Low ceruloplasmin protein levels are associated with worse survival in AAV vs MPO

Low blood levels of the copper-containing protein ceruloplasmin at diagnosis are associated with worse survival in adults with ANCA-associated vasculitis (AAV) who have autoreactive antibodies against the enzyme myeloperoxidase (MPO), a new study from France has found. .

“This is the first study to associate low ceruloplasmin levels (in the blood) at diagnosis of anti-MPO ANCA-associated vasculitis with worse survival,” the researchers wrote. If confirmed in larger studies, “it will allow early identification of patients at risk of adverse development in order to tailor treatment.”

Studying, “Clinical impact of ceruloplasmin levels on the diagnosis of ANCA-associated vasculitis“was published in the magazine PLOS One.

In AAV, self-targeting antibodies called ANCA mistakenly target immune neutrophil cell enzymes, most commonly MPO or proteinase 3, known as PR3. This leads to overactivation of neutrophils—a type of white blood cell that helps the body fight infection—leading to inflammation and damage to small blood vessels.

Although any tissue can be affected, the most common manifestation of AAV is damage to blood vessels in the lungs and kidneys.

The worst prognosis is observed in patients with anti-MPO AAV and low ceruloplasmin levels.

Ceruloplasmin is a protein produced in the liver that transports copper into the bloodstream and plays a role in iron metabolism. It is believed to be produced in large quantities in response to inflammatory conditions and has anti-inflammatory effects. In fact, it can bind to MPO on the surface of activated neutrophils and block its pro-inflammatory effects.

“Insufficient inhibition of MPO by low levels of ceruloplasmin may contribute to a more severe (clinical profile of) ANCA-associated vasculitis by increasing…tissue damage through increased MPO activity and interaction with ANCA-anti-MPO,” the researchers wrote.

To understand whether low blood levels of ceruloplasmin in AAV are associated with a worse prognosis, a team of researchers from Caen University Hospital Center retrospectively analyzed data from 92 adults with microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). most common types of AAV.

All were diagnosed between January 2010 and January 2022 at the center and had blood samples available from the time of diagnosis. A total of 50 patients (54.3%) tested positive for ANCA anti-MPO (anti-MPO AAV), while the remaining 42 (45.7%) had ANCA anti-PR3.

In patients with anti-MPO AAV, the mean blood ceruloplasmin level at diagnosis was 0.44 g/L. Based on this score, patients were then divided into groups with low and high ceruloplasmin levels.

Several clinical factors were comparable between the two groups, such as severity of AAV assessed by the Birmingham Vasculitis Activity Score (BVAS), incidence of renal failure and recurrence of AAV, and treatment to prevent infections.

Patients were followed for up to 86 months, or about seven years. After a median follow-up of 40 months, or slightly longer than three years, significantly more patients in the low-ceruloplasmin group died than in the high-ceruloplasmin group (40% versus 12%).

Reduced ceruloplasmin levels appear to be a marker of poor prognosis in anti-MPO ANCA-associated vasculitis.

Among 10 patients with low ceruloplasmin levels who died, the most common cause of death was infection (40%), followed by unknown causes (30%), thrombus-related events (20%), and recurrent AAV (10%). Two of three deaths in the high ceruloplasmin group were due to blood clot-related events, and the remaining deaths were due to infection.

Overall, survival among anti-MPO AAV patients with low ceruloplasmin levels was significantly lower than that of patients with high ceruloplasmin levels. There were no significant differences in the length of stay of patients with their own kidneys.

Using a cut-off blood ceruloplasmin level of 0.43 g/L, the team was able to identify patients with better and worse survival rates with 65% accuracy.

“Reduced ceruloplasmin levels appear to be a marker of poor prognosis in anti-MPO ANCA-associated vasculitis,” the researchers wrote.

There are no significant differences in survival among other AAV groups.

The team then performed the same analysis on a group of patients with ANCA versus PR3. They found no significant differences between the low and high ceruloplasmin groups in terms of the incidence of renal failure, AAV recurrence, overall survival, and renal survival.

In addition, there were no significant differences in overall survival or renal survival between the low and high ceruloplasmin groups among either MPA or GPA patients.

“This study suggests that low ceruloplasmin levels (in the blood) at diagnosis of anti-MPO ANCA vasculitis are associated with worse survival,” the researchers wrote, adding that “this prognostic impact was not found in patients with anti-PR3 ANCA.” -associated vasculitis.”

The results highlight the role of MPO in AAV, “confirming that a defect in MPO inhibition may be responsible for a more severe disease profile,” the team wrote, noting that larger studies are needed to confirm these findings.

“In addition, our data and previous basic research allow us to evaluate the effect of a ceruloplasmin agonist,” or a drug that increases ceruloplasmin activity, the researchers noted. “Enhancing ceruloplasmin activity with agonist drugs may… limit tissue damage and provide protection against bacterial infections.”

More research is needed to better understand the role of ceruloplasmin in AAV and to find ways to “target…the ceruloplasmin/MPO complex in ANCA-associated vasculitis,” the team concluded.