Heart disease and rheumatoid arthritis: understanding the risks.

Patients with rheumatoid arthritis (RA) are at increased risk of mortality compared with the general population. Evidence suggests that this increased mortality can largely be attributed to increased cardiovascular death. In a retrospective study of an inception cohort of RA patients in Rochester, MN, the contribution of traditional and RA-specific risk factors was investigated to this increased risk of cardiovascular morbidity and mortality. Several traditional cardiovascular risk factors were found to behave differently in RA patients. In addition, their associations with cardiovascular disease are weaker in RA patients as increased inflammation associated with RA also appears to contribute substantially to the increased cardiovascular mortality. Furthermore, the impact of disease-modifying antirheumatic drugs and biologicals on cardiovascular disease in RA patients is unclear. Cardiovascular risk scores for the general population may underestimate the risk for RA patients. Together with other studies that have demonstrated similar associations between RA and cardiovascular mortality, these data suggest that optimal control of cardiovascular risk factors is important, but not sufficient in RA patients. RA-specific cardiovascular risk prediction tools are needed, as well as clinical trials to assess the impact of therapies and tight control of inflammation in RA patients on cardiovascular outcomes and mortality.

Novel human bronchial epithelial cell lines for cystic fibrosis research.

Immortalization of human bronchial epithelial (hBE) cells often entails loss of differentiation. Bmi-1 is a protooncogene that maintains stem cells, and its expression creates cell lines that recapitulate normal cell structure and function. We introduced Bmi-1 and the catalytic subunit of telomerase (hTERT) into three non-cystic fibrosis (CF) and three DeltaF508 homozygous CF primary bronchial cell preparations. This treatment extended cell life span, although not as profoundly as viral oncogenes, and at passages 14 and 15, the new cell lines had a diploid karyotype. Ussing chamber analysis revealed variable transepithelial resistances, ranging from 200 to 1,200 Omega.cm(2). In the non-CF cell lines, short-circuit currents were stimulated by forskolin and inhibited by CFTR(inh)-172 at levels mostly comparable to early passage primary cells. CF cell lines exhibited no forskolin-stimulated current and minimal CFTR(inh)-172 response. Amiloride-inhibitable and UTP-stimulated currents were present, but at lower and higher amplitudes than in primary cells, respectively. The cells exhibited a pseudostratified morphology, with prominent apical membrane polarization, few apoptotic bodies, numerous mucous secretory cells, and occasional ciliated cells. CF and non-CF cell lines produced similar levels of IL-8 at baseline and equally increased IL-8 secretion in response to IL-1beta, TNF-alpha, and the Toll-like receptor 2 agonist Pam3Cys. Although they have lower growth potential and more fastidious growth requirements than viral oncogene transformed cells, Bmi-1/hTERT airway epithelial cell lines will be useful for several avenues of investigation and will help fill gaps currently hindering CF research and therapeutic development.

Why do people with rheumatoid arthritis still die prematurely?

Premature death has been long recognised as a manifestation of rheumatoid arthritis (RA). Three lines of evidence can explain why patients with RA die prematurely and why the mortality gap between patients with RA and the general population appears to widening. First, patients with RA have a higher risk of several serious comorbid conditions and they tend to experience worse outcomes after the occurrence of these illnesses. Second, patients with RA do not appear to receive optimal primary or secondary preventive care. And third, the systemic inflammation and immune dysfunction associated with RA appears to promote and accelerate comorbidity and mortality. This paper provides a brief summary and interpretation of the data underlying these findings. Together, these results provide a compelling argument in favour of a focused research programme aimed specifically at eliminating premature death in patients with RA.

Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients?

OBJECTIVE: To compare the frequency of traditional cardiovascular (CV) risk factors in rheumatoid arthritis (RA) compared to non-RA subjects, and examine their impact on the risk of developing selected CV events (myocardial infarction (MI), heart failure (HF) and CV death) in these two groups. METHODS: We examined a population-based incidence cohort of subjects with RA (defined according to the 1987 American College of Rheumatology criteria), and an age- and sex-matched non-RA cohort. All subjects were followed longitudinally through their complete community medical records, until death, migration, or 1 January 2001. Clinical CV risk factors and outcomes were defined using validated criteria. The chi2 test was used to compare the frequency of each CV risk factor at baseline. Person-years methods were used to estimate the rate of occurrence of each CV risk factor during follow-up. Cox models were used to examine the influence of CV risk factors on the development of CV outcomes. RESULTS: A total of 603 RA and 603 non-RA subjects (73% female; mean age 58 years) were followed for a mean of 15 and 17 years (total: 8842 and 10,101 person-years), respectively. At baseline, RA subjects were significantly more likely to be former or current smokers when compared to non-RA subjects (p<0.001). Male gender, smoking, and personal cardiac history had weaker associations with CV events among RA subjects, compared to non-RA subjects. There was no significant difference between RA and non-RA subjects in the risk imparted with respect to the other CV risk factors (ie, family cardiac history, hypertension, dyslipidaemia, body mass index, or diabetes mellitus). CONCLUSION: While some traditional CV risk factors imparted similar risk among RA compared with non-RA subjects, others (ie, male gender, smoking and personal cardiac history) imparted significantly less risk for the development of CV disease. These differences in the overall impact of traditional CV risk factors suggest that strategies to prevent CV disease and mortality focused solely on controlling traditional CV risk factors may be relatively less beneficial in RA subjects than in the general population. Further research is needed to determine optimal approaches to reducing CV morbidity and mortality in persons with RA.

Quality Measures 101: what every rheumatologist should know.

In this paper, we review the essentials of quality measurement for rheumatologists. We will focus on four specific issues: why should rheumatology focus on quality measures now? how can rheumatology construct and assess quality measures? what can rheumatologists expect to achieve with quality measures? will quality measures be used for reimbursement?

Raised erythrocyte sedimentation rate signals heart failure in patients with rheumatoid arthritis.

BACKGROUND: Inflammatory markers are associated with heart failure. Patients with rheumatoid arthritis have twice the risk of heart failure compared with people without rheumatoid arthritis. OBJECTIVE: To assess whether heart failure in patients with rheumatoid arthritis is preceded by an inflammatory activation as shown by erythrocyte sedimentation rate (ESR), a systemic marker of inflammation. METHODS: A population-based inception cohort of 575 patients with rheumatoid arthritis, free of heart failure at their rheumatoid arthritis incidence date, was followed up longitudinally until death or 2001. During 15 years of follow-up, they had a median of 15 ESR tests, and 172 patients had new-onset heart failure (Framingham Heart Study criteria). The follow-up period, beginning with the rheumatoid arthritis incidence date and ending with date of the last follow-up, was divided into 6-month intervals. The proportions of patients with at least one ESR value >/=40 mm/h and with anaemia (haemoglobin <11 g/dl) within each 6-month interval were plotted against time from fulfilment of heart failure criteria. A binomial test was used to compare proportions. RESULTS: In patients with rheumatoid arthritis who developed heart failure, the proportion with ESR >/=40 mm/h was highest (23%) during the 6-month period immediately preceding the new-onset heart failure, as compared with the average ESR during the entire remaining follow-up period, both before and after heart failure (10.6%; p<0.01). The proportion of patients with anaemia peaked (54%) during the 6-month period after heart failure. CONCLUSIONS: Inflammatory stimuli may be involved in the initiation of heart failure among patients with rheumatoid arthritis.

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.

Cost-equivalence of different osteoporotic fractures.

METHODS: Among 985 Olmsted County, Minnesota, residents who experienced an osteoporotic fracture (distal forearm, humerus, clavicle/scapula/sternum, ribs, vertebrae, pelvis, hip, other femur or tibia/fibula [the latter in women only]), we estimated the incremental cost of direct medical care in the following year compared with age- and sex-matched controls without a fracture randomly sampled from the same community. RESULTS: The overall median incremental (case minus control) cost in the succeeding year was $2,390, with a particularly high incremental cost for hip fractures ($11,241). There was fair concordance between the incremental cost of the different fractures, relative to hip fracture alone, and the previously published disutility associated with each fracture type relative to hip fracture. Overall, the incremental cost for all osteoporotic fractures combined was 46% greater than that for hip fractures alone in women and 47% greater in men. This is consistent with the earlier report that overall morbidity from all osteoporotic fractures combined is 47% and 39% greater in women and men, respectively, than the morbidity attributable solely to hip fractures. CONCLUSION: These data lend support to the notion that other osteoporotic fractures can be quantified relative to hip fracture on the basis of their cost, as well as their morbidity and mortality. This may simplify health economic analyses by allowing all fracture outcomes to be modeled relative to hip fractures (i.e., hip fracture 'equivalents') and will provide a more comprehensive assessment of osteoporosis outcomes than is possible by focusing only on hip fractures.

Direct medical costs attributable to osteoporotic fractures.

Osteoporotic fractures are a major cause of morbidity in the elderly, the most rapidly growing segment of our population. We characterized the incremental direct medical costs following such fractures in a population-based cohort of men and women in Olmsted County, Minnesota. Cases included all County residents 50 years of age and older with an incident fracture due to minimal or moderate trauma between January 1, 1989 and January 1, 1992. For each case, a control of the same age (+/- 1 year) and sex who was attended in the local medical system in the same year was identified. Total incremental costs (cases - controls) in the year after fracture were estimated. Unit costs for each health service/procedure were obtained through the Mayo Cost Data Warehouse, which provides a standardized, inflation-adjusted estimate reflecting the national average cost of providing the service. Regression analysis was used to identify factors associated with incremental costs. There were 1263 case/control pairs; their average age was 73.8 years and 78% were female. Median total direct medical costs were $761 and $625, respectively, for cases and nonfracture controls in the year prior to fracture, and $3884 and $712, respectively, in the year following fracture. The highest median incremental costs were for distal femur ($11756) and hip fractures ($11241), whereas the lowest were for rib fractures ($213). Although hip fractures resulted in more incremental cost than any other fracture type, this amounted to only 37% of the total incremental cost of all moderate-trauma fractures combined. Regression analyses revealed that age, prior year costs and type of fracture were significant predictors of incremental costs (p<0.03 for all comparisons). The incremental costs of osteoporotic fractures are therefore substantial. Whereas hip fractures contributed disproportionately, they accounted for only one-third of the total incremental cost of fractures in our cohort. The use of incremental costs in economic analyses will provide a more accurate reflection of the true cost-effectiveness of osteoporosis prevention.

Progress towards an OMERACT-ILAR guideline for economic evaluations in rheumatology.

A working report from the OMERACT Health Economics Group. The group is working towards creating common standards for economic evaluation in rheumatology and also towards improving the scientific underpinning of economic evaluation, particularly pertaining to the rheumatic diseases. Preliminary recommendations for "reference cases" in osteoporosis, rheumatoid arthritis, and osteoarthritis are proposed.

A clinical and economic review of disease-modifying antirheumatic drugs.

Rheumatoid arthritis is one of the most common chronic systemic inflammatory diseases, affecting approximately 1% of the adult population. Disease-modifying antirheumatic drugs (DMARDs) have been the mainstay of treatment for rheumatoid arthritis when combined with physical therapy and aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory drugs. Recently, a number of new biological therapies have been introduced for the treatment of this condition and will have a major impact on the future management of this disabling disease. In this review, we summarise data on the efficacy and tolerability of the currently available DMARDs, including gold compounds, antimalarials, penicillamine, cytotoxic drugs (azathioprine and cyclophosphamide), sulfasalazine, methotrexate, leflunomide, cyclosporin, anti-tumour necrosis factor agents, combination therapy and apheresis. A literature review and quality assessment of economic evaluations of DMARDs is presented, illustrating that there has been a paucity of economic evaluations on these agents and showing the variable quality of those studies that are available. The manuscript also addresses the pharmacoeconomic implications of the new agents for rheumatoid arthritis; the need for formal long term economic evaluations in order to determine the cost effectiveness of these costly, but highly effective, new treatments is emphasised.

Adverse gastrointestinal effects of NSAIDs: consequences and costs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most widely consumed medications. They are available by prescription and 'over the counter'. The same pharmacological properties which make them effective in the treatment of a variety of painful and/or arthritic conditions are responsible for a variety of adverse gastrointestinal effects, ranging from relatively mild dyspepsia to potentially lethal gastrointestinal (GI) bleeding and perforated ulcers. Yearly medical costs of GI complications associated with the use of NSAIDs are very high and likely to increase with the growth of the ageing US population. A review of the literature (1970-2000) on consequences and costs of NSAID-associated GI adverse effects, including iatrogenic cost factors of NSAIDs, was performed. The results were tabulated and compared. Knowledge and comparison of the consequences and costs of NSAID-associated GI adverse effects in various populations and across various health care systems are important for clinical care, pharmacoeconomics and policy arenas.

Genetic linkage and transmission disequilibrium of marker haplotypes at chromosome 1q41 in human systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies to a wide range of self-antigens. Recent genome screens have implicated numerous chromosomal regions as potential SLE susceptibility loci. Among these, the 1q41 locus is of particular interest, because evidence for linkage has been found in several independent SLE family collections. Additionally, the 1q41 locus appears to be syntenic with a susceptibility interval identified in the NZM2410 mouse model for SLE. Here, we report the results of genotyping of 11 microsatellite markers within the 1q41 region in 210 SLE sibpair and 122 SLE trio families. These data confirm the modest evidence for linkage at 1q41 in our family collection (LOD = 1.21 at marker D1S2616). Evidence for significant linkage disequilibrium in this interval was also found. Multiple markers in the region exhibit transmission disequilibrium, with the peak single marker multiallelic linkage disequilibrium noted at D1S490 (pedigree disequilibrium test [PDT] global P value = 0.0091). Two- and three-marker haplotypes from the 1q41 region similarly showed strong transmission distortion in the collection of 332 SLE families. The finding of linkage together with significant transmission disequilibrium provides strong evidence for a susceptibility locus at 1q41 in human SLE.

Is rheumatoid arthritis care more costly when provided by rheumatologists compared with generalists?

OBJECTIVE: Controversy surrounds the cost-effectiveness of rheumatologist care compared with generalist care for patients with rheumatoid arthritis (RA). Rheumatologists can provide 2 distinct types of care for RA patients: primary care and specialist care. We sought to examine the relationship between cost and type of care in a population-based cohort of patients with RA. METHODS: Data regarding specialty of care and use of health services (i.e., total direct medical costs, surgeries, radiographs, laboratory tests, hospital days) were collected from a community sample of 249 patients with RA (defined using the 1987 American College of Rheumatology diagnostic criteria) among Rochester, Minnesota residents > or =35 years of age. In a randomly selected subset of 99 of these RA patients, detailed information on all physician encounters was collected and categorized according to whether or not the care received constituted "primary care" according to the Institute of Medicine definition. Using these data, we evaluated the influence of type of care as well as specialty of provider on utilization. For these analyses, total direct costs included all inpatient and outpatient health care costs incurred by all local providers (excluding outpatient prescription drugs). RESULTS: The 249 patients with RA (mean age 64 years, 75% women) were followed up for a median of 5.4 years, while the subset of 99 RA patients (mean age 64 years, 77% women) were followed up for a median of 4.7 years. The overall median direct medical costs per person per year were $2,749 and $2,929 for the total cohort and for the subset of 99 patients, respectively. Generalized linear regression analyses (considering all visits of the 249 RA patients) revealed that after adjusting for demographics and disease characteristics, rheumatologist care (compared with nonrheumatologist care) was not associated with higher total direct medical costs (P = 0.85) or more hospital days (P = 0.35), but was associated with slightly more radiographs (P = 0.037) and significantly more laboratory tests (P < 0.0001). When considering only primary care, such care by rheumatologists was, again, not associated with higher total direct medical costs (P = 0.11) or more hospital days (P = 0.69) or more laboratory tests (P = 0.54), but was associated with slightly more radiographs (P = 0.035). CONCLUSION: Rheumatologist care is not more costly than generalist care for patients with RA. Important differences (especially in the use of laboratory tests) become apparent when the type of care provided as well as the specialty of the provider are considered in the analyses.

The epidemiology of rheumatoid arthritis.

Studies of the descriptive epidemiology of RA indicate a population prevalence of 0.5% to 1% and a highly variable annual incidence (12-1200 per 100,000 population) depending on gender, race/ethnicity, and calendar year. Secular trends in RA incidence over time have been shown in several studies, supporting the hypothesis of a host-environment interaction. People with RA have a significantly increased risk of death compared with age- and sex-matched controls without RA from the same community. The determinants of this excess mortality remain unclear; however, reports suggest increased risk from gastrointestinal, respiratory, cardiovascular, infectious, and hematologic diseases among RA patients compared with controls. Despite extensive epidemiologic research, the etiology of RA is unknown. Several risk factors have been suggested as important in the development or progression of RA. These include genetics, infectious agents, oral contraceptives, smoking, and formal education. Epidemiologic research is an essential contributor to our understanding of RA.

Increased mortality in adults with a history of juvenile rheumatoid arthritis: a population-based study.

OBJECTIVE: To assess mortality in a population-based cohort of adults with a history of juvenile rheumatoid arthritis (JRA). METHODS: The Rochester Epidemiology Project database was used to identify all cases of JRA diagnosed among Rochester, Minnesota residents under the age of 16 between January 1, 1960 and December 31, 1993. Fifty-seven patients in this cohort are now adults (ages 18-53 years, mean age 34.3 years), and this subgroup was contacted for a long-term followup study. The average length of followup from the time of diagnosis was 25.6 years. RESULTS: Four deaths occurred in this cohort of 57 adults with a history of JRA. All 4 deceased patients had other autoimmune illnesses and died of complications of these diseases. The observed frequency of 4 deaths was significantly greater (P < 0.0026 by one-sample log-rank test) than the 1 death that would be expected among Minnesota whites of similar age and sex, and corresponds to a mortality rate of 0.27 deaths per 100 years of patient followup compared with an expected mortality rate of 0.068 deaths per 100 years of followup in the general population. CONCLUSION: The results indicate a significant, unexpected increase in mortality in this population-based cohort of adults with a history of JRA in comparison with the rate in the general population. The deaths in this group were all associated with other autoimmune disorders, suggesting that special emphasis should be given to the diagnosis and treatment of other autoimmune diseases, including immunodeficiencies, in JRA patients. The frequency of deaths in this cohort suggests that JRA patients are at substantial risk for mortality, and highlights the need for longitudinal followup and care into adulthood.

Expression and localization of epithelial aquaporins in the adult human lung.

Aquaporins (AQPs) facilitate water transport across epithelia and play an important role in normal physiology and disease in the human airways. We used in situ hybridization and immunofluorescence to determine the expression and cellular localization of AQPs 5, 4, and 3 in human airway sections. In nose and bronchial epithelia, AQP5 is expressed at the apical membrane of columnar cells of the superficial epithelium and submucosal gland acinar cells. AQP4 was detected in basolateral membranes in ciliated ducts and by in situ in gland acinar cells. AQP3 is present on basal cells of both superficial epithelium and gland acinus. In these regions AQPs 5, 4, and 3 are appropriately situated to permit transepithelial water permeability. In the small airways (proximal and terminal bronchioles) AQP3 distribution shifts from basal cell to surface expression (i.e., localized to the apical membrane of proximal and terminal bronchioles) and is the only AQP identified in this region of the human lung. The alveolar epithelium has all three AQPs represented, with AQP5 and AQP4 localized to type I pneumocytes and AQP3 to type II cells. This study describes an intricate network of AQP expression that mediates water transport across the human airway epithelium.

A comparative study of the clinical manifestations of systemic lupus erythematosus in Caucasians in Rochester, Minnesota, and Chinese in Singapore, from 1980 to 1992.

OBJECTIVE: To examine the relationship between ethnicity and major organ involvement at and after diagnosis in community-based cohorts of Caucasian and Chinese systemic lupus erythematosus (SLE) patients resident in Rochester, Minnesota, and Singapore, respectively. METHODS: Clinical manifestations at and after diagnosis were compared in Caucasian and Chinese SLE patients. The association between ethnicity and disease manifestations at and after diagnosis was determined using logistic regression and Cox proportional hazards models, respectively, adjusting for the influence of demographic, socioeconomic, disease-related, and therapy-related factors. RESULTS: At diagnosis, Caucasian SLE patients were 3 times more likely than Chinese SLE patients to have serositis (odds ratio [OR] 3.11, 95% confidence interval [CI] 1.01-9.71), nearly 7 times more likely to have a hematologic disorder (OR 6.95, 95% CI 2.20-21.97), and far less likely to have a malar rash (OR 0.19, 95% CI 0.07-0.54) or positive antinuclear antibodies (OR 0.11, 95% CI 0.03-0.52). Ethnicity was not associated with the prevalence of proteinuria or central nervous system (CSN) and other major organ involvement at diagnosis. After diagnosis, there was a trend toward less development of proteinuria and other major organ involvement in Caucasians (relative risk [RR] 0.47, 95% CI 0.19-1.15, and RR 0.22, 95% CI 0.05-1.04, respectively). CONCLUSION: Chinese SLE patients are far less likely to have serositis or a hematologic disorder at diagnosis and may be more likely to develop proteinuria or CNS or other major organ involvement over the course of the disease, compared with Caucasian SLE patients. This may contribute to the increased mortality seen in Chinese SLE patients.