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.

Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes an adenosine 3',5'-monophosphate (cyclic AMP)-activated chloride channel. In cystic fibrosis (CF) patients, loss of CFTR function because of a genetic mutation results in defective cyclic AMP-mediated chloride secretion across epithelia. Because of their potential role as an animal model for CF, mice with targeted disruption of the murine CFTR gene [CFTR(-/-)] were tested for abnormalities in epithelial chloride transport. In both freshly excised tissue from the intestine and in cultured epithelia from the proximal airways, the cyclic AMP-activated chloride secretory response was absent in CFTR(-/-) mice as compared to littermate controls. Thus, disruption of the murine CFTR gene results in the chloride transport abnormalities predicted from studies of human CF epithelia.

Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model.

The effect of the number of cystic fibrosis (CF) alleles on cholera toxin (CT)-induced intestinal secretion was examined in the CF mouse model. CF mice that expressed no CF transmembrane conductance regulator (CFTR) protein did not secrete fluid in response to CT. Heterozygotes expressed 50 percent of the normal amount of CFTR protein in the intestinal epithelium and secreted 50 percent of the normal fluid and chloride ion in intestinal epithelium and secreted 50 percent of the normal fluid and chloride ion and fluid secretion suggests that CF heterozygotes might possess a selective advantage of resistance to cholera.

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.

Analysis of TFIIA function In vivo: evidence for a role in TATA-binding protein recruitment and gene-specific activation.

Activation of transcription can occur by the facilitated recruitment of TFIID to promoters by gene-specific activators. To investigate the role of TFIIA in TFIID recruitment in vivo, we exploited a class of yeast TATA-binding protein (TBP) mutants that is activation and DNA binding defective. We found that co-overexpression of TOA1 and TOA2, the genes that encode yeast TFIIA, overcomes the activation defects caused by the TBP mutants. Using a genetic screen, we isolated a new class of TFIIA mutants and identified three regions on TFIIA that are likely to be involved in TBP recruitment or stabilization of the TBP-TATA complex in vivo. Amino acid replacements in only one of these regions enhance TFIIA-TBP-DNA complex formation in vitro, suggesting that the other regions are involved in regulatory interactions. To determine the relative importance of TFIIA in the regulation of different genes, we constructed yeast strains to conditionally deplete TFIIA levels prior to gene activation. While the activation of certain genes, such as INO1, was dramatically impaired by TFIIA depletion, activation of other genes, such as CUP1, was unaffected. These data suggest that TFIIA facilitates DNA binding by TBP in vivo, that TFIIA may be regulated by factors that target distinct regions of the protein, and that promoters vary significantly in the degree to which they require TFIIA for activation.

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?

Inhibiting conductive Cl uptake in membrane vesicles: specificity of alpha-phenylcinnamate.

alpha-Phenylcinnamate has been investigated in comparison to other inhibitors of chloride ion transport into porcine jejunal brush-border membrane vesicles. The transport modes studied included uptake driven only by a chemical Cl gradient, Cl uptake dependent on a transmembrane potential, self-exchange of Cl with no chemical or potential gradient, and Cl uptake dependent on a chemical gradient for bicarbonate. Uptake driven by the chemical gradient for Cl was strongly inhibited by millimolar concentrations of diphenylamine-2-carboxylate, 5-nitro-2-(2-phenylethylamino)benzoate (NPEB), and to a lesser extent by 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (SITS). Similar concentrations of alpha-phenylcinnamate did not reduce this mode of Cl uptake. Conductive Cl uptake driven by a potassium gradient was inhibited by approx. 50% at 2.5 mM alpha-phenylcinnamate. alpha-Phenylcinnamate was equally effective in reducing the initial rate of conductive chloride accumulation in vesicles with naturally opened Cl channels (conductance activation by cyclic AMP and Ca2+), or with Cl channels opened by exposure to tetramethylammonium (TMA) buffer. In comparison with diphenylamine-2-carboxylate, NPEB and SITS, alpha-phenylcinnamate had the least effect on Cl-HCO3 exchange at inhibitor concentrations which reduced conductance activity. Self-exchange rates of physiological concentrations of Cl were also relatively unaffected by low mM concentrations of alpha-phenylcinnamate. Kinetic analysis indicated that alpha-phenylcinnamate was an uncompetitive inhibitor, requiring the presence of the normal Cl ligand for binding to, and inhibition of, conductive Cl transport by pig intestinal brush-border vesicles.

Scleromyxedema: a scleroderma-like disorder with systemic manifestations.

Scleromyxedema is a rare fibromucinous connective tissue disorder characterized by papular skin lesions associated with sclerosis and a serum monoclonal gammopathy. Little is known about either the natural history or the systemic manifestations of this disease. We reviewed the medical records of 19 patients with biopsy-proven scleromyxedema seen from 1950 to 1985 for evidence of systemic disease. There were 10 males and 9 females with a median age at diagnosis of 53 years. Monoclonal gammopathy was present in 13 patients. Eight patients complained of dysphagia; 3 had proximal esophageal dysfunction and 1 had total esophageal aperistalsis on barium swallow. Proximal muscle weakness was noted in 5, with an inflammatory myopathy in 3. Six patients complained of dyspnea on exertion. Of these, 5 had reduced diffusing capacity, 3 had reduced volumes, and 2 developed cor pulmonale. Pathologic changes characteristic of "scleroderma kidney" were demonstrated in 1 patient at postmortem. One patient had Raynaud's phenomenon and 2 had arthralgias/arthritis with noninflammatory synovial fluids. Although 8 of 12 patients treated with melphalan noted regression of their skin changes, no consistent improvement in the extracutaneous manifestations was demonstrated. Furthermore, 2 patients died of sepsis related to melphalan-induced myelosuppression, and 4 developed hematological malignancies following melphalan therapy. In conclusion, systemic manifestations in scleromyxedema are more prevalent than previously recognized, and can resemble those of scleroderma. Significant toxicity occurred with the use of alkylating agents in these patients, with treatment-related complications developing in 45% of patients treated with melphalan. The lack of definitive data regarding the natural history of this disease complicates the question of optimal therapy, but the use of alkylating agents should be reserved for those patients with severe debilitating skin disease.

Management of coronary risk factors by registered nurses versus usual care in patients with unstable angina pectoris (a chest pain evaluation in the emergency room [CHEER] substudy).

This study examined whether nurses could manage coronary risk factors in patients with unstable angina more effectively than physicians practicing usual care. Three hundred twenty-six patients were randomized in the emergency room to a 6-month program of risk factor management by a registered nurse versus participation in usual care. The nurse intervention consisted of a 30-minute counseling visit at 6 to 10 days after the chest pain episode and a second 30-minute session 1 month later. Multiple risk factors were assessed and addressed: smoking, blood lipids, blood pressure, blood glucose, physical inactivity, weight, psychological stress, and social isolation. Compared with usual care, nurse intervention patients significantly reduced both triglycerides (-29 +/- 8 vs 5 +/- 6 mg/dl; p <0.0004) and weight (-0.9 +/- 3.3 vs +0.1 +/- 2.1 kg; p = 0.0071), and had corresponding improvements in self-reported diet compliance and exercise (+34 +/- 106 vs +9 +/- 98 minutes, p = 0.0491). No significant differences between groups were observed in terms of 6-month changes in total, high-density lipoprotein, or low-density lipoprotein cholesterol, blood pressure, fasting blood glucose, percent body fat or waist-hip ratio, or psychological distress scores. The 6-month rate of recurrent events (cardiac death, out-of-hospital cardiac arrest, myocardial infarction) and/or revascularizations (coronary artery bypass surgery or coronary angioplasty) was lower in the nurse intervention group (1% vs 9%; p = 0.002). We conclude that a nurse-delivered risk factor intervention program for patients with chest pain is feasible and more effective than usual care in terms of fostering lifestyle changes that may lower coronary risk.

Primary care: specialists or generalists.

A critical appraisal of the literature on the cost and quality trade-offs of primary care provided by specialists in comparison with that provided by generalists is presented.

Rheumatoid arthritis: can the long-term outcome be altered?

Although several agents (for example, intramuscularly administered gold, auranofin, D-penicillamine, hydroxychloroquine, and methotrexate) are of clinical benefit in the management of rheumatoid arthritis (RA), their effect on the long-term outcome of the disease is controversial. Assessment of the influence of therapeutic interventions in RA is difficult because the natural history of the disease remains poorly defined and unpredictable, and neither the traditional clinical and laboratory measurements of inflammation nor radiographic analyses of progression of joint destruction provide an accurate estimate of the long-term outcome of RA. Furthermore, there is little evidence that second-line agents yield benefits beyond 3 years. Therefore, adequately tested comprehensive measures should be used in large, long-term, multicenter controlled clinical trials to determine whether the long-term outcome of RA can be altered.

Increasing the proportion of women in academic medicine: one institution's response.

OBJECTIVE: To increase gender diversity among the physician consulting staff (PCS) at a major medical center. DESIGN: Because the proportion of female PCS at academic medical centers in the United States has not increased commensurately with increases in the proportion of female graduates from American medical schools, a modeling and graphing technique was developed to analyze this problem and recommend solutions for one large academic medical center. MATERIAL AND METHODS: Personnel data, by gender and year from 1980 through 1994, were collected for all PCS at Mayo Clinic Rochester (MCR). These data were compared with similar data from other US academic medical centers and were used to develop models to predict the proportion of female PCS at MCR yearly until 2005, assuming various hiring and resignation patterns. Novel techniques were developed to illustrate and compare the models. Model-based predictions were compared with national projections, and a realistic target proportion of female PCS was defined on the basis of assumptions about the proportion of female graduates from medical school and internship programs during the next 10 years as well as probable hiring, retention, and resignation rates at MCR. To identify issues critical to recruitment, retention, and professional growth of female PCS at MCR, we used factor analysis to assess responses to a confidential questionnaire sent to all female faculty members. RESULTS: In 1994 and 1995, the proportion of female PCS was 25% at US academic medical centers but only 15% at MCR, and the rate at which this proportion increased from 1980 through 1994 at MCR was also lower than the national rate. Model-based predictions demonstrated that gradually (1.5% per year) increasing the female percentage of new recruits from 26% in 1995 to 40% in 2005 would achieve the targeted 25% female PCS in 13 years. Questionnaire responses from 119 (68%) of the 175 female PCS at MCR identified 6 important recommendations for recruitment and retention of female PCS: survey resignees and candidates who decline positions; appoint more qualified women to policy-making committees; require sensitivity and diversity training for all staff (especially leaders); develop explicit, gender-sensitive criteria for selecting department and division chairs; compare Mayo gender and diversity data with national data at the department or division level; and develop mechanisms for mentoring junior female staff members. CONCLUSION: We developed useful methods for analyzing the PCS gender distribution, defined feasible hiring strategies, and identified specific recommendations to enhance the professional experience of female PCS. These methods can provide a model for other institutions seeking to optimize gender diversity among their staff.

Trends in the utilization of non-steroidal anti-inflammatory drugs in the United States, 1986-1990.

National estimates of NSAID utilization were obtained from two databases available from IMS America. These data illustrate that in contrast to the rapid rise in NSAID prescriptions from 1973 (27.5 million) to 1983 (66.7 million), NSAID prescriptions have recently been remarkably stable. Over the same time period, a 46 fold increase in the use of gastro-protective and/or anti-ulcer drugs concomitantly with NSAID was demonstrated. It is hypothesized that the stabilization of NSAID prescription usage coupled with the dramatic increase in usage of concomitant anti-ulcer and gastro-protective agents has occurred due to physician awareness of the increased relative risk for adverse gastrointestinal events among NSAID users compared to non-users.

A mathematical model that improves the validity of osteoarthritis diagnoses obtained from a computerized diagnostic database.

We developed an algorithm, using recursive partitioning, that utilized information from a computerized, diagnostic database to predict the diagnosis of osteoarthritis as determined by medical record review. The complete (inpatient and outpatient) medical records for a random sample of 400 Olmsted County, Minnesota residents with a database diagnosis consistent with osteoarthritis were reviewed, and confirmation or rejection of the diagnosis was accomplished. Of the 387 patients in our sample, only 232 (a positive predictive value of 60%) fulfilled diagnostic criteria for osteoarthritis following medical record review. A classification tree was created that used information from the diagnostic database to partition the study population according to the proportion of individuals with a "true" diagnosis of osteoarthritis (based on medical record review). The receiver-operating characteristic curve generated from these data illustrated that the algorithm substantially improved the validity of the database diagnosis, yielding a positive predictive value of 89% and a negative predictive value of 70% (sensitivity of 75% and specificity of 86%) at a selected cutoff point. This model also provides the capability of selecting the cutoff point to favor either specificity or sensitivity. These data demonstrate that a mathematical model can substantially improve the validity of computerized diagnostic databases in osteoarthritis.

A comparison of two comorbidity instruments in arthritis.

Comorbidity (CM) is a powerful predictor of health outcome and cost, as well as an important confounder in many epidemiologic studies. However, choosing the most appropriate CM measurement instrument is difficult because comparative data on how the available instruments perform in various disease settings are limited. We collected CM data (from the complete medical records) for two population-based prevalence cohorts with rheumatoid arthritis (RA) and osteoarthritis (OA) and a comparison cohort without arthritis (NA), using two different CM instruments: the Charlson CM index (Charl), which is based on 17 diagnoses each weighted by mortality risk, and the Index of Coexistent Diseases (ICED), which estimates the severity and frequency of 14 comorbid conditions and provides an assessment of the impairment or disability caused by each. Cox proportional hazards modeling was used to assess the impact of the two types of comorbidity scores (Charl and ICED) on survival after prevalence (index) date, adjusting for the age, sex, and disease status. There were 450, 441, and 889 individuals in the RA, OA, and NA groups, respectively, with a mean follow-up period of 10.6 years. During the follow-up, 293, 307, and 546 deaths occurred in the RA, OA, and NA groups, respectively. The mean age and percent females were: 63.3 years, 74%; 70.7 years, 74%; and 67.5 years, 75% for the RA, OA, and NA groups, respectively. Comorbidity was highest in RA, intermediate in OA, and lowest in NA by both Charl and ICED. Cox proportional hazards modeling demonstrated that both Charl and ICED were highly statistically significant predictors of mortality (P<0.0001) after adjusting for age, sex, and disease state (RA, OA, or NA) and that ICED remained highly significant as a predictor of mortality, even after adjusting for Charl. We conclude that estimating CM from medical records using ICED, an instrument that incorporates an assessment of impairment and disability, is feasible and that such as assessment provides information that independently predicts mortality, even after adjusting for the results of traditional diagnosis-based CM measures, such as Charl.

Trends in the utilization of silicone breast implants, 1964-1991, and methodology for a population-based study of outcomes.

Using the unique data resources of the Rochester Epidemiology Project, we have designed a population-based retrospective cohort study to examine the risks and complications of silicone breast implants among 749 Olmsted County, Minnesota, women who received these devices between 1964 and 1991, and 1498 control women who did not receive such devices. In this paper, we present data describing the population-based trends in the utilization of these devices from 1964 to 1991. In addition, we discuss the case ascertainment, outcome assessment, and reliability of the data collection for the outcomes study. The utilization of breast implants increased markedly over the past 30 yr with the rate of new implants per 100,000 women (> or = 15 years of age) rising from 3.5 in 1964 to 95 in 1979, remaining stable thereafter. The prevalence of breast implants among Olmsted County women > or = 15 years of age on 1 January 1992 was approx. 1%. An examination of the characteristics of these women reveals that recent utilization of breast implants has increased more rapidly among rural than among urban women, that the proportion of women receiving implants for breast cancer mastectomy reconstruction has increased in recent years, and that the great majority of women receiving implants are married at the time of implant. These trends also revealed that the average age of women who receive implants is rising and that in more recent years both much younger and much older women are receiving implants.

A population-based case-control study of temporal arteritis: evidence for an association between temporal arteritis and degenerative vascular disease?

The first population-based incident case-control study of temporal arteritis (TA) in the US was conducted using the unique data resources of the Rochester Epidemiology Project. During the period 1950-1985, 88 newly diagnosed cases of biopsy-proven TA were identified among residents of Olmsted County, Minnesota. Cases were each matched to four Olmsted County community controls on age, sex and duration of community medical record. Odds ratios (OR) were calculated for marital status, education, Quetelet index, pregnancy, age at menopause, thyroid disease, diabetes, smoking, hypertension, angina, myocardial infarction, peripheral vascular disease, and stroke. Multivariable conditional logistic regression analysis identified statistically significant adjusted OR for smoking (2.3, 95% CI = 1.3-4.1). Elevated ORs which were not statistically significant were noted for angina, myocardial infarction, and peripheral vascular disease. These data suggest that TA and arteriosclerosis may share a common causal pathway. Alternatively, histopathological misclassification of temporal artery biopsies may have resulted in the observed association. Due to the limited power of this population-based study, multicentre collaboration should be encouraged to more precisely define the epidemiology of TA.

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.

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.