Evaluation of classical complement pathway activation in rheumatoid arthritis - Measurement of C1q-C4 complexes as novel activation products

Objective. Novel activation products that are stable and minimally susceptible to in vitro artefacts have recently been described in the classical complement pathway. The present study assessed circulating levels of these products, i.e., covalent complexes between the recognition molecule of the classical pathway (C1q) and activated C4, in plasma samples from patients with rheumatoid arthritis (RA) to establish the relationship between these levels and the clinical and immunologic parameters in these patients. Methods. C1q-C4 levels were measured in plasma samples from 41 patients with active RA and 43 patients with inactive RA. These levels were related to other complement activation products and to disease activity according to the Disease Activity Score in 28 joints (DAS28), using Spearman's rank correlations. Results. C1q-C4 plasma levels were significantly higher in patients with active RA as compared with patients with RA in clinical remission (median 3.3 arbitrary units [AU], range 0.4-13.4 versus 1.7 AU, range 0.2-5.5; P = 0.0001), suggesting that activation of the classical complement pathway reflects disease activity. This was supported by a significant correlation between C1q-C4 levels and the DAS28 (r = 0.398, P = 0.0002). Levels of other complement activation products, such as activated C4 (C4b/c), were also significantly elevated in patients with active disease compared with patients with inactive disease (P = 0.03), and were correlated with C1q-C4 levels (r = 0.329, P = 0.002). Levels of C1q-C4 complexes were higher in synovial fluid samples than in plasma samples from the 4 patients tested. Conclusion. Systemic complement activation via the classical pathway in patients with RA correlates with disease activity. These results indicate that C1q-C4 complexes may be used as a biomarker for RA.