Diane Lacaille

Risk of cardiovascular mortality in patients with rheumatoid arthritis: A meta-analysis of observational studies

OBJECTIVE To determine the magnitude of risk of cardiovascular mortality in patients with rheumatoid arthritis (RA) compared with the general population through a meta-analysis of observational studies. METHODS We searched Medline, EMBase, and Lilacs databases from their inception to July 2005. Observational studies that met the following criteria were assessed by 2 researchers: 1) prespecified RA definition, 2) clearly defined cardiovascular disease (CVD) outcome, including ischemic heart disease (IHD) and cerebrovascular accidents (CVAs), and 3) reported standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs). We calculated weighted-pooled summary estimates of SMRs (meta-SMRs) for CVD, IHD, and CVAs using the random-effects model, and tested for heterogeneity using the I(2) statistic. RESULTS Twenty-four studies met the inclusion criteria, comprising 111,758 patients with 22,927 cardiovascular events. Overall, there was a 50% increased risk of CVD death in patients with RA (meta-SMR 1.50, 95% CI 1.39-1.61). Mortality risks for IHD and CVA were increased by 59% and 52%, respectively (meta-SMR 1.59, 95% CI 1.46-1.73 and meta-SMR 1.52, 95% CI 1.40-1.67, respectively). We identified asymmetry in the funnel plot (Eggers test P = 0.002), as well as significant heterogeneity in all main analyses (P < 0.0001). Subgroup analyses showed that inception cohort studies (n = 4, comprising 2,175 RA cases) were the only group that did not show a significantly increased risk for CVD (meta-SMR 1.19, 95% CI 0.86-1.68). CONCLUSION Published data indicate that CVD mortality is increased by approximately 50% in RA patients compared with the general population. However, we found that study characteristics may influence the estimate.

Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies

Objective To determine the magnitude of the risk of incident cardiovascular disease (CVD; fatal and non-fatal), including acute myocardial infarction (MI), cerebrovascular accidents (CVA) and congestive heart failure (CHF), in patients with rheumatoid arthritis (RA) compared to the general population through a meta-analysis of controlled observational studies. Methods The authors searched the Medline, Embase, LILACS and Cochrane databases from their inception to June 2011. Observational studies meeting the following criteria were included: (1) prespecified RA criteria; (2) predefined CVD criteria for incident CVD (MI, CVA or CHF); (3) a comparison group; and (4) RR estimates, 95% CI or data for calculating them. The authors calculated the pooled RR using the random-effects model and tested for heterogeneity using the bootstrap version of the Q statistic. Results Fourteen studies comprising 41 490 patients met the inclusion criteria. Overall, there was a 48% increased risk of incident CVD in patients with RA (pooled RR 1.48 (95% CI 1.36 to 1.62)). The risks of MI and CVA were increased by 68% (pooled RR 1.68 (95% CI 1.40 to 2.03)) and 41% (pooled RR 1.41 (95% CI 1.14 to 1.74)). The risk of CHF was assessed in only one study (RR 1.87 (95% CI 1.47 to 2.39)). Significant heterogeneity existed in all main analyses. Subgroup analyses showed that inception cohort studies were the only group that did not show a significantly increased risk of CVD (pooled RR 1.12 (95% CI 0.97 to 1.65)). Conclusions Published data indicate that the risk of incident CVD is increased by 48% in patients with RA compared to the general population. Sample and cohort type influenced the estimates of RR.

Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis

OBJECTIVE Rheumatoid arthritis (RA) is associated with increased frequency of and mortality from infections, which may be related to host factors, RA itself, inflammation, or medication side effects. This study was undertaken to determine the effect of nonbiologic disease-modifying antirheumatic drugs (DMARDs) on infection risk in RA. METHODS We performed a retrospective, longitudinal study of a population-based RA cohort in British Columbia, Canada, followed from January 1996 to March 2003 using administrative data. We evaluated mild infections (requiring a physician visit or antibiotics) and serious infections (requiring or complicating hospitalization). Adjusted risk of mild and serious infections associated with DMARD exposure was estimated using generalized estimating equation extension of multivariate Poisson regression models, after adjusting for baseline covariates (age, sex, RA duration, socioeconomic status) and time-dependent covariates (corticosteroids, comorbidity, prior infections). RESULTS A total of 27,710 individuals with RA provided 162,710 person-years of followup. Of these, 25,608 (92%) had at least 1 mild infection and 4,941 (18%) had at least 1 serious infection. Use of DMARDs without corticosteroids was associated with a small decrease in mild infection risk of statistical significance but unclear clinical significance (adjusted rate ratio [RR] 0.90, 95% confidence interval [95% CI] 0.88-0.93 relative to no corticosteroid or DMARD use). Use of DMARDs without corticosteroids was not associated with increased serious infection risk (adjusted RR 0.92, 95% CI 0.85-1.0). Use of corticosteroids increased the risk of mild and serious infections. CONCLUSION Our results indicate that use of nonbiologic DMARDs, including methotrexate, does not increase the risk of infection in RA, whereas use of corticosteroids does. This has important implications for counseling individuals with RA concerning risks and benefits of DMARDs.

Steroid-sparing effects of methotrexate in systemic lupus erythematosus: A double-blind, randomized, placebo-controlled trial

OBJECTIVE To assess the potential benefits of methotrexate in patients with systemic lupus erythematosus (SLE). METHODS A 12-month, double-blind, placebo-controlled trial of methotrexate with folic acid was conducted. Intent-to-treat analyses were performed with mixed linear models and alpha = 0.04 (96% confidence interval [96% CI]) to account for interim analysis of longitudinal data to assess the treatment effects on lupus disease activity and daily steroid dose across monthly measurements, and to test if the treatment effects depended on selected participant characteristics. RESULTS Of 215 participants screened, 94 were excluded, 35 declined, and 86 were randomized (methotrexate = 41, placebo = 45). The groups were balanced for demographic and disease characteristics. Antimalarial use was more frequent in the placebo group, which was adjusted for in multivariable analyses. Sixty participants (27 methotrexate, 33 placebo) completed the study and 26 terminated early. Among participants who had the same baseline prednisone dose, those taking methotrexate received, on average, 1.33 mg/day less prednisone during the trial period (96% CI 0.06, 2.72 mg/day; a 22% reduction of their average-during-trial daily dose) compared with those in the placebo group. For the primary measure of disease activity (revised Systemic Lupus Activity Measure), methotrexate use was also associated with a marginally significant reduction in the mean during-trial score of 0.86 units (96% CI 0.01, 1.71; P = 0.039). A significant interaction between treatment and baseline damage was found (P = 0.001). CONCLUSION Methotrexate conferred a significant advantage in participants with moderately active lupus by lowering daily prednisone dose and slightly decreasing lupus disease activity. As a therapeutic option in moderate SLE, methotrexate can be considered to be steroid sparing.

Association between dinucleotide repeat in non-coding region of interferon-gamma gene and susceptibility to, and severity of, rheumatoid arthritis

BACKGROUND Rheumatoid arthritis ranges from a mild, non-deforming arthropathy with little long-term disability to severe, incapacitating, deforming arthritis which may be refractory to conventional disease-modifying agents. Epidemiological studies show an important genetic influence in rheumatoid arthritis, and MHC region genes and cytokine genes within and outside this region have been considered as candidates. We did a case-control study to test whether polymorphisms in the interferon-gamma gene are associated with severity of rheumatoid arthritis. METHODS Interferon gamma dinucleotide repeat polymorphisms were examined with quantitative genescan technology, and HLA-DR alleles were identified by PCR and restriction-fragment-length polymorphism analysis. We studied 60 patients with severe rheumatoid arthritis, 39 with mild disease, and 65 normal controls. FINDINGS Susceptibility to, and severity of, rheumatoid arthritis were related to a microsatellite polymorphism within the first intron of the interferon-gamma gene. A 126 bp allele was seen in 44 (73%) of 60 patients with severe rheumatoid arthritis, compared with eight (21%) of 39 with mild disease (odds ratio 10.66 [95% CI 4.1-24.9]), and with eight (12%) of 65 normal controls (19.59 [7.7-49.9]). Conversely, a 122 bp allele at the same locus was found in four (7%) patients with severe disease compared with 25 (64%) of those with mild disease (0.04 [0.01-0.1]) and with 52 (80%) of controls (0.018 [0.005-0.06]). INTERPRETATION This association may be valuable for understanding the mechanism of disease progression, for predicting the course of the disease, and for guiding therapy.

Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment

Objective: To provide context for the malignancy experience in the rheumatoid arthritis (RA) abatacept clinical development programme (CDP) by performing comparisons with similar RA patients and the general population. Methods: Malignancy outcomes included total malignancy (excluding non-melanoma skin cancer (NMSC)), breast, colorectal, lung cancers and lymphoma. Comparisons were made between the observed incidence in patients within the abatacept CDP and RA patients on disease-modifying antirheumatic drugs (DMARD) identified from five data sources: the population-based British Columbia RA Cohort, the Norfolk Arthritis Register, the National Data Bank for Rheumatic Diseases, the Sweden Early RA Register and the General Practice Research Database. Age and sex-adjusted incidence rates (IR) and standardised incidence ratios (SIR) were used to compare events in the abatacept trials with the RA DMARD cohorts and the general population. Results: A total of 4134 RA patients treated with abatacept in seven trials and 41 529 DMARD-treated RA patients in the five observational cohorts was identified for study inclusion. In the abatacept-treated patients, the 51 malignancies (excluding NMSC), seven cases of breast, two cases of colorectal, 13 cases of lung cancer and five cases of lymphoma observed were not greater than the range of expected cases from the five RA cohorts. The SIR comparing RA patients with the general population were consistent with those reported in the literature. Conclusions: The IR of total malignancy (excluding NMSC), breast, colorectal, lung cancers and lymphoma in the abatacept CDP were consistent with those in a comparable RA population. These data suggest no new safety signals with respect to malignancies, which will continue to be monitored.

A systematic review identifies valid comorbidity indices derived from administrative health data

OBJECTIVES To conduct a systematic review of studies reporting on the development or validation of comorbidity indices using administrative health data and compare their ability to predict outcomes related to comorbidity (ie, construct validity). STUDY DESIGN AND SETTING We conducted a comprehensive literature search of MEDLINE and EMBASE, until September 2012. After title and abstract screen, relevant articles were selected for review by two independent investigators. Predictive validity and model fit were measured using c-statistic for dichotomous outcomes and R(2) for continuous outcomes. RESULTS Our review includes 76 articles. Two categories of comorbidity indices were identified: those identifying comorbidities based on diagnoses, using International Classification of Disease codes from hospitalization or outpatient data, and based on medications, using pharmacy data. The ability of indices studied to predict morbidity-related outcomes ranged from poor (C statistic ≤ 0.69) to excellent (C statistic >0.80) depending on the specific index, outcome measured, and study population. Diagnosis-based measures, particularly the Elixhauser Index and the Romano adaptation of the Charlson Index, resulted in higher ability to predict mortality outcomes. Medication-based indices, such as the Chronic Disease Score, demonstrated better performance for predicting health care utilization. CONCLUSION A number of valid comorbidity indices derived from administrative data are available. Selection of an appropriate index should take into account the type of data available, study population, and specific outcome of interest.

Reliability, validity, and responsiveness of five at‐work productivity measures in patients with rheumatoid arthritis or osteoarthritis

Arthritis often impacts a workers ability to be productive while at work. However, the ideal approach to measuring arthritis‐attributable at‐work productivity loss remains unclear. Our objective was to evaluate the relative strengths and weaknesses of 5 measures aimed at quantifying health‐related at‐work productivity loss and to determine the best available instrument for this population.

Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population-based study

OBJECTIVES To determine the effect of glucocorticoids (GCs) on acute myocardial infarction (MI) risk in patients with RA. METHODS Using administrative health data, we conducted a population-based cohort study of 8384 incident RA cases (1997-2006). Primary exposure was incident GC use. MI events were ascertained using hospitalization and vital statistics data. We used Cox proportional-hazards models and modelled GC use as four alternative time-dependent variables (current use, current dose, cumulative dose and cumulative duration), adjusting for demographics, comorbidities, cardiovascular drug use, propensity score and RA characteristics. Sensitivity analyses explored potential effects of unmeasured confounding. RESULTS Within 50 238 person-years in 8384 RA cases, we identified 298 incident MI events. Multivariable models showed that current GC use was associated with 68% increased risk of MI [Hazard ratio (HR) = 1.68, 95% CI 1.14, 2.47]. Similarly, separate multivariable models showed that current daily dose (HR = 1.14, 95% CI 1.05, 1.24 per each 5 mg/day increase), cumulative duration of use (HR = 1.14, 95% CI 1.00, 1.29 per year of GC use) and total cumulative dose (HR = 1.06, 95% CI 1.02, 1.10 per gram accumulated in the past) were also associated with increased risk of MI. Furthermore, in the same multivariable model, current dose and cumulative use were independently associated with an increased risk of MI (10% per additional year on GCs and 13% per 5 mg/day increase). CONCLUSION GCs are associated with an increased risk of MI in RA. Our results suggest a dual effect of GCs on MI risk, an immediate effect mediated through current dosage and a long-term effect of cumulative exposure.

Impact of statin adherence on cardiovascular disease and mortality outcomes: a systematic review

While suboptimal adherence to statin medication has been quantified in real‐world patient settings, a better understanding of its impact is needed, particularly with respect to distinct problems of medication taking. Our aim was to synthesize current evidence on the impacts of statin adherence, discontinuation and persistence on cardiovascular disease and mortality outcomes.