Association of enhanced superoxide generation by neutrophils with low superoxide scavenging activity of the peripheral blood, joint fluid, and their leukocyte components in rheumatoid arthritis: effects of slow-acting anti-rheumatic drugs and disease activity.

Abstract

To study the role of the superoxide radical (O2-) in the pathogenesis of rheumatoid arthritis (RA), both the O2- generation of peripheral blood (PB) polymorphonuclear cells (PMN) and the superoxide scavenging activity (SSA) of PB-PMN, plasma, joint fluid (JF) and PB- or JF-mononuclear cells (MNC) were measured in forty-five patients with RA using the highly sensitive and specific 2-methyl-6-methoxyphenyl-3,7-dihydroimidazo[1,2-alpha] pyrazin-3-one dependent chemiluminescence and the electron paramagnetic resonance/spin trapping methods, respectively. Since many drugs, particularly the slow-acting anti-rheumatic drugs (SARDs) used in RA, may alter O2- metabolism, the effects of SARDs on SSA were also studied. The basal O2- release and opsonized zymosan- or phorbol myristate acetate-stimulated O2- generation by PB-PMN from RA patients were significantly increased, while the SSA of PMN was decreased as compared to those from healthy controls. In addition, the SSA of PMN showed a negative correlation with their O2- generation rates. The JF-PMN showed lower SSA levels than PB-PMN. A negative correlation was also found between the SSA of the plasma and the erythrocyte sedimentation rates. The SSA of the plasma, PB-PMN, JF and JF-PMN were significantly higher in patients treated with SARDs than those without. In cell-free systems, sulfasalazine (SAP) and its metabolite, 5-amino-salicylic acid, had a direct SSA within a millimolar range. The other metabolites of SASP and D-penicillamine had an indirect SSA, since they affected the O2- generating system. Auranofin and bucillamine had no SSA. However, none of the SARDs examined could scavenge O2- at concentrations reported in patients' plasma.(ABSTRACT TRUNCATED AT 250 WORDS)