Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years

Objective: To investigate the trends in incidence of extra-articular rheumatoid arthritis (ExRA) in a well defined community based cohort of patients with rheumatoid arthritis (RA), and to examine possible predictors of ExRA occurrence. Methods: Using the resources of the Rochester Epidemiology Project, a retrospective medical record review was conducted of a cohort of 609 cases of RA in Olmsted County, MN, diagnosed during 1955–94. These cases had been previously classified using the ACR 1987 criteria for RA. Patients were followed up from 1955 to 2000 (median follow up 11.8 years; range 0.1–42.8), and incident ExRA manifestations were recorded according to predefined criteria. Time to first presentation of ExRA was compared in patients with RA by decade of diagnosis. Possible ExRA risk factors were identified in case record reviews. Results: ExRA occurred in 247 patients (40.6%). A subgroup of 78 patients (12.8%) had ExRA manifestations considered to be severe in a previous study from Malmö, Sweden. The incidence of severe ExRA did not change significantly over the decades (p=0.165). In a multivariate analysis the main predictors of severe ExRA were smoking at RA diagnosis (risk ratio (RR)=2.94; 95% confidence interval (95% CI) 1.68 to 5.13) and early disability (Steinbrocker class III-IV at diagnosis) (RR=2.45; 95% CI 1.51 to 4.00). The effect of smoking overwhelmed the weaker effect of rheumatoid factor seropositivity. Conclusion: There was no decrease in the incidence of extra-articular manifestations in patients with RA diagnosed up to 1995. Smoking and early disability are independent risk factors for extra-articular 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 > or =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 > or =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.     

Extraarticular Manifestations of Rheumatoid Arthritis in a Multiethnic Cohort of Predominantly Hispanic and Asian Patients

We conducted a study to determine the prevalence of extraarticular manifestations (ExRA) in a cohort of predominantly Hispanic and Asian patients with rheumatoid arthritis (RA), to identify factors associated with the development of ExRA, and to compare the prevalence of ExRA between Hispanic and Asian patients.Patients with RA followed in the outpatient rheumatology clinics of a public hospital were included if they were aged ≥18 years and met the 1987 American College of Rheumatology criteria for the diagnosis of RA. We performed a cross-sectional analysis in which patients with ExRA were identified based on predefined criteria. We compared sociodemographic and clinical characteristics in patients with and without ExRA. Multivariate logistic regression was used to examine the association between sociodemographic variables, clinical characteristics, and the presence of ExRA.The prevalence of ExRA was 21.5%, and the most common manifestations were subcutaneous nodules (17.2%) and interstitial lung disease (3.6%). Hispanic patients were significantly more likely to develop ExRA than Asian patients (odds ratio, 2.53; 95% confidence interval, 1.26–5.09). The development of ExRA was also associated with disease duration, male sex, and seropositivity for serum rheumatoid factor.     

Extra-articular rheumatoid arthritis: prevalence and mortality.

OBJECTIVE: The prevalence and distribution of extra-articular manifestations of rheumatoid arthritis (ExRA) and associated mortality were studied retrospectively in a cohort of RA patients admitted to University Hospital, Malm?, Sweden, during the period 1990-94. RESULTS: Of 489 patients who fulfilled the 1987 ACR criteria for RA, 37 manifested onset of ExRA, predominantly serositis and cutaneous vasculitis, during the period, corresponding to a cumulative incidence of 7.9%. The occurrence of ExRA was independent of disease stage. Among patients with ExRA, 1 death/4.3 person-years at risk (pyr) occurred, as compared with 1 death/11.4 pyr in the non-ExRA subgroup. The age- and sex-adjusted mortality rate ratio was 2.49 (95% confidence interval 1.43-4.03). The major cause of death among ExRA cases was heart disease, which occurred in 9/13 cases (69%) in comparison to the expected 2.4 cases. CONCLUSION: In this series, serositis and cutaneous vasculitis were predominant extra-articular manifestations of RA; and mortality was greater in the ExRA than in the non-ExRA subgroup, perhaps due to a high frequency of associated heart disease.     

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.

     

Predictors of extra-articular manifestations in rheumatoid arthritis

OBJECTIVE: To identify clinical and genetic risk factors for extra-articular manifestations of rheumatoid arthritis (ExRA). METHODS: ExRA patients were identified retrospectively using predefined criteria in two hospital-based cohorts of RA patients, and compared to non-extraarticular RA controls from one of the cohorts, matched for disease duration. RESULTS: Forty-nine living and thirteen deceased cases of ExRA were identified. Extra-articular disease was predicted by the demonstration of antinuclear antibodies (Odds ratio (OR) 3.6; 95% CI: 1.4-9.1) and the presence of rheumatoid nodules within two years from RA diagnosis (OR 3.4; 95%, CI: 1.1-10.9) or at any time before ExRA onset (OR 2.8; 95% CI: 1.1-7.2). Male sex and rheumatoid factor did not affect the risk of ExRA. Although present in the majority of cases as well as controls, the disease associated HLA-DRB1 subtypes were not significant predictors of ExRA. CONCLUSION: Extra-articular manifestations of rheumatoid arthritis in a hospital based population were predicted by antinuclear antibodies and rheumatoid nodules.     

Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations

OBJECTIVE: To investigate the incidence of noncardiac vascular disease in patients with rheumatoid arthritis (RA) and its relationship to systemic extraarticular disease in a community-based cohort. METHODS: A retrospective medical record review of 609 patients with incident RA diagnosed during 1955-1994 was carried out in Olmsted County, Minnesota. Patients were followed up from 1955 to 2000 (median followup 11.8 years). Incident noncardiac vascular disease and severe extraarticular RA manifestations (including pericarditis, pleuritis, and vasculitis) were recorded according to predefined criteria, and incidence rates were estimated. Using Cox proportional hazards models, the risk (hazard ratio [HR]) of developing vascular events was assessed in patients with and without severe extraarticular RA. RESULTS: Cerebrovascular and peripheral arterial events occurred in 139 patients (22.8%). The 30-year cumulative incidence rates of peripheral arterial events, cerebrovascular events, and venous thromboembolic events were estimated to be 19.6%, 21.6%, and 7.2%, respectively. The presence of severe extraarticular RA manifestations was found to be associated with all subgroups of noncardiac vascular disease except cerebrovascular disease alone (HR 2.3, 95% confidence interval [95% CI] 1.2-4.3 for peripheral arterial events; HR 3.7, 95% CI 1.3-10.3 for venous thromboembolic events; HR 1.5, 95% CI 0.7-3.2 for cerebrovascular events) after adjusting for age, sex, body mass index, smoking, and rheumatoid factor status. CONCLUSION: This is the first study to assess the incidence of noncardiac vascular disease in RA. Severe extraarticular RA was associated with all forms of noncardiac vascular disease except cerebrovascular disease alone. Similar to cardiac disease, the excess risk of noncardiac vascular disease in RA is likely to be related, in part, to the systemic inflammation associated with the extraarticular manifestations of RA.     

A population based assessment of the use of orthopedic surgery in patients with rheumatoid arthritis

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, MN, during the years 1955-85. Patients were followed until 1998. All joint surgeries were recorded, including joint reconstructive surgeries, total joint arthroplasty (TJA), and other joint reconstructive procedures (JRP) such as tendon transfers and resections, joint fusions, and surgeries for fractures and infections involving joints. RESULTS: Of the total 424 RA incident cases, 148 (34.9%) patients underwent one or more (maximum of 20/patient) surgical procedures involving joints during their followup (median 14.8 yrs, range 0.2-42.8 yrs). Overall, this RA cohort had 9.7 surgeries per 100 person-yrs of followup. The estimated cumulative incidence of surgical procedures for RA at 30 yrs was 52.7% +/- SE 4.2. Surgeries for arthritis related joint disease of RA included: primary TJA 76 patients (31.3 +/- 4.1); JRP joint fusion 78 patients (29.4 +/- 3.5); JRP soft tissue 92 patients (29.8 +/- 3.3); and cervical spine fusion one patient. Non-RA (trauma and other) joint surgeries included TJA 26 patients (13.5 +/- 3.4) and arthrotomy for septic arthritis 8 patients (2.4 +/- 0.9). Based on Cox proportional hazards regression, the risk of having a disease related joint surgery for RA is increased in patients who are younger (p < 0.001), have positive rheumatoid factor (p = 0.01), and those with rheumatoid nodules (p < 0.001). There was a borderline significant increase in the risk of first joint surgery in women (p = 0.09). Women also had significantly more joint surgeries (11.5/100 person-yrs) than men (4.9/100 person-yrs; p < 0.001). Survival of patients who had surgery for RA related joint disease was similar to those who did not. CONCLUSION: This is the first population based assessment of joint surgeries performed in patients with RA. Reconstructive surgeries were common, and women had significantly more surgeries than men. Survivorship among patients with RA undergoing surgeries was similar to that of the RA patient population at large.     

Association of HLA-C3 and smoking with vasculitis in patients with rheumatoid arthritis

OBJECTIVE: To compare HLA-C genotypes and smoking habits in patients with vasculitis or other severe extraarticular manifestations of rheumatoid arthritis (ExRA) with those in RA patients without extraarticular disease. METHODS: Patients were recruited from a large research database of patients with RA at the Mayo Clinic, from 2 Swedish cohorts of prevalent RA cases, and from a regional Swedish early RA cohort. Patients with severe ExRA (n = 159) and control patients with RA but no history of ExRA (non-ExRA controls) (n = 178) were matched for duration of RA and for clinical center. Data on smoking at RA onset, rheumatoid factor (RF) status, and antinuclear antibodies (ANAs) were extracted from the medical records. Polymerase chain reaction-based HLA-C genotyping was performed using a sequence-specific primer kit. RESULTS: The distribution of HLA-C alleles was significantly different between patients with RA-associated vasculitis and non-ExRA controls (P = 0.014). This was mainly due to a positive association of the HLA-C3 allele with vasculitis (allele frequency 0.411 in vasculitis patients versus 0.199 in non-ExRA controls; P < 0.001) and a decreased frequency of HLA-C7 (0.122 and 0.243, respectively; P = 0.018). The association between HLA-C3 and vasculitis was not due to linkage disequilibrium with HLA-DRB1. Smoking (P = 0.001), RF positivity (P < 0.0001), and presence of ANAs (P < 0.0001) were all associated with ExRA. HLA-C3 and smoking were both significant predictors of vasculitis in a multivariate model. CONCLUSION: Vasculitis in RA is associated with HLA-C3. Smoking is an independent predictor of vasculitis and other types of severe ExRA. Our results suggest that these variables are among the genetic and environmental factors that contribute significantly to the pathomechanisms of systemic RA.     

Epidemiology of extra-articular manifestations in rheumatoid arthritis

Extra-articular RA (ExRA) includes a wide variety of disease manifestations. Although rheumatologists in general are aware that such events are clinically important, the heterogeneity of available data, including discrepancies in case definitions, has complicated constructive discussions on this aspect of the RA disease phenotype. In recent years, there has been a growing recognition of the importance of co-morbidity in patients with RA. ExRA manifestations are not uncommon, explain excess mortality in RA and are predicted by smoking and autoantibodies. Further studies of the mechanisms underlying these associations are likely to be important in improving our understanding of the systemic nature of RA. This article discusses the methodological issues involved in the study of ExRA manifestations, presents suggested criteria that have been used in clinical studies, and reviews important surveys of the epidemiology of extra-articular RA.     

Association of HLA–C3 and smoking with vasculitis in patients with rheumatoid arthritis

Objective

To compare HLA–C genotypes and smoking habits in patients with vasculitis or other severe extraarticular manifestations of rheumatoid arthritis (ExRA) with those in RA patients without extraarticular disease.

Methods

Patients were recruited from a large research database of patients with RA at the Mayo Clinic, from 2 Swedish cohorts of prevalent RA cases, and from a regional Swedish early RA cohort. Patients with severe ExRA (n = 159) and control patients with RA but no history of ExRA (non‐ExRA controls) (n = 178) were matched for duration of RA and for clinical center. Data on smoking at RA onset, rheumatoid factor (RF) status, and antinuclear antibodies (ANAs) were extracted from the medical records. Polymerase chain reaction–based HLA–C genotyping was performed using a sequence‐specific primer kit.

Results

The distribution of HLA–C alleles was significantly different between patients with RA‐associated vasculitis and non‐ExRA controls (P = 0.014). This was mainly due to a positive association of the HLA–C3 allele with vasculitis (allele frequency 0.411 in vasculitis patients versus 0.199 in non‐ExRA controls; P < 0.001) and a decreased frequency of HLA–C7 (0.122 and 0.243, respectively; P = 0.018). The association between HLA–C3 and vasculitis was not due to linkage disequilibrium with HLA–DRB1. Smoking (P = 0.001), RF positivity (P < 0.0001), and presence of ANAs (P < 0.0001) were all associated with ExRA. HLA–C3 and smoking were both significant predictors of vasculitis in a multivariate model.

Conclusion

Vasculitis in RA is associated with HLA–C3. Smoking is an independent predictor of vasculitis and other types of severe ExRA. Our results suggest that these variables are among the genetic and environmental factors that contribute significantly to the pathomechanisms of systemic RA.

     

Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis

OBJECTIVE: To study antibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor in patients with active, severe extra-articular rheumatoid arthritis (ExRA) compared with controls without ExRA. METHODS: 35 consecutive patients with severe ExRA manifestations according to predefined criteria were studied. 70 patients with rheumatoid arthritis, but no ExRA manifestations, individually matched for age, sex and disease duration, served as controls. Patients were included when ExRA was diagnosed, before any new treatment was started. Anti-CCPs were detected with ELISA, rheumatoid factor was quantified using nephelometry and anti-nuclear antibodies (ANA) were investigated using indirect immune fluorescence. RESULTS: Anti-CCPs were detected in 77% of patients with ExRA versus 56% of controls without ExRA (p = 0.03). Anti-CCP levels also tended to be higher in patients with ExRA (p = 0.09). Rheumatoid factor was detected in 94% v 71% of patients and controls, respectively (p = 0.006), and rheumatoid factor levels were higher in patients with ExRA (median interquartile range (IQR) 245 IU/ml (94-604) v 73 IU/ml (not detected-165); p = 0.001). Levels and occurrence of ANA did not differ between patients with ExRA and controls. Patients with ExRA had higher swollen joint counts and C reactive protein levels, but no correlations were found between anti-CCP or rheumatoid factor levels and these measures within the ExRA group. CONCLUSION: Rheumatoid factor is strongly associated with severe ExRA manifestations in patients with rheumatoid arthritis, and a similar but weaker association exists for anti-CCPs. This suggests a role for rheumatoid factor and anti-CCP in the pathogenesis of ExRA.     

Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis

BACKGROUND: Rheumatoid arthritis is associated with increased cardiovascular mortality and morbidity. OBJECTIVE: To assess the effect of severe extra-articular rheumatoid arthritis (ExRA) manifestations on the risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis. METHODS: Patients with ExRA (n = 81) according to predefined criteria and controls (n = 184) without evidence of extra-articular disease were identified from a large research database of patients with rheumatoid arthritis. In a structured review of the medical records, the occurrence and the date of onset of clinically diagnosed CVD events were noted. Cox proportional hazards models were used to estimate the effect of ExRA on the risk of first ever CVD events after the diagnosis of rheumatoid arthritis. ExRA manifestations were modelled as time-dependent covariates, with adjustment for age, sex and smoking at the diagnosis of rheumatoid arthritis. Onset of erosive disease and rheumatoid factor seropositivity were entered as time-dependent variables. Patients were followed until onset of CVD, death or loss to follow-up. RESULTS: ExRA was associated with a significantly increased risk of first ever CVD events (p<0.001), and also with an increased risk of new-onset coronary artery disease, adjusted for age, sex and smoking (hazard ratio (HR): 3.16; 95% confidence interval (95% CI: 1.58 to 6.33). The association between ExRA and any first ever CVD event remained significant when controlling for age, sex, smoking, rheumatoid factor and erosive disease (HR: 3.25; 95% CI: 1.59 to 6.64). CONCLUSION: Severe ExRA manifestations are associated with an increased risk of CVD events in patients with rheumatoid arthritis. This association is not due to differences in age, sex, smoking, rheumatoid factor or erosive joint damage. It is suggested that systemic extra-articular disease is a major determinant of cardiovascular morbidity in rheumatoid arthritis.     

Predictors of infection in rheumatoid arthritis

OBJECTIVE: Patients with rheumatoid arthritis (RA) have been shown to have an increased susceptibility to the development of infections. The exact causes of this increased risk are unknown, but may relate to immunologic disturbances associated with the disease or to the immunosuppressive effects of agents used in its treatment. This study was undertaken to identify predictors of serious infections among patients with RA. Identification of such factors is the necessary first step in reducing the excess risk of infection in RA. METHODS: Members of a population-based incidence cohort of Rochester, Minnesota residents ages >or=18 years, who had been diagnosed with RA between 1955 and 1994, were followed up longitudinally through their complete medical records until January 1, 2000. We examined potential risk factors for the development of all objectively confirmed (by microbiology or radiology) infections and for infections requiring hospitalization. Potential risk factors included RA severity measures (rheumatoid factor positivity, elevated erythrocyte sedimentation rate, extraarticular manifestations of RA, and functional status), comorbidities (diabetes mellitus, alcoholism, and chronic lung disease), and other risk factors for infection (presence of leukopenia, smoking). Predictors were identified using multivariate time-dependent Cox proportional hazards modeling. RESULTS: The 609 RA patients in the cohort had a total followup time of 7,729.7 person-years (mean 12.7 years per patient). A total of 389 patients (64%) had at least 1 infection with objective confirmation, and 290 (48%) had at least 1 infection requiring hospitalization. Increasing age, presence of extraarticular manifestations of RA, leukopenia, and comorbidities (chronic lung disease, alcoholism, organic brain disease, and diabetes mellitus), as well as use of corticosteroids, were strong predictors of infection (P < 0.004) in both univariate and multivariate analyses. Notably, use of disease-modifying antirheumatic drugs was not associated with increased risk of infection in multivariate analyses, after adjustment for demographic characteristics, comorbidities, and disease-related variables. CONCLUSION: We identified a number of strong predictors of infections in a population-based cohort of patients with RA. These results can be used to prospectively identify high-risk patients, who may benefit from closer followup and implementation of preventive strategies.     

Cardiovascular disease is associated with extra-articular manifestations in patients with rheumatoid arthritis

The objective of this study was to examine the clinical and genetic variables associated with extra-articular rheumatoid arthritis (ExRA). This was a cross-sectional study in which 538 Northwestern Colombian patients with rheumatoid arthritis (RA) were included. Information about demographics and clinical characteristics including disease activity, inflammatory markers, co-morbidities, cardiovascular (CV) risk factors, history of familial autoimmunity and therapy was recorded. The presence of HLA “shared epitope” (SE) alleles and TNF gene polymorphism was assessed. A multivariate statistical analysis was performed. ExRA was found in 32% of the patients, of which nodulosis, Sjögren’s syndrome, and lung involvement were registered in 21%, 9%, and 4% of patients, respectively. Patients with ExRA were older than patients without it and they presented longer disease duration as well. Thus, an association between disease duration and ExRA manifestations was also observed. Patients with ExRA presented significant higher titers of anti-CCP antibodies as compared to patients without ExRA. Hypertension and thrombosis were significantly associated with ExRA. Never having smoked constituted a protective factor against ExRA onset. Associations between ExRA and the presence of traditional CV risk factors were also found. Our results show that duration of RA, CV disease and high titers of anti-CCP antibodies are associated with ExRA in Colombian patients with RA, and highlight the importance of preventing smoking in those who are prone to develop autoimmune diseases including RA.     

Increased endothelial expression of HLA-DQ and interleukin 1alpha in extra-articular rheumatoid arthritis. Results from immunohistochemical studies of skeletal muscle.

OBJECTIVE: To investigate markers of endothelial activation in muscle biopsies from rheumatoid arthritis (RA) patients with and without extra-articular manifestations (ExRA). PATIENTS AND METHODS: Nine consecutive ExRA patients were compared with nine RA controls without ExRA, matched for age, sex and duration of RA. Muscle biopsies were obtained from the lateral vastus or anterior tibial muscle. Macrophage and lymphocyte CD markers, HLA molecules, cytokines and adhesion molecules were investigated using immunohistochemistry, and stainings were evaluated using computer image analysis and conventional microscopy. Serum concentrations of soluble adhesion molecules, tumour necrosis factor alpha (TNF-alpha) and rheumatoid factor (RF) were determined using immunoassays. RESULTS: The number of HLA-DQ-positive capillaries (P=0.039) and the expression of interleukin 1alpha (IL-1alpha) in endothelial cells (mean pairwise difference 0.26%; 95% confidence interval 0-0.52) were increased in ExRA patients compared with non-ExRA controls. There were no signs of inflammatory cell infiltrates or fibre degeneration. Serum levels of TNF-alpha, the soluble form of intercellular adhesion molecule 1, the soluble form of vascular cell adhesion molecule 1 and IgM RF were increased in the ExRA group. CONCLUSION: The increased expression of HLA-DQ and IL-1alpha may indicate systemic endothelial activation in extra-articular RA, which could be of importance for cardiovascular comorbidity and mortality in such patients.     

Mortality trends in rheumatoid arthritis: the role of rheumatoid factor

OBJECTIVE: We previously demonstrated a widening in the mortality gap between subjects with rheumatoid arthritis (RA) and the general population. We examined the contribution of rheumatoid factor (RF) positivity on overall mortality trends and cause-specific mortality. METHODS: A population-based RA incidence cohort (1955-1995, and aged >or= 18 yrs) was followed longitudinally until death or January 1, 2006. The underlying cause of death as coded from national mortality statistics and grouped according to ICD-9/10 chapters was used to define cause-specific mortality. Expected cause-specific mortality rates were estimated by applying the age-, sex-, and calendar-year-specific mortality rates from the general population to the RA cohort. Poisson regression was used to model the observed overall and cause-specific mortality rates according to RF status, accounting for age, sex, disease duration, and calendar year. RESULTS: A cohort of 603 subjects (73% female; mean age 58 yrs) with RA was followed for a mean of 16 years, during which 398 died. Estimated survival at 30 years after RA incidence was 26.0% in RF+ RA subjects compared to 36.0% expected (p < 0.001), while in RF- RA subjects, estimated survival was 29.1% compared to 28.3% expected (p = 0.9). The difference between the observed and the expected mortality in the RF+ RA subjects increased over time, resulting in a widening of the mortality gap, while among RF- RA subjects, observed mortality was very similar to the expected mortality over the entire time period. Among RF+ RA subjects, cause-specific mortality was higher than expected for cardiovascular [relative risk (RR) 1.50; 95% confidence interval (CI) 1.22, 1.83] and respiratory diseases [RR 3.49; 95% CI 2.51, 4.72]. Among RF- RA subjects, no significant differences were found between observed and expected cause-specific mortality. CONCLUSION: The widening in the mortality gap between RA subjects and the general population is confined to RF+ RA subjects and largely driven by cardiovascular and respiratory deaths.     

Mortality in rheumatoid arthritis: have we made an impact in 4 decades?

OBJECTIVE: To evaluate trends in survival among patients with rheumatoid arthritis (RA) over the past 4 decades. METHODS: Three population based prevalence cohorts of all Rochester, Minnesota, residents age > or =35 years with RA (1987 American College of Rheumatology criteria) on January 1, 1965, January 1, 1975, and January 1, 1985; and an incidence cohort of all new cases of RA occurring in the same population between January 1, 1955 and January 1, 1985, were followed longitudinally through their entire medical records (including all inpatient and outpatient care by any provider) until death or migration from the county. Mortality was described using the Kaplan-Meier method and the influence of age, sex, rheumatoid factor (RF) positivity, and comorbidity (using the Charlson Comorbidity Index) on mortality was analyzed using Cox proportional hazards models. RESULTS: Mortality was statistically significantly worse than expected for each of the cohorts (overall p<0.0001). A trend toward increased mortality in the 1975 and 1985 prevalence cohorts compared to the 1965 prevalence cohort was present, even after adjusting for significant predictors of mortality (age, RF positivity, and comorbidity). Survival for the general population of Rochester residents of similar age and sex improved in 1975 compared to 1965, and in 1985 compared to 1975. CONCLUSION: The excess mortality associated with RA has not changed in 4 decades. Moreover, people with RA have not enjoyed the same improvements in survival experienced by their non-RA peers. More attention should be paid to mortality as an outcome measure in RA.     

Proposal of revised criteria for malignant rheumatoid arthritis

The diagnostic criteria for malignant rheumatoid arthritis (MRA), which was proposed by the Research Group of MRA and periarteritis nodosa supported from the Ministry of Health and Welfare has been widely used since 1973. This diagnostic criteria was established for selecting RA patients with life-threatening extraarticular manifestations caused by vasculitis. However, in practice, RA patients with extraarticular involvements related to vasculitis, as well as, cases which were not related to vasculitis were diagnosed as MRA in this criteria. Because of the aforementioned and after research, we revised the diagnostic criteria for MRA. At first, we defined MRA as RA patients having intractable and severe extraarticular manifestations by various causes including vasculitis. One hundred and sixty-nine patients with MRA and 227 patients with RA from 39 medical facilities were analysed. Sixteen extraarticular clinical manifestations and 9 laboratory findings were compared between MRA and RA patients. Comparison of specificity in each criterion for MRA was made by using the Second quantitative analysis. Thereafter, the combinations of the variables which were most specific to MRA were studied. At the same time, sensitivity and specificity for MRA were also studied. The revised criteria are as follows: A. Clinical and Laboratory Findings--(1) visceral infarction, (2) myocarditis, (3) skin ulcer or skin infarction, (4) episcleritis or iritis, (5) polyneuritis, (6) high titers of rheumatoid factor, (7) immune complexes or low complement levels, (8) subcutaneous nodule, (9) pleuritis or pericarditis, (10) interstitial pneumonitis or lung fibrosis. B. Histopathological Findings from Biopsy Specimens--necrotizing vasculitis and/or granulomatous vasculitis and/or endoarteritis obliterans in small and/or medium size arteries.(ABSTRACT TRUNCATED AT 250 WORDS)     

The widening mortality gap between rheumatoid arthritis patients and the general population

OBJECTIVE: Overall mortality rates in the general US population have declined substantially over the last 4-5 decades, but it is unclear whether patients with rheumatoid arthritis (RA) have experienced the same improvements in survival. The purpose of this study was to determine the mortality trends among RA patients compared with those in the general population. METHODS: A population-based incidence cohort of RA patients was assembled, comprising all residents of Rochester, Minnesota ages > or = 18 years in whom RA was first diagnosed (according to the American College of Rheumatology [formerly, the American Rheumatism Association] 1987 criteria) between 1955 and 1995 and all residents of Olmsted County, Minnesota in whom RA was first diagnosed between 1995 and 2000. The patients were followed up longitudinally through their complete (inpatient and outpatient) medical records until death or January 1, 2007. Expected mortality was estimated from the National Center for Health Statistics life tables on the white population in Minnesota, using person-year methods. Poisson regression was used to model the observed mortality rates, adjusting for age, sex, and disease duration. RESULTS: A cohort of 822 RA patients (72% women, mean age at RA incidence 58 years) was followed up for a median of 11.7 years, during which 445 of the RA patients died. Between 1965 and 2005, the mortality rates across the calendar years for female and male RA patients were relatively constant at 2.4 and 2.5 per 100 person-years, respectively. In contrast, the expected mortality rate in the Minnesota white population decreased substantially over the same time period in both sexes. Mortality in the female general population declined from 1.0 per 100 person-years in 1965 to 0.2 per 100 person-years in 2000. Mortality in the male general population decreased from 1.2 per 100 person-years in 1965 to 0.3 per 100 person-years in 2000. Therefore, the difference between the observed and expected mortality rates increased in more recent years, resulting in a widening of the mortality gap. CONCLUSION: Our findings show that RA patients have not experienced improvements in survival over the past 4 decades, despite dramatic improvements in the overall rates of mortality in the general US population. Further research into the causes of the widening gap in mortality between RA patients and the general population, and the influence of current therapeutic strategies on mortality, is needed in order to develop strategies to reduce the excess mortality observed in RA patients.