Michael R. Liebling

Abetimus sodium for renal flare in systemic lupus erythematosus: Results of a randomized, controlled phase III trial†

OBJECTIVE To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-double-stranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare. METHODS We conducted a randomized, placebo-controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high-affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening. RESULTS Abetimus did not significantly prolong time to renal flare, time to initiation of high-dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus-treated patients [12%] versus 24 of 153 placebo-treated patients [16%]). Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced > or =50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated. CONCLUSION Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.

Circulating Immune Complexes: Their Immunochemistry, Detection, and Importance

The size and molecular composition of circulating immune complexes depend on various factors, including the concentrations and valences of antigens and antibodies and the antigen-antibody ratio. The composition and biological properties of circulating immune complexes, in turn, influence their fate in vivo as well as the likelihood of their detection by various assays. Several assays clearly detect circulating immune complexes, but no single assay has yet been shown to be the most sensitive and the most specific for the entire spectrum of circulating immune complexes. Assays correlate poorly with each other, but this may be desirable if we are to determine which circulating immune complexes have diagnostic, prognostic, or pathogenic importance. Circulating immune complexes are found in numerous rheumatologic disorders and infectious diseases. Their presence in the circulation statistically correlates with disease activity; however, the assays currently used have limited value for diagnosing or aiding in therapeutic decisions. Nevertheless, the future holds promise for such uses.

Substrate competition between DNase I and anti-DNA antibody

Sera from rabbits immunized with DNA and patients known to have SLE were shown to inhibit the digestion of 125I-labeled ss-DNA by pancreatic DNase I. Similarly, DNase present in the serum of a patient with SLE was found to digest the radio-labeled DNA at one-sixth the rate of an equal quantity of DNase present in NHS. The inhibition was shown to be due to isolated anti-DNA antibody in both the immunized rabbit sera and the SLE sera. The type of inhibition involved was demonstrated to be of the competitive variety in which the binding of antibody to DNA presumably blocks enzyme access to the substrate. The possible pathogenetic implications of these findings are discussed.

Specific suppression of anti-DNA production in vitro

To investigate the regulation of anti-DNA antibody production, we generated anti-DNA-specific suppressor cells by exposing normal human T cells and a small percentage of adherent cells to high concentrations of DNA. These cells suppressed the production of anti-DNA by both autologous peripheral blood mononuclear cells (PBMC) and allogeneic PBMC derived from systemic lupus erythematosus (SLE) patients. Anti-DNA production was suppressed significantly more than anti-RNA, antitetanus, or total immunoglobulin production. Specific suppression was enhanced by increasing the numbers of DNA-primed CD8+ cells and was obliterated by irradiation of the DNA-primed cells. In contrast to T cells from normal individuals, T cells obtained from two intensively studied SLE patients were unable to generate specific suppressor cells for anti-DNA production in both autologous and allogeneic test systems. Despite this defect, these patients were still capable of generating specific suppressor cells for antibody production directed against an exogenous antigen, tetanus toxoid.

Substrate competition in systemic lupus erythematosus clinical relevance

In an attempt to determine additional serologic correlates of lupus glomerulonephritis, 32 patients with systemic lupus erythematosus (SLE) and positive DNA binding were divided into three groups on the basis of six parameters: biopsy, urine sediment, creatinine clearance, proteinuria, C′H100 or C3, and anti-DNA binding. The three groups were: Group Ia, active renal disease; Group Ib, inactive renal disease; Group II, no renal disease. Samples of 42 sera from these patients, as well as samples from 10 normal controls, were assayed for their ability to inhibit the action of bovine pancreatic DNase on 125I-labeled DNA (substrate competition). The mean levels of DNase activity for the groups were as follows: Group Ia, 9.42 ± 1.19 (SEM); Group Ib, 16.89 ± 1.09; Group II, 22.71 ± 1.74. The mean values for Group Ia and either of the other two groups were significantly different at the P < 0.001 level. Additional correlations were drawn between counterimmunoelectrophoresis for detection of precipitating antibody to DNA (C.I.E.) and DNase inhibition. The combination of high DNase inhibition and negative C.I.E. was highly predictive for SLE glomerulonephritis. This test may prove useful as an additional prognostic tool to determine which patients with SLE and positive anti-DNA binding will go on to get renal disease.