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1.  Rheumatoid factor and anti-citrullinated protein antibody positivity, but not level, are associated with increased mortality in patients with rheumatoid arthritis: results from two large independent cohorts 
Introduction
This study aimed to investigate rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status and levels as predictors of mortality in two large cohorts of patients with early inflammatory arthritis (EIA).
Methods
Data from the Norfolk Arthritis Register (NOAR) and Leiden Early Arthritis Clinic (EAC) cohorts were used. At baseline, patients had demographic data and smoking status recorded; RF, ACPA and inflammatory markers were measured in the local laboratories. Patients were flagged with national death registers until death or censor date. Antibody status was stratified as negative, low or high positive by RF and ACPA levels individually. In addition, patients were grouped as seronegative, RF positive, ACPA positive or double antibody (RF and ACPA) positive. Cox regression models explored associations between antibody status and mortality adjusting for age, sex, smoking status, inflammatory markers and year of enrolment.
Results
A total of 4962 patients were included, 64% were female. Median age at onset was 56 (NOAR) and 54 (EAC) years. In NOAR and EAC respectively, 35% and 42% of patients were ACPA/RF positive. When antibody status was stratified as negative, low or high positive, there were no consistent findings between the two cohorts. Double antibody positivity was associated with excess mortality in both cohorts compared to seronegative patients: NOAR and EAC respective adjusted HR (95% confidence interval) 1.35 (1.09 to 1.68) and 1.58 (1.16 to 2.15).
Conclusions
Patients with EIA who are seropositive for both RF and ACPA have increased mortality compared to those who are single positive or seronegative. Antibody level in seropositive patients was not consistently associated with excess mortality.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0483-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13075-014-0483-3
PMCID: PMC4272533  PMID: 25471696
2.  Health Assessment Questionnaire disability progression in early rheumatoid arthritis: Systematic review and analysis of two inception cohorts 
Objective
The Health Assessment Questionnaire is widely used for patients with inflammatory polyarthritis (IP) and its subset, rheumatoid arthritis (RA). In this study, we evaluated the progression of HAQ scores in RA (i) by systematically reviewing the published literature on the methods used to assess changes in functional disability over time and (ii) to study in detail HAQ progression in two large prospective observational studies from the UK.
Methods
Data from two large inception cohorts, ERAS and NOAR, were studied to determine trajectories of HAQ progression over time by applying latent class growth models (LCGMs) to each dataset separately. Age, sex, baseline DAS28, symptom duration, rheumatoid factor, fulfilment of the 1987 ACR criteria and socio-economic status (SES) were included as potential predictors of HAQ trajectory subgroup membership.
Results
The literature search identified 49 studies showing that HAQ progression has mainly been based on average changes in the total study population. In the HAQ progression study, a LCGM with four HAQ trajectory subgroups was selected as providing the best fit in both cohorts. In both the cohorts, older age, female sex, longer symptom duration, fulfilment of the 1987 ACR criteria, higher DAS28 and lower SES were associated with increased likelihood of membership of subgroups with worse HAQ progression.
Conclusion
Four distinct HAQ trajectory subgroups were derived from the ERAS and NOAR cohorts. The fact that the subgroups identified were nearly identical supports their validity. Identifying distinct groups of patients who are at risk of poor functional outcome may help to target therapy to those who are most likely to benefit.
doi:10.1016/j.semarthrit.2014.05.003
PMCID: PMC4282305  PMID: 24925692
Systematic review; Latent class growth model; Health Assessment Questionnaire; Rheumatoid arthritis; Inflammatory polyarthritis; Predictors
3.  Use of Bayesian Multivariate Meta-Analysis to Estimate the HAQ for Mapping Onto the EQ-5D Questionnaire in Rheumatoid Arthritis 
Value in Health  2014;17(1):109-115.
Background
In health technology assessment, decisions about reimbursement for new health technologies are largely based on effectiveness estimates. Sometimes, however, the target effectiveness estimates are not readily available. This may be because many alternative instruments measuring these outcomes are being used (and not all always reported) or an extended follow-up time of clinical trials is needed to evaluate long-term end points, leading to the limited data on the target clinical outcome. In the areas of highest priority in health care, decisions are required to be made on a short time scale. Therefore, alternative clinical outcomes, including surrogate end points, are increasingly being considered for use in evidence synthesis as part of economic evaluation.
Objective
To illustrate the potential effect of reduced uncertainty around the clinical outcome on the utility when estimating it from a multivariate meta-analysis.
Methods
Bayesian multivariate meta-analysis has been used to synthesize data on correlated outcomes in rheumatoid arthritis and to incorporate external data in the model in the form of informative prior distributions. Estimates of Health Assessment Questionnaire were then mapped onto the health-related quality-of-life measure EuroQol five-dimensional questionnaire, and the effect was compared with mapping the Health Assessment Questionnaire obtained from the univariate approach.
Results
The use of multivariate meta-analysis can lead to reduced uncertainty around the effectiveness parameter and ultimately uncertainty around the utility.
Conclusions
By allowing all the relevant data to be incorporated in estimating clinical effectiveness outcomes, multivariate meta-analysis can improve the estimation of health utilities estimated through mapping methods. While reduced uncertainty may have an effect on decisions based on economic evaluation of new health technologies, the use of short-term surrogate end points can allow for early decisions. More research is needed to determine the circumstances under which uncertainty is reduced.
doi:10.1016/j.jval.2013.11.005
PMCID: PMC3919215  PMID: 24438724
Bayesian analysis; health technology assessment; meta-analysis; multiple end points; rheumatoid arthritis; surrogate end points
4.  Biologic treatment response among adults with juvenile idiopathic arthritis: results from the British Society for Rheumatology Biologics Register 
Rheumatology (Oxford, England)  2013;52(10):1905-1913.
Objective. To describe the use of and response to biologic therapies commenced in adults with JIA.
Methods. Patients with arthritis onset <16 years were identified from the British Society for Rheumatology Biologics Register for rheumatoid arthritis (BSRBR-RA) and stratified into ILAR JIA subtypes. Patterns of biologic use and treatment persistence were explored, with disability levels (HAQ) and remission rates [28-Joint Disease Activity Score (DAS28)] evaluated at 6 and 12 months.
Results. Arthritis with an onset of <16 years was confirmed in 225 patients and the ILAR subtype was determined in 154 (68%). Only 58 (26%) patients had a diagnosis of JIA recorded in the BSRBR-RA. The median age at biologic commencement was 31 years [interquartile range (IQR) 23–39] and 76% were female. The biologic therapies were etanercept (49%), infliximab (28%), adalimumab (22%) and anakinra (1%). Fifty per cent of patients received more than one biologic during follow-up (2 agents, n = 64; ≥3 agents, n = 49). Treatment persistence at 1 year was 78% (95% CI 71%, 82%), falling to 42% (95% CI 34%, 49%) at 5 years. Both the HAQ and DAS28 improved significantly at 6 months, with 21% and 28% of patients in remission (DAS28 < 2.6) at 6 and 12 months, respectively.
Conclusion. This study describes patterns and identifies outcomes of biologic use in a national cohort of adults with JIA. With no national guidance currently available in this area, the choice of first biologic was inconsistent, although treatment outcomes were good. These data confirm that biologic therapies are an important treatment option in adults with active JIA in adulthood.
doi:10.1093/rheumatology/ket248
PMCID: PMC3775296  PMID: 23873820
anti-TNF therapy; disease activity; treatment outcome; juvenile idiopathic arthritis
5.  High density genetic mapping identifies new susceptibility loci for rheumatoid arthritis 
Nature genetics  2012;44(12):1336-1340.
Summary
Using the Immunochip custom single nucleotide polymorphism (SNP) array, designed for dense genotyping of 186 genome wide association study (GWAS) confirmed loci we analysed 11,475 rheumatoid arthritis cases of European ancestry and 15,870 controls for 129,464 markers. The data were combined in meta-analysis with GWAS data from additional independent cases (n=2,363) and controls (n=17,872). We identified fourteen novel loci; nine were associated with rheumatoid arthritis overall and 5 specifically in anti-citrillunated peptide antibody positive disease, bringing the number of confirmed European ancestry rheumatoid arthritis loci to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at six loci and association to low frequency variants (minor allele frequency <0.05) at 4 loci. Bioinformatic analysis of the data generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
doi:10.1038/ng.2462
PMCID: PMC3605761  PMID: 23143596
6.  Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register 
Annals of the Rheumatic Diseases  2012;72(2):229-234.
Introduction
Anti-tumour necrosis factor (TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). In 2001, BSRBR was established to evaluate the safety of these agents. This paper addresses the safety of anti-TNF therapy in RA with specific reference to serious skin and soft tissue infections (SSSI) and shingles.
Methods
A cohort of anti-TNF-treated patients was recruited alongside a comparator group with active RA treated with non-biological disease-modifying antirheumatic drugs (nbDMARD). 11 881 anti-TNF and 3673 nbDMARD patients were analysed. Follow-up was by 6-monthly questionnaires to patients and clinicians. Analyses considered SSSI and shingles separately. Incidence rates (IR) were calculated and then compared using survival analyses.
Results
The crude IR for SSSI were: anti-TNF 1.6/100 patient-years (95% CI 1.4 to 1.8); nbDMARD 0.7/100 patient-years (95% CI 0.5 to 1.0) and shingles: anti-TNF 1.6/100 patient-years (95% CI 1.3 to 2.0); nbDMARD 0.8/100 patient-years (95% CI 0.6 to 1.1). Adjusted HR were SSSI 1.4 (95% CI 0.9 to 2.4), shingles 1.8 (95% CI 1.2 to 2.8). For SSSI, no significant differences were seen between anti-TNF agents. For shingles, the lowest risk was observed for adalimumab (adjusted HR vs nbDMARD) 1.5 (95% CI 1.1 to 2.0) and highest for infliximab (HR 2.2; 95% CI 1.4 to 3.4)).
Conclusion
A significantly increased risk of shingles was observed in the anti-TNF-treated cohort. The risk of SSSI tended towards being greater with anti-TNF treatment but was not statistically significant. As with any observational dataset cause and effect cannot be established with certainty as residual confounding may remain. This finding would support the evaluation of zoster vaccination in this population.
doi:10.1136/annrheumdis-2011-201108
PMCID: PMC3595979  PMID: 22532633
7.  Learned helplessness predicts functional disability, pain and fatigue in patients with recent-onset inflammatory polyarthritis 
Rheumatology (Oxford, England)  2013;52(7):1233-1238.
Objectives. Cross-sectional studies have found that learned helplessness (LH) is associated with disease outcome in patients with RA. However, little is known about the longitudinal impact of LH. The aim of this study was to investigate whether LH is associated with future disease outcome (disability, pain and fatigue) and to investigate whether LH changes over time in patients with recent-onset inflammatory polyarthritis (IP), the broader group of conditions of which RA is the major constituent.
Methods. Patients included in this investigation had been recruited to the Norfolk Arthritis Register, a primary-care-based inception cohort. LH was measured at baseline as patients’ total score on the Rheumatology Attitudes Index (RAI). A total of 443 patients completed the HAQ and visual analogue scales of pain and fatigue at baseline and after 2 years of follow-up.
Results. Greater feelings of LH at baseline were associated with higher HAQ scores at follow-up [difference in HAQ score per 1-point increase in RAI score (β-coefficient) 0.02; 95% CI 0.01, 0.04]. Greater baseline LH was also associated with more pain (β-coefficient 1.0; 95% CI 0.4, 1.5) and more fatigue (β-coefficient 1.0; 95% CI 0.2, 1.4) at follow-up. LH was highly changeable during follow-up, with 87% of patients showing any change and 50% improving.
Conclusion. Baseline LH independently predicted disability, pain and fatigue at follow-up. Half of patients reported fewer feelings of helplessness after 2 years of follow-up, suggesting that LH may potentially be a modifiable risk factor for disease outcome in IP and a target for intervention.
doi:10.1093/rheumatology/kes434
PMCID: PMC3685331  PMID: 23424265
inflammatory polyarthritis; rheumatoid arthritis; learned helplessness; functional disability; pain; fatigue
8.  Risk of cancer in patients receiving non-biologic disease-modifying therapy for rheumatoid arthritis compared with the UK general population 
Rheumatology (Oxford, England)  2012;52(1):91-98.
Objectives. To quantify the risk of cancer and compare it with that for the general population in a modern cohort of UK patients with RA and to identify risk factors for cancer among this cohort.
Methods. The study population comprised biologic-naïve RA subjects receiving non-biologic disease-modifying therapy recruited to the British Society for Rheumatology Biologics Register from 2002 to 2009. Standardized incidence ratios (SIRs) for cancers were calculated using age- and gender-specific cancer rates in the English population. Poisson regression models adjusted for age and gender using England general population data were used to determine the association of other predictors with incident malignancy.
Results. The cohort comprised 3771 individuals with RA contributing 13 315 person-years of follow-up. One hundred and eighty-two cancers were reported: 156 solid and 26 myelo- or lymphoproliferative cancers. The overall SIR was 1.28 (95% CI 1.10, 1.48). Risks of lung cancer (SIR 2.39, 95% CI 1.75, 3.19), Hodgkin lymphoma (SIR 12.82, 95% CI 4.16, 29.92) and non-Hodgkin lymphoma (SIR 3.12, 95% CI 1.79, 5.07) were higher compared with the general population and risks of prostate cancer (SIR 0.35, 95% CI 0.11, 0.82) and cancers of the female genital organs (SIR 0.35, 95% CI 0.10, 0.90) were reduced. Within the cohort, cancer risk was more than 2-fold higher in current or ex-smokers than in non-smokers.
Conclusion. The overall incidence of cancer was increased in this national cohort of subjects with RA. The association of RA with certain cancers needs to be considered when studying the effects of biologic therapy, such as anti-TNF, on cancer risk.
doi:10.1093/rheumatology/kes350
PMCID: PMC3521445  PMID: 23238979
rheumatoid arthritis; cancer; lymphoma; standardized incidence ratio
9.  Influence of Inflammatory Polyarthritis on Quantitative Heel Ultrasound Measurements 
Background
There are few data concerning the impact of inflammatory polyarthritis (IP) on quantitative heel ultrasound (QUS) measurements. The aims of this analysis were i) to determine the influence of IP on QUS measurements at the heel and, ii) among those with IP to determine the influence of disease related factors on these measurements.
Methods
Men and women aged 16 years and over with recent onset IP were recruited to the Norfolk Arthritis Register (NOAR). Individuals with an onset of joint symptoms between 1989 and 1999 were included in this analysis. At the baseline visit subjects underwent a standardised interview and clinical examination with blood taken for rheumatoid factor. A population-based prospective study of chronic disease (EPIC-Norfolk) independently recruited men and women aged 40 to 79 years from the same geographic area between 1993 and 1997. At a follow up assessment between 1998 and 2000 subjects in EPIC-Norfolk were invited to have quantitative ultrasound measurements of the heel (CUBA-Clinical) performed. We compared speed of sound (SOS) and broadband ultrasound attenuation (BUA), in those subjects recruited to NOAR who had ultrasound measurements performed (as part of EPIC-Norfolk) subsequent to the onset of joint symptoms with a group of age and sex matched non-IP controls who had participated in EPIC-Norfolk. Fixed effect linear regression was used to explore the influence of IP on the heel ultrasound parameters (SOS and BUA) so the association could be quantified as the mean difference in BUA and SOS between cases and controls. In those with IP, linear regression was used to examine the association between these parameters and disease related factors.
Results
139 men and women with IP and 278 controls (mean age 63.2 years) were studied. Among those with IP, mean BUA was 76.3 dB/MHz and SOS 1621.8 m/s. SOS was lower among those with IP than the controls (difference = −10.0; 95% confidence interval (CI) –17.4, -2.6) though BUA was similar (difference = −1.2; 95% CI −4.5, +2.1). The difference in SOS persisted after adjusting for body mass index and steroid use. Among those with IP, disease activity as determined by the number of swollen joints at baseline, was associated with a lower SOS. In addition SOS was lower in the subgroup that satisfied the 1987 ACR criteria. By contrast, disease duration, steroid use and HAQ score were not associated with either BUA or SOS.
Conclusions
In this general population derived cohort of individuals with inflammatory polyarthritis there is evidence from ultrasound of a potentially adverse effect on the skeleton. The effect appears more marked in those with active disease.
doi:10.1186/1471-2474-13-133
PMCID: PMC3441510  PMID: 22834652
10.  Long-term stability of anti-cyclic citrullinated peptide antibody status in patients with early inflammatory polyarthritis 
Arthritis Research & Therapy  2012;14(3):R109.
Introduction
The utility of reassessing anti-cyclic citrullinated peptide (anti-CCP) antibody status later in disease in patients presenting with early undifferentiated inflammatory polyarthritis, particularly in those who test negative for both anti-CCP and rheumatoid factor (RF) at baseline, remains unclear. We aimed therefore to determine the stability of CCP antibody status over time and the prognostic utility of repeated testing in subjects with early inflammatory polyarthritis (IP).
Methods
Anti-CCP and RF were measured at baseline and 5 years in 640 IP patients from the Norfolk Arthritis Register, a primary care-based inception cohort. The relation between change in anti-CCP status/titer and the presence of radiologic erosions, the extent of the Larsen score, and Health Assessment Questionnaire (HAQ) score by 5 years was investigated.
Results
With a cut-off of 5 U/ml, 28% subjects tested positive for anti-CCP antibodies, 29% for RF, and 21% for both at baseline. Nine (2%) anti-CCP-negative patients seroconverted to positive, and nine (4.6%) anti-CCP-positive individuals became negative between baseline and 5 years. In contrast, RF status changed in 17% of subjects. However, change in RF status was strongly linked to baseline anti-CCP status and was not independently associated with outcome. Ever positivity for anti-CCP antibodies by 5 years did not improve prediction of radiographic damage compared with baseline status alone (accuracy, 75% versus 74%). A higher baseline anti-CCP titer (but not change in anti-CCP titer) predicted worse radiologic damage at 5 years (P < 0.0001), even at levels below the cut-off for anti-CCP positivity. Thus, a titer of 2 to 5 U/ml was strongly associated with erosions by 5 years (odds ratio, 3.6 (1.5 to 8.3); P = 0.003).
Conclusions
Repeated testing of anti-CCP antibodies or RF in patients with IP does not improve prognostic value and should not be recommended in routine clinical practice.
doi:10.1186/ar3834
PMCID: PMC3446486  PMID: 22571727
11.  Modifiable risk factors for RA: prevention, better than cure? 
Rheumatology (Oxford, England)  2011;51(3):499-512.
Objective. To perform a meta-synthesis of the evidence for modifiable lifestyle risk factors for inflammatory polyarthritis (IP) and RA.
Methods. We performed a MEDLINE literature search. Case–control and cohort studies and systematic reviews published from 1948 through February 2011 and studying modifiable risk factors for RA were retrieved. The main outcome measure was diagnosis of RA according to the standard criteria.
Results. Smoking contributes up to 25% of the population burden of RA. The risk is dose related, stronger in males and especially strong for anti-citrullinated peptide antibody positive (ACPA+) RA through an interaction with the shared epitope. After smoking cessation, there is, however, a latency of up to 20 years to return to baseline risk. Other associations are less definitive; however, prospective studies suggest that dietary antioxidants and breastfeeding may be protective and that high coffee consumption may increase RA risk. An inverse association with alcohol intake (especially in smokers) and with education/social class (especially seropositive RA) and an increased risk with obesity (seronegative RA) is also noted.
Conclusion. There is a need for further large-scale prospective studies with a consistent definition of RA phenotype (undifferentiated IP through to ACPA+/RF+ disease). This will ultimately afford the opportunity to evaluate preventative population strategies for RA akin to the well-established programmes for cardiovascular disease and cancer, targeting common risk factors.
doi:10.1093/rheumatology/ker299
PMCID: PMC3281496  PMID: 22120459
rheumatoid arthritis; review; risk factors; epidemiology; lifestyle; environment; smoking; alcohol; diet; social class
12.  Seropositivity is associated with insulin resistance in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register (NOAR): an observational study 
Arthritis Research & Therapy  2011;13(5):R159.
Introduction
Cardiovascular disease (CVD) is the leading cause of death in patients with inflammatory polyarthritis (IP), especially in seropositive disease. In established rheumatoid arthritis (RA), insulin resistance (IR) is increased and associated with CVD. We investigated factors associated with IR in an inception cohort of patients with early IP.
Methods
Patients with early IP (two or more swollen joints for four or more weeks), aged 18 to 65 years, seen within 24 months of symptom onset were recruited from the Norfolk Arthritis Register (NOAR), a primary-care-based inception cohort. Assessment included joint examination, current and prior therapy and completion of the Health Assessment Questionnaire. Fasting blood was taken for measurement of CVD risk factors, rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), C-reactive protein (CRP), and insulin levels. IR was calculated using the homeostatic model assessment (HOMA-IR). We examined factors associated with IR using univariate and multivariable linear regression models.
Results
A total of 196 patients, including 59 (30%) males, were studied with a median (interquartile range, IQR) age and IP symptom duration of 49 (40 to 57) years and 6.7 (4.6 to 10.7) months, respectively. After age and gender adjustment, HOMA-IR was associated with obesity, (β-Coefficient (95% CI); 1.60 (0.96, 2.24)), higher systolic and diastolic blood pressure (0.03 (0.01, 0.05) and 0.04 (0.01, 0.08) respectively), triglycerides (1.06 (0.54, 1.57)), and HDL (-1.38 (-2.17,-0.58)). HOMA-IR was associated with serological status and this association persisted after adjustment for classic CVD risk factors and other IP-related variables (RF β-Coefficient (95% CI); 0.87 (0.20, 1.53) and ACPA β-Coefficient (95% CI); 1.42 (0.70, 2.15)).
Conclusions
Seropositivity for RF or ACPA was associated with IR in this early IP cohort. This association may, in part, explain why seropositive patients have excess CVD mortality.
doi:10.1186/ar3476
PMCID: PMC3308090  PMID: 21959060
13.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
Objective
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Methods
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
Results
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
Conclusion
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
doi:10.1002/art.27580
PMCID: PMC3077961  PMID: 20872596
14.  In patients with early inflammatory polyarthritis, ACPA positivity, younger age and inefficacy of the first non-biological DMARD are predictors for receiving biological therapy: results from the Norfolk Arthritis Register 
Annals of the Rheumatic Diseases  2011;70(8):1428-1432.
Objectives
To identify baseline disease-related predictors in patients with early inflammatory polyarthritis (IP) for starting subsequent biological therapy and to determine if patients who failed their first non-biological disease-modifying antirheumatic drug (DMARD) within 6 months were more likely to need biological therapy.
Methods
Patients with early IP recruited between 1990 and 1994 (cohort 1) and between 2000 and 2004 (cohort 2) in the Norfolk Arthritis Register were included in this study. The association between possible predictors with the start of biological therapy was assessed using Cox proportional hazards regression models.
Results
32/407 (7.9%) patients in cohort 1 and 45/416 (10.8%) patients in cohort 2 received biological therapy during follow-up. In both cohorts, anti-citrullinated protein antibody (ACPA) positivity (cohort 1, HR 7.62, 95% CI 2.46 to 23.58; cohort 2, HR 4.68, 95% CI 2.23 to 9.78) was the strongest predictor for starting biological therapy. In cohort 2, younger patients (HR 0.97, 95% CI 0.95 to 0.99) and patients who failed their first non-biological DMARD within 6 months due to inefficacy were also more likely to receive biological therapy (HR 2.35, 95% CI 1.05 to 5.27).
Conclusion
Patients with early IP who are ACPA positive, are younger or who fail their first non-biological DMARD due to inefficacy within 6 months are more likely to need biological therapy.
doi:10.1136/ard.2010.148106
PMCID: PMC3128326  PMID: 21551505
15.  Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register 
Annals of the Rheumatic Diseases  2011;70(5):823-826.
Objective
The British Society for Rheumatology Biologics Register (BSRBR) has collected data on adverse events including pregnancies in patients with rheumatoid arthritis treated with anti-tumour necrosis factor (anti-TNF) therapy. The purpose of this report is to summarise the pregnancy outcomes in women treated with anti-TNF in the BSRBR.
Methods
Patients were categorised according to anti-TNF exposure as follows: (1) exposure to anti-TNF and to methotrexate (MTX) and/or leflunomide (LEF) at conception (n=21 pregnancies); (2) exposure to anti-TNF at conception (n=50); (3) exposure to anti-TNF prior to conception (n=59); (4) no exposure to anti-TNF (control group; n=10).
Results
Eighty-eight live births in a total of 130 pregnancies were reported in patients who received anti-TNF before or during pregnancy. The rate of spontaneous abortion was highest among patients exposed to anti-TNF at the time of conception (with MTX/LEF 33% and without MTX/LEF 24%). This compared with 17% spontaneous abortions in those with prior exposure to anti-TNF and 10% spontaneous abortions in the control group. Ten terminations were performed.
Conclusion
Although the results to date have been promising, no firm conclusions can be drawn about the safety of anti-TNF during pregnancy and, without further evidence, guidelines which suggest these drugs should be avoided at the time of conception cannot yet be changed.
doi:10.1136/ard.2010.140822
PMCID: PMC3070273  PMID: 21362710
16.  Impact of concomitant use of DMARDs on the persistence with anti-TNF therapies in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register 
Annals of the Rheumatic Diseases  2011;70(4):583-589.
Objective
To evaluate the effect of different concomitant disease modifying antirheumatic drugs (DMARDs) on the persistence with antitumour necrosis factor (anti-TNF) therapies in patients with rheumatoid arthritis (RA).
Method
This analysis included 10 396 patients with RA registered with the British Society for Rheumatology Biologics Register, a prospective observational cohort study, who were starting their first anti-TNF therapy and were receiving one of the following DMARD treatments at baseline: no DMARD (n=3339), methotrexate (MTX) (n=4418), leflunomide (LEF) (n=610), sulfasalazine (SSZ) (n=308), MTX+SSZ (n=902), MTX+ hydroxychloroquine (HCQ) (n=401) or MTX+SSZ+HCQ (n=418). Kaplan–Meier survival analysis was used to study the persistence with anti-TNF therapy in each DMARD subgroup up to 5 years. Multivariate Cox proportional hazard models, stratified by anti-TNF used and start year and adjusted for a number of potential confounders, were used to compare treatment persistence overall and according to the reason for discontinuation between each of the DMARD subgroups, using MTX as reference.
Results
One-year drug survival (95% CI) for the first anti-TNF therapy was 71% (71% to 72%) but this dropped to 42% (41% to 43%) at 5 years. Compared with MTX, patients receiving no DMARD, LEF or SSZ were more likely to discontinue their first anti-TNF therapy while patients receiving MTX in combination with other DMARDs showed better treatment persistence.
Conclusions
These results support the continued use of background DMARD combinations which include MTX. Consideration should be given to the discontinuation of LEF and SSZ monotherapy at the time anti-TNF therapies are started, with the possible exception of the SSZ+ETN combination.
doi:10.1136/ard.2010.139774
PMCID: PMC3048625  PMID: 21330639
17.  Excess risk of hospital admission for cardiovascular disease within the first 7 years from onset of inflammatory polyarthritis 
Annals of the Rheumatic Diseases  2010;69(9):1660-1664.
Objectives
Subjects with rheumatoid factor positive inflammatory polyarthritis (IP) are known to have increased mortality from cardiovascular disease (CVD). A study was undertaken to examine the risk and baseline predictors of admission with CVD in patients with recent-onset IP.
Methods
Subjects are recruited by the Norfolk Arthritis Register if they present to primary or secondary care with ≥2 swollen joints lasting ≥4 weeks. This analysis includes subjects recruited between 1995 and 1999. Baseline data on lifestyle, demographic characteristics, disease and treatment characteristics were collected. CVD admissions were identified through record linkage with the only acute care hospital in the study region. First-episode hospitalisation rates were compared with those of the general population. Poisson regression was used to calculate the relative risk (RR) of admission for patients with IP (overall and for each risk factor). Death certificates were obtained from the national death register.
Results
800 patients with recent-onset IP were followed for a median of 7.0 years. 64 CVD-related hospitalisations were observed (11.7 per 1000 person-years). Patients with IP were twice as likely (RR=2.0; 95% CI 1.5 to 2.5) to be hospitalised for CVD as the general population. Difficulty walking at baseline was a significant predictor of CVD admission and baseline non-steroidal anti-inflammatory drug use was associated with a reduced risk of CVD admission.
Conclusions
Patients with IP are at increased risk of CVD-related hospitalisation, within 7 years of symptom onset. Informing patients about lifestyle modification may reduce the risk of CVD.
doi:10.1136/ard.2009.121871
PMCID: PMC2938882  PMID: 20498206
18.  Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly 
Rheumatology (Oxford, England)  2010;50(1):124-131.
Objectives. To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages.
Methods. Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients.
Results. A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)]. Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)].
Conclusions. These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments.
doi:10.1093/rheumatology/keq242
PMCID: PMC3105607  PMID: 20675706
Rheumatoid arthritis; Anti-TNF therapy; Epidemiology; Serious infection; Elderly; Outcome
19.  Changes in disease characteristics and response rates among patients in the United Kingdom starting anti-tumour necrosis factor therapy for rheumatoid arthritis between 2001 and 2008 
Rheumatology (Oxford, England)  2010;50(1):117-123.
Objectives. Anti-TNF therapy has significantly improved outcomes for patients with severe RA. In the UK, changing financial restrictions and increasing experience with their use may have resulted in changes to the way physicians use anti-TNF therapies. The aim of this analysis was to examine changes in disease characteristics and response rates among patients starting anti-TNF therapy for RA over an 8-year period.
Methods. A total of 11 216 RA patients registered between 2001 and 2008 with the British Society for Rheumatology Biologics Register were included and stratified according to year of first anti-TNF prescription. Baseline characteristics and treatment response were compared year on year using logistic and linear regression models.
Results. Mean RA disease activity and severity of new anti-TNF-treated patients decreased between 2001 and 2008. The mean disease duration remained high (11 years in 2008) although the proportion of patients having disease duration <5 years increased significantly (2001: 9%; 2008: 29%; P < 0.001). The majority of patients had failed three DMARDs on average before the first anti-TNF prescription. There was an increase in both the proportion of EULAR good responders at 1 year (2001: 18%; 2008: 30%; P < 0.001) and in the number of patients achieving remission (2001: 8%; 2008: 17%; P < 0.001). Drug survival remained relatively stable over the study years.
Conclusions. There is a significant trend towards earlier use of anti-TNF therapies in patients with less severe disease, although the mean disease duration at first treatment remains high. This has correlated with improvements in outcome. These results support the earlier use of anti-TNF therapies in RA.
doi:10.1093/rheumatology/keq209
PMCID: PMC2999956  PMID: 20671021
Rheumatoid arthritis; Anti-TNF therapy; Prescription pattern; Treatment response; Treatment outcome; Remission
20.  Disease activity and severity in early inflammatory arthritis predict hand cortical bone loss 
Rheumatology (Oxford, England)  2010;49(10):1943-1948.
Objectives. To determine the influence of disease-related variables on hand cortical bone loss in women with early inflammatory arthritis (IA), and whether hand cortical bone mass predicts subsequent joint damage.
Method. Adults aged ≥16 years with recent onset of IA were recruited to the Norfolk Arthritis Register between 1990 and 1998, and followed prospectively. At baseline, patients had their joints examined for swelling and tenderness and had CRP and disease activity 28-joint assessment score (DAS-28) measured. Radiographs of the hands were performed in a subgroup of patients at Year 1 and at follow-up, which were assessed using digital X-ray radiogrammetry (DXR). They were also evaluated for the presence of erosions using Larsen’s method. Linear mixed models were used to investigate whether disease-related factors predicted change in DXR–areal bone mineral density (BMDa). We also evaluated whether DXR–BMDa predicted the subsequent occurrence of erosive disease.
Results. Two hundred and four women, mean (s.d.) age 55.1 (14.0) years, were included. Median follow-up between radiographs was 4 years. The mean within-subject change in BMDa was 0.024 g/cm2 equivalent to 1% decline per year. After adjustment for age, height and weight, compared with those within the lower tertile for CRP, those in the upper tertile had greater subsequent loss of bone. This was true also for DAS-28 and Larsen score. Among those without erosions on the initial radiograph (121), DXR–BMDa at baseline did not predict the new occurrence of erosions.
Conclusion. Increased disease activity and severity are associated with accelerated bone loss. However, lower BMDa did not predict the new occurrence of erosive disease.
doi:10.1093/rheumatology/keq181
PMCID: PMC2936948  PMID: 20573690
Inflammatory arthritis; Digital X-ray radiogrammetry; Norfolk Arthritis Register; Radiological erosions
21.  Influence of arthritis and non-arthritis related factors on areal bone mineral density (BMDa) in women with longstanding inflammatory polyarthritis: a primary care based inception cohort 
Background
The aim of this analysis was to determine the relative influence of disease and non-disease factors on areal bone mineral density (BMDa) in a primary care based cohort of women with inflammatory polyarthritis.
Methods
Women aged 16 years and over with recent onset inflammatory polyarthritis were recruited to the Norfolk Arthritis Register (NOAR) between 1990 and 1993. Subjects were examined at both baseline and follow up for the presence of tender, swollen and deformed joints. At the 10th anniversary visit, a sub-sample of women were invited to complete a bone health questionnaire and attend for BMDa (Hologic, QDR 4000). Linear regression was used to examine the association between BMDa with both (i) arthritis-related factors assessed at baseline and the 10th anniversary visit and (ii) standard risk factors for osteoporosis. Adjustments were made for age.
Results
108 women, mean age 58.0 years were studied. Older age, decreasing weight and BMI at follow up were all associated with lower BMDa at both the spine and femoral neck. None of the lifestyle factors were linked. Indices of joint damage including 10th anniversary deformed joint count and erosive joint count were the arthritis-related variables linked with a reduction in BMDa at the femoral neck. By contrast, disease activity as determined by the number of tender and or swollen joints assessed both at baseline and follow up was not linked with BMDa at either site.
Conclusion
Cumulative disease damage was the strongest predictor of reduced femoral bone density. Other disease and lifestyle factors have only a modest influence.
doi:10.1186/1471-2474-11-106
PMCID: PMC2889849  PMID: 20509941
22.  Working status in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: results from the British Society for Rheumatology Biologics Register 
Rheumatology (Oxford, England)  2010;49(8):1570-1577.
Objective. To describe working status in patients with RA, AS and PsA treated with anti-TNF therapy registered with the British Society for Rheumatology Biologics Register.
Methods. Patients with RA (n = 3291), AS (n = 229) and PsA (n = 254) treated with anti-TNF therapy were included in this study. In addition, biologic-naive patients with RA (n = 379) were included. At baseline and 3 years after registration, all patients reported their working status. Baseline characteristics between working and work-disabled patients were compared. Logistic regression analysis was applied to identify factors associated with new work disability in patients with RA.
Results. At baseline, work disability rates were already high: 49% for RA, 39% for PsA, 41% for AS and 36% for biologic-naive patients. Work-disabled patients had a higher HAQ score and worse disease activity than working patients. Working patients with a high HAQ score [odds ratio (OR) 2.79; 95% CI 1.89, 4.12] and a manual job (OR 2.31; 95% CI 1.52, 3.52) at baseline were more likely to become work disabled at follow-up, while those patients in remission 6 months after commencing anti-TNF therapy were less likely to become work disabled. However, use of anti-TNF therapy did not prevent patients with RA from becoming work disabled (OR for RA control patients vs RA anti-TNF patients 0.80; 95% CI 0.36, 1.81, adjusted for baseline variables).
Conclusion. A high percentage of patients with RA, AS and PsA were already work disabled at the start of anti-TNF therapy. There is less future work disability in working patients with RA who responded to anti-TNF therapy.
doi:10.1093/rheumatology/keq131
PMCID: PMC2903312  PMID: 20444856
Rheumatoid arthritis; Ankylosing spondylitis; Psoriatic arthritis; Work disability; Anti-TNF therapy
23.  Is shared care with annual hospital review better value for money than predominantly hospital‐based care in patients with established stable rheumatoid arthritis? 
Annals of the Rheumatic Diseases  2006;66(5):658-663.
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 (4700) in the SCSC group and £4440 (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 ⩾£2000 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.
doi:10.1136/ard.2006.061234
PMCID: PMC1954606  PMID: 17124249
24.  Early functional disability predicts both all‐cause and cardiovascular mortality in people with inflammatory polyarthritis: results from the Norfolk Arthritis Register 
Annals of the Rheumatic Diseases  2007;66(4):486-492.
Objective
To investigate the predictive value of early functional disability in patients with inflammatory polyarthritis (IP), for all‐cause and cardiovascular disease (CVD) mortality.
Methods
1010 subjects with new‐onset IP from the Norfolk Arthritis Register were studied. All were seen at baseline and at 1 year. Health Assessment Questionnaire (HAQ) scores were obtained at both time points. Vital status at 10 years from registration was established through central records. Mortality (all‐cause and CVD) per 1000 person‐years were calculated by HAQ stratum (HAQ scores <1, 1–2 and ⩾2). The predictive value of HAQ (per unit increase) at the two time points, adjusted for age at onset of symptom, sex and other factors found to predict mortality, was assessed using Cox regression models. The analysis was repeated for those who satisfied the 1987 American College of Rheumatology criteria for rheumatoid arthritis (RA) by 5 years.
Results
By 10 years, 171 (16.9%) subjects had died. 89 deaths (52%) were attributed to CVD. Mortality was greatest in the highest HAQ group at both time points. Following adjustment for other predictors, HAQ score at year 1 remained a significant predictor of all‐cause mortality (HR 1.46; 95% CI 1.15 to 1.85) and CVD mortality (HR 1.49; 95% CI 1.12 to 1.97). The predictive value of HAQ at year 1 was similar in the RA subgroup.
Conclusions
Our data show that at 1 year of follow‐up, HAQ score is an important independent predictor of subsequent all‐cause and CVD mortalities in people with IP and RA. Baseline HAQ scores are of less value.
doi:10.1136/ard.2006.056390
PMCID: PMC1856031  PMID: 17090565
25.  The role of rheumatoid arthritis genetic susceptibility markers in the prediction of erosive disease in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register 
Rheumatology (Oxford, England)  2010;50(1):78-84.
Objectives. Recent whole-genome and candidate gene association studies in RA have identified a number of single nucleotide polymorphisms (SNPs) that predispose to disease with moderate risk. It remains poorly understood how recently identified genetic factors may contribute to RA severity. We therefore sought to investigate the role of recently identified RA susceptibility SNP markers in predicting erosive outcome in patients with recent-onset inflammatory polyarthritis (IP).
Methods. DNA and X-ray data were available for 1049 patients who were registered between 1990 and 2003 with the Norfolk Arthritis Register (NOAR); a primary care-based inception cohort of patients with recent-onset IP. Demographic and clinical data were recorded at inclusion, and at yearly assessments thereafter. Patients were genotyped for 18 SNP markers. The presence of serum anti citrullinated peptide antibodies (ACPAs) was assessed in samples collected at inclusion to the NOAR. The association of serological and genetic markers with poor radiological (Larsen) score at Years 1 and 5, and erosions at Years 1 and 5 was investigated.
Results. Baseline ACPA positivity was associated with erosive disease and higher radiological damage. SNP markers within the TRAF1/C5 locus were associated with erosive disease at Year 1 [rs2900180: odds ratio (OR) 1.53 (95% CI 1.14, 2.05)] and Year 5 [rs2900180: OR 1.47 (95% CI 1.07, 2.02)]. None of the SNP markers tested was associated with Larsen score.
Conclusion. Our results are in keeping with a previous report and suggest that the TRAF1/C5 region is associated with risk of development of radiological erosions in IP/RA patients. The finding requires replication in other large data sets.
doi:10.1093/rheumatology/keq032
PMCID: PMC2999953  PMID: 20219786
Genetic association; Erosions; Inflammatory polyarthritis; Rheumatoid arthritis

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