Objective. To analyze changes in autoantibodies occurring in patients with systemic lupus erythematosus (SLE) treated with 4 infusions of the chimeric anti-tumor necrosis factor ␣ (TNF␣) antibody infliximab. Methods. In an open-label safety study, 7 patients with SLE were treated with infliximab at weeks 0, 2, 6, and 10 in combination with azathioprine or methotrexate. Antibodies to double-stranded DNA (dsDNA) were determined by radioimmunoassay and the Crithidia luciliae indirect immunofluorescence assay; anticardiolipin antibodies (aCL) and antibodies to histone and chromatin were measured by enzyme-linked immunosorbent assay. Antihistone antibodies were also analyzed by immunoblotting. Peripheral blood mononuclear cells from healthy individuals and SLE patients were incubated for 2 weeks with or without TNF␣. TNF␣ was removed by washing and by the addition of infliximab. Apoptotic cells were stained with annexin V and analyzed by flow cytometry. Results. Autoantibodies to dsDNA increased in 5 of 7 patients. Histone, chromatin, and IgM aCL levels were increased in 4 of 7, 6 of 7, and 4 of 7 patients, respectively, peaking 4-10 weeks after the last infliximab infusion, but falling to baseline levels or lower thereafter. In the in vitro experiments, TNF withdrawal after long-term incubation with recombinant human TNF led to increased percentages of apoptotic cells. Conclusion. While TNF blockade was clinically effective, the majority of SLE patients treated with infliximab showed an increase in autoantibodies to nuclear antigens and phospholipids. These increases were transient and were not associated with disease flares. Increased availability of apoptotic antigens after TNF blockade may play a role in the autoantibody formation induced by TNF blockade.
Tumor necrosis factor (TNF) has long been known to function as an immunoregulatory cytokine. TNF has immunosuppressive properties, and Jacob and McDevitt (1) have demonstrated that a genetic deficiency in TNF plays a significant role in the onset of autoimmunity in (NZB ϫ NZW)F 1 mice, a finding that was more recently supported by the observation of severe lupus-like disease in TNF-deficient NZB mice (2). However, TNF is also a proinflammatory cytokine that is pivotal in the pathogenesis of a variety of inflammatory diseases.
When therapeutic TNF blockade became available, patients receiving infliximab were found to develop antinuclear and other autoantibodies and, rarely, lupuslike syndromes (3). Studies on autoantibody formation in patients with RA, spondylarthritis, or Crohn's disease suggest that TNF blocker therapy induces new-onset antinuclear antibodies (ANAs) in 25-70% of initially ANA-negative patients (3,4), with occurrence being partially dependent on the underlying disease. Antibodies to double-stranded DNA (dsDNA) emerge in 10-30% of patients receiving infliximab therapy; the vast majority of these antibodies to dsDNA are of the IgM isotype and are usually nonpathogenic. In contrast, the formation of IgG anti-dsDNA, a relatively rare event, may be more closely associated with the development of a syndrome like systemic lupus erythematosus (SLE)