Validity of a vasculitis activity index for systemic necrotizing vasculitis.

OBJECTIVE: To establish the validity of an index designed to measure activity in systemic necrotizing vasculitis (SNV). METHODS: The Vasculitis Activity Index (VAI) was designed to incorporate appropriately weighted clinical measurements that reflect disease activity in SNV. We performed a pilot study to guide the modification and subsequent testing of the initial design. The data necessary to calculate the VAI are direct ratings by a clinical observer of the degree of activity in 9 organ systems and 3 indirect measures of vasculitis activity. These data are recorded on 0-4 visual analog scales. Physician's global assessment (PGA) is used as the "gold standard" measurement of disease activity. The VAI was validated using 2 independent data sets: the questionnaire data set, derived from test case histories ("paper cases") sent to 100 practicing rheumatologists, and the clinic data set, obtained from use of the VAI in 204 regular care visits of 74 patients with SNV. RESULTS: The VAI correlated highly with the PGA: Pearson's correlation coefficient R = 0.84 (95% confidence interval [95% CI] 0.80-0.88) for the questionnaire data set, and R = 0.92 (95% CI 0.90-0.94) for the clinic data set. The mean of the interobserver coefficients of variation for the test case histories was lower for the VAI than for the PGA (mean difference 0.45; P = 0.002), indicating that the VAI has less interobserver variation than does the PGA. The change in VAI between clinic visits for individual patients correlated highly with the change in PGA (R = 0.88, 95% CI = 0.83-0.91). The VAI data collection form requires about 1 minute to complete, including computation of the score. CONCLUSION: The VAI is a valid measure of vasculitis activity that correlates highly with the PGA. In addition, the VAI has less interobserver variation than the PGA and has a high level of sensitivity to change over time. Additional testing of the VAI appears warranted.

Dyspnea in ambulatory patients with SLE: prevalence, severity, and correlation with incremental exercise testing.

OBJECTIVE: We sought to determine the prevalence and severity of dyspnea, and to correlate dyspnea with clinical features and exercise limitation in ambulatory patients with systemic lupus erythematosus (SLE). METHODS: Twenty-five consecutive patients were evaluated with a validated pulmonary questionnaire, chest radiograph, 2-dimensional echocardiography, resting pulmonary function tests, and incremental exercise testing. RESULTS: Dyspnea was reported by 60% (95% CI 39-79) of patients; 20% (95% CI 7-40) had severe dyspnea (inability to dress without dyspnea) and 12% (95% CI 3-31) had moderate dyspnea (dyspnea after walking 100 yards). Compared to patients without dyspnea, patients with dyspnea were more likely to have had a history of clinical lupus involving the lung (80 vs 40%, p = 0.05), a lower total lung capacity (77.5 vs 94.8%, p = 0.002), and a reduced maximum oxygen consumption (VO2max of 53.4 vs 67.7%, p = 0.01). Patients with severe dyspnea and patients without dyspnea did not differ in duration of prednisone use, activity of disease, weight, or in frequency of Raynaud's phenomenon (p > 0.05). Only 4% of all patients had abnormal left ventricular motion on 2-dimensional echo; patients with moderate or severe dyspnea had normal left ventricular motion. Of the 5 patients with severe dyspnea, 4 (80%) had restrictive lung disease and 1 (20%) had an isolated diffusion defect. All patients with dyspnea had an abnormal exercise test, but so did 9/10 without dyspnea (p > 0.05). Severity of dyspnea correlated highly with maximum exercise tolerance measured by VO2max (R2 = 0.51, p = 0.0001). CONCLUSION: In ambulatory patients with SLE, dyspnea is common, frequently disabling, associated with a history of lupus involvement of the lung, and correlates highly with objective measures of exercise limitation.

Methotrexate and histologic hepatic abnormalities: a meta-analysis.

STUDY OBJECTIVE: To determine the risk of liver toxicity from the long-term administration of methotrexate in patients with rheumatoid arthritis or psoriatic arthritis. DESIGN: A meta-analysis of 15 studies examining the relationship between long-term, low-dose methotrexate administration and biopsy evidence of liver fibrosis. PATIENTS: A total of 636 patients from 15 studies. RESULTS: The incidence of progression of liver disease (defined as worsening of at least one grade on the histologic classification of Roenigk) among 636 patients was 27.9% (95% confidence intervals 24.3 to 31.6). The rate of progression of liver disease in the 15 studies was associated with the cumulative dose of methotrexate (p = 0.01). Patients on average had a 6.7% (95% confidence intervals 2.1 to 11.4) chance of progressing at least one histologic grade on liver biopsy for each gram of methotrexate taken. The overall incidence of advanced pathologic changes on liver biopsy (grades IIIB or IV) among 636 patients was 5.0% (95% confidence intervals 3.5 to 7.0). The development of advanced histologic changes was not associated with the cumulative dose of methotrexate (p = 0.08). Patients who according to their history were heavy drinkers (at least 100 g of alcohol per week) were more likely to have advanced changes on liver biopsy (17.8% versus 4.5%, p = 0.0003) and to show histologic progression (73.3% versus 25.9%, p = 0.0002). Patients with psoriasis were more likely than patients with rheumatoid arthritis to have advanced changes (7.7% versus 2.7%, p = 0.003) and histologic progression (33.1% versus 24.3%, p = 0.02). CONCLUSIONS: The risk of liver toxicity in patients undergoing long-term, low-dose methotrexate therapy is substantial, and that risk increases with the total cumulative dose and with heavy consumption of alcohol. Heavy users of alcohol should not receive long-term methotrexate therapy. For most patients who are not heavy users of alcohol, liver biopsies should be done periodically to monitor for the occurrence of liver toxicity.

Oral cimetidine improves the accuracy and precision of creatinine clearance in lupus nephritis.

OBJECTIVE: To determine whether short-term use of oral cimetidine improves the precision of creatinine clearance (CCr) and reduces the overestimation of glomerular filtration rate (GFR) that occurs with this test in patients with lupus nephritis (because creatinine is secreted by injured renal tubular cells). DESIGN: Double-blind, placebo-controlled, crossover clinical trial. PATIENTS: Thirteen patients with lupus nephritis with mild renal insufficiency (mean serum creatinine, 230 mumol/L [2.6 mg/dL]; median, 106 mumol/L [1.2 mg/dL]). INTERVENTIONS: Patients were given placebo or cimetidine tablets, 400 mg four times daily for 2 days, with ambulatory 24-hour urine collection during the second 24 hours ("outpatient study"). Simultaneous 4-hour technetium-99-diethylenetriamine penta-acetic acid (Tc99-DTPA) and CCrs were measured immediately after each 24-hour collection ("simultaneous study"). MEASUREMENTS AND MAIN RESULTS: Use of cimetidine improved the accuracy of CCr, as measured by the CDTPA-to-CCr ratio (1.07 [cimetidine] compared with 1.33 [placebo]; P less than 0.05). Cimetidine use also improved the precision of CCr (P less than 0.05). In addition, when compared with standard clinical estimators of GFR, creatinine clearance with cimetidine rendered the most precise estimates of GFR and explained more of the variation in GFR estimation than did any other method (R2 = 0.78 compared with R2 = 0.52 to 0.63). These effects were shown under both simultaneous and outpatient conditions. No side effects due to cimetidine occurred. CONCLUSIONS: In patients with lupus nephritis, the cimetidine-aided CCr offers a compromise between the precise and accurate but expensive and inconvenient research techniques (inulin, iothalamate, or DTPA clearances) and the grossly inaccurate and imprecise but convenient technique (CCr) for determining GFR.

Serial assessment of glomerular filtration rate in lupus nephropathy.

In patients with lupus nephropathy (LN), previous studies have shown that creatinine clearance (CCr) overestimates true glomerular filtration rate as measured by inulin clearance (CIn), and that among patients the degree of overestimation is highly variable. We sought to determine whether the discrepancy between CCr and CIn remains constant over time (months, years) in each individual patient, and therefore whether serial measurements of CCr reliably reflect the direction and magnitude of change in CIn. Twenty-five patients with LN underwent simultaneous determinations of CCr and CIn performed two to four (mean 3.3) times over three years. In a given patient, it was found that the ratio of CCr/CIn changed substantially over time (mean SD 0.16 with 95% confidence interval of 0.12 to 0.20). Thus, in about 32% of cases the ratio of CCr/CIn will vary more than +/- 16% from a previously measured value of CCr/CIn. Patients with both high and low values of CIn showed similar variability in CCR/CIn over time. Variability in CCr/CIn was found regardless of whether CIn was increasing, decreasing, or constant over time. In nearly one-half of all measurements of CCr, the corresponding change in CIn was directionally discordant. Iothalamate and technetium-DTPA renal clearances correlated highly with CIn (R2 = 0.99). We conclude that the discrepancy between CCr and CIn can vary greatly over time in an individual patient. Consequently, serial CCr does not accurately measure the direction or magnitude of change in glomerular filtration rate in lupus nephropathy.

Mononeuritis multiplex: the yield of evaluations for occult rheumatic diseases.

We identified 35 patients who had electrodiagnostic evidence of mononeuritis multiplex and did not have diabetes or multiple nerve compressions. Their charts were reviewed to determine the etiologies of the mononeuritis multiplex and to determine how often the laboratory examination revealed a rheumatic disease in patients whose initial history and physical examination did not suggest that a rheumatic disease was present. In 11/35 (31%; CI = 17-49) a disorder capable of causing mononeuritis multiplex was diagnosed before the symptoms of mononeuritis multiplex began. Ten had a rheumatic disease; 1 had lymphoma. Nine of the other patients were suspected, on the basis of the history and physical examination, of having new onset of a rheumatic disease. Subsequent laboratory evaluation showed that 5/9 (56%; CI = 21-86) had a rheumatic disease, and 4/9 (44%; CI = 14-79) were unknowns. In 15/35 (43%; CI = 26-61) patients with mononeuritis multiplex, no rheumatic disease was suspected on the basis of the initial history and physical examination. The subsequent laboratory examination revealed an underlying rheumatic disease in 0/15 (0%; CI = 0-18). Mean clinical follow-up of 16 +/- 16 months in the patients with mononeuritis multiplex of unknown cause also failed to identify a rheumatic disease. Overall 19/35 (54%; CI = 37-71) did not have a rheumatic disease or any other known cause. Of the 14 patients with mononeuritis multiplex associated with a rheumatic disease, 5/14 (36%; CI = 13-15) had systemic lupus erythematosus; an additional patient had both lupus and the CREST syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal infections in systemic lupus erythematosus: the role of opportunistic organisms.

The causes of death were examined in patients with systemic lupus erythematosus (SLE) who were cared for at the University of California, San Francisco and who died after 1969. Of the 44 deaths analyzed, 33 patients had autopsies. Infections were common and often determined to be the cause of death. Overall, infections were present in 55 percent (22/44), and judged to be a cause of death in 30 percent (13/44) of all deaths. The infections could be divided into 2 groups: those due to common bacterial organisms and those due to opportunistic infections. These two types of infections occurred with similar frequency. When compared to common bacterial infections, however, the opportunistic infections were more likely to be first diagnosed at autopsy (p = .001). In only 3 of the 15 patients with an opportunistic infection was the diagnosis made antemortem. Failure to diagnose an opportunistic infection early occurred when the infection simulated active SLE, and when the possibility of an opportunistic infection was not aggressively investigated. The most common opportunistic infections were Candida albicans and Pneumocystis carinii. The most common site of opportunistic infection was the lung. Seventeen patients had 27 common bacterial infections, chiefly sepsis from Staphylococcus aureus and aerobic gram-negative organisms. Eight patients had both a common bacterial and an opportunistic infection. Stepwise linear regression analysis showed that death from infection correlated most strongly with prednisone and cytotoxic drug use in the 3 months before final admission. No measure of lupus activity was found to correlate with death from infection, except that hypocomplementemia correlated with death from bacterial infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized, double-blind, placebo-controlled study of the treatment of the painful shoulder.

The effect of triamcinolone subacromial bursa injection versus naproxen therapy was compared in a randomized, double-blind, placebo-controlled study of 100 patients who had painful shoulders. Outcome was compared using degree of active abduction, pain, limitation of function, and a clinical index that combined equally weighted measures of all of these. In a time-adjusted analysis, triamcinolone was superior to placebo in all clinical variables. Naproxen was superior to placebo in all variables except pain. Triamcinolone was superior to naproxen in the relief of pain (P = 0.04) and the clinical index (P = 0.04). Multiple linear regression analysis showed that naproxen and triamcinolone treatment accounted for only 16% of the variation in outcome, compared with 44% accounted for by the clinical index prior to treatment. Thus, patients with a poor pretreatment clinical index (those with the most room for improvement) were least likely to improve. We conclude that both triamcinolone (P = 0.00005) and naproxen (P = 0.02) are superior to placebo in the treatment of the painful shoulder.

Antinuclear antibody, lupus anticoagulant, and anticardiolipin antibody in women with idiopathic habitual abortion. A controlled, prospective study of forty-four women.

In a controlled, prospective study of 44 consecutive women with idiopathic habitual abortion, only 5% had symptoms of rheumatic disease. Patients did not differ from control subjects in the frequency of positive results on tests for antinuclear antibody or anti-double-stranded DNA. Levels of C3 and C4 were higher in the habitual aborters. No patients had anti-Ro. The antiphospholipid antibody results were analyzed using 2 methods: the frequency of antiphospholipid antibodies was 9% by lupus anticoagulant using the Russell viper venom time (95% confidence interval 22-2.5) and 11% by anticardiolipin antibody assay (95% confidence interval 25-3.7), which was not significantly different from that in control subjects. However, the mean levels in the aborters (although within the normal range) were significantly higher than those in control subjects for anti-double-stranded DNA (P = 0.004), lupus anticoagulant (by Russell viper venom time; P = 0.05), and anticardiolipin antibody (P = 0.0007), when examined by multiple linear regression analysis corrected for age and concurrent pregnancy. Of the 3 patients with antiphospholipid antibodies and subsequent successful pregnancies, only 1 was treated with prednisone and aspirin. We conclude that, in the majority of women, subclinical lupus, anti-Ro, the lupus anticoagulant, and anticardiolipin antibodies are not associated with idiopathic habitual abortion.

The frequency of lupus anticoagulant in systemic lupus erythematosus. A study of sixty consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level.

Recent reviews have suggested a higher frequency of the lupus anticoagulant or related antiphospholipid antibodies in patients with systemic lupus erythematosus (21% to 65%) than was found in earlier studies (6% to 18%). In our study of 60 consecutive patients, we found the frequency of the lupus anticoagulant by Russell viper venom time was 6.7% (95% confidence interval, 16.2 to 1.8) and by anticardiolipin antibody assay was 25% (95% Cl, 37.0 to 15.7), compared with 0% (p = not significant) and 2.5% (p = 0.002), respectively, in the normal control population. The Russell viper venom time (p = 0.0001 by t-test) and anticardiolipin antibody levels (p = 0.01) were significantly associated with presumed thrombotic events (stroke, deep venous thrombosis, and digital gangrene). No association with miscarriage or pulmonary hypertension was detected. The Russell viper venom time was more specific than the anticardiolipin antibody level in the prediction of past presumed thrombotic events, miscarriage, or pulmonary hypertension (100% compared with 84%, p = 0.01).

Clinical response to regional intravenous guanethidine in patients with rheumatoid arthritis.

A novel therapy for rheumatoid arthritis, regional sympathetic blockade using guanethidine, was investigated in 24 patients with active disease. In a randomized double blind short-term (14 days) study, we evaluated the effect of therapy on subjective responses, change in pain, stiffness, and morning stiffness and no objective responses, change in pinch strength, grip strength, and joint tenderness. Compared to placebo, guanethidine produced a decrease in pain (p less than 0.025) and an increase in pinch strength (less than 0.025) over the 2-week duration of the study. The therapeutic effect of guanethidine may be mediated by an interruption of the proinflammatory effects of the sympathetic nervous system.

A computerized summary medical record system can provide more information than the standard medical record.

We assessed the ability of a computerized outpatient medical record (MR) system, the Summary Time-Oriented Record (STOR), to communicate information to clinicians in two randomized single-blind studies. In the first study, physicians were better able to predict their patients' future symptom changes and laboratory test results from outpatient visits to an arthritis clinic when STOR was added to the standard MR than when the standard MR was used alone. In a separate study, the removal of the standard MR did not result in important decrease in the physicians' ability to predict their patients' symptoms and laboratory test results if they had the option of using the full paper record when they thought they needed it. In 134 (26%) of 514 visits, the physicians exercised this option. We conclude that for outpatient visits, the computerized record system STOR operationally added information to that supplied by the full paper MR. This improved flow of information could improve the clinical decision process.

Choosing the correct unit of analysis in Medical Care experiments.

The statistical methodology of health research experiments published in Lancet, the New England Journal of Medicine, and Medical Care between 1975 and 1980 for the presence or absence of an error of experimental design and analysis was examined. The error is the result of inappropriately using patient-related observations as the unit of analysis to form conclusions about provider behavior or outcomes determined jointly by patients and providers. The error was present in 20 of 28 (71%) health care experiments addressing an issue of health provider professional performance. Its usual effect is to increase erroneously the power of an experiment to detect differences between experimental and control groups. It is likely that this type of error could be avoided by the explicit and prospective definition of hypotheses and the populations to which they are intended to pertain.

Local area networks and the hospital.

Hospital information systems are characterized by their complexity of individual functions, heterogeneity of functions, and dependence upon integration. A distributed computerized information system is well suited to meeting the needs of hospitals. A local area communications network (LACN) removes a major impediment to the use of distributed systems. An advanced microprocessor-based LACN using fiberoptic communications has been developed by the Applied Physics Laboratory of The Johns Hopkins University and has been implemented at the University of California, San Francisco Hospital.

A prototype generalized network technology for hospitals: initial implementation.

A demonstration implementation of a distributed data-processing hospital information system using an intelligent local area communications network (LACN) technology is described. This system is operational at the UCSF Medical Center and integrates four heterogeneous, stand-alone minicomputers. The applications systems are PID/Registration, Outpatient Pharmacy, Clinical Laboratory, and Radiology/Medical Records. Functional autonomy of these systems has been maintained, and no operating system changes have been required. The LACN uses a fiber-optic communications medium and provides extensive communications protocol support within the network, based on the ISO/OSI Model. The architecture is reconfigurable and expandable. This paper describes system architectural issues, the applications environment, and the local area network.

Recognition of information in renal biopsies of patients with lupus nephritis.

To evaluate the informational value of renal biopsy in nephritis of systemic lupus erythematosus, we selected the records of 30 patients who had a renal biopsy done and also had a known clinical outcome. Detailed case histories were prepared, and three distinct randomly chosen cases were given to 197 academic rheumatologists. The rheumatologists estimated the probability of future clinical events (worsened serum creatinine, worsened urine protein, renal death, and aggressive therapy) at 3 and 12 months after the biopsy. Biopsy results were given in detail, and probability estimates were made of the same clinical events using the additional information. The accuracy of each probability estimate was measured using a scoring function that depends on the estimates and the actual outcomes. Knowledge of the renal biopsy failed to improve predictive accuracy scores of estimates of future serum creatinine levels, urine protein levels, and renal death at 3 and 12 months (p less than 0.0001), and for estimates of the probability of the use of aggressive therapy at 12 months (p less than 0.007). The renal biopsy information improved only the accuracy of predictions concerning the use of aggressive therapy at 3 months (p less than or equal to 0.0003). Knowledge of the renal biopsy results failed to add important prognostic information about the future course of treated lupus nephritis to information already obtained from history, physical examination, and laboratory tests.