Low ceruloplasmin protein linked to worse survival in anti-MPO AAV
Blood levels at diagnosis could help predict patients' health outcomes
Low blood levels of the copper-carrying protein ceruloplasmin at diagnosis are associated with worse survival in adults with ANCA-associated vasculitis (AAV) who test positive for self-reactive antibodies against the myeloperoxidase (MPO) enzyme, a new study from France has shown.
“This is the first study associating low [blood] ceruloplasmin level at the diagnosis of anti-MPO ANCA-associated vasculitis with poorer survival,” the researchers wrote. If confirmed in larger studies, “it would allow an early identification of patients at risk of unfavorable evolution in order to adapt treatments.”
The study, “Clinical impact of ceruloplasmin levels at ANCA-associated vasculitis diagnosis,” was published in the journal PLOS One.
In AAV, self-directed antibodies, called ANCAs, mistakenly target enzymes on immune neutrophil cells, most commonly MPO or proteinase 3, known as PR3. This overactivates neutrophils — a type of white blood cell that helps the body fight infection — leading to inflammation and damage to small blood vessels.
While any tissue can be involved, blood vessel damage in the lungs and kidneys is the most common manifestation of AAV.
Poorer prognosis seen for anti-MPO AAV patients with low ceruloplasmin
Ceruloplasmin is a protein made in the liver that transports copper in the bloodstream and plays a role in iron metabolism. Produced in large quantities in response to inflammatory conditions, it is thought to have anti-inflammatory effects. In fact, it can bind to MPO at the surface of activated neutrophils and block its pro-inflammatory effects.
“Inadequate inhibition of MPO by low ceruloplasmin levels may contribute to a more severe [clinical profile] in ANCA-associated vasculitis by enhancing … tissue damage through increased MPO activity and interaction with ANCA anti-MPO,” the researchers wrote.
To understand whether low blood ceruloplasmin levels in AAV were linked to a worse prognosis, a team of researchers at the University Hospital Center of Caen retrospectively analyzed data from 92 adults with either microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA), the two most common types of AAV.
All had been diagnosed between January 2010 and January 2022 at the center, and had available blood samples from the time of their diagnosis. A total of 50 patients (54.3%) tested positive for ANCAs against MPO (anti-MPO AAV), while the remaining 42 (45.7%) had anti-PR3 ANCAs.
Of the anti-MPO AAV patients, the median blood ceruloplasmin level at diagnosis was 0.44 g/L. The patients were then divided into low and high ceruloplasmin groups based on this figure.
Certain clinical factors were comparable between the two groups, such as AAV severity, as assessed with the Birmingham vasculitis activity score (BVAS), the rates of kidney failure and AAV relapse, and treatment to prevent infections.
Patients were followed for up to 86 months, or about seven years. After a median follow-up period of 40 months, or slightly longer than three years, a significantly greater proportion of patients in the low ceruloplasmin group had died compared with those in the high ceruloplasmin group (40% vs. 12%).
Decreased ceruloplasmin levels appear to be a marker of poor prognosis in anti-MPO ANCA-associated vasculitis.
Among the 10 patients with low ceruloplasmin who died, the most common cause of death was infection (40%), followed by unknown causes (30%), blood clot-related events (20%), and AAV relapse (10%). Two of the three deaths in the high ceruloplasmin group were due to blood clot-related events, while the remaining death was associated with infection.
Overall, the survival rate among anti-MPO AAV patients with low ceruloplasmin was significantly lower than those with high ceruloplasmin. There were no significant differences in terms of the time patients lived 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 versus poorer survival with an accuracy of 65%.
“Decreased ceruloplasmin levels appear to be a marker of poor prognosis in anti-MPO ANCA-associated vasculitis,” the researchers wrote.
No significant differences in survival among other AAV groups
The team then conducted the same analysis on the group of patients with ANCAs against PR3. They found no significant differences between low and high ceruloplasmin groups in terms of rates of kidney failure, AAV relapse, overall survival, and kidney survival.
Further, no significant differences were found regarding overall survival or kidney survival between low and high ceruloplasmin groups among either MPA patients or GPA patients.
“This study suggests that a low [blood] ceruloplasmin level at diagnosis of anti-MPO ANCA-associated vasculitis is associated with a worse survival,” the researchers wrote, adding that “this prognostic impact was not found in patients with anti-PR3 ANCA-associated vasculitis.”
The results emphasize the role of MPO in AAV, “supporting 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 the previous fundamental studies invite to assess the effect of a ceruloplasmin agonist,” or a drug that increases ceruloplasmin activity, the researchers noted. “Reinforcing ceruloplasmin activity with agonist drugs could … limit tissue damage and insure a protection against bacterial infections.”
Additional research is needed to better understand ceruloplasmin’s role in AAV and to find ways of “targeting … the ceruloplasmin/MPO complex in ANCA-associated vasculitis,” the team concluded.
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