Background/Purpose: Autoantibodies have long been recognized to be present in patients with RA, but it is more recent that autoantibodies against citrullinated proteins (anti-CCP) are emerging as contributors to Rheumatoid Arthritis (RA) pathogenesis. While depletion of CD20 B cells by rituximab clearly has a major beneficial effect in RA, it remains unclear whether this effect is associated with decreased autoantibody production. We recently reported that tocilizumab, a monoclonal antibody to the IL-6 receptor (IL-6R), specifically reduces the levels of IgG4 anti-CCP antibodies (Abs), but not IgG1 anti-CCP Abs, and that IL-6 promotes isotype switching to IgG4. No previous studies have examined whether rituximab treatment has an isotype-specific effect on autoantibody production. The objective of this study was to determine if rituximab has a specific effect on IgG4 versus IgG1 anti-CCP Abs in RA

Methods: RA patients who were starting a new biologic treatment or switching to a new biologic were consented to enter an accompanying laboratory study. Blood specimens were obtained prior to the first treatment (time 0), and 6-9 months later. Serum samples and peripheral blood mononuclear cells were collected. Levels of total anti-CCP antibodies (Abs), IgG1-anti-CCP and IgG4-anti-CCP Abs in serum were determined. Total levels of IgG1 and IgG4 in serum were also determined

Results: While some RA patients have no detectable IgG4 anti-CCP Abs, there is a fraction of RA patients with higher levels of IgG4 anti-CCP Abs than IgG1 anti-CCP Abs (about 40%). Rituximab treatment had no significant effect on IgG1 anti-CCP Abs levels, but it caused a marked reduction in the levels of IgG4 anti-CCP Abs. The total anti-CCP Abs levels were significantly reduced with rituximab, but the reduction was less pronounced due to the minimal effect on the IgG1 subclass antibodies. The reduction in IgG4 anti-CCP Ab levels by rituximab was not caused by a reduction in the total IgG4 serum immunoglobulin levels, as determined by spearman correlation

Conclusion: Rituximab specifically reduces the levels of IgG4 anti-CCP antibodies but has minimal effect on IgG1 levels and IgG1 anti-CCP antibodies. This effect on IgG4 could be masked if total Ig anti-CCP antibody levels are tested. The results from these studies reveal a novel effect of rituximab on autoantibody levels that has been questioned. Considering the emerging relevance of anti-CCP antibodies in the pathogenesis of RA, the specific effect of rituximab on IgG4 autoantibodies could be a novel mechanism for this biologic.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-effect-of-rituximab-on-igg4-anti-ccp-autoantibodies-in-rheumatoid-arthritis-patients/