Table 1

Pathogenetic pathways thought to lead to anti-DNA and antiphospholipid (thrombophilic) autoantibodies in patients with RA receiving TNFα blockers

DNA antibodies
  1. Apoptosis induced by TNFα leads to increased tissue and systemic levels of chromatin-DNA complexes39

  2. Blockade of TNFα leads to a fall in the acute phase reactants serum amyloid P, as well as in CRP40

  3. Low levels of serum amyloid P decrease the clearance of chromatin-DNA complexes41

  4. High antigen levels (DNA, chromatin, etc) may induce loss of tolerance and the development of autoantibodies in genetically susceptible hosts42

aPL (aCL, anti-β2-glycoprotein I, or LAC)
  1. TNFα mediates CD8+cytotoxic T lymphocyte capability of eliminating autoreactive B cells. Blockade of TNFα allows survival of autoreactive B cell clones43

  2. TNFα protects against infections. Blockade of TNFα leads to more infections, more lipopolysaccharide stimulation of IL6 by monocytes/macrophages and through the bacterial CpG DNA, more activation of B cells44

  3. Infectious agents, through a molecular mimicry mechanism, have been shown to lead to anti-β2-glycoprotein I, to aCL, and to clinical and biological manifestations of the antiphospholipid syndrome in experimental animals45