Excess mortality emerges after 10 years in an inception cohort of early rheumatoid arthritis

Objective

To investigate mortality rates, causes of death, time trends in mortality, prognostic factors for mortality, and the relationship between disease activity and mortality over a 23‐year period in an inception cohort of rheumatoid arthritis (RA) patients.

Methods

A prospective inception cohort of RA patients diagnosed between January 1985 and October 2007 was followed for up to 23 years after diagnosis. Excess mortality was analyzed by comparing the observed mortality in the RA cohort with the expected mortality based on the general population of The Netherlands, matched for age, sex, and calendar year. Period analysis was used to examine time trends in survival across calendar time. Prognostic factors for mortality and the influence of the time‐varying Disease Activity Score in 28 joints (DAS28) on mortality were analyzed using multivariable Cox proportional hazards models. Causes of death were analyzed.

Results

Of the 1,049 patients in the cohort, 207 patients died. Differences in observed and expected mortality emerged after 10 years of followup. No improvement in survival was noted over calendar time. Significant baseline predictors of survival were sex, age, rheumatoid factor, disability, and comorbidity. Higher levels of DAS28 over time, adjusted for age, were associated with lower survival rates, more so in men (hazard ratio [HR] 1.58, 95% confidence interval [95% CI] 1.35–1.85) than in women (HR 1.21, 95% CI 1.04–1.42).

Conclusion

Excess mortality in RA emerged after 10 years of disease duration. Absolute survival rates have not improved in the last 23 years and a trend toward a widening mortality gap between RA patients and the general population was visible. Higher disease activity levels contribute to premature death in RA patients.     

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.

     

No increased mortality in patients with rheumatoid arthritis treated with biologics: results from the biologics register of six rheumatology institutes in Japan

Objective

To investigate the influence of biologics on mortality and risk factors for death in rheumatoid arthritis (RA) patients.

Methods

RA patients treated with at least one dose of biologics in daily practice in six large rheumatology institutes (“biologics cohort”) were observed until 15 May 2010 or death, whichever occurred first. Mortality of the biologics cohort and the “comparator cohort” (comprising patients among the IORRA cohort who had never been treated with biologics) was compared to that of the Japanese general population. Factors associated with mortality were assessed by a Cox model.

Results

Among 2683 patients with 6913.0 patient-years of observation, 38 deaths were identified in the biologics cohort. The probability of death in patients lost to follow-up, calculated using the weighted standardized mortality ratio (SMR), was 1.08 [95 % confidence interval (CI) 0.77–1.47] in the biologics cohort and 1.28 (95 % CI 1.17–1.41) in the comparator cohort. Pulmonary involvement was the main cause of death (47.4 %), and the disease-specific SMR of pneumonia was 4.19 (95 % CI 1.81–8.25). Risk factors for death included male gender [hazard ratio (HR) 2.78 (95 % CI 1.24–6.22)], advanced age (HR 1.07, 95 % CI 1.03–1.11), and corticosteroid dose (HR 1.08, 95 % CI 1.01–1.17).

Conclusion

Mortality in RA patients exposed to biologics did not exceed that in patients not exposed to biologics, but death from pulmonary manifestations was proportionally increased in RA patients exposed to biologics.     

HLA–DRB1 and persistent chronic inflammation contribute to cardiovascular events and cardiovascular mortality in patients with rheumatoid arthritis

Objective

Cardiovascular (CV) disease is the most common cause of mortality in patients with rheumatoid arthritis (RA). We assessed the contribution of epidemiologic features, clinical features, routine laboratory markers of inflammation, and HLA–DRB1 alleles to CV mortality in patients with RA prospectively followed at a single referral center in Spain.

Methods

Patients fulfilling the 1987 American College of Rheumatology classification criteria for RA seen at the rheumatology outpatient clinic of Hospital Xeral‐Calde, Lugo between March and September 1996 were included. HLA–DRB1 phenotype, epidemiologic data, and clinical data were assessed at that time. Patients were prospectively followed and clinical records were examined until patient's death or September 1, 2005.

Results

A total of 182 consecutive patients were assessed. Compared with the general Spanish population, the age‐ and sex‐standardized mortality ratio by CV cause was 1.78. CV mortality adjusted by age at disease onset and sex was associated with chronic inflammation determined by C‐reactive protein level (CRP; hazard ratio [HR] 1.14, P < 0.001) and erythrocyte sedimentation rate (ESR; HR 1.05, P = 0.003). Patients with HLA–DRB1*04 shared epitope alleles (HR 4.15, P = 0.030), in particular those HLA–DRB1*0404 positive (HR 6.65, P = 0.002), had increased risk of CV mortality. Increased risk of CV events was also associated with CRP level (HR 1.09, P = 0.001), ESR (HR 1.03, P = 0.003), and HLA–DRB1*0404 (HR 4.47, P = 0.002).

Conclusion

Our results suggest that a chronically high inflammatory response in genetically predisposed individuals promotes an increased risk of CV events and CV mortality in RA.     

The mortality of rheumatoid arthritis

Objective. To determine the risk and causes of death and to quantify mortality predictors in patients with rheumatoid arthritis (RA). Methods. RA patients (n = 3,501) from 4 centers (Saskatoon n = 905, Wichita n = 1,405, Stanford n = 886, and Santa Clara n = 305) were followed for up to 35 years; 922 patients died. Results. The overall standardized mortality ratio (SMR) was 2.26 (Saskatoon 2.24, Wichita 1.98, Stanford 3.08, Santa Clara 2.18) and increased with time. Mortality was strikingly increased for specific causes: infection, lymphoproliferative malignancy, gastroenterologic, and RA. In addition, as an effect of the SMR of 2.26, the expected number of deaths was increased nonspecifically across all causes (except cancer), with a large excess of deaths attributable to cardiovascular and cerebrovascular diseases. Independent predictors of mortality included age, education, male sex, function, rheumatoid factor, nodules, erythrocyte sedimentation rate, joint count, and prednisone use.     

Rheumatoid arthritis and mortality. A longitudinal study in pima indians

Objective. To determine the effect of rheumatoid arthritis (RA) on mortality rates. Methods. Longitudinal analyses of data from a cohort of Pima Indians from the Gila River Indian Community in Arizona, who were followed up during the period February 1965 through December 1989. Results. Among 2,979 study subjects aged ≤25 years, there were 858 deaths, 79 of which occurred in subjects with RA (36 men, 43 women). Age and sex-adjusted mortality rates were slightly higher in subjects with RA than in those without (mortality rate ratio 1.28, 95% confidence interval [95% CI] 1.01–1.62). Among those with RA, mortality rates were higher in older subjects (mortality rate ratio 1.51 per 10-year increase in age, 95% CI 1.22–1.88), in male subjects (mortality rate ratio 2.23, 95% CI 1.44–3.45, adjusted for age), and in subjects with proteinuria (mortality rate ratio 1.88, 95% CI 1.02–3.46, adjusted for age and sex). Mortality rate ratios for these risk factors were similar in subjects without RA. In addition, among subjects with RA, rheumatoid factor (RF) positivity was predictive of death (mortality rate ratio 1.94, 95% CI 1.10–3.43), and the excess mortality was found primarily among subjects who were seropositive. The death rate from cardiovascular disease (mortality rate ratio 1.77, 95% CI 1.10–2.84) and from liver cirrhosis or other alcohol-related disease (mortality rate ratio 2.52, 95% CI 1.06–6.01) was increased in persons with RA. Conclusion. The results of this population-based study suggest that although the risk of mortality in subjects with RA is significantly higher than in those without RA, the risk ratio is in the lower range of that described previously in studies of clinic-based cohorts. RF positivity as a predictor of early death among subjects with RA indicates that the immunologic processes in seropositive RA may contribute to the events that eventually lead to early death.     

Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis

OBJECTIVE: To assess mortality in patients with rheumatoid arthritis (RA) treated with tumour necrosis factor (TNF) inhibitors, compared with a standard RA population. METHODS: Patients were recruited from a regional register, which includes over 90% of patients with RA treated with TNF blockers in the area in 1999 or later, and a local community-based cohort of patients with RA, established in 1997. Of a total of 1430 patients in the combined cohort <80 years old, 921 received treatment with TNF inhibitors during the study period. The total cohort was linked with the national register for cause of death. Overall mortality in those treated versus those not treated with TNF blockers was estimated using standardised mortality ratios and time-dependent Cox proportional hazards. RESULTS: There were 188 deaths per 7077 person-years at risk in the total cohort. Controlling for age, sex, disability and baseline comorbidity, the adjusted HR for death was 0.65 (95% CI 0.46 to 0.93) in those treated with anti-TNF versus those not treated. The effect was significant in women (HR = 0.52, 95% CI 0.33 to 0.82) but not in men (HR = 0.95, 95% CI 0.52 to 1.71). CONCLUSION: After adjusting for disease severity, treatment with TNF inhibitors was found to be associated with a reduced mortality in women but not men with RA. These findings are compatible with a critical role for inflammation in RA-associated premature mortality.     

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.

     

Trends in incidence of dementia among patients with rheumatoid arthritis: A population-based cohort study

ObjectiveWe aimed to assess the incidence of dementia over time in patients with incident rheumatoid arthritis (RA) as compared to non-RA referents.MethodsThis population-based, retrospective cohort study included Olmsted County, Minnesota residents with incident RA by ACR 1987 criteria, diagnosed between 1980 and 2009. We matched non-RA referents 1:1 on age, sex, and calendar year and followed all individuals until 12/31/2019. Incident dementia was defined as two codes for Alzheimer's disease and related dementias (ADRD) at least 30 days apart. Cumulative incidence of ADRD was assessed, adjusting for the competing risk of death. Cox proportional hazards models calculated hazard ratios (HR) with 95% confidence intervals (CI) for incident ADRD by decade.ResultsAfter excluding individuals with prior dementia, we included 897 persons with incident RA (mean age 56 years; 69% female) and 885 referents. The 10-year cumulative incidence of ADRD in individuals diagnosed with RA during the 1980s was 12.7% (95%CI:7.9–15.7%), 1990s was 7.2% (95%CI:3.7–9.4%), and 2000s was 6.2% (95%CI:3.6–7.8%). Individuals with RA diagnosed in 2000s had insignificantly lower cumulative incidence of ADRD than those in the 1980s (HR 0.66; 95%CI:0.38–1.16). The overall HR of ADRD in individuals with RA was 1.37 (vs. referents; 95%CI:1.04–1.81). When subdivided by decade, however, the risk of ADRD in individuals diagnosed with RA was higher than referents in the 1990s (HR 1.72, 95%CI:1.09–2.70) but not 2000s (HR 0.86, 95%CI:0.51–1.45).ConclusionsThe risk of dementia in individuals with RA appears to be declining over time, including when compared to general population referents.     

Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: results of eighteen years of followup from the early rheumatoid arthritis study

OBJECTIVE: To determine whether the HLA-DRB1 shared epitope (SE) is associated with early mortality and specific causes of death in rheumatoid arthritis (RA). METHODS: HLA-DRB1 genotyping was carried out on blood samples from 767 patients recruited for the Early RA Study (ERAS), a multicenter, inception cohort study with followup over 18 years. Dates and causes of death (n = 186) were obtained from the Office of National Statistics. The association of HLA-DRB1 alleles with risk of mortality was assessed using Cox proportional hazards regression analyses. Multivariate stepwise models were used to assess the predictive value of HLA-DRB1 genotypes compared with other potential baseline risk factors. RESULTS: The SE was not significantly associated with overall mortality. However, the presence of 2 SE alleles was associated with risk of mortality from ischemic heart disease (hazard ratio [HR] 2.02 [95% confidence interval 1.04-3.94], P = 0.04), and malignancy (HR 2.18 [95% confidence interval 1.17-4.08], P = 0.01). Analysis of specific SE genotypes (corrected for age and sex) revealed that the HLA-DRB1*0101/*0401 and 0404/*0404 genotypes were the strongest predictors of mortality from ischemic heart disease (HR 5.11 and HR 7.55, respectively), and DRB1*0101/*0401 showed a possible interaction with smoking. Male sex, erythrocyte sedimentation rate, and Carstairs Deprivation Index were also predictive, but the Health Assessment Questionnaire score, rheumatoid factor, nodules, and swollen joint counts were not. Mortality due to malignancy was particularly associated with DRB1*0101 genotypes. CONCLUSION: The risk of mortality due to ischemic heart disease or cancer in RA is increased in patients carrying HLA-DRB1 genotypes with particular homozygous and compound heterozygous SE combinations.     

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.

     

Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis

OBJECTIVE: Various etiologic mechanisms have been implicated in the observed increase in cardiovascular mortality in rheumatoid arthritis (RA). Body mass index (BMI) is associated with cardiovascular mortality in the general population. This study compared the effect of BMI on cardiovascular mortality in a population-based cohort of subjects with RA with that in a cohort of individuals without RA from the same population. METHODS: The RA cohort comprised all members of an incidence cohort of Rochester, Minnesota residents ages > or =18 years who were first diagnosed with RA (by the American College of Rheumatology 1987 criteria) from 1955 through 1994. An age- and sex-matched comparison cohort of subjects without RA was assembled. Both cohorts were followed up longitudinally through their complete (inpatient, outpatient) medical records beginning at age 18 years and continuing until death, migration, or January 1, 2001, and the details of weight and height changes during this period were recorded. High BMI was defined as a BMI >30 kg/m(2) and low BMI as <20 kg/m(2). Cox regression models were used to estimate the effect of BMI on cardiovascular mortality after accounting for traditional cardiac risk factors and malignancies. RESULTS: RA subjects with low BMI at incidence had a significantly higher risk of cardiovascular death (hazard ratio [HR] 3.34, 95% confidence interval [95% CI] 2.23-4.99) compared with non-RA subjects with normal BMI, after adjusting for age, sex, personal cardiac history, smoking status, and presence of diabetes, hypertension, and malignancies. RA subjects with normal BMI at incidence who experienced low BMI during followup also had a higher risk of cardiovascular death (HR 2.09, 95% CI 1.50-2.92) when compared with non-RA subjects who maintained normal BMI throughout followup. CONCLUSION: Among patients with RA, low BMI is associated with a significantly increased risk of cardiovascular death.     

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.

     

Mortality in patients with rheumatoid arthritis treated with low-dose oral glucocorticoids. A population-based cohort study

OBJECTIVE: To evaluate mortality and causes of death in patients with rheumatoid arthritis (RA) treated with low-dose oral glucocorticoids. METHODS: Mortality was analyzed in population-based data of 604 patients with RA. In the original study in 1988, state of general health, severity of RA, and treatment including the use of oral glucocorticoids were recorded. In 1999 vital status and causes of death were evaluated. Mortality in patients with RA who had not received glucocorticoids (Group A, n = 209) was compared to that in patients treated with glucocorticoids for less than 10 years (Group B, n = 276) or for more than 10 years (Group C, n = 119). RESULTS: From onset of RA to 1999, 395 (65%) patients had been treated with oral glucocorticoids. In 1999 a total of 160 (26%) patients had died, 23% of patients in Group A, 21% in Group B, and 45% in Group C. In multivariate Cox regression analysis, male sex (hazard ratio 2.50; 95% CI 1.74-3.59), impaired functional capacity by Health Assessment Questionnaire (HR 2.11; 95% CI 1.65-2.96), heart failure (HR 1.96; 95% CI 1.36-2.84), and diabetes (HR 1.87; 95% CI 1.17-3.01) predicted increased mortality. In the same analysis glucocorticoid treatment for 1 year increased the mortality risk by 14% (HR 1.14; 95% CI 0.98-1.27, p = 0.057) and treatment over 10 years by 69% (HR 1.69; 95% CI 1.12-2.56, p = 0.011) compared to RA patients without treatment. The major cause of death was cardiovascular disease in all groups, but infections and intestinal perforations due to amyloidosis were more frequent in patients with long-lasting glucocorticoid therapy. Lymphomas were more frequent in all patients treated with glucocorticoids (Groups B and C) than in those not receiving glucocorticoids. CONCLUSION: Patients with RA treated with low-dose oral glucocorticoids for more than 10 years had increased mortality compared to those who did not receive glucocorticoids or whose duration of treatment was less than 10 years. The increased mortality was related mainly to infections and complications caused by systemic amyloidosis.     

Prevalence and extent of calcification over aorta,coronary and carotid arteries in patients with rheumatoid arthritis

Objective. To evaluate the prevalence and pattern of arterial calcification in patients with rheumatoid arthritis (RA). Background. Patients with RA are prone to premature atherosclerosis; nonetheless the prevalence and extent of atherosclerosis in different vascular beds and their relationship to each other remain unknown. Methods. We studied the distribution and extent of arterial calcification in 85 RA patients and 85 age‐and sex‐matched controls. Arterial calcification as determined by calcium score (CS) were measured using multi‐detector computed tomography in thoracic aorta, coronary and carotid arteries. Results. Compared with controls, RA patients had a significantly higher average CS and prevalence of CS > 0 in aorta, coronary and carotid arteries and overall arteries (all P < 0.05). After adjusting for age and sex, RA patients had a significantly higher relative risk of developing calcification in the aorta [Odds Ratio (OR) = 19.5, 95% Confidence Interval (CI): 8.0–47.6], followed by the carotid arteries (OR = 5.7, 95% CI:1.7–18.7) and coronary arteries (OR = 5.0, 95% CI:2.2–11.1) compared with controls (all P < 0.01). Amongst RA patients aged >60, 90% had diffuse arterial calcification, especially over the thoracic aorta, compared with 55% of controls who had arterial calcification clustered in the coronary arteries (P < 0.05). RA patients with total CS > 0 were older with a higher urea level and C‐reactive protein than those without arterial calcification, no factor was found to be independently predictive for arterial calcification (all P > 0.05). Conclusions. Our results demonstrated that RA patients had earlier onset, more diffuse arterial calcification over multiple vascular beds and more preferential involvement of thoracic aorta, rather than coronary artery when compared with control.     

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.

     

Association of a rheumatoid arthritis susceptibility variant at the CCL21 locus with premature mortality in inflammatory polyarthritis patients

Objective

To investigate whether recently identified rheumatoid arthritis (RA) susceptibility loci are also associated with disease severity, specifically all‐cause and cardiovascular disease (CVD) mortality, in patients with inflammatory polyarthritis (IP).

Methods

Subjects with recent‐onset IP were recruited from the Norfolk Arthritis Register. Seventeen RA susceptibility single‐nucleotide polymorphisms (SNPs) were tested using Sequenom MassArray iPLEX chemistry. Vital status was ascertained from central records. The association of SNP allele carriage with mortality risk was assessed using Cox proportional hazards models after adjusting by sex. The mortality risks of those SNP alleles found to be associated were then stratified by baseline anti–citrullinated peptide (anti‐CCP) antibody and shared epitope (SE) status.

Results

All SNPs were successfully genotyped in 2,324 IP subjects. The presence of 2 copies of the risk allele rs2812378 mapping to the CCL21 gene predicted all‐cause mortality (hazard ratio [HR] 1.40, 95% confidence interval [95% CI] 1.04–1.87), whereas risk allele carriage also predicted increased CVD mortality (HR 1.33, 95% CI 1.01–1.75). The highest mortality risks were seen in anti‐CCP antibody–positive subjects with 2 copies of the CCL21 risk alleles and 2 copies of the SE (all‐cause HR 3.20, 95% CI 1.52–6.72; CVD HR 3.73, 95% CI 1.30–10.72).

Conclusion

In this large study, we found that carriage of CCL21 risk alleles was associated with premature mortality in IP independently of anti‐CCP antibody and SE status. Interestingly, CCL21 expression has been reported in atherosclerotic plaques supporting the thesis that the increased CVD mortality in IP patients may be mediated by shared inflammatory mechanisms.     

Incidence of herpes zoster in Japanese patients with rheumatoid arthritis from 2005 to 2010

Abstract

Objective. To clarify the incidence and the risks of herpes zoster infection in Japanese patients with rheumatoid arthritis (RA).

Methods. By using a self-report of occurrence of herpes zoster in patients with RA in a large observational cohort study from 2005 to 2010, the standardized incidence rate was calculated. A Cox model was used to analyze risk factors for occurrence of herpes zoster.

Results. A total of 7,986 patients (female 83.1%) accumulated 30,140 patient-years of observation, and 366 events were confirmed. The standardized incidence rate per 1,000 patient-years was 9.1 (95% confidence interval (CI) 6.2–12.9) in total, 7.8 (3.6–14.8) in men, and 10.3 (6.8–15.0) in women. The risk factors for herpes zoster were age [/10 years: Hazard ratio (HR) 1.268, 95% CI 1.153–1.393, p < 0.0001), high disease activity compared with remission (HR 1.642, 95% CI 1.067–2.528, p < 0.05), prednisolone (< 5 mg/day compared with 0 mg/day: HR 1.531, 95% CI 1.211–1.936, p < 0.001; ≥ 5 mg/day compared with 0 mg/day: HR 1.471, 95% CI 1.034–2.093, p < 0.05), and methotrexate (HR 1.382, 95% CI 1.076–1.774, p < 0.05).

Conclusion. This study quantified the historical incidence and risk for herpes zoster in Japanese RA patients, and is a benchmark for future studies.     

Prevalence of cardiac and aortic enlargement in rheumatoid arthritis and its relationship to some characteristics of the patients

Summary The chest radiographs of 309 patients with rheumatoid arthritis (RA) were compared with those of 309 controls matched for sex and age. Cardiac enlargement was more frequent in RA females than in controls (P<0.05) and the frequency of aortic shadow enlargement was higher in RA patients aged 60 years than in controls (P<0.05). Both cardiac and aortic enlargement was significantly related to several parameters of the severity and the activity of RA, corticosteroid therapy, and elevated blood pressure. A high mortality was present in patients with aortic enlargement and in patients with ECG signs of myocardial ischaemia.