Association of the TRAF1/C5 locus with increased mortality,particularly from malignancy or sepsis,in patients with rheumatoid arthritis

Objective

Recent genome‐wide association studies have identified TRAF1/C5 as a rheumatoid arthritis (RA) susceptibility locus. Tumor necrosis factor receptor–associated factor 1 (TRAF1) has been implicated in the regulation of antiapoptotic pathways, whereas C5 has a well‐established role in defense against infection. The purpose of this study was to examine the association of the TRAF1/C5 locus with death in patients with RA.

Methods

Genomic DNA samples were collected from a prospective cohort of 400 RA patients. TRAF1/C5 rs3761847 was identified using real‐time polymerase chain reaction and melting curve analyses. The association of TRAF1/C5 rs3761847 alleles with the risk of death was assessed using Cox proportional hazards regression analyses.

Results

TRAF1/C5 rs3761847 GG homozygote status was associated with an increased risk of death (hazard ratio 3.96 [95% confidence interval 1.24–12.6], P = 0.020) as compared with AA homozygote status. The excess mortality was attributed to deaths due to malignancies and sepsis but not cardiovascular disease (CVD). This polymorphism was one of the strongest predictors of death in RA (for TRAF1/C5 GG versus AA, hazard ratio 3.85 [95% confidence interval 1.18–12.59], P = 0.026) alongside the erythrocyte sedimentation rate, triglyceride level, prednisolone use, and age.

Conclusion

The risk of death in RA is increased in TRAF1/C5 rs3761847 GG homozygotes and appears to be independent of RA activity and severity as well as comorbidities relevant to CVD. If this finding is replicated in future studies, TRAF1/C5 genotyping could identify patients at increased risk of death, particularly death due to malignancy or sepsis.

     

Genetically determined high serum levels of mannose‐binding lectin and agalactosyl IgG are associated with ischemic heart disease in rheumatoid arthritis

Objective

Patients with rheumatoid arthritis (RA) have excess morbidity and mortality due to ischemic heart disease. It has been suggested that high serum levels of mannose‐binding lectin (MBL) and agalactosyl IgG (IgG‐G0) are associated with increased inflammation in RA. MBL also enhances inflammation‐mediated tissue injury during postischemic reperfusion. This study was undertaken to examine whether these factors are associated with increased risk of ischemic heart disease in RA.

Methods

MBL alleles were genotyped in 229 Danish patients with RA. In addition, serum levels of MBL and IgG‐G0 were measured. Incidences of ischemic heart disease, myocardial infarction, and death due to ischemic heart disease after the diagnosis of RA were assessed in a prospective study.

Results

During a median followup of 9.5 years, ischemic heart disease was diagnosed in 8 of 27 patients with genetically determined high serum levels of MBL, as compared with 24 of the remaining 192 patients (data not available on 10 patients). After correction for other known risk factors, the hazard ratio (HR) was 3.6 (95% confidence interval [95% CI] 1.4–9.2). The corrected HR for myocardial infarction was 9.0 (95% CI 2.2–36.4). High serum levels of MBL also conferred an increased risk of death due to ischemic heart disease (age‐ and sex‐adjusted HR 10.5, 95% CI 2.7–41.3). However, further analyses showed that these associations were present only in patients with high serum levels of IgG‐G0.

Conclusion

Genetically determined high serum levels of MBL and high serum levels of IgG‐G0 are associated with increased risk of ischemic heart disease, myocardial infarction, and premature death in patients with RA.

     

Survival in rheumatoid arthritis: A population‐based analysis of trends over 40 years

Objective

To evaluate trends in and risk factors for mortality among patients with rheumatoid arthritis (RA) over a 40‐year period.

Methods

A population‐based inception cohort was assembled from among all Rochester, Minnesota residents ages ≥18 years who were first diagnosed with RA (fulfilling the 1987 American College of Rheumatology criteria for RA) between January 1, 1955 and December 31, 1994. Patients were followed up longitudinally through their entire medical records (including all inpatient and outpatient care by any provider) until death or migration from the county. Survival was described using the Kaplan‐Meier method. Observed and expected survival were compared using the log‐rank test, and standardized mortality ratios (SMRs) with expected survival were based on the sex and age of the study population and death rates from the Minnesota life tables. Cox proportional hazards models were used to estimate the influence of extraarticular manifestations and comorbidities, controlling for age, sex, body mass index (BMI), smoking, and rheumatoid factor positivity.

Results

Survival in this RA cohort was significantly lower than that expected in the population (P < 0.001) over the entire time period. Patients with RA were at significantly higher risk of death, with an SMR of 1.27 (95% confidence interval 1.13–1.41). Excess mortality among women was more pronounced than among men, with SMRs of 1.41 and 1.08, respectively. Presence of ≥1 extraarticular manifestation was the strongest predictor of mortality after adjusting for age, sex, BMI, smoking, and rheumatoid factor positivity.

Conclusion

Survival in RA patients is significantly lower than expected. The strongest predictors of survival appear to be those related to RA disease complications, specifically, extraarticular manifestations of the disease and comorbidities. More attention should be paid to mortality as an outcome measure in RA.

     

Incidence and mortality of interstitial lung disease in rheumatoid arthritis: A population‐based study

Objective

Interstitial lung disease (ILD) has been recognized as an important comorbidity in rheumatoid arthritis (RA). We undertook the current study to assess incidence, predictors, and mortality of RA‐associated ILD.

Methods

We examined a population‐based incidence cohort of patients with RA and a matched cohort of individuals without RA. All subjects were followed up longitudinally. The lifetime risk of ILD was estimated. Cox proportional hazards models were used to compare the incidence of ILD between cohorts, to investigate predictors, and to explore the impact of ILD on survival.

Results

Patients with RA (n = 582) and subjects without RA (n = 603) were followed up for a mean of 16.4 and 19.3 years, respectively. The lifetime risk of developing ILD was 7.7% for RA patients and 0.9% for non‐RA subjects. This difference translated into a hazard ratio (HR) of 8.96 (95% confidence interval [95% CI] 4.02–19.94). The risk of developing ILD was higher in RA patients who were older at the time of disease onset, in male patients, and in individuals with more severe RA. The risk of death for RA patients with ILD was 3 times higher than in RA patients without ILD (HR 2.86 [95% CI 1.98–4.12]). Median survival after ILD diagnosis was only 2.6 years. ILD contributed ∼13% to the excess mortality of RA patients when compared with the general population.

Conclusion

Our results emphasize the increased risk of ILD in patients with RA. The devastating impact of ILD on survival provides evidence that development of better strategies for the treatment of ILD could significantly lower the excess mortality among individuals with RA.

     

The risk of congestive heart failure in rheumatoid arthritis: A population‐based study over 46 years

Objective

It is hypothesized that the systemic inflammation associated with rheumatoid arthritis (RA) promotes an increased risk of cardiovascular (CV) morbidity and mortality. We examined the risk and determinants of congestive heart failure (CHF) in patients with RA.

Methods

We assembled a population‐based, retrospective incidence cohort from among all individuals living in Rochester, Minnesota, in whom RA (defined according to the American College of Rheumatology 1987 criteria) was first diagnosed between 1955 and 1995, and an age‐ and sex‐matched non‐RA cohort. After excluding patients in whom CHF occurred before the RA index date, all subjects were followed up until either death, incident CHF (defined according to the Framingham Heart Study criteria), migration from the county, or until January 1, 2001. Detailed information from the complete medical records (including all inpatient and outpatient care provided by all local providers) regarding RA, ischemic heart disease, and traditional CV risk factors was collected. Cox models were used to estimate the effect of RA on the development of CHF, adjusting for CV risk factors and/or ischemic heart disease.

Results

The study population included 575 patients with RA and 583 subjects without RA. The CHF incidence rates were 1.99 and 1.16 cases per 100 person‐years in patients with RA and in non‐RA subjects, respectively (rate ratio 1.7, 95% confidence interval [95% CI] 1.3–2.1). After 30 years of followup, the cumulative incidence of CHF was 34.0% in patients with RA and 25.2% in non‐RA subjects (P< 0.001). RA conferred a significant excess risk of CHF (hazard ratio [HR] 1.87, 95% CI 1.47–2.39) after adjusting for demographics, ischemic heart disease, and CV risk factors. The risk was higher among patients with RA who were rheumatoid factor (RF) positive (HR 2.59, 95% CI 1.95–3.43) than among those who were RF negative (HR 1.28, 95% CI 0.93–1.78).

Conclusion

Compared with persons without RA, patients with RA have twice the risk of developing CHF. This excess risk is not explained by traditional CV risk factors and/or clinical ischemic heart disease.

     

Effect of intensive lipid‐lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease

Objective

To examine the effect of intensive lipid‐lowering therapy on a composite cardiovascular outcome (cardiovascular disease [CVD]), consisting of mortality and morbidity end points, in patients with inflammatory joint disease (rheumatoid arthritis [RA], ankylosing spondylitis [AS], or psoriatic arthritis [PsA]) by post hoc analysis of 2 prospective trials of statins with a secondary end point of CVD outcome (the Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] studies).

Methods

Of the 18,889 patients participating in the 2 trials, 199 had RA, 46 had AS, and 35 had PsA. Lipid‐lowering therapy consisted of an intensive regimen of atorvastatin 80 mg or a conventional/low‐dose regimen of atorvastatin 10 mg or simvastatin 20–40 mg. The median duration of followup was nearly 5 years. Changes in lipid levels were examined by analyses of covariance. The effect on CVD was examined by Cox regression analyses, and heterogeneity tests were performed.

Results

Patients with RA and those with AS had lower baseline cholesterol levels than patients without inflammatory joint disease (least squares mean ± SEM 180.7 ± 2.3 mg/dl and 176.5 ± 4.7 mg/dl, respectively, versus 185.6 ± 0.2 mg/dl; P = 0.03 and P = 0.05, respectively). Statin treatment led to a comparable decrease in lipid levels and a 20% reduction in overall risk of CVD in both patients with and those without inflammatory joint disease.

Conclusion

Our findings indicate that patients with and those without inflammatory joint disease experience comparable lipid‐lowering effects and CVD risk reduction after intensive treatment with statins.

     

How much of the increased incidence of heart failure in rheumatoid arthritis is attributable to traditional cardiovascular risk factors and ischemic heart disease?

Objective

To compare the proportion of the risk for the development of heart failure (HF) that is attributable to traditional cardiovascular (CV) risk factors, ischemic heart disease (IHD), and alcohol abuse between subjects with and subjects without rheumatoid arthritis (RA).

Methods

A population‐based inception cohort of RA patients was assembled along with a similar cohort of subjects without RA. All individuals were followed up through their complete medical records, until HF incidence, death, migration, or January 1, 2001. The attributable risk of HF was estimated as the difference between the observed cumulative incidence of HF in each cohort (estimated from multivariable Cox models and adjusted for the competing risk of death) and the predicted cumulative incidence of HF in the absence of risk factors, with results expressed as a percentage of the observed cumulative incidence.

Results

A total of 575 RA subjects and 583 non‐RA subjects (mean age 57 years, 73% women) without HF at incidence/index date had a mean followup of 15.1 and 17.0 years, respectively. During that period, 165 RA and 115 non‐RA subjects had a first episode of HF, with a cumulative incidence of 36.3% and 20.4%, respectively, at age 80 years. Among non‐RA subjects, 77% of the HF at age 80 years was attributable to CV risk factors, IHD, and alcohol abuse combined, whereas among RA subjects, only 54% of the HF at age 80 years was attributable to these factors (P < 0.01).

Conclusion

The excess risk of HF among RA patients is not explained by an increased frequency or effect of CV risk factors and IHD.

     

Propensity‐adjusted association of methotrexate with overall survival in rheumatoid arthritis

Objective

While medications used to treat rheumatoid arthritis (RA) may affect survival in RA, few studies take into account the propensity for medication use, which may reflect selection bias in treatment allocation in survival models. We undertook this study to examine the relationship between methotrexate (MTX) use and mortality in RA, after controlling for individual propensity scores for MTX use.

Methods

We studied 5,626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use, modeled in time‐varying Cox regression models. We used the random forest method to generate individual propensity scores for MTX use at study entry and during followup in a time‐varying manner; these scores were included in the multivariate model. We also investigated whether selective discontinuation of MTX immediately prior to death altered the risk of mortality, and we examined the association of duration of MTX use with survival.

Results

During followup, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30 [95% confidence interval 0.09–1.03]). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use.

Conclusion

MTX use was associated with a 70% reduction in mortality in RA.

     

The safety of anakinra in high‐risk patients with active rheumatoid arthritis: Six‐month observations of patients with comorbid conditions

Objective

To determine in a placebo‐controlled, double‐blind trial the safety profile of daily anakinra (Kineret) use in patients with active rheumatoid arthritis (RA) and concurrent comorbid conditions.

Methods

In 169 centers in 9 countries, 1,414 patients with active RA were randomly assigned to receive either anakinra (100 mg) or placebo treatment (4:1 anakinra‐to‐placebo allocation ratio), with study drug administered by daily subcutaneous injection for 6 months. The current post hoc analysis assessed baseline comorbid conditions, and patients were considered at high risk for the occurrence of adverse events if they had a history of at least one of the following: cardiovascular event, pulmonary event, central nervous system–related event, infection, diabetes, malignancy, or renal impairment. Within each treatment group (anakinra or placebo), incidence rates were summarized for serious adverse events, infectious events, and serious infectious events in high‐risk patients and compared with these incidence rates in patients without comorbid conditions.

Results

The majority of patients in the trial had one or more comorbid conditions. In these high‐risk patients, there were no differences in the incidence of serious adverse events or infectious events between treatment groups. The incidence of serious infectious events with anakinra use was similar between high‐risk patients (2.5%) and the entire study population (2.1%) and was not attributable to any single comorbidity.

Conclusion

Results of the analysis of adverse events in patients with active RA and coexisting comorbidities suggest that the favorable safety profile of anakinra is maintained in a high‐risk patient population.

     

Association of the HLA–DRB1 gene with premature death,particularly from cardiovascular disease,in patients with rheumatoid arthritis and inflammatory polyarthritis

Objective

To examine the role of the variants of the PTPN22 and HLA–DRB1 genes as predictors of mortality in inflammatory polyarthritis (IP) and rheumatoid arthritis (RA).

Methods

Patients were recruited from a primary care–based inception cohort of patients with IP and were followed up prospectively. For patients who died, the cause and date of death was obtained. Cox proportional hazards regression models were used to assess the association of the HLA–DRB1 (including the shared epitope [SE]) and PTPN22 genes with the risk of death from all causes and from cardiovascular disease (CVD) and to assess the interactions between SE, smoking, and anti–cyclic citrullinated peptide (anti‐CCP) status, adjusted by age at symptom onset and sex.

Results

DNA samples were available from 1,022 IP patients. During followup, 751 of them (74%) satisfied the American College of Rheumatology 1987 criteria for RA, and 242 of them (24%) died. Carriage of 2 copies of SE alleles predicted death from all causes (hazard ratio [HR] 1.57 [95% confidence interval (95% CI) 1.1–2.2]) and from CVD (HR 1.68 [95% CI 1.1–2.7]). This effect was most marked for individuals with the HLA–DRB1*01/*04 combination. An interaction of smoking, SE alleles, and anti‐CCP antibodies was observed and was associated with the greatest risk of death from CVD (HR 7.81 [95% CI 2.6–23.2]). No association of the PTPN22 gene with mortality was detected.

Conclusion

SE alleles, particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoantibody status. However, the combination of SE, smoking, and anti‐CCP antibodies is associated with a high risk of premature death in patients with IP and RA, which raises the possibility of a targeted strategy to prevent CVD in these patients.

     

Perioperative all‐cause mortality and cardiovascular events in patients with rheumatoid arthritis: Comparison with unaffected controls and persons with diabetes mellitus

Objective

Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) burden similar to that of diabetes mellitus (DM). This risk may warrant preoperative CV assessment as is performed for patients with DM. We aimed to determine whether the risks of perioperative death and CV events among patients with RA differed from those among unaffected controls and patients with DM.

Methods

We used 1998–2002 data from the Nationwide Inpatient Sample (NIS) database of the Healthcare Cost Utilization Project (HCUP) to identify hospitalizations of patients undergoing elective noncardiac surgery. Using established guidelines, surgical procedures were categorized as either low risk, intermediate risk, or high risk of having CV events. Logistic models provided the adjusted odds of study end points in patients with RA, DM, or both relative to patients with neither condition.

Results

Among 7,756,570 patients undergoing a low‐risk, intermediate‐risk, or high‐risk noncardiac procedure, 2.34%, 0.51%, and 2.12%, respectively, had a composite CV event, and death occurred in 1.47%, 0.50%, and 2.59%, respectively. Among those undergoing an intermediate‐risk procedure, death was less likely in RA patients than in DM patients (0.30% versus 0.65%; P < 0.001), but the difference in mortality rates among those undergoing low‐risk versus high‐risk procedures was not significant. Patients with RA were less likely to have a CV event than were patients with DM for procedures of low risk (3.38% versus 5.30%; P < 0.001) and intermediate risk (0.34% versus 1.07%; P < 0.001). In adjusted models, RA was not independently associated with an increased risk of perioperative death or a CV event.

Conclusion

RA was not associated with adverse perioperative CV risk or mortality risk, which suggests that current perioperative clinical care does not need to be changed in this regard.

     

Do rheumatoid arthritis and lymphoma share risk factors?: A comparison of lymphoma and cancer risks before and after diagnosis of rheumatoid arthritis

Objective

Patients with rheumatoid arthritis (RA), in particular those with the most severe disease, are at increased risk of developing malignant lymphoma. Whether this increase is entirely a consequence of the RA disease and/or its treatment or is reflective of shared susceptibility to the two diseases remains unclear. We undertook this study to assess whether patients with RA are already at increased risk of lymphoma or of other cancers before the diagnosis of RA, and if the relative risk increases with time since RA diagnosis.

Methods

Patients with incident RA (symptom duration <1 year) (n = 6,745) registered in the Swedish Early Arthritis Registry from 1997 through 2006 were identified. For each patient, 5 general population controls were randomly matched by sex, age, marital status, and residence (n = 33,657). For all study subjects, inclusion in the nationwide Swedish Cancer Register in 1958–2006 was determined. Relative risks (RRs) (with 95% confidence intervals [95% CIs]) of lymphoma and of cancer overall, before and after diagnosis of RA, were estimated using conditional logistic regression and Cox regression, respectively.

Results

Before diagnosis of RA, there was no observed increase in the risk of lymphoma (RR [odds ratio] 0.67 [95% CI 0.37–1.23]) or other cancers (RR 0.78 [95% CI 0.70–0.88]). During the first 10 years following diagnosis of RA, the overall RR (hazard ratio) of lymphoma development was 1.75 (95 % CI 1.04–2.96).

Conclusion

These findings indicate that overall, a history of cancer, including lymphoma, does not increase the risk of subsequent RA development. Shared susceptibility to RA and lymphoma may thus be of limited importance. In contrast, increased lymphoma risks were observed within the first decade following RA diagnosis.

     

Glucocorticoids and cardiovascular events in rheumatoid arthritis: A population‐based cohort study

Objective

To determine the relationship between glucocorticoid exposure and cardiovascular (CV) events in patients with rheumatoid arthritis (RA).

Methods

A total of 603 adult residents of Rochester, Minnesota with incident RA between 1955 and 1995 were followed up through their medical records for a median of 13 years (total of 9,066 person‐years). Glucocorticoid exposure was defined 3 ways: tertiles of cumulative exposure; recent use (≤3 months) versus past use (>3 months); and average daily dosage (≤7.5 mg/day or >7.5 mg/day). CV events, including myocardial infarction, heart failure, and death from CV causes, were defined according to validated criteria. Cox regression models were adjusted for demographic features, CV risk factors, and RA characteristics.

Results

Rheumatoid factor (RF)–negative patients with exposure to glucocorticoids were not at increased risk of CV events, irrespective of the glucocorticoid dosage or timing of use, as compared with the reference group of RF‐negative patients who had never been exposed to glucocorticoids. In contrast, RF‐positive patients were at increased risk of CV events, particularly with higher cumulative exposure, higher average daily dosage, and recent use of glucocorticoids. RF‐positive patients with high cumulative exposure to glucocorticoids had a 3‐fold increased risk of CV events (hazard ratio 3.06 [95% confidence interval 1.81–5.18]), whereas RF‐negative patients with high cumulative exposure were not at increased risk (hazard ratio 0.85 [95% confidence interval 0.39–1.87]).

Conclusion

RF‐positive but not RF‐negative patients were at increased risk of CV events following exposure to glucocorticoids. These findings suggest that glucocorticoids interact with RF status to modulate the occurrence of CV events in patients with RA. The mechanisms underlying this interaction are unknown and should be the subject of further research.

     

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors

Objective

To compare the incidence of cardiovascular (CV) events in persons with rheumatoid arthritis (RA) with that in people from the general population, adjusting for traditional CV risk factors.

Methods

Two hundred thirty‐six consecutive patients with RA were assessed for the 1‐year occurrence of 1) CV‐related hospitalizations, including myocardial infarction, stroke or other arterial occlusive events, or arterial revascularization procedures, or 2) CV deaths. Both outcomes were ascertained by medical records or death certificates. For comparison, we used CV events that occurred during an 8‐year period among participants in an epidemiologic study of atherosclerosis and CV disease who were ages 25–65 years at study entry. We calculated the age‐ and sex‐stratified incidence rate ratio (IRR) of CV events between the 2 cohorts and used Poisson regression to adjust for age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index.

Results

Of the 236 RA patients, 234 were observed for 252 patient‐years, during which 15 CV events occurred. Of these, 7 incident events occurred during the 204 patient‐years contributed by patients ages 25–65 years, for an incidence of 3.43 per 100 patient‐years. In the comparison cohort, 4,635 community‐dwelling persons were followed up for 33,881 person‐years, during which 200 new events occurred, for an incidence of 0.59 per 100 person‐years. The age‐ and sex‐adjusted IRR of incident CV events associated with RA was 3.96 (95% confidence interval [95% CI] 1.86–8.43). After adjusting for CV risk factors using Poisson regression, the IRR decreased slightly, to 3.17 (95% CI 1.33–6.36).

Conclusion

The increased incidence of CV events in RA patients is independent of traditional CV risk factors. This suggests that additional mechanisms are responsible for CV disease in RA. Physicians who provide care to individuals with RA should be aware of their increased risk of CV events and implement appropriate diagnostic and therapeutic measures.

     

Association of autoantibodies to glucose‐6‐phosphate isomerase with extraarticular complications in rheumatoid arthritis

Objective

In the K/BxN mouse model, autoantibodies against glucose‐6‐phosphate isomerase (GPI) cause arthritis. The relevance of this model for human disease remains a subject of controversy. We set out to determine whether GPI autoantibodies occur in patients with rheumatoid arthritis (RA) and, if so, at what stage of the RA.

Methods

Using an enzyme‐linked immunosorbent assay, serum from 131 RA patients and 28 healthy controls was tested for autoantibodies against recombinant human GPI. Patients were grouped according to disease duration and presence of rheumatoid nodules, rheumatoid vasculitis, and Felty's syndrome, which are extraarticular complications of RA.

Results

Elevated levels of autoantibodies against GPI were present in 5% of patients with uncomplicated RA and 4% of controls. In RA complicated by extraarticular manifestations, anti‐GPI antibodies were observed in 18% of patients with rheumatoid nodules, 45% of patients with rheumatoid vasculitis, and 92% of patients with Felty's syndrome.

Conclusion

In patients with RA, autoantibodies to GPI are associated with the occurrence of extraarticular complications.

     

Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first‐degree relatives

Objective

Patients with rheumatoid arthritis (RA) are at increased risk for malignant lymphomas. Both conditions display a familial aggregation, and there are reports of RA and malignant lymphomas occurring in the same families. This study was undertaken to determine the risk of malignant lymphomas in first‐degree relatives of RA patients, in order to investigate whether the increased risk of malignant lymphomas in RA could be due to genetic or environmental risk factors common to both conditions, rather than being a consequence of the rheumatic disease.

Methods

Using Swedish nationwide and population‐based registers, we identified 76,527 patients hospitalized with RA in 1964–1999 and 70,290 first‐degree relatives of a subset of these patients. These subjects were followed up for more than 3 decades, and information on cancer occurrence was recorded.

Results

Patients with RA had a significantly increased risk of malignant lymphomas (535 cases; standardized incidence ratio [SIR] 2.00, 95% confidence interval [95% CI] 1.83–2.17), which was apparent for up to 2 decades of followup. Among the first‐degree relatives without RA, no increased risk of malignant lymphomas was found overall, although modest and nonsignificantly elevated risk estimates were observed in subgroups. With respect to childhood cancer (0–14 years of age), we observed an increased risk of Hodgkin's lymphoma (5 cases; SIR 3.18, 95% CI 1.03–7.42).

Conclusion

Patients with RA are at a markedly, but possibly time‐limited, increased risk for malignant lymphomas. There is little to suggest a prominent role for coinherited or common environmental risk factors in malignant lymphomas arising in the context of RA. Instead, lymphomas complicating RA appear to be a direct consequence of the inflammation or its treatment.

     

Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: Associations with prednisone,disease‐modifying antirheumatic drugs,and anti–tumor necrosis factor therapy

Objective

Pneumonia is a major cause of mortality and morbidity in rheumatoid arthritis (RA). This study was undertaken to determine the rate and predictors of hospitalization for pneumonia and the extent to which specific RA treatments increase pneumonia risk.

Methods

RA patients (n = 16,788) were assessed semiannually for 3.5 years. Pneumonia was confirmed by medical records or detailed patient interview. Covariates included RA severity measures, diabetes, pulmonary disease, and myocardial infarction. Cox proportional hazards regression was used to determine the multivariable risk associated with RA treatments.

Results

After adjustment for covariates, prednisone use increased the risk of pneumonia hospitalization (hazard ratio [HR] 1.7 [95% confidence interval 1.5–2.0]), including a dose‐related increase in risk (≤5mg/day HR 1.4 [95% confidence interval 1.1–1.6], >5–10 mg/day HR 2.1 [95% confidence interval 1.7–2.7], >10 mg/day HR 2.3 [95% confidence interval 1.6–3.2]). Leflunomide also increased the risk (HR 1.2 [95% confidence interval 1.0–1.5]). HRs for etanercept (0.8 [95% confidence interval 0.6–110]) and sulfasalazine (0.7 [95% confidence interval 0.5–1.0]) did not reflect an increased risk of pneumonia. HRs for infliximab, adalimumab, and methotrexate were not significantly different from zero.

Conclusion

There is a dose‐related relationship between prednisone use and pneumonia risk in RA. No increase in risk was found for anti–tumor necrosis factor therapy or methotrexate. These data call into question the belief that low‐dose prednisone is safe. Because corticosteroid use is common in RA, the results of this study suggest that prednisone exposure may have important public health consequences.

     

Identification of modifiable work‐related factors that influence the risk of work disability in rheumatoid arthritis

Objective

To define work‐related factors associated with increased risk of work disability (WD) in people with rheumatoid arthritis (RA).

Methods

Questionnaires were mailed to all RA patients who used a province‐wide arthritis treatment program between 1991 and 1998 (n = 1,824). The association between risk factors and WD (defined as no paid work due to RA for at least 6 months) was assessed using multiple logistic regression analysis, controlling for significant sociodemographic and disease‐related variables.

Results

Of the original 1,824 patients, 581 were eligible and responded to the questionnaire. Work survival analysis revealed a steady rate of WD starting early, with 7.5%, 18%, and 27% work disabled at 1, 5, and 10 years, respectively. Significant determinants in multiple logistic regression were physical function (Health Assessment Questionnaire), pain (visual analog scale), and 6 work‐related factors: self employment, workstation modification, work importance, family support toward employment, commuting difficulty, and comfort telling coworkers about RA.

Conclusion

Work disability occurs early in RA. Novel work‐related factors were identified, which are potentially modifiable, to help RA patients stay employed.

     

Serum uric acid is an independent predictor of all‐cause mortality in patients at high risk of cardiovascular disease: A preventive cardiology information system (PreCIS) database cohort study

Objective

Uric acid is a product of the activity of xanthine oxidase, an enzyme linked to oxidative stress, endothelial dysfunction, and heart failure. It is unclear whether adding uric acid levels to the assessment of cardiovascular risk might contribute to the improved ability to stratify cardiovascular risk. The purpose of this study was to evaluate the prognostic value of serum uric acid levels in a large cohort of men and women at high risk of cardiovascular disease.

Methods

Serum uric acid levels were determined in all patients seen for primary/secondary cardiovascular disease prevention at the Cleveland Clinic Section of Preventive Cardiology and Rehabilitation between 1998 and 2004, and all data were entered into the Preventive Cardiology Information System (PreCIS) database. Vital status of the patients was determined through the Social Security Death Index. Death from all causes was summarized across quartiles of uric acid values.

Results

A total of 3,098 patients (age range 18–87 years) were identified in the database, among whom 43% had cardiovascular disease. There were 156 deaths (5%) during the 14,262 person‐years of followup. For each 1‐mg/dl increase in the serum uric acid level, there was a 39% increase in the risk of death (by Cox regression analysis). After adjusting for age, sex, smoking status, alcohol consumption, weight, body mass index, waist circumference, blood pressure, history of cardiovascular disease, estimated glomerular filtration rate, levels of cholesterol fractions, and plasma glucose levels, the serum uric acid level continued to predict the risk of death (hazard ratio = 1.26 [95% confidence interval 1.15–1.38], P < 0.001). This association was present regardless of diuretic use. Concordance index (C statistic) analyses showed that uric acid significantly improved the predictive accuracy of a model that included Framingham Heart Study score factors, metabolic syndrome components, and fibrinogen levels.

Conclusion

Serum uric acid levels are an independent predictor of death in patients at high risk of cardiovascular disease. Further studies are warranted to evaluate its prognostic implications and potential utility in the monitoring of therapy.

     

Declining use of orthopedic surgery in patients with rheumatoid arthritis? Results of a long‐term,population‐based assessment

Objective

To describe the use of orthopedic surgery, including joint replacement surgery, in a well‐defined, population‐based cohort of patients with rheumatoid arthritis (RA) and to identify characteristics that predict such use.

Methods

A retrospective medical record review was performed of cases of RA incident in Rochester, Minnesota, during the years 1955–1995. All joint surgeries were recorded.

Results

Of the total 609 RA incident cases, 242 patients underwent 1 or more (maximum of 20/patient) surgical procedures involving joints during their followup. Overall, this RA cohort had 7.4 surgeries per 100 person‐years of followup; the cumulative incidence for joint surgery for RA‐related joint disease at 30 years was 33.7% ± SEM 3.8%. The risk of having a disease‐related joint surgery for RA is increased in patients who are women, younger, positive for rheumatoid factor, and have rheumatoid nodules. When adjusted for duration of followup, patients with RA diagnosed after 1985 were significantly less likely to have undergone joint surgery for RA (P < 0.001). Survival of patients who underwent total joint arthroplasty was similar to those who did not.

Conclusion

Reconstructive surgeries are common in RA, although patients diagnosed after 1985 are less likely to require joint surgery. These findings may reflect trends in medical disease management and have importance for health care resource utilization planning.