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Biomedical subjects

D E Furst

Publications and source records attributed to D E Furst.

At least 109 records · Page 6Linked to original sources
PubMed1994

Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events.

PURPOSE: The purpose of this study was to better define the toxicity of low dose (less than or equal to 15 mg/d prednisone or equivalent) long-term (greater than 1 year) corticosteroids in the treatment of rheumatoid arthritis (RA). PATIENTS AND METHODS: We examined an historical cohort of 112 RA patients on low dose (6.1 +/- 3.1 mg/d, mean +/- SD) long-term (6.2 +/- 4.6 years) prednisone (CS) and compared them to 112 matched RA patients not using prednisone (CO). CS were matched one-to-one with CO for sex (75% women), age (+/- 5 yrs), race (98% white), and duration of disease (+/- 5 yrs). Subjects were determined by review of unselected medical records from three distinct rheumatology practice settings. For CS, charts were abstracted from the date of prednisone start for predefined adverse events (AEs). RESULTS: Ninety-two (92) AEs were noted in CS versus 31 in CO and included: fracture (CS:21 versus CO:8), serious infections (CS:14 versus CO:4), gastrointestinal (GI) bleed or ulcer (CS:11 versus CO:4), and cataracts (CS:17 versus CO:5). At time of first AE, CS prednisone average dose was 7.0 +/- 2.6 mg with a duration of 4.9 +/- 3.9 years. Stepwise multiple logistic regression analysis was used to create a model which included all clinically relevant variables and all parameters significantly different at the cohort inception. Prednisone average dose of greater than 10 to less than or equal to 15 mg/d correlated most strongly with the development of an AE (Odds Ratio (OR) = 32.3, 95% Confidence Interval (CI) 4.6, 220). Average prednisone 5 to 10 mg (OR = 4.5, 95% CI 2.1, 9.6), RA nodules (OR = 3.9, 95% CI 1.9, 8.0), and bony erosions (OR = 2.4, 95% CI 1.2, 4.7) also entered the final model. Kaplan Meier survival curves for the development of the first AE showed a dose-response relationship between prednisone and AE occurrence, independent of rheumatoid nodules. Subset analyses utilized a nested case control design for the development of three serious AEs: fractures, serious infections, and GI events. These analyses revealed possible relationships between prednisone use and the development of each specific AE (prednisone use OR: fracture 3.9, 95% CI 0.8, 18.1; infection 8.0, 95% CI 1.0, 64.0; and GI event 3.3, 95% CI 0.9, 12.1). CONCLUSIONS: Although disease severity is an important confounding factor, low dose long-term prednisone use equal to or greater than 5 mg/d is correlated with the development of specific adverse events in a dose-dependent fashion.

Adult↗
PubMed1994

Should methotrexate be used to treat early rheumatoid arthritis?

A number of studies show the efficacy of methotrexate (MTX) for rheumatoid arthritis (RA) in general. However, is there any reason to single this drug out for early RA? Mechanistically, it probably works differently in RA than in cancer, at least in part. Thus, in addition to dihydrofolate reductase-related effects, MTX inhibits aminoimidazocarboxamide transformylase, decreases leukotriene B4 production, and increases adenosine release at concentrations achieved with low-dose MTX regimens. Clinically, it is well tolerated over relatively long periods. Further, a recent meta-analysis of radiology studies shows that MTX compares favorably with intramuscular gold and is better than azathioprine. Toxicity remains a concern in treating early RA, particularly as pulmonary "hypersensitivity reactions" continue (1% to 7.6%), infections (both fungal and perioperative) are documented, and more cirrhosis is found. With all of the above in mind, the use of MTX seems reasonable but not necessarily uniformly appropriate and not yet proved for early RA. Studies of MTX in early RA, particularly in combination with other drugs, are only beginning.

Adenosine↗
PubMed1994

Interrelationships between pulmonary and extrapulmonary involvement in systemic sclerosis. A longitudinal analysis.

PURPOSE: (1) To evaluate the relationship between the degree of pulmonary involvement by systemic sclerosis (SSc) and the degree of involvement of other organ systems by SSc at baseline. (2) To assess the degree of impairment in lung function at presentation and the annual rate of change in lung function to predict the rate of progression of involvement of extrapulmonary organ systems by SSc over time. (3) To determine whether survival in patients with SSc can be predicted from the degree of lung function impairment at baseline or from the annual rate of change in lung function. METHODS: Semiquantitative indices of pulmonary and extrapulmonary involvement and pulmonary function tests (PFTs) were analyzed and compared in 62 nonsmoking scleroderma patients enrolled in a 3-year prospective drug trial, vs 47 in a "study group" who underwent serial evaluation. The other 16 "early withdrawals" withdrew prior to the second evaluation. The indices of organ system involvement were based on clinical, physiologic, and biochemical findings as previously published. The PFTs included total lung capacity (TLC), forced vital capacity (FVC), FEV1, and single-breath diffusing capacity for carbon monoxide (Dsb). Annualized rates of change in PFTs and indices of extrapulmonary involvement were calculated for each subject from data collected on at least 2 separate occasions at least 6 months apart. Spearman rank correlations were performed between individual baseline PFTs (expressed as percent predicted) and (a) indices of extrapulmonary involvement at baseline, (b) annualized rates of change in PFTs, and (c) annualized rates of change in indices of extrapulmonary involvement. Correlations also were performed between the rate of change in each lung function measure and rates of change in indices of extrapulmonary involvement. The ability of PFTs at baseline and their rates of change to predict cumulative survival was assessed by Cox stepwise regression. RESULTS: The degree of impairment in baseline PFTs was related to involvement of the right side of the heart but not to other extrapulmonary system involvement. Baseline PFTs were not related to the rate of subsequent decline of lung function or worsening of extrapulmonary organ system involvement. Subsequent annual rates of decline in lung function were related to worsening skin and upper gastrointestinal involvement. Cumulative survival may be related to the rate of decline in DCO, TLC, and FVC, but was not predicted by impairment in any measure of lung function. CONCLUSION: With the exception of involvement of the right side of the heart consistent with cor pulmonale, the degree of pulmonary involvement by SSc was not correlated with the extent of extrapulmonary involvement. The degree of pulmonary involvement by SSc did not predict subsequent worsening of either pulmonary or extrapulmonary involvement. Worsening pulmonary involvement by SSc, in general, does not correlate with worsening involvement of extrapulmonary organ systems, except for the skin and upper gastrointestinal tract. A rapid decline in DCO or lung volumes may predict poor survival.

Bone Diseases↗
PubMed1994

DC-ART: decreased inflammatory synovitis.

As part of the proposal for drug development using the SMARD/DC-ART definitions, "decreased inflammatory synovitis" needs to be defined. We review the literature with respect to each of the indirect, clinical measures of decreased inflammatory synovitis and recommend a preliminary, testable definition based on a per patient response. It includes minimum disease activity criteria for patients entering studies and improvement in at least 5 of the following 6 criteria: greater than 20% improvement in joint swelling count; greater than 20% improvement in joint tenderness count; greater than 20% improvement in erythrocyte sedimentation rate; greater than 30% improvement in physician/assessor global assessment; greater than 30% improvement in pain. While this definition is sensible within the confines of our knowledge to date, using these criteria prospectively in several clinical trials will allow better definition of the appropriate pooled index to define decreased inflammatory synovitis.

Antirheumatic Agents↗
PubMed1994

Predictors of worsening clinical variables and outcomes in rheumatoid arthritis.

Predictors of disease activity severity and outcome have both been reviewed. Although data to date have usually examined one predictor at a time, it is likely that a combination of genetic factors (HLA-DR4 or its subsets), joint tenderness or swelling, RF positivity, presence of erosions early in disease, and gender can be combined to predict disease activity/severity. The precise "mix" and contribution of these factors, however, still needs to be determined. Longer-term functional outcome can best be predicted by accounting for baseline functional disability (which reflects disease activity/severity), disease severity per se, and psychologic variables (such as depression). Again, the precise variables of most importance still need some research. Finally, mortality appears to be predicted by functional factors (thus also by disease severity), but medications (e.g., prednisone), social factors, and age (not surprisingly) also contribute to mortality.

Arthritis, Rheumatoid↗
PubMed1994

Analysis of elevated serum interleukin-6 levels in rheumatoid arthritis: correlation with erythrocyte sedimentation rate or C-reactive protein.

The purpose of this study was to determine whether selected antirheumatic drugs would suppress elevated circulating interleukin-6 (IL-6) levels in patients with rheumatoid arthritis (RA). The 267 patients who enrolled in a double-blind randomized protocol received placebo, naproxen (1500 mg/day), or prinomide (1500 mg/day) for up to 16 weeks. Serum samples from 143 of the patients completing the trial and from 135 normal donors were analyzed by quantitative sandwich enzyme-linked immunosorbent assay for IL-6 concentrations. A mean normal IL-6 value was determined to be 3 pg/ml (95th percentile value = 10 pg/ml). IL-6 levels at baseline for the patients with RA were significantly higher than those for control subjects (p < 0.0001). Elevated IL-6 levels (> 10 pg/ml) at baseline were found in 80% of subjects with RA (median = 36 pg/ml, range 12 to 403). For patients with elevated levels of either IL-6, C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR) at baseline, initial median values of IL-6, CRP, and ESR were compared with those from the final visit for each treatment group. There was no significant decrease in IL-6 levels with treatment. Median CRP levels decreased significantly, from 1.9 to 0.8 mg/dl (p = 0.002), as did median ESR (37 to 34 mm/hr, p = 0.013), only in the prinomide-treated group.

Adolescent↗
PubMed1993

Optimizing combination chemotherapy for rheumatoid arthritis.

A potential approach toward rational decision making when using combinations of DMARDs has been presented. This approach combines knowledge of DMARD mechanisms of action, kinetics, and toxicities to look for "nonoverlapping" combinations. When using this approach to predict responses and comparing them to studies that have been done, some encouraging results were obtained. Nevertheless, as exemplified by the combination of D-penicillamine and hydroxychloroquine, this approach is not infallible. The use of refinements of such rational choices, however, should be continued in an effort to improve the chances of success and decrease the costs of testing drug combinations.

Arthritis, Rheumatoid↗
PubMed1993

Differential effects of diclofenac and aspirin on serum glutamic oxaloacetic transaminase elevations in patients with rheumatoid arthritis and osteoarthritis.

OBJECTIVE: To examine elevations in levels of serum glutamic oxaloacetic transaminase (SGOT) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) taking placebo, aspirin, or diclofenac, and to seek possible explanations for the occurrence of these elevations. METHODS: We conducted a meta-analysis of individual case reports from 3 RA protocols and 5 OA protocols, encompassing 814 diclofenac-treated patients, 443 aspirin-treated patients, and 359 placebo-treated patients. All of the RA protocols had nearly identical inclusion and exclusion criteria, as well as safety studies and followup; the same was true for the OA protocols. Analysis included correlation analysis and multiple linear and logistic regression, accounting for numerous potential confounding variables, with the SGOT as the dependent variable. F tests were used for hypothesis testing. RESULTS: By several analytic approaches, the principal determinants of SGOT concentrations were found to be baseline SGOT value, the use of aspirin in RA patients, and the use of diclofenac in OA patients. Other significant factors contributing to an increase in SGOT concentrations were duration of therapy and, perhaps, daily dosage (mg/lb). Hypothesis testing supported these results. Given a statistically average patient, we predicted a 1-2% chance of a mildly elevated SGOT level occurring among placebo-treated patients, a 6-7% chance among diclofenac- or aspirin-treated patients with RA, a 12% chance among diclofenac-treated patients with OA, and a 2% chance among aspirin-treated patients with OA. CONCLUSION: This study demonstrates a powerful method for performing meta-analysis, using available individual patient data to examine numerous factors that may affect an outcome of interest. In this case, mild elevations of SGOT were examined and found to be related to baseline SGOT levels, diclofenac use (in OA), and aspirin use (in RA). Of numerous other potential factors examined, including age, sex, alcohol use, concomitant medications, and concomitant diagnoses, only duration of therapy and, to a small extent, daily dosage, were also consistent determinants of SGOT elevation. The SGOT elevations were minimal and were not related to the occurrence of clinical hepatitis: No clinical hepatitis occurred.

Arthritis, Rheumatoid↗
PubMed1993

Comparing the strengths and weaknesses of observational and experimental studies using a postmarketing surveillance study as a protypic example.

A recent prospective, observational study in rheumatoid arthritis patients indicated that the addition of hydroxychloroquine to either aspirin or methotrexate therapy decreased the incidence of hepatic enzyme abnormalities. This interesting finding is of potential clinical importance, but its validity needs to be examined in terms of the potential confounders inherent in observational studies. Although one of the study's strengths is its derivation from "real-life" data, some potential confounders that might weaken the data include a need to examine whether any scientific rationale can be discerned for the observation; examination of control-case matching (issues of randomization and baseline disease characteristics); the potential for attribution bias; data-collection methods (prospective versus retrospective, uniform versus chart review); and equivalency of treatment protocols, dosing regimens, and concomitant medications. Potential scientific rationale exists for the observed interaction, and data collection is both uniform and prospective. These strengths are confounded by the inevitable lack of randomization in observational studies, the potential for differences in baseline disease characteristics, attribution bias, a lack of controlled dosing regimens and treatment protocols, and an assumption that all nonsteroid antiinflammatory drugs are alike (which is not true). On balance, the hypothesis generated by these data is compelling enough to deserve further testing in both observational and experimental settings.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Radiological progression in rheumatoid arthritis: how many patients are required in a treatment trial to test disease modification?

OBJECTIVE: To determine whether the number of patients required in a therapeutic trial that uses progression of radiological abnormalities as the outcome measure would be similar for multiple centres. METHODS: The progression of radiological damage to the fingers and wrists of patients with rheumatoid arthritis in five centres, three in North America and two in Europe, was examined. The reproducibility of repeated readings by the same and multiple observers was examined. The number of patients required in a two group trial was calculated for several combinations of power and significance. RESULTS: Scoring progression of radiological abnormalities in sequential films taken between 0.5 and 2.1 years was found to be highly reproducible. When the scores of a single reader were used the rate of change of radiological scores was similar in all centres. Based on the mean progression rate for all centres it was estimated that 153 patients in each group would be required to assure 90% power for detecting a 50% slowing of radiological progression at a significance of 0.05. Review of the experience in three trials showed a large variability in the radiological progression rates. CONCLUSION: The progression of scores for radiological damage in rheumatoid arthritis is relatively uniform in North America and Europe and thus the number of patients required in a trial would be similar. Experience in three trials showed that patient selection is of paramount importance in setting up a successful study.

Adult↗
PubMed1993

Aspirin is not associated with more toxicity than other nonsteroidal antiinflammatory drugs in patients with rheumatoid arthritis treated with methotrexate.

OBJECTIVE: To compare the clinical and laboratory toxicities of aspirin vs nonsteroidal antiinflammatory drugs (NSAID) in combination with low dose methotrexate (MTX). METHODS: We retrospectively examined 34 patients with rheumatoid arthritis (RA) who completed 12 months of a prospective MTX trial. Analysis included descriptive and logistic regression. RESULTS: Twelve patients took an average of 4.5 g aspirin daily; 22 patients took other NSAID at stable doses. Limiting toxicity was not different between aspirin and NSAID treatment groups, respectively, for stomatitis (33 vs 27%), gastrointestinal symptoms (25 vs 18%), hepatic (25 vs 27%), or other toxicity. However, using logistic regression procedures, weight adjusted weekly MTX dose and prednisone dose correlated with toxicity. CONCLUSION: While toxicity is common when aspirin or NSAID are used with MTX to treat RA, there is no clinical difference between aspirin and NSAID with respect to that toxicity during 12 months of therapy.

Adolescent↗
PubMed1993

Methotrexate: new mechanisms and old toxicities.

Over the last several years, information on methotrexate's mechanism(s) of action (which affects its efficacy) and toxicities continue to evolve. This popular second line agent (DMARD) is a potent anti-inflammatory drug, with effects on LTB4 and adenosine release (EC-50: 1-13 nM). As such, it may be a sufficiently potent anti-inflammatory drug to affect rheumatoid arthritis's basic course, as shown by a recent meta-analysis where methotrexate equalled gold and was better than azathioprine, when examining radiographic erosions. Its toxicities continue to be documented, with cirrhosis occurring between 2:100 and 1:1000 cases. Pneumonitis continues to be found. NSAID-MTX interactions, too, have been documented, although their kinetic mechanisms remain controversial.

Adenosine↗