Scand J Rheumatology 19: 71-75, 1990

Effects of Non-steroidal Anti-inflammatory Drugs and Prednisolone on Synovial Fluid White Cells, Prostaglandin EZ, Leukotriene B4 and Cyclic AMP in Patients with Rheumatoid Arthritis

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E. SEPPALA, M . NISSILA,’ H. ISOMAKI,’ H. WUORELA and H. VAPAATALO Department of Biomedical Sciences, University of Tampere, and ‘the Rheumatism Foundation Hospital, Heinola, Finland

Seppala S, Nissila, M, Isomaki H, Wuorela H, Vapaatalo H. Effects of non-steroidal antiinflammatory drugs and prednisolone on synovial fluid white cells, prostaglandin El, leukotriene B4 and cyclic AMP in patients with rheumatoid arthritis. Scand J Rheumatology 1990; 19: 71-75. Altogether 53 patients (31 women, 22 men) with definite rheumatoid arthritis were randomly divided into groups of 5-6 patients and treated for one day only with one of the following non-steroidal anti-inflammatory drugs (NSAIDs): acetylsalicylic acid, carprofen, diclofenac, indomethacin, naproxen, proquazone, timegadine, tolfenamic acid or paracetamol, and with prednisolone, in recommended doses. Synovial fluid samples were collected before and after the treatment. White cell count and its differentiation as well as the concentrations of protein, cyclic adenosine-3’,5’-monophosphate(CAMP), prostaglandin Ez (PGE2) and leukotriene B4 (LTB,) were measured from the synovial fluid. Synovial fluid leukocyte counts correlated with PGEz concentrations, but showed no correlation with LTB4 levels before treatment. Significant changes were seen in the form of lowered PGEz values following treatment with the clinically and experimentally most potent NSAIDs, and as depressed LTB, levels following prednisolone treatment. The other markers of inflammation are obviously more resistant, changing only slowly during prolonged treatment, and may thus be, at least in part, secondary to the changes in prostanoids.

Key words: anti-inflammatory drugs, synovial fluid in RA, PGEz, LTB4, cAMP Erkki Seppalii, Depurtment of Biomedical Sciences. University of Tumpere, Box 607, SF-33101 Tumpere, Finland.

INTRODUCTION Arachidonic acid metabolites, such as prostaglandins, thromboxanes and leukotrienes, are regarded as important mediators of inflammation (14, 15, 25, 29). Prostaglandins are present in the classic signs of inflammation, together with thromboxane A2 (8, 13), and also take part in the regulation of cellular functions during the inflammatory process (10). Prostanoids (prostaglandins and thromboxane) have been detected in the joint fluids of patients with rheumatoid arthritis (RA). In patients treated with NSAIDs, prostanoid levels have been shown to be low (3, 17, 26). However, there are few published studies where prostanoid concentrations have been measured in the same patients both before and after drug treatment (2, 24). In the present study, the effects of a one-day treatment with nine different NSAIDs and prednisolone were compared by measuring the concentrations of prostaglandins Ez (PGE2) and leukotriene B4 (LTB4) as well as by leukocyte counting, protein and cAMP contents, in synovial fluid from patients with RA, both before and after the treatment.

12 E . Seppala et al.

Scand J Rheumatology 19

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PATIENTS AND METHODS The patients (31 women, 22 men) in this study had classical or definite RA according to the criteria of the American Rheumatism Association (ARA), and also exudative inflamed knee joints. The clinical data on the patients are given in Table I. Before the study was started, the patients abstained for at least 2 weeks from taking all NSAIDs. Dextropropoxyphene or paracetamol were prescribed when an analgetic was needed. A sample of joint fluid was drawn by puncture under local anaesthesia in the morning before the medication commenced, and another after the 24-h drug treatment. The following drugs and dosages were given to the patients, divided into groups of 5-6 subjects in a randomized order: acetylsalicylic acid (1 000 mg q.i.d.), carprofen (300 mg t.i.d.), diclofenac (50 + 50 + 100 mg), indomethacin (50 + 50 + 100 mg), naproxen (500 mg b.i.d.), paracetamol (1000 mg t.i.d.), prednisolone (20 mg in the morning), proquazone (300 mg t.i.d.), timegadine (125 mg q.i.d.) and tolfenamic acid (200 mg t.i.d.1. Informed consent was obtained from the patients and the study plan was approved by the Medical Ethics Committee of the Rheumatism Foundation Hospital. Synovial fluid leukocyte counts and cell differentiations were determined microscopically. Protein concentration in joint fluid was determined ad modum Doumas (4). Cyclic AMP was determined by radio-immunoassay (7). For the analysis of PGE2, synovial fluid was drawn into chilled tubes containing 10 mg of disodium EDTA and 0.18 mg of acetylsalicylic acid per 10 ml of synovial fluid. The samples were centrifugated for 15 min at 800 g at 4"C, and frozen at -20°C until assayed. The extraction of the samples and the radio-immunoassay of PGEZ were performed by the method described in detail by us elsewhere (15). LTB4 concentrations were measured by radio-immunoassay ad rnodum Salmon et al. (18). Dunnet's t-test between the drug groups, and Student's t-test for paired observations within each drug group were used in the statistical analysis.

RESULTS The leukocyte count in synovial fluid before the treatment was ( 8 . 4 f 1.4) x 109/1,protein content 43k18 g/l and the level of CAMP, 6 5 f 4 6 pmol/l. The PGEz and LTB4 concentrations were 410f 114 pg/ml and 1 4 2 f 9 pg/ml, respectively. The correlation coefficient between synovial fluid leukocyte number and PGE2 concentration was 0.418 ( ~ ~ 0 . 0 5 ) . Polymorphonuclear leukocytes showed a positive correlation with PGE2 concentration (r=0.400, p

Effects of non-steroidal anti-inflammatory drugs and prednisolone on synovial fluid white cells, prostaglandin E2, leukotriene B4 and cyclic AMP in patients with rheumatoid arthritis.

Altogether 53 patients (31 women, 22 men) with definite rheumatoid arthritis were randomly divided into groups of 5-6 patients and treated for one day...
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