Other PAD Antibodies
Other research is looking into the potential role of antibodies to other forms of PAD. For example, one study showed antibodies to PAD2 were actually associated with less severe joint and lung disease.9 “There were very few patients who had both PAD2 and PAD4 antibodies,” says Dr. Darrah. “The PAD2-positive patients had fewer swollen joints and were less likely to have lung disease. If we looked at the progression of their disease over time, they had less progression of their erosive joint disease.”
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Explore This IssueJanuary 2020
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Another interesting area of research is exploring the subset of people who have antibodies that show cross-reactivity to both PAD3 and PAD4 (about half of the people positive for the PAD4 antibody). “This subset seems to identify a group of patients that have the most severe disease with the higher erosive burden,” notes Dr. Darrah. “PAD4 in general is associated with severe joint disease, but that PAD3/PAD4 group was enriched with those with the most severe manifestations.”10,11 These smaller
nested subgroups within CCP-positive patients may give clinicians an even better idea of who might need more aggressive treatments.
Pathophysiology & Future Research Avenues
Much work is still needed to flesh out the pathophysiological processes that might make PAD autoantibodies relevant to RA. Dr. Holers explains that PAD antibodies probably do not play a role in initiating disease development in asymptomatic individuals, as other autoantibodies appear to precede their development. “But they could play a role in the transition to developing arthritis, and they could play roles in modulating the disease process, to increase or decrease it,” he says.
Dr. Darrah suggests studying these antibodies earlier in the disease course may hold the potential for exploring a therapeutic window in which early intervention may prevent joint damage.
As it stands, the issue is quite complex. Antibodies to the different isozymes of PAD might have different effects (e.g., PAD2 vs. PAD4 autoantibodies). Additionally, an individual might have polyclonal antibodies to a specific isozyme of PAD, which may have different physiological impacts. For example, unique anti-PAD4 autoantibodies might react with different sites on the PAD4 enzyme. Depending on the context, distinct PAD4 autoantibodies might either increase or decrease the process of citrullination, known to play an important role in inflammation. Or they might have a variety of other different downstream effects.2,7 As Dr. Holers asks, “What are the effects and functional capacities of individual monoclonal anti-PAD antibodies? I think that’s an important question.”