Rheumatoid Arthritis: Symmons D

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.

Thornton J, Ashcroft D, O'Neill T, Elliott R, Adams J, Roberts C, Rooney M, Symmons D. · Arthritis Research Campaign Epidemiology Unit, School of Translational Medicine, University of Manchester, UK. · Health Technol Assess. · Pubmed #18284894 links to  free full text

Abstract: OBJECTIVES: To review outcome measures and treatment costs in children with juvenile idiopathic arthritis (JIA) and low bone mineral density (BMD) and/or fragility fractures. To review evidence for effectiveness and safety of bisphosphonates and calcium and/or vitamin D in these children.To assess long-term bone health in adults with JIA. DATA SOURCES: Major databases were searched up to July 2005 for effectiveness studies and up to January 2005 for costs. REVIEW METHODS: A structured search strategy was conducted. For the evaluation of long-term bone health, outcome data were derived from two cohorts of adult patients with JIA. As there were few published cost data, an ongoing UK longitudinal study (CAPS) provided background data on the cost of managing JIA. RESULTS: Sixteen studies (78 children with JIA) were included. At baseline, the children had BMD below the expected values for age- and sex-matched children; treatment with bisphosphonates increased BMD with mean percentage increases in spine BMD varying from 4.5 to 19.1%. None of the studies with control groups compared results between the intervention and control groups, they only compared each group with its own baseline. Overall, studies were heterogeneous in design, of variable quality and with no consistency in methods of assessing and reporting outcomes. Hence, data could not be combined or an effect size calculated. A further 43 papers were included in the safety review; side-effects were generally transient. Two studies assessed treatment with calcium and/or vitamin D; BMD was increased from 0.75 to 0.830 g/cm2 after 6 months and BMD Z-score from -2.8 to -2.3 after 6 months and -2.4 after 1 year. There are relatively few long-term studies on the occurrence of low BMD and fragility fractures in children with JIA, with most studies only following children for 1 or 2 years. However, the long- and short-term data indicate that children with JIA have a lower BMD and more fractures than children without JIA. There are very few data on long-term bone health from adults who have JIA, but studies indicate that low BMD persists into adulthood, although adults in remission from JIA may attain the same BMD as healthy adults. From the available data, any predictors of low BMD and fractures in children and adults with JIA remain uncertain. No studies were found that discussed the costs of treating children with JIA and low BMD and/or fragility fractures. In CAPS, 297 of 457 children with JIA attended a 12-month follow-up visit. The mean annual total cost per child in the first year after diagnosis was 1649 pounds (standard deviation 1093 pounds, range 401-6967 pounds). The highest cost component was appointments with paediatric rheumatologists. The study is continuing to accrue and follow up patients and further analyses will be undertaken as the study progresses. CONCLUSIONS: BMD, adjusted for size, should be assessed as the primary outcome in studies of bone health in children with JIA. Quantitative computed tomography could be used where equipment is available as it offers the advantage of measuring volumetric density. Bisphosphonates are a promising treatment for osteoporosis in children with JIA, but the quality of the current evidence is poor. The accurate assessment of outcome is crucial. There are still uncertainties about the use of bisphosphonates in children, including whether the positive effects of treatment continue over time, the length of treatment and the maximal bone mass gain that can be achieved. Adults with JIA may have persistent low BMD compared with an otherwise healthy population together with an increased risk of fracture. There are no studies evaluating the costs of treating children with JIA and low BMD and/or fragility fractures. There are few data evaluating the costs of treating JIA in general. In the first 12 months after diagnosis, children with all JIA disease subtypes consume large, but highly variable, quantities of health service resources, the largest component being the consultant rheumatology appointments. Data from a larger cohort, over a longer period, are required to substantiate these results further. Further research is needed to assess more clearly the role and permit licensing of bisphosphonates for treatment of children, and in particular, longer-term studies.

Thornton J, Ashcroft DM, Mughal MZ, Elliott RA, O'Neill TW, Symmons D. · Arthritis Research Campaign Epidemiology Unit, Division of Epidemiology and Health Sciences, University of Manchester, UK. · Arch Dis Child. · Pubmed #16690698 No free full text.

Abstract: AIMS: To evaluate the currently available evidence for the effectiveness of bisphosphonates in children with low bone mineral density (BMD) and fragility fractures associated with juvenile idiopathic arthritis (JIA), and the safety of bisphosphonates in JIA and other conditions. METHODS: Literature databases were searched using a structured search strategy. The effectiveness review included any studies of children with JIA treated with bisphosphonates. The safety review also included studies of osteogenesis imperfecta. Quantitative data analysis was not undertaken because of the heterogeneity of the studies; findings were summarised using tables and narrative synthesis. RESULTS: Ninety four studies were identified. Sixteen studies (78 JIA children) were included in the effectiveness review: one randomised controlled trial, three controlled cohort studies, 11 case series, and one case report. At baseline, children had low BMD below the expected values for age and sex matched children. In all studies, treatment with bisphosphonates increased BMD compared with baseline: the mean percentage increase in spine BMD ranged from 4.5% to 19.1%. Overall, studies were heterogeneous and of variable quality. A total of 59 papers were included in the safety review; treatment durations were up to three years. The most common side effect was a flu-like reaction with intravenous treatment. This occurred during the first infusion and was transient; the symptoms were managed with paracetamol and did not occur during subsequent cycles. CONCLUSIONS: Bisphosphonates are a promising treatment for low BMD and fragility fractures in children with JIA. However, the quality of the current evidence is variable and better studies are needed to more clearly assess their role.

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.

Goodson N, Symmons D. · ARC Epidemiology Unit, University of Manchester Medical School, UK. · Ann Rheum Dis. · Pubmed #12379514 links to  free full text

This publication has no abstract.

Ollier WE, Harrison B, Symmons D. · ARC Epidemiology Unit, University of Manchester Medical School, Oxford Road, Manchester, M13 9PT, UK. · Best Pract Res Clin Rheumatol. · Pubmed #11358413 No free full text.

Abstract: Inflammatory polyarthritis can be a self-limiting disease, develop into rheumatoid arthritis (RA) or differentiate into another form of chronic arthritis. It remains a clinical and scientific challenge to understand the relationship between these phenotypes, determine their aetiologies and predict the course and outcome for individual patients. Even patients labelled as having RA show a wide spectrum of clinical phenotypes. Disease definition is a major problem in studying the aetiology of RA as currently used classification criteria were derived using patients with established disease. RA is thought to result from the combination of genetic susceptibility and exposure to an appropriate environmental trigger. The genetic component is probably oligogenic. The association with HLA has been known for over 25 years. RA is now thought to be associated with a conserved sequence of amino acids in a number of HLA-DRB1 alleles, called the RA shared epitope. However, the shared epitope appears to be associated with RA chronicity and severity more than with susceptibility. Other potential RA susceptibility genes include IL-1, aromatase, corticotropin-releasing hormone and a region on the X chromosome. Hormonal and reproductive factors also influence RA susceptibility and severity. RA is more common in women than men, especially before the menopause. Men may be protected by hormonal factors and require a stronger genetic component to develop disease. Although infectious triggers of RA have long been suspected, no definitive evidence has been obtained. Previous blood transfusion, smoking and obesity are also possible risk factors. Chronicity and remission are important aspects of the natural history of early RA. Although we can identify patients at risk of adverse prognosis with some accuracy, we remain unable to predict remission. Functional disability and radiological damage are the most studied outcomes in RA. Radiological damage often occurs early in the course of RA, but patients may show erosion for the first time several years after symptom onset. Many studies have demonstrated a relationship between HLA and features of severe RA in established patients. This appears to be related to gene dosage.

Harrison B, Symmons D. · Withington Hospital, Manchester, UK. · Rheumatology (Oxford). · Pubmed #10986297 links to  free full text

This publication has no abstract.

Symmons D, Harrison B. · ARC Epidemiology Unit, University of Manchester Medical School, Oxford Road, Manchester and East Cheshire NHS Trust, Macclesfield and. Withington Hospital, Manchester, UK. · Rheumatology (Oxford). · Pubmed #10952736 links to  free full text

This publication has no abstract.

Thornton J, Lunt M, Ashcroft DM, Baildam E, Foster H, Davidson J, Gardner-Medwin J, Beresford MW, Symmons D, Thomson W, Elliott RA. · Arthritis Research Campaign Epidemiology Unit, Division of Epidemiology and Health Sciences, University of Manchester, Manchester, UK. · Rheumatology (Oxford). · Pubmed #18417528 links to  free full text

Abstract: OBJECTIVES: There are few data on the treatment patterns and associated cost of treating children with inflammatory arthritis including juvenile idiopathic arthritis (JIA), in the short or long term. The aim of this study was to obtain patient-based costs for treating children with JIA in the UK, in the first year from diagnosis and from the secondary health care payer perspective. METHODS: The Childhood Arthritis Prospective Study (CAPS) is an ongoing longitudinal study recruiting children with inflammatory arthritis from four UK hospital centres. Included children are newly diagnosed, <or=16 years old with inflammatory arthritis of one or more joints, which has persisted for at least 2 weeks. Health service resource use data were collected as part of routine clinical care at study entry, 6 months and 1 year. Reference unit costs were applied to these data and the cost of treatment per child calculated for the first year from diagnosis. RESULTS: A total of 297 children attended a 12-month follow-up visit. The mean annual total cost per child was pound1649 (s.d. pound1093, range pound401- pound6967). The highest cost component was for appointments with paediatric rheumatologists. Mean total costs were highest for children with enthesitis-related, systemic JIA or extended oligoarthritis. CONCLUSIONS: In the first 12 months after diagnosis, children with all JIA disease subtypes consume large, but highly variable quantities of health service resources. Individual patient costs are required to reflect the wide variation in cost between patients and allow appropriate recouping of costs for contracted services and for assessing the economic impact of interventions.

Lorenzi AR, Clarke AM, Wooldridge T, Waldmann H, Hale G, Symmons D, Hazleman BL, Isaacs JD. · Newcastle University, Newcastle-upon-Tyne, UK. · Arthritis Rheum. · Pubmed #18240243 links to  free full text

Abstract: OBJECTIVE: To assess immunologically relevant outcomes in a cohort of rheumatoid arthritis (RA) patients with prolonged therapy-induced lymphopenia. METHODS: Morbidity (infection or malignancy) and mortality were assessed in 53 RA patients who were treated with the lymphocytotoxic monoclonal antibody alemtuzumab between 1991 and 1994. Data were obtained by interview, medical record review, and Office for National Statistics mortality monitoring. Lymphocyte subsets were enumerated by flow cytometry. A retrospective, matched-cohort study of mortality was performed with 102 control subjects selected from the European League Against Rheumatism database of patients with rheumatic disorders. RESULTS: Lymphopenia persisted in the patients: median CD3+CD4+, CD3+CD8+, CD19+, and CD56+ lymphocyte counts measured at a median followup of 11.8 years from the first administration of alemtuzumab were 0.50 x 10(9)/liter, 0.26 x 10(9)/liter, 0.11 x 10(9)/liter, and 0.09 x 10(9)/liter, respectively. Twenty-seven of 51 cases and 46 of 101 controls with available data had died, yielding a mortality rate ratio of 1.20 (95% confidence interval 0.72-1.98). Causes of death were similar to those that would be expected in a hospital-based RA cohort. No opportunistic infections were noted, and only 3 infections were documented following 36 elective orthopedic procedures. CONCLUSION: Despite continued lymphopenia 11.8 years after therapy, our patient cohort did not exhibit excess mortality or unusual infection-related morbidity, and surgery was well tolerated. These data should be reassuring for clinicians and patients who are considering lymphocytotoxic or other immunomodulatory therapy for RA.

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.

Thomson W, Barton A, Ke X, Eyre S, Hinks A, Bowes J, Donn R, Symmons D, Hider S, Bruce IN, Anonymous00005, Wilson AG, Marinou I, Morgan A, Emery P, Anonymous00006, Carter A, Steer S, Hocking L, Reid DM, Wordsworth P, Harrison P, Strachan D, Worthington J. · Arthritis Research Campaign (arc)-Epidemiology Unit, Stopford Building, The University of Manchester, Manchester M13 9PT, UK. · Nat Genet. · Pubmed #17982455 links to  free full text

Abstract: The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-5) - 5 x 10(-7) in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 x 10(-8)) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-alpha-induced protein 3 (TNFAIP3).

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.

Brennan A, Bansback N, Nixon R, Madan J, Harrison M, Watson K, Symmons D. · Health Economics and Decision Science, School of Health and Related Research (ScHARR), The University of Sheffield, UK. · Rheumatology (Oxford). · Pubmed #17562686 links to  free full text

Abstract: OBJECTIVE: To evaluate the cost effectiveness of TNF-alpha antagonist therapies for rheumatoid arthritis (RA) in the United Kingdom using data from the British Society for Rheumatology Biologics Registry (BSRBR). METHODS: A simulation model is constructed to quantify the cost effectiveness of the TNF-alpha antagonist therapies (infliximab, etanercept and adalimumab) as a group versus traditional disease-modifying anti-rheumatic drugs, with a time horizon over the full patient lifetime. Participants are UK NHS patients in the BSRBR with RA who have failed at least two traditional disease-modifying anti-rheumatic drugs. The BSRBR aims to recruit all RA patients starting on a TNF-alpha antagonist agent and follows them 6 monthly via consultant and patient administered questionnaires. Data collected include disease activity scores (DAS28), the Health Assessment Questionnaire and the SF-36. Costs include drug, monitoring and hospitalisations. Benefits are measured in disability and quality of life improvements. The main outcome measure is the incremental cost per quality adjusted life-year gained (discounted). RESULTS: The basecase cost per quality adjusted life-year gained by using TNF-alpha antagonist therapies is estimated at pound23 882, with probabilistic uncertainty analysis suggesting that the probability that treatments are below 30,000 pounds per QALY is around 84%. The results are most sensitive to assumptions concerning long-term disability progression, discount rates and the validity or otherwise of SF6D derived utility measures. Subgroup analysis, monotherapy versus combination with methotrexate, and a limited analysis of sequential therapy with two TNF-alpha antagonist agents, suggest cost-effectiveness ratios around 20,000 pounds to 30,000 pounds. CONCLUSIONS: The BSRBR data provide valuable evidence for estimating cost-effectiveness. The analysis concludes that current policies and practice for the use of TNF-alpha antagonist therapies, after RA patients have failed at least two traditional disease-modifying anti-rheumatic drugs, appear cost-effective in the context of the NICE re-appraisal of 2006 for England and Wales, thus supporting their decision to continue their reimbursement. Decision-makers worldwide might adapt this analysis because differential costs, discount rates and other factors could affect results. There remains uncertainty, particularly on long-term disease progression. Further data collection using the BSRBR is recommended, together with a revision to this analysis when data become available.

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.

Davies LM, Fargher EA, Tricker K, Dawes P, Scott DL, Symmons D. · Health Economics Research at Manchester, University of Manchester, Manchester, UK. · Ann Rheum Dis. · Pubmed #17124249 No free full text.

Abstract: OBJECTIVE: To assess the cost effectiveness and cost effectiveness acceptability of symptom control delivered by shared care (SCSC) and aggressive treatment delivered in hospital (ATH) for established rheumatoid arthritis (RA). METHODS: Economic data were collected within the British Rheumatoid Outcome Study Group randomised controlled trial of SCSC and ATH. A broad perspective was used (UK National Health Service, social support services and patients). Cost per quality adjusted life year (QALY) gained, net benefit statistics and cost effectiveness acceptability curves were estimated. Costs and outcomes were discounted at 3.5%. Sensitivity analysis tested the robustness of the results to analytical assumptions. RESULTS: The mean (SD) cost per person was 4540 pounds (4700) in the SCSC group and 4440 pounds (4900) in the ATH group. The mean (SD) QALYs per person for 3 years were 1.67 (0.56) in the SCSC group and 1.60 (0.60) in the ATH group. If decision makers are prepared to pay > or = 2000 pounds to gain 1 QALY, SCSC is likely to be cost effective in 60-90% of cases. CONCLUSIONS: The primary economic analysis and sensitivity analyses indicate that SCSC is likely to be more cost effective than ATH in 60-90% of cases. This result seems to be robust to assumptions required by the analysis. This study is one of a limited number of randomised controlled trials to collect detailed resource use and health status data and estimate the costs and QALYs of treatment for established RA. This trial is one of the largest RA studies to use the EuroQol.

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.

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.

Symmons D, Tricker K, Harrison M, Roberts C, Davis M, Dawes P, Hassell A, Knight S, Mulherin D, Scott DL, Anonymous00305. · Arc Epidemiology Unit, University of Manchester, Manchester M13 9PT, UK. · Rheumatology (Oxford). · Pubmed #16263778 links to  free full text

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) should start treatment early with the aim of suppressing the inflammatory process completely. It is not known if this strategy should, or can, be continued in later disease. METHODS: In a multicentre, randomized, observer-blinded, controlled trial, 466 patients with established RA (>5 yr), on stable therapy for at least 6 months, were randomized to adequate symptom control/shared care setting (SCSC) or aggressive treatment/hospital setting (ATH). All were reviewed annually by a rheumatologist. The primary outcome after 3 yr was the Health Assessment Questionnaire (HAQ). Others included the OMERACT core set and the Disease Activity Score (DAS) 28. RESULTS: Three hundred and ninety-nine patients completed the trial. There was a significant deterioration in HAQ in both arms. Only the physician global score differed between the arms. CONCLUSIONS: The trial showed no additional benefit of intensified treatment with traditional disease modifying anti-rheumatic drugs (DMARDs) in patients with stable, established RA. It proved hard to suppress C-reactive protein levels. Patients in the SCSC arm were able to initiate treatment changes when their symptoms deteriorated without frequent hospital assessment. Pending further evidence, the model of shared care with annual hospital review is as good as 4-monthly hospital review for these patients.

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.

Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL. · ARC Epidemiology Unit, University of Manchester, UK. · Health Technol Assess. · Pubmed #16153351 links to  free full text

Abstract: OBJECTIVES: To examine the effectiveness and cost-effectiveness of symptomatic versus aggressive treatment in patients with established, stable rheumatoid arthritis (RA). DESIGN: A randomised observer-blinded controlled trial and economic evaluation with an initial assessment at randomisation and follow-ups at 12, 24 and 36 months. SETTING: Five rheumatology centres in England. The 'symptomatic care' patients were managed predominantly in primary care with regular visits by a rheumatology specialist nurse. The 'aggressive care' patients were managed predominantly in the hospital setting. PARTICIPANTS: Patients with RA for more than 5 years were screened in rheumatology clinics. INTERVENTIONS: The symptomatic care patients were seen at home every 4 months by a rheumatology specialist nurse and annually by the rheumatologist. The aim of treatment was symptom control. The aggressive care patients were seen at least every 4 months in hospital. Their treatment was altered (following predefined algorithms) with the aim of suppressing both clinical and laboratory evidence of joint inflammation. MAIN OUTCOME MEASURES: The main outcome measure was the Health Assessment Questionnaire (HAQ). Others included the patient and physician global assessment, pain, tender and swollen joint counts, the erythrocyte sedimentation rate and the OSRA (Overall Status in Rheumatoid Arthritis) score. X-rays of the hands and feet were performed at the beginning and end of the study. The EQ-5D was used in the health economic evaluation. Comprehensive costs were also estimated and were combined with measures of outcome to examine between-group differences. RESULTS: A total of 466 patients were recruited; 399 patients completed the 3 years of follow-up. There was a significant deterioration in physical function (HAQ) in both arms. There was no significant difference between the groups for any of the clinical outcome measures except the physician global assessment [adjusted mean difference 3.76 (95% CI 0.03 to 7.52)] and the OSRA disease activity component [adjusted mean difference 0.41 (95% CI 0.01 to 0.71)], both in favour of the aggressive arm. During the trial, second-line drug treatment was changed in 77.1% of the aggressive arm and 59.0% of the symptomatic arm. There were instances when the rheumatologist should have changed treatment but did not do so, usually because of mild disease activity. The symptomatic arm was associated with higher costs and higher quality-adjusted life-years (QALYs). There was a net cost of 1517 Pounds Sterling per QALY gained for the symptomatic arm. Overall, the primary economic analysis and sensitivity analyses of the cost and QALY data indicate that symptomatic treatment is likely to be more cost-effective than aggressive treatment in 58-90% of cases. CONCLUSIONS: This trial showed no benefit of aggressive treatment in patients with stable established RA. However, it was difficult to persuade the rheumatologist and/or the patient to change treatment if the evidence of disease activity was minimal. Patients in the symptomatic arm were able to initiate changes of therapy when their symptoms deteriorated, without frequent hospital assessment. Approximately one-third of current clinic attenders with stable RA could be managed in a shared care setting with annual review by a rheumatologist and regular contact with a rheumatologist nurse. Further research is needed into disease progression and the use of biological agents, minimum disease activity level below which disease progression does not occur, cost-effectiveness through shared care modelling, the development of a robust and fail-safe system of primary-care based disease-modifying anti-rheumatic drug (DMARD) monitoring, and predicting response to DMARDs.

Symmons D. · ARC Epidemiology Unit, School of Epidemiology and Health Sciences, Room 2.600 Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK. · Int J Epidemiol. · Pubmed #15851394 links to  free full text

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