Robert A. Turner

Decreases in health care resource utilization in patients with rheumatoid arthritis following a cognitive behavioral intervention

We previously reported the efficacy of a multicomponent cognitive-behavioral intervention including biofeedback to decrease pain, affective distress, and objective measures of disease activity in patients with rheumatoid arthritis (RA). In the present article we report evidence that this intervention is associated with reductions in RA-related clinic visits and days hospitalized as well as reductions in the costs of these medical services. Data were independently and objectively collected over an 18-month interval as part of a controlled group outcome study. The importance of documenting economic as well as clinical benefits of our treatments in specific patient populations is noted.

SOluble and insoluble immune complex-platelet interactions in rheumatoid inflammation.

The interactions of soluble and insoluble immunoglobulin G (IgG) complexes with macromolecular rheumatoid factor (RF) and platelets were examined in an in vitro system permitting observation of platelet activities which may contribute to rheumatoid inflammation. Studies of the aggregation phenomenon by the nephalometric technique and by selective sedimentation of 51Cr-labelled platelets revealed no aggregation by platelets exposed to heat aggregated IgG (HAIgG) complexes or their RF precipitates in a plasma test system. Release of serotonin was demonstrated by the increasing radioactivity of platelet supernates to 45 min by 14C-serotonin labelled platelets exposed to insoluble IgG heat aggregates. Significantly less release was shown with saline, native IgG, and soluble IgG complexes. When RF was added to soluble HAIgG complexes, the resulting precipitate caused significantly higher release than controls. No concomitant release of the lysosomal enzyme beta-glucuronidase was detected. Thus, although soluble complexes do not cause significant release of biologically active amines, conversion of soluble complexes to insoluble immune precipitates by RF is associated with this activity which is independent of platelet aggregation and/or lyosomal enzyme release in our test system. Release of biologically active amines from platelets exposed to insoluble complexes may be important in the initiation and propagation of inflammation in rheumatoid arthritis.

Fenoprofen, aspirin, and gold induction in rheumatoid arthritis

Fenoprofen calcium (2,400 mg/day) or aspirin (3,900 mg/day) was administered in double‐blind fashion to 20 rheumatoid patients during 6 months of gold induction therapy, and to 20 rheumatoid patiellts not receiving gold. Among both the gold‐treated and nongold‐treated patients, the fenoprofen and aspirin groups improved equally in all but one parameter of disease activity. Fenoprofen and aspirin did not differ significantly in the observed prevalences of abdominal discomfort, guaiac‐positive stools, or peptic ulcers. Aspirin was associated with significantly higher mean serum glutamic oxaloacetic transaminase (SGOT) levels than fenoprofen, but only among patients undergoing gold induction. Comparison of efficacy parameters between patients treated with gold and patients treated with oral drugs alone revealed significant differences famring gold.

Evaluation of Tenidap (CP-66,248) on human neutrophil arachidonic acid metabolism, chemotactic potential and clinical efficacy in the treatment of rheumatoid arthritis.

Ten patients with rheumatoid arthritis (RA) were evaluated in a placebo-controlled, double-blind study examining the clinical efficacy of a novel nonsteroidal anti-inflammatory agent: Tenidap (CP-66,248). RA patients receiving active drug therapy (n=6) demonstrated clinically significant improvements in observer assessment of pain (p<0.025), painful joint count (p<0.010), and overall clinical assessment as based on a modified rheumatoid activity index, MRAI (p<0.025). In parallel laboratory assays, Tenidap was found to exhibit a significantin vitro dose-dependent inhibition of ionophore-stimulated neutrophil production of the 5-lipoxygenase product: [3H]leukotriene B4 (LTB4). Although more importantly, Tenidap was also found to exhibit anin vitro dose-dependent inhibition (IC50 20 μM) of the ionophore-stimulated release (deacylation) of the precursor [3H]arachidonic acid (AA) from membrane phospholipids. In further studies, Tenidap did not have any effect on fMLP-induced neutrophil chemotactic response. These results suggest that one of the possible mechanisms for the clinical effectiveness of this agent, may be through its effect at inhibiting the release of free AA from membrane phospholipids and therefore limiting its further metabolism into certain biologically-active inflammatory lipids.

Neutrophil enzyme activities in rheumatoid inflammation.

This study analyzed the neutrophils and sera of patients with rheumatoid arthritis and of normal controls. No significant differences were found in the activities of the granular enzymesβ-glucuronidase and lysozyme or the cytoplasmic enzyme lactic dehydrogenase (LDH). Normal neutrophils were found to release significant (P < 0.05) amounts of the granular enzymes, but not of LDH in response to immunoglobulin G aggregates. There was no difference in the percent release exhibited by rheumatoid versus control neutrophils. Studies delineating the effects of rheumatoid factor sera and normal sera on aggregateinduced enzyme release revealed a significant negative correlation between the amount of rheumatoid factor in the sera and the percent release ofβ-glucuronidase and lysozyme but not of LDH. These studies thus demonstrate no abnormalities in rheumatoid neutrophil or rheumatoid serum enzyme activities or in neutrophil response to immunoglobulin G aggregates. They suggest, however, that rheumatoid factor may partially inhibit the release of lysosomal enzymes, thus suppressing this important component of the rheumatoid inflammatory process.

Characterisation of soluble and cell associated phospholipase A2 from rheumatoid synovial fluid.

The hydrolysis of radiolabelled Escherichia coli phospholipids, and micellar dispersions of phosphatidylethanolamine and phosphatidylcholine, were used to characterise the phospholipase A2 activity in synovial fluid from patients with rheumatoid arthritis. Cell free fractions of synovial fluid contain a phospholipase A2 enzyme that preferentially releases [14C]oleic acid from E coli biomembranes (specific activity 291.3 (SEM 27.6) pmol/min/mg). This enzyme requires calcium and is optimally active at neutral pH. Purified dispersions of phosphatidylethanolamine are also readily degraded by the soluble enzyme, but it is not active against phosphatidylcholine. The substitution of [14C]oleic acid by [3H]arachidonic acid for the labelling of E coli allowed differentiation between the soluble phospholipase A2 and the cell associated phospholipase A2 present in sonicates of mononuclear cells and neutrophils from peripheral blood and synovial fluid. The cell associated phospholipase A2 preferentially releases [3H]arachidonic acid from E coli cardiolipin. In this paper the phospholipid substrate specificity of phospholipase A2 from rheumatoid synovial fluid, the optimal assay conditions for its detection, and a standardised expression of activity in terms of pmol per minute per mg of protein are established.

Antirheumatic Drug Effects on Neutrophil Response to Chemotactic Factors: A Comparison of Analytical Techniques

Abstract A recently reported technique employing the leukotactic index which represents all migrating cells in in vitro neutrophil chemotaxis systems, was compared to the leading front technique for assaying antirheumatic drug effects on this important neutrophil function. Normal human neutrophils were treated with therapeutic concentrations of aspirin, gold sodium thio-malate, D-penicillamine, and azathioprine. The responses of these cells and of control cells to neutrophil-immune complex-serum-derived chemotactic factors were assayed in Boyden chambers. Significant (P < 0.05) inhibition was observed by the leading front technique only for D-penicillamine at high concentrations. Significant (P < 0.01) inhibition was seen with D-penicillamine at therapeutic plasma levels with the leukotactic index technique. Gold sodium thiomalate and aspirin at high concentrations also produced significant (P < 0.01 and P < 0.05) inhibition of chemotaxis as assayed by the leukotactic index procedure. Azathioprine had no significant effects when studied with either technique. These results indicate that the leukotactic index may be a more sensitive technique for quantitating neutrophil migration in response to chemotactic factors and may therefore provide useful additional information for determining the effects of antirheumatic drugs on this important neutrophil function.

Pirprofen and aspirin in the treatment of rheumatoid arthritis

Pirprofen (800 mg/day) or aspirin (3,600 mg/day) was administered in double‐blind fashion for up to one yr to 40 adult outpatients with rheumatoid arthritis, after a short, single‐blind placebo period. There were no statistically significant differences in efficacy between pirprofen and aspirin, as evidenced by patient opinion, observer opinion, grip strength, walking time, number of tender joints, number of swollen joints, or erythrocyte sedimentation rate. Clinically significant pain of gastrointestinal origin occurred in an equal number of patients from each group. Audiologic evaluation revealed 3 pirprofen‐treated patients and 5 aspirin‐treated patients in whom a sensorineural hearing loss progressed during therapy and required either discontinuation or reduction of drug dosage. Ophthalmologic evaluation disclosed a high prevalence of lesions, the most common being decreased visual acuity and cataracts not explained by previous antiarthritic therapy. The high prevalence of audiologic and ophthalmologic pathology reported in the literature in patients with rheumatoid arthritis makes it difficult to establish in our study whether pirprofen or aspirin affected these organ systems.

Hepatic and renal tolerability of long-term naproxen treatment in patients with rheumatoid arthritis

Clinical and laboratory assessments of hepatic and renal function in rheumatoid arthritis (RA) patients who received naproxen for up to 6 months during two randomized, double-blind studies comparing naproxen 375 mg twice daily (n = 286) with naproxen 750 mg twice daily (n = 300) were analyzed. Patient groups were segregated by dosage, duration of treatment, and age at entry (less than 65 years v greater than or equal to 65 years), and laboratory measurements of SGOT, SGPT, serum creatinine (Scr), and BUN were examined. Records of individual patients with clinically meaningful abnormalities in laboratory tests or adverse events of hepatic or renal origin were examined in detail. Over the duration of these studies, there were no clinically meaningful changes in mean laboratory values or differences in occurrences of abnormal values among the different patient groups. In both dosage groups, pretreatment incidences of clinically meaningful abnormalities in laboratory tests were similar to those in serial observations during treatment. Six patients who received naproxen 375 mg twice daily and four patients who received naproxen 750 mg twice daily had a hepatic or renal clinical event or distinctly abnormal laboratory value, but only three of these withdrew because of these problems. Occasional transient abnormalities of conventional laboratory tests of hepatic and renal function occurred in some patients during naproxen treatment. Such abnormalities called for careful patient monitoring but generally did not warrant immediate drug withdrawal.

Neutrophil responsiveness to chemoattractant tripeptide in rheumatoid arthritis.

Abstract Neutrophils isolated from medication-free rheumatoid arthritis (RA) patients were assayed for responsiveness to the bacterial chemoattractant tripeptide formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). Rheumatoid arthritis neutrophil preparations contained significantly lower percentages of rapidly migrating cells. This relative hyporesponsiveness of RA neutrophils was related to impaired sensing of chemotactic gradients. Rheumatoid neutrophil abnormalities in sensing of and responding to chemotactic gradients were not associated with resting or f-Met-Leu-Phe-induced changes in arachidonic acid metabolism.