Attempts to apply curve fitting models to the analysis of progression of radiographic damage in rheumatoid arthritis are laudable, but are the results believable?
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Arthritis, Rheumatoid↗
Biomedical subjects
J T Sharp
Publications and source records attributed to J T Sharp.
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↗
Acute ozone-induced lung injury in rats: structural-functional relationships of developing alveolar edema.
As part of a study on the effects of acute ozone stress on the lung surfactant system, we correlated morphometric, biochemical, and functional indices of lung injury using male rats exposed to 3 ppm ozone for 1, 2, 4, and 8 hr. Evaluation of lung mechanics, using the Pulmonary Evaluation and Diagnostic Laboratory System, revealed a significant decrease in dynamic lung compliance (ml/cmH2O/kg) from a control value of 0.84 +/- 0.02 (SEM) to 0.72 +/- 0.04 and 0.57 +/- 0.06 at 4 and 8 hr, respectively. At 2 hr there was a transient increase in PaO2 to 116 torr (control = 92 torr) followed by a decrease at 4 hr (65 torr) and 8 hr (55 torr). Morphometry of lung tissue, fixed by perfusion of fixative via the pulmonary artery at 12 cm H2O airway distending pressure, demonstrated an increase in the area of the intravascular compartment at 8 hr, in association with a 65 and 39% replacement of the alveolar area by fluid in ventral and dorsal lung regions, respectively. There was a positive correlation (r = 0.966) between alveolar edema and transudated proteins in lavage fluid. A stepwise multiple regression model, with edema as the dependent variable, suggested that pulmonary vasodilatation, hypoxemia, and depletion of surfactant tubular myelin in lavage fluid were indices for predicting alveolar edema. In a second model, with lavage protein concentration as the dependent variable, decreasing dynamic compliance and hypoxemia were predictors of progressive, intraalveolar transudation of plasma proteins. The above structural-functional relationships support the concept that ozone-induced high-protein alveolar edema is pathogenetically linked to pulmonary hyperemia, deficiency of surfactant tubular myelin, and associated lung dysfunctions.
Animals↗
Structural change of the thorax in chronic obstructive pulmonary disease.
This study examines structural changes of the thorax in hyperinflated subjects with chronic obstructive pulmonary disease (COPD). Age-matched normal subjects were used for comparison. Thoracic dimensions were determined using anteroposterior and lateral chest radiographs performed at total lung capacity, functional residual capacity, and residual volume. Rib cage dimensions (lateral diameter, rib angle, anteroposterior diameter) and diaphragm position were determined at each lung volume. There were no significant differences in rib cage dimension between the COPD and normal subjects for all lung volumes. In contrast, the diaphragm was significantly lower in the COPD subjects. The change of rib cage dimensions in the COPD subjects (for a similar volume change) was not different from that in normal subjects, whereas the change of diaphragm position in the COPD subjects (for a similar volume change) was reduced. In conclusion, the primary structural change of the thorax in COPD with chronic hyperinflation is confined to the diaphragm, with no appreciable structural change in the rib cage.
Aged↗
The progression of erosion and joint space narrowing scores in rheumatoid arthritis during the first twenty-five years of disease.
Erosions and cartilage destruction are nearly universal features in peripheral joints that have been chronically affected by rheumatoid arthritis. Scoring methods to measure the extent of these abnormalities in hands and wrists have been developed and have been thoroughly tested in several studies to establish their reproducibility. In this study, we utilized one of these scoring methods to examine the progression of radiologic damage as related to duration of disease. Two hundred ninety-two patients from 3 different participating centers in the Arthritis, Rheumatism, and Aging Medical Information System were included. Six hundred fifty films of the hands and wrists, obtained from 210 patients, were scored for erosions and joint space narrowing. The average annual rate of progression of the total radiologic score, which sums erosion and joint space abnormalities and has a maximum possible score of 314, was approximately 4 units per year over the first 25 years after onset; this progression was more rapid in the earlier years of disease and slightly slower in the later years. Data were insufficient to accurately determine the progression rate in disease of more than 25 years duration.
Arthritis, Rheumatoid↗
Respiratory muscle strength in congestive heart failure.
In experimental animals, conditions which drastically decrease cardiac output may reduce the strength and endurance of respiratory muscles leading to hypercapnic respiratory failure. Because patients with chronic CHF have reduced cardiac output and vital capacity (FVC), we measured PImax and PEmax and maximal handgrip force in 16 patients with CHF and 18 AMNs. The patients with CHF had a mean left ventricular ejection fraction of 26 +/- 7 percent. Maximal respiratory pressures were significantly reduced; group mean values (+/- SD) for PImax at FRC were 41.4 +/- 5.6 cm H2O (CHF) and 102.1 +/- 27.4 cm H2O (AMN) (p less than 0.001), with PImax values in five patients with CHF as low as 20 to 30 cm H2O. In most patients, PEmax was comparably reduced. Handgrip force was less dramatically reduced, suggesting selective respiratory muscle weakness. Possible explanations include reduction in respiratory muscle blood flow or generalized muscular atrophy and weakness related to cardiac cachexia.
Forced Expiratory Volume↗
Radiologic assessment as an outcome measure in rheumatoid arthritis.
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Anti-Inflammatory Agents↗
Scoring radiographic abnormalities in rheumatoid arthritis.
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Arthritis, Rheumatoid↗
Dyspnea and diaphragmatic fatigue in patients with chronic obstructive pulmonary disease. Responses to theophylline.
This study sought answers to 2 questions: (1) Is severe dyspnea to the point of exhaustion regularly accompanied by diaphragmatic fatigue in patients with moderately severe chronic obstructive pulmonary disease (COPD)? (2) When diaphragmatic fatigue occurs in such patients, does theophylline prevent or delay its onset? Eight eucapnic patients with moderately severe COPD were subjected to 2 different stresses to the point of severe dyspnea requiring cessation of the stress. The stresses were cycle exercise and inspiratory resistive breathing, the latter requiring a tidal Pdi equal to 60% of Pdimax. Despite incapacitating dyspnea, objective evidence of diaphragmatic fatigue was not encountered during cycle exercise. During inspiratory resistive breathing, diaphragmatic fatigue was encountered in all patients as defined by consistent inability to attain a target Pdi during final moments of the resistance run. Patients were uniformly extremely dyspneic at this point. In neither stressful maneuver did oral sustained-release theophylline show a convincing or significant advantage over placebo when administered in a randomized double-blind crossover protocol. These results suggest that the diaphragmatic fatigue encountered in this sort of COPD patient may be of predominantly central rather than peripheral (myogenic) origin and that theophylline may not be effective in this type of fatigue.
Diaphragm↗
Inspiratory muscle training with a pressure threshold breathing device in patients with chronic obstructive pulmonary disease.
The inspiratory pressure load is an important variable in inspiratory muscle training (IMT), but previous studies with chronic obstructive pulmonary disease (COPD) patients have not controlled for this variable. We compared the effects of two months of IMT with a pressure threshold breathing device at inspiratory pressure loads equal to either 15 or 30% of each patient's maximal inspiratory pressure (Plmax). This study was double blind and patients were randomly assigned to the treatment groups, 12 in the 15% group and ten in the 30% group. Dependent variables were measured at baseline, and after one and two months of IMT. Patients who exercised with the 30% load improved the following: Plmax by a mean of -12 +/- 9 cm H2O (p less than 0.01), endurance time while breathing against an inspiratory pressure load equal to 66% of Plmax by 5 +/- 9 min (p less than 0.01), and 12-min distance walk (12MD) by 199 +/- 90 feet (p less than 0.01). Patients who exercised with the 15% load demonstrated no improvements in Plmax, endurance time, and 12MD. There were no changes in patients' report of functional impairment (Sickness Impact Profile), mood (Profile of Mood States), health status (Health Perceptions Questionnaire), and pulmonary symptoms (respiratory symptom log). We conclude that the 30% load was more effective than the 15% load in this sample.
Affect↗
Dyspnea: mechanisms, evaluation and treatment.
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Biomechanical Phenomena↗
Pulse methotrexate therapy in rheumatoid arthritis. A controlled prospective roentgenographic study.
STUDY OBJECTIVE: To assess whether weekly pulse methotrexate therapy alters radiographic progression of joint disease in patients with rheumatoid arthritis. DESIGN: Prospective, controlled study. Hand, wrist and foot roentgenograms obtained before, at the onset of, and during methotrexate treatment were scored for degree of joint-space narrowing and erosions by three rheumatologists using a standard method. PATIENTS: Sequential sample of 24 patients with active definite or classical rheumatoid arthritis and previous unsuccessful treatment; of these, 3 were excluded due to drug ineffectiveness; 2, due to side effects; and 1, due to refusal to take methotrexate. INTERVENTIONS: Treatment with nonsteroidal anti-inflammatory drugs and prednisone was continued. Methotrexate was given weekly to control clinical evidence of disease in patients. MEASUREMENTS AND MAIN RESULTS: After having had an average of 30 months of therapy, the 18 patients who continued to receive methotrexate therapy showed significant (p less than 0.05) clinical improvement, as evidenced by their decreased joint counts and joint scores, duration of morning stiffness, pain scales, and sedimentation rates. Despite patients' prolonged clinical improvement, the mean rate of development of erosions and joint-space narrowing during methotrexate therapy was not significantly different from the rate of radiographic progression before methotrexate therapy (0.043 compared with 0.041; p greater than 0.05). CONCLUSIONS: Weekly pulse methotrexate is effective for the long-term management of clinical disease activity in patients with refractory rheumatoid arthritis but may not be a disease-modifying agent by roentgenographic criteria.
Adult↗
Ranitidine protects against gastroduodenal mucosal damage associated with chronic aspirin therapy.
A randomized, double-blind, placebo-controlled study examined whether concomitant administration of ranitidine could protect against the gastroduodenal mucosal damage associated with long-term aspirin therapy in healthy men. Twenty-four subjects received ranitidine (150 mg twice daily) plus aspirin (650 mg four times daily), and 19 received placebo twice daily plus aspirin (650 mg four times daily) for four weeks. Gastric injury and duodenal injury were assessed separately according to a numerical rating scale for incidence and severity of lesions observed during endoscopic examinations at baseline and after four weeks of treatment. The ranitidine/aspirin group had significantly less mucosal damage in the stomach and duodenum than the placebo/aspirin group. Mean serum salicylate levels were similar between treatment groups after two and four weeks of aspirin therapy. Therefore, the protective effect of ranitidine was achieved with no compromise in salicylate absorption.
Adolescent↗
Assessment of radiologic progression in rheumatoid arthritis. A randomized, controlled trial.
Radiologic assessment of progressive joint destruction in rheumatoid arthritis is generally considered to be the ultimate standard for evaluation of treatment. We compared alternative radiologic techniques by performing a randomized, controlled trial in which hand films of rheumatoid arthritis patients were read by several skilled observes. The number of joints evaluated (34 versus 18) was found to make relatively little difference, but the number of readers and their experience level was critical. Films should be read in pairs. Joint space narrowing and erosion scores were shown to contribute independent information. Use of recommended techniques can reduce the number of patients required and, thus, can reduce the cost of a clinical trial by more than half and can substantially increase the sensitivity and efficiency of a trial. Therefore, critical selection of the method of assessing study endpoint is of great importance.
Arthritis, Rheumatoid↗
Theophylline in chronic obstructive pulmonary disease.
Although prolonged use of maintenance theophylline therapy in chronic obstructive lung disease remains controversial, evidence from well-designed studies indicates that it produces patient improvement as gauged by both objective and subjective measurements. An important reason to use sustained-release theophylline is to prevent episodes of bronchospasm by providing a smooth around-the-clock bronchodilator effect and thus reducing the need for periodic aerosolized beta agonists. Theophylline also increases diaphragmatic contractility and endurance, although there is disagreement concerning the practical clinical significance of this effect. The drug improves cardiovascular function by increasing myocardial contractility and by reducing pulmonary and systemic vascular resistances. The increased central respiratory drive produced by theophylline may be important in reducing the ventilatory depressant effects of oxygen therapy. The drug also acts to inhibit mediator release and improves several aspects of mucociliary function, although, again, the clinical significance of these actions has not been established.
Adrenergic beta-Agonists↗
Reduction of aspirin-induced gastroduodenal mucosal damage with ranitidine.
A randomized, double-blind, placebo-controlled study was conducted to determine if concomitant administration of ranitidine, an H2-receptor antagonist, could reduce the gastroduodenal mucosal damage associated with short-term (3 day) aspirin therapy. Nineteen subjects received ranitidine 150 mg b.i.d. plus aspirin 650 mg q.i.d., and 21 received placebo b.i.d. plus aspirin 650 mg q.i.d. for 3 days. Gastric injury and duodenal injury were assessed separately on the basis of pre- and posttreatment endoscopic examinations. The ranitidine/aspirin group had significantly less mucosal damage in the stomach (p less than or equal to 0.01) and duodenum (p less than 0.05) than the placebo/aspirin group. There was no significant difference in mean serum salicylate levels between treatment groups after 3 days of aspirin consumption, indicating that the protective effect was achieved without compromising salicylate absorption.
Adolescent↗
The rib cage in normal and emphysematous subjects: a roentgenographic approach.
The configuration and motion of the bony rib cage were studied from lateral chest roentgenograms in 10 young normal subjects (YN), 12 elderly normal subjects, and 12 hyperinflated emphysematous patients [chronic obstructive pulmonary disease subjects (COPD), mean total lung capacity (TLC) 133% of predicted]. The acute angles formed by the fourth through seventh ribs with an axial reference plane were measured at residual volume, functional residual capacity, and TLC in both supine and standing positions and correlated with corresponding lung volumes. both rib angles (RA) and changes in RA with lung volume were greatest with the fourth rib and decreased progressively going down (caudad) the chest. At TLC the RA of upper ribs was significantly less in EN and significantly greater in COPD than in YN. RA's were greater supine than standing. When RA information was used together with autopsy data on the angles formed by intercostal muscles with adjacent ribs, intercostal muscle lengths in hyperinflation could be calculated. Computed intercostal muscle length data suggested that hyperinflation should not be associated with degrees of intercostal muscle shortening or overstretching, that would interfere seriously with tension generation.
Adult↗
Diaphragmatic responses to body position changes in obese patients with obstructive sleep apnea.
Patients with severe obesity and obstructive sleep apnea (OSA) have been shown to have abnormalities in respiratory muscle function and respiratory control. The present study was done to evaluate diaphragmatic function and the diaphragm fiber-length-compensating reflex in morbidly obese patients with OSA (1). Twelve normal subjects and 13 morbidly obese patients with OSA were studied in recumbent and upright positions. In the normal subjects, the diaphragm fiber-length-compensating reflex operated normally causing the diaphragm's inspiratory EMG to increase when the diaphragm's fibers shortened with assumption of the upright position. However, 8 of the 13 obese patients with OSA showed a decrease rather than an increase in the inspiratory diaphragmatic EMG on assuming the upright posture. Further data indicate greater diaphragmatic efficiency in the upright than in the supine position in a majority of the obese patients, a reversal of the normal response. Two possible explanations of these observations are: an abnormality of central respiratory control in obese patients with OSA and overstretching of the diaphragm in the recumbent obese patient. The observation of reduced maximal transdiaphragmatic pressures in the recumbent position in some of the obese patients with OSA supports the second explanation. Diaphragmatic overstretching may be an important mechanism in the development of hypoventilation in the morbidly obese.
Adult↗