Levels of antibodies against peptidylarginine deiminase (PAD)4 predict the risk for persistent disease activity and radiographic progression in individuals with rheumatoid arthritis (RA) given anti-tumor necrosis factor (TNF)-α therapy, study findings suggest.
"We and others have demonstrated that a sub-set of RA patients have serum autoantibodies against recombinant human PAD4," write Eirik Hornes Halvorsen (University of Oslo, Norway) and fellow researchers.
They suggest: "The citrullinated epitopes targeted by the RA-specific anti-citrullinated protein antibodies may be generated in vivo by PAD4."
For the current study, Halvorsen and team studied serum samples taken from 40 individuals with RA before they started anti-TNF-α therapy, and 33 of those patients after 1 year of such treatment.
The scientists discovered that 42.5% of patients expressed antibodies against recombinant human PAD4 before treatment started and that levels of these antibodies were not significantly altered after a year of therapy.
Patients positive for anti-PAD4 antibodies generally had more severe disease than those negative for the antibodies, as demonstrated by persistently high 28-joint Disease Activity Scores and worsening Sharp scores, the investigators report.
"From our observations, TNF-inhibitor therapy was inadequate to suppress disease activity and prevent radiographic progression in the majority of the anti-human PAD4-positive RA patients," the researchers summarize.
The investigators say the mechanisms behind this observation are unclear, but suggest that "blocking of the TNF-α-induced nuclear translocation of PAD4 by TNF-inhibitors may skew the balance from nuclear to cytoplasmic PAD4, possibly making PAD4 susceptible to leaking from dying cells and, therefore, more easily targeted by autoantibodies."
The authors conclude that, as their study was relatively small, a larger trial should be undertaken to clarify the potential roles of anti-human PAD4 antibodies in the pathogenesis of RA.
The findings are published in the Annals of the Rheumatic Diseases.