Hodgkin's lymphoma in systemic lupus erythematosus.

OBJECTIVE: In systemic lupus erythematosus (SLE), there is a well-documented increased risk of non-Hodgkin's lymphoma (NHL), but little is known about the risk of Hodgkin's lymphoma (HL). The purpose of our work was to describe the phenomenon of HL in SLE. METHODS: A multi-site cohort of 9547 SLE subjects was assembled; HL cases were ascertained through cancer registry linkage, and the standardized incidence ratio (SIR) for HL was determined. We also performed a literature search for HL cases in SLE, and compared these with our sample. Finally, we pooled results from our cohort study with two large population-based cohort studies providing SIR estimates for HL in SLE. RESULTS: Five cases of HL occurred in our SLE cohort during the observation interval, for an SIR of 2.4 (95% CI 0.8, 5.5). The literature review documented 13 HL case reports developing in patients with SLE. A pooled analysis combining our data with the other large cohort studies yielded a standardized incidence ratio of 3.16 (95% CI, 1.63-5.51) for HL in SLE. CONCLUSIONS: Data suggest that risk in SLE is increased not only for NHL, but also for other malignancies arising from B-lymphocytes, including HL.

Integrating public health applications with commercial EMRs.

At HIMSS 2007, we demonstrated how three processes of public health agencies could be facilitated through use of a prototype health information exchange, satisfying the AHIC biosurveillance use case.

Mortality in systemic lupus erythematosus.

OBJECTIVE: To examine mortality rates in the largest systemic lupus erythematosus (SLE) cohort ever assembled. METHODS: Our sample was a multisite international SLE cohort (23 centers, 9,547 patients). Deaths were ascertained by vital statistics registry linkage. Standardized mortality ratio (SMR; ratio of deaths observed to deaths expected) estimates were calculated for all deaths and by cause. The effects of sex, age, SLE duration, race, and calendar-year periods were determined. RESULTS: The overall SMR was 2.4 (95% confidence interval 2.3-2.5). Particularly high mortality was seen for circulatory disease, infections, renal disease, non-Hodgkin's lymphoma, and lung cancer. The highest SMR estimates were seen in patient groups characterized by female sex, younger age, SLE duration <1 year, or black/African American race. There was a dramatic decrease in total SMR estimates across calendar-year periods, which was demonstrable for specific causes including death due to infections and death due to renal disorders. However, the SMR due to circulatory diseases tended to increase slightly from the 1970s to the year 2001. CONCLUSION: Our data from a very large multicenter international cohort emphasize what has been demonstrated previously in smaller samples. These results highlight the increased mortality rate in SLE patients compared with the general population, and they suggest particular risk associated with female sex, younger age, shorter SLE duration, and black/African American race. The risk for certain types of deaths, primarily related to lupus activity (such as renal disease), has decreased over time, while the risk for deaths due to circulatory disease does not appear to have diminished.

Mortality related to cerebrovascular disease in systemic lupus erythematosus.

The objective of this study was to examine mortality rates related to cerebrovascular disease in systemic lupus erythematosus (SLE) compared to the general population. Our sample was a multisite Canadian SLE cohort (10 centres, n = 2688 patients). Deaths due to cerebrovascular disease were ascertained by vital statistics registry linkage using ICD diagnostic codes. Standardized mortality ratio (SMR, ratio of deaths observed to expected) estimates were calculated. The total SMR for death due to cerebrovascular disease was 2.0 (95% confidence interval [CI] 1.0, 3.7). When considering specific types of events, the category with the greatest increased risk was that of ill-defined cerebrovascular events (SMR 44.9 95% CI 9.3, 131.3) and other cerebrovascular disease (SMR 8.4, 95% CI 2.3, 21.6). Deaths due to cerebral infarctions appeared to be less common than hemorrhages and other types of cerebrovascular events. Our data suggest an increase in mortality related to cerebrovascular disease in SLE patients compared to the general population. The large increase in ill-defined cerebrovascular events may represent cases of cerebral vasculitis or other rare forms of nervous system disease; alternately, it may reflect diagnostic uncertainty regarding the etiology of some clinical presentations in SLE patients. The suggestion that more deaths are attributed to cerebral hemorrhage, as opposed to infarction, indicates that inherent or iatrogenic factors (eg, thrombocytopenia or anticoagulation) may be important. In view of the paucity of large-scale studies of mortality attributed to neuropsychiatric outcomes in SLE, our findings highlight the need for additional research in large SLE cohorts.

Non-Hodgkin's lymphoma in systemic lupus erythematosus.

BACKGROUND: Recent evidence supports an association between systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL). OBJECTIVES: To describe demographic factors, subtypes, and survival of patients with SLE who develop NHL. METHODS: A multi-site cohort of 9547 subjects with definite SLE was assembled. Subjects at each centre were linked to regional tumour registries to determine cancer cases occurring after SLE diagnosis. For the NHL cases ascertained, descriptive statistics were calculated, and NHL subtype frequency and median survival time of patients determined. RESULTS: 42 cases of NHL occurred in the patients with SLE during the 76,948 patient-years of observation. The median age of patients at NHL diagnosis was 57 years. Thirty six (86%) of the 42 patients developing NHL were women, reflecting the female predominance of the cohort. In the patients, aggressive histological subtypes appeared to predominate, with the most commonly identified NHL subtype being diffuse large B cell (11 out of 21 cases for which histological subtype was available). Twenty two of the patients had died a median of 1.2 years after lymphoma diagnosis. CONCLUSIONS: These data suggest aggressive disease in patients with SLE who develop NHL. Continuing work should provide further insight into the patterns of presentation, prognosis, and aetiology of NHL in SLE.

An international cohort study of cancer in systemic lupus erythematosus.

OBJECTIVE: There is increasing evidence in support of an association between systemic lupus erythematosus (SLE) and malignancy, but in earlier studies the association could not be quantified precisely. The present study was undertaken to ascertain the incidence of cancer in SLE patients, compared with that in the general population. METHODS: We assembled a multisite (23 centers) international cohort of patients diagnosed as having SLE. Patients at each center were linked to regional tumor registries to determine cancer occurrence. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. Cancers expected were determined by multiplying person-years in the cohort by the geographically matched age, sex, and calendar year-specific cancer rates, and summing over all person-years. RESULTS: The 9,547 patients from 23 centers were observed for a total of 76,948 patient-years, with an average followup of 8 years. Within the observation interval, 431 cancers occurred. The data confirmed an increased risk of cancer among patients with SLE. For all cancers combined, the SIR estimate was 1.15 (95% confidence interval [95% CI] 1.05-1.27), for all hematologic malignancies, it was 2.75 (95% CI 2.13-3.49), and for non-Hodgkin's lymphoma, it was 3.64 (95% CI 2.63-4.93). The data also suggested an increased risk of lung cancer (SIR 1.37; 95% CI 1.05-1.76), and hepatobiliary cancer (SIR 2.60; 95% CI 1.25, 4.78). CONCLUSION: These results support the notion of an association between SLE and cancer and more precisely define the risk of non-Hodgkin's lymphoma in SLE. It is not yet known whether this association is mediated by genetic factors or exogenous exposures.

Feasibility of data exchange with a Patient-centered Health Record.

A patient-centered health record is a personal health record that is patient-owned, patient-managed, and that represents the health information important to patients in the ways they prefer to represent it. The Patient-centered Health Record (PcHR) was developed to address these needs. Integration with traditional electronic health records adds significant value, and we used a national showcase to demonstrate the feasibility of exchanging health information through document level interoperability with commercial enterprise clinical systems.

Radiographic damage in rheumatoid arthritis correlates with functional disability but not direct medical costs.

OBJECTIVE: Few longitudinal data exist on the relationship between radiographic damage and self-reported functional disability and direct medical costs in rheumatoid arthritis (RA). We assessed these relationships. METHODS: One hundred thirty patients with RA (at time of the first available radiograph, mean age 56.6 yrs, 16.9% male, mean disease duration 16.8 yrs) were followed for up to 13.4 years. Semiannually, they reported on functional disability (0 = no difficulty, 3 = unable to do), global severity (0 = very well, 100 = very poor), pain (0 = no pain, 3 = severe pain), and health services utilization through completion of the Stanford Health Assessment Questionnaire (HAQ). Concurrent hand radiographs were scored for erosions and joint space narrowing using the Genant method and a single score summing both erosions and joint space narrowing for both hands was calculated (0 = no damage, 200 = maximum damage). The univariate association of functional disability, global severity, pain, or direct medical costs with concurrent radiographic damage was assessed through Spearman correlations and hierarchical regression models. The hierarchical models permit exploitation of the between-patient and within-patient variation present in our longitudinal data. RESULTS: At the time of the first available radiograph, mean (SD) levels of functional disability, global severity, and pain were 1.3 (0.7), 39.4 (21.0), and 1.1 (0.7), respectively. At entry into the study, the average radiograph score was 49.7 and upon leaving the study it was 66.9. Patients were followed an average of 6.7 years, with radiograph scores increasing at an average rate of 2.5 units/yr. The Spearman correlation [95% confidence interval (CI)] between average per-patient radiograph score and average per-patient HAQ disability index, average per-patient global severity, average per-patient pain score, and average per-patient direct medical costs was, respectively, 0.42 (0.26, 0.55), 0.23 (0.06, 0.39), 0.20 (0.03, 0.36), and 0.06 (-0.11, 0.23). The mean slope (95% CI) for disability on radiograph score was 0.0186 (0.0132, 0.0226), for severity on radiographs 0.1889 (0.1295, 0.2498), and for pain on radiographs 0.0057 (0.0027, 0.0084). As an example, over 10 years, a 25 unit (i.e., 50%) increase in radiograph scores would, on average, be associated with a 0.46 unit (i.e., 35%) increase in disability, a 4.72 unit (12%) increase in global severity score, and a 0.14 unit (13%) increase in pain, all expressed on the HAQ scales. There was little association between radiograph score and direct medical costs. CONCLUSION: A clinically meaningful association exists between radiographic damage and self-reported functional disability, suggesting that interventions that slow radiographic progression may improve the patient's health status. Such a relationship was not observed between radiographic damage and direct medical costs.

Systemic lupus erythematosus and the risk of malignancy.

The objective of this study was to determine the relative risks of malignancy and of site-specific malignancies in patients with systemic lupus erythematosus (SLE). A cohort of 297 patients (91% Caucasian) with SLE were seen between 1975 and 1994 and followed for a mean of 12 years at the University of Saskatchewan Rheumatic Disease Unit. Expected cancer incidence rates were determined based on Province of Saskatchewan population statistics matched to each study patient for age, sex and calendar year of follow-up. Standardized incidence ratios (SIRs) of observed to expected cancers and 95% confidence intervals (95% CI) were calculated. A total of 27 cases of cancer were observed, whereas only 16.9 were expected (SIR 1.59 (95% CI 1.05-2.32)). For site-specific malignancies, an excess of cancer of the cervix (SIR 8.15 (95% CI 1.63-23.81)) as well as hemopoietic malignancy (SIR 4.9 (95% CI 1.57-11.43)) was found. The hemopoietic cancers were predominantly non-Hodgkin's lymphoma (SIR 7.01 (95% CI 1.88-17.96)). We did not find an association of malignancy with known risk factors, including use of cytotoxic agents. Increased risk of malignancy, notably non-Hodgkin's lymphoma and perhaps cervical cancer, should be regarded as a complication of SLE.

A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma.

OBJECTIVE: Early diffuse scleroderma (systemic sclerosis; SSc) has no proven treatment. This study was undertaken to examine the efficacy of methotrexate (MTX) in improving the skin and other disease parameters in early diffuse SSc. METHODS: Seventy-one patients with diffuse SSc of <3 years' duration were enrolled in a multicenter, randomized, placebo-controlled, double-blind trial. Thirty-five patients were treated with MTX and 36 with placebo. Treatment was administered for 12 months. The primary outcome measures were skin score (as determined with 2 different indices) and physician global assessment. RESULTS: At baseline, there were no statistically significant differences in skin scores, carbon monoxide diffusing capacity (DLco), physician global assessment, or other secondary outcome measurements between the 2 treatment groups. At study completion, results slightly favored the MTX group (mean +/- SEM modified Rodnan skin score 21.4+/-2.8 in the MTX group versus 26.3+/-2.1 in the placebo group [P < 0.17]; UCLA skin score 8.8+/-1.2 in the MTX group versus 11.0+/-0.9 in the placebo group [P < 0.15]; DLco in the MTX group 75.7+/-4.6 versus 61.8+/-3.4 in the placebo group [P < 0.2]). In addition, physician global assessment results favored MTX (P < 0.035), whereas patient global assessment did not differ significantly between groups. When between-group differences for changes in scores from baseline to 12 months were examined using intent-to-treat methodology, MTX appeared to have a favorable effect on skin scores (modified Rodnan score -4.3 in the MTX group versus 1.8 in the placebo group [P < 0.009]; UCLA score -1.2 in the MTX group versus 1.2 in the placebo group [P < 0.02]), but differences in the degree of change in the DLco and physician global assessment were not significant. For the UCLA skin score, these differences in results were not statistically significant after adjustment for baseline differences in sex distribution and steroid use. Dropout rates were similar in the 2 groups. CONCLUSION: Although results of this trial demonstrated a trend in favor of MTX versus placebo in the treatment of early diffuse SSc, the between-group differences were small and the power to rule out false-negative results was only 50%. Our findings do not provide evidence that MTX is significantly effective in the treatment of early diffuse SSc.

Management of corticosteroid-induced osteoporosis.

OBJECTIVES: To educate scientists and health care providers about the effects of corticosteroids on bone, and advise clinicians of the appropriate treatments for patients receiving corticosteroids. METHODS: This review summarizes the pathophysiology of corticosteroid-induced osteoporosis, describes the assessment methods used to evaluate this condition, examines the results of clinical trials of drugs, and explores a practical approach to the management of corticosteroid-induced osteoporosis based on data collected from published articles. RESULTS: Despite our lack of understanding about the biological mechanisms leading to corticosteroid-induced bone loss, effective therapy has been developed. Bisphosphonate therapy is beneficial in both the prevention and treatment of corticosteroid-induced osteoporosis. The data for the bisphosphonates are more compelling than for any other agent. For patients who have been treated but continue to lose bone, hormone replacement therapy, calcitonin, fluoride, or anabolic hormones should be considered. Calcium should be used only as an adjunctive therapy in the treatment or prevention of corticosteroid-induced bone loss and should be administered in combination with other agents. CONCLUSIONS: Bisphosphonates have shown significant treatment benefit and are the agents of choice for both the treatment and prevention of corticosteroid-induced osteoporosis.

Predicting the short term direct medical costs incurred by patients with rheumatoid arthritis.

OBJECTIVE: With increasing interest in revising the mechanisms of health care funding, the ability to anticipate patients' medical expenditures as well as to identify potentially modifiable predictors would be informative for health care providers, payers, and policy makers. METHODS: Eight hundred fifty-eight patients with rheumatoid arthritis from 2 Canadian centers reported semi-annually on their health services utilization and health status for up to 12 years. Annual direct costs were calculated using 1994 Canadian prices. Regression models for the variation in total direct costs and the individual resource components (i.e., physicians, tests, medications, acute and non-acute hospital care) were estimated using previous values of age, sex, disease duration, education, methotrexate availability, employment status, global well being, pain, duration of morning stiffness, and functional disability as predictor variables. The models were developed using all available data except the last 2 observations (i.e., data collected on the last 2 self-report questionnaires) from each patient, which were reserved for model validation. The predictive abilities of the models were assessed by comparing the most recent costs with those predicted by the model using values of the predictor variables from the previous time period. Further, to assess whether the models conferred any advantage over cost estimates based only on previous costs, most recent observed costs were also compared with costs observed in the preceding time period. RESULTS: Self-reported indices of either global well being, pain, or functional disability predicted total direct costs as well as the costs of the 5 individual resource components. Being younger, female, disabled from the work force, having shorter disease duration, and receiving more formal education also predicted higher costs in at least on health resource category. However, being older predicted higher acute and non-acute care hospital costs. Regression models incorporating longitudinal data did not perform better than average costs in the preceding time period in predicting future short term costs. CONCLUSION: Global well being, pain, functional disability, and previous costs are the most important predictors of short term direct medical costs. Although we have demonstrated that regression models do not perform better than previous costs in predicting future short term costs, previous costs are a much less informative predictor than health status variables. Variables such as functional disability and pain identify potentially modifiable disease features and suggest interventions that may improve patient well being and reduce costs.

A case of peripartum eosinophilic myocarditis.

A 19-year-old postpartum patient with a previous history of asthma and eosinophilic myocarditis is described. Eosinophilic myocarditis is thought to be caused by exacerbation of the idiopathic hypereosinophilic syndrome by pregnancy. The diagnosis was made by a right ventricular endomyocardial biopsy, which showed an eosinophilic infiltrate with a few scattered foci of myonecrosis, but no fibrosis, vasculitis or granulomas. The patient's myocardial function continued to decline over a two-year follow-up period, despite normal levels of eosinophils. She developed echocardiographic evidence of diastolic and systolic dysfunction.

Rheumatoid arthritis and the risk of malignancy.

OBJECTIVE: To determine the relative risks of malignancy and of site-specific malignancies in patients with rheumatoid arthritis (RA). METHODS: In a prospective cohort study, 862 patients with RA (96% white) were enrolled from 1966 to 1974 and were followed up for up to 35 years (mean 17.4 years) at the University of Saskatchewan Rheumatic Disease Unit. All diagnoses of cancer were cross-referenced with the Provincial Cancer Registry. Expected cancer incidence rates were determined based on province of Saskatchewan population statistics matched to each study patient for age, sex, and calendar year. Standardized incidence ratios (SIRs) of the observed-to-expected cancer incidence and 95% confidence intervals (95% CI) were then calculated. RESULTS: A total of 136 cases of cancer were observed compared with 168 expected (SIR 0.80, P = 0.011 [95% CI 0.67-0.95]). The relative risk of colorectal malignancy was significantly reduced in the RA study population (SIR 0.52, P = 0.037 [95% CI 0.25-0.96]). A significant excess of leukemia was found (SIR 2.47, P = 0.026 [95% CI 1.12-4.69]), whereas the incidence rates for Hodgkin's disease and non-Hodgkin's lymphoma and all other site-specific malignancies were not found to be significantly different from general population rates. CONCLUSION: In our cohort of RA patients, colorectal cancer was detected in only half the expected number of patients. This risk reduction may be related to long-term nonsteroidal antiinflammatory drug (NSAID) use in RA, as has been suggested in several other studies of long-term NSAID use. An increased risk of leukemia was confirmed. This may be due to the persistent immune stimulation associated with RA itself, since other potential explanatory factors for increased leukemia were not apparent. Despite the excess of hemopoietic malignancy and despite treatment of RA with potentially oncogenic agents, the overall risk of malignancy was reduced in this RA cohort.

The influence of systemic lupus erythematosus on fetal development: cognitive, behavioral, and health trends.

In 1985, Gualtieri and Hicks proposed the immunoreactive theory to explain the higher prevalence of childhood neurodevelopmental disorders in males. The theory claimed that male fetuses are more antigenic to mothers, resulting in increased immunologic attack on the developing central nervous system, and increased probability of atypical brain development. Individuals with systemic lupus erythematosus (SLE) provide a unique situation in which to investigate this theory. We evaluated the parent-reported prevalence of five developmental problems (stuttering, other speech problems, hyperactivity, attention deficit, and reading problems) in two groups: 154 individuals ages 8-20 years born to women with SLE, drawn from six cities, and 154 controls of comparable age and sex whose mothers did not have SLE. Controls were drawn from a comparison group ascertained from randomly selected schools in one of the cities. Questions about handedness, immune disorders, and pregnancy and birth complications were also evaluated. Children of SLE mothers were shown to have more evidence of developmental difficulties, immune related disorders, and nonrighthandedness. For developmental problems, these findings were most marked in male children of SLE mothers. These results suggest that maternal immunoreactivity, as represented by women with SLE, may present a special risk factor for subsequent learning difficulties in their children, particularly males.

Direct and indirect medical costs incurred by Canadian patients with rheumatoid arthritis: a 12 year study.

OBJECTIVE: To perform the first prospective longitudinal study of direct (health services utilized) and indirect costs (diminished productivity represented by income loss) incurred by patients with rheumatoid arthritis (RA) in Saskatoon and Montreal, followed for up to 12 and 4 years, respectively. METHODS: 1063 patients reported on health status, health services utilization, and diminished productivity every 6 months. RESULTS: Annual direct costs were $3788 (1994 Canadian dollars) in the late 1980s and $4656 in the early 1990s. Given that the average age exceeded 60 years, few participated in labor force activities or considered themselves disabled from the labor force and their indirect costs were substantially less, $2165 in the late 1980s and $1597 in the early 1990s. Institutional stays and medications made up at least 80% of total direct costs. Lengths of stay in acute care facilities remained constant, but the rate of hospitalization increased in the early 1990s, increasing average hospital costs per patient from $1563 in the late 1980s to $2023 in the early 1990s. For nonacute care facilities, rate of admission as well as length of stay increased over time, increasing costs per patient in Saskatoon 5-fold, from $291 to $1605. Those with greater functional disability incurred substantially higher direct and those under 65 years incurred higher indirect costs. CONCLUSION: Direct costs are higher than indirect costs. The major component is due to institutional stays that, in contrast to other direct cost components, is increased in the older and more disabled. Measures to reduce longterm disability by earlier, more aggressive intervention have the potential to produce considerable cost savings. However, it is unknown which strategies will have the greatest effect on outcome and accordingly, how resources can be optimally allocated.

Apophysial joint degeneration, disc degeneration, and sagittal curve of the cervical spine. Can they be measured reliably on radiographs?

STUDY DESIGN: Interexaminer reliability study. OBJECTIVES: To determine the reliability of grading apophysial joint and disc degenerative changes and the reliability of measuring sagittal curves on lateral cervical spine radiographs. SUMMARY OF BACKGROUND DATA: Several authors have proposed that the presented of degenerative changes and the absence of lordosis in the cervical spine are indicators of poor recovery from neck injuries caused by motor vehicle collisions. The validity of those conclusions is questionable because the reliability of the methods used in their studies to measure the presence of degenerative changes and the absence of lordosis has not been determined. METHODS: Kellgren's classification system for apophysial joint and disc degeneration, as well as the pattern and magnitude of the sagittal curve on 30 lateral cervical spine radiographs were assessed independently by three examiners. RESULTS: Moderate reliability was demonstrated for classifying apophysial joint degeneration with an intraclass correlation coefficient of 0.45 (95% confidence interval, 0.09-0.71). Classifying degenerative disc disease had substantial reliability, with an intraclass correlation coefficient of 0.71 (95% confidence interval, 0.23-0.88). Measuring the magnitude of the sagittal curve from C2 to C7 had excellent interexaminer agreement, with an intraclass correlation coefficient of 0.96 (95% confidence interval, 0.88-0.98) and an interexaminer error of 8.3 degrees. CONCLUSIONS: The classification system for degenerative disc disease proposed by Kellgren et al and the method of measurement of sagittal curves from C2 to C7 demonstrated an acceptable level of reliability and can be used in outcomes research.