Relationship of Circulating Anti-C3b and Anti-C1q IgG to Lupus Nephritis and Its Flare

Abstract

Background and objectives: Autoantibodies to complement C1q (anti-C1q) are associated with the diagnosis of lupus nephritis. In this study, we compare anti-C1q IgG with another complement autoantibody, anti-C3b IgG, as a biomarker of lupus nephritis and lupus nephritis flare.

Design, setting, participants, & measurements: Our investigation involved the Ohio SLE Study, a prospective observational cohort of patients with recurrently active lupus who were followed bimonthly. Serum anti-C1q and anti-C3b IgG levels were assessed cross-sectionally by ELISA in 40 normal controls and 114 patients in the Ohio SLE Study (41 nonrenal and 73 lupus nephritis) at study entry, and longitudinally in a subset of patients in the Ohio SLE Study with anti-C1q-positive lupus nephritis in samples collected every 2 months for 8 months leading up to lupus nephritis flare (n=16 patients).

Results: In the cross-sectional analysis, compared with anti-C1q IgG, anti-C3b IgG was less sensitive (36% versus 63%) but more specific (98% versus 71%) for lupus nephritis. Only anti-C3b IgG was associated with patients with lupus nephritis who experienced at least one lupus nephritis flare during the Ohio SLE Study period (P<0.01). In the longitudinal analysis, circulating levels of anti-C1q IgG increased at the time of lupus nephritis flare only in patients who were anti-C3b positive (P=0.02), with significant increases occurring from 6 (38% increase) and 4 months (41% increase) before flare. Anti-C3b IgG levels also trended up at lupus nephritis flare, although the change did not reach statistical significance (P=0.07). Neither autoantibody increased 2 months before flare.

Conclusions: Although not as prevalent as anti-C1q IgG, anti-C3b IgG showed nearly complete specificity for lupus nephritis. The presence of anti-C3b IgG identified patients with lupus nephritis who were prone to flare and in whom serial measurements of markers associated with complement, such as anti-C1q IgG, may be useful to monitor lupus nephritis activity.

Keywords: anti-C1q; anti-C3b; autoantibodies; complement C1q; cross-sectional studies; flare; humans; immunoglobulin G; lupus nephritis; prospective studies.

Figure 1.

Anticomplement IgG levels. The degrees of IgG reactivity (measured by ELISA OD₄₅₀) to the coated complement proteins in serum samples from eight patients with lupus nephritis (LN) and five normal controls are shown. Also shown are the baseline values in the absence of serum (diluent). The P values refer to the levels of significance for the difference in IgG levels between controls and patients with LN for each coated complement protein (two-tailed unpaired t test [for normalized data] or the Mann–Whitney test [for non-normalized data]). C1INH, C1 inhibitor; C4BP, C4 binding protein; FH, Factor H; FI, Factor I.

Figure 2.

Autoantibodies to complement C1q (anti-C1q) and anti-C3b IgG levels in normal controls and patients with SLE. (A) Anti-C1q IgG and (B) anti-C3b IgG levels, expressed as normalized OD₄₅₀ values, are shown for controls compared with patients in the Ohio SLE Study (OSS), nonrenal patients compared with patients in the OSS with lupus nephritis (LN), and patients in the OSS with LN who did not experience an LN flare (LNF; LN no LNF) compared with those who did (LN yes LNF) during the OSS. The horizontal dashed line represents the positive cutoff for each autoantibody. The number of patients tested in each category is shown at the bottom.

Figure 3.

Temporal relationship between autoantibodies to complement C1q (anti-C1q) or anti-C3b IgG levels and onset of lupus nephritis (LN) flare. Individual levels (normalized OD₄₅₀) and least squares (LS) means are shown for (A and B) anti-C1q IgG and(C and D) anti-C3b IgG for five flare interval months (−8, −6, −4, −2, and 0). In A and B, the anti-C1q levels are shown for both C3b-negative patients with LN (white circles) and C3b-positive patients with LN (black circles). The two intervals excluded from the anti-C3b regression model are shown in C as white circles. P=0.02. Neg, negative; pos, positive.