TNFalpha gene does not seem to be associated with severity as assessed by erosive outcome at 5 years in patients with IP.

Silman A, Symmons D, Scott DG, Griffiths I. · ARC Epidemiology Unit, University of Manchester, UK. · Ann Rheum Dis. · Pubmed #14532144 links to  free full text

Abstract: The British Society for Rheumatology (BSR) established a register of patients newly treated with biological agents, the BSR Biologics Register (BSRBR), which became active in January 2002. The goal is to register all patients in the United Kingdom with rheumatic diseases, newly starting treatment with these agents and to follow them up to determine the incidence of any short and long term hazards to health. The Register is also recruiting a comparison cohort of patients with rheumatoid arthritis treated with standard disease modifying antirheumatic drugs to determine the relative contributions of disease factors and other treatments apart from biological agents on any risks observed.

Morgan C, Lunt M, Brightwell H, Bradburn P, Fallow W, Lay M, Silman A, Bruce IN. · Arthritis Research Campaign (ARC) Epidemiology Unit, University of Manchester Medical School, Oxford Road, Manchester, M13 9PT, UK. · Ann Rheum Dis. · Pubmed #12480663 links to  free full text

Abstract: BACKGROUND: There is a wide variation in responses to standard disease modifying antirheumatic drug (DMARD) treatment in rheumatoid arthritis (RA). Whether multidrug resistance, failure to respond to several DMARDs, is a specific entity over and above that expected by chance alone is unclear. OBJECTIVE: To identify patients with RA who demonstrate a multidrug resistant phenotype and to determine what proportion of the variance in drug responses is due to patient related factors. METHODS: Patients with RA (1987 American College of Rheumatology criteria) were identified from clinics at Manchester Royal Infirmary and through the Arthritis Research Campaign National RA Repository. The clinic records were reviewed and multidrug resistance was defined as stopping three or more DMARDs owing to lack of efficacy after an adequate trial of the drug. Logistic regression measured by a random effects model was used to determine the relative contribution of the drug and subject related differences to the multidrug resistance. RESULTS: 265 patients (210 (79.3%) female) were studied. The mean (SD) age and disease duration were 52.2 (12.9) and 10.7 (8.8) years, respectively. Patients had a median (range) of 2 (1-8) DMARD courses. Failure of at least one DMARD due to inefficacy occurred in 105 (40%) and 13 (5%) were multidrug resistant. Overall, 35% of the variance in drug responses was due to between-subject differences (p=0.02). Rheumatoid factor (RF) status contributed significantly to this (OR=2.15, 95% confidence interval (95% CI) 1.00 to 4.62) but explained only 3% of the total variance in drug inefficacy. CONCLUSION: Multidrug resistance occurs in an uncommon (5%) but important subgroup of patients with RA. The between-subject variance is not fully explained by demographics and RF status. Understanding the biological mechanisms that contribute to multidrug resistance may suggest new therapeutic approaches and targets in RA.

Enzer I, Dunn G, Jacobsson L, Bennett PH, Knowler WC, Silman A. · Manchester University Medical School, Manchester, UK. · Arthritis Rheum. · Pubmed #12124855 links to  free full text

Abstract: OBJECTIVE: Previous population studies have suggested that both rheumatoid factor (RF) production and rheumatoid arthritis (RA) may be declining in occurrence, and both secular and birth-cohort influences have been implicated. Since Pima Indians have a very high incidence of RA and also have shown recent evidence of a decline in RA, this study evaluated the relative contributions of age, secular, and birth-cohort influences on RF seropositivity in the Pima Indian population. METHODS: RF data, as assayed by both the bentonite flocculation test (BFT) and the sheep cell agglutination test (SCAT), were available on 5,345 Pima Indians born between 1886 and 1975, who were surveyed at biennial intervals between 1966 and 1995. An age-period-cohort analysis was conducted using data on 18,295 examinations undertaken during the period of study. RESULTS: There was a decline in the proportion of positive test results for RF (titer > or = 1:32) by both BFT and SCAT, in both male and female subjects from 1966-1975 to the later decades of the study (1976-1985 and 1986-1995). Across all periods, by both assays, the crude proportion of positive titers increased with increasing age of the subjects. There was a very clear birth-cohort effect: the highest likelihood of seropositivity was in those individuals born around the end of the nineteenth century, with continuing decline in seropositivity up to the most recent birth cohort. A logistic regression analysis, adjusting for Pima heritage and sex, demonstrated a substantially greater influence of birth cohort than of calendar year on the frequency of RF positivity. CONCLUSION: In the Pima Indian population, environmental influences in early life are important predictors of the lifelong likelihood of RF positivity. This may have implications for understanding the epidemiology and etiology of RA.