Jennifer Humphreys

The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register

Objectives The development of new classification criteria for rheumatoid arthritis (RA) calls for a re-estimation of RA incidence rates. The objectives of this study were to estimate the age and sex-specific incidence rates (IR) of RA in Norfolk, England using the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism criteria, and to compare those with IRs estimated using the 1987 ACR criteria. Setting The Norfolk Arthritis Register (NOAR), a large primary care inception cohort of patients with inflammatory oligo- and polyarthritis (IP) aged ≥ 16. Methods All patients notified to NOAR from 1990-5 with symptom onset in 1990 were included. The former Norwich Health Authority population was the denominator. Age and sex specific IRs using 1987 and 2010 classification criteria were calculated at baseline visit, annually for the first 3 years and at 5 years. Results 260 patients were notified to NOAR with symptom onset in 1990 and without an alternative diagnosis. IRs applying the 2010 criteria at baseline were 54/100 000 for women and 25/100 000 for men. Age and sex-specific IRs using the 2010 classification criteria at baseline were similar to cumulative IRs applying the 1987 criteria up to 5 years. However, some patients only ever satisfied one set of criteria and a proportion of IA patients (20%) did not satisfy either criteria set over 5 years. Conclusions The 2010 criteria classify similar numbers of patients as having RA at baseline, as the 1987 criteria would have taken up to 5 years to identify.

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

IntroductionThis 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).MethodsData 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.ResultsA 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).ConclusionsPatients 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.

How Do We Classify Rheumatoid Arthritis in Established Disease — Can We Apply the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria?

Objective. Individual dermatomyositis (DM)-associated autoantibodies are associated with distinct clinical phenotypes. This study was undertaken to explore the association of these autoantibodies with specific muscle biopsy features. Methods. DM subjects with a muscle biopsy reviewed at Johns Hopkins had sera screened for autoantibodies recognizing Mi-2, transcriptional intermediary factor 1-γ (TIF1-γ), NXP2, MDA5, Ro52, PM-Scl, and Jo1. We also included anti-Jo1–positive patients with polymyositis (PM) who had a biopsy read at Johns Hopkins. Analyzed histological features included perifascicular atrophy, perivascular inflammation, mitochondrial dysfunction, primary inflammation, and myofiber necrosis. Duration of disease, biopsy location, and treatment at biopsy were also analyzed. Results. We studied 91 DM and 7 anti-Jo1–positive patients with PM. In univariate analyses, TIF1-γ+ patients had more mitochondrial dysfunction (47% vs 18%; p = 0.05), NXP2+ patients had less primary inflammation (0% vs 28%; p = 0.01), Mi-2+ patients had more primary inflammation (50% vs 19%; p = 0.03), and PM-Scl+ patients had more primary inflammation (67% vs 18%; p = 0.004) than those who were negative for each autoantibody. Although reliability was limited because of small sample numbers, multivariate analysis confirmed that TIF1-γ+ patients had more mitochondrial dysfunction [prevalence ratio (PR) 2.6, 95% CI 1.0–6.5, p = 0.05] and PM-Scl+ patients had more primary inflammation (PR 5.2, 95% CI 2.0–13.4; p = 0.001) independent of disease duration at biopsy, biopsy site, and treatment at biopsy. No differences in muscle biopsy features were noted between anti-Jo1–positive patients diagnosed with DM and PM. Conclusion. The prevalence of different histological features varies according to autoantibody status in DM. Muscle biopsy features are similar in anti-Jo1 patients with and without a rash.The creation of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA; Figure 1)1 sought to address some of the criticisms of the previous ACR criteria set published in 1987 (Figure 2)2 — namely that they were insensitive, particularly early in the disease course, and that this led to the exclusion of many patients with early disease from clinical trials and research studies3. As a result, there was an absence of evidence regarding the efficacy of new treatments in this group of patients, who may have had the potential to benefit the most4,5. Thus, 1 aim of the 2010 criteria was to identify those patients with early RA with the key purpose of rapid disease-modifying antirheumatic drug (DMARD) initiation. However, the ability to classify patients as having RA is important at all phases of the disease, early and late. A case definition is required as an entry criterion not only to clinical trials, but also a consensus for inclusion in longterm observational studies and the whole spectrum of research in RA. Numerous studies have tested the validity of the new criteria since their publication against various standards6, but they have generally been applied in patients with relatively short duration of symptoms, ranging from < 3 months to < 2 years. Thus, the question remains, can we extend these classification criteria to patients with established disease? Figure 1. 2010 ACR/EULAR Classification criteria for RA1. ACR: American College of Rheumatology; EULAR: European League Against Rheumatism; RF: rheumatoid factor; ACPA: anticitrullinated protein antibodies; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; RA: rheumatoid arthritis. From Aletaha, et al. Ann Rheum Dis 2010;69:1580–8; with permission. Figure 2. 1987 ACR Classification criteria for RA2. ACR: American … Address correspondence to Professor D.P.M. Symmons, Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, The University of Manchester, Manchester Academic Health Science Centre, UK. E-mail: deborah.symmons{at}manchester.ac.uk

Anticarbamylated protein antibodies are associated with long-term disability and increased disease activity in patients with early inflammatory arthritis: results from the Norfolk Arthritis Register

Objectives Anticarbamylated protein (anti-CarP) antibodies are a novel family of autoantibodies recently identified in patients with inflammatory arthritis. The aim of this study was to investigate their association with long-term outcomes of disability and disease activity over 20 years’ follow-up in a cohort of patients with inflammatory polyarthritis (IP). Methods Norfolk Arthritis Register recruited adults with recent-onset swelling of ≥2 joints for ≥4 weeks from 1990 to 2009. At baseline, Health Assessment Questionnaire (HAQ) and 28 joint disease activity scores (DAS28) were obtained, and C reactive protein, rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA) and anti-CarP antibodies were measured. Further HAQ scores and DAS28 were obtained at regular intervals over 20 years. Generalised estimating equations were used to test the association between anti-CarP antibody status and longitudinal HAQ and DAS28 scores; adjusting for age, gender, smoking status, year of inclusion and ACPA status. Analyses were repeated in subgroups stratified by ACPA status. The relative association of RF, ACPA and anti-CarP antibodies with HAQ and DAS28 scores was investigated using a random effects model. Results 1995 patients were included; 1310 (66%) were female. Anti-CarP antibodies were significantly associated with more disability and higher disease activity, HAQ multivariate β-coefficient (95% CI) 0.12 (0.02 to 0.21), and these associations remained significant in the ACPA-negative subgroups. The associations of RF, ACPA and anti-CarP antibodies were found to be additive in the random effects model. Conclusions Anti-CarP antibodies are associated with increased disability and higher disease activity in patients with IP. Our results suggest that measurement of anti-CarP antibodies may be useful in identifying ACPA-negative patients with worse long-term outcomes. Further, anti-CarP antibody status provided additional information about RF and ACPA.

Anticitrullinated protein antibodies and rheumatoid factor are associated with increased mortality but with different causes of death in patients with rheumatoid arthritis: a longitudinal study in three European cohorts.

Objective Patients with rheumatoid arthritis (RA)-related autoantibodies have an increased mortality rate. Different autoantibodies are frequently co-occurring and it is unclear which autoantibodies associate with increased mortality. In addition, association with different causes of death is thus far unexplored. Both questions were addressed in three early RA populations. Methods 2331 patients with early RA included in Better Anti-Rheumatic Farmaco-Therapy cohort (BARFOT) (n=805), Norfolk Arthritis Register (NOAR) (n=678) and Leiden Early Arthritis Clinic cohort (EAC) (n=848) were studied. The presence of anticitrullinated protein antibodies (ACPA), rheumatoid factor (RF) and anticarbamylated protein (anti-CarP) antibodies was studied in relation to all-cause and cause-specific mortality, obtained from national death registers. Cox proportional hazards regression models (adjusted for age, sex, smoking and inclusion year) were constructed per cohort; data were combined in inverse-weighted meta-analyses. Results During 26 300 person-years of observation, 29% of BARFOT patients, 30% of NOAR and 18% of EAC patients died, corresponding to mortality rates of 24.9, 21.0 and 20.8 per 1000 person-years. The HR for all-cause mortality (95% CI) was 1.48 (1.22 to 1.79) for ACPA, 1.47 (1.22 to 1.78) for RF and 1.33 (1.11 to 1.60) for anti-CarP. When including all three antibodies in one model, RF was associated with all-cause mortality independent of other autoantibodies, HR 1.30 (1.04 to 1.63). When subsequently stratifying for death cause, ACPA positivity associated with increased cardiovascular death, HR 1.52 (1.04 to 2.21), and RF with increased neoplasm-related death, HR 1.64 (1.02 to 2.62), and respiratory disease-related death, HR 1.71 (1.01 to 2.88). Conclusions The presence of RF in patients with RA associates with an increased overall mortality rate. Cause-specific mortality rates differed between autoantibodies: ACPA associates with increased cardiovascular death and RF with death related to neoplasm and respiratory disease.

Postpublication validation of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: where do we stand?

Purpose of reviewTo summarise the results of the validation studies testing the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA) to date and highlight the areas for future research. Recent findingsThe 2010 ACR/EULAR classification criteria for RA were developed aiming to identify patients early in the natural history of the disease. Validation studies conducted since their publication have demonstrated that, compared with the 1987 ACR criteria for RA, the 2010 criteria identify more patients earlier in the disease course. Sensitivity for the initiation of disease-modifying antirheumatic drugs and persistent disease is increased, with decreased specificity. Patients who are seronegative may not satisfy the 2010 criteria despite meeting the 1987 criteria at presentation. The 2010 criteria may also incorrectly classify some patients with self-limiting disease as RA. SummaryThe 2010 criteria appear to be superior to the 1987 criteria in terms of identifying individuals with early RA. Their validity in established disease and their ability to predict worse prognosis in the long term have yet to be determined.

Smoking is associated with the concurrent presence of multiple autoantibodies in rheumatoid arthritis rather than with anti-citrullinated protein antibodies per se: a multicenter cohort study.

BackgroundThe contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies.MethodsA population-based Japanese cohort (n = 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands (n = 678), the United Kingdom (n = 761), and Sweden (n = 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression.ResultsIn the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32–6.58).In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78–1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04–1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53–2.73).ConclusionsSmoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA.

Patient perceptions of glucocorticoid side effects: a cross-sectional survey of users in an online health community

Objectives To identify the side effects most important to glucocorticoid (GC) users through a survey of a UK online health community (Healthunlocked.com). Design Online cross-sectional survey. Setting Participants were recruited through Healthunlocked.com, an online social network for health. Participants Adults who were currently taking GCs, or had taken GCs in the past month. Method Responders scored the importance of listed side effects from 1 to 10, with 10 being of high importance to them. For each side effect, histograms were plotted, and the median rating and IQR were determined. Side effects were ranked by median ranking (largest to smallest) and then IQR (smallest to largest). The scores were categorised as low (scores 1–3), medium (scores 4–7) and high (scores 8–10) importance. Results 604 responders completed the survey. Histograms of side effect scores showed a skew towards high importance for weight gain, a U-shaped distribution for cardiovascular disease (CVD), diabetes, eye disease and infections, and a skew towards low importance for acne. When ranked, the side effect of most importance to responders was weight gain (median score=9, IQR 6–10) followed by insomnia and moon face with equal median score (8) and IQR (5–10). Three serious side effects, CVD, diabetes and infections, were ranked of lower importance overall but had wide ranging scores (median score=8, IQR 1–10). Conclusions The three most highly rated side effects were not clinically serious but remained important to patients, perhaps reflecting their impact on quality of life and high prevalence. This should be taken into consideration when discussing treatment options and planning future GC safety studies.

Association of anti-carbamylated protein antibodies with long-term disability and increased disease activity in patients with early inflammatory arthritis: results from the Norfolk Arthritis Register

BACKGROUND Anti-citrullinated protein antibodies (ACPA) predict increased disease activity and disability in patients with inflammatory arthritis such as rheumatoid arthritis. However, the absence of these antibodies does not confer universally good prognosis. Recently, a new set of antibodies, anti-carbamylated (anti-CarP) antibodies, have been identified in patients with rheumatoid arthritis. This study aimed to investigate the association between anti-CarP antibodies, disability, and disease activity in these patients. METHODS Adults with two or more swollen joints for at least 4 weeks were recruited from the Norfolk Arthritis Register (NOAR). At baseline patients completed the health assessment questionnaire (HAQ). The Disease Activity Score in 28 joints (DAS28) was calculated and rheumatoid arthritis classification criteria applied. ACPA and anti-CarP antibodies were measured on stored serum samples obtained within the first year of the study. The HAQ was repeated after 1, 2, 3, 5, 7, 10, 12, 15, and 20 years, and DAS28 scores done every 5 years. Generalised estimating equations (GEE) tested the association between anti-CarP antibodies and longitudinal HAQ and DAS28 scores. FINDINGS 1995 patients were included; 1310 (66%) were women and median age at onset was 55 years (IQR 43-66). Anti-CarP antibodies were positive in 460 patients (23%), and 1221 (61%) met rheumatoid arthritis classification criteria. Median follow-up was 7 years (IQR 5-11). Patients who were anti-CarP antibody positive had significantly more disability over time and higher levels of disease activity than those who were negative (multivariate GEE adjusted for age, sex, smoking status, ACPA, and year of recruitment to NOAR: β coefficient for HAQ 0·13, 95% CI 0·03-0·23, and for DAS28 0·31, 0·12-0·49). Statistically significant associations were also seen in a subanalysis of 1092 ACPA-negative patients (HAQ 0·15, 0·02-0·29; DAS28 0·37, 0·11-0·63). In ACPA-positive and rheumatoid arthritis subgroups, anti-CarP antibodies were significantly associated with DAS28 (0·30 [0·02-0·57] and 0·21 [0·04-0·37], respectively), and positive associations were also seen with HAQ scores, but these did not meet statistical significance. INTERPRETATION In this study the presence of anti-CarPA was associated with increased burden of disability as measured by the HAQ and higher disease activity in patients with inflammatory arthritis. Since GEE models include outcome data at all timepoints, these associations are long term. Our results suggest that anti-CarP antibodies might provide additional prognostic information to ACPA and in particular identify ACPA-negative patients with poor prognosis. FUNDING Arthritis Research UK.

Association of chemokine CXC ligand 12 gene polymorphism (rs1746048) with cardiovascular mortality in patients with rheumatoid arthritis: results from the Norfolk Arthritis Register

Patients with rheumatoid arthritis (RA) are at increased risk of premature mortality, with cardiovascular disease (CVD) forming the primary cause.1 Previous studies have identified correlations between genetic polymorphisms located both inside2 and outside3 the human leucocyte antigen locus with increased risk of CVD morbidity and mortality, independent of traditional CVD risk factors. A recent genome-wide association study identified a genetic variant (rs1746048) proximal to the CXCL12 gene on chromosome 10q11.21, that is strongly associated with coronary artery disease (p=8.1×10−9),4 increased carotid intimal–medial thickness5 and plasma levels of CXCL12.6 Several studies have highlighted an important role for CXCL12 in RA by demonstrating increased levels of CXCL12 in synovial fluid, as well as upregulation of CXCL12 mRNA in synovial fibroblasts, which may contribute to sustained inflammation.7 However, a large study of Spanish patients with established RA did not detect an association with CVD outcome and a …