Rheumatoid Arthritis: Bunn D

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.

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.

Morgan C, Lunt M, Bunn D, Scott DG, Symmons DP. · ARC Epidemiology Unit, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK. · Rheumatology (Oxford). · Pubmed #18032539 No free full text.

Abstract: OBJECTIVES: To establish whether patients with inflammatory arthritis plus psoriasis have a different outcome from those who do not have psoriasis. METHODS: Seventy-nine patients with inflammatory arthritis plus psoriasis were recruited by the Norfolk Arthritis Register (NOAR) in 1990-94 and followed for 5 yrs. Their outcome was compared with the remainder (n = 755) of the NOAR cohort. We then restricted the analysis to subjects who were rheumatoid factor (RF)-negative, and compared those with and without psoriasis. Outcomes studied included remission, deformed joint count, the presence and extent of erosive damage and physical function. RESULTS: Patients with psoriasis were younger, more likely to be male, less likely to be RF-positive and more likely to have been treated with disease-modifying drugs than patients without psoriasis. After adjustment for age, gender and treatment, the only differences between the psoriasis and non-psoriasis groups were in RF positivity (adjusted odds ratio 0.44; 95% CI 0.25, 0.78) and in the Larsen score in patients with erosions. CONCLUSIONS: Patients with inflammatory arthritis plus psoriasis have a similar outcome to other RF-negative patients with arthritis.

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.

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.

Oswald AE, Pye SR, O'Neill TW, Bunn D, Gaffney K, Marshall T, Silman AJ, Symmons DP. · ARC Epidemiology Unit, The University of Manchester, UK. · J Rheumatol. · Pubmed #16482644 No free full text.

Abstract: OBJECTIVE: To determine the one-year period prevalence and factors associated with falls in a community based cohort of women with established inflammatory polyarthritis (IP). METHODS: The Norfolk Arthritis Register is a primary-care based inception cohort of subjects with IP aged 16 years and over. At the 10-year visit, subjects completed the Health Assessment Questionnaire (HAQ) and were examined for both active and inactive joint involvement. A subset of subjects was invited to complete a questionnaire about falls in the previous 12 months and questions about putative risk factors for falls. Logistic regression was used to determine whether there was any association between falls in the previous year and both putative disease and non-disease related risk factors. RESULTS: Of the 316 women (mean age 59 yrs) who completed the falls questionnaire, 34% reported a fall in the previous year. Falls were more frequent in those over age 75 years, although there was no significant linear increase in risk with age. Swollen joint count [per 10 joints, odds ratio (OR) 1.7; 95% confidence interval (CI) 1.0, 2.8] and increasing visual analog scale pain score (per 10 mm, OR 1.1; 95% CI 1.0, 1.2) were associated with an increased risk of falls. Those who fell had higher overall HAQ scores (OR 1.7; 95% CI 1.3, 2.3) as well as higher scores for all of the individual domains of the HAQ (OR 1.7 to 2.2). Similarly, low levels of outdoor physical activity (OR 3.3; 95% CI 1.7, 6.5), impaired vision (OR 2.7; 95% CI 1.2, 6.3), and impaired general health (OR 2.9; 95% CI 1.7, 4.8) were associated with an increased risk of falls. In a multivariate model, HAQ score, low levels of physical activity, impaired vision, and impaired general health were independently linked with falls. Sixty-one percent of subjects with 3 of these risk factors had reported a fall in the previous year. CONCLUSION: In this inception cohort of women with longstanding IP, one in 3 reported falling in the previous year. Using a simple measure, a group that had particularly high risk can be identified.

Goodson NJ, Symmons DP, Scott DG, Bunn D, Lunt M, Silman AJ. · University of Manchester, UK. · Arthritis Rheum. · Pubmed #16052597 links to  free full text

Abstract: OBJECTIVE: To test the hypothesis that the C-reactive protein (CRP) concentration at baseline is an independent predictor of death from cardiovascular disease (CVD) in newly diagnosed patients with inflammatory polyarthritis (IP). METHODS: Patients with IP (n = 506) who were recruited from the Norfolk Arthritis Register between 1990 and 1992 were followed up to the end of 2001, and complete data on mortality were obtained. At baseline, subjects underwent a structured interview and joint examination and completed a Health Assessment Questionnaire (HAQ). Blood was obtained and analyzed for rheumatoid factor (RF) and CRP concentration. Cox regression was used to calculate hazards ratios (HRs) for risk of death from CVD. RESULTS: The median followup was 10.1 years (interquartile range 9.3-10.8). There were 104 deaths, 40 of which were the result of CVD. Elevated CRP levels (> or=5 mg/liter) predicted death from CVD in univariate analyses: HR 3.9 (95% confidence interval [95% CI] 1.2-13.4) for men, and HR 4.22 (95% CI 1.4-12.6) for women. After adjusting for age and sex, the CVD mortality association was strongest in the subgroup of patients who were RF positive at baseline (adjusted HR 7.4 [95% CI 1.7-32.2]). Multivariate analysis revealed that elevated CRP levels remained a significant independent predictor of death from CVD, even after adjusting for age, sex, smoking status, HAQ score, RF positivity, and swollen joint counts (HR 3.3 [95% CI 1.4-7.6]). CONCLUSION: The CRP concentration at baseline is an important predictor of subsequent death from CVD in patients with new-onset IP and is independent of other indicators of disease severity. This supports the theory that CRP may play a direct role in the pathogenesis of CVD.