153 z 1 z SYNOVIAL FLUID LEVELS O F COMPLEMENT SCSb-9 AND FRAGMENT Bb ARE ELEVATED IN PATIENTS WITH RHEUMATOID ARTHRITIS JAMES P. BRODEUR, SHAUN RUDDY, LAWRENCE B. SCHWARTZ, and GEORGE MOXLEY To determine whether complement turnover in synovial fluids of patients with rheumatoid arthritis zyxwvu (RA) reflects activation by the classical or alternative pathway, we used novel immunoassays to measure products of complement activation (the membrane at- tack complex SCSb-9 and the cleavage fragments Bb and C4d). Mean synovial fluid levels of SC5b-9 were more than 8 times higher in RA than in crystal-induced arthritis (gout and pseudogout) and over 16 times higher than in degenerative joint disease (D JD). Similarly, Bb levels were more than 3 times higher in RA synovial fluids than in crystal-induced arthritis and over 7 times higher than in DJD. Levels of C4d did not differ among the groups. SC5b-9 levels correlated with synovial fluid C3 anaphylatoxin (C3a), Bb, and C4d levels (r zyxwv = 0.81, 0.62, and 0.51, respectively). In patients with RA, synovial fluid SC5b-9 levels correlated with C3a and Bb (r = 0.6 and 0.56, respectively) but not with C4d. Therefore, novel assays for complement activation indi- cate that both classical and alternative pathways are involved in complement turnover and that the alterna- tive pathway contributes more to complement activation in RA than in DJD or crystal-induced arthritis. Proteolytic cleavage of the third component of complement (C3) links the two different paths of From the Division of Rheumatology,Allergy and Immunol- ogy, the Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond. James P. Brodeur. MD; Shaun Ruddy, MD; Lawrence B. Schwartz, MD, PhD; George Moxley, MD. Address reprint requests to George Moxley. MD. Division of Rheumatology, Allergy and Immunology. Medical College of Virginia, Box 263. MCV Station, Richmond, VA 23298-0263. Submitted for publication April 3, 1991; accepted in revised form July 7, 1991. initiation, classical and alternative, with the membrane lysis function served by the late-acting components C5b-9 (1). For the classical pathway, the proteolytic cleavage of C4 and C2 results in a complex of C4b, which is covalently bound to a cell or immune com- plex, with C2b (formerly known as CZa), which has C3-cleaving activity. C2b may dissociate from the complex, and C4b decays by proteolytic cleavage to form C ~ C , which diffuses away, and C4d, which re- mains covalently bound. The alternative pathway C3 convertase is generated by cleavage of C3 and factor B, resulting in a complex of C3b and Bb that is stabilized by properdin. When either the classical or alternative pathway C3 convertase cleaves C3, it pro- duces C3b that may then associate with the C3 con- vertase to result in a CS-cleaving enzyme. If C5b activation occurs in the fluid phase, the naturally occurring S protein binds to form the inactive SC5b-9 complex, whereas if C5b activation and binding of C6 and C7 occur near a cell membrane, the membrane attack complex is formed and lysis ensues. Certain components of complement are depos- ited in synovial tissues of patients with rheumatoid arthritis (RA). Levels of complement in RA synovial fluid are often depressed, reflecting consumption, and levels of cleavage fragments of complement components are commonly elevated (2). Therefore, complement activation is important in the pathogenesis of RA. The mast cell neutral protease, tryptase. has been shown in vitro to consume C3 (3) and to activate prostromelysin (4). Although large numbers of mast cells are present in inflamed rheumatoid synovium z (5,6), whether the mast cells secrete granule-derived mediators, such as tryptase, has not been determined. It is conceivable that sufficient tryptase is released that Arthritis and Rheumatism, Vol. 34, No. 12 (December 1991)