Rheumatoid Arthritis: Silman AJ

Silman AJ. · No affiliation provided · Nat Clin Pract Rheumatol. · Pubmed #19252512 No free full text.

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Hyrich KL, Silman AJ. · No affiliation provided · J Rheumatol. · Pubmed #16652412 links to  free full text

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Hider SL, Buckley C, Silman AJ, Symmons DP, Bruce IN. · No affiliation provided · J Rheumatol. · Pubmed #15700388 links to  free full text

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Hider SL, Bruce IN, Silman AJ, Symmons DP. · No affiliation provided · J Rheumatol. · Pubmed #15630715 links to  free full text

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Symmons DP, Silman AJ. · No affiliation provided · Arthritis Rheum. · Pubmed #15188344 links to  free full text

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Symmons DP, Hazes JM, Silman AJ. · No affiliation provided · J Rheumatol. · Pubmed #12734878 No free full text.

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Carty SM, Snowden N, Silman AJ. · No affiliation provided · J Rheumatol. · Pubmed #12610794 No free full text.

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Silman AJ. · No affiliation provided · Arthritis Rheum. · Pubmed #11920391 links to  free full text

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Silman AJ. · No affiliation provided · Scand J Rheumatol. · Pubmed #10898064 No free full text.

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Harrison BJ, Silman AJ. · No affiliation provided · J Rheumatol. · Pubmed #10743790 No free full text.

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Symmons DP, Silman AJ. · arc Epidemiology Unit, University of Manchester, UK. · Arthritis Res Ther. · Pubmed #16817941 links to  free full text

Abstract: Over 3500 patients with recent onset inflammatory polyarthritis (IP) have been recruited by the Norfolk Arthritis Register (NOAR) since 1990. Longitudinal data from this cohort have been used to examine the prevalence and predictors of remission, functional disability, radiological outcome, cardiovascular mortality and co-morbidity and the development of non-Hodgkin's lymphoma. Rheumatoid factor titre, high baseline C-reactive protein and high baseline HAQ score are all predictors of a poor outcome. There is a strong association between possession of the shared epitope and the development of erosions. Patients who satisfy the American College of Rheumatology criteria for rheumatoid arthritis (RA) have a worse prognosis than those who do not. However, it appears that these patients are a poorly defined subset of all those with IP rather than having an entirely separate disease entity. New statistical techniques offer exciting possibilities for using longitudinal datasets such as NOAR to explore the long-term effects of treatment in IP and RA.

Oliver JE, Silman AJ. · arc Epidemiology Unit, Manchester University, School of Epidemiology and Health Sciences, Manchester, UK. · Scand J Rheumatol. · Pubmed #16766362 No free full text.

Abstract: There is increasing interest in attempting to understand what the risk factors are that lead to the development of rheumatoid arthritis (RA). Twin studies have proved a genetic role but also quantified the non-genetic risk. There is thus scope for identifying environmental predictors that might offer a strategy to prevent the disease. Changes in the female hormonal environment such as in pregnancy, breastfeeding and the use of the oral contraceptive (OC) pill appear to have a role. Of the traditional lifestyle exposures, cigarette smoking has been associated with a consistently increased risk that might also apply to the passive inhalation of smoke. Occupation probably has a minor influence, although exposure to silica dust is of aetiological importance. Recent studies have highlighted a role for diet, with suggestions that diets high in caffeine, low in antioxidants and high in red meat may contribute to an increased risk. The most plausible environmental exposure is infection and although several decades of study have produced few definitive candidate organisms, Epstein-Barr virus (EBV) remains an interesting target.

Symmons DP, Silman AJ. · arc Epidemiology Unit, University of Manchester, UK. · Lupus. · Pubmed #16634363 No free full text.

Abstract: In March 2002 the National Institute for Health and Clinical Excellence (NICE) published guidelines for the use of anti-TNF therapy for patients with rheumatoid arthritis (RA). The guidelines recommended that all RA patients treated with these drugs should be enrolled on a national register which had been established by the British Society for Rheumatology (the BSRBR). A comparison cohort of RA patients treated with traditional disease modifying drugs (DMARDs) is also being recruited. The main role of the BSRBR is to study the long-term safety of biologic drugs. Up to the end of March 2005, 9508 patients with RA had been enrolled on the BSRBR. Four thousand, three-hundred and six had been treated with etanercept, 3561 with infliximab, 1500 with adalimumab and 141 with anakinra. With regards to anti-TNF drugs, 79% remained on their original drug at six months, 65% of whom could be classified as responders. Co-prescription with methotrexate was associated with a 70% response rate. Patients with a high baseline level of disability were less likely to respond. Overall the rates of serious infection were not increased in the anti-TNF versus the comparison cohort. However the rates of skin and soft tissue infection and of intracellular infections (eg, salmonella, listeria, legionella) were increased. There were 11 cases of tuberculosis (seven extra-pulmonary). There was concern about the high mortality rates among patients with baseline pulmonary fibrosis treated with anti-TNF therapy. It is unclear whether this is related to the drug or to the underlying disease. The rates of malignancy and mortality were not increased compared to the DMARD treated group in the short term. Further follow-up is needed to determine the long term safety of these drugs.

Oliver JE, Worthington J, Silman AJ. · arc Epidemiology Unit, Manchester University, School of Epidemiology and Health Sciences, Manchester, UK. · Curr Opin Rheumatol. · Pubmed #16462519 No free full text.

Abstract: PURPOSE OF REVIEW: This review aims to summarize articles published between October 2004 and November 2005 that have investigated the genetic epidemiology of rheumatoid arthritis. RECENT FINDINGS: The consistent replication of an association between the R620W single nucleotide polymorphism in PTPN22 and rheumatoid arthritis clearly establishes this polymorphism as an important risk factor for rheumatoid arthritis. SUMMARY: Genetic investigations of rheumatoid arthritis have predominantly been single nucleotide polymorphism-based candidate gene association studies searching for markers of susceptibility, severity or treatment response. Studies of the human leukocyte antigen region have refined and added to our understanding of the complex associations to polymorphisms with this locus. PTPN22 has emerged strongly as a genuine rheumatoid arthritis susceptibility gene with replications of the association to the R620W single nucleotide polymorphism. Many investigations have been conducted on the genetics of treatment response -- some 'generic' and others specific in terms of identifying genetic influences to the mode of action and metabolism of particular agents.

Franklin JP, Symmons DP, Silman AJ. · ARC Epidemiology Unit, Manchester University Medical School, UK. · Ann Rheum Dis. · Pubmed #15834052 links to  free full text

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Carty SM, Snowden N, Silman AJ. · Rheumatology Department, University Hospital of Wales, Cardiff, Wales, UK. · Ann Rheum Dis. · Pubmed #15479871 links to  free full text

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Hyrich KL, Silman AJ, Watson KD, Symmons DP. · ARC Epidemiology Unit, University of Manchester, Oxford Road, Manchester M13 9PT, UK. · Ann Rheum Dis. · Pubmed #15242866 links to  free full text

Abstract: Anti-TNFalpha therapy may have associated risks of serious infection, congestive heart failure, malignancy, and multiple sclerosis. The magnitude of these risks is difficult to assess. This article reviews publications on the current knowledge about the safety of these agents.

Symmons DP, Silman AJ. · Arthritis Research Campaign Epidemiology Unit, School of Epidemiology and Health Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom. · Clin Exp Rheumatol. · Pubmed #14969058 No free full text.

Abstract: The Norfolk Arthritis Register (NOAR) has been recruiting and following patients with early inflammatory polyarthritis (IP) since 1989. Approximately three-quarters of the patients followed satisfy classification criteria for rheumatoid arthritis (RA) by 5 years from symptom onset. This paper summarises the publications which have been based on the NOAR cohort with respect to the incidence and prevalence of IP and RA, genetic and environmental risk factors for the development of IP, outcome following the development of IP and predictors of outcome. It also discusses methodological issues in examining the treatment effect in observational cohorts and the costs to the healthcare system of patients with early IP.

Silman AJ, Pearson JE. · ARC Epidemiology Unit, School of Epidemiology & Health Sciences, University of Manchester, UK. · Arthritis Res. · Pubmed #12110146 No free full text.

Abstract: The prevalence of rheumatoid arthritis (RA) is relatively constant in many populations, at 0.5-1.0%. However, a high prevalence of RA has been reported in the Pima Indians (5.3%) and in the Chippewa Indians (6.8%). In contrast, low occurrences have been reported in populations from China and Japan. These data support a genetic role in disease risk. Studies have so far shown that the familial recurrence risk in RA is small compared with other autoimmune diseases. The main genetic risk factor of RA is the HLA DRB1 alleles, and this has consistently been shown in many populations throughout the world. The strongest susceptibility factor so far has been the HLA DRB1*0404 allele. Tumour necrosis factor alleles have also been linked with RA. However, it is estimated that these genes can explain only 50% of the genetic effect. A number of other non-MHC genes have thus been investigated and linked with RA (e.g. corticotrophin releasing hormone, oestrogen synthase, IFN-gamma and other cytokines). Environmental factors have also been studied in relation to RA. Female sex hormones may play a protective role in RA; for example, the use of the oral contraceptive pill and pregnancy are both associated with a decreased risk. However, the postpartum period has been highlighted as a risk period for the development of RA. Furthermore, breastfeeding after a first pregnancy poses the greatest risk. Exposure to infection may act as a trigger for RA, and a number of agents have been implicated (e.g. Epstein-Barr virus, parvovirus and some bacteria such as Proteus and Mycoplasma). However, the epidemiological data so far are inconclusive. There has recently been renewed interest in the link between cigarette smoking and RA, and the data presented so far are consistent with and suggestive of an increased risk.

Oliver JE, Silman AJ. · Arthritis Research Campaign, Copeman House, St Mary's Court, St Mary's Gate, Chesterfield, Derbyshire S41 7TD, UK. · Arthritis Res Ther. · Pubmed #19490599 links to  free full text

Abstract: This article will review how epidemiological studies have advanced our knowledge of both genetic and environmental risk factors for rheumatic diseases over the past decade. The major rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, osteoarthritis, gout, and fibromyalgia, and chronic widespread pain, will be covered. Advances discussed will include how a number of large prospective studies have improved our knowledge of risk factors, including diet, obesity, hormones, and smoking. The change from small-scale association studies to genome-wide association studies using gene chips to reveal new genetic risk factors will also be reviewed.

Goodson NJ, Brookhart AM, Symmons DP, Silman AJ, Solomon DH. · Academic Rheumatology Unit, University Hospital Aintree, Liverpool University, Lower Lane, Liverpool, L9 7AL, UK. · Ann Rheum Dis. · Pubmed #18408253 links to  free full text

Abstract: OBJECTIVES: There is controversy about the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular disease (CVD) mortality. The aim of this study was to explore associations between NSAID use and mortality in patients with inflammatory polyarthritis (IP). SUBJECTS AND METHODS: A total of 923 patients with new onset (IP), recruited to the UK Norfolk Arthritis Register (NOAR) between 1990-1994, were followed up to the end of 2004. Current medication was recorded annually for the first 6 years and then every 2-3 years. Rheumatoid factor (RF) and C-reactive protein (CRP) were measured. Logistic regression was used to calculate all cause and CVD mortality odds ratios (OR) for NSAID use at baseline and during follow-up, adjusting for gender and time-varying covariates: RF, CRP, joint counts, smoking, steroid use, DMARD use and other medication use. RESULTS: By 2004 there were 203 deaths, 85 due to CVD. At baseline, NSAIDs were used by 66% of patients. In final multivariate models, baseline NSAID use was inversely associated with all cause mortality (adjusted OR 0.62, 95% CI 0.45 to 0.84) and CVD mortality (adjusted OR 0.54, 95% CI 0.34 to 0.86). Interval NSAID use had weaker mortality associations: all cause mortality (adjusted OR 0.72, 95% CI 0.52 to 1.00), CVD mortality (adjusted hazard ratio (HR) 0.66, 95% CI 0.40 to 1.08). CONCLUSION: No excess CVD or all cause mortality was observed in NSAID users in this cohort of patients with IP. This is at variance with the literature relating to NSAID use in the general population. It is unclear whether this represents unmeasured confounders influencing a doctor's decision to avoid NSAIDs in the treatment of IP.

Hider SL, Silman AJ, Thomson W, Lunt M, Bunn D, Symmons DP. · arc Epidemiology Unit, University of Manchester, UK. · Ann Rheum Dis. · Pubmed #18292102 links to  free full text

Abstract: PURPOSE: Methotrexate (MTX) is the first choice conventional disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It is not universally effective, however; although to date it is not possible to predict with any accuracy which patients will respond to treatment. The aim of this analysis was to examine whether clinical and genetic variables could be used to predict response to MTX. METHODS: Patients recruited to the Norfolk Arthritis Register (NOAR), a primary care based inception cohort of patients with inflammatory polyarthritis, were eligible for this analysis if they were commenced on MTX as their first DMARD within 3 months of their baseline visit and had at least 2 years of follow-up data. Outcome on MTX was defined as: (1) stopped for adverse events; (2) stopped for inefficacy or second DMARD added; (3) stopped for other reasons; or (4) remained on MTX monotherapy. Multiple logistic regression was used to establish which variables (including demographics, disease activity and Health Assessment Questionnaire score) predicted stopping monotherapy for inefficacy or adverse event (with those remaining on treatment taken as the referent category). The area under the Receiver Operating Characteristic curves (AUC ROC), were used to determine how accurate the model was at predicting outcome. RESULTS: 309 patients were included in this analysis. At 1 year (2 years), 34 (46) patients had stopped for adverse events and 25 (49) had either stopped monotherapy for inefficacy or had a second DMARD added. 231 (188) patients remained on MTX monotherapy. The strongest predictor of inefficacy at both time points was shared epitope positivity: odds ratios (OR) 5.8 (95% confidence intervals (CI) 1.3 to 25.6) at 1 year, OR 3.0 (95% CI 1.3 to 7.3) at 2 years. High Health Assessment Questionnaire score (OR 1.84 95% CI 1.12 to 3.01) and female gender (OR 2.2, 95% CI 0.92 to 5.28) were associated with adverse events on MTX at 1 year. However, even the most optimal combinations of the factors analysed were only weakly predictive of treatment outcome: AUC ROC for adverse events 0.68 (95% CI 0.58 to 0.78) and for inefficacy AUC ROC 0.71 (95% CI 0.6 to 0.81). CONCLUSIONS: Within this cohort, routine clinical and laboratory factors were poor at predicting outcome of treatment with MTX. Given the major therapeutic advantage to be derived from accurate prediction of treatment outcome, further studies will need to investigate novel biological and other markers.

Farragher TM, Goodson NJ, Naseem H, Silman AJ, Thomson W, Symmons D, Barton A. · Arthritis Research Campaign Epidemiology Unit, University of Manchester, Manchester, UK. · Arthritis Rheum. · Pubmed #18240242 links to  free full text

Abstract: OBJECTIVE: To examine the role of the variants of the PTPN22 and HLA-DRB1 genes as predictors of mortality in inflammatory polyarthritis (IP) and rheumatoid arthritis (RA). METHODS: Patients were recruited from a primary care-based inception cohort of patients with IP and were followed up prospectively. For patients who died, the cause and date of death was obtained. Cox proportional hazards regression models were used to assess the association of the HLA-DRB1 (including the shared epitope [SE]) and PTPN22 genes with the risk of death from all causes and from cardiovascular disease (CVD) and to assess the interactions between SE, smoking, and anti-cyclic citrullinated peptide (anti-CCP) status, adjusted by age at symptom onset and sex. RESULTS: DNA samples were available from 1,022 IP patients. During followup, 751 of them (74%) satisfied the American College of Rheumatology 1987 criteria for RA, and 242 of them (24%) died. Carriage of 2 copies of SE alleles predicted death from all causes (hazard ratio [HR] 1.57 [95% confidence interval (95% CI) 1.1-2.2]) and from CVD (HR 1.68 [95% CI 1.1-2.7]). This effect was most marked for individuals with the HLA-DRB1*01/*04 combination. An interaction of smoking, SE alleles, and anti-CCP antibodies was observed and was associated with the greatest risk of death from CVD (HR 7.81 [95% CI 2.6-23.2]). No association of the PTPN22 gene with mortality was detected. CONCLUSION: SE alleles, particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoantibody status. However, the combination of SE, smoking, and anti-CCP antibodies is associated with a high risk of premature death in patients with IP and RA, which raises the possibility of a targeted strategy to prevent CVD in these patients.

Dixon WG, Symmons DP, Lunt M, Watson KD, Hyrich KL, Anonymous00189, Silman AJ, Anonymous00190. · University of Manchester, Manchester, UK. · Arthritis Rheum. · Pubmed #17763441 links to  free full text

Abstract: OBJECTIVE: In a recent observational study, we found that the risk of serious infection following anti-tumor necrosis factor alpha (anti-TNFalpha) therapy in patients with rheumatoid arthritis (RA) was not importantly increased compared with the background risk in routinely treated RA patients with similar disease severity. Observational data sets are, however, subject to a number of important biases related to selection factors for the timing of starting and stopping therapy. Infection risk is also likely to vary with duration of therapy. This study was undertaken to examine the influences of these biases and of the method of analysis on the risk of infection. METHODS: We compared the risk of serious infection in 8,659 patients treated with anti-TNFalpha with that in 2,170 patients treated with traditional disease-modifying antirheumatic drugs (DMARDs) recruited to the British Society for Rheumatology Biologics Register. We applied a number of statistical models in which we varied the length of the followup period by using different definitions of the date of discontinuation of treatment and different lag periods of risk following drug cessation. RESULTS: When the at-risk period was defined as "receiving treatment", the adjusted incidence rate ratio comparing patients receiving anti-TNFalpha therapy with patients receiving DMARD therapy was 1.22 (95% confidence interval [95% CI] 0.88-1.69). Limiting followup to the first 90 days, however, revealed an adjusted incidence rate ratio of 4.6 (95% CI 1.8-11.9). Rates of infection were increased in the 90 days immediately following drug discontinuation and beyond, explained by selection factors for drug discontinuation. CONCLUSION: These findings show that overall, the way in which UK rheumatologists select patients for starting and discontinuing anti-TNFalpha therapy explains our previous finding of no increase in risk. However, there may be important increases in true risk, notably early in the course of treatment, that would become more evident depending on the definition of at-risk period.

Dixon WG, Watson KD, Lunt M, Hyrich KL, Anonymous00184, Silman AJ, Symmons DP, Anonymous00185. · University of Manchester, Manchester, UK. · Arthritis Rheum. · Pubmed #17763428 links to  free full text

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is associated with an increased risk of coronary artery disease, possibly acting via shared mechanisms of inflammation. This study was undertaken to test the hypothesis that the powerful antiinflammatory effect of anti-tumor necrosis alpha (anti-TNFalpha) therapy might lead to a reduction in the incidence of myocardial infarction (MI) in patients with RA. METHODS: Using data from the British Society for Rheumatology Biologics Register, a national prospective observational study, we compared MI rates in 8,670 patients with RA treated with anti-TNFalpha and 2,170 patients with active RA treated with traditional disease-modifying antirheumatic drugs (DMARDs). RESULTS: Through July 2006, 63 MIs occurred in the anti-TNFalpha cohort during 13,233 person-years of followup and 17 MIs occurred in the DMARD cohort during 2,893 person-years of followup, equivalent to a rate of 4.8 events per 1,000 person-years and 5.9 events per 1,000 person-years, respectively. After adjustment for baseline risk factors, there was no reduction in the rate of MI in the anti-TNFalpha cohort compared with the DMARD cohort (incidence rate ratio 1.44 [95% confidence interval 0.56-3.67]). In an analysis of anti-TNFalpha-treated patients who responded to the treatment within 6 months versus those who did not, MI rates were found to be 3.5 events per 1,000 person-years in responders and 9.4 events per 1,000 person-years in nonresponders. The adjusted incidence rate ratio (95% confidence interval) for responders compared with nonresponders was 0.36 (0.19-0.69). CONCLUSION: These results indicate that RA patients treated with anti-TNFalpha do not have a lower incidence of MI compared with RA patients treated with traditional DMARDs. However, the risk of MI is markedly reduced in those who respond to anti-TNFalpha therapy by 6 months compared with nonresponders. This finding supports the notion that inflammation plays a pivotal role in MI.