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Objective: Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVEs in RA patients. Methods: A randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P < 0.05. RA patients age >50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety. Results: A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [IQR] 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [HR] 0.66 [95% confidence interval (95% CI) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [IQR 0.94, 6.08] versus 3.60 mg/liter [IQR 1.47, 7.49]; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar. Conclusion: Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists' Collaboration meta‐analysis of statin effects in other populations. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to compare the incidence of cancer and all-cause and cause-specific mortality rates among a cohort of patients with severe PsA receiving TNF inhibitor (TNFi) with those of the general UK population. Methods Cancers and deaths were identified from the national cancer and the national death registers in patients with PsA included in the British Society for Rheumatology Biologics Register from start of TNFi until 31 December 2012. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated using published cancer and death rates for the general population. SIRs were calculated for both overall cancer risk and non-melanoma skin cancer. SMRs were calculated for (1) all-cause mortality, (2) death from malignancy and (3) death from circulatory disease. Gender-specific analyses were also performed. Results Thirty-four cancers and 41 deaths among 709 patients were observed. The risk of malignancy overall was not increased (SIR 0.94; 95% CI: 0.65, 1.34). However, there was a significantly increased incidence of non-melanoma skin cancer (SIR 2.12; 95% CI: 1.19, 3.50). The all-cause mortality rate in our cohort was increased (SMR 1.56; CI: 1.12, 2.11). Death from malignancy was not increased, but death from coronary heart disease was increased (SMR 2.42; 95% CI: 1.11, 4.59). Conclusion In our cohort of patients with severe PsA, the overall incidence of malignancy was similar to that of the general population, although the incidence of non-melanoma skin cancer was increased. All-cause mortality was significantly increased, in part due to excess of deaths attributed to coronary heart disease. [ABSTRACT FROM AUTHOR]

Objectives Both TNF inhibitors (TNFi) and rituximab (RTX), a B-cell depleting biologic, can disrupt the immune system in RA. RTX is licensed in Europe for use following TNFi failure. However, safety data on serious infections (SIs) are scarce for RTX in daily practice. This analysis aims to compare the risk of SIs in the first year after a switch to either TNFi or RTX in patients who have failed a first TNFi. Methods This study included patients with RA registered with the British Society for Rheumatology Biologics Register (BSRBR-RA) who switched to either a second TNFi or RTX after failing a first TNFi. Patients were followed until first SI, treatment discontinuation, last recorded follow-up or the end of the first year after the switch, whichever came first. SI was defined as requiring hospitalization, intravenous antibiotics or resulting in death. The risk of first SI was compared between TNFi and RTX using Cox proportional hazard models adjusted using propensity scores using inverse probability of treatment weighting. Results This analysis included 3419 TNFi and 1396 RTX patients contributing 2765 and 1224 person-years (pyrs), respectively. SI occurred in 164 (4.8%) TNFi and 81 (5.8%) RTX patients giving a crude rate of 59 and 66 SI/1000 pyrs, respectively. The adjusted hazard ratio for SI was 1.0 (95% CI: 0.7, 1.4). Conclusion The risk of SIs was comparable over the first year of treatment between TNFi and RTX treatment in patients who had failed a single prior TNFi. [ABSTRACT FROM AUTHOR]

Objective To describe the outcome in patients with rheumatoid arthritis (RA) over 20 years from symptom onset, and to assess the association between early treatment (with disease-modifying antirheumatic drugs/steroids) and mortality and disability during follow-up. Methods Patients recruited to the Norfolk Arthritis Register (NOAR) between 1990 and 1994 who met the 2010 American College of Rheumatology/European League Against Rheumatism RA criteria at baseline were included in this analysis. Demographic and clinical variables were collected at baseline and at years 1-3, 5, 7, 10, 15, and 20. Disease activity (swollen joint count [SJC]/tender joint count [TJC]), disability (Health Assessment Questionnaire disability index [HAQ DI]), and mortality over 20 years were determined. Associations between treatment group (early treatment [ET], treatment ≤6 months after symptom onset; late treatment [LT], treatment >6 months after symptom onset; never treatment [NT], no treatment) and mortality and disability were assessed using weighted pooled logistic regression and weighted multilevel mixed-effects linear regression, respectively. Inverse weights were used to account for confounding by indication and censoring. Results This study included 602 patients with RA (median age 56 years [interquartile range 44-68 years]; 65.9% women). The median SJCs and TJCs were low during the follow-up period (1-3 swollen joints and 3-6 tender joints). The median HAQ DI score increased after year 1 but remained at low/moderate levels (median 1.25 after year 10). The risk of mortality was reduced in the ET and LT groups compared with that in the NT group. The ET group and the NT group had comparable HAQ DI scores during the follow-up period (β = 0.03, 95% confidence interval [95% CI] −0.06, 0.12), while the HAQ DI score was increased in the LT group (for LT versus NT, β = 0.10 [95% CI 0.02, 0.17]). Conclusion The results of this study indicate the importance of early treatment with regard to the long-term outcomes in patients with RA. [ABSTRACT FROM AUTHOR]

Objective Rheumatoid arthritis (RA) susceptibility HLA-DRB1 haplotypes based on amino acid positions 11/13, 71, and 74 predict radiographic damage. The mechanism of action is unknown, but it may be mediated by inflammation. We undertook this study to systematically investigate the effect of these amino acids on nonradiographic measures of disease activity/outcomes. Methods We tested the association of RA susceptibility HLA-DRB1 amino acids with the C-reactive protein (CRP) level, the tender joint count (TJC), the swollen joint count (SJC), the Disease Activity Score in 28 joints (DAS28), and the Health Assessment Questionnaire (HAQ) score in the Norfolk Arthritis Register (NOAR) and Early Rheumatoid Arthritis Study (ERAS) cohorts. Longitudinal modeling of disease activity/outcomes was performed using generalized linear latent and mixed models. Mediation analysis was performed using directed acyclic graphs to investigate the paths from genetic factors to outcome. Results A total of 2,158 patients were available for analysis in the NOAR cohort. Valine at position 11 showed the strongest association with the CRP level ( P = 2.21 × 10−6), the SJC ( P = 7.51 × 10−6), and the DAS28 ( P = 0.002); it was marginally associated with the HAQ score ( P = 0.044) but not with the TJC. The same amino acid and haplotype risk hierarchy observed for susceptibility and radiographic severity was observed for the CRP level and nonradiographic measures of disease activity/outcome, apart from the TJC. The results were replicated in the ERAS cohort. The effect of valine at position 11 on the SJC was mainly mediated by anti-citrullinated protein antibody status, the effect of which was mainly mediated by inflammation; however, the effect of valine at position 11 was also independent of the CRP level ( P = 1.6 × 10−4). Conclusion Genetic markers of RA susceptibility located within HLA-DRB1 determine the levels of clinical and systemic inflammation independently, and also determine all objective measures of disease activity and outcome. [ABSTRACT FROM AUTHOR]

Objectives. Early remission is the current treatment strategy for patients with inflammatory polyarthritis (IP) and RA. Our objective was to identify baseline factors associated with achieving remission: sustained (SR), intermittent (IR) or never (NR) over a 5-year period in patients with early IP. Methods. Clinical and demographic data of patients with IP recruited to the Norfolk Arthritis Register (NOAR) were obtained at baseline and years 1, 2, 3 and 5. Remission was defined as no tender or swollen joints (out of 51). Patients were classified as NR or PR, respectively, if they were in remission at: no assessment or ≽3 consecutive assessments after baseline, and IR otherwise. Ordinal regression and a random effects model, respectively, were used to examine the association between baseline factors, remission group and HAQ scores over time. Results. A total of 868 patients (66% female) were included. Of these, 54%, 34% and 12% achieved NR, IR and SR, respectively. In multivariate analysis, female sex (odds ratio, OR 0.47, 95% CI: 0.35, 0.63), higher tender joint count (OR = 0.94, 95% CI: 0.93, 0.96), higher HAQ (OR = 0.59, 95% CI: 0.48, 0.74), being obese (OR = 0.70, 95% CI: 0.50, 0.99), hypertensive (OR = 0.67, 95% CI: 0.50, 0.90) or depressed (OR = 0.74, 95% CI: 0.55, 1.00) at baseline were independent predictors of being in a lower remission group. IR and SR were associated with lower HAQ scores over time and lower DAS28 at year 5. Conclusion. Women with higher tender joint count and disability at baseline, depression, obesity and hypertension were less likely to achieve remission. This information could help when stratifying patients for more aggressive therapy. [ABSTRACT FROM AUTHOR]

Objective Patients with rheumatoid arthritis (RA) are at an increased risk of ischemic stroke. Tumor necrosis factor inhibitors (TNFi) may influence risk and mortality after ischemic stroke by reducing inflammation. This study was undertaken to examine the association of TNFi with the risk of incident ischemic stroke and with 30-day and 1-year mortality after ischemic stroke. Methods Patients with RA starting therapy with TNFi and a biologics-naive comparator group treated with synthetic disease-modifying antirheumatic drugs (DMARDs) only were recruited to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis from 2001 to 2009. Patients were followed up via clinical and patient questionnaires as well as the national death register. Incident strokes were classified as ischemic if brain imaging reports suggested ischemia or if ischemic stroke was reported as the underlying cause of death on a death certificate. Patients with a previous stroke were excluded. Risk of ischemic stroke was compared between patients receiving synthetic DMARDs only and those ever-exposed to TNFi using a Cox proportional hazards regression model adjusted for potential confounders. Mortality after ischemic stroke was compared between synthetic DMARD-treated patients and TNFi-treated patients using logistic regression, adjusted for age and sex. Results To April 2010, 127 verified incident ischemic strokes (21 in 3,271 synthetic DMARD-treated patients and 106 in 11,642 TNFi-treated patients) occurred during 11,973 and 61,226 person-years of observation, respectively (incidence rate 175 versus 173 per 100,000 person-years). After adjustment for confounders, there was no association between ever-exposure to TNFi and ischemic stroke (hazard ratio 0.99 [95% confidence interval (95% CI) 0.54-1.81]). Mortality 30 days or 1 year after ischemic stroke was not associated with concurrent TNFi exposure (odds ratio 0.18 [95% CI 0.03-1.21] and 0.60 [95% CI 0.16-2.28], respectively). Conclusion Exposure to TNFi does not appear to influence the occurrence of ischemic stroke in the medium term in patients with RA. The impact on mortality after ischemic stroke remains inconclusive. [ABSTRACT FROM AUTHOR]

Objectives. To investigate levels of self-reported adherence to biologic treatment and establish the contribution of demographic, physical and psychological factors to biologic medication adherence in an RA cohort. Methods. Adalimumab-treated patients were recruited through the British Society for Rheumatology Biologics Register for RA between May 2007 and April 2009. Demographic and baseline psychological measures including illness and medication beliefs were collected. Disease activity (28-item DAS), physical function (HAQ) and quality of life (36-item Short Form Health Survey) were also measured at baseline and at 6, 12 and 18 months. Adherence was assessed at each follow-up using the patient self-completed Compliance Questionnaire for Rheumatology (CQR). Multilevel mixed effects modelling analysis was performed to investigate predictors of adherence. Results. Of the 329 Adalimumab-treated patients included, low adherence (CQR score <65) was reported in 23%, with 41% reporting low adherence at at least one time point. After controlling for age and disease duration, factors independently predictive of increased adherence were increased belief in medication necessity, with baseline effect diminishing over time [β coefficient 1.68 (S.E. 0.19), P = 0.0001], lower medication concerns [0.50 (0.15), P = 0.001], with this effect remaining throughout follow-up, increased professional or family member support [0.81 (0.32), P = 0.01], strong views of illness being chronic [0.32 (0.14), P = 0.025] and increased treatment control [0.41 (0.19), P = 0.032]. Conclusion. Wider recognition of the importance of psychological factors, particularly medication beliefs, in driving medication adherence could have substantial clinical and health economic benefits in RA. The psychological factors we have identified are putative targets for strategies to improve adherence in RA. [ABSTRACT FROM AUTHOR]

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; &geq;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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM PUBLISHER]

Rheumatoid arthritis (RA) associates with excess cardiovascular risk and there is a need to assess that risk. However, individual lipid levels may be influenced by disease activity and drug use, whereas lipid ratios may be more robust. A cross-sectional cohort of 400 consecutive patients was used to establish factors that influenced individual lipid levels and lipid ratios in RA, using multiple regression models. A further longitudinal cohort of 550 patients with RA was used to confirm these findings, using generalized estimating equations. Cross-sectionally, higher C-reactive protein (CRP) levels correlated with lower levels of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol ([HDL-C] P ≤ .015), whereas lipid ratios did not correlate with CRP. The findings were broadly replicated in the longitudinal data. In summary, the effects of inflammation on individual lipid levels may underestimate lipid-associated cardiovascular disease (CVD) risk in RA, thus lipid ratios may be more appropriate for CVD risk stratification in RA. [ABSTRACT FROM PUBLISHER]

The article discusses a study which compared the risk of pneumocystis jirovecil (PJP) infection in rheumatoid arthritis (RA) patients treated with TNFi to that in RA patients treated with sDMARDS alone. It aimed to describe the time of onset of PJP after starting TNFi, concomitant drug therapy and patient co-morbidities. Resulting data suggests that pneumocystis pneumonia occurs early in the treatment with TNFi, which has also been demonstrated for tuberculosis.

A letter to the editor is presented in response to the article "The Risk of Serious Infections in Patients Receiving Anakinra for Rheumatoid Arthritis: Results From the British Society for Rheumatology Biologics Register," which appeared in a previous issue of "Rheumatology."