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For the first time, investigators are gaining a clearer understanding of what causes drug-induced antineutrophil cytoplasmic autoantibody (ANCA) vasculitis.

 published in The Journal of Clinical Investigation, researchers from the University of North Carolina (UNC) Department of Medicine and Kidney Center revealed that hydralazine—a drug commonly used to treat high blood pressure—alters the structure of myeloperoxidase (MPO), a key immune-related protein. These changes may trigger the autoimmune response seen in ANCA vasculitis.

More specifically, the study found that the addition of a carbonyl group to MPO allows hydralazine to bind and form hydrazone adducts. These structural changes in MPO appear to set off an immune reaction.

“Now we have an idea of what’s happening at the molecular and cellular level that could actually trigger this autoimmune response and lead to disease,” Meghan Free, PhD, an associate professor of medicine in the UNC Division of Nephrology and Hypertension said.

Hydralazine has long been associated with drug-induced ANCA vasculitis, but the exact mechanism behind that link wasn’t well understood, until now.

, published in the same issue, details how the study sheds light on the mechanisms by which hydralazine induces vasculitis. It serves as an example for understanding haptenation and drug-induced allergic or autoimmune diseases. Given the increasing number of allergic and autoimmune responses associated with drugs, the editorial also suggests the work of Gang Xi, PhD, an associate professor in the UNC Division of Nephrology and Hypertension, may provide a rational basis for tests which may predict whether a drug will lead to allergic and autoimmune responses prior to its prescription.

Study Details

Five clinicians reviewed medical records to identify patients with hydralazine-associated vasculitis based on predetermined criteria. Ten patients with hydralazine-related disease were included in the study and compared with patients who had ANCA vasculitis but had not taken hydralazine.

Notably, most of the patients on hydralazine tested positive for both proteinase 3 (PR3)- and MPO-ANCA antibodies.

“Patients with idiopathic vasculitis typically make antibodies to either MPO or PR3, not both,” Dr. Free said. “So clinically, if a patient tests positive for both antibodies, it’s a signal the disease could be drug-induced.”

Still, one big question remains: Why do only some patients on hydralazine develop this autoimmune reaction, while others do not?

Since drug-induced autoimmunity can act like a “natural experiment,” uncovering its mechanisms may also shed light on how other autoimmune diseases, especially those with no known cause, develop.

The study is titled, “” and was published by Gang Xi, Elizabeth McInnis, Olivier Lardinois, Peiqi Hu, John Poulton, Meghan Fre, Dhruti Chen, Evan Zeitler, Eveline Wu, Nicole Orzechowski, Vimal Derebail, J. Charles Jennette and Ronald Falk.