Phospholipid metabolism in polymorphonuclear leukocytes from rheumatoid arthritis patients: effects of non-steroidal anti-inflammatory agents and clotrimazole.

Arachidonic acid (AA) metabolism and phospholipase A2 (PLA2) activity were measured in the peripheral blood polymorphonuclear leukocytes (PMNL) from ten patients with rheumatoid arthritis (RA) on treatment with various non-steroidal anti-inflammatory agents (NSAIA). AA metabolism and PLA2 activity were measured both initially and after treatment with either placebo or Clotrimazole, a broad spectrum anti-mycotic agent, as a possible anti-rheumatic drug. AA metabolism was also measured in PMNL from ten patients with active RA untreated with any NSAIA and ten normal volunteers. Using 3H-AA prelabeled cells, we show that there was a significantly higher (P less than 0.025) production of 3H-LTB4 in response to stimulation with the calcium ionophore A23187 in untreated RA patients than in normal volunteers (mean +/- S.D.:4.8 +/- 1.6% and 3.1 +/- 1.0%, respectively). The production of 3H-LTB4 by PMNL from patients on NSAIAs was less elevated (mean +/- S.D.:4.1 +/- 1.5%) and was not significantly different from normal controls. Concurrently we examined PLA2 activity in PMNL-sonicates from ten of our study patients using autoclaved [14C]oleate-labeled E. coli biomembranes as an exogenous substrate. Using linear regression analysis, we demonstrate a significant correlation between in vitro PLA2 activity and the release of 3H-AA from the cellular phospholipids (deacylation) in response to A23187 stimulation (r = -0.526, P less than 0.025). We also demonstrate significant correlations between the overall clinical state of the RA patient, as evaluated by a modified rheumatoid activity index (MRAI), and both the release of 3H-AA from the cellular phospholipids and its production of total [3H]eicosanoids (r = -0.557, P less than 0.025 and r = 0.644, P less than 0.005, respectively). This data suggests that: PLA2 activity may, in part, account for the higher generation of LTB4 by RA PMNL; NSAIAs may be capable of modulating this abnormality; and Clotrimazole may affect the clinical or laboratory data of RA patients already on treatment with NSAIA.