B cell depletion therapy in systemic lupus erythematosus: Effect on autoantibody and antimicrobial antibody profiles

Abstract

Objective. Autoantibody production in patients with systemic lupus erythematosus (SLE) is associated with abnormalities of B cell function and phenotype. Clinical responses to B cell depletion therapy (BCDT), based on rituximab, are encouraging. Therefore, we undertook this study to investigate the effect of BCDT on antibody profiles.Methods. Serial sera from 16 patients with active, refractory SLE were assayed for antinucleosome antibodies, anti-double-stranded DNA (anti-dsDNA), antiextractable nuclear antigen, anti-tetanus toxoid, and antibodies to pneumococcal capsular polysaccharide for at least 1 year following BCDT. Anti-dsDNA antibodies derived from the V H 4.34 immunoglobulin germ line gene (9G4؉) were also measured.Results. All patients achieved peripheral B cell depletion and improved clinically for at least 3 months. Antinucleosome and anti-dsDNA antibodies decreased to a mean ؎ SD of 64 ؎ 37% and 38 ؎ 33% of baseline values, respectively, by 6-8 months post-BCDT. Levels of other autoantibodies and antimicrobial antibodies were generally unchanged. In the 9 of 16 patients who were still well at 1 year, anti-dsDNA antibodies fell to 42 ؎ 36% of baseline values at 6-8 months and to 37 ؎ 33% at 10-14 months. In patients who had disease flares within 1 year of BCDT, levels of these antibodies decreased to 60 ؎ 40% and 83 ؎ 93% of baseline values at 6-8 months and at 10-14 months, respectively. Circulating anti-dsDNA antibodies were positive for 9G4 expression in 4 of 6 patients tested, and flares in 2 of these patients were accompanied by rises in 9G4؉ anti-dsDNA antibodies.Conclusion. These observations suggest that B cell clones committed to producing antinucleosome and anti-dsDNA antibodies, including the V H 4.34 subpopulation of anti-dsDNA antibodies, have a relatively rapid turnover compared with B cell clones producing other antibodies. There was also a trend toward a greater and more sustained decrease in anti-dsDNA antibodies in patients with clinical benefit lasting >1 year.

CD40-activated B cells from patients with systemic lupus erythematosus can be modulated by therapeutic immunoglobulins in vitro

“…Furthermore, the effects of IVIg were observed even when BAFF (also known as BLyS), which is considered to be an important element in SLE pathology (Carter et al 2005), was added to the cytokine cocktail. BAFF levels are elevated in the serum of SLE patients (up to 20 ng/ml) (Cambridge et al 2006;Zhang et al 2001) and an IVIg-induced reduction in proliferation was observed even when SLE B cells were stimulated in the presence of similarly elevated BAFF concentrations (25 ng/ml).…”

Immunologic and Metabolic Biomarkers of -Cell Destruction in the Diagnosis of Type 1 Diabetes

“…These investigators suggested that these differences indicate a more rapid turnover of the anti-dsDNA antibody-producing B cells such as the V H 4.24 subpopulation. (Cambridge et al 2006). The therapeutic effects of Rituximab and, in particular, how Rituximab reduces the titer of serum antibodies without altering the overall antibody titers are not clear.…”

Idiopathic Membranous Nephropathy

“…Our original "ANCA-centric" hypothesis has recently been tempered by our treatment success with this agent in several ANCA-negative patients with WG (103). Finally, caution is advised about extrapolation from one autoimmune disease to another, because the pathogenic mechanisms, B lymphocyte depletion and autoantibody responses to rituximab therapy, are too heterogeneous among the different autoimmune diseases, particularly SLE, rheumatoid arthritis, and AAV (104,105).…”